danlewisfoundation

Restoring Communication in the Injured Brain

Tue, 17 Mar 2026 14:49:33 GMT

A Neuroengineer’s Approach to Rebuilding Neural Circuits

Note: Justin Burrell is the 2025 winner of the DLF Prize for Post-Doctoral Research. This article emphasizes the regenerative potential of improving the connectivity of replenished neural material.

The central nervous system functions through organized networks of neurons that communicate along long extensions called axons. These pathways enable movement, sensation, cognition, and memory. When trauma, stroke, or other neurological injury disrupts them, communication fails, often resulting in permanent loss of function.

My research is focused on a clear objective: restoring communication within damaged neural circuits.

My interest in this problem began early. When I was young, my grandfather, an electrical engineer, told me the “wiring” in his back was broken. I knew from my father, an electrician, that wires could be reconnected. I was confused when my grandfather said it was impossible. That question stayed with me: why can damaged electrical systems be repaired, but damaged neural circuits cannot?

We pursue this through four complementary strategies: stopping axons from dying, reconnecting severed axons, replacing what is lost, and interfacing with restored circuits to measure and guide function. In practical terms, this means stopping the wiring from breaking, reconnecting broken connections, installing new wiring when needed, and ensuring that the repaired system is functioning properly. Together, these form an integrated framework for repairing the damaged brain.

This work is highly collaborative. At the University of Pennsylvania, I work with colleagues in neural tissue engineering, stem cell biology, neurosurgery, traumatic brain injury research, and neural interfaces. We also collaborate with partners at UT Austin, Mount Sinai, Dartmouth, Jefferson, and the VA Medical Center system. Repairing the nervous system requires coordinated expertise across disciplines.

1. Stop Axons from Dying

After injury, many axons do not disappear immediately. Instead, they enter a vulnerable period during which they may degenerate, expanding the functional impact of the initial insult.

This window presents an opportunity. If we can stabilize axons early and preserve their structural and metabolic integrity, we may retain critical pathways that would otherwise be lost. Even partial preservation of long tracts in the brain or spinal cord can yield meaningful functional benefit. Preservation does not eliminate the need for regeneration; rather, it raises the floor for successful recovery.

2. Reconnect Severed Axons

In some cases, axons are physically disconnected. Traditionally, such injury has been considered irreversible in the central nervous system. However, emerging research suggests that, under carefully controlled conditions, severed axonal membranes may be rejoined, restoring structural continuity.

If electrical conduction resumes across the repaired segment, the original neuron may continue to function. Rather than replacing neurons, we repair them.

We are evaluating how preservation strategies and membrane repair approaches interact in advanced preclinical models. Stabilizing axons early may increase the likelihood that reconnection succeeds. While not universally applicable, axon reconnection represents a meaningful shift in thinking: in certain contexts, damaged circuits may be directly repaired rather than rebuilt from scratch.

3. Replace What Is Lost

When damage cannot be repaired and native pathways cannot be restored, reconstruction becomes necessary. This is where engineered neural tissue plays a central role.

Our laboratory develops structured, living neural tissue derived from human stem cells, designed with aligned axonal tracts that function as organized conduits. Instead of injecting dispersed cells into an injury site, we implant tissue that already contains directional architecture.

We test whether these constructs can integrate with host circuitry and function as relays, transmitting signals across an area of injury. Using anatomical analysis, electrical recordings, and behavioral testing in chronic injury models, we evaluate both structural integration and functional transmission. The central question is whether signals can cross a previously silent gap.

This strategy is relevant to traumatic brain injury, stroke, spinal cord injury, peripheral nerve injury, and other conditions involving disrupted neural pathways, including optic nerve damage and Parkinson’s disease. Even partial restoration of communication could yield meaningful functional gains.

4. Interface with Restored Circuits

Restoring structure is only part of the challenge. Even when circuits are preserved, reconnected, or rebuilt, we must determine whether they are functioning as intended and how they can be optimized.

Recovery is rarely all or nothing. Signals may be weak, delayed, or incompletely coordinated. Without precise measurement, we cannot know whether a reconstructed pathway is transmitting information effectively or how to refine it.

We are therefore exploring biohybrid interfaces that allow engineered neural tissue to communicate with carefully designed electronic systems. These interfaces enable real time monitoring of electrical activity within restored pathways and may ultimately provide controlled stimulation to stabilize or enhance circuit performance.

Beyond validation, interfacing expands what recovery can mean. If neural signals can be reliably captured and interpreted, they may be used to guide assistive technologies, from functional stimulation systems to advanced prosthetic devices. In this way, biological repair and engineering augmentation need not be competing approaches. They can work together.

Biohybrid strategies do not replace biological repair. They strengthen it by improving safety assessment, validating performance, and increasing precision in guiding and extending restored neural function.

From Laboratory Science to Translation

Brain repair requires more than isolated breakthroughs. Preservation, reconnection, reconstruction, and circuit interfacing must operate within a coordinated framework. Reproducibility is essential. Engineered neural tissue must be manufactured consistently, with defined quality standards and measurable function to advance toward clinical use.

Over the past decade, advances in stem cell biology, neural engineering, and systems neuroscience have created capabilities that did not previously exist. The scientific tools are now in place, and the field has reached an inflection point. The challenge is no longer whether restoration is conceivable, but how to translate these capabilities into scalable, reliable therapies.

To advance this work beyond the laboratory, I am co-founding a mission-driven organization with Dr. D. Kacy Cullen, Will Houston, and Victoria Rothwell focused on scalable manufacturing and clinical development of engineered neural tissues. In parallel, through the Speculative Technologies BRAINS Fellowship, I am addressing this challenge at a systems level, integrating biological repair with precise circuit interfacing and translational infrastructure.

Progress will depend on partnership across sectors. Philanthropic investment can catalyze high-risk efforts. State and federal funding can sustain foundational science and shared infrastructure. Institutional commitment can align talent and long-term vision. With coordinated support, the tools now emerging in the laboratory can be responsibly advanced toward restoring neural communication in patients.

Why This Matters

For individuals living with paralysis, cognitive impairment, or sensory loss after nervous system injury, disrupted neural communication is life altering. Restoring even partial connectivity across damaged circuits could translate into regained independence and improved quality of life.

The approach outlined here, preserving vulnerable pathways, repairing what can be repaired, rebuilding what is lost, and interfacing with restored circuits to guide function, reflects a comprehensive strategy for recovery. Although significant challenges remain, advances in stem cell biology, neural engineering, and systems neuroscience have created capabilities that did not exist a decade ago.

The nervous system is not simply a metaphorical wiring system. It is a living network that demands both biological insight and engineering precision. When communication within that network is lost, meaningful recovery may require not only rebuilding structure but ensuring that restored circuits are functioning as intended.

I am deeply grateful to the Dan Lewis Foundation for supporting bold efforts in brain repair and regeneration. The scientific foundation is stronger than ever. The responsibility now is to translate these capabilities into therapies that restore neural communication and improve lives.

Making Headway: An Evening of Scientific Advances and Musical Interludes

Tue, 17 Mar 2026 14:49:31 GMT

The Dan Lewis Foundation proudly presents Making Headway: An Evening of Scientific Advances and Musical Interludes

DLF INFOTAINMENT FUNDRAISER WILL STREAM ON MARCH 26, 2026

The Dan Lewis Foundation will stream a program filled with up-to-date information about brain regeneration and terrific music on Thursday, March 26th. The event will be co-hosted by Dr. Jonathan LaPook, Chief Medical Correspondent for CBS News and Dr. David Margulies, biomedical and biotechnology writer and innovator and co-founder of the Dan Lewis Foundation. The musical performers will be Low Strung , a tremendous group of cellists who arrange and perform classic rock on their acoustic cellos and the Yale Symphony Orchestra playing two pieces from their 2025 season repertoire. The program will stream at 5:00 P.M. (Pacific), 6:00 P.M. (Mountain), 7:00 P.M. (Central), 8:00 P.M. (Eastern). This free program will be approximately one hour in length.

The link to the event, which will activate on Thursday, March 26th at the above time(s) is: here .

In late June, a similar program will be presented with additional information about the neuroscience and biotechnology of brain regeneration. This program will feature the Bill Hill Jazz Project and jazz pianist and Pulitzer Prize winning opera composer, Anthony Davis. Details of that event will be distributed in mid-June.

We hope you will join us for this event. An informative and enjoyable program is promised!

New DLF Board of Directors Members Introduced

Tue, 17 Mar 2026 14:39:28 GMT

Jonathan Lifshitz, PhD , leads the Neurotrauma & Social Impact research team as a joint venture between the University of Michigan Concussion Center, Michigan Medicine Physical Medicine & Rehabilitation, and the VA Ann Arbor Health Care System. He is a Michigan Impact Professor and VA Research Health Scientist. Research projects focus on investigative, restorative, and regenerative treatments for traumatic brain injury as it develops into chronic neurodegenerative disease. We investigate domestic violence, child abuse, gender imbalance, and Veteran mental health, with focus on inflammation and circuit reorganization to detect and intervene. The goal is to train generations of investigators to apply rigorous data to work for social impact, including health and medical outcomes.

Dr. Ronen Friedman is an experienced MD/MBA Board Certified Healthcare Executive with a demonstrated history of working in inpatient and outpatient settings. Skilled in start-ups, leadership, strategic planning, change management, operations, and business development, HR, and team building, with a strong emphasis on evidence-based business development, evidence-based medicine, clinical outcomes, and continuous improvement. Dr. Friedman has been a clinical researcher since 1999 starting at the military branch of the CDC, and then concentrating on trauma surgery, post surgical and post injury inflammation, intensive care, and traumatic brain injuries.

What Does “Ambiguous Loss” Mean?

Fri, 05 Dec 2025 16:05:23 GMT

My daughter, currently nearing completion of a graduate program in counselling, recently introduced me to the term “ambiguous loss”. This term applies to a loss that is unclear and lacks certainty, leaving family members and close friends feeling stuck because it is so difficult to mourn or find closure. One type of ambiguous loss is when the person is physically present but psychologically absent because their personality, memory, cognition, or emotional connection has been altered. Examples might include a family member with dementia, a progressive disease, a severe emotional disorder, or substantial brain injury. A second type of ambiguous loss is when the person is psychologically present but physically absent. This could include a missing person due to a natural disaster, a long- term incarceration, a kidnapping, or severe estrangement from the family. This type of loss can lead to intense confusion, frozen grief, and a prolonged sense of helplessness.

As the father of a young man who sustained a severe brain injury over seventeen years ago (at age 20) and has continued to live an extremely limited life ever since, I find this term quite descriptive of what I have experienced. Prominent issues that family members may be vulnerable to as the result of ambiguous loss are:

Lack of closure: Without a death or clear end, there are no traditional mourning rituals to help process the loss.
Frozen grief: The uncertainty prevents the grief process from moving forward, leaving people in a constant state of limbo. When grief cannot be fully expressed it can lead to guilt and despair.
Realism versus hope: In past paradigms, this conflict may have been labelled “acceptance versus denial”. Some friends/helpers may urge “realism” (that is, acceptance) while others urge “hope (that is, denial). But a balance between the two may be necessary to clearly perceive the present situation and also keep doing what you believe may lead to a better future outcome.
Social misunderstanding: Others may not understand the pain or recognize the loss since there is no physical absence, making it difficult to get support. Family members’ social interactions or social availability may be curtailed because of feelings of shame, depression, resentment, or even basic practical factors which inhibit scheduling for socializing.
Impact on daily life: It can be hard to make decisions about the future when the present is so uncertain, leading to feelings of being immobilized, exhausted, and hopeless.
Difficulty identifying and accepting negative feelings: Such feelings, if left unexpressed, can lead to sadness and self-recriminating thoughts. Underlying feelings of anger or resentment, even if irrational in some respects, would be better directed toward fate, a higher power, to another person or party thought to be responsible, or even to the “lost” person himself or herself. If identified and expressed, such feelings can be better understood and put into perspective to reduce distorted interactions and other troubling negative effects.
Family dysfunction and disruption: The heightened stress that accompanies ambiguous loss can lead to conflict, disagreement, and argumentativeness among family members. Communication may falter as tension and distancing increase. Disruption in family routines may occur and expressions of support and affection within the family may lessen.

To clarify, not all families or family members who are experiencing ambiguous loss will experience these issues powerfully. But most, if not all, families are vulnerable to these kinds of issues showing up in some form given the intensity of experiencing ambiguous loss.

Open communication that includes both expressive speaking and supportive listening is a key to helping family members overcome the emotional stress of ambiguous loss. Agreement on every feeling, perception, or plan of action is not necessary but a sense of being safe and being listened to when expressing oneself is important for all family members. Destructive communication, passive aggressive actions, blaming, and open hostility should be avoided to the greatest extent possible. Social support from trusted friends and community groups can be of great assistance. If necessary, outside help from a clergyman or therapist can be not only comforting but growthful as well. Above all, it is important to recognize that the confusion, stress, pain and other complex emotions that often accompany ambiguous loss are real, not imaginary or over-blown. And that open communication and support from others can lead to relief and improved coping.

Marchell’s Story

Tue, 02 Dec 2025 19:35:04 GMT

Marchell is an engaging and energetic middle-aged man who was enthusiastic about being interviewed for the DLF newsletter. He is an activist working to promote the rights and well-being of persons in the brain injury community, with a particular emphasis on helping persons with brain injury who are incarcerated or have been released from prison. Marchell is a successful businessman, proud of the company he co-founded--the Association of Young Business Owners (AYBOS), a marketing company in the Denver, Colorado area. He also works for Well Power (Denver’s Mental Health Center system) as a Zero Suicide Certified Peer and Family Specialist.

Marchell is clearly a man on the move to get a lot of positive things done. But this wasn’t always the case. Marchell spent much of his younger adult life incarcerated himself for a variety of crimes including robbery and assault. He had a history of recidivism following multiple releases.

He had serious difficulties with substance abuse and addiction. However, Marchell realized that learning was the key to bettering himself. So, for many years, most often still in prison, Marchell studied law, psychology, and marketing. In 2003, he co-founded AYBOS with help from another prisoner and from his brother Corey.

In 2016, Marchell participated in a neuropsychological assessment which identified a serious brain injury that occurred when Marchell was 10 years old. The injury, which happened when Marchell was a young passenger in a bad car accident, was identified as a factor in Marchell’s emotional dysregulation, poor judgement, deficient reasoning, anxiety, and agitation.

Marchell credits an insightful public defender who suspected Marchell’s history of childhood trauma and brain injury and referred him to the Men’s Transition Unit of the Denver County jail. In this program, Marchell participated in individual counselling and group services coordinated by Dr. Kim Gorgens, a psychologist teaching and doing research at the University of Denver. In this program, he learned the basics of mental health, a better understanding of his emotional problems, and an array of coping skills that help him direct his behavior in a positive direction and achieve stability and success.

It wasn’t until later in 2016 that Marchell, after so many years of being in and out of prison and facing consecutive sentences of lengthy duration, was paroled for the final time. He achieved parole largely because of his many years of study, the mental health services he received following the identification of his brain injury, and his determination in organizing fellow prisoners around the need for mental health services. He also motivated a cohort of about 40 prisoners to launch a letter writing campaign to legislators and other Colorado business and political leaders to increase awareness of mental health issues among the disproportionate number of prisoners with a history of brain injury.

When asked for advice to other brain injury survivors, Marchell lamented that most brain injury survivors in underrepresented communities have little knowledge about brain injury and its potential consequences; and often don’t understand the medical/psychological terms that professionals typically use when addressing them. As a peer counselor, Marchell translates such terms into simpler language that his peers can understand and relate to. Education is a key, in Marchell’s view, to understanding and coping with one’s deficits. He feels strongly that access to mental health services and community support is crucial. He also says that self-awareness and communicating about oneself with others is very important. According to Marchell, if feelings of anxiety, depression, agitation, fearfulness and shame remain hidden and unspoken they are likely to cause disorganized, self-destructive, or counter-productive behavior.

Like others that we have interviewed for the DLF newsletter, Markell is an inspiring individual. For most of his life, Marchell was not aware of how his childhood brain injury contributed to the many crises and mistakes in his adult life. Marchell has educated himself and worked hard to overcome the deficits and losses he has experienced. In this context, his achievements and positive attitude speak volumes about the man he has become. Marchell continues to work hard to develop professional skills and self-understanding, to be a positive force in his community…and to express gratitude for those who have assisted him along the way.

A New Frontier in Brain Regeneration Research

Tue, 02 Dec 2025 19:26:34 GMT

For most of modern medical history, the brain has been viewed as incapable of regeneration. While skin, bone, and even parts of the liver can regenerate after injury, damage to the brain—whether due to stroke, traumatic brain injury (TBI), or neurodegenerative disease—has long been considered largely irreversible.

Over the past decade, however, advances across stem-cell biology, neuroengineering, and computational neuroscience are challenging this dogma. Today, a broad set of scientific strategies is aimed at enabling true repair of damaged neural circuits . Many of these scientific strategies have been highlighted in previous editions of the DLF newsletter Neural Connections ( archived at the DLF website ). Although each approach faces obstacles, the collective progress is significant enough to shift expectations about what may one day be possible.

This article focuses on one strategy that has produced some of the most dramatic and tangible preclinical results: transplantation of human stem-cell–derived neural tissue.

Stem-Cell Derived Neural Grafts: A Breakthrough Approach

Induced pluripotent stem cells (hiPSCs) can be derived from adult cells and guided to form neurons, glia, or even complex three-dimensional brain organoids . These tissues resemble early-stage human cortical structures: they contain multiple neural cell types, fire action potentials, and develop rudimentary circuit motifs.

Over the past decade, several laboratories have shown that when hiPSC-derived neural tissue is transplanted into injured rodent brains, the grafts can:

Survive and differentiate
Extend axons into host tissue
Form synapses with surrounding neurons
Participate in local circuit activity
Contribute to measurable behavioral improvements

These findings do not imply fully restored function, but they do provide clear proof of concept that newly added human neurons can integrate into injured mammalian brains.

Several lines of research clearly illustrate the progress that is being made in the area of stem-cell derived neural grafts.

Stroke Models: Human Neurons Integrating into Damaged Cortex

In a landmark series of experiments, researchers transplanted human iPSC-derived cortical neurons into the stroke-injured cortex of rodents.

In 2013, Tornero and colleagues showed that the transplanted neurons matured, fired action potentials, received synaptic input, and extended projections into host tissue. Animals receiving grafts displayed partial improvements in motor function , demonstrating that the human neurons were contributing functionally.
In 2020, Palma-Tortosa and colleagues extended this work by demonstrating long-range axonal projections from human grafts, synaptic integration, and electrophysiological activity coordinated with the host cortex. Behavioral tests again showed improved, though not fully restored, performance .

These studies demonstrated that transplanted human neurons can join functional circuits in a living mammalian brain.

The Most Striking Evidence: Human Organoids Processing Visual Input

Human organoids responding to visual stimuli in mice

A 2022 study from UC San Diego implanted human cortical organoids into the retrosplenial cortex of adult mice. Using transparent graphene electrodes and imaging, the researchers found:

The human organoids became vascularized
They synchronized with host neural activity
They produced reliable, time-locked responses to visual stimuli , such as light flashes and moving patterns

These results do not show that organoids independently “interpret” vision, but they demonstrate that human neural tissue can become an active participant in a sensory circuit.

Human organoids integrating into an injured rat visual cortex

In 2023, a University of Pennsylvania group transplanted human forebrain organoids into rats with lesions in their visual cortex. Over months, the grafts:

Survived and became vascularized
Received inputs from the rat’s retina
Formed synaptic connections
Exhibited orientation-selective neural responses —a hallmark of visual processing

These findings show that transplanted human tissue can develop sophisticated sensory tuning when incorporated into injured neural circuits.

Training the Grafts: Why Computational Prostheses May Be Essential

While it is extraordinary that human neural tissue can integrate into rodent brains, integration alone is not enough . For meaningful functional recovery, grafts must develop appropriate wiring, refine their activity patterns, and avoid maladaptive signaling.

This is where advanced neurotechnology will play a major role. Machine-learning–guided electrical stimulation, closed-loop activity shaping, and high-resolution interfaces may help:

Guide the maturation of grafted neurons
Encourage correct long-range connections
Reinforce task-relevant activity
Accelerate recovery
Reduce variability

Just as physical therapy is essential after orthopedic repair, computational training may be essential for neural grafts to reach their full therapeutic potential.

From Rodents to Primates: The Next Step

To move toward clinical translation, the field must test these grafts in brains that more closely resemble our own. Ethical analyses and scientific commentaries have begun outlining the frameworks and challenges associated with future studies using human brain organoids in non-human primates .

To date, no such primate studies have been published, but many leaders in the field consider them a necessary next step—one that will require careful ethical oversight, significant resources, and multidisciplinary collaboration.

A Long Road Ahead—But No Longer an Impossible One

Despite encouraging progress, clinical application of brain organoid grafts remains years away. Challenges include:

Ensuring long-term safety (e.g., avoiding tumorigenesis)
Achieving stable vascularization
Controlling immune interactions
Ensuring proper circuit-level integration
Developing computational systems for training
Managing ethical concerns about human neural tissue in animals

Yet for the first time, the evidence suggests that the conceptual barriers once thought insurmountable may not be fundamental after all. Preclinical studies show that new human neurons can integrate, process information, and contribute to recovery in injured brains.

Realizing this vision will require:

Philanthropic investment to fund early-stage, high-risk research
Strong scientific leadership spanning stem-cell biology, neurosurgery, neuroengineering, and computational modeling
Thoughtful ethical governance
Sustained collaboration across institutions

If these elements come together, the possibility of repairing the injured brain—long dismissed as science fiction—may ultimately become a clinical reality.

Selected References

Functional neural grafts in stroke models

1 Tornero et al., Brain (2013). “Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery.”

2 Palma-Tortosa et al., PNAS (2020). “Activity of transplanted human cortical neurons contributes to functional recovery after stroke.”

Organoid integration into visual systems
3 Wilson et al., Nature Communications (2022). “Functional integration of human cortical organoids in adult mouse cortex responding to visual stimuli.”
4 Jgamadze et al., Cell Stem Cell (2023). “Structural and functional integration of human forebrain organoids with the injured adult rat visual system.”

Reviews on organoid transplantation and ethics
5 Shen et al., Cells (2025). “Brain organoid transplantation: scientific progress, challenges, and ethical guidance.”
6 Di Lullo & Kriegstein, Nat Rev Neurosci (2017). “The emerging role of brain organoids in studying human development and disease.”

DLF Announces Exciting Online Concert

Tue, 02 Dec 2025 19:26:00 GMT

The DLF is very pleased to announce its first online concert to be streamed on the evening of March 28th, 2026 (starting 8:00 P.M. Eastern). The concert will feature a variety of wonderful musical performers from across the country including:

Low Strung Cellos : terrific acoustic ensemble featuring original interpretations of rock and pop hits
Denver Spirituals Choir : inspiring choral arrangements of spirituals and gospel music
Bill Hill and friends : extraordinary percussionist and composer in small ensemble setting
Anthony Davis : lauded jazz pianist and Pulitzer Prize winning composer
Yale Symphony Orchestra : selections from its superb repertoire

This event will be emceed by Jonathan LaPook, M.D., Chief Medical Correspondent for CBS News. Dr. LaPook will introduce performers and provide brief informational segments between performances about brain injury, objectives of the DLF, and innovation/leadership within the field of brain regeneration research. Donations to support the DLF will be welcomed during the concert.

Further details about the concert will be sent to you in January and February. In the meantime, please save the date and plan to join us. This promises to be an entertaining and stimulating event!

ARPA-H Announcement Seeks Research Projects in Brain Regeneration

Thu, 31 Jul 2025 13:12:31 GMT

On July 10, 2025, the Advanced Research Projects Agency for Health (ARPA-H) announced a major initiative titled Functional Repair of Neocortical Tissue or FRONT. The announcement states “FRONT will pioneer a curative therapy for the more than 20 million adults in the US living with chronic neocortical brain damage from neurodegeneration, stroke, trauma, and other causes, which costs the country an estimated $800 billion per year. Worldwide, more than 200 million people live with debilitating after-effects of brain damage.”

A set of informational meetings about this program and a due date for outlines of potential proposals have been set for August. Full proposals are due by September 25, 2025. Complete instructions, specifications, and expectations are delineated in the ARPA-H FRONT announcement. The FRONT announcement includes a clear expectation that the successful brain regeneration methods that are discovered will be used in clinical trials with persons with brain injury by the fifth year of the program.

The DLF lauds ARPA-H for initiating this program. We are discussing possibilities for playing a supportive role as proposals develop. This exciting program is congruent with the original overarching goals of the DLF and confirms the validity of its mission.

2025 DLF Prize Awarded to Justin Burrell, Ph.D.

Thu, 31 Jul 2025 13:07:49 GMT

Dr. Burrell is a translational neuroengineer in the Departments of Neurosurgery and Oral & Maxillofacial Surgery at the University of Pennsylvania. His research integrates advanced neural repair strategies with clinical translation, focusing on axon protection, nerve fusion, and engineered neural tissue for neurotrauma recovery. Dr. Burrell has led the development of multiple first-in-field innovations—including the first large-animal model of nerve fusion, delayed axonal fusion protocols, and the first orally active axonal protectants—positioning him as a recognized leader in regenerative neurotechnologies. He is co-founder of Neurostorative LLC and plays a central role in several other platforms aimed at neural reconnection, long-term preservation, and bio-integrated prosthetic systems.

With over 40 publications and six patents, Dr. Burrell brings a unique combination of rigorous scientific expertise and translational vision. His interdisciplinary collaborations span academia, industry, and government, including contributions to multi-PI NIH and DOD-funded initiatives. A committed educator and mentor, he has trained numerous graduate and undergraduate students and taught academic entrepreneurship to hundreds of trainees across disciplines. Motivated by a personal connection to paralysis and a deep commitment to impact-driven science, Dr. Burrell continues to advance novel platforms to restore lost function and reshape the future of neural repair.

Dr. Burrell writes “My research program is dedicated to developing integrated therapeutic strategies to stimulate meaningful functional recovery following severe acquired brain trauma, by preserving injured neural circuitry, promoting regeneration, and reconstructing long-distance pathways. My work spans three interconnected areas: pharmacological neuroprotection, engineered neural tissue for circuit reconstruction, and targeted molecular delivery using high-throughput discovery platforms”.

Dr. Burrell also states “My research is directly aligned with the Dan Lewis Foundation’s priorities to advance pharmacological, cellular, and molecular strategies for neural repair. I am committed to developing therapies that stimulate meaningful functional recovery after acquired brain trauma by preserving residual neural circuits, reactivating intrinsic repair programs, and reconstructing long-distance connectivity through engineered tissue.

The DLF is very enthusiastic about Dr. Burrell’s research. He stands out among a growing cadre of young investigators who will bring meaningful brain regeneration into reality in the near future.

New Members of DLF Board of Directors Introduced

Thu, 31 Jul 2025 12:54:26 GMT

Dr. Kim Gorgens is a board-certified rehabilitation psychologist and Professor of Psychophysiology, Clinical Neuropsychology and Psychology of Criminal Behavior at the University of Denver . She manages a large portfolio of brain injury related research and has lectured extensively on those issues around the world. She has a 2010 TED talk on youth sports concussion and a 2018 TED talk on brain injuries in criminal justice with 3.5M views. She has been interviewed on CNN with Anderson Cooper, NPR, and on 20/20 and her work with brain injuries has been featured in USNews , Newsweek , the Economist , People Magazine , and more. She has a small forensic neuropsychology practice with juvenile and death penalty cases and is active in legislative and policy development around best practices in brain injury. Her research studies the reported injury history, cognitive function, and brain biomarkers of all vulnerable populations including young and older athletes, probationers and inmates, persons who are unhoused, and women who have been exposed to interpersonal violence.

Lisa A. Brenner, Ph.D. , is a Board-Certified Rehabilitation Psychologist, and a Professor of Physical Medicine and Rehabilitation, Psychiatry, and Neurology at the University of Colorado, Anschutz Medical Campus. Dr. Brenner is a Senior Clinical Investigator at the Department of Veterans Affairs Rocky Mountain Regional Medical Center. She co-leads the VA Brain Health Coordinating Center (BHCC) and the Military and Veteran Microbiome Consortium for Research and Education (MVM CoRE). She is the past Chair of the International Brain Injury Association and a past President of Division 22 (Rehabilitation Psychology) of the American Psychological Association (APA), as well as an APA Fellow. She serves as an Associate Editor of the Journal of Head Trauma Rehabilitation. Dr. Brenner is a leading expert in the field of traumatic brain injury and comorbid psychiatric disorders. She has over 250 peer-reviewed publications, participates on national advisory boards, and has co-authored a book titled: Suicide Prevention After Neurodisability: An Evidence-Informed Approach. She is also a Co-Editor of the APA Handbook of Rehabilitation Psychology (3rd Edition) and is the current Editor of the Oxford University Press Academy of Rehabilitation Psychology Series.

Dan Lewis Update

Thu, 31 Jul 2025 12:47:33 GMT

The story of Dan’s 2007 accident and severe brain injury was first posted to the DLF website in 2020. You can read “Dan’s Story” here .

Over the past five years, Dan has worked hard to make progress and regain the most basic abilities. He has had to deal with many medical procedures and many challenges. Dan has done so with a calm determination that has helped him move well beyond early predictions of what his long-term status would be.

Progress

Dan’s medical status has greatly stabilized and his general health has been good for a number of years. Seizures that were prolonged, dangerous and often required hospitalization in the several years after his accident are now much less frequent and much more mild. He has not required hospitalization in almost 10 years.

Dan’s receptive language skills have improved noticeably. He demonstrates understanding by following any motor direction (including some multi-step sequences) that he is capable of doing physically. He is more engaged in conversations and responds more quickly to questions. His expressive language has also improved. He now uses personal pronouns. He often uses 2-word phrases and sometimes up to 4-word phrases to respond to questions about preferences and feelings.

Dan’s cognitive status has improved a good deal as well. He is able to count to 100 and to verbally answer simple addition, subtraction and multiplication questions. He understands the idea of “opposites” and seems to enjoy answering the question “What’s the opposite of…..?” to which he usually gets the correct answer.

Dan’s schedule is filled with therapies, activities, and social experiences. He goes swimming once or twice a week, enjoys attending the Colorado Symphony most Saturday evenings, and participates in an integrated dance company called Spoke ‘N’ Motion which rehearses on Sunday afternoons and gives performances several times per year.

Playing the cello remains important to Dan. With assistance, he practices his cello for ½ hour every weekday morning. He is able to bow correctly about half of the songs in Suzuki Cello Book #1 and he enjoys playing scales using different rhythmic patterns.

Challenges

Dan’s responsiveness has improved a good bit but he still has great difficulty initiating actions, intentions, and communication. He can make a choice when several options are presented but he rarely expresses what he wants spontaneously.

It is unclear to what degree Dan experiences emotion. From an outside perspective it appears that he is exceptionally even keeled. He rarely seems to be either happy or sad, but sometimes he demonstrates interest or enjoyment by moving his very expressive eyebrows upward. Observing the relative absence of emotional expression in Dan’s everyday experience is difficult for those who love and care for him, particularly in comparison to the vibrant individual we remember.

Dan continues to have very significant motor planning and motor control difficulties. He has almost no functional movement on the left side. Controlled purposeful movement on the right side shows improvement but he has a way to go.

Dan has what is called cortical visual impairment. This means that while his eyes themselves are not damaged, the vision centers in his brain which process visual input work very poorly. Functionally, this means he doesn’t “see” very much. Moving himself in his power wheelchair has helped to engage his visual system and supported some integration of his vision.

Dan still gets 100% of his water and food via his g-tube. His swallow has been evaluated as inadequate to allow oral feeding. Hopefully, this is something we can work on in the next few years without endangering Dan’s health.

In the first several years after Dan’s accident, family and friends would often ask “Is Dan making progress?” I would imagine Dan at the one yard line of a one hundred yard football field, needing to travel 99 yards to get to the other end zone at the rate of one inch per week to be fully recovered and restored. That’s a long, long journey…but Dan hasn’t stopped moving forward, however gradually.

The DLF is tracking and supporting a growing cadre of researchers in the field of brain regeneration who are capitalizing on stunning biomedical, biotechnological, and bioengineering advances to bring the hope of meaningful brain regeneration into a reality. Although it is unclear whether Dan will be a candidate for emerging brain regeneration methods, it is rather certain that within 5 years, perhaps 10 years at the most, brain regeneration procedures will be effective and increasingly available to people with serious brain injuries. The DLF is proud to play a small part in supporting the important and inexorable movement forward in brain regeneration.

Unlocking the Brain’s Healing Potential: Recent Advances in Brain Regeneration Research

Wed, 30 Jul 2025 20:06:17 GMT

The human brain is remarkable in its complexity, adaptability, and resilience. Yet, millions worldwide face dramatically impaired quality of life due to traumatic brain injuries, strokes, and degenerative neurological diseases. Today, there are no medicines that stimulate the restoration of lost brain functions. Recent research is showing us a path to new medicines that may activate the brain’s inherent capacity for regeneration following severe injury.

One notable researcher in this pioneering field is Jared Tangeman at Johns Hopkins University. Tangeman investigates the extraordinary regenerative capabilities of the axolotl, a salamander species uniquely capable of completely regenerating its central nervous system (CNS), including brain and spinal cord tissues. Through sophisticated genetic and cellular analyses, his lab has uncovered essential genetic programs activated during neural regeneration. Tangeman’s laboratory employs innovative models of optic nerve injuries, such as whole-eye enucleation (temporary removal and reimplantation of the entire eye in the salamander) to explore how retinal cells survive extreme conditions and regenerate nerve connections. Utilizing advanced genomic techniques, including single-cell RNA sequencing and chromatin profiling, paired with AI-driven structural modeling, Tangeman identifies critical genes such as ATF3 and RUNX1, which regulate neuronal survival, axon regeneration, and the activation of progenitor cells into new neurons¹. Identifying specific genes involved in regeneration provides precise molecular targets for developing new therapeutic approaches. Once these targets are validated in human cell-based models, they can guide the development of novel medicines, particularly genomically targeted drugs, to enable human brain regeneration after severe injury.

Complementing Tangeman’s fundamental research is work led by Justin Burrell at the University of Pennsylvania. Burrell is focused on rapidly translating laboratory findings into clinically viable therapies. His team discovered boldine, a compound with remarkable neuroprotective effects. This compound has been shown to reduce nerve damage and promote nerve regeneration in animal studies². These findings have potential implications for treating nerve injuries and TBI. Additionally, Burrell’s team has developed engineered neural scaffolds, biomaterials designed to guide nerve fibers across injury sites, which have successfully reconnected severed nerves in preclinical studies³. These tissue-engineered constructs, when combined with pharmacological interventions such as boldine, offer promising dual-action treatments capable of dramatically improving recovery outcomes for severe brain injuries.

The innovative research by Tangeman and Burrell showcases a powerful synergy—Tangeman’s foundational insights into molecular regeneration mechanisms provide precise targets for novel therapies, while Burrell’s work demonstrates practical strategies immediately applicable in clinical settings.

A promising therapeutic frontier inspired by these fundamental discoveries involves genomically targeted medicines such as antisense oligonucleotides (ASOs) and RNA interference (RNAi) molecules. ASOs are short, synthetic molecules designed to precisely modulate gene expression by targeting specific RNA sequences, thus influencing cellular behaviors and disease processes⁴. ASOs have demonstrated clinical efficacy in treating genetic diseases, including spinal muscular atrophy, underscoring their therapeutic potential for neurological conditions⁵. Similarly, RNAi-based therapies, designed to silence specific genes involved in disease progression, have recently entered clinical practice for conditions such as hereditary amyloidosis, further underscoring their potential⁶. Notably, ASO-based therapies are currently being tested in clinical trials for spinal cord injuries, aiming to harness the CNS’s innate ability to restructure itself. These pioneering trials, led by neuroscientists such as Stephen Strittmatter at Yale University, indicate a viable pathway toward applying similar strategies to brain injuries⁷.

The convergence of Tangeman’s foundational genetic discoveries and Burrell’s translational approaches positions genomically targeted therapies, including ASOs and RNAi, as highly promising tools for stimulating regeneration and recovery. Once validated in human cell-based models, these targeted genomic strategies can significantly enhance regenerative capacities in human brains after severe injury. Concurrent advances in biomaterials, nanomedicine, and artificial intelligence (AI) further bolster regenerative research. For example, nanotechnologies enable the targeted delivery of therapeutics directly to injured brain regions, increasing efficacy and precision⁸. AI-driven tools rapidly analyze complex genetic and molecular data, swiftly identifying promising targets and therapeutic strategies. Collectively, the groundbreaking efforts of researchers like Jared Tangeman and Justin Burrell, alongside advances in genomically targeted therapies, nanomedicine, and AI, hold transformative potential. These innovations significantly advance our understanding and ability to promote neural regeneration, offering renewed hope and improved quality of life for millions affected by severe neurological injuries.

Citations

Leigh, N. D. et al. Transcriptomic landscape of the blastema niche in regenerating adult axolotl limbs at single-cell resolution. Nat. Commun. 9 , 5153 (2018).
Burrell, J. C. Neuroprotective regenerative potential boldine nerve injury models. Frontiers Cellular Neuroscience 17 , (2023).
Daly, W. T. Engineered scaffolds neural tissue regeneration: cellular molecular considerations. Journal Tissue Engineering 9 , (2018).
Crooke, S. T., Baker, B. F., Crooke, R. M. & Liang, X.-H. Antisense technology: an overview and prospectus. Nat. Rev. Drug Discov. 20 , 427–453 (2021).
Finkel, R. S. et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N. Engl. J. Med. 377 , 1723–1732 (2017).
Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379 , 11–21 (2018).
Griffin, J. M. Progress toward therapeutic interventions spinal cord injury: Antisense oligonucleotides promising strategy. Neurotherapeutics 17 , 471–486 (2020).
Sahni, J. K. Nanotherapeutic approaches treatment neurodegenerative disorders. Drug Discovery Today 24 , 1145–1153 (2019).

Announcing the 2025 DLF Prize

Wed, 02 Apr 2025 18:01:42 GMT

For the third consecutive year, the Dan Lewis Foundation for Brain Regeneration is proud to announce the DLF Prize competition. The 2025 DLF Prize, a $20,000 award, will recognize an outstanding early career scientist (2 to 5 years post-doc) conducting innovative research in neuroscience, pharmacology, or biotechnology. This prestigious prize honors researchers whose work aligns with the DLF mission to drive breakthroughs in neural regeneration and repair.

The current research priorities of the DLF are:

Pharmacological Reactivation of Neural Repair: Research into pharmacological methods of reactivating or augmenting synaptogenesis, neurogenesis or axonal repair.
Cell-Based Cortical Repair: Investigating the potential of derived cortical neurons to restore function in damaged cortical regions.
Transcriptomics of Neural Recovery: Characterizing transcriptomic profiles of cortical neurons in the recovery phase following brain injury to identify pathways that drive repair.
Molecular Inhibitor Targeting: Advancing anti-sense oligonucleotides (ASO’s) or small-molecule therapeutics designed to downregulate inhibitors of neural regeneration in the cortex or spinal cord.

Application for the 2025 DLF Prize can be made by going to our website— danlewisfoundation.org —and clicking on the Tab “ 2025 DLF Prize ”. This will bring you into the application portal. The application portal opened in March, 2025 and will remain open through May 31st. Once in the portal, you will find complete information about the DLF prize, eligibility requirements, and an application form which can be filled in and submitted online.

The winner of the 2023 DLF Prize, Dr. Roy Maimon, continues his research indicating that downregulation of PTBP1, an RNA-binding protein, can convert glial cells into neurons in the adult brain (Maimon et al. 2024) .* Dr. Maimon, currently a post-doc at the

University of California, San Diego is currently interviewing for a faculty position at several prominent neuroscience departments.

The winner of the 2024 DLF Prize, Dr. William Zeiger is a physician-scientist in the Department of Neurology, Movement Disorders Division, at UCLA. Dr. Zeiger has expertise in interrogating neural circuits using a classic “lesional neurology” approach.

He states, “Our lab remains focused on understanding how neural circuits become dysfunctional after lesions to the cortex and on investigating novel circuit-based approaches to reactivate and restore damaged cortex”.

* Maimon, Roy, Carlos Chillon-Marinas, Sonia Vazquez-Sanchez, Colin Kern, Kresna Jenie, Kseniya Malukhina, Stephen Moore, et al. 2024. “Re-Activation of Neurogenic Niches in Aging Brain.” BioRxiv. https://doi.org/10.1101/2024.01.27.575940.

Alan’s Story

Wed, 02 Apr 2025 17:55:31 GMT

Alan was injured in 2021, at age 42. An art teacher in Lakewood, Colorado, Alan was riding his bicycle after school and was crossing at an intersection when a truck turned into the crosswalk area and hit him. Alan reports no memory of the event but has been told this is what happened. Alan says “My frontal lobe took the brunt of the impact, particularly the left frontal lobe”.

Alan had a 2 ½ week stay at a nearby hospital where he, “re-learned to talk, to walk, and drink”-- although again he reports no memory of his stay there. Alan was then transferred to Craig Rehabilitation Hospital, in Englewood, Colorado. Alan says, “The only reason I knew I was at Craig is that I rolled over in bed and saw “Welcome to Craig” on the dry erase board.” During this stage of recovering, Alan repeatedly denied that he had been in an accident. Twice he tried to leave Craig on his own accord despite his wife’s and his therapists’ assurances that it was important for him to stay to recuperate from his injuries.

Alan’s wife was 8 months pregnant at the time of his accident and gave birth to their son while Alan was an inpatient at Craig. Alan’s wife brought his newborn son to visit him days after the birth and Alan held him while sitting in his wheelchair, but Alan wistfully reports this is another thing he can’t remember.

Alan reports that he still has significant difficulties with memory. Alan has also experienced several other neuropsychological difficulties. He states that for months after his injury, he could not experience emotion. “I could not laugh, I couldn’t cry.” Even after three years, his emotional experience is constricted. However, an emotion that is sometimes elevated is irritation and anger. Sometimes, dealing with people can be difficult because he may have temper flare-ups with little reason. This is something that Alan regrets and he is working hard with his neuropsychologist to improve the regulation of his emotions.

Alan also has difficulty with organization, motivation, and distractibility. Earlier in his recovery, he had trouble sequencing and had difficulty carrying out personal and household routines. Alan has benefited greatly from therapy and his own hard work to make improvements in these areas.

A chief reason that Alan works so hard in his recovery is so that he can be a good father to his son who is now almost 3 years old. He recognizes that it is important not to get frustrated when it seems that he can’t provide what his son wants or needs at a given moment. “I’m trying to raise my son the best I can…he’s at such a pivotal time in his life.”

Alan’s financial situation was helped for a time by Social Security Disability Insurance payments but these payments ended. He is trying to get SSDI reinstated but the process of doing so is confusing and is taking a lot of time. Alan returned to work about 11 months ago at a liquor store (after about 2 years of not being able to work), the same store where he previously worked part time while teaching. He works in the wine department. “I sell wine and make recommendations.”

When asked for advice to other brain injury survivors, Alan’s words were: “No matter how confused or upset you are or how frustrated you get, keep pressing on and moving forward because there is light at the end of the tunnel even though it may seem long. Keep moving forward and don’t give up no matter what anyone says to you”. Alan added that supports for individuals with brain injury are very important. He has found support groups, retreats, and seminars/events where brain injury survivors can share their experience to be very helpful. The volunteer work he does at Craig Hospital has been valuable for him.

Alan is an inspiring individual. Despite having scarce memory of his accident and some confusion about the functional losses he has experienced, Alan has worked hard to make his recovery as complete as possible. He continues to work hard to progress and to express gratitude for those who have assisted him along the way.

Letter from DLF Co-Directors

Wed, 02 Apr 2025 17:49:58 GMT

The overarching goal of the Dan Lewis Foundation for Brain Regeneration Research (the DLF) has been, for the past five years, to support biomedical and biotechnological discoveries that will bring the promise of regenerating and repairing the seriously damaged brain into reality. We pursue this goal by sponsoring neuroscientific conferences, publishing a quarterly newsletter, funding early career scientists with the DLF Prize program, sharing promising research nationwide, and posting brain injury information on social media. We strongly believe that biomedical and biotechnological solutions and options for regenerating the seriously injured brain are not only possible but inevitable. The key question is not an “if” question but rather a “how soon” question.

Unfortunately, the current U.S. administration has adopted a somewhat negative stance towards the sciences in general, including the health sciences and biomedical research. With disregard for the way scientific knowledge accumulates, the budget slashers at DOGE, under the direction of the President and his Cabinet, have threatened serious cuts to NIH and NIMH research grants as well as to funds supporting students and faculty in neuroscience and biomedical training programs. Serious cuts to funding have already been made and further reductions can be expected. This short-sighted policy approach will significantly delay important discoveries across various scientific fields. Specifically, for DLF’s constituency, discoveries and related clinical trials that were potentially only a few years away may now be postponed by 5 to 10 years.

The DLF continues to stand in support of neuroscientific and biomedical programs, their students, trainees, faculty, and researchers that have contributed so much to the field of regenerating the damaged brain. If you visit our website—danlewisfoundation.org—you will see “Donate” buttons scattered throughout the content. Please consider a donation, no matter how small or large—to help us continue our work to catalyze progress in brain regeneration research and to urge policy makers to correct course and return to solid support of biomedical and biotechnological advances that will be of so much value to the American public and to persons with serious brain injuries worldwide.

Hal C. Lewis Ph.D.

DLF Co-Director

David Margulies, M.D,

DLF Co-Director

Unlocking the Brain’s Regenerative Potential: The Future of Repairing the Injured Brain

Wed, 02 Apr 2025 17:29:27 GMT

Introduction: The Paradigm Shift in Brain Regeneration

For decades, scientists believed that the adult brain was incapable of meaningful regeneration. Unlike skin or muscle, the central nervous system (CNS) appeared to lack the ability to repair itself after injury, and lost neurons were considered irreplaceable. However, cutting-edge research now demonstrates that this is no longer the case. The brain possesses dormant repair mechanisms—pathways that were active during development but have been shut down in adulthood. By reactivating these pathways, it may be possible to induce neurogenesis (the birth of new neurons), axonal repair, and synaptogenesis (the formation of new neuronal connections) after devastating injuries like stroke, traumatic brain injury, and spinal cord damage.

A growing body of evidence from both the spinal cord and the central nervous system (the CNS) shows that regeneration can be stimulated by downregulating the repressing factors that prevent neuron growth and repair. For clarity, “downregulation” means reducing the activity or number of something. In the case of a repressing factor, downregulation means lowering its levels or making it less active. A repressor is a protein that blocks a process—often by preventing a gene from being turned on. When the repressor is downregulated, it no longer effectively blocks that process, allowing the underlying function to be released or activated.

These advances open the door to new treatments that could restore function to patients with neurological injuries, potentially reversing what were once thought to be permanent disabilities.

The Science Behind Reactivating Brain Repair

Neurodevelopmental genes and pathways that promote neuronal growth and plasticity are switched off after early development. However, researchers have identified key molecular regulators that act as “brakes” on brain regeneration. The “brakes” act as repressors of brain regeneration. By inhibiting these repressors, the brain’s intrinsic ability to regrow neurons and axons can be reactivated.

Recent breakthroughs include:

Neurogenesis in the Adult Brain : Research has shown that downregulation of PTBP1, an RNA-binding protein, can convert glial cells into neurons in the adult brain. Studies using antisense oligonucleotide (ASO) therapy to transiently suppress PTBP1 have successfully induced the formation of functional neurons in mouse models of neurodegeneration. For clarity, an antisense oligonucleotide (ASO) is a short strand of DNA or RNA designed to bind to a specific mRNA and regulate gene expression. By binding to its target, an ASO can block protein production, modify splicing, or mark the mRNA for destruction, effectively acting as a precise “off switch” for genes. In this context ASOs can be used to release glial cells to develop into functional neurons. Work is now underway to create ASOs that can be safely administered to humans, thereby stimulating the creation of new neurons.
Axonal Regeneration in the CNS: Another major discovery involves unlocking nerve fiber regrowth by downregulating specific nerve growth inhibition, which prevents nerve fiber regrowth. Studies have demonstrated that suppressing these inhibitors leads to long-distance axonal regeneration, restoring function in spinal cord injury models.
Synaptic Repair in Neurodegenerative Disease: Scientists have shown that modulating key synaptic receptors—such as mGluR5—can restore lost synaptic connectivity, improving brain network function in neurodegenerative diseases like Alzheimer’s. The neuronal connections and circuits in the brain are maintained in a stable state by the balanced action of different synaptic receptors. By modifying this balance, the rate of brain synapse formation can be increased or decreased.

Together, these findings confirm that neural repair is possible when the appropriate repressive factors are removed, unlocking the brain’s natural regenerative capacity.

Quiver’s Scalable Human Neuronal Platform: Accelerating Discovery

While these discoveries are promising, translating them into effective therapies requires precise, scalable, and high-throughput screening technologies that can screen out or discover biomolecules that address a specific biomedical target by the thousands with great rapidity. One such technology has been developed by Quiver Biosciences using an all-optical electrophysiology platform. (Note: the author of this article is a co-founder of Quiver Biosciences)

Quiver has developed a human induced pluripotent stem cell (hIPSC)-derived neuronal platform that allows researchers to measure functional activity in human neurons at an unprecedented scale. This platform is uniquely capable of:

Directly measuring neuronal excitability, synaptic transmission, and network connectivity using optogenetics and advanced imaging techniques.
Screening for new factors that inhibit brain repair, helping scientists identify additional repressors that need to be targeted.
Evaluating small molecules and ASO-based therapies that may upregulate brain regeneration, assessing their efficacy and toxicity before advancing to clinical trials.

The potential of this platform is vast. Scientists can now systematically search for drugs that mimic the effects of PTBP1 suppression, Nogo-A blockade, or mGluR5modulation—treatments that could one day be used to regrow neurons, reconnect severed axons, and restore lost synapses in patients with brain injuries.

Key advantages of Quiver’s platform include:

Scalability: Unlike traditional animal models, this system enables high- throughput drug screening on human neurons, increasing the efficiency of therapeutic discovery.
Relevance: Because the neurons are derived from human stem cells, they offer a more accurate model of human brain function and disease than animal-based approaches.
Safety Screening: The platform allows for early identification of toxic effects, ensuring that only the safest and most effective compounds move forward in development.

By integrating AI and machine learning, Quiver’s platform also enables pattern recognition of successful drug candidates, identifying compounds with optimal efficacy and minimal side effects.

The Role of Philanthropy: Funding the Future of Brain Repair

Scientific breakthroughs alone are not enough to bring regenerative therapies to patients. Translational research—the process of developing basic discoveries into real-world treatments—is slow, expensive, and underfunded. This is where philanthropic support can make an immediate impact.

Many of the pioneering studies on brain regeneration were initially considered too risky or unconventional for traditional funding sources. Yet, thanks to early philanthropic investments, these ideas have now been validated and are shaping the next generation of treatments. Today, funding is urgently needed to:

Expand screening for regeneration-promoting drugs
Optimize ASO-based approaches for inducing neurogenesis and axonal repair.
Accelerate clinical trials for promising regenerative therapies.

A New Era for Brain Regeneration

For the first time, we have the tools to reactivate the brain’s own repair mechanisms, offering hope for individuals with severe neurological injuries. The path forward is clear: by investing in innovative research, scaling up discovery efforts, and supporting translational studies, we can bring brain-regenerating therapies to patients faster.

The DLF raises funds and uses them to inspire, catalyze, and accelerate work towards brain regeneration. We increase public awareness of possibilities in brain regeneration through our social media, news “blasts”, and quarterly newsletter. And, we promote neuroscientific advances through consultation, networking, conferences, and seed grants. This is especially important when federal funding is limited. By supporting this work, we can help transform groundbreaking scientific insights into real treatments that restore lost function and improve lives.

Rethinking Stroke Recovery: New Insights into Neuronal Remapping and Rehabilitation Potential

Wed, 13 Nov 2024 20:48:31 GMT

Stroke is a common neurological condition that damages brain cells (neurons) in the affected area, leading to a loss of the functions controlled by that region. A hopeful aspect of stroke recovery is that, over time and with rehabilitation, many individuals regain some abilities. This recovery has been linked to a process called “remapping,” where neurons in unaffected areas of the brain adapt to take over the functions of the damaged areas. Although many studies have explored this remapping phenomenon, most evidence has been indirect, based on changes in brain activation patterns or neuron connections after stroke in animal models. Direct proof that neurons change functionality after stroke has been lacking, partly because measuring neuron activity in the brain over time, especially at the necessary scale and duration, is challenging.

With advances in neuroscience and microscopy, we set out to test the remapping hypothesis and obtain direct evidence. We induced precise strokes in the part of a mouse’s brain responsible for processing sensory information from whiskers—the somatosensory whisker barrel cortex. While humans don’t have whiskers, the whisker barrel cortex in mice has key features that make it ideal for studying fundamental neuroscience questions. Mice use their whiskers as a primary sensory tool, and the whisker barrel cortex has a precise anatomy where each whisker’s sensory data is processed in distinct columns (or barrels) in the cortex, arranged just as whiskers are on the snout. This setup allows us to pinpoint brain areas activated by specific whisker stimulation.

Using specialized microscopy to observe hundreds of neurons in real-time, we tested remapping by targeting a stroke to a specific barrel of neurons, the “C1” barrel. Before the stroke, only a few neurons in neighboring barrels responded to the C1 whisker. Based on the remapping theory, we anticipated that after the stroke, these nearby neurons would take on the C1 barrel’s function. Surprisingly, we found the opposite: fewer neurons responded to the C1 whisker, and this low response rate persisted for up to two months. When we stimulated other whiskers, these same neurons responded normally, indicating they weren’t damaged but had lost responsiveness specifically to the C1 whisker.

We then applied a rehabilitation technique known as forced use therapy, trimming all whiskers except the C1 whisker, akin to encouraging stroke patients to use a weaker limb during physical therapy. This approach didn’t increase the number of neurons responding to the C1 whisker, but the few neurons that did respond showed more reliable responses with forced use therapy. Our

findings indicate that remapping doesn’t occur naturally after stroke; instead, rehabilitation may work by enhancing the function of existing neurons rather than promoting remapping.

Our study has some limitations. Humans don’t have whiskers, so our results might not translate directly. Additionally, we focused on the sensory system, and other brain areas, like the motor cortex, might recover differently. However, our work adds to evidence suggesting that adaptive plasticity and remapping in brain areas spared by stroke are limited, not enhanced. While this might seem discouraging, it opens new avenues for brain recovery. We may be able to restore function by targeting spared neurons that are dysfunctional but not irreversibly damaged, creating a critical window for post-stroke interventions like optimized physical therapy.

In future work, instead of assuming spontaneous brain remapping, we aim to investigate the specific circuits and molecular mechanisms that limit adaptive plasticity after brain injury. We’re expanding our whisker barrel cortex model and using genetic tools to examine how different types of neurons are affected by stroke. We are studying interactions between neuron populations to understand how these relationships affect remapping potential. Additionally, by analyzing changes in gene expression within neuron populations, we hope to identify new molecular targets that could lead to therapies promoting plasticity, remapping, and recovery for stroke and other brain injuries.

Devon’s Journey – Two Years Post-Accident

Wed, 06 Nov 2024 19:22:51 GMT

After a life-altering accident in October 2022, Devon Guffey’s story is about resilience and determination. His journey has been profiled in the summer 2023 issue of the Making Headway Newsletter: https://www.danlewisfoundation.org/devons-story . Hit by a drunk driver, Devon sustained severe brain and physical injuries, including axonal shearing, a traumatic frontal lobe injury, and facial fractures. Even after contracting meningitis while in a coma, Devon fought hard to survive – and today, his recovery continues to inspire us all.

In late 2023, Devon worked as an assistant basketball coach at Blue River Valley, where he had once been a student. His love for sports and dedication to regaining his physical strength returned him to the gym, where his hard work paid off. Devon’s persistence earned him another job at the YMCA, guiding gym members and supporting facility upkeep.

Through all the challenges—deafness in one ear, blindness in one eye, and a permanent loss of taste and smell—Devon perseveres. He recently regained his driving license, a significant milestone that symbolizes his increasing independence and cognitive and physical recovery. While each day may not show significant changes, Devon now sees his progress over time.

Today, Devon speaks to groups about his journey, the dangers of drunk driving, and finding strength in adversity. His message is clear: recovery is a process, and sometimes, "can't" simply means "can't do it yet ."

Every TBI is unique, and Devon’s story powerfully reminds us of the strength that comes from resilience and community. We are grateful to Devon for continuing to share his story and for his role in uplifting others facing difficult paths. His journey is a testament to the fact that we are stronger together.

#BrainInjuryAwareness #DevonsJourney #Resilience #EndDrunkDriving #MakingHeadway

Advancing Brain Regeneration Therapies

Wed, 10 Jul 2024 18:22:03 GMT

Scientists worldwide are working to find ways to stimulate healing and functional recovery after severe brain injuries. This work is driven by the desperate needs of persons who have suffered brain damage. It is inspired by the knowledge that the information required to create new brain cells, cause these cells to interconnect, and stimulate new learning is contained in our genome. Now that we can readily generate stem cells from adult tissue, we have access to the genomic program that can control all of the intricate details of brain tissue formation.

A number of different research themes are being pursued productively. These include: (1) enabling injured neurons to self-repair (“axonal repair”) ^1,2 ; (2) replacing damaged tissue by increasing the growth of new neurons (“neurogenesis”) ^3-5 ; (3) transplanting new brain cells that are derived from a person’s own stem cells (“autologous cellular repletion”) ^6-8 ; (4) stimulating the re-wiring of new or surviving tissue by encouraging the formation of new connections (“synaptogenesis”) ^9,10 ; and (5) augmenting the function of a damaged brain by the use of bio-computational prostheses (“brain-computer interfaces”) ^11,12 ; We’ve explored these themes in previous newsletters.

The goal of stimulating meaningful brain regeneration is now sufficiently plausible that a large-scale, well-funded campaign needs to be funded to bring meaningful new therapies to patients within the foreseeable future. Here, we suggest a high-level outline of the research themes for such a campaign. A ‘moon shot’ program towards brain regeneration would leverage cutting-edge technologies in stem cell research, gene therapy, synaptic plasticity, neuronal repair, and brain-computer interfaces (BCIs) to develop innovative treatments for brain injuries and neurodegenerative diseases. These treatments would target the restoration of lost brain functions and improvement in the quality of life for individuals affected by severe brain injuries. This research agenda aims to catalyze serious discussion about creating a federal program with funding, organizational resources, and expert governance to enable brain regeneration in our lifetimes.

Major Themes For a Brain Regeneration “Moon Shot” Program

1: Promote the formation of new neurons

1.1 Stimulate the brain to create new neurons

1.2 Create new neurons from patient-derived induced pluripotent stem cells to be transplanted back into the patient. Create new glial cells to support neurogenesis.

2: Stimulate new synaptic formation

2.1 Develop drugs that enhance synaptic plasticity and promote the formation of new synaptic connections

3: Stimulate self-repair of damaged neurons

3.1 Develop drugs that de-repress neurons and, thereby, enable axonal regrowth

4: Develop brain-computer interfaces (BCIs) for brain-injured patients

4.1: Develop and test BCIs that enable the brain to control behaviors or external devices and, thereby, augment or replace impaired functions.

4.2: Develop and test BCIs that can accelerate the training of remapped brain tissue in persons with brain injuries to optimize functional recovery.

4.3: Combine BCIs with other strategies (e.g., cell repletion, synaptogenesis, and enhanced plasticity) to accelerate adaptation and functional improvement.

The proposed research themes can underpin targeted research to stimulate meaningful brain regeneration, offering new hope for patients with brain injuries and neurodegenerative diseases. While the scientific challenges are profound, there has been sufficient progress to justify substantial investment in brain regeneration research. Any such large-scale program will require coordinated collaborations among academic and commercial partners, skillful governance and management, and a shared sense of profound commitment to the goal.

The recent pace of advances in cell biology, stem cell technology, bio-computational interfaces, and genomically targeting medicines suggests that large-scale investment will yield meaningful clinical advances toward brain regeneration after injury. With robust funding and skilled leadership, this comprehensive research agenda has a realistic potential to transform scientific breakthroughs into tangible medical therapies, offering hope to millions affected by brain damage.

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Maimon, R. et al. Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB. Nat. Neurosci. 24 , 1089–1099 (2021).
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Lust, K. et al. Single-cell analyses of axolotl telencephalon organization, neurogenesis, and regeneration. Science 377 , eabp9262 (2022).
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Fischer, I., Dulin, J. N. & Lane, M. A. Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat. Rev. Neurosci. 21 , 366–383 (2020).
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Samejima, S. et al. Brain-Computer-Spinal Interface Restores Upper Limb Function After Spinal Cord Injury. IEEE Trans. Neural Syst. Rehabil. Eng. 29 , 1233–1242 (2021).

DLF Science Advisory Board Spotlight

Wed, 10 Jul 2024 18:14:12 GMT

Stephen Mark Strittmatter, MD, PhD , earned his undergraduate degree from Harvard, and completed doctoral training at Johns Hopkins. His medical internship and neurology residency were at Massachusetts General Hospital. He joined the Yale faculty in 1993, and is now Chair and Professor of Neuroscience and Vincent Coates Professor of Neurology. He is Director of the Kavli Institute for Neuroscience at Yale, the Yale Cellular Neuroscience, Neurodegeneration and Repair Program, the Yale Alzheimer Disease Research Center and the Yale Memory Disorders Clinic.

His work on developmental axonal guidance led to his discovery of a Nogo Receptor pathway critical for axonal re-growth after injury. He showed that glia-derived inhibitors bind this receptor, activate RhoA and prevent neural repair. He developed a soluble Nogo Receptor decoy protein that blocks the endogenous ligand-receptor interaction, promoting recovery from spinal cord injury and stroke. This therapeutic protein is now in clinical trials for patients with chronic spinal cord injury. Strittmatter has also translated discoveries in neurodegeneration to clinical approaches. Using innovative screens, he identified the roles of Prion Protein and metabotropic glutamate receptor 5 (mGluR5) as Aß oligomer receptors. He linked activation of these receptors to a pair of synaptic tyrosine kinases, the Tau-interacting Fyn and the AD risk gene PTK2B. Critically, this pathway contributes to synapse loss and memory deficits in preclinical models. He subsequently identified a Fyn inhibitor which was tested in an AD clinical trial. Strittmatter has developed additional methods for targeting this pathway with robust preclinical efficacy. One approach uses novel mGluR5 silent allosteric modulators, which are now in clinical trials.

An author of over 280 original reports, Dr. Strittmatter has been recognized by the King Faisal International Prize in Medicine, Ameritec Award for Spinal Injury Research, McKnight Brain and Memory Disorders Award, Alzheimer Association Zenith Fellow Award, Senator Jacob Javits Award in the Neurosciences, and an NINDS Outstanding Investigator Award.

Sophia's Story

Wed, 10 Jul 2024 18:09:40 GMT

Every Traumatic Brain Injury story is different, and the outcome for individuals is often unpredictable

This is Sophia Augier's story

On February 26th, 2023, I glided over the freshly powdered slopes of Vermont as the flurries melted against my wind-burned cheeks. The twists and turns of the Rollercoaster Trail left me with an adrenaline high. Each jump I landed fed the thrill of the ride until I was suddenly consumed by darkness, and after the accident, my senior year turned into a nightmare. High school had gone exactly as planned. After years of hard work, late-night study sessions, and an activity-packed resume, I was set to attend the Massachusetts Institute of Technology (MIT) in the fall. My future was brighter than ever, but that single moment on the slopes left my future in jeopardy. Instead of celebrating my achievements, I was confined to a dark basement, stripped of social interaction, grappling with excruciating physical pain and overwhelming fear. Day after day, I sat there alone, trying to weed through the unknowns and search for a glimpse of hope. My dreams of MIT felt impossible as I struggled with memory loss, severe headaches, and an inability to read or even step outside.

As the days passed, the events of that fateful day slowly returned to me. The edge of my board clipped the snow so fast, sending me tumbling before I could react. When I regained consciousness, I was met with blood-stained snow through waves of darkness. Having lost control of my bladder, I found myself soaked to the bone and gasping for air as my face pressed against the snow. Despite this, I forced myself to get up and make it down the mountain. Embarrassed, I brushed off the incident and continued with my day. With the fresh snow the following morning, I ignored a nagging headache and returned to the slopes. It wasn't until the ride home that overwhelming nausea forced me to acknowledge something was wrong. Days later, my symptoms worsened, but they aligned with a typical flu rather than a traumatic brain injury. Initially misdiagnosed with mononucleosis by my physician, it took an emergency room visit to finally confirm my concussion. The unfortunate waiting period had consequently worsened my symptoms and prolonged my recovery. Finally, a specialist confirmed my worst fears. While the flu-like symptoms faded, my blurry vision, memory loss, and headaches persisted. The prospect of MIT seemed more distant than ever. Returning to school felt surreal; I could barely participate in classes. Watching my friends celebrate their college commitments, I felt like a kindergartner in a 12th-grader's body while I sat in a dimly lit corner, unsure if I'd ever think like myself again.

Months of vision therapy and rehabilitation followed. The drive and grit that fueled my academic success now drove my recovery. Slowly but surely, the darkness lifted, and I began to see a future again. My hard work paid off, and I regained the ability to pursue my dreams.

Today, I have just completed my first year at MIT. I joined the Division 1 crew team, worked for the MIT ambulance service and made lifelong friends. As I write this from my apartment in Cape Town, South Africa, where I'm conducting engineering research, I reflect on my journey.

My experience taught me that life's path is unpredictable. Adversity can strike at any moment, but it's how we respond that defines us. The pain and fear I endured were real, but they also revealed a resilience I didn't know I had. Embracing this resilience, I learned to navigate the unexpected and emerge into the strong woman I am today. In the grand scheme of life, our challenges are as much a part of our story as our achievements. My traumatic brain injury was a test of my strength and determination, and it reshaped my understanding of success. True success isn't just about reaching our goals; it's about finding the courage to keep going when those goals seem out of reach. My journey through concussion and recovery has been my greatest teacher, showing me that resilience, determination, and hope are the keys to navigating life's rollercoaster ride.

Sophia Augier

Pioneering Pathways: Advancing Traumatic Brain Injury Repair

Wed, 10 Jul 2024 18:06:56 GMT

Towards Brain Regeneration and Functional Recovery

A significant brain injury can result in the loss of brain tissue, disruption of nervous system connections, destruction of brain regions controlling various functions, and chaotic biochemical and electrical activity. To minimize the initial injury’s impact, it is important to control bleeding and swelling, limit ongoing damage and scarring, and limit harmful cascading metabolic processes. Human brain tissue does not regenerate, but some functional recovery can occur as surviving brain regions retrain to take over lost functions. Survivors of severe brain injury often experience only modest improvement over time.

Recent research has indicated that developing biomolecular medicines that can stimulate brain regeneration and functional recovery is plausible, even years after the injury. The DLF is dedicated to supporting the creation of biomedical therapies for brain regeneration for persons with severe brain damage. Their strategies include repletion of neurons, enhancement of synaptic connections, reconnection of severed axons, targeted training of brain regions, and innovative use of brain-computer interfaces.

The DLF newsletter has and will continue to showcase cutting-edge research to inspire support for this important work. The DLF relies on charitable contributions and grants to fund research. Every donation, whether large or small, helps to make our vision of meaningful brain regeneration and improved functional outcomes closer to reality.

To learn more: https://www.danlewisfoundation.org/towards-brain-regeneration-and-functional-recovery

The Synapse and Brain Regeneration

The brain largely consists of interconnected neurons carrying electrical currents. These currents are transmitted by neurotransmitters at a microscopically small gap (the synapse) between neurons. Neurotransmitters carry the signal across the synapse, thus allowing the signal to pass from one neuron to the next. The brain relies on trillions of these synaptic connections, which form established pathways but also allow the brain to alter itself in response to stimulation to adapt to new experiences.

Recent breakthroughs in research have significantly advanced our understanding of synaptic formation, neurotransmitter roles, and the effects of drugs on cross-synaptic communication. After severe brain injury, the formation of new synaptic connections is crucial for functional recovery. Studies have shown that stimulating the connection between neurons is a highly promising strategy for brain regeneration. Another innovative approach involves replacing lost neurons by stimulating new growth or transplanting cells. Providing a rich environment that supports synaptic connections through retraining helps promote neuroplasticity.

To learn more: https://www.danlewisfoundation.org/the-synapse-and-brain-regeneration

Can Damaged Brain Tissue Be Replaced?

Brain regeneration research, a novel and cutting-edge area, is dedicated to the regrowth or regeneration of brain tissue. Recent advances involve creating induced pluripotent stem cells (iPSCs) from skin cells, which can form any mature tissue, including nerve tissue. Researchers hope to restore lost brain functions by reintroducing these stem cells into damaged brains. For instance, iPSCs can generate dopamine-producing neurons to replace those lost in Parkinson’s disease. Studies in monkeys show that transplanted iPSC-derived neurons can survive, integrate, and improve motor function, with promising results in human clinical trials. Despite progress, many scientific, technical, and ethical challenges remain. However, cultivating induced pluripotent stem cells from an individual’s own existing cells offers significant hope for meaningful regeneration of the injured brain and better recovery.

To learn more: https://www.danlewisfoundation.org/can-damaged-brain-tissue-be-replaced

Targeting the Genome to Promote Brain Regeneration

The entire set of DNA instructions in a cell (the genome) directs the brain’s development, growth, and maturation. DNA, containing the genetic code unique to each individual, is encoded into a similar molecule called RNA. The RNA then carries genetic information that is translated into various proteins necessary for neuronal proliferation and health

Researchers are exploring several methods to stimulate brain regeneration at the genetic level:

Gene Therapy: This method introduces new genetic material into adult cells using an engineered “de-activated” virus to carry DNA to target cells to promote neuronal repletion. This method has shown promise in terms of the production of proteins necessary to protect existing neurons or to regenerate neurons in neurodegenerative diseases.
Gene Editing: Techniques like CRISPR-Cas9 enable precise genomic corrections. Successful trials for genetic blindness offer hope for similar applications in brain regeneration.
Antisense Oligonucleotides (ASOs): These are small synthetic chains of amino acids that bind to RNA molecules to modulate gene activity. ASOs can inhibit the production of proteins harmful to neurological development or promote the production of beneficial proteins, showing great promise in diseases like spinal muscular atrophy, Huntington’s disease, and ALS.

To learn more: https://www.danlewisfoundation.org/targeting-the-genome-to-promote-brain-regeneration

Unlocking the Regenerative Powers of Antisense Oligonucleotides for Brain Injury Recovery

The brain’s inherent limitations in regeneration pose significant challenges in the recovery from brain injuries and neurological disorders like Alzheimer’s and Parkinson’s. Recent strides in molecular biology and genetics, particularly with antisense oligonucleotides (ASOs), hold immense promise for novel and effective treatments.

ASOs interact with RNA to block gene expression, potentially enhancing regeneration by:

Promoting neurogenesis by targeting genes that regulate neuron formation.
Reducing inflammation by silencing inflammatory process genes.
Enhancing axon (portion of the nerve cell that sends signals at the synapse) regrowth to re-establish functional connections.

Challenges for ASO therapies include ensuring specificity to avoid off-target effects and ensuring effective delivery across the blood-brain barrier. Nevertheless, ASOs represent a very exciting path towards brain regeneration.

To learn more: https://www.danlewisfoundation.org/unlocking-the-regenerative-powers-of-antisense-oligonucleotides-for-brain-injury-recovery

Brain Regeneration via Brain Tissue Transplantation: A Glimpse into the Future of Medicine

Replacing a severely damaged liver with a healthy portion is possible; replacing brain tissue is far more challenging. The first major hurdle in brain tissue transplantation is sourcing replacement brain tissue. With recent breakthroughs, scientists are now able to transform readily available blood or skin cells into pluripotent stem cells (iPSCs) and reprogram them into neurons. When cultured, these neurons can mimic intact brain neurons and are not rejected as foreign tissue when transplanted back into the individual.

A decade ago, scientists successfully grew derived neurons into organoids -- small ‘mini-brains’ with many features of a living brain. Despite limited survival in cell cultures, these organoids demonstrated that derived neurons possess all the necessary information to create a partially functional brain in the laboratory setting. With their ability to develop new neural connections, organoids hold immense potential in compensating for damaged brain tissue and promoting recovery. However, their application in humans necessitates the creation of suitable transplantation sites, developing surgical techniques, and optimizing tissue integration without disrupting brain activity.

To learn more: https://www.danlewisfoundation.org/brain-regeneration-via-brain-tissue-transplantation

Brain-Computer Interfaces to Augment Brain Regeneration

A Brain-Computer Interface (BCI) enables direct communication between the brain and external devices, allowing control through thought. BCIs facilitate actions like typing, playing music, controlling prosthetics, or steering wheelchairs by thinking. They can also reconnect brain regions to the body or external world after neuronal connections are lost, providing sensory input or motor output.

How Do BCIs Work?

BCIs are not just about decoding and encoding the brain’s electrical signals. They are a complex interplay of technology and biology. BCIs use sensors placed on the scalp (non-invasive) or within the brain (invasive) to detect these signals. Sophisticated algorithms are the key to making BCIs work. These algorithms interpret the signals, enabling control of prosthetic limbs, cursors, or other devices and transmitting sensory information directly to the brain.

BCIs hold immense potential to transform the lives of individuals with severe brain injuries. They can empower paralyzed individuals to regain control over their limbs, expedite brain reprogramming, and enable the use of external devices.

Biologic Augmentation of BCI Benefits

New medicines that stimulate neuron formation, repair damaged axons, and enhance synaptic connections have the potential to amplify the benefits of brain-computer interfaces. These treatments might aid BCI recipients by preconditioning the brain or replacing lost tissue. However, challenges remain, including ethical considerations, technological limitations, and the need for personalized rehabilitation. Despite these hurdles, BCI technology shows promising potential for restoring abilities to those with severe brain injuries.

To learn more: https://www.danlewisfoundation.org/brain-computer-interfaces-to-augment-brain-regeneration

Dr. William Zeiger is the 2024 recipient of the $20,000 DLF Prize

Wed, 10 Jul 2024 17:46:41 GMT

The Dan Lewis Foundation for Brain Regeneration Research (the DLF) is extremely pleased to introduce the recipient of the 2024 DLF Prize, Dr. William Zeiger. The DLF Prize recognizes an early career scientist in neuroscience, pharmacology, or biotechnology whose research record and future research plans align with one or more of the DLF’s current research priorities. These research priorities are:

Research into pharmacological methods of reactivating or augmenting synaptogenesis
Research into trials of repleting damaged cortex using derived cortical neurons
Research into transcriptomic profiles of cortical neurons during recovery phase post brain injury
Research furthering effective design of anti-sense oligonucleotides and/or other small molecule medicines to down-regulate inhibitors of regeneration in the cortex and spinal cord

Dr. Zeiger is a physician-scientist in the Department of Neurology, Movement Disorders Division, at UCLA. Dr. Zeiger was born in Burlington, Wisconsin and grew up in the suburbs of Chicago. He attended the University of Illinois at Urbana-Champaign where he majored in Molecular and Cellular Biology. He then completed the M.D.,Ph.D. program at the University of Chicago.

Dr. Zeiger’s doctoral research focused on understanding the cell biology of the stress-induced protein Stanniocalcin 2, and the role of calcium homeostasis in regulating amyloid beta production. Dr. Zeiger completed clinical residency training in neurology at the Johns Hopkins Hospital and UCLA. He then did a fellowship, specializing in movement disorders at UCLA and completing post-doctoral research in the laboratory of Dr. Carlos Portera-Cailliau. Dr. Zeiger has expertise in the diagnosis and medical treatment of movement disorders, including Parkinson's disease, atypical Parkinsonism, tremors, and dystonia, among others. His research interest includes understanding mechanisms of cortical circuit function in the healthy brain and how dysfunction of cortical circuits contributes to pathophysiology and symptoms of neurologic disorders such as stroke and Parkinson's disease.

Dr. Zeiger has had extensive training in both clinical neurology and in research neuroscience. In Dr. Zeiger’s words, “During my time in clinical training, I came to appreciate that many neurologic disorders, particularly those resulting from stroke or other acute brain injuries, operate on the level of neural circuits and that I would need to acquire new research skills to investigate neural circuits. Toward that end I joined the laboratory of Dr. Carlos Portera-Cailliau where I developed expertise in interrogating neural circuits using a classic “lesional neurology” approach. Our lab remains focused on understanding how neural circuits become dysfunctional after lesions to the cortex and on investigating novel circuit-based approaches to reactivate and restore damaged cortex”.

The DLF is enthusiastic regarding the content and quality of Dr. Zeiger’s work. We believe he will make significant contributions to the field of brain regeneration in the future. We look forward to his participation in and contributions to the DLF.

DLF Science Advisory Board Spotlight

Thu, 11 Apr 2024 19:24:13 GMT

Graham Dempsey, Ph.D., is a founder and Chief Scientific Officer (CSO) at Quiver Bioscience, a Cambridge, Massachusetts-based biotechnology company focused on the development of medicines for disorders of the nervous system. Dr. Dempsey and his team are working to develop treatments for some of the most challenging unsolved medical issues patients and their families face. Using advanced technologies in human stem cell biology, optogenetics, machine learning, and drug screening, progress is being made to develop medicines that will one-day treat conditions that have been largely untreatable. As the lead scientist for Quiver, formerly Q-State Biosciences, Dr. Dempsey enjoys working with world-class teams to invent, develop, and apply cutting-edge technologies to solve the most difficult challenges in biopharma for the betterment of patients.

Dr. Dempsey’s inspiration to dedicate his professional life to science and medicine started at the early age of seven with the tragic loss of his father to an aggressive form of cancer, an experience that has deeply motivated him to this day. He completed his undergraduate studies at the University of Pennsylvania and his doctorate at Harvard University. As a graduate student in the biophysics program at Harvard Medical School, he co-developed ‘Stochastic Optical Reconstruction Microscopy’ or STORM , a light microscope with the ability to resolve nanometer (billionth of a meter, e.g. a hair is 100,000 nanometers thick) scale details of biological materials, an achievement that had been thought to be impossible for over a century. STORM has enabled what researchers call ‘super-resolution imaging’ for visualizing the intricate details of life’s most fundamental unit, the cell. Understanding the inner workings of a cell provides a path to a deeper understanding of the ways in which life is constructed and diseases can manifest. The technology was commercialized by Nikon Instruments for researchers worldwide.

Dr. Dempsey left academic science to join Q-State Biosciences as the first hired employee with the goal of bringing advanced technologies developed at Harvard to the study of the brain. The brain, arguably the most complex structure in the known universe, works through electrical communication between brain cells or neurons. This communication is disrupted in all brain disorders but has been near impossible to study for the purposes of effectively developing medicines. Dr. Dempsey and his team over the course of ten years built a technology system that creates human brain models from patient stem cells (i.e. a ‘disease-in-a-dish’) and converts electrical activity of those brain cells into light signals that can be detected with ultra-sensitive microscopes. The resulting signals are analyzed using machine learning to find the patterns of how electrical activity is altered in disease, which can be used to find medicines that correct those changes. The team at Quiver is deploying this technology to take on previously untreatable brain conditions, including rare genetic diseases, such as certain seizure and neurodevelopmental disorders, to common conditions, such as chronic pain and Alzheimer’s disease.

Dr. Dempsey’s passion outside of science starts with his family, his wife (and high school sweetheart) and three young daughters, be it traveling the globe to experience new cultures (or simply stare at the ocean), cooking elaborate meals on a Saturday evening, night-time reading of novels to his daughters, or attending live music around Boston. As a native of NJ, he celebrates his roots with visits to family near the Jersey Shore and, whenever possible, attendance at Springsteen concerts and Giants games. Dr. Dempsey is an avid student of history’s great entrepreneurs, spending the sparse remaining minutes of the day reading biographies and listening to podcasts, looking to extract every bit of learning towards taking on the challenges of building a great business while staying true to his family, his Quiver teammates, and his professional mission.

Sheryl’s Story

Thu, 11 Apr 2024 19:22:10 GMT

Sheryl Suzanne Nibbs, a legal secretary in a top law firm, started the process of becoming a paralegal as she approached her 40th birthday. She was fancy in her appearance, always making sure her hair, nails, and clothing were in order, a well-kept person, an avid traveler, and her mother’s best friend. Sheryl celebrated her 40th birthday in December 2007. It was a grand celebration. Sheryl danced the night away with her family and friends. At the party, I recalled my sister stating, “I planned this party because I don’t know what next year holds, so I choose to celebrate my life today in great style.” Sheryl could not have known nor expected what the following year would hold.

On December 3, 2008, Sheryl planned to do something quiet for her 41st birthday, simply choosing to go out with friends. A few days later, one of the coldest days in December 2008, Sheryl was scheduled for a laparoscopic procedure. Her surgery was supposed to be a simple outpatient procedure. Sheryl arrived home several hours after the routine procedure. Unfortunately, the nightmare that eventually led to Sheryl’s traumatic brain injury was just about to unfold. Sheryl started experiencing excruciating pain and was rushed to the hospital. On Thursday, December 8, 2008, the family learned that she had a perforated bowel. Her diagnosis led to emergency surgery to repair her perforated bowel.

The surgery was deemed successful, but while in recovery, her blood pressure dropped dramatically, and she experienced cardiac arrest. Sheryl sustained a traumatic brain injury during this event. Little did we know, my sister, as we knew her, would be no more. The person we once knew was gone. Everything about Sheryl’s life changed: her appearance, her gait, and most of all, her memory. My sister’s life, what we once considered “normal,” was gone. She was no longer looking forward to going to the job that she loved, running around shopping, dancing, and continuing the life she had built for herself. Sheryl’s family’s life changed as well. Our family was challenged with medical and rehabilitation challenges and obtaining guardianship through court appearances and dealing with multiple lawyers. It was a nightmare!

Today, 16 years later, Sheryl’s sister, brother, and nephew remain her backbone. She requires 24-hour care and has several caregivers because her cognitive skills are minimal. We try our best to keep her active. She attends social events; we take her on day trips during the summer and spend time as a family. It’s a difficult situation to see your loved one change in an instant. She might be different in appearance and abilities, but she is our sister, and we are grateful she is here with us. Our experience and the change required from all family members is difficult to understand, except for those who live it.

Authored by Janice Nibbs, sister of Sheryl Nibbs

Brain-Computer Interfaces to Augment Brain Regeneration

Thu, 11 Apr 2024 19:18:48 GMT

In prior newsletters, we’ve discussed research strategies that bring hope to persons with severe disabilities after a major brain injury. We’ve discussed research focused on creating and transplanting new brain cells to replace damaged tissue [ “cellular repletion” ]. We’ve reviewed progress towards stimulating the brain to regrow [ “regeneration” ] and rewire itself [ “axonal repair” ] as it seeks to compensate for damage. We’ve explored evidence that the brain can be induced to regenerate new connections [ “synaptogenesis” ].

This edition will discuss how biomechanical devices called brain-computer interfaces (“BCIs”) can help a person compensate for an injured brain. We will also explore how new medicines may help a person maximize the benefits of BCIs. The idea of a direct connection between a person’s brain and the external world mediated by a computer sounds like an idea from science fiction. Nevertheless, brain-computer interface devices have been developed and are beginning to be implanted in patients.

What is a BCI?

At its essence, a brain-computer interface is a system that allows direct communication between the human brain and the world, either for sensory inputs or motor outputs. Imagine typing a message, playing a song, controlling an artificial limb, or steering a wheelchair merely by thinking about it. Picture a blind person having a camera-like device that is hardwired to the visual cortex to enable sight or a glove that transmits sensory information directly to the cortex for interpretation. More formally, a BCI is a type of prosthesis that allows regions of the brain to be reconnected to parts of the body or the outside world after the natural neuronal connections have been lost. BCIs connect the world to the brain for interpretation and the brain to the world for action.

How Do BCIs Work?

The magic behind BCIs lies in their ability to decode and encode the brain's electrical signals. Our thoughts and intentions spark neural activity, generating distinctive electrical patterns. Our sensations exist as patterns of neuronal excitation in the brain. BCIs can control limbs or external devices by detecting the electrical patterns of intentions and then translating these signals into commands that can control a prosthetic limb, a cursor on a screen, or the hand of a person whose spinal cord has been severed. BCIs tap into the brain’s electrical activity using various sensors placed on the scalp (non-invasively) or directly within the brain (invasively) to detect and record these signals. Once these signals are captured, they are fed into a computer that interprets them using sophisticated algorithms. This process translates the brain's electrical activity into commands controlling external devices or encoding sensory information to be transmitted directly to the brain (see Figure 1).

The Potential Impact of BCIs:

There are numerous potential impacts of BCIs for persons who have suffered a severe brain injury. A BCI can allow someone who is paralyzed to control a limb again. BCIs may be used to stimulate regions of the brain to accelerate the brain’s reprogramming after a major injury. Some will be able to use a BCI to directly control an external device by sending signals from the brain to an external device. For individuals living with paralysis or severe communication barriers, BCIs offer the hope of regaining some abilities to interact with the world. In the future, devices may enable the blind to see via a direct connection between an electronic device and the brain. ¹ Brain-computer interfaces have begun to enable individuals with traumatic injuries of the central nervous system to regain components of lost neurologic function, restore communication and mobility, and gain more independence. ² Here are two short video clips about BCIs to help you better understand the technology and its implications. The first describes what these devices are and how they work [ BCI overview ]. The second demonstrates the benefit of such a device for a patient with ALS [ BCI in ALS ].

BCIs in Clinical Trials:

Several BCIs are being tested in clinical trials, each involving a few patients (see Table 1). Different devices and trials target different capabilities. One trial is focused on allowing a paralyzed patient to control a computer cursor by thought alone. Several trials are using BCIs to bypass a spinal cord injury and restore (partial) control over a limb. ³ Finally, a range of devices are being developed or trialed to accelerate brain recovery after injury. ⁴

Biologic Augmentation of BCI Benefits:

As discussed elsewhere, there is real hope that new medicines will be able to unlock the brain’s ability to regenerate after a devastating injury. Future medicines that stimulate the formation of new neurons, repair of damaged axons, or the enhanced plasticity of synaptic connections are all likely to promote functional recovery without the use of a brain-computer prosthetic device. These medicines may also be quite useful for recipients of BCIs. More specifically, preconditioning the brain through stimulating neurogenesis, providing autologous-derived neurons, or enhancing plasticity may amplify the benefits of (BCIs) for recipients with traumatic brain injuries. Even after the BCI is successfully implanted, the person will need protracted training and rehabilitation to learn how to use the device. Providing autologously derived neurons to replace lost tissue may be helpful for those whose injuries resulted in a substantial loss of viable brain tissue.

To be clear, the path towards useful BCIs will be challenging. Ethical considerations, technological limitations, and the need for personalized rehabilitation strategies remain pivotal areas requiring further exploration and refinement. Despite these hurdles, the trajectory of BCI technology is undeniably promising, driven by ongoing research, clinical trials, and the real promise of restoring meaningful ability to those who have suffered a devastating brain injury.

Table 1: Selected BCI Trials

Figure 1: A BCI Example ⁵

References

Hart, Robert. 2024. “Elon Musk Teases First Neuralink Products After Company Implants First Brain Chip In Human.” Forbes Magazine , January 30, 2024. https://www.forbes.com/sites/roberthart/2024/01/30/elon-musk-teases-first-neuralink-products-after-company-implants-first-brain-chip-in-human/ .
Pulse, Ieee. 2023. “The Future of Brain–computer Interfaces.” IEEE Pulse. January 25, 2023. https://www.embs.org/pulse/articles/the-future-of-brain-computer-interfaces/ .
Samejima, Soshi, Abed Khorasani, Vaishnavi Ranganathan, Jared Nakahara, Nicholas M. Tolley, Adrien Boissenin, Vahid Shalchyan, Mohammad Reza Daliri, Joshua R. Smith, and Chet T. Moritz. 2021. “Brain-Computer-Spinal Interface Restores Upper Limb Function After Spinal Cord Injury.” IEEE Transactions on Neural Systems and Rehabilitation Engineering: A Publication of the IEEE Engineering in Medicine and Biology Society 29 (July): 1233–42.
Simon, Colin, David A. E. Bolton, Niamh C. Kennedy, Surjo R. Soekadar, and Kathy L. Ruddy. 2021. “Challenges and Opportunities for the Future of Brain-Computer Interface in Neurorehabilitation.” Frontiers in Neuroscience 15 (July): 699428.
Vansteensel, Mariska J., Elmar G. M. Pels, Martin G. Bleichner, Mariana P. Branco, Timothy Denison, Zachary V. Freudenburg, Peter Gosselaar, et al. 2016. “Fully Implanted Brain–Computer Interface in a Locked-In Patient with ALS.” The New England Journal of Medicine 375 (21): 2060–66.

Cajal's Challenge

Thu, 11 Apr 2024 12:36:29 GMT

Overcoming the Barriers in Making New Neurons in the Adult Brain: Lessons from Nature

Almost 100 years ago, the father of modern neuroscience Santiago Ramón y Cajal, a Spanish physician, recognized that the injured brain could not repair or regrow damaged neurons. Cajal stated, “In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated. It is key for the science of the future to change, if possible, this decree.” ¹ Cajal recognized that for individuals with devastating brain diseases or brain injuries, there was little that could be done to repair or regenerate neurons. He proposed that it was up to future scientists to solve the problem of regeneration. There lies Cajal’s Challenge.

The Federation of European Neuroscience Societies (FENS) will meet in Vienna from June 25th to 29th, covering all areas of neuroscience from basic to translational. On June 24th, a one-day pre-FENS workshop will be held with 100 young researchers. This one-day meeting, started in 2021, is designed to create a strong and interactive community among young researchers in the fields of neurogenesis and glia to neuron conversion in Europe, the U.S., and beyond. Our vision is to promote the free exchange of ideas and results among the research groups working in this area. Neurogenesis and Glia-to-Neuron conversion is one of the most exciting research fields of our times.

Cajal’s Challenge Speakers:

Alejandro Schinder, PhD

Benedict Berninger, PhD

Don Cleveland, PhD

Enric Llorens, PhD

Elly Tanaka, PhD

Magdalena Gotz, PhD

Noelia Urban, PhD

Sumru Bayin, PhD

Sofia Grade, PhD

Sven Falk, PhD

For more information and free registration:

https://roymaimonel.wixsite.com/cajalschalange

1. Ramón y Cajal S.

Degeneration and Regeneration of the Nervous System.

Haffner Publishing Company, New York, NY1926

The Church Ushers Association of New York State

Tue, 09 Jan 2024 21:15:40 GMT

On November 11, 2023, the Church Ushers Association of New York State held their annual meeting in Brooklyn, New York. The Dan Lewis Foundation was the recipient of their yearly charitable donation. Annually, the Church Ushers Association selects non-profits that seek to improve the lives of others. Janice Nibbs, President of the Church Ushers Association, spoke poignantly of her sister’s struggle with traumatic brain injury and the need to do better. Madeline Meryash and Lynda Helton accepted the donation on behalf of the Dan Lewis Foundation.

DLF Science Advisory Board Spotlight

Tue, 09 Jan 2024 17:16:00 GMT

David Margulies, M.D. founded, co-founded, and participated as a director and senior executive of a number of companies in the clinical computing, molecular diagnostics, and biotechnology fields. The central theme of his work over 4 decades has been ‘precision medicine’, creating systems which provide the medical knowledge, clinical data, genomic insights, and personalized treatments to physicians and their patients.

In the early 1980s, he co-founded and led BRS Medical, later acquired by WB Saunders and, ultimately, Elsevier North Holland (NYSE:RELX). This company was the first commercial supplier of full text searching and online biomedical books and journals for physicians and researchers. Its product (BRS/ Colleague) was the first online experience for nearly 100,000 physicians.

In the mid 1980s, while Chief Information Officer (CIO) at Boston Children’s Hospital, his team created software which was then acquired by Cerner Corporation and became the basis for Cerner Corporation’s Enterprise clinical applications. Margulies became EVP and Director at Cerner (NASDAQ:CERN) as it grew to be the dominant supplier of clinical computing systems in the US.

In 1996, he co-founded and was a Director of CareInsite (NASDAQ:CARI), acquired by WebMD in 2000.

In 2000, he became co-founder, CEO, and Chairman of Correlagen Diagnostics, which pioneered highly automated DNA diagnostic sequencing and interpretation and was acquired by LabCorp (NYSE:LH) in 2011 to be its genomic center of excellence.

He returned to Boston Children’s Hospital in 2011 as VP of Strategy and led the development of the institution’s genomic medicine strategy. In 2013, he co-founded and was Chairman of Q-State Biosciences, a Cambridge-based biotechnology company which invented methods to create genomically-targeting medicines using patient-derived, CRISPR-edited human iPSCs, optogenetics, and antisense oligonucleotides.

In 2023, he and a colleague acquired the assets of Q-State and formed Quiver Bioscience (www.quiverbioscience. com). He is currently Chairman of that company.

Dr. Margulies co-founded the Dan Lewis Foundation in 2020, a non-profit group supporting scientific research focused on both brain regeneration research and improving awareness of traumatic brain injury. He sits on the board of directors and the science advisory board.

He joined the Board of Variantyx in December 2022 and became Chairman shortly thereafter. Over the years, he has served as a Director and advisor for numerous public and private Boards (including, among others, D2 Hawkeye (Verisk) (NASDAQ:VRSK), Ixxion Biotechnologies, ObMedical (acquired by Philips (NYSE:PHG), Circulation (acquired by Logisticare), Generation Health (acquired by CVS (NYSE:CVS), Travera (www.travera. com), and Commonwealth Care Alliance.

Dr. Margulies received his B.A. from Amherst College (1973), and his M.D. from Harvard Medical School (1977). He completed his clinical training in Internal Medicine at Columbia College of Physicians and Surgeons (1982) and retains both licensure and board certification. He has DLF Science Advisory Board Spotlight subsequent training, experience, and/or publications in commercial computer science, neuroscience, bioinformatics, and genomics. He recently retired from the faculties of Genetics and Bioinformatics at the Harvard Medical School.

Chase’s Story

Tue, 09 Jan 2024 17:13:08 GMT

Chase’s life turned unexpectedly when he was just six years old. As a loving grandmother, I witnessed the remarkable strength and resilience of my grandson as he faced a traumatic brain injury caused by F.I.R.E.S. (Febrile Infection-Related Epilepsy Syndrome). This harrowing journey has not only transformed Chase’s life but has also highlighted the incredible power of hope and the potential of unconventional treatments.

It all began when Chase had just started first grade. Three weeks into the school year, he developed strep throat and was prescribed amoxicillin. However, Chase’s condition worsened, and by day five of treatment, he began experiencing continuous seizures. In a desperate race against time, he was airlifted from a local emergency department to the Pediatric Intensive Care Unit at the Children’s Hospital of Philadelphia (CHOP).

Chase’s life hung in the balance as he was put on life support, administered high doses of antiseizure medications, underwent medically induced hypothermia, and received a ketogenic diet through an IV. The odds were stacked against him, with doctors giving him only a 30% chance of survival, and the prognosis for F.I.R.E.S. was grim. My daughter, a single parent at the time, and I scoured the internet for any glimmer of hope, any treatment that could offer a lifeline to our precious Chase.

After weeks of relentless research, we stumbled upon a small mention of a clinical trial involving cannabis oil for children with intractable epilepsy, specifically Dravet and Lennox-Gastaut syndromes. We approached CHOP with this information and were granted permission for the “compassionate use program” of Epidiolex, a new medication developed by GW Pharmaceuticals undergoing clinical trials. A compassionate use program, also known as expanded access, provides access to investigational drugs, biologics, and medical devices. These programs are used to treat patients with serious or lifethreatening diseases or conditions for which there are no satisfactory treatment options. The results were nothing short of miraculous; Chase’s seizures began to decrease almost immediately.

With the help of Epidiolex, Chase’s seizures eventually stopped completely. However, the journey was far from over. He was transferred to CHOP’s rehabilitation center, where he had to relearn basic functions, such as swallowing, chewing, standing, sitting, toileting, and speaking. As a former registered nurse, I had witnessed countless medical challenges, but this experience was one of the most emotionally taxing. I had entered the ordeal believing that a top-tier children’s hospital would provide all the answers, but the reality was far more complex.

Today, Chase is 15 years old, a testament to the power of perseverance and medical innovation. While he continues to require a ketogenic diet, several antiseizure medications, and a device implanted in his chest to interrupt breakthrough seizures, Epidiolex remains a vital part of his treatment regimen. The traumatic brain injury he sustained has left him with receptive and expressive aphasia, necessitating his use of a communication board for interaction. He is enrolled in high school special education, defying the odds stacked against him since that fateful day when F.I.R.E.S. left a lasting mark on his life.

Chase’s journey demonstrates the unyielding spirit of children and the power of families who refuse to give up in the face of adversity. It underscores the importance of medical research and compassionate use of emerging treatments and inspires all those facing their battles with rare life-threatening and debilitating conditions. Chase’s story reminds us that even in the darkest times, there is always a glimmer of hope, and with determination, love, and medical breakthroughs we can overcome the greatest challenges.

Brain Regeneration via Brain Tissue Transplantation

Tue, 09 Jan 2024 17:08:47 GMT

In previous editions of this newsletter, we’ve discussed some of the research strategies being pursued to enable a severely injured brain to regrow healthy and functional brain tissue. Today, we will explore progress toward replacing lost or damaged brain tissue with new brain matter to support the recovery of lost capabilities.

At first, it seems implausible that new brain tissue can be created and successfully transplanted into someone who has survived a devastating brain injury. While it is now possible to replace a severely damaged liver with a portion of a healthy liver, and the transplanted fragment can grow into a complete, fully functional liver, it is hard to imagine that the same can be done with brain tissue. Several barriers must be overcome if damaged brain tissue is ever to be replaced by new and functional brain tissue.

The first challenge is to identify a suitable source for replacement brain tissue. In recent years, it has become possible to transform cells found in our blood or snippets of skin into pluripotent stem cells. These induced pluripotent stem cells (iPSCs) can be reprogrammed into many different types of cells, including neurons. The reprogrammed iPSCs are called derived neurons. It is now possible, even common, to create vast numbers of these derived neurons, which can be grown in cell culture and attain the electrical properties of the neurons in an intact brain.

If the derived neurons created from an individual are then transplanted back into that individual, these transplanted neurons will not be rejected as foreign since they contain the identity markers of the same individual.

Ten years ago, Lancaster and colleagues¹ demonstrated that it is possible to grow these derived neurons from a 2-dimensional sheet of neurons into an organoid, a small ‘mini-brain,’ a structure that is a few millimeters in diameter. These organoids develop to have many cell types and features found in a living whole brain. Organoids can only live in cell culture for a matter of months, though. They’re not connected to a circulatory system, so their growth is limited.

Nevertheless, the creation of self-organizing organoids demonstrates a crucial principle – derived neurons contain all the information necessary to create a complete brain.

Once organoids were successfully created, teams of researchers began efforts to transplant these organoids into living brains. The typical experimental system used for these experiments is a brain-injured rodent with a depleted immune system. Experiments focused on creating conditions so that a human organoid can be transplanted into such an animal. The goal was to see if organoids can connect to the host animal. Can these transplanted organoids grow new blood vessels? Can the neurons grow functional connections into the brains of the host? Recently, there have been convincing demonstrations that human brain organoids can not only connect to the host animal,² but these transplanted tissues can become functionally active in conjunction with the host’s brain tissue. It has been unequivocally demonstrated that visual stimulation of the mouse causes activation of the transplanted human organoid tissue. Functional synapses (connections) between the human transplanted organoid tissue and the mouse brain are present.³ It appears that the transplanted organoids are ‘seeing’ the mouse’s visual inputs!

Transplanted organoids can even develop new long projections and compensate for infarcted brain tissue and cause functional recovery.⁴ Since it is now possible, in principle, to create new brain cells that can be grown into transplantable tissue that will functionally connect to the host brain, what other challenges will have to be addressed if this approach is to become practical for a brain-injured person? One challenge will be to create a suitable anatomical site for the transplantation of new tissue. Severe brain injuries result in a tangle of scar, debris, and partially active islands of residual brain tissue. The surgical techniques necessary to permit transplantation of brain tissue will have to be developed. But even if it becomes possible to implant new, viable tissue into a person’s brain and support its growth and proliferation, the next challenge will be to optimize the ability of the new tissue to form new connections without disrupting the synaptic activity of the host’s intact brain. There is a growing science and pharmacology of ‘synaptic plasticity.’ What drugs or stimulation patterns can cause neurons to respond to stimulation and create new functional connections?

Optimizing the plasticity of a transplanted organoid in the brain, while ensuring that the existing synaptic connections in the rest of the brain are not disrupted, is a complex challenge. The process will involve careful modulation of various factors to promote the integration of the organoid into the existing neural network without causing adverse effects. A number of strategies are being considered. Some are focused on applying specific growth factors and neurotrophins to the organoid. Others are focused on carefully targeted electrical stimulation, genetic engineering to modify organoids to activate or suppress plasticity genes, or local administration of drugs that modulate synaptic plasticity. This challenge en route to clinical use of organoid tissue is not yet solved. In general terms, we know that newly transplanted tissue must be ‘programmed’ to become functionally useful and integrated into pre-existing brain tissue. One of the fundamental ideas of brain science is that ‘neurons which fire together, wire together…’. New connections between neurons are created and reinforced by experience. If new brain tissue is introduced into an adult brain, the challenge will be to create conditions that optimize the capability of the new tissue to become programmed by external stimulation while not disrupting the stable connections of the pre-existing brain. We’ll likely learn, over the years to come, about techniques to enhance the programmability of the new tissue without causing loss of function in preexisting tissue. One aspect of programming new brain tissue will involve the interfacing of computational devices and algorithms to translate external ‘real-world’ signals into neuronal stimulation patterns and to train new neuronal tissue to control motor behaviors. “Closed loop” devices will, inevitably, accelerate the training of newly implanted brain tissue. The progress in organoid biology allows us to envision a (hopefully) not-too-distant future where new neuronal tissue grown from a person’s own induced stem cells can be transplanted into a damaged brain. This transplantable tissue, grown from iPSC-derived organoids, will contain the information to ‘self-organize’ and will not proliferate uncontrollably. This tissue will be (in this future scenario) introduced into a surgically optimized environment. It will mature, differentiate, grow new blood vessels, and create connections to preexisting functional brain tissue. A pharmacologic formula to optimize new synaptic programming will be developed. At that point, the transplanted DLF organoid tissue will need to be programmed by experience and by biomechanical prostheses to restore lost functions.

An entirely new field of bioengineering is just now emerging. It is called “organoid intelligence“ ⁵ we’ll devote a future column to this topic, but, in essence, this is the study of techniques used to train and program organoids to analyze signals and direct outputs. Biomechanical methods to program organoids will inevitably be applied to help newly engrafted tissue become functionally useful. To recap… It is now possible to envision a realistic path to a future in which severe brain injuries will be treated by the transplantation of healthy neurons derived from a person’s own tissues and stimulated to grow, differentiate, connect, and learn. The learning will be achieved by putting the new tissue into a maximally adaptive (‘plastic’) state and stimulating it with biomechanical systems. There is, of course, a long way to go until these concepts are perfected and clinical trials are possible. Very substantial financial, technical, and intellectual resources will be required. It is encouraging that the quest to heal a damaged brain is becoming a bioengineering challenge, not a basic science challenge, and engineering challenges can be addressed by focus and resources.

It is the goal of the DLF to raise awareness of the paths toward healing the severely damaged brain, identify strategies to advance the required technologies and focus the resources required to do the work necessary to bring life-transforming therapies to patients.

References

Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501 , 373–379 (2013).
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36 , 432–441 (2018).
Wilson, M. N . et al. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. Nat. Commun. 13 , 7945 (2022).
Cao, S.-Y. et al. Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke. NPJ Regen Med 8 , 27 (2023).
Smirnova, L. et al. Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish. Front. Sci. Ser. 1 , (2023).

The Dan Lewis Foundation for Brain Regeneration Research Announces 2024 Prize Open for Applications

Tue, 09 Jan 2024 17:03:10 GMT

The Dan Lewis Foundation for Brain Regeneration Research (the DLF) is happy to announce the 2024 DLF Prize. This $20,000 prize will be awarded to an early career scientist in neuroscience, pharmacology, or biotechnology whose research record and future research plans align closely with one or more of the DLF’s current research priorities. These research priorities are:

Research into pharmacological methods of reactivating or augmenting synaptogenesis
Research into trials of repleting damaged cortex using derived cortical neurons
Research into transcriptomic profiles of cortical neurons during the recovery phase post brain injury
Research furthering the effective design of antisense oligonucleotides and/or other small molecule medicines to down-regulate inhibitors of regeneration in the cortex and spinal cord.

The successful applicant must be an early career scientist in neuroscience, molecular biology, pharmacology, or biotechnology. The “early career scientist” should be within 2-5 years post-completion of their doctoral degree. Full consideration is given to those scientists working in an academic setting (university or non-profit) or commercial setting (e.g., pharmaceutical or biotech company). The application is due March 31, 2024. Full details are available online through the linked application portal below. The winner of the DLF Prize 2024 will be notified in early June 2024.

https://www.danlewisfoundation. org/application-portal

The winner of the 2023 DLF Prize, Dr. Roei Maimon has focused on stimulating the brain to create new neurons, an important process in mitigating the detrimental effects of neurodegenerative diseases and injuries. Most recently, Dr. Maimon and colleagues designed and executed tests using a certain type of biomolecular “medicines” called antisense oligonucleotides (ASOs) to generate glia-to-neuron conversion in the adult rodent nervous system. These new neurons matured and functionally integrated into endogenous circuits over a two month period, ultimately positively influencing the behavior of the mice.

Dr. Maimon has demonstrated his enthusiasm for the DLF and for the field of brain regeneration research by participating in several DLF activities designed to increase public awareness of our mission. We look forward to meeting the next DLF Prize winner and to supporting the development of young neuroscientists and their accomplishments in the field of brain regeneration.

Unlocking the Regenerative Powers of Antisense Oligonucleotides for Brain Injury Recovery

Wed, 04 Oct 2023 20:05:19 GMT

The human brain's limited regenerative capacity makes recovery from injury slow and often incomplete. Traumatic and neurodegenerative brain injuries continue to pose significant challenges to medical science. Brain injuries, including traumatic brain injury (TBI) and neurodegenerative conditions like Alzheimer's and Parkinson's disease, often result in neuronal damage, inflammation, and scar tissue formation. Unlike other tissues in the body, the central nervous system (CNS) has limited regenerative capabilities. Neurons in the brain do not readily replicate, and the scarring response inhibits repair. Thus, finding ways to stimulate regeneration in the CNS has been a longstanding challenge. However, recent advances in molecular biology and genetics have opened exciting possibilities to harness antisense oligonucleotides (ASOs) to address brain injuries. As a result, these advances have the potential to create new brain injury treatment options in the foreseeable future. ^1,2 ASOs are short, single-stranded nucleic acids that can interact with RNA molecules and block gene expression. They can either promote or inhibit the production of proteins, making them invaluable tools in genetic therapies and drug development. In the context of brain injuries, ASOs can potentially enhance regeneration via several mechanisms:

Promoting Neurogenesis: One of the primary strategies for addressing brain injuries is to promote the formation of new neurons. ASOs can be designed to target specific genes that inhibit or regulate neurogenesis, effectively "turning on" these genes to stimulate the growth of new neurons.
Reducing Inflammation: Chronic inflammation is a common response to brain injuries and contributes to tissue damage. By silencing pro-inflammatory genes, ASOs can potentially help reduce inflammation and create a more conducive environment for regeneration.
Breaking down scar tissue: Scar tissue in the brain can hinder the repair process. ASOs can potentially be tailored to target genes involved in the formation and maintenance of scar tissue, potentially allowing for its breakdown and replacement with healthy tissue.
Enhancing axon regrowth: Axons are the long projections of nerve cells that transmit signals. ASOs can potentially be designed to stimulate axon regrowth, which is crucial for re-establishing functional connections in the damaged brain.

While ASOs in brain injury treatment may be promising, some challenges and considerations must be addressed, including:

Specificity: ASOs must be highly specific to avoid off-target effects. Unintended gene silencing can lead to adverse consequences and side effects.
Delivery: Getting ASOs to the target site in the brain can be challenging due to the blood-brain barrier. Innovative delivery methods, such as nanoparticles or viral vectors, are being explored.
Safety: Long-term safety and potential side effects of ASO therapies need extensive evaluation to ensure they do not pose additional risks to the patient.
Ethical and Regulatory Issues: Genetic therapies, including ASOs, raise ethical and regulatory questions about potential misuse, consent, and access to these treatments.

The regenerative powers of ASOs for brain injuries have many future applications in medical research. Before long, neurologists may be able to tailor ASO therapies to individual patients based on their genetic profiles and injury characteristics to maximize effectiveness. Combination therapies will be developed to explore the synergistic effects of ASOs with other therapies, such as stem cell treatments or neuroprotective drugs, to enhance regenerative outcomes. Several disorders currently targeted for ASO-based treatments include:¹,³

Spinal Muscular Atrophy (SMA): Nusinersen is an ASO that has been approved to treat SMA, a neuromuscular disease.
Duchenne Muscular Dystrophy (DMD): ASOs are in development to target specific mutations in the DMD gene, aiming to slow disease progression.
Amyotrophic Lateral Sclerosis (ALS): Tofersen is an ASO that is being investigated for their potential to treat ALS by reducing the production of harmful proteins.
Huntington's Disease: ASOs are being explored to target the mutant HTT gene responsible for Huntington's disease.
Familial Amyloid Polyneuropathy (FAP): Inotersen (Tegsedi) is an ASO approved for treating FAP, a rare genetic disease.
Spinal Cerebellar Ataxias: ASOs are under investigation for several types of spinocerebellar ataxias to reduce the levels of disease-causing proteins.

These are just a few examples demonstrating the versatility and promise of this technology in treating a range of conditions. Unlocking the regenerative powers of ASOs offers a promising avenue for addressing the challenges posed by brain injuries and neurodegenerative diseases. While hurdles remain, the potential to stimulate neurogenesis, reduce inflammation, break down scar tissue, and enhance axon regrowth holds immense promise for improving the lives of millions affected by these conditions. As research advances, ASOs may pave the way for transformative therapies that enable the brain to heal and regenerate, offering hope for a brighter future in brain injury treatment.

The Dan Lewis Foundation for Brain Regeneration Research encourages research partnerships between scientists in academic and business settings to explore the potential of ASOs and small molecule medicines to accelerate brain recovery, particularly in the context of rigorous therapy services and repletion of key populations of CNS cells.

References

Brunet de Courssou, J.-B., Durr, A., Adams, D., Corvol, J.-C. & Mariani, L.-L. Antisense therapies in neurological diseases. Brain 145 , 816–831 (2022).
Quemener, A. M. et al. The powerful world of antisense oligonucleotides: From bench to bedside. Wiley Interdiscip. Rev. RNA 11 , e1594 (2020).
Van Laar, A. D. & Van Laar, A. V. S. Antisense Oligonucleotide Therapies. PracticalNeurology.com https://practicalneurology.com/articles/2019-sept/antisense-oligonucleotide-therapies.

Devon’s Story

Wed, 04 Oct 2023 20:05:12 GMT

On October 7, 2022, I was nineteen years old and out with four friends for what we all thought would be a fun evening of partying with friends. Our group was about 20 seconds from arriving at the party when a teenage drunk driver hit us head-on in Indiana. The drunk driver’s alcohol level was more than twice the legal limit. I was the most critically injured of the group, suffering massive life-threatening head injuries and bleeding from my head that emergency medical technicians could not stop. Taken to the local hospital, it quickly became apparent that my life hung in the balance, and survival would hinge on transferring me to a major trauma center. I was quickly life-lined by helicopter to Indiana University Methodist Hospital, one of only four level-one trauma centers in the state, to treat my traumatic brain injuries (TBI). My family learned it was unlikely I would survive. For a month, I remained in a coma. I had broken multiple bones on my face and had two major brain injuries: severe axonal shearing and a frontal lobe injury. Axonal shearing occurs when the brain shifts rapidly inside the skull, and long fibers in the brain (axons) scrape against the skull’s hard bone, causing traumatic brain injury. Axonal shearing often results in a coma and can impact multiple brain areas, as in my case. My frontal lobe injury is often associated with muscle weakness on one side of the body, depression, memory, and attention problems, all experiences I had. While still in a coma, two weeks after admission to Methodist Hospital, I contracted meningitis, complicating my recovery. While I had no memory of the week before and for weeks after, I slowly regained consciousness. Once stabilized, I was transferred to the rehabilitation unit at the Rehabilitation Hospital of Indiana (RHI), where I remained for another month. At that time, I was wheelchair-bound, and it was unclear if I would ever walk again or regain my memory and attention skills.

Before my accident, I secured a car salesman job at Ray Skillman in Indiana. I felt the job was a good fit and thought I had a promising career working as a car salesman. Outside of work, I always considered myself a serious athlete; I loved playing basketball, working out in the gym, and fishing as often as possible. My determination, fitness, and “athlete mentality” contributed to my survival and recovery. While my recovery, as viewed by my doctors, is nothing less than miraculous, I still have multiple residual problems that may or may not be resolved through therapy. As a result of the accident, I am deaf in my right ear, blind in my left eye, have right-sided tremors, poor balance, and periods of extreme cold chills even in hot weather. One of the most serious challenges I faced as I began my recovery was the emotional turmoil and depression I experienced. I felt furious with friends and family when they tried to stop me from attempting activities I thought I could do. Eventually, I made peace with the problem when I realized those who cared most about me struggled with the “new” Devon. I gradually understood they were struggling too, and their concern that I “shouldn’t do” certain things was their way of showing they cared. I continue to attend group therapy with those who have also experienced TBI. Despite the challenges ahead, I am grateful for my recovery so far and hope to return to selling cars and playing basketball, goals that I believe are within reach. My doctors have told me that my attention and memory, two areas they would not have expected the degree of recovery I have achieved, are impressive and continue to improve.

I think that there are several positive outcomes from the accident. First, I hope to be able to share my fight for recovery with young people who have experienced similar problems. Next, I want to make others aware of the dangers of drunk driving. And finally, I believe I am a kinder, gentler person willing to reach out and support others dealing with complex problems. I believe God reached out and has a plan for me.

Editor’s Note: Devon recently received notification that he was a nominee for patient of the year at the Rehabilitation Institute of Indiana. On September 18, 2023 Devon was chosen as Patient of the Year. We wish Devon all the best as he continues his journey towards recovery.

DLF Science Advisory Board Spotlight

Wed, 04 Oct 2023 13:33:22 GMT

Judy Carmody, Ph.D. , is a leading figure in the life sciences industry, boasting a rich career characterized by innovation, leadership, and a steadfast commitment to improving quality and safety in pharmaceutical products. As the founder and Principal Consultant of Carmody Quality Solutions, LLC, she spearheads initiatives that champion patient safety and deliver quality products to a diverse client base, ranging from life science startups to global Fortune 500 organizations.

Before establishing herself as a prominent consultant, Dr. Carmody held the prestigious position of president at Avatar Pharmaceutical Services, a GMP and FDA-registered contract research organization and manufacturer. During her tenure, she guided the company to heights that culminated in its acquisition by Vertex Pharmaceuticals in 2010. This pivotal moment paved the way for her to assume senior-level roles in various pharmaceutical firms, further honing her expertise in constructing robust quality systems. Dr. Carmody’s roots in the industry stretch back to a decade-long stint in the (bio)pharmaceutical sector before founding Avatar. Here, she was instrumental in developing methods for small molecules and oligonucleotides, in addition to managing QC, Analytical, and Validation groups. Her drive to innovate also led her to a position at Waters Corporation in their Applied Technology and Marketing groups. This role saw her collaborating closely with colleagues and clients alike, fostering the development of novel separation methods that she then brought to market through a series of published papers and presentations at global conferences and leading (bio)pharmaceutical companies. Dr. Carmody’s scientific acumen forms the backbone of her approach to tackling complex quality and analytical challenges. Her extensive resume, which encompasses roles in applied technology, marketing, bench chemistry, validation, and quality management, has equipped her with a unique perspective that facilitates the development of creative, integrative solutions for her clients. This experience enables her to weave technologies from a range of fields into cohesive, clientoriented solutions.

Beyond her professional pursuits, Dr. Carmody is a proactive member of the scientific community, currently DLF Science Advisory Board Spotlight serving on the Scientific Advisory Board of the Dan Lewis Foundation for Brain Regeneration Research. In this role, she actively contributes to advancing research in the realm of traumatic brain injury repair and regeneration. Her genuine interest in fostering groundbreaking research in this area underscores her broader commitment to enhancing quality of life and advancing the field of medical science.

Dr. Carmody is a proud alumna of Clark University in Worcester, Massachusetts, where she earned her Ph.D. in Analytical Chemistry, a discipline that has served as the foundation for her prolific career.

Understanding IDEA and Section 504

Wed, 04 Oct 2023 13:29:10 GMT

A brief guide for parents to navigate education services

Traumatic Brain Injury (TBI) in children often changes their educational needs. Parents face the new challenge of navigating the educational system for their children after experiencing a TBI. Traumatic brain injury (including acquired brain injury) can alter the cognitive, language, social, physical, and behavioral development of the injured child. The Individuals with Disabilities Education Act (IDEA) is a federal law that ensures students with disabilities receive a free appropriate public education (FAPE) in the least restrictive environment (LRE). It applies to students aged 0 to 21 and requires schools to provide special education and related services to eligible students. IDEA also mandates the creation of an Individualized Education Program (IEP) for qualified students, which outlines their specific educational services, goals, objectives, and accommodations. Children ages 0-3 are evaluated and covered separately under IDEA, Part C, through Early Intervention Services. Every state has resources for early intervention services. The Centers for Disease Control provides an Early Intervention Services resource listing for every state: https://www.cdc.gov/ncbddd/actearly/parents/states.html#textlinks

The first step parents must take for children ages 3-21 to access services is to contact their local public school district (usually the principal or special education department) to request an evaluation. Parents must provide their concerns in writing and communicate relevant information about their child’s needs. Parents do not need a specific diagnosis; instead, they simply must provide the school district with a written request for an Understanding IDEA and Section 504 evaluation while sharing relevant concerns. The school district then has 60 calendar days to complete the evaluation at no cost to the parent and to provide the parents with a written report. The evaluation process includes gathering information/ observations from teachers, parents, and other professionals. A comprehensive set of assessments is completed to evaluate the child’s needs, and specific testing must be completed in the suspected area of disability. IQ tests are insufficient on their own; achievement tests, speech and language evaluations, occupational therapy, physical therapy, medical, and other assessments may be administered to determine if specialized educational services are warranted. The process includes a team of professionals who then meet with the parents to determine and recommend whether the child meets the criteria for a disability and, secondly, to determine the services needed. IDEA uses 13 categories for the classification of disabilities. It includes autism, deaf-blindness, deafness, emotional disturbance, hearing impairment, intellectual disability, multiple disabilities, orthopedic impairment, specific learning disability, speech or language impairment, traumatic brain injury, visual impairment including blindness, and other health impairments. For those students who require special education services, an Individualized Educational Plan (IEP) is developed with the parent’s input, including long-term goals and short-term objectives that work toward academic improvement. For those students who do not qualify for additional special education services under IDEA but have a disability, Section 504 of the Rehabilitation Act of 1973 provides protections and rights.

Section 504 ensures that students with disabilities have reasonable access to education and related services, even if they do not qualify for special education services under IDEA. Parents are often confused by the separate categories of IDEA and Section 504 and what the differences are. Unlike IDEA, Section 504 applies to individuals of all ages, not just students, but does not require academic improvement goals. It requires schools and other entities to provide reasonable accommodations and modifications to ensure equal access and participation for individuals with disabilities. For example, accommodations might include preferential seating, use of a computer, extended time on exams, access to written notes, reduced homework, modified textbooks, and other reasonable accommodations. Unlike IDEA, Section 504 covers not just school-age children but people of all ages in the workplace, transportation, and other public situations.

Finally, IDEA guarantees special education services and an IEP for eligible students. At the same time, Section 504 protects the rights of all students with disabilities to receive equal access to education and related services. Parents must understand these laws to advocate for their children’s rights and ensure they receive the support they need.

Full copy of the statute and regulations for IDEA: https://sites.ed.gov/idea/statuteregulations/

Full copy of Section 504: the Rehabilitation Act of 1973: https:// www.dol.gov/agencies/oasam/centers-offices/civil-rights-center/statutes/section-504-rehabilitationact-of-1973

THE BRAINY-BUNCH where PASSION MEETS PURPOSE

Wed, 04 Oct 2023 13:24:16 GMT

"The Brainy-Bunch," a dedicated group of social media influencers and college students, has taken up the mantle as volunteers to support The Dan Lewis Foundation for Brain Regeneration Research (DLF). Their journey began with a visit to a prominent research lab, Quiver Biosciences, located in Cambridge, Massachusetts, as they embarked on the initial steps to raise awareness and fundraise for research to support traumatic brain injury repair and regeneration. Dr. Roy Maimon, a post-doctoral research scientist at the University of California San Diego and the first recipient of the Dan Lewis Prize, joined the group in Cambridge and gave an interactive presentation on his current research on neuro-regeneration. He provided the non-science group with the novel science behind his current research on neuro regeneration.

This remarkable collaboration between The Brainy-Bunch and the (DLF) highlights the powerful potential of partnerships between social media influencers and the scientific community in propelling medical advancements forward. The social media influencers have the audience, and the scientific community has the expertise, with a commitment to work together to change the course of treatment for those in the brain injury community. At Quiver Biosciences, The BrainyBunch was privy to firsthand experiences of the groundbreaking research spearheaded by eminent figures in neuroscience. Dr. Graham Dempsey and Dr. David Margulies, pioneers in their own right, are at the helm of efforts to revolutionize the critical work for brain trauma repair. The DLF seeks to catalyze brain regeneration research and is working with multiple world-class scientists in that quest.

This unique collaboration seeks to raise awareness and funds to support cutting-edge research that holds promise that brain repair and regeneration, once thought impossible, is now plausible. At the same time, the partnership has kindled a flame of hope that actively supports and champions scientific endeavors. Through their expansive reach on social media platforms, The Brainy-Bunch has a unique opportunity to disseminate critical information about brain regeneration research, acting as a bridge between the scientific community and the general public. In the coming months, it is anticipated that this collaboration will bear fruit, generating a swell of support and funding that will catapult brain trauma research into new frontiers. With the backing of the Brainy-Bunch, the DLF hopes to accelerate the pace of research, drawing us ever closer to a world where medications will one day help the human brain to heal itself.

As the journey continues, it will be exciting to witness the synergy between influencers and scientists, a testament to the power of unity in advancing the cause of medical science. The Brainy-Bunch, with its vibrant personalities, wide-reaching influence, and the brilliant minds of world-class scientists working together, is poised to usher in a new era of hope and progress in traumatic brain injury regeneration and repair. The partnership between the Brainy-Bunch and the Dan Lewis Foundation exemplifies how modern influencers can wield their power for the greater good while making tangible differences in the real world. The collaboration serves as a reminder that when passion meets purpose, amazing things can happen.

The Therapeutic Power of Music

Fri, 14 Jul 2023 20:24:47 GMT

From ancient times to modern times, making music has been a quintessential human capacity—a powerful channel for communication, expression, and communality. The ancient Greek philosopher, Plato, wrote, “Music gives a soul to the universe, wings to the mind, flight to the imagination, and life to everything.” The modern composer, Leonard Bernstein, said, “Music can name the unnamable and communicate the unknowable.” What benefits might music have for persons recovering from brain injury?

Kimberly Sena Moore, a boardcertified music therapist and neurologic music therapist in private practice, has written, “When used properly, music can be an incredibly powerful treatment tool. And not just because it’s fun, relaxing, and motivating, but because music has a profound impact on our brains and our bodies.” Moore lists her top brainbased reasons why music works in therapy .

» Music is a core function of our brain.

» We physiologically match (entrain to) to rhythmic beats.

» Children (even infants) respond readily to music.

» Music taps into our emotions. »Music helps improve our attention skills.

» Music uses shared neural circuits with speech.

» Music enhances learning.

» Music taps into our memories.

» Music is predictable, structured, and organized.

» Music is a social experience.

» Music is non-invasive, safe, and motivating.

Several years ago, Kristi Staniszewski, The Therapeutic Power of Music RPT, along with a neurologic music therapist, Sarah Thompson, initiated music and movement groups through the Brain Injury Alliance of Colorado.

Kristi notes, “There is something magical about music and how it influences our thoughts and feelings. Music can find its way into parts of the brain that may not be accessible via other experiences. For instance, a person who cannot speak due to aphasia may hear a familiar song and be able to sing the words.”

Kristi adds, “Music is fun. It can make exercising or remembering or any of the ‘tasks’ we are asking members of the group to work on…fun. It doesn’t feel like work; it feels like fun.” Her comments raised a thought: there must be a reason we call it “playing music” rather than “working music.” Music is a wonderful vehicle for bringing people together; people from different classes and cultures can enjoy a musical experience together. In this group, the facilitators put a lot of emphasis on the group members communicating with each other. In Kristi’s words, “Whether it’s through a song or a memory or about something they learn about each other, the communication among the group members is very important. I think people with brain injuries can tend to get isolated and feel they are alone with their issues. So, when we bring people together, whether their injuries are seen or unseen, it unites us as people, and that’s an important connection to have.”

Movement, rhythm, and tempo are important aspects of music that can support cognitive, physical, and behavioral flexibility. Movement pairs well with music, particularly with the rhythmic element of music. Kristi explained, “A marching song may stimulate the movement without striking you that you are being influenced by the music. You may feel the marching rhythm and tempo in your bones even if you are not able to move to that rhythm, but you still feel that rhythm.” Kristi explained further that “… a faster tempo may be used for hand and arm movements because these movements require fewer muscles to move quickly. With the larger leg muscles, a slower regular beat may be preferable.”

Kristi explained that music might help people focus on a particular word or phrase in the lyrics or a musical phrase or motif that occurs repeatedly. In addition, fun games with music may facilitate attention or memory or even divided attention if participants are asked to listen for a certain cue versus a different cue.

BIAC’s music and movement group members are encouraged to share their thoughts, feelings, and experiences with music. One man described himself as a semiprofessional musician before his injury, able to play several instruments well and compose music. Even though his specific skills were diminished, he said he was working hard to regain as many skills as possible, and he continued to revel in his involvement with music. An older gentleman told of being in London on a business trip prior to his injury and attending a Beatles (his favorite group) concert. He encountered Paul McCartney outside of the concert hall and obtained his autograph. That autograph and listening to the Beatles’ music still lifts his spirits and is one of the purest joys of his life. A particularly poignant story was shared by a woman whose injury resulted in retrograde amnesia. Although she remembers very little of her pre-injury life, often when she hears a familiar song, she experiences emotions attached to that song. She is starting, at least sometimes, to remember events and experiences associated with the song and the feelings it has evoked. In a very real sense, music has the power to heal.

DLF Science Advisory Board Spotlight

Fri, 14 Jul 2023 20:20:51 GMT

Michael C. Crair, Ph.D., serves on the Science Advisory Board for the Dan Lewis Foundation and on its Board of Directors. Dr. Crair has been instrumental in developing the research agenda the Dan Lewis Foundation has established. He recently worked with members of the Science Advisory Board to select the first winner of the Dan Lewis Foundation Award, an award selecting a post-doctoral neuroscientist working in the field of brain regeneration.

Michael C. Crair is the William Ziegler III Professor in the Department of Neuroscience, Professor of Ophthalmology & Visual Science, and Vice Provost for Research at Yale University. Dr. Crair obtained his doctoral degree in physics from the University of California, Berkeley, and did postdoctoral training in physics and neuroscience at Kyoto University and Kyoto Prefectural Medical School in Japan and in neuroscience at the University of California, San Francisco. He was a faculty member at Baylor College of Medicine in Houston, Texas, before coming to Yale as a member of the Department of Neuroscience in 2007. He has directed Yale’s Vision Core Program, the Graduate Program in Neuroscience, was Deputy Chair of the Department of Neuroscience from 2015-2017, then Deputy Dean for Scientific Affairs (Basic Science Departments) at the School of Medicine from 2017-2020 when he became the Vice Provost for Research at Yale University.

Dr. Crair maintains an active research program that develops and employs advanced imaging techniques to examine the basic mechanisms that mediate brain circuit development. He has made fundamental contributions to our understanding of neural activity in the developing brain by demonstrating that early spontaneous neuronal activity is an essential part of normal brain development. He is currently exploring the mechanisms by which this activity is generated and how it shapes brain circuit development. He has been awarded numerous honors for his research and teaching, including the Esther A. and Joseph Klingenstein Foundation Fellowship Award in the Neurosciences, the Marc Dresden Excellence in Graduate DLF Science Advisory Board Spotlight Education Award, and a NARSADSidney R. Baer Jr. Foundation Young Investigator Award. He has also been named an Alfred P. Sloan Foundation Research Fellow, a John Merck Fund Scholar, and the March of Dimes Foundation’s Basil O’Connor Fellow.

Targeting the Genome to Promote Brain Regeneration

Fri, 14 Jul 2023 20:18:39 GMT

The human genome is the maestro of the brain’s formation, growth, and maturation. As a person develops and interacts with environmental stimuli, the genetic program in all cells gradually unfurls itself. In a beautifully coordinated process, our DNA transcribes its information into RNA, which in turn mediates the synthesis of proteins that are essential for all life functions. For axons to repair themselves, for new synapses to form, and for neurons to proliferate, the respective elements of the genome must spring into action. As the brain matures, some of the properties of the developing brain are lost or diminished. Stimulating a brain to regenerate after injury will require reactivating these dormant genomic functions.

How, then, have scientists focused explicitly on the challenge of stimulating brain regeneration at the genetic level?

One method, gene therapy, involves introducing new genetic material into adult cells. Gene therapy uses harmless viruses, specifically adeno-associated viruses (“AAVs”) to deliver new genetic material into cells and, thereby, modify cellular activities. This method may be advantageous to target the brain since the blood-brain barrier often prevents other small molecule therapeutics from accessing brain tissue. Many investigators are studying the use of AAVs in preclinical studies to deliver genes promoting neuronal survival and growth in models of neurodegenerative disease.¹ Gene therapy results in a permanent change in the cell’s genome. New genetic material is incorporated into the cell’s genome, and this new genetic information then controls the activity of the cells by creating new or modified proteins. By causing the synthesis of proteins required for the formation of new cells or connections, AAV-mediated gene therapy may, someday, drive meaningful brain regeneration.

Gene therapy is technically very challenging. Figuring out the right dose of virus to administer is difficult, and it is usually not possible to administer multiple doses, since the body develops an immune response to the virus. Notwithstanding the difficulties in this approach, one team has used a gene therapy construct to regenerate many functional new neurons in an adult mouse model after ischemic injury.² This study provides some evidence that there is a reservoir of cells in the brain that can potentially be converted into replacement neurons.

Another approach to modifying the genome is to use “gene editing.” In this approach, a molecular ‘cut-and-paste’ tool has been discovered and developed to insert specific corrections into the target genome. For example, researchers have initiated clinical trials using gene editing (“CRISPR-Cas9 gene editing”) to treat a genetic form of blindness, Leber’s Congenital Amaurosis.³ This form of gene editing has been performed on cells in the back of the eye, and the induced corrections have led to the partial restoration of vision. This groundbreaking achievement offers renewed hope for applying similar strategies in brain regeneration. However, it is more difficult to imagine how gene editing techniques can deliver their corrective ‘payload’ to targeted regions.

The spotlight is shifting towards a third approach to manipulating the genome by using small, DNA-like molecules called “antisense oligonucleotides (ASOs)” to modulate gene activity. Antisense oligonucleotides (ASOs) are short, synthetic strands of modified DNA that can bind to specific RNA molecules and alter their activity. An ASO is a small molecular ‘patch’ that finds a specific location in the RNA message created by the genome to guide the formation of proteins. By ‘patching’ the mRNA, an ASO either prevents the production of harmful proteins or increases the production of beneficial ones. This class of molecules can target and modulate the formation of proteins with exquisite specificity. ASOs may be useful to stimulate brain regeneration by silencing genes that inhibit neuronal growth and plasticity or boosting genes that promote these processes. ASOs can be developed relatively rapidly, and their dosage is easier to titrate compared to AAV gene therapy or gene editing approaches.

There are already several examples of ASOs in use to target genetic controls in the brain in a selective manner. For instance, the FDA-approved drug Nusinersen for spinal muscular atrophy (SMA) is an ASO that increases the production of a critical motor neuron protein, thereby improving motor function in affected children.⁴ After many years of research, clinical trials are now underway to treat Huntington’s disease with ASOs.⁵ Finally, ASOs are showing promise in early-stage clinical trials for amyotrophic lateral sclerosis (ALS) by reducing the levels of a harmful protein that accumulates in the brain cells of patients.⁶ Dozens of ASO drug development programs that target the brain are now underway. Scientists, families of afflicted patients, and biotech companies are fully engaged in promising collaborations to unlock the brain’s capacity for healing. In previous newsletters, we have identified several promising areas of research that aim to stimulate significant brain regeneration and functional recovery after a major brain injury. We’ve explored several of these: how nerve cells (neurons) can be induced to repair their long tract connections, ‘axonal repair’ after spinal cord injury⁷; how the growth of new connections between neurons in surviving brain regions can be stimulated, ‘synaptogenesis and induced plasticity’⁸; and how to stimulate the creation of new neurons, ‘neurogenesis’ or to integrate newly transplanted (replacement) cells in the brain simulating neurogenesis.⁹

These strategies all rely on a thorough understanding of how the human genome controls axonal repair, synaptogenesis, and neurogenesis. The same genomic information that guides the brain’s growth and development contains the information necessary to regenerate after damage. This generation of brain scientists is inexorably unlocking that potential and learning how to allow the brain to heal itself.

The Dan Lewis Foundation is closely following multiple lines of research in the field of brain regeneration. The DLF is committed to encouraging and catalyzing such research through collegial exchange, linking researchers, disseminating new research findings, awarding the DLF Prize, and directly funding research as funds become available.

References

1. Ozlu, C., Bailey, R. M., Sinnett, S. & Goodspeed, K. D. Gene Transfer Therapy for Neurodevelopmental Disorders. Dev. Neurosci. 43 , 230–240 (2021).

2. Chen, Y.-C. et al. A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion. Mol. Ther. 28 , 217–234 (2020).

3. Daich Varela, M., Cabral de Guimaraes, T. A., Georgiou, M. & Michaelides, M. Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials. Br. J. Ophthalmol . 106 , 445–451 (2022).

4. Finkel, R. S. et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N. Engl. J. Med. 377 , 1723–1732 (2017).

5. Rook, M. E. & Southwell, A. L. Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic. BioDrugs 36 , 105–119 (2022).

6. Boros, B. D., Schoch, K. M., Kreple, C. J. & Miller, T. M. Antisense Oligonucleotides for the Study and Treatment of ALS. Neurotherapeutics 19 , 1145–1158 (2022).

7. Towards Brain Regeneration and Functional Recovery. Making Headway: DLF NeuroConnections (Fall 2022).

8. The Synapse and Brain Regeneration. Making Headway: DLF NeuroConnections (Winter 2023).

9. Can Damaged Tissue Be Replaced? Making Headway: DLF NeuroConnections (2023).

The Dan Lewis Foundation Prize for Brain Regeneration Research Awarded to Dr. Roy Maimon

Fri, 14 Jul 2023 20:12:41 GMT

As co-chairs of the Dan Lewis Foundation (DLF) for Brain Regeneration Research, we are pleased to announce University of California San Diego neuroscientist Dr. Roy Maimon as the first recipient of the DLF Prize. This accolade pays tribute to his groundbreaking work in advancing our understanding of the brain's regenerative capabilities. Dr. Maimon's research focuses on stimulating the brain to create new neurons, a crucial process in mitigating the detrimental effects of neurodegenerative diseases and injuries.

Over the past three years, Dr. Maimon has worked on this problem by testing a new concept for treating neurodegeneration: using cellular identity conversion to generate new neurons in the nervous system. Most recently, Dr. Maimon and colleagues have designed and executed experimental tests using antisense oligonucleotides (ASOs) to generate glia-to-neuron conversion in the adult rodent nervous system. These new neurons, created from radial gliallike cells and other GFAP-expressing cells, matured and functionally integrated into endogenous circuits over a two-month period, ultimately altering the behavior of the mice. This therapeutically viable approach opens up exciting prospects for producing new neurons to replace those lost due to neurodegenerative disease.

The DLF will follow future developments in this exciting and cutting-edge area with great attention. We hope that unlocking the ability to generate new functional neurons from existing brain cells will prove to be of real value to those with severe brain injuries. Dr. Maimon and his colleagues have produced intriguing results.

The DLF has closely tracked the impressive record of ASOs to successfully reduce the effects of neurodegenerative diseases in mammalian models as well as in humans. We believe that the work of Dr. Maimon and others doing similar research will also apply to brain regeneration in persons who have experienced ABI or TBI.

The DLF is excited by Dr. Maimon's research findings and will continue to follow his work in the field of brain regeneration. In Dr. Maimon's own words, "In upcoming years, I will seek a position as an academic investigator with the long-term goals of leading the field of in vivo glia-into-neurons cell identity conversion, being a part of finding cures for neurogenerative diseases, and successfully mentoring a new generation of young scientists who have a passion for understanding the brain.”

The Dan Lewis Foundation is committed to the support of excellent young scientists who are developing promising approaches to unlock the regenerative capacities of the brain. We proudly award Dr. Maimon the first DLF Prize for his groundbreaking work.

Maimon, Roy, Carlos Chillon-Marinas, Cedric E. Snethlage, Sarthak M. Singhal, Melissa McAlonis-Downes, Karen Ling, Frank Rigo, et al. 2021. "Therapeutically Viable Generation of Neurons with Antisense Oligonucleotide Suppression of PTB." Nature Neuroscience 24 (8): 1089–99.

Perspectives on Classification of Brain Injuries

Tue, 04 Apr 2023 19:21:07 GMT

The medical care and medical research fields have traditionally classified brain injuries as either Acquired Brain Injuries (ABIs) or Traumatic Brain Injuries (TBIs). From a broad perspective, all brain injuries are “acquired,” except congenital disorders. But the terms ABI and TBI have each, over time, taken on specific definitions with different implications, which are discussed here.

The term ABI is usually applied to injuries caused by a wide range of factors including strokes, infections, tumors, anoxia (lack of oxygen to the brain, for instance, from drowning or choking), neurotoxic poisoning, drug overdose, aneurysms, seizures, electric shock, and other factors.

The term TBI is applied to injuries caused by an external force or physical blow to the head. Major TBI causes include falls, assaults, motor vehicle accidents, gunshot wounds, child abuse, domestic violence, military actions (blast injuries), and workplace injuries. Injuries to the brain caused by rapid extreme acceleration and deceleration of the brain within the skull (as can occur in cyclist vs. motor vehicle events or “shaken baby syndrome”) are also Perspectives on Classification of Brain Injuries considered TBIs.

The use of these classifications can be helpful to healthcare professionals in understanding the causes of an individual’s brain injury and in considering which diagnostic tests and treatments will likely be most beneficial. In research settings, the use of the terms ABI and TBI may facilitate better-designed protocols and lead to more reliable and interpretable findings regarding causes, risk factors, and treatments. Further, the lay public may benefit from understanding the different signs and symptoms that indicate an ABI versus a TBI and may gain a better appreciation of the importance of seeking timely medical attention when these signs appear.

The use of the terms ABI and TBI have received criticism as well. Categorizations, broad as the terms ABI and TBI are, can lead to overgeneralizing the symptoms and outcomes of brain injuries. The unique nature of the brain injury that any individual suffers and the evolving nature of the short-term and long-term consequences of that injury should not be obscured by a label. Additionally, a degree of stigmatization can occur by applying these labels. This can also be the case when brain injury severity labels—mild, moderate, severe-are used early in the course of an individual’s brain injury and endure for a long time despite changes in the individual’s status. Further, some studies have shown inequities in access to services, supports, and resources across different brain injury categories. More specifically, funding for services and resources, particularly government funding, is sometimes more favorable for those diagnosed with TBI than those diagnosed with ABI.

The DLF recognizes that the use of the terms ABI and TBI has different implications in different contexts. This is true for the brain injury severity ratings (“mild,” “moderate,” and “severe”) as well. The idea that these labels may be more or less beneficial depending on context and the constituency group being addressed appears to be consistent with the stance taken by the Brain Injury Association of America. The DLF supports using the more general and simpler term “brain injury” in the context of dissemination of information, referral to resources, and advocating for individuals with brain injury and their families. However, as an organization that aspires to catalyze basic research into biomolecular medicines, technological advances, and other biomedical innovations that promote regeneration of the damaged brain, we recognize that classification and clear specification of research protocols are necessary for building a reliable and progressive knowledge base.

Neurologic Physical Therapy in Recovery from Brain Injury

Tue, 04 Apr 2023 19:19:32 GMT

Stroke, spinal cord injury, and traumatic brain injury are common diagnoses treated by neurologic physical therapists (PTs). The course of treatment varies widely based on the severity of the injury and the potential for recovery. For example, a mild stroke, called a Transient Ischemic Attack, may require no therapies. On the other hand, a severe Traumatic Brain Injury or incomplete spinal cord injury may benefit from PT treatment for years if functional gains continue.

By and large, PT approaches to brain injury have one significant commonality: using sensation and feedback to elicit a response. The goal is to provide the brain with a stimulus (input) and train the brain to respond with a consciously controlled meaningful output or appropriate motion. This process has come to be referred to as part of neuroplasticity. Neuroplasticity is the “capacity of neurons and neural networks in the brain to change their connections and behavior in response to new information, sensory stimulation, development, damage, or dysfunction.”

Quite often, the causes of a particular TBI also cause damage to the musculoskeletal system. Most of these orthopedic injuries, whether fractured bones or damaged joints, will heal in a much shorter time than the recovery of the brain itself. Therefore, the healed body may be waiting for months and years to receive instructions from the brain. As the neuroplastic recovery occurs in the central nervous system, time may elapse. The musculoskeletal system will rapidly deteriorate if the Written by Jared Stehr MSPT brain cannot instruct the body to move and interact with the physical forces and stresses of the world that ordinarily keep it well-conditioned. While waiting for the brain to recover, it is imperative to keep the body “ready to go.” This is reminiscent of the classic axiom, “Use it or lose it.” Preventing joint contractures, minimizing the loss of muscle mass, and weighting the skeletal system to stimulate bone density are essential components of treatment.

Specific neurologic therapy will begin in tandem with orthopedic interventions, increasing in duration and intensity as the patient is able to tolerate new challenges. All physical therapy aims to maximize the patient’s purposefully controlled motion. For example, a relearned movement could be turning the head left to right, pointing a finger, taking one step, balancing on one foot, performing a jumping jack, or throwing a ball. As simple motions are mastered, more complex motions are layered with others to complete tasks eventually. These purposefully controlled motions are combined again and again, creating complex movements that are performed to function and interact with the world.

Immediately following a neurologic injury, PT treatment time is primarily spent on balance, gait, and transfer training. These are paramount in a patient’s ability to return home and regain the initial levels of independence. As recovery progresses, the focus changes to more advanced activities of daily living, function, and potentially return to occupation.

A new trend in neuro-PT treatment is high-intensity training, specifically High-Intensity Gait Training (HIGT). By having a patient ambulate vigorously and continuously, many bodily systems are stimulated simultaneously, creating a cascade of physiologic responses that appear more efficient at eliciting recovery than most traditional PT treatments. While conventional neuro-PT treatments focus substantially on the quality of motion, HIGT deemphasizes the quality of motion if it is safe. Research supporting this approach has caused professional PT organizations to revise their Clinical Practice Guidelines, prioritizing using HIGT as a primary treatment for many neurologically involved populations ( www.neuropt.org ).

In the proper environment, with the appropriate equipment, HIGT is a treatment option even for severely impacted neurologic patients. Adultsized gait trainers can support the full body weight of a patient if required while keeping them safely within a rolling frame. Both legs may be used to ambulate inside this device, and full weight bearing is encouraged. Ceiling-mounted track systems allow patients to don a full trunk harness and safely walk a circuit while tethered to the installed ceiling track. And finally, if the patient is medically cleared for aquatic therapy, walking in a pool arguably allows the greatest customization of HIGT treatment. The water depth can be chosen to minimize or maximize buoyancy/ impact forces. The viscosity of the water resistively slows motion, lowers fall risk, and provides constant background strengthening. The water’s temperature and enveloping sensation often normalize muscle tone and decrease spasticity. At the moment, the prime limitation of aquatic neuro-PT treatment is access. The availability of suitable therapy pool facilities is low, and the time commitment plus preparation to participate by the patient is high.

Of course, physical therapists do not treat patients in isolation. They are part of a team of allied health professionals, including occupational therapists, speech therapists, recreation therapists, and assistive technologists. Each discipline evaluates patients, determines appropriate goals, and creates a treatment plan. Ideally, each discipline will integrate nonspecialized treatments from the care plans of the other providers as the patient progresses. This reinforces functional gains for the patient. A physical therapist might integrate breathing control into exercises to support what the patient is learning in speech therapy. The occupational therapist might add a simple standing balance task into an activity to reinforce the physical therapist’s goals. A speech therapist could add accurate switch targeting into treatment to follow through with the assistive technologist’s adaptations.

Physical therapy interventions for the neurologically involved patient continue to evolve. In addition to continuously improving traditional techniques, expect to see advancements utilizing robotics, neuro-electric interfacing, and, potentially, exoskeletons. New ideas, continued research, and developing technology are all solid allies for the improved future recovery of individuals with brain injuries.

Bella’s Story

Tue, 04 Apr 2023 19:05:41 GMT

Bella’s Story

Though brain injuries usually lead to a range of physical, cognitive, and emotional issues, every person who incurs a brain injury experiences a unique set of symptoms as well as both short-term and longer-term outcomes. This is true whether the brain injury is classified as mild, moderate, or severe. Therefore, it is important to take every brain injury seriously and to get medical attention as soon as possible to prevent further damage and to improve outcomes. Bella Kellis, at age 14, experienced a traumatic brain injury. In her own words, Bella, now 16, shares her story.

From a very young age, I believed that prioritizing education and developing self-discipline was the key to success. At just five years old, I’d already fallen head-over-heels in love with school, I loved acquiring knowledge about the world and experiencing everything I could. That thinking was abruptly changed and put on hold when I was fourteen and sustained a traumatic brain injury.

It was mid-summer at Lake Murry in 2020. I was fifteen feet up in a pine tree, ready to use the rope swing to jump into the water, but things did not go as planned. Instead, I fell directly onto my head at the foot of the lake. At the time, my dad understood the potential severity of the accident and rushed me to the doctor, but they simply glued my lip together and sent me home. I walked out of urgent care with minimal bruising and no stitches. They assumed I was okay because I showed no apparent external physical damage beyond a torn lip, but what they didn’t see or understand was that I walked out an entirely different person. I thought maybe all I needed was some sleep and I’d wake up to the person I was before, but I was terribly wrong.

"I was unpredictable, defensive & exhausted . I felt out of control and I knew I was a different person. "

My sophomore year of high school started differently. Following the accident, I had multiple weekly emotional breakdowns and could not handle stress. I returned to school and found it almost impossible to stay awake in class (narcolepsy: a rare long-term brain condition that can prevent a person from choosing when to wake or sleep). I had always easily juggled sports, straight-A academics, friends, and family. However, I could no longer read without developing an instant headache. I felt abnormal anger, sadness, and mood swings daily. Maintaining healthy relationships was almost impossible.

By the end of my sophomore year, I was unpredictable, defensive & exhausted. I felt out of control and I knew I was a different person. My family could not comprehend how the girl who memorized her multiplication tables at age five was the same person sobbing over algebra 2, refusing to identify as a “math person” ever again. All of us were bewildered by the change. I spent the last two years rebuilding my academics, relationships, attending doctor appointments and therapies. Working to rebuild the life I once had is a struggle. The traumatic brain injury temporarily paused my development and left me trying to achieve what had been so simple before. I still face many obstacles in my day-to-day life, but I am making great progress. I have worked hard to compensate for the effects of my condition. It is an ongoing journey with plenty of adaptations, but the process allows me to know myself better than ever before.

Of the many struggles caused by my injury, I found the most detrimental was my loss of identity. When you cannot live your life as the person you once were, life as you know it, changes. Losing trust in yourself affects every area of your life, especially interactions with others. How can you build a strong bond with another individual if you do not have one with yourself? How could one accomplish simple, everyday tasks like communicating and reasoning with another person when the ability to communicate with myself was poor? My traumatic brain injury triggered a loss of self and disadvantaged me in every area of my life, including social, family, and academic settings.

My traumatic brain injury has transformed my attitude toward my accomplishments. It was a glimpse of reality, a reality of a world where we all have an expiration date, and in a split second, you could lose everything you have worked so hard for. All that stays with us is our experiences and those of the individuals we have impacted throughout our lives. Therefore, we don’t have time to waste on mindless activities that aren’t making a difference or bringing joy to our lives. Given the age of my injury, “brain plasticity” has allowed for what I believe is a miraculous brain recovery. However, I recognize that everyone does not share that fortune. I aspire to one day alter society’s current treatment and understanding of brain trauma by making that the focus of my studies in college and career beyond.

Can Damaged Brain Tissue be Replaced?

Tue, 04 Apr 2023 13:17:35 GMT

The idea of replacing damaged brain tissue is intriguing and, at the same time, seemingly implausible. When vital brain tissue is damaged or destroyed, the function served by this tissue is lost. Other brain regions may provide some functional compensation, but in adults, this compensatory adaptation is limited. The field of brain regeneration research is driven by the vision that a meaningful regrowth or regeneration of brain tissue might be achieved.

Embryonic cells know how to grow and form brain tissue. These cells contain all the information required to divide, migrate, connect, and differentiate into specific functional brain regions or subunits. Can this genetic knowledge somehow be unlocked or reactivated in a damaged, mature brain?

In recent decades, scientists have taken steps towards this goal. For example, scientists learned how to cause the fibroblast cells in a snippet of skin to revert to embryo-like cells, called induced pluripotent stem cells ('iPSCs'). These iPSCs have all the information necessary to form any mature tissue or organ. Under the right conditions, these cells can be guided to differentiate into nerve tissue, cardiac tissue, and many other mature structures.

Induced Pluripotent Stem Cells

Brain regeneration researchers have begun to seriously explore the possibility that cells or tissues derived from these 'reawakened' cells might be reintroduced into a damaged brain. ¹ The hope is that these cells might engraft into the brain, recreate the damaged anatomy, and reconnect with other brain regions. This embedded patch might, in this scenario, be retrained, enabling the re-acquisition of the lost functions.

There are now reports of 'derived neurons' being introduced into a damaged brain to repair a damaged brain structure. One such example involves using iPSCs to generate dopamine-producing neurons, which are the type of neurons that degenerate in Parkinson's disease. In theory, these derived neurons can be transplanted into patients' brains to replace the lost neurons and restore dopamine function.

In one study, researchers transplanted iPSC-derived dopamine neurons into the brains of monkeys with a Parkinson's-like condition. ² The transplanted neurons survived, integrated into the host brain, and produced dopamine, improving motor function. Clinical trials are underway to determine if this approach can be safe and effective in humans, with some encouraging initial results in both motor function and quality of life. ³ This highly targeted cellular replacement research is a long way from replacing large regions of the brain cortex lost from trauma. Still, its success demonstrates that, in principle, new cellular material derived from induced pluripotent stem cells can be used to replace lost brain functions.

Organoids

Several years ago, some teams observed that if iPSCs are cultured for a longer period under particular conditions, they begin to clump into tissues. The tissue aggregates that form from derived neurons begin to take on some of the forms and structures of a developing brain. These cellular aggregates are called organoids . These brain organoids contain multiple cell types and regions found in the developing brain, including neurons, astrocytes, and oligodendrocytes. Because brain organoids resemble a developing brain, they are being used to study normal brain development and disease mechanisms. ⁴

Organoids possess the ability to self-organize in a dramatic fashion. The resulting structures manifest many features of developing brains. This demonstrates that the interplay between genomic instructions inherent in derived neurons and different forms of cell-cell signaling is sufficient to guide the formation of complex structures.

While there is a long path ahead to determine if human organoids can ever replace and replete brain tissue that has been destroyed or damaged, there has been important progress toward this goal in recent years.

In a study published in 2018, a team led by Dr. Fred Gage transplanted human brain organoids into the brains of adult mice. ⁵ The study shows that organoid grafts developed into functional neuronal networks with axons that grew to multiple regions of the host brain. The grafts also had functional blood vessels and integrated microglia. They also showed that the grafts had neuronal activity and suggested that there was functional synaptic connectivity between the graft and the host brain. This study demonstrates that a human organoid can survive transplantation, grow, and create connections to an adult mouse brain.

In a more recent study, researchers transplanted human brain organoids into the brains of neonatal mice. They found that the transplanted organoids survived and extended projections over a significant distance to connect with the host brain. The transplanted human neurons could function and deeply integrate into the mouse neural circuits. Furthermore, the mice transplanted with cerebral organoids showed an increase in the startle fear response, suggesting that the organoids have the potential to modulate behavior. ⁶ This study demonstrates that the connections formed between the organoid graft and the developing mouse brain are functionally active.

Two new studies demonstrate that the circuits created between the organoid and the host brain can respond to precise sensory stimuli and be trained to influence the animal's behavior. That is, a sensation perceived in the engrafted cells could be linked to a reward such that the animal changed its behavior after stimulation. The organoid in these studies becomes rewired into both the sensory and motivational circuits of the host. ^7,8

While these and other studies ⁹ provide some evidence that brain organoids could potentially be used to treat neurological disorders in the future, there remain many scientific, technical, and ethical barriers to the success of this approach. It is still very unclear whether human brain organoids can eventually be implanted to induce functional recovery in persons who have suffered a serious brain injury.

All cautions notwithstanding, the demonstration that a small snippet of skin contains the capacity to be transformed into pluripotent stem cells, matured into derived neurons, and then nurtured into a 'mini-brain' that can be implanted into another species, grow, and functionally integrate into that animal's brain has to be viewed as miraculous. This research is a source of great hope that meaningful functional recovery after severe brain injuries may be achieved.

References

Chen, C., Kim, W.-Y. & Jiang, P. Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells. JCI Insight 1 , e88632 (2016).
Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548 , 592–596 (2017).
Doi, D. et al. Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease. Nat. Commun. 11 , 3369 (2020).
Trujillo, C. A. & Muotri, A. R. Brain Organoids and the Study of Neurodevelopment. Trends Mol. Med. 24 , 982–990 (2018).
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36 , 432–441 (2018).
Dong, X. et al. Human cerebral organoids establish subcortical projections in the mouse brain after transplantation. Mol. Psychiatry 26 , 2964–2976 (2021).
Wilson, M. N. et al. Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. Nat. Commun. 13 , 7945 (2022).
Revah, O. et al. Maturation and circuit integration of transplanted human cortical organoids. Nature 610, 319–326 (2022).
Ramirez, S. et al. Modeling Traumatic Brain Injury in Human Cerebral Organoids. Cells 10 , (2021).

Benefits of Assistive Technology

Mon, 16 Jan 2023 20:33:14 GMT

How people live and work has changed dramatically over the past decades as technology is now seamlessly integrated into our daily lives. From television remotes, computers, GPS systems, doorbell cameras, and the like, we have all moved towards dependence on technology. For many individuals with disabilities, the use of assistive technology (AT) to participate in social activities and activities of daily living (like bathing, eating, dressing, communicating, and moving from place to place) has also increased. In 1998, Congress passed the Assistive Technology Act (P.L. 105-394), which made provisions for persons with developmental or acquired disabilities to access AT that can effectively decrease barriers found in everyday life while increasing access to and improving the quality of life.

In 2004, Congress amended the Assistive Technology Act (P.L. 108-364), noting that 54 million Americans had disabilities, with half of those individuals living with a severe disability. Federal law describes AT as any item that can maintain or improve the functional capabilities of a person with a disability.

As technology has become more sophisticated, so too have the AT tools that can be used to improve the lives of those with disabilities. The best AT tools and strategies are determined by the needs and goals of the individual, in conjunction with family members and care providers. The population of individuals needing AT is diverse and covers a wide range of disabilities. For some, the needs may be AT that has been used for decades, like eyeglasses, hearing aids, and communication boards. Others may need sophisticated tools such as speech-generating devices or equipment to assist positioning and mobility. Assessing individual needs is key to finding the right AT. To the greatest extent possible, every individual needing AT should participate in establishing and implementing an AT plan. There are multiple considerations to address in establishing an AT plan, including what barriers to independence need to be overcome or removed, what supports are necessary for functional progress, how can communication be assisted to increase options and opportunities for social interaction and participation, and what plans can be established for adapting activities and materials needed to encourage active engagement. As much as possible, the individual should help assess what is working or not working in their AT plan and help the AT specialist to generate potential solutions to problems that arise. Over time, plans will need to be updated and changed to correspond with changes in current levels of functioning. Therefore, AT needs and tools should be reassessed regularly to address current goals. Benefits of Assistive Technology Individuals with significant brain injuries often benefit from AT. It is essential to determine specific areas of need that may benefit from AT, including physical, sensory, cognitive, communication, academic, environmental control, social competence, vocational, and recreational. The person experiencing brain injury, their family, therapists, educators, rehabilitation engineers, physicians, and caretakers all may play a part in determining AT solutions. Finding therapists and caretakers knowledgeable about the implementation of AT and who can work on both short and long-term goals holds the most promise for reintegrating those with disabilities into purposeful life activities. Certified AT specialists can be found through the following link: https://www.resna.org/

The process of obtaining an initial AT evaluation and accessing AT equipment or devices is not always easy. It may help to contact your state’s brain injury association and check their website (a state-by Support The Dan Lewis Foundation when you shop at smile.amazon. Thank you to our amazing donors! state listing of brain injury associations is included in this newsletter). Additionally, every state has an AT project that is funded as part of the federal guidelines established in 1998 and can be accessed through: https:// askjan.org/concerns/State-Assistive-Technology-Projects.cfm

A child’s school team may have an AT specialist, or there may be a school district-wide AT specialist who should be called upon. For any student with special needs (including students with severe brain injuries), AT needs should be considered in forming an Individualized Educational Plan (IEP) or 504 plan. For an adult, a care coordinator may help find resources to meet AT needs. Alternatively, the individual’s medical team may be helpful, particularly occupational and physical therapists. Funding sources for equipment and devices vary from state to state, given that different agencies may bear responsibility for AT in different states. Again, it may be best to contact your state’s brain injury association to find an advocate, “system navigator,” or referral specialist who can steer you toward funding sources for AT. It is vital for family members or other advocates for the individual with a severe brain injury to be assertive in identifying and procuring the AT resources that are needed.

Kristen Gray M.A., ECE, ATP is an assistive technology specialist

Life Care Planning for Catastrophic Brain Injury

Thu, 12 Jan 2023 20:31:53 GMT

Catastrophic brain injury often results in long-term physical, cognitive, emotional, and behavioral changes that can be complicated and difficult to manage. A life care plan is essential for managing catastrophic brain injury. Life care planning is needed in the legal, financial, and practical management of the needs and resources of those with significant injuries.

The life care plan serves as a road map for care, identifying needs and associated costs. The elements of a life care plan will depend on the client’s needs. They may include future medical care, surgeries, diagnostic testing, therapies, evaluations, equipment needs, drug and supply needs, home or facility care, transportation, therapeutic recreation, home modifications, and vocational and educational services.

“A Life Care Plan is a dynamic document based upon published standards of practice, comprehensive assessment, data analysis, and research which provides an organized, concise plan for current and future needs with associated costs, for individuals who have experienced catastrophic injury or have chronic health care needs.” (International Conference on Life Care Planning, 1998.) Life care plans manage health care resources, discharge planning, educational and vocational planning, administrative proceedings such as workers’ compensation and federal vaccine injury fund cases, civil litigation, mediation, Medicare set-asides, elder care, and other areas. Life care planning is a specialty practice with established methods, standards, training programs, certifications, and publications. Life care planning is a transdisciplinary practice performed by rehabilitation professionals, including rehabilitation counselors, nurses, physicians, occupational therapists, physical therapists, social workers, and psychologists. Each professional works within their scope of practice while following the standards of practice for certified life care planners. A life care plan aims to maximize a client’s functioning and quality of life. Selecting a life care planner with the requisite education, training, skills, and experience in the field of catastrophic brain injury is essential. Managing catastrophic brain injury requires that the life care planner understand the medical issues and functional implications of brain injury, know what questions to ask of treatment team members, be able to analyze and synthesize information, and understand the lifelong consequences of disability.

When selecting a life care planner, inquire about the life care planner’s education, licenses and certifications, work experience, life care planning experience, membership in related professional associations or disability-specific organizations, participation in continuing education programs, and knowledge of life care planning standards of practice, codes of ethics and methodology. To find a life care planner, life care planning associations such as the International Academy of Life Care Planning (IALCP) section of the International Association of Rehabilitation Professionals (IARP) and the American Association of Nurse Life Care Planners (AANLCP) have lists of life care planning members on their websites.

Laura Woodard is a rehabilitation counselor, life care planner, and case manager who works for ReEntry Rehabilitation Services in Lakewood, Colorado. She also serves on the board of IALCP/IARP. For more information, please visit www.reentry.com .

The Synapse and Brain Regeneration

Thu, 12 Jan 2023 20:28:42 GMT

The past decade has brought new hope that the damaged brain can heal itself. It is now within the realm of possibility that scientists will design medicines that promote brain regeneration, even long after a severe brain injury. These new medicines will be engineered to use the brain’s own genetic machinery to stimulate regeneration and functional recovery. In the last edition of the DLF newsletter, ¹ we explored progress toward creating medicines that allow nerve cells to regrow. Here, we’ll explore another primary research goal, the development of medicines that induce the growth of new connections among the nerve cells in the brain.

The idea that a brain is comprised of interconnected nerve cells (‘neurons’) carrying small electrical currents was first proposed at the end of the 19th century. ^2,3 In the 1920s, it was first demonstrated that these electrical currents are transmitted between neurons by chemical substances (‘neurotransmitters’) acting in the minute space between neurons (‘synapses’). ⁴ We now understand that ~600 trillion synaptic connections among 100 billion neurons create the brain’s function! ⁵ Perception, learning, memory, thought, emotion, and movement result from neurotransmitters’ symphony of coordinated synaptic activation of neuronal networks.

Synaptic connections must be stable and durable to store memories and learning. But synapses must also be dynamic, strengthening some connections while weakening others in response to new experiences. There is a critical balance between stability and so-called ‘plasticity,’ the capacity of synapses to grow and change. During some phases of development, the organism is most advantaged by extreme plasticity; early in life, the brain’s interconnections must rapidly and continuously evolve. Later, it is advantageous that synaptic structures become more durable. It is, in fact, harder to ‘teach an old dog new tricks’, since synaptic networks become less flexible with age. The genetic programs that control synaptic activity determine the neuronal network’s relative degree of stability or plasticity. Maintaining a balance between stability and plasticity is critical for healthy brain function. Plasticity is needed for learning, and stability is required to retain the benefits of new learning.

In recent years, there has been a growing understanding of the normal regulation of synaptic formation, the role of specific neurotransmitters in synaptic function, and the impact of various classes of drugs on the formation of new synapses. ⁶ Drugs affecting the synapse may modify the release or uptake of specific neurotransmitters or alter the activity of genetic systems that control the production or degradation of neurotransmitters. Many different neurotransmitters have been identified, and many other drugs have been identified which alter neurotransmitters or modify the formation of synapses and, as a result, change synaptic function.

A significant acquired brain injury that results in loss of function has disrupted both neurons and the synaptic connections between them. Severe injuries create conditions in brain tissue that disrupt synaptic activity in many ways immediately after injury and over the months and years after the acute event. ^7,8 Injured tissue can release substances that can cause overactivity of synapses, the disruption of pre-existing synapses, or a reduction in the ability to create new synapses.

For functional recovery to occur after a severe brain injury, new synapses must be created as other brain regions are recruited to compensate for lost function. There is now a sufficiently detailed understanding of the regulation of synaptic neurotransmission to permit the development of drugs that stimulate the formation of new synapses (“synaptogenesis”) after a significant brain injury. Recent studies indicate it is possible to stimulate the creation of new synapses in the brain. ^9,10 Several studies are underway to explore the value of drug-induced synaptic plasticity in promoting functional recovery after a severe brain injury. Other investigators have directly modified gene transcription to upregulate synaptogenesis. ¹¹ As the genomic and transcriptional controls of synaptogenesis are further clarified, investigators will inevitably seek to directly upregulate the formation of new synapses and, thereby, induce functional recovery after severe brain injury. The DLF views these lines of inquiry as promising and has, accordingly, prioritized the stimulation of synaptogenesis as a core strategy of brain regeneration research.

Another strategy to restore function after a brain injury is to replace lost neurons by either stimulating new neuronal proliferation or by transplanting cells that can become neurons in the recipient’s brain. ¹² If new neurons or neuronal precursors are introduced into an injured brain, it will be necessary to create a microenvironment that optimizes the formation of new synapses in response to intensive retraining. Some of the same drugs that stimulate synaptic plasticity may also be essential to condition the brain as it seeks to incorporate new neurons into damaged tissues. More to come about this research frontier in a future DLF newsletter.

References

Dan Lewis Foundation Newsletter, Fall 2022.
Scheuerlein, H., Henschke, F. & Köckerling, F. Wilhelm von Waldeyer-Hartz—A Great Forefather: His Contributions to Anatomy with Particular Attention to ‘His’ Fascia. Frontiers in Surgery 4 , (2017).
López-Muñoz, F., Boya, J. & Alamo, C. Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramón y Cajal. Brain Res. Bull. 70 , 391–405 (2006).
York, G. K., Iii. OTTO LOEWI: DREAM INSPIRES A NOBEL-WINNING EXPERIMENT ON NEUROTRANSMISSION. Neurology Today 4 , 54 (2004).
Wanner, M. 600 trillion synapses and Alzheimers disease. The Jackson Laboratory https://www.jax.org/news-and-insights/jax-blog/2018/december/600-trillion-synapses-and-alzheimers-disease.
Kozorovitskiy, Y., Peixoto, R., Wang, W., Saunders, A. & Sabatini, B. L. Neuromodulation of excitatory synaptogenesis in striatal development. Elife 4 , (2015).
Jamjoom, A. A. B., Rhodes, J., Andrews, P. J. D. & Grant, S. G. N. The synapse in traumatic brain injury. Brain 144 , 18–31 (2021).
Merlo, L. et al. Alteration in synaptic junction proteins following traumatic brain injury. J. Neurotrauma 31 , 1375–1385 (2014).
Ng, S. Y. & Lee, A. Y. W. Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets. Front. Cell. Neurosci. 13 , 528 (2019).
Burlingham, S. R. et al. Induction of synapse formation by de novo neurotransmitter synthesis. Nat. Commun. 13 , 3060 (2022).
Sahin, G. S. et al. Leptin stimulates synaptogenesis in hippocampal neurons via KLF4 and SOCS3 inhibition of STAT3 signaling. Mol. Cell. Neurosci. 106 , 103500 (2020).
Xiong, L.-L. et al. Neural Stem Cell Transplantation Promotes Functional Recovery from Traumatic Brain Injury via Brain Derived Neurotrophic Factor-Mediated Neuroplasticity. Mol. Neurobiol. 55 , 2696–2711 (2018).

Dan’s Story

Tue, 04 Oct 2022 19:42:25 GMT

The Dan Lewis Foundation and its mission are inspired by a remarkable young man and his dedicated family. During the summer of 2007, after his sophomore year at Yale University, Dan rode in a 4,000-mile bicycling challenge to raise funds and public awareness for Habit for Humanity. The event started at the edge of the Long Island Sound and was to end when the cyclists crossed the Golden Gate Bridge. Unfortunately, on July 7, 2007, six weeks into the ride and just past the 2,000-mile mark in Kansas, Dan was struck by a speeding motorist. Dan sustained catastrophic injuries, including severe traumatic brain injury.

Dan endured many surgeries to address brain trauma, extensive internal injuries, and many broken bones. Survival was iffy; specialists and intensivists advised his family to “let him pass .” Dan was in a coma, his vital signs fluctuated dramatically, and indices of severe brain damage constantly appeared on the monitors that beeped and rang non-stop.

Though remaining in a coma, Dan came through multiple surgeries and difficult procedures. Finally, after four weeks and still comatose, he was deemed medically stable enough to be flown to Denver, his hometown.

For the next 11 months, Dan was an inpatient at five different hospitals, each equipped to handle his sudden medical emergencies and surgical needs as they emerged. He gradually regained a minimal level of consciousness which allowed him to be admitted to Denver’s Craig Rehabilitation Hospital, one of the country’s best for treatment, rehabilitation, and research for persons with spinal cord and brain injuries.

Over the years since Dan’s terrible initial injuries and despite early dire predictions about survival and prognosis, he has endured and slowly recovered rudimentary abilities. He has been through many medical ups and downs and a string of routine yet difficult procedures that must be repeated on a regular basis. However, he has never been a complainer and always tries his best in all activities and therapies. Dan is healthy now, can do some simple reading, spelling, addition, and subtraction, and can respond successfully to some verbal directions. He can speak single words and some short phrases. Dan had been an award-winning young cellist and can now pluck some basic patterns on his cello and use his bow with minor assistance. He participates in a weekly music class and is a key member of Spoke N Motion, an inclusive dance troupe with some dancers who use wheelchairs.

Despite Dan’s rewarding progress, the damage to his brain severely limits his everyday life, and he remains almost entirely dependent on family members, therapists, and attendants for care. As a result, the promise of Dan’s active, productive, creative life has been irrevocably altered.

The Dan Lewis Foundation is based on the hope that new advances and innovations in biomedical science— particularly research into small molecule medicines, genomically targeted nucleic acid medicines, and induced pluripotent stem cells--may one day lead to better outcomes for Dan and scores of thousands of other individuals with severe brain injuries. There is optimism now that science and technology have the potential to return better functional abilities to individuals with traumatic brain injury. Science and technology hold the promise to improve the lives of individuals with brain injuries and to positively impact the families and communities in which they live. We welcome your interest and support in helping advance the mission of the Dan Lewis Foundation.

DLF Research Review Corner

Tue, 04 Oct 2022 19:40:02 GMT

The central nervous system consists of more than 80 billion nerve cells (“neurons”). These neurons are networked with each other and connected to other parts of the body by “axons,” the long projection that extends from the neuron to its target tissues. The spinal cord contains both bundles of these axons, carrying information between the brain and the periphery, and relay centers, where signals are analyzed, filtered, and amplified. The brain receives sensory information about the world. It controls the motor activities of the body using signals sent through the long axons, many of which travel in the white matter of the spinal cord. When the spinal cord is damaged or severed, the connections between nerve cells in the brain and their targets in the periphery are disrupted. The nerve fiber that is distal to the injury undergoes degeneration. Even if the nerve cell body attempts to heal by sprouting new fibers, there is no way to carry the message to the target tissue once the distal axon is gone. For many years, the prevailing view was that the nerve’s axon dies much like a flower dies if its stem is severed. The ‘vital juices’ seep out. In recent years, it was realized that this image of damage to distal (or ‘downstream’) axons is wrong. After a cord injury, the distal axon is still nourished and supported by surrounding cells. The axon downstream of an injury degenerates because an active signal is sent to it, causing its breakdown. Some believe this ‘self-destruct’ signal serves the purpose of ‘decluttering’ the spinal cord. Regardless, the process of axonal death after a spinal cord injury makes it much more difficult for the body to reestablish functional connections across the gap in the spinal cord created by the initial injury.

About a decade ago, Dr. Strittmatter and his colleagues identified a group of molecules ordinarily present in the spinal cord that limit the ability of nerve fibers to grow and regenerate. ¹ Some of the specific molecules that inhibit neuronal regrowth are called Nogo-A, MAG, and OMgp, and they exert their effects (inhibiting repair) by binding to a specific receptor (NgR1). Dr. Strittmatter and others then set out to find ways to block the effects of these molecules, which inhibit the regrowth and reconnection of axons. His team created a new drug, a molecule (NgR1-FC, also known as AXER-204) that binds to these inhibitory molecules. ² The new drug acts as a decoy; the inhibitory substances bind to the drug rather than bind to the NgR1 receptor, whose activation is limiting the ability of surviving neurons to sprout axons and reorganize their connections. The new drug has recently been proven safe and effective in animals (including primates) with spinal cord injuries. Importantly, this drug had an effect in animal models long after the initial injury, indicating that the innate capability of neurons to regenerate connections and functions persists long after an injury.

The preclinical data was sufficiently encouraging that the RESET clinical trial was launched in humans. ³ It is anticipated that the results of this trial will be available this year. A similar phase 2 clinical trial is underway in Europe; its results are also anticipated shortly. Positive results in either of these trials would be a true breakthrough in the quest to stimulate brain regeneration. Such results would demonstrate that neurons have an innate ability to self-repair that is normally inhibited but can be reactivated after a severe injury. There is good reason to believe that the same or similar mechanisms that inhibit neuronal recovery in the spinal cord are also active in the brain after a brain injury. ⁴ The DLF is following this line of research with great interest and enthusiasm. The ability to unlock the innate power of a damaged neuron to regrow and reconnect is one critical step toward brain regeneration and functional recovery after a major brain injury.

References

Schwab, M. E. & Strittmatter, S. M. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol. 27 , 53–60 (2014).
Wang, X. et al. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain 143 , 1697–1713 (2020).
AXER-204 in Participants With Chronic Spinal Cord Injury - Full Text View - ClinicalTrials.Gov. https://clinicaltrials.gov/ct2/show/NCT03989440.
Lindborg, J. A. et al. Optic nerve regeneration screen identifies multiple genes restricting adult neural repair. Cell Rep. 34 , 108777 (2021).

Towards Brain Regeneration and Functional Recovery

Tue, 04 Oct 2022 19:39:28 GMT

A major brain injury can result in the loss of brain tissue, the disruption of connections among regions of the nervous system, the destruction of specific brain regions that control various functions or sensations, and the creation of chaotic electrical activity that disrupts other brain signaling.

To maximize healing in the damaged brain, minimizing the impact of the initial injury in the early hours and days after the trauma is essential. Bleeding and swelling must be controlled. Ongoing damage and scarring of the brain as a result of inflammation and disruption of blood vessels must be limited. Metabolic damage from uncontrolled seizures must be reduced.

Eventually, the storm of the acute events subsides. A person who survives the initial injury enters a future with residual damage and loss of function. Although other tissues and organs are capable of regeneration, human brain tissue does not regrow after damage. Some functional recovery can occur over time, mainly as the person retrains surviving brain regions to take over functions that were served by the injured or disrupted neural tissue. Persons who have survived a severe brain injury usually experience only modest further improvement in the years after their injury.

Recent research has demonstrated that it is plausible to develop medicines and treatments that stimulate the brain to regenerate itself and allow for functional recovery, even years after a devastating injury. The DLF is committed to focusing on developing therapies that will induce brain regeneration and function in persons living in the chronic phase of traumatic brain damage.

Our scientific experts believe that a combination of strategies will be required to allow the brain to experience regrowth and recovery. First, it is necessary to unlock the ability of neurons to grow and replace lost brain tissue. Second, the power of the brain to form new synaptic connections must be enhanced, both in surviving brain regions and in regions repopulated with neurons. Third, the ability of neurons to reconnect to severed axons must be enhanced. Fourth, there must be highly targeted methods to train recovering and regenerating brain regions. Finally, novel devices that connect computers directly to neurons in the brain are being developed. These “brain-computer interfaces” are being designed to re-connect surviving brain regions to allow movement in paralyzed limbs and expression to people who can no longer speak. In each issue of the DLF newsletter, we will highlight one aspect of emerging research about stimulating brain regeneration (see Research Review Corner). We hope that growing awareness of dramatic scientific progress will motivate people to help support this work.

The DLF will focus resources and attention on those scientific projects and initiatives that are most likely to yield medicines that will stimulate brain regeneration and functional recovery. The DLF depends on charitable contributions and grants to fund the research, which will make these possibilities a reality. We hope you find these research updates to be informative and inspiring.

Welcome Letter

Tue, 04 Oct 2022 19:37:54 GMT

As Co-Chairs of the Dan Lewis Foundation for Brain Regeneration Research (the DLF), we are pleased to introduce you to the DLF’s first quarterly newsletter—Making Headway: DLF NeuroConnections. This newsletter will bring reviews and updates on research relevant to brain regeneration. Each issue will highlight a prominent neuroscientist contributing to the field of brain regeneration or a research program advancing medicines and methods to accelerate recovery from brain injury, especially for those in the chronic phase of recovery. In this inaugural issue, we will present the story of Dan Lewis, the namesake, and inspiration for our research foundation. You will also find a link that will take you directly to our website, which provides detailed information about the goals and methods of the DLF. In the coming months we will be adding information regarding resources and events that may be helpful for individuals with serious brain injuries and their families.

The overarching goal of the DLF is to pursue biomedical breakthroughs that will one day improve the lives of those affected by serious brain injury. We aspire to make a broad range of biomolecular medicines and other biomedical therapies available to the vast population of people with moderate and severe brain injuries. We will continue to raise funds and direct such funds toward the most promising and empirically supported biomedical therapeutics. In addition, by supporting programmatic research, the foundation aspires to expedite clinical trials - joint efforts between research institutions, biotech companies, and individuals with brain injuries and their families. The DLF is eager to stay in touch with the needs and aspirations of the brain injury community and its allies. Please visit our website. You will find much more detailed information about the DLF’s objectives and activities and ways you can contact us with questions and/or comments.

You have our sincere thanks for your interest in the DLF and your curiosity about the most cutting-edge approaches to brain regeneration and improving recovery rate and function of persons with serious brain injuries.

With best regards and hopeful wishes for the future,

David Margulies, M.D,

Hal C. Lewis Ph.D.

The 1st Annual Summit Meeting on Brain Regeneration Research

Sat, 07 Aug 2021 19:32:57 GMT

Boston, Massachusetts - August 6th and 7th, 2021

Report on Proceedings and Research Plans

DLF Mission

The mission of the Dan Lewis Foundation for Brain Regeneration Research is to create new pharmacologic treatments that promote neural cell regeneration, renewed synaptic plasticity, and axonal regrowth to improve the lives of persons with moderate and severe traumatic brain injuries and their families

Activities in support of this mission include—

Convene meetings of leading bioscientists to foster collaboration and formulation of coordinated, programmatic research plans.
Establish a blueprint for a specific step-by-step research agenda that exploits new cellular models and assays of brain function as well as new classes of medicines that can specifically target the expression of key pathways that regulate CNS plasticity.
Raise funds to support this research agenda and distribute these funds based on strict peer review of applications for funding from academic and commercial investigators.
Encourage research partnerships between scientists in academic and business settings to explore the potential of antisense oligonucleotides (ASOs) and small molecule medicines to accelerate brain recovery, particularly in the context of rigorous therapy services and repletion of key populations of CNS cells.
Promote research efforts to evaluate the safety and efficacy of various treatment regimens utilizing genomically targeting nucleic acid medicines (ASOs) and/or small molecule medicines to promote neurological recovery in the chronic phase following TBI.
Link with other TBI information and advocacy groups and organizations to disseminate information regarding ongoing research efforts in pioneering medicines to improve outcomes for persons with severe TBI.
Provide support to neuroscientists pursuing research into innovative pharmaceutical approaches to TBI recovery via information, references, professional linkages, and review and consultation regarding grant applications.

Scientific Rationale

In recent years, neuroscientists have accumulated a deeper understanding of how genes control brain plasticity — the capacity of the brain to repair or modify its connections, especially in response to injury. Several genetically controlled modulators have been identified that inhibit neuronal repletion, axonal regeneration and sprouting, and synaptic reconnection in the aging or injured brain. At the same time, there have been significant advances in tools and methods — such as human induced pluripotent stem cell (iPSC) derived cellular models, optical electrophysiology, genomically-targeted medicines, and high-throughput screening methods — that, in combination, show much promise for identifying drugs to improve outcomes associated with previously untreatable neurological conditions. For instance, there is growing evidence of the effectiveness of antisense oligonucleotides (ASOs) and other genomically-targeting small molecule medicines that interact with genetic controls and transcriptional products to ameliorate symptoms of several neurological diseases. When applied to TBI, these pharmacologic agents show potential to “downregulate” the genetic modulators which inhibit repletion, regrowth, and reconnection in the brain and central nervous system. It is now quite possible to synthesize a strand of nucleic acid — an ASO — that will bind to the messenger mRNA of a particular gene and inactivate it, effectively turning that gene “off”. Put another way, the inhibition of the inhibition of neurologic recovery is one key pathway that the Dan Lewis Foundation is exploring.

ASOs have been shown to be effective in decreasing the negative symptoms of a variety of disorders. Examples of ASO-based therapies, recently approved by the FDA, for previously untreatable disorders include Formiversen for Cytomegalovirus Retinitis, Mipomersen for Homozygous Familial Hypercholesterolemia, Eteplirsen for Duchenne Muscular Dystrophy, Nusinersen for Spinal Muscular Atrophy, and Milasen for Batten Disease. In the context of TBI drug research, we believe it may be possible to apply ASOs to “turn off” genetic regulatory systems that cause neurons to stop proliferating and which limit the formation of new synapses as part of the developmental process. Intervening with specifically designed ASOs may promote cortical regeneration and synaptic reconnections, especially in the context of consistently targeted rehabilitation therapies.

Additional research pathways that the Foundation will pursue spring from Dr. Mark Bear’s work on the mGluR theory of Fragile X mental retardation. His subsequent efforts to find drug therapies have demonstrated that restoration of cortical synaptic function is demonstrable in animal models and very likely to be possible in humans. Dr. Stephen Strittmatter’s work involving anti-NOGO antibodies to block NOGO molecules (which inhibit regeneration) (Wang et al., 2020) has shown that regrowth and sprouting of axons in the central nervous system can be achieved. Recently, a small body of literature has emerged that identifies the role of the LYNX1 gene as a down-regulator of neuroplasticity in a rodent model (Morishita et al., 2010) . A LYNX1 knock-out model seems to promote neuroplasticity that is otherwise lost. We will investigate the possibility that knock-down of this gene in a patient with cortical injury might permit cortical repair or regeneration.

In sum, the Dan Lewis Foundation for Brain Regeneration Research will empirically evaluate strategies for unlocking a regenerative capacity in the damaged adult human brain by designing genomically targeted pharmacologic agents that can reactivate cortical plasticity. A world class group of neuroscientists and biomedical innovators has been assembled to specify and prioritize the Foundation’s research goals. We will accomplish these goals by providing seed funding for programmatic research at major academic laboratories, by sponsoring post-doctoral fellowships for applicants whose preliminary work shows exceptional promise in our specified priority areas, by working with biotechnology companies, and by coordinating our work with leading brain injury advocacy and policy groups. Our overarching goal is to make safe and effective pharmacological treatments available to persons with moderate and severe brain injuries within the next 3 to 5 years.

Overview

No specific drugs exist to stimulate functional recovery in an injured brain during the months and years after a traumatic brain injury. The complexity of brain biology, structure, and function has limited, thus far, both the discovery of drug targets and the creation of medicines to help heal a damaged brain. Recent advances in cell biology, neuroscience, biotechnology, genomically-targeting medicines, and machine learning computational have converged and renewed hope that drugs can be developed to drive brain regeneration. Any such future drugs, administered in the context of intense training and supported by various biomechanical and computational prostheses, would create new hope for individuals with severe traumatic brain injuries.

The DLF’s 1st Annual Summit Meeting on Brain Regeneration Research was convened on August 6-7, 2021 in Boston, Massachusetts to explore ideas that may help to advance this field of research and to guide the DLF’s sponsored research agenda. During the initial evening of the meeting, Dr. Hal Lewis provided welcoming remarks (a transcript of those remarks is provided below).Additional presentations included orientation to the DLF’s goals, overview of the scientific underpinnings of the DLF’s mission, and a motivational presentation Dr. Michael Tranfaglia regarding the evolution of FRAXA and its mission to research and discover medicines to arrest and/or reverse the negative effects of Fragile X Syndrome.

On the second day of the meeting, round table discussions and topical focus groups considered key questions for consideration in planning and specifying the DLF’s research roadmap. Those key questions, major discussion points, and research priorities are summarized in a later section of this report.

Welcoming Remarks by H. Lewis

I want to extend a hearty greeting to each of you participating in this seminal event for the Dan Lewis Foundation whether you are here in Boston or joining via Zoom. We are grateful for the time you have given us and for the contributions you will make towards specifying the research agenda we hope to support. I know how significant and productive your work is and how valuable your time is…so we will try to utilize the time you have generously given us efficiently and productively. Welcome and thank you very, very much.

I want to extend a few additional “thank you’s”. First, to our project secretary, Margaret Nicholson, who has done a wonderful job of organizing this meeting. Margaret has efficiently operationalized our aspirations for this conference into a working management plan…and carried out that plan in a remarkably short amount of time. Thank you, Margaret, very much.

I want to express my gratitude to the members of the foundation’s Scientific Advisory Board for their enthusiasm and guidance in shaping the goals of the DLF. These very accomplished, very thoughtful, and very kind individuals have been generous with their time, expertise, and wisdom. I can’t thank them enough.

I particularly want to thank David Margulies, who assisted me in founding the Dan Lewis Foundation and has served as co-chair of the DLF Board of Directors for his leadership and hard work, especially during the early developmental stages of the DLF. David has been tremendous in sharing his wide ranging skills and his vision of what the DLF might become.

Finally, I want to express my deep appreciation to the neuroscientific community as a whole for your dedication to exploring and understanding the workings of the central nervous system. From the granular level to the systems level, astounding amounts of data are being amassed, organized, and analyzed at speeds never thought to be possible until recently. This burgeoning knowledge base has led to successful treatments for several neurological and neuromuscular disorders and will doubtless lead to many, many more. From my vantage point, this embodies what is best about we humans--the collective effort to pursue knowledge that will benefit all—it is quite wondrous.

Just a few weeks ago, all the media buzz centered on Richard Bransen’s and Jeff Bezos’ flights to the boundaries of outer space. Laudable in many ways.... Clearly, there is a strong human impulse to explore the unknown and clearly there is much unknown about outer space that is worth finding out about. But to me, what is even more spectacular, are the combined efforts of the scientific community to explore “inner space”…the inner space of the human brain. I’ve always been a fan of the film “Fantastic Voyage” and the book “The Magic School Bus Goes Inside the Human Body”. But seriously, to me, exploration of this “inner space” is of extraordinary value, representing an exciting journey of nearly infinite complexity and immeasurable benefit.

Now, I’m going to show you a video consisting of two segments that paint a picture of my son, Dan, pre- and post-accident. The first segment is from a video tribute created by his college friends, shortly after his accident. The sound track in this part is from a recording of the acoustic cello group that Dan co-founded—the group is named Low Strung —playing their version of the classic rock song Dream On by Aerosmith. On this track, you will hear Dan playing the lead cello part. The video includes pictures of Dan relaxing with friends, playing his cello in various settings, and on the road during the cross-country bicycle trip that ended so abruptly. Thankfully, no pictures of him sitting in class taking notes. How boring would that be? You wouldn’t know from this video clip, but Dan was a very serious student primarily interested in advanced mathematics, physics, computer science, and literature.

The second segment shows Dan in some rehab activities over the last few years. Each section is about three (3) minutes long.

Click here to watch the video

The contrast is stark and striking. Dan is essentially a different person now. For many years after Dan’s catastrophic injuries, my wife and I and Dan’s younger siblings, Katie and Peter, experienced two different Dans. It was as if there were two different universes in which Dan existed. This experience is very common for families of persons who have suffered severe brain injuries. It is an experience that is very difficult to reconcile with emotionally. The pain of realizing that a loved one has been so dramatically and negatively transformed in an instant—literally an instant—is very difficult to overcome.

I should note that Dan continues to make functional progress, albeit, painstakingly slowly .Now, he can do a little arithmetic, he can read and spell some simple words, and make simple choices. He is showing improvement in bowing his cello and plucking simple patterns.

Unfortunately, he cannot work the finger board with his left hand due to left side hemiparesis.

From a distance, these gains may not look like they amount to much but from up close they seem remarkable. For years, I talked to many people, many doctors, many scientists about whether there was anything that could be done to speed up Dan’s progress. The result of these conversations was almost always deflating.

After Dan had gotten to a point of reasonable medical stability, I read a lot about stem cell treatments, attended stem cell seminars, talked to anyone I could find with ideas about stem cell treatments. But the outcome data regarding stem cell treatment for TBI were not convincing, the evaluation methods were generally not rigorous, and the risks--for instance--the risk of tumor formation, led me to realize that the medical science was not yet sufficiently advanced to pursue this treatment for Dan.

About six years ago, I began to search for information about other potential paths towards regeneration of the brain that might give hope to the possibility of meaningful functional gains. The idea began to germinate that I might not have to be resigned to the tragedy of Dan’s life, that biomedical innovations might hold hope for significant improvement. Gradually in various discussions, I became aware that a multi-modal approach including genomically targeting drugs, bioengineered devices, computerized brain interfaces, and newest stem cell methodologies in the context of aggressive rehabilitation and therapies did, indeed, hold hope for brain regeneration.

About 2½ years ago, I reconnected with David, a friend from our schoolboy years in the small New Jersey town in which we were raised. Back those many years ago, we had fun working on middle school and high school projects. As we exchanged stories about our families, Dan’s situation entered the conversation. As the conversation progressed, it became clear that we both had professional experience in neurological disorders and TBI, me as a clinical and research psychologist and David as a physician as well as a bioinformatics and biotechnology expert. David picked up on my desire to do something transformational to help Dan and the hundreds of thousands of persons in the chronic stage of living with a severe brain injury. And so the seeds of the Dan Lewis Foundation for Brain Regeneration Research were planted.

This is what led to the formation of the Dan Lewis Foundation. With the help of an excellent Board of Directors and a terrific group of neuroscientists, we have decided to focus initially on supporting discovery of neurogenic drugs. We are inspired by the work of Foundations such as FRAXA, Cure SMA, and the Cystic Fibrosis Foundation---exciting work catalyzing advocacy, resources, information, and research to address the challenges associated with these disorders. You will hear from Michael Tranfaglia, co-founder of FRAXA, in a few minutes.

We, of course, recognize that TBI itself--unlike most other neurological disorders--is not linked to genetic factors. This makes our challenge quite great--but we believe that this challenge can be met by the scientific community within the next 5 to 10 years,

In sum, the overarching goal of the Dan Lewis Foundation is to pursue breakthroughs that will, one day, improve the lives of those affected by serious brain injury. We aspire to make a broad range of biomedical therapies available to the very large population of people with moderate and severe brain injuries.

We will continue to raise funds and direct such funds toward the most promising and empirically supported biomedical therapeutics. By supporting programmatic research, the foundation aspires to expedite clinical trials - joint efforts between research institutions, biotech companies, and patients and their families.

As I’ve described to you, Dan and our family have been on quite a journey. I am so grateful to all of you for lighting the path on which our journey must continue and, perhaps, for accompanying us as we travel onward. This is a journey that will delve into that part of us that makes us truly human. A journey which many philosophers would agree takes us as close as possible to the seat of the human soul. A journey into “inner space” which seeks to improve the lives of millions of individuals and their families who have experienced severe TBI, who are hoping for more than resignation and acceptance, who are hoping for real improvement in the capacity to function and participate in family and community life.

Thank you all very much!

Conference Participants

David Margulies, MD, Harvard Medical School (ret.)/Q-State Biosciences
Hal Lewis, PhD, University of Colorado (ret.)
Graham T. Dempsey, PhD, Q-State Biosciences
Michael Crair, PhD, Yale University
Stephen Strittmatter, MD, PhD, Yale University
Sudhir Agrawal, PhD, ARNAY Sciences/University of Massachusetts Medical School
Alan Kopin, MD, Tufts University School of Medicine
Daniel Geschwind, MD, PhD, UCLA
Ed Boyden, PhD, MIT
Guo-li Ming, MD, PhD, University of Pennsylvania
Hongjun Song, PhD, University of Pennsylvania
Larry Benowitz, PhD, Harvard Medical School
Jeffery D. Kocsis, PhD, Yale University
Lorenz Studer, MD, Sloan Kettering Institute
Marius Wernig, MD, Stanford University
Roman Giger, PhD, MS, University of Michigan Medical School
S Thomas Carmichael, MD, PhD, UCLA
Steve Goldman, MD, PhD, University of Rochester
Michael Tranfaglia, MD, FRAXA

Focus Group Topics

This report briefly summarizes current thinking in several key areas of research that are essential to the development of new medical treatments to improve long term outcomes for persons with moderate/severe TBI. These areas include: (a) methods to quantify brain injury; (b) methods of inducing the formation of new synapses and axonal repair after injury; (c) methods to stimulate the production of new neurons (endogenously or ex vivo) to replace lost neural substrate; and (d) methods to design, develop, and test medicines that directly interact with the control mechanisms of synaptogenesis, axonal regeneration, and neurogenesis.

A wide range of questions provided a focus for the round table discussions and the action planning sessions that comprised a majority of the meeting time. These questions are listed below:

What quantitative methods are required: (a) to more precisely characterize brain function over time following a traumatic brain injury, and (b) to evaluate the efficacy of treatments? (Smith et al., 2019; Nadel et al., 2021; Yoo and Choi, 2021)
What experimental models, organisms, techniques, or systems (in vitro and in vivo) will be crucial to develop therapies for TBI in the chronic phase after injury?
What is the role of bioactive materials in promoting brain healing? (Lacalle-Aurioles et al., 2020; Tan et al., 2020)
How is synaptogenesis regulated? (Gatto and Broadie, 2010; Harris, 2020)
What genomic networks control development and synapse formation in the human brain? (van Dyck and Morrow, 2017)
How is the transcriptional activity that mediates synaptogenesis regulated during normal development?
How do CNS synapses react to TBI? (Jamjoom et al., 2021)
How can brain synaptogenesis be reactivated after TBI? (Wen et al., 2017)
Can residual cortex be ‘remapped’ after TBI? (Wittenberg, 2010; Takase and Regenhardt, 2021)
What genomic networks control neurogenesis in the human brain? (Tirone et al., 2013; Bergmann, Spalding and Frisén, 2015; Nagappan, Chen and Wang, 2020) (Poplawski et al., 2020)
What neurogenesis normally takes place in adults? (Kumar et al., 2019)
Why don’t CNS neurons regenerate? (Schwab and Strittmatter, 2014; Wang et al., 2020)
How can neurogenesis be reactivated in different regions of the brain during adulthood? (Richardson, Sun and Bullock, 2007; Sun, 2014)
How does TBI affect neurogenesis? (Zheng et al., 2013)
How might neurogenesis and accurate axonal projections be stimulated after TBI?
Can stem cell therapy or other cellular repletion therapies play a useful role in promoting recovery during the chronic phase of recovery after a traumatic brain injury? (Zheng et al., 2013; Cox, 2018; Xiong et al., 2018)
Does work with organoids have any practical or theoretical implications for cellular repletion therapy efforts? (Oyefeso et al., 2021)
What is the current state of research to repair spinal cord injuries?
What lessons and/or analogies should be taken from SCI research and applied to brain regeneration research? (Hirokawa et al., 2017; Li et al., 2020; Mohammed et al., 2020; Puls et al., 2020)
Can genomically targeting medicines be used to reactivate neurogenesis, synaptogenesis, and axonal projection after a traumatic brain injury?
Do any existing pharmacologic therapies have efficacy in the chronic phase after an injury?
What therapies or approaches hold promise for TBI in the chronic phase? (Xiong et al., 2015) How can the results of prior clinical trials assist in the design of future trials?

Summary of Key Points and Research Directions

The need for new drugs to treat traumatic brain injuries

The magnitude of the problem of traumatic brain injury is well understood. The clinical, economic, familial, and personal impacts of a serious traumatic brain injury have been described and quantified by many others. Whether caused by war, contact sports, motor vehicle accidents, street violence, strokes, degenerative brain or other disease conditions, or other tragic mishaps, a serious brain injury has devastating and life-altering consequences for the injured individual and his/her family (Iaccarino et al., 2018) .

In recent decades, research efforts and clinical strategies have focused on brain protection and salvage in the hours to first months after the occurrence of the injury. ‘Best practices’ have been defined to reduce ischemia, infection, and inflammation surrounding the injury (Hawryluk et al., 2020) . Methods have been developed to characterize the initial and evolving scope of tissue and functional damage.[ref] Techniques to rehabilitate and retrain the injured individual have been created [ref]. Protocols have been defined for the use of medications to manage pain, spasms, residual seizures, and the neuropsychiatric sequelae of the injury.

A number of charitable foundations (Spinal Cord Team, 2020) , research institutes, and biopharmaceutical companies (Market Research Future, no date) are now focused on the challenges of biomedical treatments for TBI, although the predominant emphasis of these efforts is on the early weeks and months after an injury.

The brain’s innate abilities to recover some amount of function have been appreciated for decades (Nudo, 2013) . The prevailing understanding is that there exists a period of time after an acute injury (3-12+ months) during which the preponderance of achievable functional recovery will be realized. There is, in many cases, some modest ongoing recovery thereafter. However, the biological factors which influence this recuperation window are incompletely understood ( (Sofroniew, 2018) . Thus far, efforts to develop medicines that can extend or expand endogenous recovery mechanisms have been unsuccessful, although a variety of approaches have been trialed (Xiong et al., 2015) .

The core strategy of the DLF is to seek a better understanding of the brain’s own recuperative mechanisms and then to amplify or prolong these mechanisms to stimulate therapeutic brain regeneration. This report briefly summarizes current thinking in key areas of research that are essential to the development of new medical therapies for TBI. These areas include: (a) methods to quantify brain injury; (b) methods of inducing the formation of new synapses and axonal repair after injury; (c.) methods to stimulate the production of new neurons (endogenously or ex vivo) to replace lost neural substrate; and (d) methods to design, develop, and test medicines that directly interact with the control mechanisms of synaptogenesis, axonal regeneration, and neurogenesis.

Definition and characterization of a traumatic brain injury:

A precursor to progress towards meaningful medical therapies for TBI is to carefully characterize and quantify damage to the injured individual’s brain and to develop metrics that can be applied to cohorts. The heterogeneity of injuries (cause, severity, impact on measurable skill domains, age at onset, interval since injury) greatly complicates efforts to design trials for any candidate therapy. The paucity of specific biomarkers of injury and healing is a further challenge to progress in the field. Creating descriptive standards that characterize individuals and cohorts based on objective clinical and imaging data would help accelerate learning from future trials by permitting meaningful multicenter and cross-study data analysis.

Imaging to quantify traumatic brain injuries:

Various functional imaging techniques can be used to evaluate an initial brain injury and to assess the brain’s response to therapies [ref]. Accurate quantitative methods to characterize brain function over time and after treatments will be necessary for future clinical trials of new medicines (Smith et al., 2019; Nadel et al., 2021; Yoo and Choi, 2021) . One important recent development is the use of SV2A PET scanning, a method of quantifying new synapse formation and a potentially important metric of therapeutic efficacy (Cai et al., 2019) . Continued development of functional imaging methods with finer spatial and temporal resolution will be critical to the design and execution of future trials of new TBI medicines. Additionally, it is important to develop neuropsychological and other behavioral measures that have adequate validity and reliability so that potential changes in brain function can be mapped to observable outcomes.

Useful disease models for TBI research:

Given the heterogeneity of lesions after brain trauma, it is essential to define specific lesions to be the substrate of either basic or translational research. Some have targeted the defects in skilled motor movements after damage to the motor cortex as a fertile area for focus (Takase and Regenhardt, 2021) . Studies of motor deficits are practical since outcome measurements are relatively straightforward and there are reasonably well-defined animal models of damage to the motor cortex ( (Xiong, Mahmood and Chopp, 2013) . Others have proposed focusing future trials on expressive language production, motor planning, or vision. One particularly fertile model problem is the study of inducing plasticity to treat amblyopia. Bear et. al. have recently demonstrated the feasibility of unlocking renewed plasticity in the visual cortex of adult primates, and new drugs are now en route to the clinic for this disorder (Fong et al., 2020) . Another potentially fertile area of work is the focus on inducing retinal regeneration, where efforts are underway to restore vision by the replacement of retinal neurons (Becker, Tumminia and Chiang, 2021) .

In addition to well-validated animal models (Xiong, Mahmood and Chopp, 2013) , the field of TBI research also requires in vitro experimental models. Given the cost and ethical challenges of using non-human primates, it is important to create and validate cell- and tissue-based models that faithfully replicate key features of the biology in an intact animal. Cell culture methods (of primary neurons; derived neurons; brain slices; organoids) continue to evolve. High throughput drug screening systems have been developed that measure very subtle changes in the excitability characteristics of cells, slices, organoids, and intact animals. The most advanced of these systems utilize all-optical electrophysiology coupled with optogenetic probes to measure hundreds of excitability parameters from the interaction of thousands of compounds on many millions of single neurons (Williams et al., 2019) . While the mechanisms of TBI can’t be replicated in vitro, these in vitro models are critical to the identification of the genetic targets that influence the core processes of brain regeneration. These models can be used to screen or design drugs, study target engagement, and evaluate mechanisms of action of drugs that affect the drivers of regeneration.

Multiple potential mechanisms of brain repair and recovery:

Several different mechanisms might be activated to heal an injured brain region. Surviving neurons could create new connections (“synaptogenesis”) or repair damaged axons. Damaged neurons could be replaced with repleted populations of neurons (“neurogenesis”) or introduced from compatible exogenous sources (“cellular repletion”). Existing populations of neurons might be recruited to assume the functions formerly subtended by damaged or destroyed neurons (“remapping”). All of these processes are controlled by neuronal transcriptional machinery.

Stimulating plasticity (compensatory synaptogenesis):

After a serious TBI, the recovery from neurologic deficits will rely on the brain’s ability to form new and functional synaptic connections, since it is presumed that plasticity is a manifestation of synaptogenesis. Synaptogenesis is, in turn, a tightly regulated process that is under transcriptional controls with both developmental (temporal) and environmental inputs (Gatto and Broadie, 2010; Kolb, Harker and Gibb, 2017; Harris, 2020) . The neurochemistry of forming and regulating CNS synapses has been studied for decades and forms the basis of neuropharmacology efforts (Berry-Kravis et al., 2018) . Many different disorders are associated with or caused by abnormalities in synaptic development or function, and synaptic neurochemistry is the target of many different neuropsychiatric and neurodevelopmental drug development programs [ref] (Lüscher and Isaac, 2009) . More recently, there are insights about the details of the genomic systems that govern the creation of new synapses (Clayton et al., 2020) ; (van Dyck and Morrow, 2017) or limit neuronal repair. The activity and state of transcriptional networks which control synaptogenesis are different at different developmental stages and, presumptively, during the various phases after a brain injury (Minatohara, Akiyoshi and Okuno, 2015; Engelmann and Haenold, 2016) . Certain specific genes and pathways have been identified in the brain and spinal cord to be involved in neuronal repair and re-activated plasticity (Wen et al., 2017; Lindborg et al., 2021) . It is believed that with a sufficiently detailed understanding of CNS transcriptional networks, it will be possible to develop genomically targeting medicines that modulate synaptogenesis and can be used to treat a range of neurologic disorders and injuries. (Hutson and Di Giovanni, 2019) .

Amblyopia (cortically-mediated ocular visual impairment) has proven to be a useful model of CNS synaptic plasticity. It has long been known that the visual cortex is programmed by early life visual experiences. If the visual cortex is deprived of input from one eye during early development, certain irreversible changes occur that limit recovery even if sight is restored. Some of the factors that regulate the closure of the visual cortex plasticity window have now been identified, and these factors are being explored as druggable targets {Stritmatter; LYNX1} (Kraft, 2019) . It is hoped that successful trials to treat amblyopia may create a path toward more broadly applicable therapies to restore cortical plasticity to the adult brain.

Neurogenesis and neuronal repair:

Neurogenesis in the normal adult human brain is believed to be limited to the hippocampus and is not an important component of healing after an injury, especially in adults (Kumar et al., 2019) . Gradually, the specific genomic networks that control neurogenesis in the human brain are being identified (Tirone et al., 2013; Bergmann, Spalding and Frisén, 2015; Nagappan, Chen and Wang, 2020) .

Factors limiting the regeneration of CNS neurons have been identified (Schwab and Strittmatter, 2014; Wang et al., 2020) .

After certain injuries, populations of neurons survive but suffer damage to axonal projections. Strittmatter and colleagues have focused on unlocking neuronal repair for patients with spinal cord injuries (Wang et al., 2020) . Two different classes of factors that inhibit neuronal repair after spinal cord injury have been identified: (i) factors associated with gliosis (scarring); and (ii) factors associated with myelin (Schwab and Strittmatter, 2014) . One example of the latter is Nogo-A. It has been a drug target for 30 years, with antibodies that target Nogo-A one of the approaches that have been trialed (Sartori, Hofer and Schwab, 2020) . More recently, another approach to disinhibit neuronal repair has been to target the Nogo-66 receptor 1 (NgR1) since it is the target of several inhibitors (specifically myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein). AXER-204 is a synthetic trap for NgR1 ligands. This drug has been tested in NHPs, demonstrated increased axonal sprouting and functional recovery caudal to an induced lesion, and is now being trialed in humans with spinal cord injuries ( https://clinicaltrials.gov/ct2/show/NCT03989440 ).

There is some thought that combinatorial approaches which address both gliosis and myelin inhibition (Griffin and Bradke, 2020) may be more effective in enhancing regeneration (Hutson and Di Giovanni, 2019) than targeting one process or the other.

It is not certain that progress in unlocking repair for SCI victims will generalize to other CNS lesions (Hirokawa et al., 2017; Li et al., 2020; Mohammed et al., 2020; Puls et al., 2020) . But, in principle, there is reason to expect that other areas of the CNS can be targeted using analogous strategies.

Some injuries deplete the population of viable neurons, and, consequently, efforts are underway to stimulate active neuronal production from surviving precursor populations in situ. Further work needs to be done to determine if neurogenesis can be selectively reactivated in different regions of the brain during adulthood (Richardson, Sun and Bullock, 2007; Sun, 2014) . It is also not clear if and how a traumatic brain injury itself directly affects neurogenesis (Zheng et al., 2013) or would alter a response to drug stimulants of neurogenesis, should any such stimulants be developed.

Neuronal repletion:

Another approach that has been proposed to stimulate brain recovery and regeneration after a traumatic injury is to replace the lost neuronal population with some form of neural tissue. A number of sources have been explored, including: (i.) generation of autologously derived neurons; (ii.) transplantation with neurons derived from a donor, either as primary neurons or as iPSC-derived neurons; and (iii) neurons which are derived from more advanced stages of 3-D tissue culture (e.g., organoids) [ref]. There is some early evidence that transplanted neurons can engraft and be functional. This approach is being explored as a potential way to promote recovery during the chronic phase of recovery after a traumatic brain injury (Zheng et al., 2013; Cox, 2018; Xiong et al., 2018) . Cellular repletion therapies using a variety of cell sources are being intensively studied for spinal cord injuries, and lessons derived from these efforts will likely inform efforts to transplant cells for other CNS disorders (Assinck et al., 2017; Fischer, Dulin and Lane, 2020) . The efficacy of cells that are obtained from dissociated organoids may or may not have any practical or theoretical implications for cellular repletion therapy efforts (Oyefeso et al., 2021) .

Concurrent retraining:

It is likely that any medicine or combination of medicines that is designed to interact with genomically specified targets would need to be coupled with intensive environmental stimuli, given the deep coupling of synaptogenesis and exteroceptive experiences.

Remapping the cortex:

In principle, therapeutic synaptogenesis might target either damaged regions of cortex that are undergoing repair or, alternatively, other regions of intact cortex that can be remapped to residual sensory afferents. Some injuries might disrupt the cortex but leave sensory inputs relatively intact. In this situation, the goal of stimulating synaptogenesis would be to up-regulate the remapping of other connected regions of cortex to assume the processing tasks previously assigned to now-damaged cortex. It may be that the regulation of synapse formation in intact cortex is under different transcriptional controls than the formation of new synapses in damaged cortex (Wittenberg, 2010; Takase and Regenhardt, 2021) .

Drug development approach and strategy:

If, as anticipated, it is possible to identify genetically-defined targets that modulate synaptogenesis and neurogenesis, there are several different approaches to drug development to be explored. Repurposing of existing drugs [ref], salvage of previously trialed compounds with good safety data, small molecule screening [ref], and rationally designed genomically targeting medicines (e.g., antisense oligonucleotides (‘ASOs’)) all can be explored. The emergence of ASOs is particularly encouraging since these compounds can have exquisite specificity, good safety profiles, and very rapid development cycles [ref]. Successful drug development will likely require prioritization of the process(es) to be targeted (e.g, synaptogenesis, axonal regrowth, remyelination, neurogenesis, or some combination). The prospects for successful drug development will be enhanced if there are clear, genetically determined targets that have been substantiated in well-validated animal and ex vivo models. If genomic sequence data from well-characterized populations with good clinical data can be accessed, it may be possible to identify genomic correlates of either unusual susceptibility to injury or, alternatively, of longer and stronger regenerative processes following a brain injury. These correlates might well be useful in the identification of additional genes and networks that influence the central processes of brain healing.

Even though there have been no successful drug trials that demonstrate efficacy in the chronic phase after an injury, there is important learning from these trials (Xiong et al., 2015) .

Brain-computer interfaces:

Substantial academic and commercial efforts have been applied to augment CNS and PNS functions using various computational methods and biomechanical devices. It is now possible to create interfaces between neural tissue and computational prostheses which can have both afferent and efferent properties. Such devices have the potential to augment endogenous healing from traumatic brain injuries (Ajiboye et al., 2017) . Exploration of the roles for biomechanical devices were outside the scope of the DLF meeting reported on here and will be explored in future meetings.

An Agenda for TBI Drug Research

Support continued development of imaging methods to quantify TBI damage and response to therapy.
Focus on functional imaging studies, especially studies that can quantitate synaptic activity over time.
Support novel approaches to promotion of plasticity after injury
Contribute funding to well-focused efforts to up-regulate plasticity in well-characterized models (i.e., drug treatment of amblyopia in experimental animal models) using both small molecules (especially repurposed approved drugs or other late-stage compounds with clean safety profiles) and genomically-targeting drugs.
Contribute funding to efforts to identify gene systems that promote synaptogenesis and axonal repair in both brain and spinal cord.
Contribute funding to efforts to identify existing drugs (repurposed or salvaged) or to design novel ASOs that can stimulate synaptogenesis and axonal repair.
Participate in genome-wide association studies of suitable populations to look for gene sequence variation that is associated with protracted plasticity periods after injury. Variants that modify the duration of the recuperative window after a TBI may point to genes or networks that can be targeted by drug development efforts.
Identify gene systems that regulate neurogenesis.
Contribute funding to efforts to identify existing drugs (repurposed or salvaged) or to design novel ASOs that can stimulate neurogenesis.
Support research to use emerging and novel ex vivo models of neuronal and brain tissue function for the purposes of TBI drug development.
Support knockout screens for regulators of synaptogenesis, axonal repair, and neurogenesis in cellular models.
Participate in research efforts to couple highly-targeted external stimuli in trials of medications for TBI and SCI.
Contribute support and method development to cellular repletion trials for CNS disorders (i.e., use of iPSCs and derived dopaminergic neurons for PD).
Participate in academic and commercial efforts to develop bioengineering and computational prostheses for both brain and spinal cord injuries.
Participate in collaborative funding activities with other foundations and research institutes who share DLF’s mission.
Participate in advocacy efforts to define regulatory pathways that are suitable to the highly variable injuries in TBI and for highly individualized genomically targeting medicines.

Summary

The 1st Annual Summit Meeting on Brain Regeneration Research was a seminal event in delineating the DLF’s research priorities. Preeminent neuroscientists and biotechnologists, from outstanding universities and biotech companies across the country, came together to pose provocative questions, explore key issues, and discuss potential research solutions with enthusiasm and a high degree of collegiality. The meeting culminated in a three-hour exploration of the challenges that exist—as well as the resources and opportunities--that inhere in the field of brain regeneration.

All those involved shared the goal of promoting improved functional outcomes for persons with moderate and severe brain injuries and an increased sense of hope and well-being for those individuals and their families.

The DLF is committed to pursuing breakthroughs that will, one day, improve the lives of those affected by brain injuries. We aspire to make a broad range of biomedical therapies available to people with such injuries. We will continue to raise funds and direct such funds toward the most promising biomedical therapeutics. In doing so, the DLF seeks to improve the lives of millions of individuals and their families who have experienced severe TBI, who are hoping for more than resignation and acceptance, who are hoping for real improvement in the capacity to function and participate in family and community life.

The DLF extends our gratitude to every one of the scientists who participated in the DLF’s 1st Annual Summit Meeting on Brain Regeneration Research.

*Planning is underway for the DLF’s 2nd Annual Summit Meeting on Brain Regeneration Research anticipated to be held in the summer of 2022. The primary focus currently under consideration for this meeting is “Biomechanical and Computational Adjunctive Therapies”. Updates regarding this meeting will be posted soon on the DLF website.

Bibliography

Annotated Reading List and References on CNS Regeneration Research

Sun, 18 Apr 2021 19:29:13 GMT

Overview of TBI What is TBI?

Basic acute-phase physiology
Chronic-phase physiology and natural history

Traumatic brain injuries are common, often devastating, and, for many, poorly responsive to treatment. While methods to evaluate TBI advanced substantially during recent decades and principles of supportive care have also progressed, there are no pharmacologic therapies that seek to specifically stimulate neurogenesis (growth of new neurons) or synaptogenesis during the post-acute phase of care.

The sequelae of TBI depend on the extent, nature, and location of the initial injuries, on acute phase pathophysiologic changes, and on long term rehabilitation efforts. A number of factors interact to determine the nature of the chronic deficits from a TBI, including disruption of key structures at the site(s) of injury, residual scar formation, post-traumatic electrophysiologic abnormalities, and emergent neuropsychological states.

There is a large and growing research effort to develop TBI diagnostics (Redell et al. 2010) , to optimize care during the acute phase of a brain injury (Vella, Crandall, and Patel 2017) , and to enhance functional recovery using neuromodulation (Hofer and Schwab 2019) .

Regulation of neurogenesis and synaptogenesis in humans (Aimone et al. 2014)
Neurogenesis
Pre-natal: https://en.wikipedia.org/wiki/Neurogenesis
Perinatal:
Hippocampal: (Yang et al. 2014)
Adult: https://en.wikipedia.org/wiki/Adult_neurogenesis
Synaptogenesis (Gatto and Broadie 2010)
Regulatory factors
Neurotrophic factors: (Cacialli and Lucini 2019) (Huang and Reichardt 2001) https://www.sciencedirect.com/topics/neuroscience/neurotrophic-factors
Autocrines: (Herrmann and Broihier 2018)
Cortical plasticity: (“Evolution and Ontogenetic Development of Cortical Structures” 2019; El-Boustani et al. 2018)
Tissue regeneration in humans and animal models
non-CNS ( https://en.wikipedia.org/wiki/Regeneration_in_humans )
non-Human CNS (Ghosh and Hui 2016) (Cacialli and Lucini 2019) (Zambusi and Ninkovic 2020)
Human CNS
Regulation, dysregulation, and controlled regulation (Tsintou, Dalamagkas, and Makris 2020) (Modo 2019)

The brain’s limited ability to regenerate its cells and tissue structures is a fundamental obstacle to healing in TBI. Tissue regeneration in adult humans is limited in a number of tissues while present in other tissues. Certain structures whose spatial organization is critical to function can regenerate (e.g., liver, bone (partially)). Other structures whose spatial organization is the basis of the tissue’s physiologic function are not naturally regenerated (e.g., lung, heart, brain). (Wikipedia contributors 2020)

Presumptively, two of the critical limitations on long term recovery from TBI are the loss of cells, especially cortical cells, from the injured brain regions, and the disruption of the functional connections (tracts and synapses) in the region of injury. [ ]

One observation is that all brain regions are not equivalent with regards to the retention of the capacity to form new neurons and synapses in adulthood. Both DG and olfactory bulb have active neurogenesis ( (Weston and Sun 2018) in certain adult animal models, but the extent of this phenomenon in humans is unclear (Bhardwaj et al. 2006)

Modest advances have been made at inducing regeneration in human tissue that is not naturally regenerated using both tissue engineering techniques and by altering growth factors. (Modo 2019)

Pharmacologic therapies: past efforts and trials (Diaz-Arrastia et al. 2014)
Stem cell therapy (Weston and Sun 2018)
Autologous embryonic stem cells
In non-human models
In humans (Schepici et al. 2020)
Induced pleuripotent cells: (Omole and Fakoya 2018) (Dunkerson et al. 2014)
Role of the bioscaffold: (Modo 2019)

Unsurprisingly, as our understanding of stem cell biology has progressed in recent years, some are attempting to replete the CNS by providing it with specially engineered stem cells. The broad concept has been reviewed (Weston and Sun 2018)

Some have claimed that stem cells can repair TBI (c.f. https://www.pacificneuroscienceinstitute.org/blog/brain-trauma/can-stem-cells-repair-traumatic-brain-injury/ , but study results from an earlier trial using the same cells for patients who had suffered from an ischemic stroke were recently posted ( https://clinicaltrials.gov/ct2/show/results/NCT02448641 ). These initial trials have not yet demonstrated any meaningful level of recovery in post-stroke patients.

Development of a TBI therapy
Need for model organisms: (Shah, Gurdziel, and Ruden 2019)
Animal models
Novel mouse models: (Reimann et al. 2019) ; (Chang et al. 2018)
Tissue models
Cellular models: ( https://www.researchgate.net/profile/Ashwin_Kumaria/publication/320692835_In_vitro_models_as_a_platform_to_investigate_traumatic_brain_injury/links/5bb07ca092851ca9ed30dd12/In-vitro-models-as-a-platform-to-investigate-traumatic-brain-injury.pdf )
Enabling model components (iPSCs; assays; analytics)
Enabling pharmacology (genomically targeting molecules)
Small molecules
ASOs and other mRNA-targeting compounds (Karaki, Paris, and Rocchi 2019) (Rinaldi and Wood 2018) (definitive text: https://www.springer.com/gp/book/9781592595853 ) (Schoch and Miller 2017)
A target??
LYNX1 (Morishita et al. 2010; Miwa, Anderson, and Hoffman 2019; Higley and Strittmatter 2010; Bukhari et al. 2015; Sajo, Ellis-Davies, and Morishita 2016)
Overview LYNX1 overview (A. Cohen, 12/20/17)
Recent analogous efforts
Spinal muscular atrophy ( https://smanewstoday.com/spinraza-nusinersen-ionis-smnrx/ )
“Milasen” (Kim et al. 2019)
“Lukesen” [Q-State Biosciences -- Kopin presentation in today’s meeting]
Current efforts in this area
ReNetX Bio: https://www.renetx.com/
Q-State Bio: (Q-State’s platform)
Cells: iPSCs → various types of neurons, including excitatory and inhibitory cortical neurons (Molnár et al. 2019) ; (McCaughey-Chapman and Connor 2018) and astrocytes (Barbar et al. 2020)
Assays and analytics: (Williams et al. 2019)
Specific disease models:
Cell culture of various human and non-human primary and derived neurons with both excitation and synaptic assays
Engineered isogenic controls
“Slice” preparations of mice
Therapeutic development capabilities
New abilities to study cortex and cortical neurons using optogenetic tools ( https://spaces.hightail.com/receive/YH79qaNhlU/fi-10048c4d-dbab-422c-ad37-847578ceaae0/fv-b28c8b5f-38c4-4324-9c31-c33cc19b0a2d/20200116_Adam_Cohen-Sensory_Information_Processing_1.mp4 ) (Fan et al. 2020) and the Q-State synaptic assays
Others?
https://www.agexinc.com/company-overview-biotechnology-for-gerontology-tissue-regeneration/
https://gmpnews.net/2020/01/a-russian-drug-gets-alzheimers-patients-to-recover-the-memory/
Antisense Oligonucleotides
ASOs and TBI: ( Shohami et al. 2000) (Fluiter et al. 2014)
A plan?
Targeting LYNX1 with ASOs?

Combining LYNX1 downregulation with autologous iPSC stem cell therapy?

Scientific Advisory Board Meeting February 20, 2021

Sat, 20 Feb 2021 20:21:30 GMT

12:00-1:45 EDT

Present: Sudhir Agrawal, Mark Bear, Graham Dempsey, Alan Kopin, Hal Lewis, David Margulies, Stephen Strittmatter

Unable to attend : Kevin Eggan, David Meaney

1. H.L. presented a few DLF updates--

· Two PowerPoint presentations have been developed--one for less scientifically oriented audience (“layman’s version”) and one for scientifically versed audience.

· The BOD which met last Saturday (2/13) provided extensive feedback regarding the “layman’s version” with emphasis on making the presentation simpler, clearer, and shorter…thus, more impactful. Revisions now underway based on such feedback.

· We are seeking input from SAB members re: the “scientific version” and will revise as needed per feedback received.

· Eleanor Perfetto, Ph.D. (pharmacology) who has leadership roles in advocacy groups (in both TBI and Individualized Medicine) will be joining BOD in a few months.

· We are open to adding members to the BOD and are interested in suggestions re: persons to invite. Suggestion made to seek BOD members connected to large advocacy organizations and to persons who are connected to significant funding sources.

· The BOD discussed the nature of our RFP. Michael Crair suggested using the NIH RFP/Application format because it would be familiar to both applicants and to scoring panels.

2. D.M. introduced the topic of clarifying the nature and scope of the foundation’s research priorities in order to provide focused strategies for fundraising and planful, targeted use of such funds.

· S.A suggested consideration of a 3 stage model in which Stage 1 centers on discovery , Stage 2 centers on translational research , and Stage 3 centers on drug development . S.A. suggested that the DLF could allocate 1/3 of its funds to each of these stages initially and reconsider altering the apportionment as the research evolves

· S.S suggested that open ended discovery might be prohibitively expensive given the relatively modest size of DLF

· G.D. raised the question of identifying the most promising drugs currently in the pipeline

· A.K. similarly asked what are the most promising compounds that could be launched if there was a critical mass of interest, focus, and research effort

· M.B. cited the development of FraXa. Early on FraXa brought together a relatively small group of scientists who learned from each other and formed strong connections. This led to a great deal of momentum and progress in treatments for Fragile X syndrome.

· D.M suggested that one parameter that we likely are in consensus is a focus on the chronic rather than the acute phase of TBI recovery. S.S. strongly agreed with this saying that in his view that focus on the chronic phase is much needed and presents great opportunities.

· S.A. raised the example of research progress in treatment of Cystic Fibrosis. The pathway of discovery, to translational, to drug development has been quite successful and supported all along the way by strong advocacy efforts.

· A.K. asked what specific deficits characterize Dan’s post-TBI status. H.L. cited Initiation, Motor Planning, and Cortical Visual Impairment as three prominent deficit areas. A.K. noted the diversity, in terms of deficit area, among the TBI population and wondered whether it might be advantageous to focus fundraising, research, and advocacy on a subset of TBI survivors.

· Several members suggested using funds to “recruit” post-docs and early career faculty into research work in area of brain and CNS regeneration.

· A.K. raised topic of robotics and electrical stimulation devices or implantations that may lead meaningful functional changes in lives of people with TBI or other neuromuscular disorders.

3. Conferences

· M.B. spoke of early days of FraXa and the strong connections that developed among central research figures. He raised possibility of convening 20 or so leaders/P.I.’s in the field over an extended period of time (3 or 4 times within a year?) to create a map for the way forward and an engine to propel progress. This group would include advanced investigators but not include post-docs or graduate students.

· There was also discussion of a larger conference on TBI recovery that would focus on CNS recovery and brain regeneration in particular. A title suggested “Promoting Recovery from Chronic Neurological Damage”.

4. Funding issues (both for conferences and research)

· For conferences, outreach to pharma to seek funds is probably appropriate and ethical

· For major funding (to use to fund research projects) the following sources were brought up:

Veteran’s Administration
National Football League
Automobile Companies
Large financial institutions
Other foundations with large endowments that might see value in our collaboration
National brain injury advocacy and information organizations
Individual/family benefactors

H.L and D.M. asked participants to forward to them any leads/contacts in any of the above categories.

Meeting was adjourned at 1:45.

Scientific Advisory Board Meeting August 5th, 2020

Wed, 05 Aug 2020 19:23:40 GMT

11:00-1:30 EST

Present: David Margulies (Moderator), Hal Lewis, David Meaney, Mark Bear, Sudhir Agrawal, Stephen Strittmatter, Alan Kopin, Graham Dempsey, Kevin Eggan, Michael Crair

--David Margulies opened the meeting with orienting remarks that provided a framework for the purpose and process of the meeting

--Several participants commented on the process of developing a foundation (for instance, FRAXA). There was discussion of how

successful foundations identify a niche and promote growth/momentum in various ways—fund postdocs to inject energy into an evolving research field, fund specifically targeted research, do advocacy work, link with other organizations/associations/foundations/government agencies. Some participants offered the view that a hybrid model for growth of the Dan Lewis Foundation might be optimal.

--There was discussion about how best to categorize brain injury for purposes of intervention/outcome research. Acute vs. Chronic phase? Severity of injury? Pathophysiology of the injury? Targeted functions? Targeted neurological/neuropsychological deficits?

--There was general consensus that there is an abundance of research regarding medical approaches to limiting damage and preserving as much CNS integrity as possible during the acute phase following TBI. Conversely, there is a relative lack of research into medical approaches to regenerate CNS or to promote recovery of functioning during the chronic phase, especially in adults. Stephen Strittmatter noted that adults in the chronic phase of TBI recovery tend to have rather stable functional profiles while making slow, small functional gains. This may be seen as an advantage for doing small N outcome studies with chronic TBI subjects because even small accelerations in recovery of skills may be quite notable and significant. Hal Lewis agreed with this perspective based on observations of Dan’s consistent but painstakingly slow recovery.

--There was discussion of government agencies to which funding applications might be submitted. In particular, the general view was that both NIH and DOD have not recently prioritized medical approaches to brain regeneration in adults in chronic phase of TBI. The group generally felt that this can be viewed as encouraging rather than discouraging as opportunities are present.

--There was discussion about whether there are any pharmaceutical companies that are investing in TBI products. Stephen Strittmatter said that pharma has generally been disappointed by attempts to research/manufacture meds for post-stroke patients which may have led to reluctance to pursue drugs for TBI. Participants were not aware of any pharm companies that are invested in TBI.

--Sudhir Agrawal brought up the need for a better understanding of the natural history/course of moderate/severe brain injury. He and others spoke of the potential value of a repository of the biomarkers of TBI over time.

--There was extensive discussion of cortical blindness (or what might better be called “cerebral visual impairment) as a possible starting target for the Foundation. Positives factors for choosing this target include: existing animal research, pharmacological intervention studies with animals have been done in regards to amblyopia and cortical blindness, outcome studies could likely be fairly easy to design, positive results (if obtained) could likely provide a template that could be transferred to other CNS circuits/functions. There was a consensus forming that this could be a good area to get started.

--There is some existing evidence that down regulation of Lynx1 gene can lead to modulation of inhibition of plasticity in the visual cortex thus leading to improvement in cerebral visual impairment.

--Michael Crair took a few minutes to introduce himself as he is new to Scientific Advisory Board.

--Hal Lewis announced that the Board of Directors, which has not yet met formally, will be meeting in 6-8 weeks with following topics for discussion:

1) Presentation of the Foundation’s proposed by-laws followed by discussion and vote on ratification of by-laws

2) Ways of funding the foundation’s research agenda

3) Connecting with other foundations, advocacy organizations

4) Ensuring good communication between the Board of Directors and the Scientific Advisory Board

--David Margulies took a few minutes to summarize today’s discussion, to initiate discussion of next steps, and to propose that he will distill today’s discussion into a document that provides greater specificity to the Foundation’s initial research agenda. This document will be distributed to the Scientific Advisory Board in draft form around the beginning of September and comments, edits, suggested inclusions/exclusions will be solicited. Hopefully, when the plan is consolidated it will, via the Foundation website and also a PowerPoint presentation, provide a platform for various types of fund raising. David also encouraged all participants to forward questions/comments/suggestions etc. at any time, including before the draft research agenda is distributed.

Exploratory Discussion Meeting June 11th, 2020

Thu, 11 Jun 2020 19:26:40 GMT

11:00-4:00 EST

A meeting of the Dan Lewis Foundation for Brain Regeneration Research was held via Zoom Conference on Thursday, June 11th, 2020 from 11:00 a.m. to 4:00 p.m. EST. The primary purposes of this meeting were to promote collaboration between leading scientists in the area of cortical regeneration and to begin planning a research agenda to accomplish the mission of the Foundation. That mission—to identify new biomedical approaches that promote neural regeneration, axonal growth, and synaptogenesis to improve the lives of persons with moderate and severe traumatic brain injuries and their families—was affirmed by group consensus.

Invited scientists attending as presenters and/or discussants were David Margulies, M.D. Sudhir Agrawal, Ph.D., Mark Bear, Ph.D., Randall Carpenter, M.D., Adam Cohen, Ph.D., Graham Dempsey, Ph.D., Kevin Eggan, Ph.D., David Gerber, Ph.D., Alan Kopin, M.D., and Stephen Strittmatter, M.D., Ph.D. David Margulies ably moderated this meeting, kept the agenda flowing, and allowed ample room for discussion after each of the thought- provoking presentations which are very briefly described below.

Hal Lewis gave an overview of the causes, the biomechanical and the biochemical effects of brain injury, particularly moderate and severe brain injury. Hal also provided a synopsis of his son Dan’s story (which can also be accessed elsewhere on our site).

Mark Bear spoke about regulation of cortical synaptogenesis particularly in the visual cortex of infra-human study subjects.

Stephen Strittmatter’s presentation explored molecular restraints on axon plasticity and neural repair; and explained some of his lab’s findings regarding promotion of axonal growth and sprouting in the spinal cords of infra-human study subjects.

Kevin Eggan gave an overview of progress in induced pluripotent stem cells and the promise of CNS neuronal cultures. He also spoke about the plausibility of creating useful models for the study of TBI and response to potential pharmaceutical treatment of TBI.

Adam Cohen spoke about cutting-edge technologies in the biosciences with particular attention to optogenetic tools that provide new abilities to study cortex and cortical neurons.

Sudhir Agrawal presented an overview of strategies for using anti-sense oligoneucleotide (ASO) therapies targeted to the central nervous system. He also talked about how research labs and biomedical companies can and have worked efficiently together to develop curative pharmaceuticals for many neurological disorders, particularly those for which specific genetic targets can be identified.

Alan Kopin provided a case study that illustrated how genomic analysis can lead to “down regulation” of a specific gene that is implicated in the neurodevelopmental disorder of a 9 year old boy.

Following this set of presentations, group discussion focused on envisioning and planning a research agenda to find therapeutics to improve outcomes for individuals in the chronic phase of post-TBI recovery. It was generally agreed that a plausible research-based path forward could be formulated. This was a very exciting and forward looking meeting—a meeting in which the collaborative and enthusiastic atmosphere lent promise to reaching the Foundations desired outcomes. We want to express our deep gratitude to each of these renowned and highly respected scientists who contributed to the success of this meeting. A second meeting of the Scientific Advisory Board of the Foundation, with additional invited participants, will be held during late July or the first part of August.

danlewisfoundation

Restoring Communication in the Injured Brain

A Neuroengineer’s Approach to Rebuilding Neural Circuits

1. Stop Axons from Dying

2. Reconnect Severed Axons

3. Replace What Is Lost

4. Interface with Restored Circuits

From Laboratory Science to Translation

Why This Matters

Making Headway: An Evening of Scientific Advances and Musical Interludes

New DLF Board of Directors Members Introduced

What Does “Ambiguous Loss” Mean?

Marchell’s Story

A New Frontier in Brain Regeneration Research

Stem-Cell Derived Neural Grafts: A Breakthrough Approach

Stroke Models: Human Neurons Integrating into Damaged Cortex

The Most Striking Evidence: Human Organoids Processing Visual Input

Human organoids responding to visual stimuli in mice

Human organoids integrating into an injured rat visual cortex

Training the Grafts: Why Computational Prostheses May Be Essential

From Rodents to Primates: The Next Step

A Long Road Ahead—But No Longer an Impossible One

DLF Announces Exciting Online Concert

ARPA-H Announcement Seeks Research Projects in Brain Regeneration

2025 DLF Prize Awarded to Justin Burrell, Ph.D.

New Members of DLF Board of Directors Introduced

Dan Lewis Update

Progress

Challenges

Unlocking the Brain’s Healing Potential: Recent Advances in Brain Regeneration Research

Announcing the 2025 DLF Prize

Alan’s Story

Letter from DLF Co-Directors

Unlocking the Brain’s Regenerative Potential: The Future of Repairing the Injured Brain

Introduction: The Paradigm Shift in Brain Regeneration

The Science Behind Reactivating Brain Repair

Quiver’s Scalable Human Neuronal Platform: Accelerating Discovery

The Role of Philanthropy: Funding the Future of Brain Repair

A New Era for Brain Regeneration

Rethinking Stroke Recovery: New Insights into Neuronal Remapping and Rehabilitation Potential

Devon’s Journey – Two Years Post-Accident

Advancing Brain Regeneration Therapies

DLF Science Advisory Board Spotlight

Sophia's Story

Every Traumatic Brain Injury story is different, and the outcome for individuals is often unpredictable

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This is Sophia Augier's story

Pioneering Pathways: Advancing Traumatic Brain Injury Repair

Towards Brain Regeneration and Functional Recovery

The Synapse and Brain Regeneration

Can Damaged Brain Tissue Be Replaced?

Targeting the Genome to Promote Brain Regeneration

Unlocking the Regenerative Powers of Antisense Oligonucleotides for Brain Injury Recovery

Brain Regeneration via Brain Tissue Transplantation: A Glimpse into the Future of Medicine

Brain-Computer Interfaces to Augment Brain Regeneration

How Do BCIs Work?

Biologic Augmentation of BCI Benefits

Dr. William Zeiger is the 2024 recipient of the $20,000 DLF Prize

DLF Science Advisory Board Spotlight

Sheryl’s Story

Brain-Computer Interfaces to Augment Brain Regeneration

What is a BCI?

How Do BCIs Work?

The Potential Impact of BCIs:

BCIs in Clinical Trials:

Biologic Augmentation of BCI Benefits:

Table 1: Selected BCI Trials

Cajal's Challenge

The Church Ushers Association of New York State

DLF Science Advisory Board Spotlight

Chase’s Story

Brain Regeneration via Brain Tissue Transplantation

The Dan Lewis Foundation for Brain Regeneration Research Announces 2024 Prize Open for Applications

Unlocking the Regenerative Powers of Antisense Oligonucleotides for Brain Injury Recovery

Devon’s Story

DLF Science Advisory Board Spotlight

Understanding IDEA and Section 504

A brief guide for parents to navigate education services

THE BRAINY-BUNCH where PASSION MEETS PURPOSE

The Therapeutic Power of Music