lunes, 4 de noviembre de 2013

Human genetics successes and failures: ASHG stories of disease genes.

Human genetics successes and failures: ASHG stories of disease genes.

Genetics’ Rite of Passage

Find a gene, slap high-fives around the lab, publish to huzzahs, and then … uh-oh.

Digital representation of the human genome
A visitor views a digital representation of the human genome on Aug. 15, 2001, at the American Museum of Natural History in New York City.
Photo by Mario Tama/Getty Images
If you want a look at a high-profile field dealing with a lot of humbling snags, peer into #ASHG2013, the Twitter hashtag for last week’s meeting of the American Society of Human Genetics, held in Boston. You will see successes, to be sure: Geneticists are sequencing and analyzing genomes ever faster and more precisely. In the last year alone, the field has quintupled the rate at which it identifies genes for rare diseases. These advances are leading to treatments and cures for obscure illnesses that doctors could do nothing about only a few years ago, as well as genetic tests that allow prospective parents to bear healthy children instead of suffering miscarriage after miscarriage.
But many of the tweets—or any frank geneticist—will also tell you stories of struggle and confusion: The current list of cancer-risk genes, the detection of which leads some people to have “real organs removed,” likely contains many false positives, even as standard diagnostic sequencing techniques are missing many disease-causing mutations. There’s a real possibility that the “majority of cancer predisposition genes in databases are wrong.” And a sharp team of geneticists just last week cleanly dismantled a hyped study from last year that claimed to find a genetic signature of autism clear enough to diagnose the risk of it in unborn children.
This sample reads like an abstract of the entire field of genetics. In researching a book about genetics over the past four years, I’ve found a field that stands in a bizarre but lovely state of confusion—taken aback, but eager to advance; balanced tenuously between wild ambition and a deep but troubling humility. In the 13 years since the sequencing of the first human genome, the field has solved puzzles that 14 years ago seemed hopeless. Yet geneticists with any historical memory hold a painful awareness that their field has fallen short of the glory that seemed close at hand when Francis Collins, Craig Venter, and Bill Clinton announced their apparent triumph in June 2000.
Many geneticists gained this awareness directly. Two years ago I spent a day walking around Cambridge University with Daniel MacArthur, a young geneticist who was then a postdoc. It made a good spot for perspective-taking on genetics: At Cambridge almost a century ago, a biologist named William Bateson coined the term “genetics” for the field he and the university would play key roles in establishing. At Cambridge—or rather at the Eagle, a campus-side pub that might as well be part of the university, so thoroughly do their histories entwine—James Watson and Francis Crick first announced, at lunchtime one day in 1953, that they had figured out the structure of DNA.
MacArthur moved last year to a lab at Harvard Medical School, where he hunts and finds rare-disease genes. But that summer day two years ago, as we walked the history-soaked campus, he told me a tale of comeuppance that parallels his discipline’s.
Back in the early 2000s, soon after the sequencing of the human genome, MacArthur was working on his doctorate in Australia when he and some colleagues identified a gene that appeared to give a huge boost to athletic performance. The gene is called ACTN3. Everyone carries two copies of this gene, one from each parent. In some people, one or both of these ACTN3 genes are crippled by a variant of another gene. People with two damaged ACTN3 genes tend to be on the slow side and rarely excel in sports. Most elite sprinters, meanwhile, carry two good copies. ACTN3 looked to be a sort of sprinting gene, creating a speed effect both profound and straightforward.
MacArthur and his colleagues published their findings in 2003, to many huzzahs. This, it seemed, was the sort of thing sequencing the human genome made possible.
So far, so great. Nice clean story. The state of your ACTN3 genes, in the words of a company that later sought to sell tests for it, “may determine the type of athlete you were born to be.”
But as MacArthur explained that day in Cambridge (and later in a blog post), this nice, clean story got muddier as he and others studied the gene more closely. They realized that the 2003 study had relevance only to a tiny fraction of humanity—elite-level sprinters—in whom the gene’s effect looked larger and more straightforward than it actually was.
In addition, the gene appeared to boost performance mainly in sprinting. For other sports, it probably had no effect or even substantial downsides.

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