Genomics Promises Revolution In Psychiatric Treatment

Breakneck advances in genomics promise to usher in an era of“ individualized medicine” based on a thorough understanding of the molecular pathophysiology of mental illness.

So said Thomas Insel, M.D., director of the National Institute of Mental Health, in the Judd Marmor Award Lecture at APA's 2005 annual meeting in May in Atlanta.

Insel sketched a portrait of a not-too-distant future when clinicians will treat precise targets along a pathophysiological chain from genes to cells to distributive systems within the brain based on a patient's unique genetic variation.

This is an ambitious, even visionary, portrait, but one that Insel said is already taking shape in the treatment of cancer, diabetes, and cardiovascular disease. While this vision depends on some technological virtuosity yet to be attained in psychiatric research, he noted that these advances are already being pursued with “breakneck speed.”

For instance, merely knowing the location of genes, as was achieved with the completion of the Human Genome Project, is barely a beginning. That accomplishment has been likened to writing the “White Pages,” a“ text” made up of 3 billion base-pairs of DNA, with every gene having an address and a phone number to locate it within the text.

But what is really necessary, Insel explained, is the “Yellow Pages”—a catalog of where and how genes are expressed and how they function. So a critical research goal is to go “gene by gene along the White Pages, ask if the gene is expressed in the brain, and if so where.”

That goal is being advanced by the Gene Expression Nervous System Atlas (GEN-SAT) Initiative at Rockefeller University, among other places.

And that is not all. Insel noted that scientists possess a“ consensus” genome sequence derived from the handful of people who contributed their DNA to the public and private arms of the Genome Project.

But, like the proverbial snowflake, no two people who are not identical twins will ever have the exact same genome. What is really necessary to close the link between the genome and human health or disease is a map of variations across the 3 billion base-pairs of DNA.

“That is the challenge,” Insel said, “making the leap between genomic variation and behavioral or functional variation at the level of individuals.”

Fortunately, variations in genomic sequence (known as single nucleotide polymorphisms) occur in inherited units known as “haploid genotypes,” or haplotypes— meaning that scientists do not have to map all 3 billion base-pairs of DNA for variations; they only have to map the haplotypes.

Spearheading this project is the International HapMap Project, a multicountry effort to identify and catalog haplotypes. The next version of the map is scheduled to be completed this summer, Insel said.

“This tells us for the first time that we can begin to study individual variation at a level and a speed and at a lower expense than we ever thought possible,” he said. “The question of how you relate individual variation in sequence to function is now a tractable question.”

The upshot of these developments is likely to be transformative.

“Where this may take us is to a very different vision of what psychiatry could look like in a postgenomic era,” Insel said. “We are talking about moving us from where we currently diagnose by symptoms and treat empirically to an era where we really do understand something about the molecular pathophysiology of [psychiatric] disorders.”

Turning a Paradigm on Its Head

Insel predicted that the current and long-standing strategy by which treatments for mental illness are derived will be looked back on as anachronistic—and somewhat illogical.

Today, he said, the pathophysiology of mental illness is surmised from the mechanism of action of pharmaceutical compounds that are themselves chanced upon serendipitously, as a result of tweaking other formulations already proven successful.

It is a process that stands scientific logic on its head. “It's like trying to find out if the mechanism of aspirin is related to the pathophysiology of headache,” Insel said. “Thinking that way is not going to lead you to new discoveries, but to a lot of knock-offs of aspirin. Yet that is very much what has happened in psychiatric research. We haven't had any new classes of compounds in 30 years.”

The modern molecular genomic model reverses this paradigm. Already, in areas of research such as cancer, diabetes, and cardiovascular disease, scientists are elucidating specific variations in genetic sequence that result in alterations in cellular and systems functioning; then animal studies are designed to test targets along the chain from genes, to cells, to systems, to function.

“That's the way you get to new classes of drugs—not by taking drugs we already have and modifying them to find a market,” he said.

In psychiatry, the task is complicated by the fact that all of the psychiatric conditions are considered “complex” disorders involving multiple genes and multiple brain systems.

The way in which the genomic text itself is “read out” in cells, systems, and functioning is proving more baroque than previously imagined. One curiosity emerging from the completion of the Human Genome Project, for instance, is the relatively small number of genes; of 3 billion base-pairs of DNA, there are just 23,000 genes, or intelligible“ sentences” in the text.

A question this raises is the nature and purpose of the great bulk of nongenetic material in the genome, and Insel said much recent research is focused on these noncoding areas: What are they there for? And what are they doing?

Research within the last year reveals that it is in the process of transcription (by which an RNA copy is built from a DNA sequence) and translation (the process by which the RNA copy is translated into the amino acid sequence of a protein) that these noncoding regions play a critical role.

For instance, “promoter” regions of DNA appear to influence where and how much of a protein is read out, so that a variation in a promoter region can have an enormous influence on cell and system function, he said.

For this reason, Insel said it is the complex processes of transcription and translation—not merely the gene itself—that holds the key to understanding how the genetic blueprint expresses itself in cells, systems, and function.

Putting It All Together

Some recent and ongoing research is managing to put all the pieces of this puzzle together, a model for a true molecular genomic understanding of mental illness (see box).

Insel suggested that a midterm goal of this revolution-in-progress would be the development of “biodiagnostics” using, for instance, neuroimaging tools as biomarkers for specific mental illness.

“What we are talking about is developing treatments that go after the core pathology,” Insel said.

But the real breadth of his vision for the revolution in molecular neurobiology was suggested in his comments about the“ endgame”—when psychiatrists could use knowledge of individual genomic variation to prevent and cure major mental disorders, rather than merely manage and treat them.

“The endgame is individualized care,” Insel said. “It is not hard to imagine a time when you would know which person was at very high risk for schizophrenia, and you would have the neuroimaging data you would need to watch a patient very carefully. At age 16 when the patient begins to develop a sleep disturbance and ideas that are even stranger than those of his peers, you would know that this was a patient with whom you would want to intervene.”

He asked, “Why aren't we thinking about preventing the first break and putting together the kind of science that we need to do that?”

Information about the International HapMap Project is posted online at<www.hapmap.org/>.▪