2 July, 2009

A Schizophrenia Gene Debacle

The state of science journalism has been much lamented lately, with reporters criticized for describing research carelessly, in gee-whiz terms, and without proper context. For a perfect example of this, one need only look at the coverage produced by three studies published Wednesday in Nature on the genetic roots of schizophrenia.

The studies were conducted by three separate teams, numbering dozens of researchers around the world. Using cutting-edge genomic tools and techniques, they pored through the DNA of more than 50,000 people. They painstakingly searched for patterns, for essential genetic differences between people who can clearly apprehend reality, and those who can’t. They didn’t find them.

Instead they found 10,000 different genetic variants, each of them relatively rare and responsible for a 0.2% increase in disease risk. That percentage is somewhat misleading — it’s gene networks and interactions that matter, not single genes — but even in their totality, genes accounted for just 30% of total risk. The other 70% remains hidden. Schizophrenia and manic depression appear to have some degree of etiological overlap, and some of these genes proved to cluster in a region associated with immune function, though it’s impossible to draw any causal conclusions from either of these tendencies.

At best, these findings represent a fragmented, shadowy pinhole glimpse into the incredibly complex condition called schizophrenia. It may very well turn out to be an useful glimpse; only time will tell, and it might be decades before we know. In the meantime, there are many more aspects of the disease to be studied and triangulated: environmental influences, epigentic regulation, chromosome topography, bacterial imbalances. And on and on.

From a journalistic perspective, there are two possible stories here. First, the straight story: schizophrenia is extraordinarily complicated, and genetics can’t now explain it in any useful way. And two, the contextual angle: for years, the public has expected, and scientists have sometimes promised, that genetics would illuminate this disease — and it failed, just as it has for nearly every disease.

(Useful perspective: search Eurekalert for "schizophrenia" and "gene.")

When these studies showed up in my pre-embargo pipeline, I made a quick note of them — see above — and moved on. I’m already reporting for a long-form article on the disappointment of genomics, and this didn’t feel like a Wired daily news story. It would require at least a half-dozen interviews, and ultimately produce a narrative preaching caution, tempered expectations and patience. Instead I chose to write about an interesting finding on salamander limb regeneration, and waited for the inevitable onslaught of “Schizophrenia! Unlocked!” stories.

And they were inevitable, pure and simple. Nature made sure of it: they announced their findings in a press conference held at the World Conference on Science Journalism. Their press package contained five different press releases, full of glowing language — “breakthrough,” “landmark,” “major step forward.” Given that Nature recently published a series of essays on the problems of science journalism — that it’s uncritical, depends on press releases, etc. etc. — their behavior could be seen as schizophrenic.

On the stories came, pulling straight from the PR and sailing on hype. “Schizophrenia and manic depression: new link that could help millions.” “A huge international study has discovered the first common genetic mutations involved in schizophrenia." "Common variations in genes may underlie schizophrenia.” “Possible Gene Regions for Schizophrenia Located." "Unlocked: the secrets of schizophrenia.”

More balanced were Science News, the Associated Press and BBC. But the only reporter to get the story right was Nicholas Wade of the New York Times. Not long ago, Wade could be relied upon for reductionist coverage of genetic links to disease. (On the subject of genes and schizophrenia, here’s Wade in July 2002: “Researchers hope they are now starting to close in on some of the genes that go awry in schizophrenia.” In December 2002: “The long search for a gene that helps cause schizophrenia may at last be bearing fruit after many false starts and disappointments, scientists are reporting.” In April 2006: “Researchers have made progress in understanding how a variant gene linked to schizophrenia may exert its influence in the brain.”)

But Wade, who arrived at the Times in 1981, seems to have finally lost patience with the “gene-linked-to-(fill in the blank)” narrative that he and so many others told, and were sold, for so long. In April, he did provided excellent coverage of a series of New England Journal of Medicine articles debating the usefulness of assorted genome-scanning methods. Underlying that debate was the failure of genome association studies to provide useful insights into disease. Appropriately enough, schizophrenia was used to illustrate the problems:

Dr. Goldstein argues that the genetic burden of common diseases must be mostly carried by large numbers of rare variants. In this theory, schizophrenia, say, would be caused by combinations of 1,000 rare genetic variants, not of 10 common genetic variants.
This would be bleak news for those who argue that the common variants detected so far, even if they explain only a small percentage of the risk, will nonetheless identify the biological pathways through which a disease emerges, and hence point to drugs that may correct the errant pathways. If hundreds of rare variants are involved in a disease, they may implicate too much of the body’s biochemistry to be useful.
“In pointing at everything,” Dr. Goldstein writes in the journal, “genetics would point at nothing.”

Goldstein’s position is perhaps pessimistic. Pathways might still be discovered, with genome-wide scans guiding the first few steps. But that’s a far cry from from “Unlocked: the secrets of schizophrenia.” It’s a far cry from what was expected from the billions of dollars poured into disease genetics. And in a blog post published yesterday, Wade gets it right.

"Who is helped by dressing up a severely disappointing setback as a ‘major step forward?" he writes. He calls the findings a landmark — ”the kind that says you have 10,000 miles yet to go” — and says they represent not a breakthrough but “a historic defeat, a Pearl Harbor of schizophrenia research.”

My only disagreement is with his metaphor. Pearl Harbor was a surprise, and provoked the United States into a war that it eventually won. The better World War II analogy may be the Battle of Dunkirk: the British army stormed the shores of France, was soundly beaten, and fled back across the English Channel under the cover of night, their nation in need of rescue.