Translating Iceland's Genes into Medicine

Reclined in a chair at a clinic outside Reykjavik, Iceland, Benedikt Arnason tells the story of the day, 11 years ago, that he had a heart attack. In a deep, rich voice cultivated by years as a stage actor and director with Iceland’s national theater, he describes the chest pain that gripped him after one performance. He got to the hospital just in time. “The last thing I remember is the doctor asking me about my medical history,” Arnason says. When he woke up, he found burn marks across his chest. Doctors had shocked him back to life. Now Arnason comes every two weeks to this suburban clinic, so doctors can monitor his progress as a participant in a trial of a new experimental drug – one that physicians hope might spare him from having a second, and possibly deadly, heart attack.

If it works, Arnason will have a whole nation to thank, as well as the vision of one of the world’s most ambitious biotech companies. Three years after Arnason had his heart attack, deCode Genetics, which is headquartered in a modern building just a 10-minute drive away from the clinic, embarked on a nationwide hunt for the genes that underlie heart disease, diabetes, asthma, and other common ailments. The company was betting that if it could identify those genes by rifling through this tiny country’s genetic heritage, it would gain critical clues about how to fight the diseases they cause. Eight years later, the tests on Arnason and other Icelanders suffering from heart problems are allowing the company to take the final steps in proving that its bet was correct.

The tests’ success would mean not only deCode’s first marketable medicine and a better heart attack drug but possibly the advent of a new generation of treatments based on a mastery of genetics. “We have been able to make more sense out of the genetics of common diseases than I think any other group in the world,” says deCode’s founder and CEO, Kari Stefansson. That has led to a handful of drugs, including one for peripheral artery disease, that are nearing the end of the development pipeline right behind the heart attack medication, which could be on the market before the end of the decade. DeCode is also working with pharmaceutical giants Roche and Merck to develop more drug candidates, even as it beefs up its internal drug-development capabilities.

There are, of course, no guarantees that deCode’s first drugs will make it through human tests. But if they do, the repercussions could be felt far beyond this remote North Atlantic island. If Stefansson and his team succeed, they will be providing not only hope for Arnason and countless other sufferers of common diseases but also real-world evidence of genomics’ power to transform medicine.

Population Power

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.

Such scientific understanding is still a huge step away from having a drug in hand, though. The deCode researchers still needed to find a compound that could safely hit the target. But luck was on their side. During the 1980s and ’90s, pharmaceutical companies had developed drugs to inhibit precisely this same protein, which they believed to be involved in asthma and other inflammatory diseases. DeCode decided to license a compound made by German drugmaker Bayer, says Mark Gurney, deCode’s head of drug discovery. The drug had proved safe and had already made it to the last stage of human trials before Bayer shelved it because it wasn’t much more effective than existing asthma drugs. Since deCode didn’t have to make a new drug from scratch, it saved itself five to seven years of work, says Gurney.

So far, the company’s scientists have discovered 15 drug targets – proteins implicated in common diseases such as osteoporosis and schizophrenia. That’s more “than any other individual research group,” says James Weber, director of the Center for Medical Genetics at the nonprofit Marshfield Clinic Research Foundation in Marshfield, WI. “Most other labs in universities don’t have the scale to crank the genes out like deCode.”

Not only is the quantity of the drug targets they identify unusual, say deCode researchers, but so is their quality. Traditional methods of uncovering targets – studying lab animals or cells in petri dishes – often result in drug candidates that aren’t very effective, says Gurney. “DeCode has unique assets that allow one to do more powerful and vastly more successful genetics studies of common, complex diseases,” says Klaus Lindpaintner, head of the Roche Center for Medical Genomics. “This helps us feel more confident that the targets are more relevant to disease, and medicine derived against them will actually work.”

The result: while traditional pharmaceutical companies will pursue half a dozen or more different targets in parallel for one disease, deCode places its bets on just one or two. That means less work, time, and money devoted to research on targets that turn out to be irrelevant, says Gurney.

That efficiency is starting to pay off. In addition to the heart-attack-drug clinical trials already under way, deCode plans to begin human trials of three more drugs by next year. Two of those trials will involve drugs that, like the heart attack drug, were originally developed by other companies for other uses. But early next year, deCode will begin human tests of its first drug made from scratch: a treatment for peripheral arterial disease, a narrowing of the arteries in the limbs. DeCode is also working on six other drug targets in partnership with Roche and Merck. All in all, what eight years ago started out as a quirky, off-the-beaten-path gene-hunting startup is starting to look a lot like a real drug company.

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.