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From Iceland to White House, Precision Medicine’s Promises & Hurdles

Xconomy National — 

[Updated and corrected, 4/5/15, 6:51 pm. See below.] There is talk, and there is action. In the drive toward healthcare tailored for smaller and smaller groups of people, there was both last week, and both illustrated not just the promise of precision medicine, but the long haul until that promise is fulfilled.

First, Iceland’s deCODE Genetics published a series of papers with a treasure trove of detailed genomic information about that island nation’s people. (Total population: 329,000.)

DeCODE, a wholly owned subsidiary of Amgen (NASDAQ: AMGN), captured the genetic details of nearly one third of them.

DeCODE sequenced the full genomes of 2,636, then used genomic sampling and sophisticated statistical estimates on 104,000 more. At first, it might be puzzling to think what the detailed genomes of 100,000-plus Icelanders—most of which weren’t even fully sequenced—can do to push precision (or, as some prefer to say, personalized) medicine forward.

It’s the largest group of people ever analyzed from a single population. Sure, Iceland is small and, compared to immigrant-rich nations like the U.S., very homogeneous. But results from the study, which we’ll get to in a moment, are already opening avenues of investigation into some diseases and giving confidence to drug researchers who want to map their work to underlying genetics.

“The Iceland study represents the tip of the iceberg (couldn’t resist this pun) in what I expect will be a major theme in the future in drug discovery,” Robert Plenge, a vice president at Merck Research Laboratories in Boston, wrote on his blog this weekend.

One paper that deCODE published last week implicates a gene called ABCA7 in Alzheimer’s disease. ABCA7 was previously suspected of being close to a gene that conferred Alzheimer’s risk, but the deCODE work pinpointed ABCA7 itself, as well as the specific mutation within it.

But as one geneticist notes, there’s a lot of biology to uncover, especially in a mysterious disease like Alzheimer’s, before a variation of a gene can truly be linked to sick people. “Just because a variant is correlated to a disease or trait, doesn’t mean it causes it,” says David Mittelman, chief scientific officer of Tute Genomics in Provo, UT. “We will also eventually want some biochemistry to support a causal relationship between variant and traits. You would need that before you jump into drug discovery.”

In another paper, deCODE described what it called human knockouts: people who are completely missing a gene that most of us have. There were more of these people—nearly 8 percent of the Icelandic population—than expected, and the 1,171 missing genes were a greater variety than expected, too. (As the New York Times noted last week, a 2012 study led by geneticist Daniel MacArthur only found 253 knocked-out genes.)

Why is it important that a small group of Icelanders are walking around missing genes the way a few of us only have one kidney, or don’t have an appendix, or only nine fingers? For one thing, people in the drug business are keenly interested in who those people are, and what other health problems they might have.

I asked Michael Gilman, a biopharma veteran who, among other things, has overseen research for Biogen (NASDAQ: BIIB). He’s now running a startup, Padlock Therapeutics, which aims to block enzymes known as PAD2 and PAD4 that are implicated in autoimmune diseases.

Michael Gilman

Gilman: Checking Icelandic genes.

When he heard about the deCODE knockout study, Gilman went right to the list of 1,171 knocked out genes. Sure enough, PAD2 and PAD4 were there. Three people were missing PAD2, and 10 were missing PAD4. The oldest person in each group was 68 and 90 years old, respectively. And among the 10 PAD4 knockouts, the earliest known death was a 75 year old. What that means, says Gilman, is people can live long lives without either of these enzymes. “We think we know the role PAD2 and PAD4 play in human disease, but we don’t know their normal function,” says Gilman. “Presumably it’s to do something healthy, but the fact is, they’re so poorly studied.”

Perhaps normal PAD enzymes are important to human health, and it’s possible these PAD-less Icelanders lived a long life of illness. “But they didn’t die as kids, and that’s reassuring to us,” Gilman says. “We’d love to go back and see what else is going on with these people.”

For example, if any of them has rheumatoid arthritis or lupus, he says, “that would throw our whole hypothesis into question.”

But if not, Gilman can feel better that knocking out bad PADs won’t have dire unintended consequences. “It’s a window on human biology that we never had before,” he says. “I’ve got a presentation Tuesday, and I’ve already changed the slide with the strikethrough in mice”—signifying that PAD knockout experiments haven’t cut short any mouse lives—“to show humans.”

DeCODE says it will do exactly what Gilman would like to do: follow up with study participants for fuller pictures of their health. It’s not all about life-threatening disease, either. For example, researchers found 17 people who lack one of two genes (LRIG3 and OTOP1) that, in mice, are crucial for normal formation of inner-ear structures. The paper noted that deCODE would like to recruit those people for full examinations, “especially for their sense of balance.”

As rich as the Iceland data are, they’re a drop in the bucket of data available now or coming soon. And a big problem, say those at … Next Page »

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  • Great article. The future of health is with the data, and with the patients. Make the data patient-centered and patient-owned if you want the broadest, deepest, fastest collaborations, learnings and results.