Made to Order Medicine: A Revolution in Genetic Research Is Targeting Treatments to Patients' Unique Characteristics. It Can Mean the Difference between Life and Death

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Jill was only 2 when the diagnosis came: acute lymphoblastic leukemia (ALL). This rare childhood cancer, the doctors assured her parents, is highly curable with a cocktail of four chemotherapy drugs. But from the very beginning the chemo made Jill acutely ill: her white-cell, red-cell and platelet counts plummeted, and even with biweekly transfusions "her counts kept going lower and lower," says Dr. Mary Relling of St. Jude Children's Research Hospital in Memphis, where Jill was treated. Doctors didn't know whether the leukemia was knocking out her blood production--or whether the chemo itself was. But they had a way to find out. Researchers at St. Jude and at the Mayo Clinic in Rochester, Minn., had recently discovered that patients with a single mistake in a gene called TPMT fail to produce the enzyme that metabolizes the chemo drug, 6-mercaptopurine. As a result, the drug builds up in the body to toxic levels. Jill belonged to the 0.3 percent of the population--one person in 300--that carries two copies of the misspelled TPMT gene, and as a result her enzyme level was almost nil. But her DNA didn't doom her; instead, it told doctors how to custom-tailor a therapy for her. They slashed her mercaptopurine dose, knocking out the leukemia but not her blood production, and today Jill has no recollection at all of her brush with death.

But doctors do, even if they don't know Jill. Recognizing that a single misspelled gene means the difference between being poisoned and being cured was the first victory for the new science of pharmacogenetics. By marrying the discoveries of the human genome project to technologies like DNA chips as well as traditional medicine, pharmacogenetics promises to target treatments to a patient's genetic profile, the 34,000 or so genes spelled out by sequences of four chemicals known as A, T, C and G. The genes in every human cell can affect your response to drugs in three ways. Some genes make receptors, molecules on cell surfaces that drugs must dock with in order to do any good. No gene, no receptor, no drug benefit. Other genes make enzymes that affect how you absorb, metabolize and eliminate drugs, explains Dr. William Evans of St. Jude. Finally, genetic changes in cancer cells make the cells vulnerable to some drugs but not others. If pharmaco-genetics works, the days of one-size-fits-all therapy could go the way of bleeding by leeches. Instead of treating a disease called breast cancer, oncologists will determine the genetic fingerprints of this patient's breast cancer and tailor treatment to it; instead of treating a disease called asthma, doctors will individualize drug therapies to produce the greatest good and avoid the worst side effects. Medicine, in other words, is getting personal.

This, of course, will be a huge departure from how doctors and drug companies traditionally do business. Today pharmaceutical firms develop, and physicians prescribe, the therapy that has helped the most people. If your genetic makeup means that you're not "most people," you're out of luck. Pharmacogenetics, though, promises to identify the minority of people who would benefit from a different drug, and thus a market for it. And not least, the new research should slash the death rate from drug adverse reactions, which kill more than 100,000 Americans annually. "What's shocking is the rapidity of the pharmacogenetics revolution," says Dr. Richard Weinshilboum of Mayo, one of the discoverers of the link between genes and reaction to mercaptopurine. "And I do believe it is a revolution."

One promising target for personalized medicine is genes called cytochrome P450s. These genes produce enzymes responsible for metabolizing one third to one half of all drugs now in use, including cholesterol-lowering statins, antibiotics and antipsychotics. The enzymes act like little tugboats, ferrying the drugs around the body, metabolizing them into a useful form or sending them out the body's exits once they've done their jobs. …