Research Review Corner

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.

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.

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.

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

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.

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.

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.

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.