The State of Biomedicine

Your dirt-biking expedition has ended painfully-a few ribs broken in a tumble on the trail-and the emergency-room doctor has sent you home with a bottle of codeine. It should be enough to tide you over until the bones heal, unless you’re one of the 20 million Americans who have a mutated form of an enzyme called cyp2d6, which normally converts codeine into the morphine that soothes pain. If you are, the enzyme won’t work, and the pills won’t even take the edge off. Worse yet, neither you nor your physician will know that until you take the drug.

Such is the reality of medicine today. Physicians can prescribe a drug based on a patient’s symptoms, but the hidden details of an individual’s genetic or molecular makeup can make him or her the wrong patient for that drug. Medications work differently in different people. What’s more, in the case of diseases like cancer or arthritis, a patient’s symptoms alone don’t always tell doctors exactly what’s wrong; subtle molecular differences can underlie seemingly similar illnesses. So choosing the treatment most likely to fix the problem is a hit-or-miss proposition. But that one-drug-fits-all reality is beginning to give way to a new era of “personalized medicine,” in which physicians can diagnose their patients with unprecedented accuracy and treat each of them with drugs tailored not only to the disease, but also to the patient’s genetic or metabolic profile.

“It’s going to totally transform medicine, there’s no question about it,” says Susan Lindquist, director of MIT’s Whitehead Institute for Biomedical Research. “And it’s going to be happening soon.” Mark Levin, CEO of Cambridge, MA-based Millennium Pharmaceuticals, offers one vision of what personalized medicine might mean for a patient: “When we walk into the doctor’s office 10 years from now, we’ll have our genome on a chip.” Using that chip, Levin says, a doctor will be able to determine what diseases a patient is predisposed to and what medicines will provide the most benefit with the fewest side effects. Even the way we think about disease will be different, says Jeffrey Augen, director of life sciences strategy at IBM, because doctors will make diagnoses based on genes and proteins rather than on symptoms or the subjective analysis of tissue samples under a microscope. “So instead of a person having chronic inflammation or cancer, he or she will have a cox-2 enzyme disorder or a specific set of genetic mutations,” Augen predicted at a recent conference in Boston.

The change is possible due in large part to emerging technologies that enable researchers to identify and analyze genes and proteins with phenomenal speed-thereby pinpointing the exact nature of different diseases and predicting individuals’ responses to drugs. Even using conventional DNA and protein analysis technologies, researchers have already taken some first steps toward personalized medicine. A woman with breast cancer, for example, can take a gene- or protein-based test that reveals whether her cancer will respond to certain drugs. But the key to gathering the massive amounts of genetic and molecular information that will expand personalized medicine’s reach-and make it a commonplace tool in the doctor’s office-is the thumbnail-sized biochip. These chips can analyze thousands of genes, proteins and other molecules at once from a single drop of blood.

One of the first triumphs for biochips in uncovering the molecular differences between diseases was a study led by biologists Patrick Brown at Stanford University and Louis Staudt at the National Cancer Institute in 2000. Using DNA microarrays-glass wafers spotted with thousands of DNA strands-the researchers examined patterns of gene activity underlying a type of cancer called non-Hodgkin’s lymphoma. After examining nearly 18,000 genes, they discovered that what was once thought to be one disease was in fact two distinct diseases. What’s more, the chemotherapy regimen normally prescribed for non-Hodgkin’s lymphoma patients was significantly less successful for patients with one of those two diseases-a clear indication that better knowledge of what’s going on at the genetic level could help doctors make better decisions about treatment.

DNA chips might soon begin to inform physicians’ decisions about how they prescribe some of the most commonly used pharmaceuticals. Santa Clara, CA-based Affymetrix and Basel, Switzerland-based Roche Diagnostics have teamed up to develop biochips that could help predict patients’ responses to such drugs as antidepressants and blood pressure regulators. The devices will be able to screen for several different mutations in the gene for the cyp2d6 enzyme-which helps metabolize a number of drugs in addition to codeine-and in another key enzyme gene. Roche aims to have the chips on the market by early 2003.

Even-more-sophisticated biochips might ultimately provide a quicker means of reading genetic fingerprints right in the doctor’s office. One drawback of existing DNA chips, for example, is that researchers first have to modify the sample of DNA in order for the chip to detect it. But physicist Scott Manalis and his group at MIT’s Media Laboratory are fabricating a silicon microchip that could potentially provide instant notification when it detects specific gene sequences in a sample of blood. In their device, micrometer-sized silicon cantilevers sense the molecular charges associated with biological molecules such as DNA and could produce a telltale electrical signal. “This opens up the possibility of making a simple biosensor for point-of-care diagnostics,” says Manalis.

Sometimes, however, DNA doesn’t tell the whole story. It’s often the proteins encoded by the DNA that actually determine whether a person is sick or well, and whether a drug is beneficial or toxic. Biologist David Sabatini at the Whitehead Institute found a way to look at the real-life activity of proteins by building arrays of living cells on glass chips. Sabatini recently cofounded the biotech firm Akceli in Cambridge, MA, to commercialize his technology, which he hopes to start selling to drug companies by mid-2003. Drug researchers could, for instance, equip each cell on the chip with a different variant of the body’s drug-metabolizing enzymes, and then expose the chip to a variety of drugs. By monitoring the cells’ responses, researchers could determine if a drug is toxic across the board, only to people with a particular enzyme variant, or not at all. “You can essentially create drug side-effect profiles,” says Sabatini. If a drug is toxic to some people but otherwise looks promising, a company may decide to pursue its development, targeting it to only those patients it benefits. Such a drug, developed specifically for people with not only a particular disease but a particular metabolic profile as well, would be the epitome of a personalized medication.

In the next decade, more and more such drugs, and the diagnostic tests necessary to choose among them, will begin to hit the market. So in the future, when you go to pop a pill you haven’t tried before, you won’t have to wonder if it’s really the right drug for you. You’ll know.