Mapping Estonia
Estonia takes on an ambitious project to outline the country's genome

By Karin Palmquist

Plans to map the genetic makeup of countries are usually controversial. Mention leasing this information to commercial interests, and the debate tends to get really heated. In Estonia, such a proposal has met less opposition than one might expect. The Estonian parliament recently approved a plan to map the genome of around seventy per cent of Estonia's 1.4 million citizens in order to create the largest gene bank in the world. The Estonian Genome Project Foundation, tasked with setting up the gene bank, was established in March of this year. The project now depends on two things: funding and participation. The money, between 80 and 100 million USD, will have to come from abroad. 

Only Iceland has a project similar to the Estonian Genome Project. Three years ago, Icelandic biotech company DeCode started a project mapping the country's genome, together with Swiss pharmaceutical giant Hoffman La Roche. The Icelandic project relies on the automatic inclusion of all Icelanders in the project, and Icelanders wishing not to participate must apply to be excluded. 

When the minds behind the Estonian Genome Project, Dr. Jaanus Pikani and Dr. Andres Metspalu, started discussing the idea of setting up an Estonian gene bank, the conversation often circled around how to avoid the mistakes of others. Participation, they decided, would have to be voluntary. Chairman of foundation Dr. Pikani believes this difference is very important. "While the Icelandic project starts from a point of presumed consent, we will rely on informed consent," he says. 

Another important difference is the ownership of the data. While the Icelandic gene bank belongs to DeCode, the Estonian database will belong to the Estonian people. Biotech companies will then pay for access to the database on a long-term lease agreement basis. 

As always when public money is mixed with private money, there is a conflict of interests. While the interest of the Estonian state is to keep the information generated by the project public, commercial interests will demand exclusivity in return for their investments. Dr. Pikani thinks the foundation has found the golden middle way by keeping the database public, but restricting the access. 

Another vital difference, not just from a scientific point of view, but also from an economic perspective, is the methods used to set up the database. A few years ago, when DeCode started mapping the Icelandic genome, such projects required an isolated, homogenous population. Iceland's quarter million population, all descendants from the same few thousand Norse eighth and ninth century immigrants, was regarded as the ideal population for such a project. Advancing technologies however have made it possible to use a more diverse group. 

The method, mapping snips of genetic markers, rather than the markers themselves, requires less data. It also concentrates on the 0.1 per cent of our genome that differs from person to person, the part where the potentially harmful genes are. Scientific reports in February stated that people have around 30,000 genes, a lot less than initially thought. Of these genes, around 10,000 genes have been pinpointed. 

Less data means great reductions in the cost of mapping a large population. Dr. Pikani expects to be able to map the country's genome at a price of around 15 USD per patient for the doctor's visit, and around 60 USD per patient for the actual mapping. 

The tests will be accompanied with by a questionnaire, to try to pin down the relations between genome and environment. 

The law enabling the Estonian genome project passed through parliament in less than ten months. The state controls the foundation's board with three representatives from government and three representatives from parliament, to the science community's three representatives. The Estonian government, through the Estonian Genome Project Foundation, will create the framework for the gene bank, and cover the costs of setting up the commercial entity and establishing a sick fund. 

The first task of the foundation will be to find out the feasibility of the project, and to explain the potential benefits to the Estonian people. The Estonian Genome Project Foundation can only inform Estonians of the project, and it cannot encourage participation. Still, Dr. Pikani is positive the Estonian people will indeed take part in the project. An initial test study carried out last year showed an encouraging participation rate of 95 per cent. "We asked patients at the hospital here in Tartu to participate," he says. "The only thing is people are usually in the hospital because they're not feeling well. The patients who declined to participate did so because they were simply too sick to stay the extra hour it takes to do the test and fill out the questionnaire."

Next task will be to establish a commercial entity, which will accept investments in return for exclusive, long-term contracts to access the foundation's database. Investments in the biotech field are usually high-risk investments, appealing to a limited group of investors. These hit-or-miss investments can bring great returns if a project turns out to be a success, and no returns in a worst-case scenario. Dr. Pikani believes investments will either come from technology investors investing in intellectual capital, or from smart venture capital investors. Interest from foreign investors has been positive, Dr. Pikani says, though he declines to comment on who these investors might be. 

Tailored prescriptions 
It will be the task of the commercial entity to decide which diseases to target, but Dr. Pikani hopes the Estonian project will help find the causing genes of some common diseases. A modern, developed nation like Estonia is optimal for finding the genes causing several diseases that plague the developed world. The top three causes of death in Estonia are cardiovascular diseases, cancer and trauma. "Most of these diseases are universal," Dr. Pikani says. "They affect people of all races and backgrounds." 

One of the great advantages with gene-based medicines is that they can be tailored to a patient's needs. Which drugs are prescribed will depend less on the patient's symptoms, than on his or her genetic predisposition for the disease in question. Medications will be prescribed with greater precision, and the risk of adverse reactions greatly reduced. 

The first round of mapping will be a general one, to narrow down groups in the population with certain genes for further study. "It is important to remember that finding the causing gene does not mean finding a cure. This is not genetic testing," Dr. Andres Metspalu, head of the biotechnology department at Tartu University, and one of the minds behind the gene bank plan, points out. "It's not testing for particular diseases, but an attempt to map the landscape. We want to test for risk. In 1997, 104,000 people died in the United States from taking the wrong drugs. We want to reduce this risk by finding out who might not respond well to a certain drug. Before prescribing a drug, a physician must type in certain markers. In that way drugs get individualized, taking into consideration such factors as the patient's metabolism." 

There are substantial savings to be made from prescribing the right drug from the start. In fact, these savings could finance a project like the Estonian genome project, Dr. Metspalu says. 

Controversy surrounding the project
The project is not without critics. While some worry what could happen if the information got into the wrong hands, others question the appropriateness of spending money on such a project before improving the national health care system. 

Dr. Pikani waves off both concerns. Sophisticated encryption and strict laws will ensure the information is not used in ways other than those intended. All data will be coded using a sixteen-digit code and the coding keys of any participants opting out of the project will be destroyed. 

In Estonia, where health care is provided by the state, the potential damage that could be done if the information got into the hands of for example insurance companies is less than it would be in countries with no public health care, where insurance companies routinely take out higher premiums for high-risk patients. 

As far as what should be prioritized, health care spending or investments in a project that could greatly benefit the country economically, Dr. Pikani picks the latter. Economic growth will lead to better health care, he says. "We were wondering what could be Estonia's Nokia. Investors don't want to invest in traditional fields. High tech and IT is more attractive to the investor. We were looking for something that would give us a competitive position, economically speaking. This could do for Estonia what Nokia did for Finland."

The private sector is following the project very closely. "The project could have a tremendous impact on Estonia," Dr. Reet Volkmann, General Manager of Pfizer Estonia, says. "Since it is still in the early stages, we don't have any cooperation with them, but we are intrigued by the project."

Why Estonia?
If the base requirement for gene mapping no longer is an isolated, homogenous population, and this kind of research could be done virtually anywhere, then what are the reasons for doing it in Estonia? 

The greatest advantage with Estonia, Dr. Pikani says is that the country is "small and dynamic." 

Then there is the cost level. "People's time is so much cheaper here," he says. "Estonia has a very competitive cost level, and the cost of setting up such a database here is lower than it would be elsewhere. The average salary of a general practitioner is between 300 and 400 dollars a month. We need to map the genome of one million citizens. Estonian general practitioners will see patients at between ten and fifteen dollars per patient. In the United States you can't walk in the door for less than ten dollars. Here the whole visit will cost ten dollars." 

If there is one legacy the Soviet Union left behind, it is a highly educated workforce. "We have highly achieved scientists. The results here are trustworthy. This really couldn't be done better somewhere else," Dr. Metspalu underlines.

The inheritance from the Soviet Union is evident in other ways as well. "When people are hungry they are willing to work harder. People here are ready to sacrifice," Dr. Pikani says. "One morning in 1992, we woke up and we were each good for 20 Deutsche Mark. In ten years, we've seen quite a tremendous change. And the basis of that success is that we had to do something. There is a readiness here to do something extraordinary." 

Side effects for the public and Estonian academia 
Besides the obvious positive effects the gene bank could have on the Estonian economy, it could bring other advantages for the Estonian people. Participants would get a thorough medical examination, and predisposition for certain diseases could be discovered and tracked. "Better records mean better care afterwards," Dr. Pikani says. "We'll be able to predict the risks of certain patients developing certain conditions." 

Another nice side effect of the project is that it could repatriate Estonian scientists now working abroad, and reverse recent years' trend of brain drain in the scientific fields. 

Access to the database will be free for academics, and any intellectual property created from this access will belong to the foundation. The biotechnology department at Tartu University, though growing, is still rather small. Eighty students per year are accepted to the department. Besides biotech, the 12,000 student university has strong departments for material technology, environmental technology and, together with the Technical University in Tallinn, it is one of the country's two leading schools for information technology. 

The Science Park at Tartu University has generated spin-off companies in technology fields, and it is the hope of vice rector Dr. Hele Everaus that the genome project will generate even more. The science park works as an incubation center, providing its start-ups with advice, legal help, patent applications, research and expertise. "It's important for Estonia to find a niche in Europe," Dr. Everaus says. "There are enormous possibilities for Estonia in biotechnology and medical technology. And this project provides a big possibility for Tartu Univestity as well. Biotech companies and pharmaceutical companies using our research facilities would really benefit the university." 

"One good idea can make the world a better place. This is a great place to realize that idea. We have the education, the laws to protect intellectual property, all the conditions for successful scientific research projects," Dr. Volkmann of Pfizer says.

But Estonia has to move quickly. Several European countries have expressed interest in creating gene banks of their own, the closest one being Latvia. Some competition is healthy, even necessary, Dr. Metspalu says, since reference populations are needed to verify the findings. But the really big financial gains will come to the groundbreakers in the field. Because, as Dr. Metspalu says, "you can only discover a gene once."