Murky Gene Pool

Unexpected shallowness of map won't simplify development of drugs

Tom Abate / SF Chronicle 13feb01

Celera President J. Craig Venter's shadow was cast against a human genome map yesterday in Washington, D.C. Associated Press photo by Ron Edmonds

Gene hunter Craig Venter's eyes gleamed as he considered the business implications of his co-discovery that a strand of human DNA contains only a third as many genes as once supposed.

"I go around all the time giving these lectures on the future of drug development," Venter said during a recent interview at the Maryland headquarters of Celera Genomics. Venter, who is Celera's president, shared the stage yesterday with public scientists from the Human Genome Project as they together unveiled the first maps of the human genome.

"Pharmaceutical and biotech executives have bought into the notion that one gene made one protein, made one billion-dollar drug," Venter said, adding, "But it's not true."

Previously, it had been widely expected that the publication of the genome maps would reveal the genetic causes of diseases and speed the search for medicines. Now, given the unexpected shallowness of the gene pool, the question arises whether this will help or hinder the job of turning this raw scientific knowledge into therapies.

Steve Fodor, chief executive of Santa Clara's Affymetrix Inc., said the relative scarcity of genes doesn't simplify drug discovery. If anything, it intensifies the challenge, because the gene mappers showed that many human genes make several proteins.

Fodor, whose firm makes glass chips used to study gene activity in sick cells, said it won't be enough to understand which genes are involved in a disease. Researchers must also need to know which variations of the genes are implicated.

"We know of one gene that makes 12 different proteins," Fodor said. One of these proteins causes cells to commit suicide. A different protein variant of the gene stops the suicide process. "The perception that things get simpler (with fewer genes) is wrong," Fodor said.

Paul Godowski, senior research director at Genentech Inc. in South San Francisco, said the low gene count forces drug developers to take a step back and consider that genes are just one player, albeit an important one, in causing illness or promoting health.

Celera Stock Price. Chronicle Graphic

"If anything, the fact that there are fewer genes points out that the complex interactions that occur within a cell or an organism are determined by more than a gene," Godowski said. "We have to understand how proteins work in networks, and how they are modified by other proteins."

Although the low gene count has grabbed headlines, one overlooked aspect of the genome mapping effort is already helping drug development.

In addition to mapping the average human genome, scientists from Celera and the Human Genome Project have both started to identify those places where subtle changes in the genetic code cause physical differences between individuals.

Understanding these differences has spawned the field of pharmacogenetics, which explores how genetic variations influence the way people react to medicines.

Professor Kathleen Giacomini, a pharmacogenetics researcher at the University of California at San Francisco, said scientists already know, for instance, that 1 out of 300 children with leukemia show a very low tolerance for one medicine. Some clinics have already devised tests that identify whether children have this genetic variant and change the drug dose accordingly. She says the genome mapping effort will extend this capability to more drugs.

"If we could predict beforehand that if you had this variant you would have this reaction, we could give you a lower dose," she said.

E-mail Tom Abate at tabate@sfchronicle.com