The X/(7 billion)-Men

Interesting piece in MIT Tech Review by Antonio Regalado, The Search for Exceptional Genomes: They walk among us. Natural experiments, living ordinary lives, unaware that their genes may hold the clue to the next superdrug. As you certainly know by now a lot of the hype over the Human Genome Project turns out to have been unwarranted. But one thing about technology is that often people overestimate the short-term windfall, and underestimate the long-term consequences. Here’s the science & tech:

Ten years ago, scientists discovered that some people are naturally missing working copies of a gene known as PCSK9. The consequences of the mutation were extraordinary. These people, including a Texas fitness instructor, a woman from Zimbabwe, and a 49-year-old Frenchman, had almost no bad cholesterol in their blood. Otherwise, they were perfectly normal.

Drug companies pounced on the clue. To lower cholesterol, they would also try to block PCSK9. Now two separate drugs that disable the gene’s activity are nearing FDA approval. People taking the medications have seen their cholesterol levels plummet dramatically, sometimes by 75 percent.

Most large-scale genetic research is a search for the causes of disease, not the nature of health. But in 2008, Daniel MacArthur, a computational geneticist now at the Massachusetts General Hospital, became interested in how frequently genes are completely dysfunctional in healthy people. Along with collaborators, he scrutinized the genomes of 185 people.

MacArthur’s analysis, completed in 2012, found that each of us has, on average, one entirely defective copy of about 80 genes, and another 20 genes for which neither copy works. In other words, everyone’s genome is a little dysfunctional. (Most genes are present in matching pairs—one inherited from your mother, and one from your father.)

But here’s a fascinating personal twist. Just a heads up, I met and Sonia at ASHG.

That turns out to be a question of urgent importance to husband and wife scientists Eric Minikel and Sonia Vallabh, who have been working alongside MacArthur at Massachusetts General Hospital. Vallabh’s mother died of fatal familial insomnia, an extraordinarily rare disease in which a misfolded protein builds up in the brain, causing dementia and early death. Vallabh has inherited the gene mutation that causes FFI, and has a 100 percent chance of developing the illness, unless some kind of treatment is developed.

Before her diagnosis three years ago, Minikel was an urban planner and Vallabh had gone to law school. But they switched careers and became scientists in order to try to cure Vallabh before she falls ill.

Vallabh’s mutation is the opposite of a knockout—it adds an unwanted function, causing her prion protein to fold in a way that it shouldn’t. This month she switched to another Boston laboratory to explore whether an advanced form of gene therapy, called genome editing, might allow her to eliminate the prion gene from her brain cells altogether.

But would doing so be dangerous? Knockout mice that have been genetically engineered to lack the prion gene seem to be mostly normal, but that’s no guarantee that the same is true of humans. For instance, the knockout surveys carried out by MacArthur’s lab have found more than 40 healthy people with mutations known to prove fatal to mice. Vallabh says she worries that if she were to succeed in eliminating her prion gene it could cause another disease, perhaps equally grave.

In the compressed time frame Vallabh faces—she has perhaps 20 years to cure herself—finding a living person without the prion gene would be one important clue. This year, she and Minikel carried out such a search across DNA sequences of more than 60,000 people as part of MacArthur’s Knockout Project.

They turned up three individuals missing one copy of the prion gene—but, so far, no one who is missing both copies.

Minikel says it may mean that people can’t live without the gene. Or it could be that their database isn’t yet big enough. The gene is small and therefore less likely to be affected by mutations. Working quickly with a pad and paper, with Vallabh looking over his shoulder, Minikel roughly estimated it might take a database of a billion people to know for sure.

If Sonia has 20 years is a billion people doable? I haven’t done the math, but the way the technology is advancing it seems plausible, and the eventual rate limiting step is going to be sociological.

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