Until recently, diagnosing the condition required a liver biopsy–not a procedure you’d undertake lightly. But Miscoi didn’t have to go that route. Scientists isolated the gene for hemochromatosis a few years ago, and developed a test that can spot it in a drop of blood. Miscoi tested positive, and the diagnosis may well have saved her life. Through a regimen of weekly blood lettings, she was able to reduce her iron level before her organs sustained lasting damage. She’s now free of symptoms, and as long as she gives blood every few months she should live a normal life span. “Without the DNA test,” she says, “I would have had a hard time convincing any doctor that I had a real problem.”
Hemochromatosis testing could save millions of lives in coming decades. And it’s just one early hint of the changes that the sequencing of the human genome, now in its final stages, could bring. By 2010, says Dr. Francis Collins of the National Human Genome Research Institute, screening tests will enable anyone to gauge his or her unique health risks, down to the body’s tolerance for cigarettes and cheeseburgers. Meanwhile, genetic discoveries will trigger a flood of new pharmaceuticals–drugs aimed at the causes of disease rather than the symptoms–and doctors will start prescribing different treatments for different patients, depending on their genetic profiles. The use of genes as medicine is probably farther off, but Collins believes even that will be routine within a few decades. “By 2050,” he said recently, “many potential diseases will be cured at the molecular level before they arise.”
That may be a bit optimistic, but the trends Collins foresees are already well in motion. Clinical labs now perform some 4 million genetic tests each year in the United States. Newborns are routinely checked for sickle cell anemia, congenital thyroid disease and phenylketonuria, a metabolic disorder that causes mental retardation. Like hemochromatosis, these conditions are catastrophic if they go undetected, but highly manageable when they’re spotted early. Newer tests can help people from cancer-prone families determine whether they’ve inherited the culpable mutation. “My mother died of colon cancer at age 47,” says Dr. Bert Vogelstein, an oncologist at Johns Hopkins and the Howard Hughes Medical Institute. “If we’d known she was [genetically] at risk, we could have screened for the disease and caught it early.”
Early detection is just the beginning. Genes help determine not only whether we get sick but also how we respond to various treatments. “In the past,” says Dr. William Evans of St. Jude Children’s Research Hospital in Memphis, Tenn., “the questions were, ‘How old are you and how much do you weigh?’ " Now, thanks to recent genetic discoveries, physicians can sometimes determine who stands to benefit from a given drug, and who might be harmed by it. At St. Jude, doctors gauge the aggressiveness of children’s leukemia cells before settling on chemotherapy or bone-marrow transplantation. And kids who qualify for chemo receive additional gene tests to gauge their tolerance. Most can handle standard doses of the drug mercaptopurine. But one person in 10 produces low levels of the enzyme needed to metabolize it, and for those folks a standard dose can be up to 20 times too high. By identifying those patients ahead of time, doctors can avoid poisoning them.
Cancer drugs aren’t the only ones that vary in their effects. Experts estimate that 10 to 40 percent of the people taking any medication respond less than perfectly to it. The result is that 2 million Americans are hospitalized for adverse reactions each year, and 100,000 die. Only a handful of clinics are using gene tests to guide drug therapy, but the practice (known as pharmacogenetics) is spreading fast. Researchers are now learning to predict reactions to treatments for asthma, diabetes, heart disease and migraines–and firms like Incyte Genomics are developing chips that can analyze thousands of genes at a time. “My vision is that everyone will be sequenced at birth,” says Dr. Mark Ratain of the University of Chicago. “Parents will get a CD-ROM with their child’s genetic sequence. When physicians prescribe drugs, they’ll use it to optimize treatment.”
Unfortunately, knowledge is not always power. Knowing you’re at extreme risk of breast cancer, or highly sensitive to a particular drug, may help you protect yourself. But suppose your family is plagued by Huntington’s disease, or early-onset Alzheimer’s. “There’s nothing you can do about it if you test positive,” says Nancy Wexler, a neuropsychologist at Columbia University. “You’re not even spared of uncertainty, because you never know when the disease will start.” Even testing negative for such a condition can complicate your life. Fifty-six-year-old Joyce Korevaar had spent years watching family members die of Huntington’s when the first tests became available in the mid-1980s, so she was eager to know her own fate. Learning that she didn’t have the mutation was like having a death sentence lifted. But the good news left her racked with guilt, and it distanced her from her less fortunate siblings. “Up until that point, we had all been in this together,” she says. “Then I stepped out of the circle.”
The hope, of course, is that we’ll use genetic science to fix health problems, not just to predict them. After two decades of research, only a few gene-based therapies have entered clinical practice. But genetic science now informs every branch of medicine, from oncology to infectious disease, and it’s opening countless possibilities. To paraphrase Francis Collins, we ain’t seen nothing yet.
Classic gene therapy rests on a seductively simple idea. Since genes direct the assembly of every cell in the body, it should be possible to treat chronic health problems by slipping corrective genes into patients. Scientists have gotten good at isolating useful strands of DNA and splicing them into vehicles, or “vectors,” that can penetrate cells. But getting the body to adopt and express therapeutic genes has been hellishly difficult. The most common vector–a genetically altered cold virus, or adenovirus–sets off an immune response that destroys the needed gene and can en- danger the patient. When Jesse Gelsinger, a volunteer in a University of Pennsylvania gene-therapy experiment, died last year from adenovirus side effects, some experts demanded a halt to such trials. But newer vectors, such as “adeno-associated virus,” are yielding better results with fewer side effects.
Even with the new vectors, gene therapy is at least a decade away from wide clinical use. But there are simpler ways to harness DNA. At Maryland-based Human Genome Sciences, for example, researchers are splicing human genes into bacterial cells that can be grown in culture. The cells then churn out proteins that can be given to patients as drugs. One of the company’s products, known as MPIF-1, could help protect bone-marrow cells from the toxic effects of chemotherapy. Another protein, called KGF-2, may speed wound healing. These drugs are still in early clinical trials, but oncologists are already using similar agents to replenish immune cells decimated by chemotherapy.
While some teams race to harness useful genes, others are working to handcuff harmful ones. Genes, you’ll recall, are functional segments of the long, double-stranded DNA molecules that make up chromosomes. They generate proteins by transcribing their codes onto single-stranded RNA molecules, which serve as templates for protein construction. The process begins when a so-called transcription factor grabs onto the gene’s opening segment, or “promoter region,” and crawls the length of the gene, generating an RNA molecule that carries the blueprint for a protein. Researchers have found that by flooding cells with fake copies of a gene’s promoter region, they can divert transcription factors away from the actual gene, thus stalling the production of RNA. The technique has yet to reach the clinic, but that could happen soon. In one recent study, a team from Boston’s Brigham and Women’s Hospital found that decoy promoters slowed the buildup of scar tissue in veins used as bypass grafts. Veins doused with decoy promoters before surgery were less likely to become clogged.
If you can’t keep a gene from making RNA, it’s sometimes possible to keep the RNA from generating a harmful protein. The trick is to bombard it with tiny “antisense” molecules that block out parts of its sequence. And if that strategy fails, you can sometimes counter the protein itself. Consider the case of HER-2. It’s a receptor protein that dots the surfaces of breast cells, enabling them to absorb growth signals. Most women have two copies of the gene for HER-2, but roughly a third of advanced breast-cancer patients have extra copies of the gene scattered about chromosome 17. As a result, their cells display up to 100 times the normal number of growth-signal receptors–not a winning feature when those cells happen to be malignant.
That was Ginger Empey’s predicament five years ago. Her breast cancer had spread to her lymph nodes and liver by the time it was diagnosed, and conventional treatment did nothing for her. So the 50-year-old public-health nurse called UCLA from her home in Bakersfield, Calif., to see if she could join a clinical trial. As it happened, Dr. Dennis Slamon was testing a genetically engineered antibody called Herceptin, which blocks the HER-2 receptor. When tests showed that Empey’s cells were swarming with the rogue protein, she was in. Her tumors shrank by a stunning 25 percent over the next year, so the researchers kept treating her. And after three and a half years of weekly injections, the tumors had essentially vanished. “My lesions were so small that the doctors couldn’t tell whether they were cancer or scar tissue,” she recalls.
Empey’s lesions are still negligible after five years of treatment. Herceptin has made it to market, and researchers are now launching new studies to see how it affects patients with less-advanced disease. The drug is no panacea; most patients in the UCLA study responded for less than a year. But it stands as an emblem of how understanding the genome could advance the art of medicine. “Instead of building bigger bombs,” says Slamon, “we’ve developed a smart bomb to target a specific problem.” Let’s hope that strategy prevails.
