Goffrey Cowley and Anne Underwood - A Revolution in Medicine 汉译

The Search for Cures: From oncology to infectious disease, genetic science is transforming medical practice. The dream of outfitting people with therapeutic genes may still be decades away, but scientists are finding simpler ways to harness the power of DNA.

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 he cured at the molecular level before they arise.”

That may be a bit optimistic, hut 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.

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.

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.

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.”

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.

Classic gene therapy rests on a seductively simple idea. Since genes direct the assembly of every cell in the body, it should he 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 endanger 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 he grown in culture. The cells then churn out proteins that can be given to patients as drugs.

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.