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Brain Trust

Fueled by recent advances in our understanding of behavior, UCLA is writing a dramatic new chapter in the study of the human mind.

By Dan Gordon

UCLA is writing a dramatic new chapter in the study of the human mind.When Peter Whybrow, M.D. , was studying medicine at the University of London in the 1960s, scientists had a limited understanding of what various parts of the brain did. It is remarkable how much can change in just 50 or so years. "Within my professional lifetime," Dr. Whybrow reflects, "we've learned more about the brain than we had in the whole of human history." 

So much more that scientists today can actually create detailed maps that illuminate the relationship among various structures and their functions in the brain, providing them with a tool to more fully understand the physical processes that underlie human sensation, awareness and cognition. With those clearer insights comes a wealth of applications, from the design of medical and surgical interventions to the treatment  of psychological and psychiatric disorders.

At the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, of which Dr. Whybrow is director, and the Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA, where he is C.E.O., much of this new knowledge is being developed, evaluated, enhanced and applied. Together, these two centers have helped to propel the ongoing breakthroughs in our understanding of the workings of the brain, behavior and mental illness, and in so doing, they have transformed the lives of untold numbers of people who suffered from debilitating conditions.

Even as these life-altering innovations are underway, a dramatic new chapter is being written. Fueled by recent advances in our understanding of behavior, both normal and abnormal, the expansion of the Semel Institute's research portfolio and a substantial investment of private and federal dollars, both the Semel Institute and the Resnick Hospital are being transformed.

The vision for this transformation includes not only addressing mental illness, but also answering questions about other behaviors that affect people's lives. How, for example, do genetics and the environment conspire to drive unhealthy lifestyle choices, such as those that are contributing to the national obesity epidemic? Or how can we develop strategies to improve resilience and wellness in people on all points of the continuum between what is thought to be normal behavior and what is considered serious mental illness?

"These are bold questions," says Dr. Whybrow, chair of psychiatry and biobehavioral sciences. "And the public looks to great universities like UCLA to help find the answers."

The transformation now underway is embodied in two major initiatives: Healthy Campus, which will use innovative science and behavioral techniques to assist UCLA students, staff and faculty to better understand brain function and to make healthier lifelong choices, and The Nexus Project, an ambitious effort to integrate leading-edge research, bringing together prevention, health promotion and treatment strategies to the community through translational research in genomics and the behavioral neurosciences.

At around the same time as Dr. Whybrow was earning his M.D., the California Legislature decided to make an $8-million investment in a facility for neuropsychiatric research, education and clinical care. The doors to UCLA's Neuropsychiatric Institute (NPI) - the forerunner of today's Resnick Neuropsychiatric Hospital and the Semel Institute - opened in 1961.

Jane and Terry Semel

Steward and Lynda Resnick
The naming gifts by Jane and Terry Semel (top) and Stewart and Lynda Resnick (bottom) were essential to putting a human face on issues that
continue to be stigmatized. Photos: (Semels) Getty Images; (Resnicks) Dan Chavkin

As with other neuropsychiatric institutes that were established at this time, the focus of UCLA's facility was not limited to treating developmental disorders and mental illness. "There was a sense that, beyond the humanitarian efforts, we might be able to understand the underlying causes of mental illness," Dr. Whybrow explains. That, in turn, "would create a new vision for the future."

Exploiting UCLA's concentration of renowned neuroscientists and clinicians (university hospitals rarely are located adjacent to the general campus), the NPI developed an infrastructure and culture of scientific collaboration that became one of its significant strengths. "The magic of the NPI, and today as the Semel Institute, has always been that I can go across the street to consult with a world-famous neuropsychologist, upstairs to talk to a geneticist or someone who is doing biological chemistry, and down the hall to visit with a world-authority on the immune system," says Fawzy I. Fawzy, M.D., the Louis Jolyon West Professor of Psychiatry and Biobehavioral Sciences and executive associate director of the Semel Institute. "If you have a question here, you have a greater chance of finding collaborators within the institute, in the medical school or on the campus at large than if you were almost anywhere else."

That infrastructure has enabled today's Semel Institute to take full advantage of the advances in technology that have paralleled its growth. Buoyed by the ever-more-powerful tools of molecular biology, genetics, neuropsychology, neuroimaging and informatics, institute researchers and clinicians have contributed to tremendous progress in how brain disorders are understood. Research and clinical programs that encompass the span from early childhood development through degenerative diseases such as Parkinson's and Alzheimer's do more than ensure that the institute can serve all types of patients. The comprehensive nature of the enterprise has provided fertile ground for the type of cross-talk among experts that promotes progress and for the development of visionary programs.

Thus, the achievements for which the Semel Institute and Resnick Hospital are known today have been built upon the foundation of those earlier efforts, from groundbreaking work on drug treatments for schizophrenia to advances in the understanding of memory and frontal-lobe function. Fundamental research at the NPI and at today's Semel Institute has explored multiple sclerosis and epilepsy and led to the invention of the nicotine patch and the cloning of receptor sites for opiate addictions. Many contributions have come from internationally recognized programs in autism, early childhood intervention, eating disorders and aging.

Today, the Semel Institute draws more federal, foundation and private competitive research funding than any other neuropsychiatric institute in the country - approximately $170 million per year. This support also has led to UCLA becoming one of the nation's leading academic training grounds for research psychiatrists and neuroscientists.

One cannot overstate the significance of the contributions from Jane and Terry Semel and Stewart and Lynda Resnick that led to renaming the NPI's research and clinical arms nearly a decade ago. Beyond the financial support, lending their names put a human face on issues that continue to be stigmatized.

"There is still a basic prejudice about psychiatry in general and mental illness particularly," Dr. Whybrow says. "The Semel name helped to focus that this translational-research institute is where science drives innovative mental-health programs. And in the same way, the Resnicks giving their name to the hospital said that they were proud to be associated with a place where people are treated for severe behavioral and brain disorders, rather than those patients just being brushed aside, apart from the public view."

Dr. Peter Whybrow

In the span of Dr. Peter Whybrow’s career, “we’ve learned more about the brain than we had in the whole of human history.” Photo: Mark Berndt
Huge strides in psychopharmacology have been made in the context of an explosion in the basic neurosciences - in the identification and study of neurotransmitter systems and in the molecular biology of complex human behavior; in the genetics of behavior and psychiatric illness; and in insights about the brain and the nature of mental disorders, driven by ever-more sophisticated structural and functional neuroimaging.

Unlike the many neuropsychiatric institutes that are devoted primarily or exclusively to patient care, UCLA's boasts an unsurpassed neuroscience infrastructure that drives the clinical progress. "We have invested a great deal in understanding the basic functions of the brain, so that we can better understand how it goes wrong," Dr. Whybrow says.

As such, the advances coming out of UCLA and other leading neuropsychiatric institutes are fundamentally changing the way mental disorders are understood and treated. For example, in recent years, the Semel Institute has undertaken a major effort to focus on the behaviors that become disturbed rather than on the diagnosis per se. "Disruption in areas such as sleep, mood, attention and memory are involved in many different diagnoses," Dr. Whybrow notes. "By looking for common threads in diagnoses, we can begin to ask how these reflect changes in brain function and how we can better treat those changes, rather than just focusing on diagnostic categories."

Thomas Strouse, M.D., medical director of the Resnick Hospital, notes that when the NPI first opened its doors, the prevailing theories were that manic depression, severe depression and even schizophrenia were attributable to parental missteps. "Now," says Dr. Strouse, "we tend to understand most major mental illnesses as brain diseases that are the manifestation of a complex interaction between genetic and environmental factors."

This recognition of a genetic-environmental interplay comes after a period some 20-to-30 years ago, during which most of the focus was on the biological. "Biology is not destiny. That also is something we have learned in this explosion of knowledge that is behavioral neuroscience," says Dr. Whybrow. "The brain learns from what it encounters. Thus, while the genes inherited from parents help to shape our path and the vulnerabilities we carry, it is experience and those who nurture us that eventually determine who we are."

The implications of this understanding are profound. Where once it was thought that people were entirely responsible for their own mood and behavior, and then it was believed that any aberrant behavior was simply a product of wayward brain chemistry, it's now clear that both a person's developmental path and his or her biology play a role, along with a third significant factor: the social environment. Even with medication interventions, the best results are achieved with medication and supportive therapy that calls for an understanding of the person, the family and the environment.

The realization that mental disorders probably fall on a continuum and that the difference between a healthy brain and a disordered one may be small - with individual choices and social environment playing an important role - has led to a greater focus at the Semel Institute and Resnick Hospital on studying normal behavior as a vehicle for better understanding mental illness. It has also underscored the harmful effects of the stigma that continues to be associated with mental illness. The institute has tackled the latter issue head-on, thanks in part to The Friends of the Semel Institute, a volunteer organization founded by philanthropist Vicky Goodman, which hosts highly attended educational programs for the public.

Dr. Whybrow has written about the "cruel but simple logic" to the anatomy of a stroke: When one side of the brain is damaged, the opposite side of the body is paralyzed. By contrast, understanding the factors influencing memory, human emotion and disabilities of the mind is far more complicated. But that doesn't mean mental disorders don't have an anatomy. In fact, researchers are looking for subtle changes on MRI scans that may have a genetic basis, which could lead to better diagnosis and treatment of brain disorders.

"Unlike other diseases in medicine, major mental illnesses such as schizophrenia, depression, bipolar disorder and autism don't have biological markers we can use to make diagnoses or assess the effectiveness of our treatments," says Nelson Freimer, M.D., professor of psychiatry and biobehavioral sciences and director of the Semel Institute's Center for Neurobehavioral Genetics. "So we're left to rely on clinical judgments about people's behavior or what they reveal about how they're thinking." The promise of genetics, Dr. Freimer explains, is that it might reveal biological differences associated with major mental illnesses, enabling diagnosis and therapy based on more objective grounds than in the past.

The Nexus Project within the campus context.

The courtyard garden invites the broader university community to participate in the activities of The Nexus Project.

The entry area will offer information and directions to Nexus services, interactive exhibits and activities. Architectural

Renderings: Courtesy of Kohn Pedersen Fox Associates (KPF)

This challenge is but one of many. Indeed, for all that's been learned about the brain and human behavior since the UCLA Neuropsychiatric Institute was established barely more than 50 years ago, far more remains undiscovered. The questions seem to become ever more complex, calling for an army of basic and clinical researchers, all located within walking range of each other, who together cover neuroscience and behavior from every possible angle within a medical complex serving neuropsychiatric patients across the lifespan.

That is the thrust of The Nexus Project, the new translational-research program being developed by the Semel Institute and Resnick Hospital. Launched by two major federal grants - one for operations and the other to renovate facilities that will be the first step in creating a translational center - Nexus will be a first-of-its-kind effort to answer big questions involving behavior and serious disability through interdisciplinary teams that draw from the entire campus. It will be characterized by innovative science, a community focus and a building design that fosters collaboration. "Science is now a team enterprise, not just one person sitting in a lab," says Dr. Whybrow. "At UCLA, we are in the rare position of being able to put together, in connected facilities, a group of people who can conduct studies of molecular genetics and how cells communicate with each other in the brain and use that knowledge to refine diagnoses and develop strategies to help people behave in ways that are more conducive to their health."

With the Resnick Hospital now a part of the Ronald Reagan UCLA Medical Center complex, a $15-million federal grant will convert part of the old hospital units that were located in the NPI tower into a facility that will house outpatient-clinical-care and translational-research programs. The transformed physical plant will be the first step in a fundraising initiative, supported by the Semel family and part of a larger UCLA campaign, to build a new research tower, conceived by the New York-based architectural firm Kohn Pedersen Fox Associates (KPF), which will be contiguous with the renovated existing Semel Institute towers. This Nexus research tower has been designed to foster faculty innovation and entrepreneurship across disciplines, with the goal of rapid translation of scientific advances into public practice. The light-filled public spaces of the first two floors will, through education and participation, invite public and student interaction with the work of UCLA faculty.

In the meantime, the renovated facilities, which will be completed in 2013, will serve as the initial home for the federally funded $25-million, five-year research initiative organized by Semel Institute faculty that is already underway. Focused on developing prevention strategies via high-throughput studies in molecular genetics and behavioral assessment, using laboratory models as well as human subjects, this initiative involves 52 faculty collaborators from across the UCLA campus. It is an example of how The Nexus Project eventually will serve as a magnet for the most talented researchers on the brain and behavior at UCLA and beyond. 

In addition to supporting research, the new Nexus tower will serve as a destination for health-promotion and disease-prevention activities for UCLA students and the general public alike. Nexus will also be the research engine that drives innovative outreach programs in the community, such as the first UCLA Family Commons, a Santa Monica-based initiative to support and assist families in adopting a healthful lifestyle, Dr. Whybrow says.

It has been estimated that as much as 70 percent of healthcare expenditures can be attributed to illness fostered by life choices. Unhealthy diet, alcohol and tobacco abuse, lack of exercise, poor sleep habits - these are among the most obvious illustrations of how poor decisions, even in the face of scientific evidence, contribute to behavioral disorders, chronic disease, long-term disabilities and premature mortality. "The keys to disease prevention are both scientific discovery and behavioral change based on self-understanding," says Dr. Whybrow, who, along with the Semels, has been a leading proponent of the Healthy Campus initiative. "While a minority of disease is genetically predetermined, the vast majority of all illness is shaped by our inherited biology interacting with the environment, an interaction that is mediated in large part by the way we take care of ourselves."

He acknowledges that converting discoveries about the brain into effective behavioral strategies for healthier living is no simple task. Despite extraordinary advances in neuroscience, the current understanding of brain processes and their relationship to behavior - both normal and abnormal - lags behind our knowledge of other, simpler body systems. But through the Nexus Project, and the participation of the UCLA student body and local community via the Healthy Campus initiative, the Semel Institute and Resnick Neuropsychiatric Hospital are taking on that challenge.

And as a storied institution endeavors to enable more members of the next generation to lead lives that are healthy in both mind and body, it is illustrating a fascinating paradox about the human brain. The same organ that is at the root of so much anguish and self-destruction can also be harnessed to find ways to repair itself. This is particularly true when the effort involves hundreds of differently focused brains working together in a coordinated effort at one of the world's leading sites for unraveling the mysteries of the mind and human behavior.

Dan Gordon is a regular contributor to U Magazine.


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