A new collaboration of scientists works to push solutions to brain diseases out of the lab and into the hands of patients.
As an organ, the brain is staggeringly complex. Every thought, feeling, sensation, or memory you’ve ever experienced is held and processed by a mysterious web of matter inside your skull, from your first bike ride to the place you left your keys five minutes ago.
Because of its complexity, it’s one of the organs scientists understand the least. Yet the medical disciplines involving the brain are strangely siloed; there’s neurology, which deals with one set of medical disorders, and there’s psychiatry, which deals with another set of disorders generally relating to mood and behavior.
“The fact that these are two separate disciplines is a historical artifact,” says Judy Liu, MD, PhD, a neurologist at Brown who studies severe epilepsy. “The reality is that neurologists and psychiatrists both must strive for an understanding of nervous system function in the course of treating brain disorders.”
Liu came to Brown in 2017, joining forces with her longtime colleague Eric Morrow, MD, PhD, the Mencoff Family Professor of Biology, to find a better approach. They founded the Brown Center for Translational Neuroscience, a research group that aims to break down barriers between disciplines studying the brain. Its goal: to develop not only a new understanding of how the brain works, but new ways of diagnosing and treating the diseases that affect it.
“Translational science—taking lab research and applying it to new treatments in the clinic—by nature requires collaborations, especially when it comes to the brain,” says Morrow, both a psychiatrist and a molecular neuroscientist, who is founding director of the new center. “You really need multidisciplinary teams; a certain diversity of skill sets ranging from patient-oriented work to experimental basic lab science, involving genetics, and cell biology. There are also various exciting new ways to model disease processes in the lab, and to test new treatment strategies.”
The center has five main areas of focus: autism, epilepsy, Alzheimer’s disease, rare neurogenetic disorders, and psychiatric disorders, such as schizophrenia and stress-induced conditions. The infrastructure necessary to embark on these multidisciplinary approaches is difficult to maintain in one laboratory alone. As a formal center, by contrast, all scientists under its umbrella can share staff with high-level expertise, such as in patient-oriented studies or in human stem cells. The investigators also share expensive laboratory equipment, such as advanced microscopes and equipment for high-throughput studies of cells and treatments. Location is critical, too. With the juxtaposition of many of the laboratories, collaboration is as simple as walking down a hallway and talking to a colleague. There’s room for improvement there, however. Although most of the center’s affiliated faculty are within the Laboratories for Molecular Medicine at 70 Ship Street, others span a number of different buildings, including some on Brown’s main campus.
“The center really avails itself to team approaches,” says Morrow, who’s also an associate professor of neuroscience and of psychiatry and human behavior. “I believe that we are now able to work on more projects and, importantly, more ambitious projects than we could prior to forming the center.”
STARTING WITH PATIENTS
The Center for Translational Neuroscience’s projects stem from clinical problems that families face, and the goal is to find solutions through collaboration between bench scientists and clinicians. The group’s philosophy, which they loosely call a “bench to bedside to bench” model, brings patients, researchers, and physicians together early in the process to help focus the search on important problems that present in the clinic.
This is exactly the type of integrated team approach that the Brown Institute for Translational Science (BITS) fosters. CTN is one of the horizontally integrated research teams within BITS, and it’s also a systematic collaboration between BITS and the Robert J. and Nancy D. Carney Institute for Brain Science.
“We have all of the ideal elements in CTN. We have invested in physician-scientists, basic scientists, and a robust program for students and trainees. On top of that, we have seamless collaboration with the relevant clinical departments as well as other areas of the University,” says Jack A. Elias, MD, senior vice president for health affairs and dean of medicine and biological sciences at Brown. “We were fortunate to receive philanthropic funds that allowed us to establish endowed professorships for both established faculty members and to recruit outstanding researchers. I have very high expectations for what this team is going to accomplish.”
“The mission of the center is really twofold,” Morrow says. “The first is to advance knowledge of the pathogenesis of brain disease. So what are the causes, and what are the mechanisms? Brain disorders are among the most enigmatic conditions affecting humankind. The second part of the mission is to translate this knowledge to improved outcomes for families affected by brain disease. That could be a new method of diagnosis, it could be a new biomarker that guides treatment, it could be a new therapy. But regardless, it all starts with observations in the clinic.”
Working directly with patients can provide families with much-needed hope, he adds. In many cases, brain diseases like severe autism can leave families feeling isolated and alone. “The disease has a huge impact on them psychologically, financially, and emotionally. It can be very powerful for them to know that there’s a laboratory or a student that’s devoting their career to better understanding and treatments for their loved one’s condition,” Morrow says.
Over the last two decades, that sort of patient-centric research has been a driving force for Morrow—and in particular, for Liu. As a young doctor completing a residency in neurology, she witnessed firsthand how devastating neurological diseases and their treatments could be.
“I helped care for one child with life-threatening epilepsy who had undergone multiple surgeries to stop his seizures,” recalls Liu, the Sidney A. Fox and Dorothea Doctors Fox Assistant Professor of Ophthalmology, Visual Sciences, and Neuroscience. “His doctors had determined that one whole side of the brain was causing seizures, and removed it entirely. But then the seizures came back, and the patient had a second procedure. With each surgery, the patient still didn’t really gain good control of the epilepsy.
“It’s that kind of desperate situation that actually makes doctors into scientists,” she adds. “After working in a clinical environment, you’re really driven to find out what could possibly be different about the cases that can’t be controlled on regular medications. What do we do differently? How can we choose treatments more precisely, and how can we better predict their outcomes?”
Answering those questions is a difficult task. But since all neurological and psychiatric disorders take place in a single organ, whatever scientists discover about one disorder may provide key information for treating another. Liu, also an assistant professor of neurology and of molecular biology, cell biology, and biochemistry, cites her collaborations with Morrow, who specializes in severe autism, as an example. By working together, it became clear that the diseases they each study may share a common thread: a high percentage of autism patients also have epileptic seizures—and vice versa—so both disorders could be triggered by common root causes.
“We’re not totally sure what initiates a seizure. Most of the time patients with epilepsy are normal. But every once in a while, something happens in a neural circuit where seizures are generated and propagated and the brain can’t put on the brakes,” Liu says. “That’s what we need to know: how neurons interact with each other and what happens during seizure generation.”
BUILDING A BETTER MODEL
Probing these interactions in a living human brain is nearly impossible for technical, medical, and ethical reasons, however. The closest the center’s researchers can get to the real thing are brain samples removed during epilepsy surgery, but even then they’re left with only the “seizure focus” or the non-functional brain tissue, which they have no way of comparing to healthy tissue from the same patient. So the group instead is working on better models of the disease that they can study in the lab.
Using genetically engineered mice, the researchers can stimulate activity that causes seizures, and measure it as it happens with cutting-edge technology like fluorescent proteins, which mark affected cells with a glowing hue, and optogenetics, a process that lets researchers trigger specific neurons with tiny pulses of light inserted into the brain through fiber optic cables. The center has also developed an emphasis on the use of CRISPR/Cas9 to generate new non-traditional models, such as in rats, which have more complex behavior and can be better models, particularly for some neurodegenerative diseases.
As sophisticated as they may be, rodent models can still only approximate the core causes of neurological disease. To really pick it apart requires finding a system that can mimic the exact activity of the human brain, says Alvin Huang, MD, PhD, a molecular biologist and neurologist who left Stanford, where he trained with Nobel Laureate Thomas Sudhof, to join the center in September 2019. Now teamed up with Morrow and Liu, Huang has increased the number of MD/PhD physician-scientists in the center even more.
Huang, the GLF Translational Assistant Professor of Molecular Biology, Cell Biology, and Biochemistry, points out: “We have come to realize that in fact there is a huge difference between humans and all the other model organisms. I mean, a mouse is a mammal and technically should be close enough, but in fact, many recent articles are showing that in terms of brain cells, they have very different behaviors.”
Instead, Huang and other researchers at the center engineer human brain cells in a dish that can replicate the disease for experiments in the lab. Using specialized methods, Huang and other center scientists are able to “reprogram” blood or skin cells from patients, causing the cells to revert to an early, stem cell-like state. These cells, called induced pluripotent stem cells (iPSC), still hold all DNA of the original patient, including the genetic mutations or disorders that may be at the root of their disease. From here, the scientists can grow the iPSC into a number of different brain cell types, including neurons and glial cells (the other important cell type in the brain), and use them to examine how a disease sets in, and how treatments may work on the cells from the very patients who may one day receive them.
A COMMON THREAD
Liu and Morrow have been using iPSC to study neurodevelopmental disorders. Huang uses them to focus in on Alzheimer’s—and says there may be some relationships between basic mechanisms in neurodevelopment and neurodegeneration.
“Many of the mechanisms that are recognized in epilepsy, for example, are not uncommon in Alzheimer’s disease. In fact, Alzheimer’s patients have a very high prevalence of epilepsy,” Huang says. “We now have evidence showing that in early stages of Alzheimer’s, the leading cause of cognitive impairment is abnormal hyperexcitability, which is very similar to what happens in epileptic patients.”
Those flashes of extra activity between neurons are so similar, he notes, that the only drug currently approved to treat Alzheimer’s is also used to treat epilepsy. “If you use those drugs to calm down this overexcited brain activity, you can restore cognitive function to some extent,” he says. “But it doesn’t work for every single patient—and even if it does work, it won’t last long, because that hyperexcitability is most pronounced in the early stage of Alzheimer’s before a lot of the neurons die off.”
Huang is collaborating with other researchers at the center to find new ways to treat Alzheimer’s and prevent it from progressing. But he’s convinced that testing drugs only in rodents won’t be effective. Instead, he’s using human iPSC to create a “brain on a chip,” a tiny flexible substrate that he can seed with stem cells. Using this method, he can effectively steer the cells’ development and grow tissue that mimics a real brain, complete with all the blood vessels and complex connections between brain cells.
“All those human structures can be generated in a dish from the same iPSC. With this technology, we can kind of assemble all those cell types ourselves to mimic the brain’s microenvironment,” Huang says. Studying the interactions of the brain cells themselves, he adds, also lets him iterate easily, growing multiple organoids that he can use to test drug targets quickly and efficiently.
MOVING PARTS
Answers to some of the broader questions about neurological diseases, such as Alzheimer’s and amyotrophic lateral sclerosis (ALS), may lie at synapses.
Gregorio Valdez, PhD, a neuroscientist who joined the center from Virginia Tech late last year, studies the effect of normal aging and age-related diseases on neurological circuits, and particularly synapses. Valdez, an associate professor of molecular biology, cell biology, and biochemistry, has made great strides into our understanding of how synapses degenerate with advancing age and in ALS, a neurodegenerative disease that affects motor neurons. While its symptoms are mainly physical—patients gradually lose the ability to move their limbs or even speak—he says its root cause may have a great deal of overlap with other neurological disorders.
Normally, when prompted by the brain, motor neurons send a chemical signal that tells muscles when to contract. The neurons themselves are separated from the muscle fibers by a tiny gap, and along with a special type of glial cell this region forms a synapse called the neuromuscular junction. In ALS, however, the synapse stops working and completely falls apart, so the brain’s signals are never received—rendering the nearby muscles effectively useless.
The study of the peripheral synapse may provide critical insights into other neurodegenerative diseases, Valdez says. The series of cellular and molecular changes that cause synapses to degenerate progressively in ALS might be the same that result in Alzheimer’s.
“Neuromuscular synapses are much more accessible than synapses in the brain, by nature of not being inside a skull,” he says. “By looking at how those junctions malfunction or disappear in ALS, we are likely to learn something about the brain by proxy.”
It might also be possible to learn about how the brain naturally degenerates as patients age, he adds. Even in the absence of disease, pathological changes start to take place as people get older. Connections between motor neurons and muscles weaken, and stop sending and receiving chemical signals in the same way.
“The synapses lose some factors that are important to keep them healthy, and thus in a youthful state,” Valdez says. “You’ll find that a lot of things associated with the initial progression of diseases like ALS and Alzheimer’s also happen during normal aging. If you look at synapses of healthy people as they get older, you’ll see similar changes to those caused by age-related neurological diseases.”
For that reason, the work that Valdez and the rest of the center is doing may not only help treat disease, but treat problems we’ll all face as we continue the inevitable journey into our golden years.
CAMPUS-WIDE COLLABORATION
The type of massively interdisciplinary work that the Center for Translational Neuroscience is doing—work that crosses disciplines, diseases, and even life stages—is a natural fit for Brown, says Diane Lipscombe, PhD, the Reliance Dhirubhai Ambani Director of the Carney Institute for Brain Science.
“Brown’s collaborative spirit, driven by the curiosity and creativity of faculty and students, is what makes this such a unique and exciting place to study the brain. The Carney Institute is invested in building on our distinguished brain scientists on campus by hiring new faculty to tackle areas of great need in society,” says Lipscombe, who is also the Thomas J. Watson, Sr. Professor of Science and a professor of neuroscience. “When a researcher joins the brain science community we want them to be able to hit the ground running, drawing on the expertise of colleagues at Brown from across the disciplines to do impactful research toward new cures and treatments.”
“That’s one of the things that really inspires me about working at the center,” Morrow adds. “Together with my colleagues and our students, I know we’re all trying to develop a knowledge base and treatments that will improve the lives of families affected by neurological and psychiatric disease. It makes me love coming into work each day—the fact that all of us are able to work together toward that common goal makes this a really special place.”
