Medicine Gets Personal: Pharmacogenetics at GUMC
During World War II, American soldiers serving in malaria-infested areas were given an antimalarial drug called primaquine. A number of soldiers—all of African ethnicity—developed a blood disease after taking the drug. It was later discovered by Arno Motulsky, MD, that a genetic variation of a certain red blood cell enzyme caused the reaction to primaquine. This genetic variation occurred mainly in populations where malaria was endemic, explaining why only the African-American soldiers were affected.
This was the first confirmed case of a drug-induced disorder caused by an interethnic genetic variation, and it was the beginning of the field of medicine called pharmacogenetics.
Every physician knows that when drugs are used to treat individuals, whether it’s for malaria or hypertension or cancer, some patients will do better than others. Some will have serious side effects, others will not. Many factors determine the effectiveness of a drug: age, sex, body size, kidney and liver function, diet, interaction with other medications, and of course, the size and schedule of dosage.
Another determinant of drug effectiveness is genetic variability.
John Deeken, MD, who graduated from Georgetown University School of Medicine in 2001, went on to study pharmacogenetics at the National Cancer Institute. He is now a medical oncologist and cancer researcher at GUMC and is currently interested in the role of genetic variability in the efficacy of cancer drugs. “Pharmacogenetics, from a wider perspective, is understanding those genetic differences in terms of how we metabolize medicines,” he explains. The goal: better prediction of the right medicine, the right dose for an individual’s disease.
This is particularly critical with cancer, both in terms of drug discovery and treatment. Genetic variability among patients in cancer clinical trials is not commonly taken into account, a factor that could skew dosage amounts and doom an otherwise promising new drug. Dosage can be a wild card in the clinic as well. “In oncology, the clock is ticking and we need to start treating immediately and aggressively. If we get that dose wrong at the get-go, it can literally be the difference between life and death,” says Deeken.
Understanding the precise molecular pathways involved and trying to be smarter at picking the right drug and the correct dose for patients, is the goal of personalized or individualized medicine—to be able to figure out for each person what is the best treatment, especially as new drugs are discovered and treatment options increase.
Another area of interest in pharmacogenetics at GUMC is drug resistance. Paul Roepe, PhD, has been studying drug resistance for 20 years—in cancer cells, bacterial cells, and in parasites. At this point, his lab is best known for studying drug resistance in malaria.
“When I think of diseases, I think in terms of the drugs we use to treat them,” says Roepe. “So when you look at all the drugs out there in hospitals and so on, roughly half to two-thirds of them are cytotoxic—drugs used to kill cells. You get drug resistance in any context where the drug is cytotoxic, because nature is trying to tell these cells to survive.”
This Darwinian struggle takes place in the genomes of both the malaria parasite and the human host. “If you take a cell, tissue, an organism, and you subject it to a drug, you will get changes in gene expression. You will maybe even get gene mutations over time,” Roepe explains.
In malaria, the environmental aspects that affect drug delivery to the target cells are complicated by the fact that the malaria parasite lives in human red blood cells. The dynamics may be different than in cancer drug resistance, but the problem remains the same—what are the genomics of how the invasive cells respond and adapt to the drug?
Understanding the genomic basis of drug metabolism, drug resistance, and genetic adaptation both in terms of the host and the parasite, is key to developing drugs or a vaccine for malaria.
Does this herald a new era of molecular medicine, which looks at how a particular patient with a particular disease responds to a given therapy based on the individual’s genome? Both Deeken and Roepe are cautiously optimistic, and stress the importance of emphasizing pharmacogenetics in the medical curriculum.
“I do envision a day where patients have their genomes tested and have that data on a credit card or on their medical record or somewhere, and when they come into the emergency room with a problem or they’re newly diagnosed with some disease, that the physicians will have that data to help come up with the best treatment for them,” says Deeken. “Whether that’s in five years or 20 years, I think this is going to happen, and we all need to adapt and be ready for it and understand it and be ready to apply it within our own fields.”
By Frank Reider, GUMC Communications
