“We now understand simple genetic disorders pretty well,” says Len A. Pennacchio, a geneticist at the Lawrence Berkeley National Laboratory, in California. For example, in the not-too-distant future, when a child with an apparent single-gene disease, such as cystic fibrosis, is born to parents who don't show symptoms, it will be possible to sequence the child's and parents' genomes “to find out whether the disease has been inherited or is de novo” — freshly appearing in the child because of some new mutation, says Pennacchio.
Scientists also have unlocked more details about cancer than many other diseases, Pennacchio says. “Cancer is all about the DNA,” with environmental events such as exposure to the sun's ultraviolet radiation triggering mutations that turn healthy cells malignant, he says.
Further, in cancer, only a localized group of cells — such as a tumor — goes awry, explains Pennachio. New technology allows doctors to examine a patient's typical DNA next to a tumor's DNA to find the exact genetic differences that have presumably turned the ordinary tissues into cancer, he says.
Nevertheless, such analysis works only for early-stage cancers, explains Anindya Dutta, a professor of biochemistry and molecular genetics at the University of Virginia. One characteristic of cancer is a “unique ability to change its repertoire” through quick, multiple gene mutations. Late-stage cancers develop rather chaotically, so a cancer that begins with the same genetic profile in two people may develop into two quite different cancers in the late stages. This accounts for the extreme difficulty of developing effective treatments for late-stage cancer, Dutta says. As multiple mutations occur, about 1 percent of the cancer cells in each new generation will have a makeup that allows them to survive whatever defenses the body and medicine mount against them.
All widespread diseases besides cancer apparently have an even more complex relationship to genes.
For Alzheimer's, for example, “there are some rare [gene] mutations that flat-out cause the disease,” and these have been found in families with a strong history of the illness, says Gerard D. Schellenberg, a professor of pathology and laboratory medicine at the University of Pennsylvania. Since these cases are essentially single-gene conditions, they have been relatively easy to track down by studying the genomes of families in which early-onset Alzheimer's is common, he says. No more rare Alzheimer's-triggering genes are likely to be found, Schellenberg adds. We “don't see any families with generation after generation getting [Alzheimer's] at an early age that we can't explain” through mutations that have already been identified, he says.
But most people who develop Alzheimer's will get the disease through a more complex route, with multiple genes helping to raise the risk of developing the disease.
To find out what those genes are, scientists scan the genomes of a large number of people who have the condition and a large number of people who don't. They're on the lookout for gene variations — not mutations, but simply alternate forms of genes, called “alleles” — that occur in both the sick and healthy populations but “a little bit more often” in people who have the disease, Schellenberg explains.
With about 10,000 Alzheimer's patients' genes sequenced, “we're up to about seven [additional] genes related to late-onset” Alzheimer's, says Schellenberg. “These are pretty much small-effect genes,” and “when we get the next 10,000” people into gene-sequencing studies, “I'm sure we'll find more.”
Like Alzheimer's, other common conditions, such as high cholesterol and high blood pressure, are related to multiple genes, each contributing only a small amount to an individual's risk of developing the condition. Scientists differ sharply on how useful these findings are for tailoring preventive-health strategies for patients or eventually developing gene therapies.
Currently, about 20 different genes have been shown to relate to heart-disease risk. Daniel J. Rader, scientific director of translational/clinical research at the University of Pennsylvania's Institute for Translational Medicine and Therapeutics, says he has argued that the genes should be used clinically to determine whether people should take a blood-fat-lowering drug based on their genetic profile, even if they don't have extremely high cholesterol.
Within the next few years, the medical field should arrive at the “point of saying to a 40-year-old male,” based on gene tests, family history and individual risk factors like smoking, that “for the average person, it's a 50 percent risk” of heart disease over the next 40 years, “but for you it's more like 80 percent,” and “if you take these steps, we can reduce it to 20 percent,” Rader says.
But others say that's too optimistic — that the so-called genome-wide association studies intended to turn up common gene variations related to disease most likely are based on a false premise.
“After doing comprehensive studies for common diseases, we can explain only a few percent of the genetic component of most of these traits,” said David B. Goldstein, a professor of molecular genetics and microbiology at Duke University. “For schizophrenia and bipolar disorder, we get almost nothing; for type 2 diabetes, 20 variants, but they explain only 2 to 3 percent of familial clustering, and so on.
The problem, Goldstein believes, is that evolution has been much more successful than many have believed at killing off people who carry disease-causing gene variations before they can reproduce. Thus, evolution has stopped most disease-causing alleles from ever becoming common. And most cases of so-called “common” diseases are probably caused instead by rare patterns of genetic variation that occur in only a few people, he speculates.
— Marcia Clemmitt