Pioneering Pathways:  Advancing Traumatic Brain Injury Repair
Dan Lewis Foundation | Summer 2024

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:


  1. 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.
  2. Gene Editing: Techniques like CRISPR-Cas9 enable precise genomic corrections. Successful trials for genetic blindness offer hope for similar applications in brain regeneration.
  3. 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:


  1. Promoting neurogenesis by targeting genes that regulate neuron formation.
  2. Reducing inflammation by silencing inflammatory process genes.
  3. 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

A gold trophy with a laurel wreath around it.

Announcing the 2025 DLF Prize

By Dan Lewis Foundation • April 2, 2025
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

By Dan Lewis Foundation • April 2, 2025
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.