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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.

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

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.

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.

Every Traumatic Brain Injury story is different, and the outcome for individuals is often unpredictable  This is Sophia Augier's story

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

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.

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 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.