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【medical-news】对基因诊疗抗争疾病的不同看法
纽约时报载文 报道人类遗传学家对基因诊疗抗争疾病的不同看法
The principal rationale for the $3 billion spent to decode the human genome was that it would enable the discovery of the variant genes that predispose people to common diseases like cancer and Alzheimer’s. A major expectation was that these variants had not been eliminated by natural selection because they harm people only later in life after their reproductive years are over, and hence that they would be common.
Get Science News From The New York Times » This idea, called the common disease/common variant hypothesis, drove major developments in biology over the last five years. Washington financed the HapMap, a catalog of common genetic variation in the human population. Companies like Affymetrix and Illumina developed powerful gene chips for scanning the human genome. Medical statisticians designed the genomewide association study, a robust methodology for discovering true disease genes and sidestepping the many false positives that have plagued the field.
But David B. Goldstein of Duke University, a leading young population geneticist known partly for his research into the genetic roots of Jewish ancestry, says the effort to nail down the genetics of most common diseases is not working. “There is absolutely no question,” he said, “that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.”
Of the HapMap and other techniques developed to make sense of the human genome, Dr. Goldstein said, “Technically, it was a tour de force.” But in his view, this prodigious labor has produced just a handful of genes that account for very little of the overall genetic risk.
“After doing comprehensive studies for common diseases, we can explain only a few percent of the genetic component of most of these traits,” he said. “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 reason for this disappointing outcome, in his view, is that natural selection has been far more efficient than many researchers expected at screening out disease-causing variants. The common disease/common variant idea is largely wrong. What has happened is that a multitude of rare variants lie at the root of most common diseases, being rigorously pruned away as soon as any starts to become widespread.
It takes large, expensive trials with hundreds of patients in different countries to find even common variants behind a disease. Rare variants lie beyond present reach. “It’s an astounding thing,” Dr. Goldstein said, “that we have cracked open the human genome and can look at the entire complement of common genetic variants, and what do we find? Almost nothing. That is absolutely beyond belief.”
If rare variants account for most of the genetic burden of disease, then the idea of decoding everyone’s genome to see to what diseases they are vulnerable to will not work, at least not in the form envisaged. “I don’t believe we should do more and more genomewide association studies for common diseases,” Dr. Goldstein said. Instead, he suggested, the “missing heritability” might be tracked by thoroughly studying the genome of specific patients.
Researchers hunting for disease genes strongly disagree. They say genomewide association studies with larger numbers of patients will bring more disease-promoting variants to light.
Dr. Kari Stefansson, chief executive of the Icelandic gene-hunting company Decode Genetics, says it does not matter whether disease-causing variants are common or rare as long as they yield insights into the biochemical pathways by which disease develops, and which will provide targets for drugs.
The HapMap project was started amid much skepticism but has proved a technical success, even if it has brought to light fewer common disease variants than hoped. “There is no doubt it has succeeded far beyond what some skeptics proposed,” said Dr. David Altshuler, an architect of the HapMap at the Harvard Medical School. He defends the common disease/common variant hypothesis, saying it meant only that some, not all, of the genetic burden of a disease would be conveyed by common variants. And the genomewide association study, currently the gold standard of gene discovery, is in his view only one step along the road.
Dr. Goldstein does not shy away from unpopular positions or research. In a new book, “Jacob’s Legacy” (Yale University Press), he recounts how he delved into the genetic history of Jews.
Given the abuses of the past, geneticists approach with caution research in the genetics of racial or ethnic groups. But genetics can provide powerful insights into history. Because some Jewish communities, for instance, have for centuries married only within their religion, they have developed certain distinctive genetic profiles. One is a genetic signature on the Y chromosome of the hereditary Jewish priests known as cohens. Dr. Goldstein, as he describes in his book, found a set of DNA variations in the signature that allowed him to estimate when that signature first appeared — about 3,000 years ago. The date fit nicely with the presumed date of King Solomon’s reign and supported the claim that cohens were indeed descended from a high priest of around that time, even if that priest may not have been Aaron, as tradition holds.
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作者:admin@医学,生命科学 2010-11-03 17:11
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