A Big Fish in a Small Gene Pool

By MARY WILLIAMS WALSH

June 5, 1998 12 AM PT

TIMES STAFF WRITER

REYKJAVIK, Iceland — The warrior-priests who brought Christianity to this remote island a millennium ago must have been visionaries, at least of the sort who could foresee any kind of a future in such forbidding fields of the Lord. But it’s a stretch to say they might have known that the exhaustive birth and death records they began to compile on the faithful might one day be the makings of a multimillion-dollar biotechnology business.

Yet such are the vagaries of DNA prospecting here in the North Atlantic. A rare combination of factors in Iceland--a national fascination with genealogy, a highly homogeneous population, a past fraught with disease and disaster, and one man’s entrepreneurial spirit--is transforming this small land into a unique and potentially lucrative font of genetic learning.

“We have an opportunity to do the best human genetics done anywhere in the world,” said Kari Stefansson, a former Harvard Medical School professor turned “DNA prospector.”

His words may sound outlandish, perhaps, but they are matched by an outsized dream, one of gathering the entire genealogy of his homeland and cross-referencing it with Iceland’s excellent collection of medical records dating to 1915.

To this one-of-a-kind database would be added the DNA samples of countless Icelandic donors, plus the information gleaned from an extraordinary collection of tissue samples, preserved in wax blocks, of every Icelander who has been autopsied since the 1930s.

The purpose: to identify the precise genetic causes of the 3,000 to 4,000 diseases that are believed to be hereditary. Armed with that information, pharmaceutical companies and others presumably will have an easier time finding treatments, diagnostic tests and preventive methods.

A population such as Iceland’s is extremely attractive to genetics researchers, who will travel the Earth--increasingly, financed by biotechnology companies--to study secluded peoples with high incidence of disease. The reason: Disease-causing genes are believed to stand out more clearly against a uniform background than against one complicated by ethnic mixing of the gene pool.

But no one has attempted anything on the scale of Stefansson’s project, for which the neuropathologist gave up a tenured professorship at Harvard Medical School two years ago.

“I have no regrets about leaving Harvard to do this,” said Stefansson, who was trying to determine the genetic causes of multiple sclerosis before returning to Iceland.

“We are creating new knowledge,” said Stefansson, adding that the database will be encoded for privacy. “We are building a new industry in Iceland.”

Despite Stefansson’s assurances of privacy, his project has set alarm bells clanging here. Some Icelanders fear that family health secrets could leak out via his database and somehow be used against them, perhaps by private insurers.

In addition, some ethicists have begun alleging that DNA prospectors like Stefansson are committing a new offense they call “bio-piracy,” exploiting remote peoples for their precious DNA, which could lead to big-money drug patents or even a Nobel prize.

Drug Giant Is Enlisted; Analysts Take Notice

But such concerns have not deterred Stefansson, who--with $12 million in venture capital in his bank account two years ago--founded a company, deCODE Genetics Inc., and equipped a research lab that eclipses anything previously available at Iceland’s best hospitals. He has hired a staff of nearly 200 and signed a multimillion-dollar contract with the Swiss drug giant Hoffmann-La Roche to seek the genes that are believed to cause 12 diseases.

In the process, he has caught the eye of biotechnology securities analysts, who expect his start-up firm to go public within 12 months.

“It’s a company that’s come a long way in a short period of time,” said Nick Woolf, an analyst at the London investment banking house of BA Robertson Stephens International. He called Stefansson’s arguments in favor of Iceland’s special features “compelling.”

Stefansson is looking for other big partners, but in the meantime, the Hoffmann-La Roche agreement has brought credibility to his project, as well as the needed funding to study such well-known scourges as schizophrenia, Alzheimer’s disease, adult-onset diabetes and stroke.

Happily for Iceland, the terms stipulate that if Stefansson’s project gives rise to any treatments, Icelanders will get them free.

Although neither Stefansson nor Hoffmann-La Roche will go into the details of the transaction, both parties said it will be worth $200 million to $300 million over five years, plus royalties, if Stefansson’s hunch is right that Iceland’s unrivaled attributes make it an irresistibly fertile hunting ground for disease-causing genes. The total of all such deals between pharmaceutical companies and genomics firms has been estimated at about $2.4 billion as of last November.

“We were very successful in convincing these guys that we’ve got a very valuable asset,” Stefansson said. “And I’m absolutely hellbent on seeing to it that they’re not disappointed.”

Iceland a Fertile Spot for Genetic Research

So just what is this asset? Why would Hoffmann-La Roche, and the other health-based firms considering partnerships with Stefansson, want to sink their millions into this treeless and volcano-studded island sitting astride a fault line in the North Atlantic?

The answer has to do with Iceland’s daunting history of disease, isolation and natural disaster. However awful these may have been to live through, they turn out to be advantages when it comes to genetic research.

Few non-Icelanders have had the stomach to move here since the Vikings first settled the island in 874. Since then, the indigenous population has twice been harshly “culled”: A bubonic plague outbreak in the 15th century wiped out more than half the population, and a volcanic eruption in the 18th century caused widespread famine.

These catastrophes severely reduced the number of people for Icelanders to choose as their mates, leaving today’s population of 270,000 nearly homogeneous.

“If you choose two [Icelanders] in the 20th century, it’s very likely that they are distantly related,” said Hakon Gudbjartsson, chief computer engineer for deCODE. “If you go back to the 15th century, you can more or less connect everybody to the same ancestors.”

Already, geneticists have scoured other odd corners of the globe, studying small, inbred populations and the diseases that afflict them. The South Atlantic islanders of Tristan da Cunha have been examined for the clues they may offer to asthma researchers, for example, while the Pima Indians of Arizona have been studied for diabetes. In the most well-known example, the genetic secrets of Huntington’s disease were revealed through research on an isolated community in Venezuela.

What makes Iceland superior even to these geneticist-friendly outbacks, said Hoffmann-La Roche research department spokesman Eckart Gwinner, is its passion for genealogy and public record-keeping.

“You have, in Australia and in underdeveloped countries, populations that are very homogeneous,” he said. “But with them, you don’t have the data. Iceland has a unique situation concerning the homogeneity of the population and the connection with information coming from blood banks and hospitals and so forth.”

As Stefansson tells it, his homeland’s public fascination with social data collection can be traced to the 9th century, when Iceland established Europe’s first parliamentary democracy, complete with courts, laws and penalties. One thing this early political system didn’t have was law enforcement, so the earliest Icelanders had to rely on their extended families to carry out any sentences the courts handed down.

“So, it was terribly important to know who was related to you,” Stefansson said.

When the Roman Catholic proselytizers arrived in their open boats, they improved upon this record-keeping tendency by maintaining complete birth, baptism, marriage and death registries at the parish level. The Lutherans kept up the habit after the Protestant Reformation, when theirs became the state religion.

These church registries are the building blocks of all genealogical research in Iceland, along with such modern-day aids as census tracts, daily genealogy columns in the newspapers and the huge supply of genealogy how-to books and software available here.

Gudbjartsson, who is overseeing the creation of deCODE’s database, said that within three years the company will have acquired and computerized all such Icelandic family data--insofar as it exists--going back to the 17th century.

While his department does that, deCODE’s laboratory researchers have begun receiving blood samples from Icelandic medical patients and extracting the DNA they contain.

The DNA, which can be preserved indefinitely, will be cross-indexed against the genealogy database. First, however, both the DNA and the family trees must be encrypted off-premises by a government Data Protection Commission to protect the participants’ privacy.

Stefansson, who says DNA-donor anonymity is the key to maintaining Icelanders’ goodwill and cooperation, has warned participants that they won’t get individual diagnoses or medical advice in exchange for their blood samples.

“We’re discovering the qualities of the group, not of the individual,” he said.

Still, Stefansson’s activities and the deeper issues they raise have shaken up this mono-industrial nation, where the main scientific preoccupation up until now has been the careful management of fish stocks.

“It was like dropping a bomb” when deCODE appeared on the scene, said Alfred Arnason, chief geneticist at the Reykjavik blood bank.

Arnason, who is closely watching Stefansson’s project, said he can see the value in acquiring, cross-referencing and encrypting Iceland’s genealogical and medical data. What he cannot understand is how Stefansson can sell this information to companies like Hoffmann-La Roche without making it proprietary.

And if Stefansson is allowed to copyright his database, Arnason said, what will become of the other scientists who now freely use Iceland’s national health records for research, lower in profile and smaller in scope though their work may be? What will happen if Stefansson’s industrial clients refrain from publishing their findings until they can secure patent rights?

“That would hinder science, not enhance it,” Arnason said. “If he wants to chase genes, that’s all right. Everybody is chasing genes nowadays. But I’m in favor of everybody having the same right to do their studies and not to monopolize data.”

Arnason and about 200 other Icelandic scientists recently sent an open letter to the government in Reykjavik urging a go-slow approach on regulating DNA prospecting.

Stefansson, for his part, said he understands the misgivings about the increasing role of private industry in medical research. But he argued that human genetics research has become so costly that it can’t progress without the big grants and enormous pools of shared data that only the private sector can provide.

“The classical university labs are simply too small to do advanced research anymore,” he said, recalling his own work on multiple sclerosis at Harvard. “The only way I saw it financially possible [to continue] would be to establish a company.”

And, despite the unease Stefansson has aroused in the Icelandic scientific community, the public here seems well disposed toward his project--to say nothing of the jobs, fame and economic diversification it could mean for Iceland.

“I view this agreement [between deCODE and Hoffmann-La Roche] as a huge step toward securing high-technology industries an important role in the Icelandic economy,” Iceland’s prime minister, David Oddsson, said in February when the deal was announced. Oddsson added that “the government of Iceland will do its best” to create a good working environment for Stefansson’s research.

And after a recent television documentary about deCODE aired here, 70% of the callers to the station’s opinion hotline said they likewise supported Stefansson’s work.

Team Looks Back at Several Generations

In his lab, where panoramic windows overlook an otherworldly landscape of treeless mountains rising out of the sea, staff geneticist Hreinn Stefansson--no relation, or at least not a close one, to Kari--demonstrated the way deCODE hopes to use Iceland’s special qualities to identify genes.

First, he called up the coded names of several generations of sick Icelanders on a computer screen.

“This is a great tool for us, like an overview of the disease,” he said, scrolling through a lengthy family tree in which the sick people appear as black dots, the well people as white dots.

Once a researcher like Hreinn Stefansson has found an extended family that looks promising, he or she takes the encrypted names back to the government Data Protection Commission, which decodes them and contacts the patients’ physicians, asking for blood samples from both patients and disease-free relatives. Although Kari Stefansson and his staff are not involved in this step, the bio-entrepreneur said he has heard of only two families so far that said no when approached.

The Data Protection Commission then reencrypts the blood samples and returns them to deCODE, which begins the process of extracting the DNA. Next, scanners analyze the DNA, comparing the genetic patterns of the sick and the disease-free relatives. These findings are sent to deCODE’s statistical department, which uses them to calculate the probabilities of damaged genes occurring in certain positions on the chromosomes.

Using these methods, Kari Stefansson said, his staff has so far been able to “map” some of the genes involved in multiple sclerosis; psoriasis; preeclampsia, a condition marked by dangerously high blood pressure during pregnancy; and familial essential tremor, a condition which causes uncontrollable trembling in the elderly. “Mapping” a gene means narrowing the number of places where it might appear on a chromosome from about 3 million to a couple hundred thousand.

Much more work must be done before the individual genes can be identified, a complicated process in diseases where more than one gene is involved. But Hreinn Stefansson said the speed with which deCODE was able to identify the location, or “locus,” of the familial essential tremor gene showed how powerful deCODE’s methods are: The search took the lab less than three months.

“We were very happy,” he said, “because many people had been working on this disease for years, and they hadn’t been able to find the locus.”