By Leigh MacMillan
June 1, 2001

The human and other genome projects are beginning to bear fruit - in the form of new research discoveries. Scientists reaping the genome's harvest described recent findings and new directions last week at the first annual Vanderbilt University Conference on Genomics. The inaugural conference - "Neurogenomics: Building a Better Brain" - featured research advances at the crossroads of neuroscience and genomics.

Scientific sessions spanned four days and explored the genes underlying brain development, neuronal plasticity, drug action, and psychiatric diseases. The value of model systems like fruit flies, worms, and zebra fish to neuroscience discoveries was also highlighted.

"The ability to move back and forth and up and down the phylogenetic scale is extraordinarily useful and is a theme that has run through this conference," said Dr. Floyd E. Bloom, chair of Neuropharmacology at the Scripps Research Institute and honorary chair of the Neurogenomics Conference.

Bloom praised the conference organizers and the Vanderbilt University scientists who hosted special topics workshops for the 160 conference participants. "You have seen that this school is filled with enormous talent and technological expertise," he told participants during closing remarks.

Speakers in each scientific session described strategies for moving to large-scale genome-wide screens for genes. Scientists who traditionally have focused on a handful of genes now must grapple with the 30,000 to 40,000 genes present in the human genome and the even larger number of resulting protein products.

J. Gregor Sutcliffe, Ph.D., from the Scripps Research Institute, explained a strategy called TOGA (Total Gene Expression Analysis) that he and colleagues are using to probe how neuropsychiatric drugs work. Although these drugs occupy receptors immediately, he said, it takes up to three weeks before they achieve therapeutic effects, suggesting that they work by changing gene expression. Sutcliffe is using the TOGA method to look for the gene expression changes induced by these drugs.

Other investigators are using "DNA chips" - nickel-sized pieces of glass spotted with thousands of different DNA samples - to screen for gene expression changes that accompany processes ranging from development of the cerebellum to neurodegeneration.

The molecular discoveries made by scientists studying brain development and neuronal communication come together in efforts to understand neurological disorders and diseases.

"Each complex trait does eventually boil down to specific genes that increase or decrease risk," said John C. Crabbe, Ph.D., from the Oregon Health Sciences University.

Speakers in one of the scientific sessions described the search for genes underlying addiction, autism, and Alzheimer's disease. These disorders represent only a fraction of the known neurological disorders, but lessons learned in one field will aid efforts in other neuropsychiatric research fields, said Dr. Eric Nestler, chair of Psychiatry at the University of Texas Southwestern Medical Center.

"We think of distinct diseases and disorders," Nestler said, "but the brain functions in overlapping circuits, using overlapping signaling mechanisms."

Nestler discussed his group's efforts to characterize the gene expression changes that induce and maintain a state of addiction. They have identified a gene, delta-FosB, whose expression increases after chronic drug exposure and after natural compulsive behaviors.

"Delta-FosB could function as a sustained molecular switch that maintains a state of addiction," Nestler said, potentially explaining why former addicts relapse after years of abstinence. The protein might also be a useful target for drugs to treat addiction, he said. Because delta-FosB is a transcription factor - a protein that turns other genes on or off - Nestler's group now is turning to DNA chip technologies to identify delta-FosB target genes.

The goal of identifying genes that cause psychiatric disorders or are involved in the pathophysiology of psychiatric disorders, the scientists agreed, is to develop new diagnostic tests, new treatments, and hopefully even preventive measures.

At least four different genes have been linked to Alzheimer's disease, and these genes have "defined a biochemical pathway that we can use to think about treatments," said Peter St. George-Hyslop, Ph.D., from the University of Toronto. "The endgame is to use our discoveries of genetic targets and our understanding of the biology to design new treatments."

>As these kinds of strategies are successfully applied to more and more diseases and disorders, Bloom said, "the world of medicine will have clearly changed."

Vanderbilt faculty members participated in the Neurogenomics conference as scientific session chairs: Ford F. Ebner, Ph.D., and Randy D. Blakely, Ph.D., presenters: David M. Miller, Ph.D., Lila Solnica-Krezel, Ph.D., and Jonathan Haines, Ph.D., and workshop leaders and speakers. Lee E. Limbird, Ph.D., associate vice chancellor for Research, was the conference convener.

Vanderbilt University will host its second Conference on Genomics, "Proteomics: the Next Grand Biological Challenge," next May.