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occur if parents were allowed to choose thesex of their children. An absence of bias isnot the only reason: “PGD is so inconve-nient and so expensive that it will have noimpact on the overall distribution of sexratios anywhere in the world. It is not apractical technique for large-scale sexselection,” Caplan said. However, othercountries, where cultural and social tradi-tions dictate that sons are more valuablethan daughters, might not be so unbiased.The possibility of sex selection has there-fore raised the question of whether it ishypocritical to advocate it in the West,while condemning countries such as Indiaand China for essentially doing the samething, although by more drastic means. “Tome, those are larger social issues that arenot best dealt with by trying to regulate thetechnology itself,” Stock said. Dahl agreesthat this question must be left to each coun-try to deal with: “We cannot punish thepeople of our countries for the crimes com-mitted in another country.” Baldwin said,“the issue of what kind of example we set inthe area of sex selection is an importantone, though, equally, we in the ‘west’ shouldnot arrogantly assume that our policies areright for everyone. There is a delicate balanceto be struck in this area.”

There are fears that PGD will eventuallybe used to select for non-medical traits suchas intelligence, appearance and physicalprowess, which concerns both advocates andopponents. Referring to his surveys in the UKand Germany, Dahl noted that this shouldnot be overestimated. Of the small propor-tion of people who would use sex selection,an even smaller subset would use geneticdiagnosis techniques to select for other traits.“I think the reference to the slippery slopepresupposes something that’s simply notright,” he said. Hughes also believes thatwidespread selection of non-medical traits isunlikely, but for different reasons. “No one intheir right mind would go through IVF tech-nology if they didn’t have to. You’re not goingto do this for a trivial reason.” But even if thepractice does not become widespread, Stockadmitted, “I think that as we move forward inthis realm, it is a certainty that everybody’ssensitivities are going to be stepped upon bysomeone.” He stressed, however, that a few

troublesome cases do not necessarily warrantstrict regulations. Hughes agreed, “You canhave a Doomsday kind of attitude about it oryou can say let’s move forward in a responsi-ble careful way, and evaluate and make surethat it’s used properly.”

Because PGD is a new technology inreproductive medicine, there are addi-tional concerns about its safety and

about its legal and commercial implications.PGD results are tracked in the UK, but pri-vate clinics in the USA are under no obliga-tion to record their successes and failures.Across Europe, the European Society ofHuman Reproduction and Embryology(ESHRE) has created a PGD consortium tomonitor its use and to produce guidelinesand recommendations. But participation inthe ESHRE’s assessment is purely voluntary.In the meantime, mistakes in PGD have beenpublicized, with at least one fetus beingfound to contain the mutated gene that it wasoriginally selected against; in a litigiouscountry like the USA, the legal repercussionscould be extensive. “I think you will movetowards various kinds of wrongful birth suitsand things of that sort,” Stock said, but cau-tioned that such lawsuits will be as likelyoutside the USA as within. Caplan worriesmore about what social and economic pres-sures will do to the future of PGD and the

selection of non-medical traits. “Those pres-sures combined with aggressive marketingand advertising are what I worry about themost with respect to future genetic testing ofgametes and embryos,” he admitted.

Given the difficulties involved in IVF,PGD will probably never become a stan-dard service for prospective parents but willbe reserved for individual cases in the mostneed. Hughes even hopes that one day itwill be obsolete. As he pointed out, 11 yearsago when PGD was first used, children withCF never had to worry about passing downthe gene—they did not live long enough tohave children. But now, modern pharma-ceuticals and medical treatments mean thatthose suffering from CF live much longer.“Today’s devastating diseases are hopefullytomorrow’s cures and that’s where we needto be focused,” he said. In the meantime,“it’s helping couples build healthy families,and what could be better than that?”

Caroline Hadleydoi:10.1038/sj.embor.7400023

Pioneers in medicineSmall countries are taking big steps towards improved genetics-based

research and health care with the creation of population databanks

Sometimes revolutions begin in themost unlikely of places. Iceland is apiece of volcanic rock in the middle of

the Atlantic Ocean, inhabited by less than300,000 people. Estonia is now the eastern-most outpost of the European Union, afteran overwhelming majority of its peoplevoted on 14 September to join the EU. Thecountry only gained its independence fromthe former Soviet Union in 1991, and theconsequences of Soviet rule are still rever-berating. But both countries are leading theway in the next revolution in medicine byestablishing DNA and health databases oftheir populations, something that most largercountries have not yet begun to consider.

“Many people are talking about populationgenetics, but you in Estonia are doing it,”said John Norton, Director and CEO of theUK Biobank Project, at the Gene Forum2003 conference in Tartu, Estonia, thisSeptember. In fact, it seems to be easier forsmaller countries, such as Iceland andEstonia, to go ahead with such initiatives.“Establishing a database is of course easierin Estonia with its small population [of 1.4million people],” agreed Arvo Tikk, chair-man of the Ethics Committee of the EstonianGenome Project (EGP) Foundation, not onlyfor logistical reasons but also because it iseasier to convince the public, and to adaptthe laws and regulations.

“I think that as we move forwardin this realm, it is a certainty thateverybody’s sensitivities are goingto be stepped upon by someone.”

“It’s helping couples buildhealthy families, and what couldbe better than that?”

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As of mid-September, deCODE, the pri-vate company that is operating theIcelandic genome and health databases,had collected genetic data for more than100,000 Icelanders. The EGP finished itspilot phase in March this year and sincethen has collected biological samples andhealth data from more than 4,000Estonians. The aim of both projects is thesame, but the similarities end there.deCODE is a high-tech company based inIceland’s capital, Reykjavik, with morethen 600 employees and state-of-the-artcomputing and sequencing facilities thatallow them to genotype up to 35 millionsamples per month. The EGP is based inTartu, Estonia’s second largest city, andhoused in a former cake factory near thebiological faculty of Tartu University.Inside, a handful of employees accept theincoming samples, health data sheets andconsent forms, and process the blood sam-ples manually to extract DNA, plasma andleukocytes to be stored in liquid nitrogen.The legal setup for both projects is also dif-ferent. deCODE is authorized by theIcelandic government, whereas the EGP isan independent institution ruled byEstonia’s Human Genome Research Act(HGRA). Regardless of the differences inlegal regulations, technical sophisticationand sheer size, Iceland and Estonia areboth pioneering a revolution in healthcare towards genome-based medicine. As such, they might very well serve as examples for other countries.

Probably the most striking feature ofthose involved with the EGP is theirapparent willingness to make do with

what they have to make it a success. Thelaboratory may be missing the sophisticatedinstrumentation that one would expectfrom a similar facility in a richer Westerncountry, but it is definitely rich with theexcitement of being a pioneer and with the keenness to improvise and solve prob-lems. Samples and consent forms are takenby physicians from nearly all over Estoniaand are delivered to the central laboratoryby a private courier service that usuallytransports cash. From the time that a physi-cian confirms that he has taken a bloodsample, the clock starts ticking, as the soft-ware allows only 48 hours before samplesand consent form must arrive in Tartu. Themost common error is that physicians for-get to sign the consent form, which meansthat the blood sample is not accepted until

the form is returned to the doctor for sign-ing. As Dagni Krinka, head of the laborato-ry, recollected, in one case, a consent formwas redelivered by the courier service after47 hours and 30 minutes—the driver hadto run a couple of red lights to make it intime. So far they have not lost a single sam-ple, she proudly claimed. On arrival at thelaboratory, the blood samples are recodedto make them anonymous—the keys arestored in a computer in a safe room towhich only a handful of people haveaccess—and processed immediately. AsKrinka said, their goal is to extract at least 1 µg of DNA from the blood samples, andthis is much easier in the winter whenmany people are sick and have moreleukocytes in their blood. “I don’t like thesummer,” she commented. At the time ofwriting, most regions in Estonia werealready participating in the project, exceptthose that are populated mainly byRussians who speak little or no Estonian.For these areas, the consent form, health-data questionnaire and all informationmaterial had to be translated into Russian.Although this was mostly complete bySeptember, the EGP was still translating theeducation materials used in training nursesand physicians—every health professionalparticipating in the EGP has to undergo afour-day training course.

Even more important than the technical and logistic setup of EestiGeenivaramu, the Estonian gene

bank, is its legal basis, the HGRA. TheGene Forum 2003 meeting was precededby the ‘From Ethics to Law’ seminar, orga-nized by the Estonian Genome ProjectFoundation and the Council of Europe,during which various speakers explainedthe rationales behind the HGRA and dis-cussed many of the legal and commercialimplications of the project. Indeed, theHGRA, which regulates how the genebank collects, stores and uses the collectedsamples and data, is a pioneering work initself; as Ants Nõmper, a lawyer at Raidla& Partners (Tallinn, Estonia), pointed out,

the Estonian parliament had to solve manyof the legal and ethical problems for thefirst time. Some basic regulations alreadyexisted in the Convention on HumanRights and Biomedicine of the Council ofEurope but those were too “broad andsoft” to provide sufficient legal basis forthe direct requirements of human genomeresearch, Nõmper said. The HGRA wasdrafted by Estonian geneticists, lawyers,physicians, ethicists, data protectors andpoliticians, and was adopted with onlyminimal changes by the Estonian parlia-ment. It maintains that the EGP operates as an independent organization and,although currently financed by theEstonian government, it is expected to cre-ate its own funds in the future by sellingaccess to its databases.

One important issue was to solve theproblem of who owns the data and tissues,in a way that allows researchers to use theinformation but also protects the rights ofthe individual, explained Tarmo Sild, alawyer at HETA Law Offices in Tallinn, whowas involved in drafting the HGRA. Theirsolution was to require participants towaive their ownership of tissue samplesand health data and transfer it to EestiGeenivaramu, which has the “right to pos-sess, use and dispose” of it under the con-ditions defined by the HGRA. This mightnot necessarily be a solution for every-one—the legal basis for the Latviangenome database, for instance, allowsindividuals to retain ownership. Waivingownership also means that participants inthe EGP cannot simply withdraw their con-sent and demand that the samples and databe destroyed, although exceptions exist.Sild also explained that the HGRA distin-guishes between three different levels ofownership: tissue, basic genetic data and“elaborate” genetic data from research. Thefirst two are owned by Eesti Geenivaramu,whereas elaborate data created throughscientific research are not regulated by theHGRA, which means that researchers andcompanies can claim patent protection oftheir findings. “In a way, [HGRA] functionsas a bridge between the collection of material and patents,” Sild commented.

Regardless of the differences inlegal regulations, technicalsophistication and sheer size,Iceland and Estonia are bothpioneering a revolution inhealth care towards genome-based medicine

“We tend to believe that theenemy of privacy is science. Ithink it’s not a good concept.”

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Nõmper further described the rationaleof the HGRA to use “open consent” toallow researchers to perform experimentsand data mining. “Population-based data-bases … have raised several new questionsthat cannot be easily answered using theclassical form of ‘informed consent’[where all future use of the material has tobe spelled out],” he explained. “Although… the consent form used within the con-text of the EGP seems to be rather broadand unconditional, it is still as specific aspossible without unduly limiting the scien-tific and healthcare value of the EstonianGene Bank.” Another feature is the require-ment for explicit consent, in which it dif-fers from the Icelandic project, which uses‘assumed consent’ with an opt-out model.Furthermore, the HGRA prohibits anyform of negative or positive sanctions,such as free drugs or remuneration.However, Nõmper pointed to public per-ception problems: “Some surveys haveshown that a big proportion of potentialgene donors are driven by incorrect imagi-nations, such as genetics will cure everydisease and there will be new drugs available for free.”

The ‘From Ethics to Law’ seminar alsodiscussed other aspects of popula-tion databases that go beyond the

immediate impact of how to operate andregulate them, most notably the naggingquestion about privacy. During the 1990s,privacy was mainly a perceived problemfor patients and families suffering frominheritable diseases, Tikk said, but “nowa-days the problem is the privacy of wholepopulations.” And this still needs to besolved, said Judit Sándor, AssociateProfessor of Law at the Central EuropeanUniversity in Budapest, Hungary. “Theconcept [of privacy] as we are using it nowwas mainly developed in Americanjurisprudence,” she said, but in generalthere is no common understanding ofwhat it means. It is also complicated by aninherent dilemma, as democracies on theone hand are based on openness and onits citizens’ right to know, but on the other,they need to protect their citizens right of privacy as well. “It is a subject of very careful and very sensitive balancingbetween different interests,” Sándor said.Furthermore, it changes over time. “Technol-ogy was always the driving force to extendprivacy,” she pointed out, noting that theinvention of the telephone was the first

case when privacy issues became impor-tant; biotechnology might be just the mostrecent one that has created the concept of‘genetic privacy’. And it has added anotherpotential dilemma, namely to protect theindividual’s right of privacy versus the rightof the researchers to perform their work.“We tend to believe that the enemy of pri-vacy is science,” Sándor commented. “Ithink it’s not a good concept.” AndresMetspalu, Professor of Biotechnology atthe University of Tartu and the father of theEstonian Genome Project, asserted in con-versation that currently there might be toomuch emphasis on the individuals’ right ofprivacy, which disregards families’ andsociety’s rights when it comes to inheriteddiseases. But that might change with fur-ther advances in biotechnology and theimplementation of population DNA data-bases, he thinks, and these problems willbe eventually replaced by other issues10–20 years from now.

Whereas the ethics seminar pro-vided an overview on the legaland ethical implications of

genome and health databanks, the GeneForum conference highlighted the hugeinterest in using population databases formedical care and research. Various speak-ers explored the new possibilities of pop-ulation genetics, from using pharmaco-genomics to make more efficient use ofexisting drugs and to circumvent sideeffects, to finding new drug targets for awide range of ailments and diseases. Butthe ultimate goal—to use health and DNAdatabases for predictive medicine—is stillat the concept stage and will requiremajor investments in biomedical researchand information technology to solve the various logistical challenges. Never-theless, the idea of personalized medicinebased on population DNA and healthdatabases is catching on. Latvia andNorway are also planning to establishtheir own population databases. In theUK, the MRC and the UK Department ofHealth plan to start the UK Biobank pro-ject to collect samples and health datafrom up to 500,000 volunteers between45 and 70 years old. By following up on

the health of these volunteers, Biobankwill provide the raw data with whichresearchers can measure the effect ofgenetic, environmental and lifestyle fac-tors on health risk, “providing clean foodfor the R&D machinery,” as Biobank’sNorton put it. Although rather limited insize compared with the EGP, he sees it asa first step for the UK. “We won’t neces-sarily have the final answer but we thinkthat Biobank will move the researchahead,” he said.

However, population DNA and healthdatabases cannot be established withoutthe participation of the public, who firstneed to be convinced. “It is essential thatwe have trust and respect from the pub-lic,” Norton said, “otherwise we areextremely vulnerable.” And that calls onthe scientists to follow good practiceguidelines to prevent backlash from boththe public and the economic sector, asLeslie Platt Jr, a principal at Ernst & YoungLLP (McLean, VA, USA) and leader of itsHealth Sciences Research ComplianceGroup, told the participants of the meet-ing. “It is very important in the new globaleconomy … that we do this properly. It isimportant that we do this responsibly.”And there is a lot of convincing to do.Whereas surveys showed that up to 80%of Icelanders support their project, the sit-uation in Estonia is not yet as positive. In a2003 poll, 40% of Estonians said theysupport the project, up from 32% in 2002.Only 2% were against it, but another 30%said that they would wait for the project todevelop before they participated. Alsointeresting is that about 19% thought thatthey needed more information. Clearly,what is needed is the education of societyat all levels on the challenges and benefitsof genome and health databases and ontheir role in personalized medicine. Thismeans more education about geneticsand biology as well. As Metspalu put it,“The problem is the misunderstanding inthe public about what genetics can doand what it cannot do.”

Holger Breithauptdoi:10.1038/sj.embor.7400024

“It is essential that we have trustand respect from the public,otherwise we are extremelyvulnerable.”

“The problem is themisunderstanding in the publicabout what genetics can do andwhat it cannot do.”