February 10, 2003 | George Orwell would be baffled by Toivo Sild. A taxi driver in Tartu, Estonia, Sild has willingly signed up to participate in a new Estonian database of personal medical information and DNA. Far from fearful of revealing his genetic heritage to the pharmaceutical industry, Sild is happy to play a tiny role in the drama of science. "I believe it will help people in the future," he says. "I am not worried. I cannot see how they can do any harm to me."
|Eye on Estonia
|Estonia is a former Soviet republic on the Baltic Sea. Since Russian troops left in 1994, the people of Estonia have been itching to rejoin the international community.
If a sufficient number of Sild's fellow Estonians feel the same way, they could steer the course of science in new directions. By filling out a database serving as the foundation of new genome-based diagnostic tests and drugs, the Estonians could also invade the turf of deCODE Genetics, the Icelandic company that mines the genealogical and medical data of that country.
The Estonian effort, formally known as the Estonian Genome Project, is coordinated through a foundation established by the Estonian government in 2001. "This project is directed into the common, global future," says Toomas Savi, chairman of the Estonian parliament.
That future involves learning from the past. The Estonians are hoping to not only leapfrog the Iceland project but also get a jump on genetic databases planned by larger nations, such as the United Kingdom, or even large medical practices, such as the Marshfield Clinic in Wisconsin, which aims to build a genetic repository from hundreds of thousands of patients.
From Wet Lab to IT Project
Estonia's secret weapon is its homegrown software and information technology. The nation's programmers cut their teeth on keeping hackers out of the banking system.
"This is an IT project," says Kalev Kask, CEO of EGeen International Inc., the Redwood City, Calif.-based company founded to sell the Estonian Genome Project data to drug companies. "It has a strong wet-lab component, but after a certain period of time it is going to be an IT project." If it works in Estonia, he says, it will be easy to clone the technology to start similar databases in other countries, perhaps with a little help from IBM Nordic's Life Sciences division, which is assisting EGeen with computer hardware and consulting services.
|Kicking IT Up, Estonian Style
|First, build a bunker. That's where the Estonian Genome Foundation's most important computer rests.
Although just getting off the ground, the Estonian Genome Project has already enlisted some key partners. Rick Myers, director of the Stanford University Genome Center, will be a key scientific advisor to EGeen. Prediction Sciences LLC, based in San Diego, Calif., will use EGeen to analyze Estonian patients for their responses to Celexa, an antidepressant. The study will attempt to develop a diagnostic test to predict an individual's response to antidepressants based on patterns of SNPs (single nucleotide polymorphisms). In January, the same two companies announced a similar deal to study Paxil, another antidepressant. That research will examine not only Estonian patients' SNPs but also how well they respond to the drug, potentially allowing doctors to predict which patients will benefit from Paxil before they swallow it.
First, though, Kask needs to enlist hundreds of thousands of Estonians — a big share of the nation's population of 1.4 million. Researchers testing a new drug may need to exclude or include patients with particular SNPs. But scientists will still need several thousand eligible participants for a medical study to be statistically meaningful. "It is a major undertaking to get these numbers of patients in a database," Kask says. "We expect to have those numbers for all major diseases." By the end of the project, a million people could be in the EGeen database.
Those sorts of numbers get Lon Cardon's attention. The quantitative geneticist at Oxford University and the Wellcome Trust Centre for Human Genetics has visited Estonia twice. He admits initially wondering if the country would be locked in a time warp, given the visible reminders of its 50 years under Soviet rule. But there is an upbeat, cooperative attitude among the people — and more sophistication than he expected. "They've got very modern labs," Cardon says.
For Cardon, the Estonian project is not so much a competitor to deCODE as a complementary effort. Cardon notes that deCODE was established to look for genes in a relatively homogenous population of Vikings and Celts — mining the "founder effect" of isolated populations.
Estonia is built on a different model, Cardon says: "Here is a population that is outbred and reflects the diversity of any other Western European country or even America." Cardon has already published preliminary data suggesting that Estonians could be perfectly representative of Caucasians in Europe or North America.
Cardon notes that deCODE's databases may be superior for mapping a particular trait or disease to a particular chromosome. But once that's done, he suggests, a database like the Estonian one — or any number of other large genetic repositories — has an advantage in locating a relevant biological target. "In the Estonian model, or outbred model," he says, "it is very difficult to find the right part of the chromosome that has your gene. But once you've found it, the Estonian approach is very powerful for finding the thing that's druggable."
Back to the Future
The reasons for Estonia's potentially lucrative genetic diversity are clear. Unlike remote Iceland, Estonia has long been a European stomping ground, ruled by a succession of Russian, Swedish, German, and Danish invaders who left their genetic heritage. Estonia's ethnic mix thus could be a major draw for pharmaceutical companies that want to find disease genes common to most Europeans.
|Your Ancestral Heritage Stored Here
|In 1985, the Swedes started a database built around the town of Västerbotten, one of the last areas of Europe to be settled.
"They are not without competition," says Klaus Lindpainter, head of Roche Genetics, part of Hoffmann-La Roche & Co. in Switzerland. He cites similar efforts in Sweden and Britain (see "Your Ancestral Heritage Stored Here," right). Still, Lindpainter sounds provisionally impressed. "It is critically important to create these databases," he says. "What these kinds of databases lend themselves very well to is to validate the hypothesis that a certain gene or gene variant is indeed connected in a causal [manner] to a disease."
But Lindpainter, a key Roche liaison with deCODE, does sound worried about the scope of the Estonian project, which aims to enroll a million patients. "I have some concerns about the mismatch between their overall goals and the funding they have been able to come up with," Lindpainter says. EGeen has raised only $4.5 million. Much will depend on the clinical databases that the Estonians are about to create. Even if the Estonians can assemble a DNA repository with 3,000 diabetics and 3,000 healthy "controls" (without the disease), Lindpainter and others in the industry would be interested in paying for the Estonian records only if they are exhaustive and detailed.
The Estonians dismiss any notion that their clinical records will not be up to Western standards. They'll be able to draw on electronic registries of cancer in Estonia, as well as paper-based information, all entered by Estonian primary care doctors. Indeed, the EGeen partisans say, Estonia is taking advantage of its technological history to attempt to construct a more searchable clinical record.
The country fell behind during the Soviet era, which could actually be a benefit. "There are no legacy information systems," says Jaak Vilo, EGeen's director of informatics. "You can plot a new page." People are comfortable with cell phones, for example, because there are not many land lines.
Vilo's previous job was at the European Bioinformatics Institute in Cambridge, England. He notes that the Estonia project will have several Oracle databases, some of which will be physically separate and not connected to the Internet. As with the deCODE effort, the security of the information is paramount.
Vilo notes that one of the largest differences between the Icelandic and Estonian projects lies in how patients are enrolled. "In Estonia there is informed consent, whereas Iceland chose presumed consent. Iceland presumed everybody would be willing to have their data analyzed [although they can opt out]. In Estonia, everybody has the right to say whether they want to participate."
That has already put many Estonians at ease, Vilo says. "In general, the support is quite good. People are already waiting to become donors. There are quite a few people asking when can they participate, and how."
Kari Stefansson, deCODE founder, president, and CEO, questions the eventual access to patients that the Estonians are promising. "They are putting together a little company that wants to compete with us," Stefansson says. "I hope they will be successful. But it sounds awfully silly of these good people in Estonia to believe the way to gain credibility is to say they have longitudinal access to people that we don't have. We are in a better position than anyone in the world to get access to people over long periods of time."
Despite Stefansson's bluster, privacy activists and physicians are worried enough about what happened in Iceland that they've begun to mobilize. The last time the World Medical Association (WMA) — representing 8 million physicians in 70 countries — got exercised about something, it issued the 1964 Helsinki Declaration, designed to protect the rights of patients in medical research.
Concerns over Patient Privacy
Last October, the WMA issued a declaration about genetic databases. According to James Appleyard, a retired British pediatrician who helped work out the language in the declaration, Icelandic doctors wanted to ensure that patients' rights were protected in the age of databases. "They were very worried about how the information was going to be used," Appleyard says.
To hear Appleyard tell it, the Icelandic government nearly convinced the population there was no risk to the country's population database. "For a while, the government was winning the hearts and minds of people," Appleyard says. "They conned the population, and only the medical association held out."
In Estonia, he says, it could prove difficult for physicians who answer to only the state. If the Estonian consent form is properly executed, Appleyard says, the country's project will be in harmony with the new WMA declaration. But in Eastern European countries, "doctors are used to working in a system where they're told what to do," he says. "I'm significantly concerned."
This could get messy: Andres Metspalu, professor of biotechnology at the University of Tartu, isolates the symbolic first DNA sample at the opening of EGeen facilities.
Perhaps he should get in touch with Andres Metspalu, an Estonian physician and professor of biotechnology at the University of Tartu. He conceived the Estonian project in 1999 and (like Stefansson in Iceland) envisioned it as something that could benefit his small country.
Metspalu, who also serves as EGeen's chief scientific officer, notes that the law authorizing the database passed overwhelmingly in the nation's parliament. The privately held project is set up to let the Estonian people — not private investors — profit if the Estonian data result in a big payoff. "The public is controlling the collection of samples and storage and keeping the confidential information," Metspalu says. "The private companies have to provide money to make all this happen. The benefits will be shared."
Metspalu is also keen to avoid antagonizing anyone. He points out that the imperial style of Stefansson may contribute to the controversy around deCODE. Metspalu adds that some of the uncertainties about deCODE's access to genetic data has been driven by doctors who were not part of the project. "Public relations is an important factor in a populationwide project," he says.
Metspalu has enlisted 80 Estonian physicians already and will be working with 800 by the time the project is in full swing. "This is unique that we can hire them for a reasonable price," says Metspalu, who received some of his medical training in the United States. "In the U.S., you can hardly get 'hello' out of your doctor if you pay only $17." EGeen is paying Estonian doctors $17 — or about 250 Estonian kroon — to enlist each patient.
Using primary care doctors in this fashion also reassures ordinary Estonians; if a medical advance would benefit someone with a similar genetic background, their physicians are required by law to close the loop and make a new diagnosis or treatment available. That is also in agreement with the new WMA declaration.
More practically, the Estonian primary care doctors will provide something to make a midlevel pharmaceutical executive swoon: long-term access to patients. Serving as intermediaries, the physicians will be able to contact a particular patient if his or her clinical history, genetic makeup, or demographic details are especially appropriate. That can be difficult to do in Western countries for a host of ethical, financial, and cultural reasons.
In Estonia, long-term access to patients over time could prove to be enticing to drug companies. "Scientists still have a positive image here," Metspalu says. "People are still altruistic. They are not after the money in every case."
EGeen, naturally, is after the money. The Estonian founders are half hoping it becomes their country's Nokia, the corporate embodiment of Finnish technical wizardry. Their other role model, somewhat surprisingly, is deCODE itself.
"DeCODE has shown that well-targeted genetics can lead quickly to drug targets," concedes EGeen CEO Kalev Kask. "They did it in the shortest time for any biotech company going from a concept to actual drug screening. DeCODE has had a major, positive socioeconomic impact in Iceland by, in essence, starting a whole new industry in the country, creating new opportunities, leading to the repatriation of numerous scientists, and enormously strengthening the global competitiveness of Iceland."
Although Estonia's population is five times larger than Iceland's, the two countries have many similarities. Geographically, both are compact enough to allow the rapid and economical collection of blood samples from which DNA can be extracted. And socially, both are sufficiently united to rally around a common goal.
But could EGeen's approach work in the United States? Kask, based in California, says he believes that Americans could be persuaded if EGeen's IT proves hack-proof. But in a nation with private medical insurance — and still without meaningful privacy legislation — genetic information will be surrendered with great reluctance for the time being. A case in point: In May of last year, workers at the Burlington Northern and Santa Fe Railway won a $2.2 million legal settlement after they learned the company had tested them without their knowledge for a possible genetic predisposition to carpal tunnel syndrome.
Other companies, to be sure, are betting that the public's fears about genetic testing are easing. Earlier this fall, Myriad Genetics Inc. of Salt Lake City launched a five-month, multimillion-dollar advertising campaign urging women at risk for breast or ovarian cancer to be tested.
Steven Nock, a privacy expert at the University of Virginia, believes it is likely that the United States will eventually have a national genetic database. "I would say it's inevitable," he says. "After 9/11, I am just astounded by how eager people seem to be to empower the federal government to monitor and control them more and more."
Which is not to say the U.S. government will be involved in a genetic database, Nock says. "I don't think Americans will swallow the federal government coming in and saying, 'You must do this.' That's not how it's going to happen," he says. "It will slowly evolve as the technology improves. At some point, genetic information will be as centrally stored and as commonly known as your credit record." In a sense, then, the Estonians could be striding into a future that might loom large in every nation's destiny.
COLLAGE ILLUSTRATION BY JASON HOWARD STATTS/THREEINABOX