Time to Apply Cutting Edge to the Brain, Nobelists Say

The time has arrived for a massive push to explore the roots of psychiatric illnesses with the latest scientific tools, according to the scientist who helped define the double-helical structure of DNA 60 years ago.

A research agenda that leads to intensified study of neural circuitry and sequencing the genomes of 100,000 individuals would push neuropsychiatric understanding ahead substantially, said James Watson, Ph.D., in an interview.

Writing in the March 26 Science, Watson and colleagues (including fellow Nobel Prize winners Sydney Brenner, M.B., B.Ch., and Eric Kandel, M.D.) called for spending $2 billion over the next decade to use “a new perspective and a combination of novel tools and analytical methods” to understand the origins of psychiatric disorders. The article grew out of a conference in December 2009 at the Cold Spring Harbor Laboratory on Long Island, where Watson is chancellor emeritus of the Watson School of Biological Sciences.

Two factors besides the prestige of the Nobelists add weight to their conclusions, said Thomas Insel, M.D., director of the National Institute of Mental Health (NIMH), who attended the December meeting.

“People outside the usual realm of psychiatric research, from oncology to immunology, now think that really exciting breakthroughs will come from research into mental illness,” Insel told Psychiatric News. “In addition, the scientific tools for studying genetics and neural circuitry have progressed dramatically in the last two years so that the field is ready for increased investment.”

These tools include high-throughput gene sequencing, quantifiable studies of brain circuitry, and the use of optogenetics to manipulate circuitry in rodent models. The last technique has transformed the study of circuits and behavior, he said.

The problem is one that is familiar to psychiatrists: few breakthroughs in treatment have occurred in the last decade, and treatment effects vary so widely among patients that a “sizable proportion are resistant to all currently available treatments.”

Still, research efforts to date have not failed, said lead author Huda Akil, Ph.D., the Gardner Quarton Distinguished University Professor of Neuroscience and Psychiatry and codirector and senior research professor at the University of Michigan's Molecular and Behavioral Neuroscience Institute.

“It's not that people haven't contributed real understanding or that different perspectives are not valid, but the techniques in genetics and neuroscience are just catching up to the challenge that psychiatric disorders demand of us,” said Akil in an interview.

The complexity of the human brain lies at the core of the challenge, said the authors.

If any of the thousands of genes that regulate neural development or function go awry, the result can lead to a variety of neuropsychiatric problems.

Some of these illnesses are heritable, as twin studies have shown, but many—possibly most—mutations occur de novo in the developing organism, and hundreds of genes may be involved in one psychiatric illness, said Watson.

Thus, many individual genomes must be analyzed to detect the patterns that characterize a disorder.

“Given the complexity of schizophrenia and most other mental illnesses, we're going to have to sequence a large number of people,” said Watson. “As long as there's this sense of urgency, and it won't bankrupt anyone, why not get it done fast?”

The cost of sequencing the genome of one individual is expected to eventually fall below $10,000. At that price, sequencing the genomes of 100,000 people would cost $1 billion. If a similar sum were allotted for imaging neural circuitry, the project Watson envisions would cost $200 million a year over a decade.

The payoff would presumably be a more precise understanding of the origins and development of mental disorders and new avenues of treatment.

Insel agreed with the added emphasis on genetics and circuitry but also noted that NIMH “needs to have a very diverse research portfolio,” a view with support from within organized psychiatry.

The focus on basic research and translational research for genetics and neurocircuitry has to be supplemented by work on clinical trials, services research, epidemiology, and health policy research, said Jeffrey Lieberman, M.D., chair of the Department of Psychiatry at the College of Physicians and Surgeons at Columbia University, director of the New York State Psychiatric Institute, and director of the Lieber Center for Schizophrenia Research.

Lieberman is chair of APA's Council on Research and Quality Care. He was invited to the Cold Spring Harbor meeting but was unable to attend because of prior commitments.

“Genetics are a high priority because genes identify pathogenic factors that influence brain development and pathology, but there are other perspectives, too,” Lieberman told Psychiatric News.

“For example, we might define phenotypes better and look at social and environmental factors, from urbanism to cannabis, which can increase susceptibility and precipitate mental illness,” he said.

Breakthroughs in understanding the origins of psychiatric illness must also be translated into therapeutics, he said. “Research has yielded genes for cystic fibrosis, Huntington's disease, and Alzheimer's disease, but not effective treatments.”

Realizing Watson's proposed agenda would demand some combination of federal, private, and foundation money.

“We want to get the White House and Congress interested,” Watson said.

One model for coordinating the enterprise might be the federal Interagency Autism Coordinating Committee, set up by Congress in 2008, said Insel. That committee pulled together all parties interested in autism, planned research directions, and identified gaps in funding.

More planning will be needed if the equivalent of a Manhattan Project for neuropsychiatry is to become a reality.

“We welcome a statement calling for increased emphasis and resources for research on the causes of mental illness from such an eminent group of scientists,” said Lieberman. “We would hope that the response to their call also considers the importance of the immediate clinical needs of patients in terms of development of more effective therapeutic agents and interventional strategies.

“We should not forget the patients who are currently affected by mental illness and need treatment and care.”

An abstract of “The Future of Psychiatric Research: Genomes and Neural Circuits” is posted at <www.sciencemag.org/cgi/content/summary/sci;327/5973/1580>.