Out of Iceland

In his spacious corner office on deCode’s top floor, overlooking both the regional airport and one of Reykjavik’s largest churches, Kari Stefansson is a little tired. He’s just back, via an overnight flight, from a trip to New Jersey to talk with a pharmaceutical company. More and more these days, he’s having to think about the real-world challenges that companies face in getting drugs on the market and ensuring they succeed there.

Before prescribing deCode’s heart attack drug, for example, doctors will at least initially need to identify people with high-risk versions of the relevant gene. DeCode is in the early stages of developing a DNA-based diagnostic tool, but that approach is less than ideal, says Hákon Hákonarson, head of deCode’s clinical programs. That’s because multiple variants of the same gene and even nongenetic factors could all cause an elevation in heart attack risk. What’s more, gene tests are more expensive and laborious than tests that measure “biomarkers” such as proteins in the blood. One of the goals of the heart-attack-drug trial, then, is to find a biomarker that is easily measured and accurately identifies all the people who have increased vascular inflammation that puts them at risk for a heart attack.

Indeed, treating people with specific genetic risk factors is just one of the ways Stefansson envisions doctors using deCode’s drugs. “This is not black and white. This is not going to diminish the complexity of medicine; it’s going to increase it,” he says. In diseases like heart attack, numerous lifestyle and environmental factors closely intertwine with genetic factors. A patient with an average-risk variant of the gene, for example, might take the heart attack drug to compensate for diet or past medical history, Stefansson says, much as some patients with normal cholesterol levels now take cholesterol-lowering drugs to compensate for other risk factors. Proving the utility of such an approach will require still more human testing.

One of the biggest challenges deCode faces, however, lies beyond Iceland’s shores. Many geneticists wonder if deCode’s research findings in Icelanders, and the drugs developed based on those findings, will be relevant to other populations. Human geneticists have a long history of finding a gene for a particular common disease in one population, then failing to find links between that gene and the disease in another population. Nobody knows for sure why that is, but “it’s critical,” says Leena Peltonen, a medical-genetics professor at the University of Helsinki, Finland, and the University of California, Los Angeles. “If you think you’ve found a gene, you have to replicate the findings and prove it’s applicable to other populations,” she says.

It’s an argument that vexes Stefansson to no end. What’s important, he argues, is the ability to pinpoint the protein or pathway that has gone awry in a particular disease – and that’s what deCode’s gene hunting does. “You walk around here and you see that most people have two legs, two arms, and a head,” he says. “It’s outrageous to believe that the biological pathways involved in common diseases in Iceland are different than the biological pathways involved with the common diseases elsewhere.” Nonetheless, deCode is working to show that the heart attack gene is correlated with disease in an American population and has already done so in a British population.

In the end, deCode is yet another biotech company working on yet another drug for heart disease. But it is also one of a handful testing a fundamentally new approach to drug development. If it pans out – and it could begin to in just a few years, with the availability of deCode’s first drugs – millions of patients around the world could benefit from the genetic legacy of Benedikt Arnason and the thousands of other Icelandic volunteers.

Corie Lok is a TR associate editor.

Population Explosion
A sampling of other population-wide DNA banking and analysis projects

Institution

Project

Estonian Genome Project (Tartu, Estonia)

Analyzing Estonian blood samples to find genetic and environmental disease factors; goal of collecting 100,000 blood samples by 2007.

Galileo Genomics (St. Laurent, Qubec)

Using the DNA of a proposed 40,000 Qubcois to look for genes associated with asthma, arthritis, schizophrenia, Crohn’s disease, and other ailments

Oxagen (Abingdon, England)

Analyzing 40,000 blood samples, primarily from northern Europeans, to develop drugs for inflammatory diseases such as asthma and rheumatoid arthritis; expects to begin its first clinical trial next year

Rockefeller University (New York, NY)

Studying the DNA of 3,200 inhabitants of Kosrae, a Micronesian island, to uncover the genetics of obesity

U.K. Biobank (Manchester, England)

Collecting blood, urine, and medical information from up to 50,000 British people; will begin next year and track subjects’ health over the next 20-plus years to study the genetic and environmental factors of disease.