On the surface, Iceland – a windy, almost barren island tucked just below the Arctic Circle – seems an unlikely place for a leading biotech company. But Icelandic scientists had recognized, long before the arrival of deCode, that their country is a good place for population-based medical research. For one thing, it has good medical record-keeping, and a self-contained population that doctors can easily reach through a high-quality, universal health-care system. DeCode was able to find Arnason, for example, because he was listed along with more than 8,000 other people in the national hospital’s registry of all the Icelanders who had had heart attacks before the age of 75 between 1981 and 2000.
The Icelandic population also has a general openness to medical research. About 110,000 Icelanders – more than half of the island’s adult population – have given their DNA to deCode, making genetics a sort of national science project. This cooperation, along with healthy investments in genetic data-mining software and DNA-reading technologies, has been instrumental in turning deCode into a gene-hunting powerhouse. In fact, Stefansson says, it has provided the company with enough data to tackle not just heart disease but 50 different ailments, ranging from asthma to diabetes to cancer. “This is a business in which critical mass is important, and they have achieved critical mass,” says David Altshuler, a population geneticist at Harvard Medical School.
To understand just how powerful deCode’s approach can be, consider the company’s discovery of the gene it believes contributed to Arnason’s heart attack. In theory, researchers could home in on such a gene by sequencing each heart attack patient’s entire genome and looking for frequently recurring gene variants, but with 30,000 genes and three billion letters of DNA to sift through per patient, that would be far too time consuming and expensive. So instead, deCode started by looking for a chromosome region likely to harbor the genetic culprit. The approach was fairly straightforward: deCode analyzed a limited number of key markers spread out along the chromosomes of heart attack victims and used them to identify chunks of chromosomes that were more highly shared than other chunks. “You can think of it as something rather magical, in the sense that you don’t need in advance to know what genes to look for or to have anything to tag the genes with,” says Augustine Kong, deCode’s lead statistical geneticist.
DeCode was aided in this process by another unique Icelandic resource: a plethora of publicly available genealogy records – church records, censuses dating back to the 1700s, even ancient stories describing the island’s settlement by Vikings in the ninth century. When launching a study like the one on heart attacks, says Kong, “We put the list [of patients with the disease] and the genealogy together, and we use that to identify the patients who are related.” Since people who are related share longer stretches of DNA than those who aren’t, Kong says, choosing clusters of relatives allows deCode to use only about 1,000 markers to find a suspect chromosome region, making the approach more cost effective. Conducting a similar hunt with unrelated patients’ DNA would require a million markers, Kong estimates.
Once deCode had used this approach to narrow its search to a section of chromosome 13, the researchers compared the heart attack patients with a group of people representing the general population. A more detailed analysis of the differences between the two groups enabled deCode to zoom in further, to an area small enough to contain just one or two genes.
Now tantalizingly close to their goal, the researchers turned to public gene databases to find out what genes had already been traced to that spot. When they saw that the stretch of DNA was home to a gene that codes for a protein involved in inflammation – a process implicated in heart disease – they knew they were onto something. Cardiologists believe that when “plaques” – fatty deposits in arterial walls – get inflamed, they are more likely to break away, form blood clots, and cause heart attacks. DeCode found that Icelanders like Arnason who have a specific variant of the chromosome-13 inflammation gene have double the normal risk of heart attack, perhaps because the variant is an overactive version of the gene and causes excessive inflammation. Blocking the protein encoded by the gene, deCode researchers reasoned, might keep the plaques from getting as inflamed, so they would remain safely attached to the arterial wall. In other words, the protein might make an excellent target for a drug.