(5 of 7)
Everyone looking for new drugs, whether genomically or in more traditional ways, wants to reduce the cost of bringing a medication to market--now estimated at $500 million. One way to do it is to limit trials to those people most likely to respond to a given drug. This too is governed by genetics. Says Ira Herskowitz, a biochemist and biophysicist at the University of California, San Francisco: "We're all different, we have different hair color and different features, right? How can we not metabolize drugs differently?"
That's why Herskowitz and his colleagues have launched a project to unravel exactly what--at the genetic level--makes some people benefit from drugs and others not. They suspect that one major factor is a class of proteins called membrane transporters. These proteins act as molecular gatekeepers, deciding which foreign substances in the bloodstream will be taken into and which rejected by individual cells. If, for example, people lack the gene for an inactivating enzyme, says Herskowitz, "a standard dose of a drug will be more potent. If they have an extra copy of the gene, a standard dose will be inadequate."
To get a handle on how these proteins vary from one person to the next, members of the Pharmacogenetics of Membrane Transporters project are focusing on 25 different transporters already known to play a role in drug absorption and elimination. The first step is to look at the genes for those transporters in DNA samples from 250 ethnically diverse people and see how they vary from one individual to the next. "Identifying the variants is rather easy," says Kathleen Giacomini, the project's principal investigator and UCSF's chairwoman of biopharmaceutical sciences. "The really hard part is in looking at whether the variants have significance for drug response."
That requires working with living cells. The researchers insert different versions of a given gene into a cell and see how its response to a particular body chemical--serotonin, for example, a neurotransmitter implicated in clinical depression--varies. Then they bathe the cells in Prozac, for instance, which works by modifying serotonin levels in the brain, and see how that response changes. "If there's a difference," says Giacomini, "I'll know that maybe your transporter interacts with the drugs a little differently from mine."
As of this month, UCSF researchers have done about 20% of the initial DNA analysis and have found more than a dozen variants, which are now being screened in cells. The scientists on tap to look for variants that haven't been analyzed yet, says Herskowitz, "are chomping at the bit, saying, 'When is my gene going to be done?'"
Clinicians, meanwhile, are assembling a list of 1,500 patients being treated for depression, whose varying responses to medication will be carefully documented. Eventually the clinical data will be combined with the genetic studies. Says Herskowitz: "It's interesting to see the changes to the cell, but what you really want to know is how someone with that change would respond differently to Prozac, or to an anticancer compound. That's more elaborate, which is why this clinical aspect is exciting stuff."