OVERVIEW: BIOTECHNOLOGY IN ESTONIA INTERVIEW: A NEW HIV VACCINE HAS BEEN SUCCESSFUL IN CLINICAL TRIALS ECONOMY: SKILLS IMPROVE MORE QUICKLY THAN THE COST OF LABOR C 0 N T E N T S

BIOTECHNOLOGY ECONOMY THE WELLCOME TRUST: ESTONIAN SKILLS IMPROVE MORE QUICKLY 4 RESEARCHERS ARE SUCCESSFUL 17THAN THE COST OF LABOR Three questions for Mary Phillips, The Wellcome Trust The Elcoteq Tallinn electronics factory was the prize-winner Scientific Programme manager. Four Estonian scientists in the first Estonian quality competition in 2002. were awarded senior research fellowships. ESTONIAN PROGRAMMERS OVERVIEW: BIOTECHNOLOGY 18 OFFER SERVICES ALL OVER EUROPE 6 IN ESTONIA By Rain Eensaar Estonia takes second place in the world in internet banking developments and eighth place in practical application of e-services.

SCANDINAVIAN QUALITY 20 AT A LOW BALTIC PRICE The UPM- Kymmene sells plywood produced at Otepää under WISA trademark troughout Europe.

FOREIGN INVESTORS 20 SECOND ROUND IN ESTONIA Interview with Andrus Viirg, the head of the state agency responsible for attracting foreign investments. Stories by Taivo Paju PHENOMENA GRAND PIANO ESTONIA  22 SALES HIT IN USA More than 80 % of production of Estonia Piano Factory is INTERVIEW exported to the US. By Andres Aarma A NEW HIV VACCINE HAS BEEN 14 SUCCESSFUL IN CLINICAL TRIALS CULTURE The vaccine is based on a new concept. 900 OLD Interview with the creator of the new vaccine, 24 BELIEVERS Professor Mart Ustav. By Õnne Pärl PRESERVE THEIR TRADITIONS AND CULTURE ESTONIAS GENE DATABASE  The biggest concentration 8 A “CRAZY IDEA” BECOMES A REALITY of Russian Old Believers is to Project for the future – the objective of the Estonian Genome be found in Peipsiääre Project is to establish a database of health and genetic data district, Estonia. By Hannes of the people of Estonia. By Õnne Pärl Tamme

QUATTROMED AND ASPER BIOTECH 12 Success stories of two Estonian CONTACT biotechnology companies. By Tiit Efert ESTONIAN BIOTECHNOLOGY 26 COMPANIES AND RESEARCH INSTITUTES Estonian biotechnology companies need foreign investments

The development of Estonian biotechnology companies has been remarkable for its speed. This success, however, is based on decades of top quality research, performed in Tartu and KAAREL TAMRE Tallinn. It seems that we are cashing in on those oil dollars that during the Soviet period were lavishly invested in molecular Population biology, the basis of biotechnology. However, I am developing a suspicion that our possibilities in the Baltic Sea ESTONIA AS could be limited in the current paradigm. I do not expect to INFORMATION SOCIETY see rapid growth in the number of new biotechnology ven- Region ESTONIAN TELEPHONE COMPANY 2003: tures, at least not in the near future, and I also cannot foresee * 45% of population rapid growth in turnover. use Internet & Internet This, of course, can be explained by the global economic Main facts: banking recession and scarcity of venture capital. On the other hand, Population: 1 356 000 (01.01.2003) * 35% of population Capital: Tallinn (435 000) have a computer at being such a small country and, as we like to think, smart, we home (69% of home Area: 45 000 sq. km (i.e. 1521 islands) should try and introduce a novel approach in order to reach a computers connected to Independence Day: February 24 higher, more refined level. the Internet) Currency: kroon (EEK) * 65% of the popula- In my vision there are two ways to do it. The first is to Currency peg: 1EUR = 15.65 EEK tion are mobile phone increase the government’s role. At present, biotechnology Public order: Parliamentary Democracy subscribers represents only a minuscule portion of the GDP. Its contribu- * All schools are con- GDP per capita: 5080 EUR (2002) nected to Internet tion should be exponentially larger. Unfortunately, the state GDP growth: 6,0% (2002) * Digital Signature budget does not grow exponentially, as we all well know. Act in force Another possibility would be to attract top-level foreign * Income Tax state- ments submitted by biotechnology companies. It could be done in partnership History: Internet with the government. To this end, in the longer perspective, 1202–1918 – Estonia invaded by Germans, * e-billing by major the government should specially promote biotechnology- Danes, Swedes, Poles and Russians companies 1918 – The Republic of Estonia was founded * Parking payments importing companies. 1940–91 – the Soviet occupation and bus tickets by mobile phone 1991 – Estonia declares its independence Toivo Maimets 2003 – The member states of NATO signed the Accession Minister of Education and Research Protocol of Estonia PhD (Molecular Biology) 2003 – Estonia signed the Treaty of Accession with the European Union

The Estonian Biotech magazine is Estonian Genome Foundation Riia 23, Director Mustamäe tee 5, Tallinn 10616, published in cooperation with the Estonian Tartu 51010, Estonia, tel. +372 56 469 494 Estonia, tel. +372 6 259494 Genome Foundation and the Director Coordinator: Rain Eensaar management magazine. [email protected] Editor: Õnne Pärl [email protected] Financed by Enterprise Estonia Designer: Andres Rõhu Cover illustration by Lauri Järvlepp ISSN 1736-0609

Copyright © Estonian Genome Foundation, 2003. Reproduction is authorised, provided the source is acknowledged. Additional information is available on the Internet (http://www.genomics.ee) BIOTECHNOLOGY The Wellcome Trust: Estonian researchers are successful

Four Estonian scientists awarded senior research fellowships in biomedical science in 2003-2007

Three questions for Mary Phillips financing agencies. They are not lacking in good The Wellcome Trust Scientific Programme people. What is needed is infrastructure to be Manager of International Programmes able to help those people.

>> What is the level of biotechnology in >> What are the decisive criteria in awarding Eastern Europe compared to the rest of the a senior research fellowship? world? The most important aspect is the quality of Speaking about Poland, Hungary, Estonia and science, the quality of the scientific proposal that the Czech Republic – all four of these countries applicants put forward. are very strong in biomedical sciences. There is scientific strength but obviously infrastructure >> Initially it was planned to award senior and financing, which are required to maintain and research fellowships in biomedical science to expand scientific strength, need to be supported. scientists in Poland, Hungary and the Czech There are very talented individual scientists, but Republic. What was the reason for including they need the support of their government and scientists from Estonia? My husband works as an academic chemist. We visited Estonia in 1998. I was here only as a visitor, to accompany my husband. I was highly impressed with the quality of biomedical science in the country. I proposed including Estonia in the award scheme. It has been a very successful inclusion. We awarded the first grants last year and out of ten or eleven awards, four were award- ed to Estonian scientists. So when compared to the size of the population more grants per capita were awarded to Estonia than any other country in the world. It is a very powerful concentration of senior research fellowships in Estonia. We are really pleased with the performance of Estonian scientists. ■ The Wellcome Trust representatives Mary Phillips and Hans The Wellcome Trust ‘blue skies’ research and applied clinical Through the International Programmes Hagen meet with The Wellcome Trust is an independent research. It also encourages the exploi- the Trust supports biomedical research Estonian scientist Priit Kogerman (on research-funding charity, established under tation of research findings for medical outside the UK. The programmes support the right) in June the will of Sir Henry Wellcome in 1936. It is benefit. research into the major diseases affecting 2003 in Tallinn. funded from a private endowment. The Wellcome Trust is one of the larg- the developing and restructuring world, Its mission is ‘to foster and promote est supporters of biomedical research in as well as the basic biomedical sciences research with the aim of improving human the world. The value of its asset base is now underpinning their causes. and animal health.’ To this end, it supports valued at £10 billion. ■

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Pärt Peterson Born in 1966, a graduate of the University of Tartu, In order to avoid the development of autoimmune reac- PhD from Tampere University, work experience from the Finnish tions, the T lymphocytes that are able to react with the Academy of Sciences, Tampere University, FIT Biotech. body’s own proteins are singled out. An essential part in Estonian this selection process is played by the AIRE (AutoImmune The objective of the four-member research team, led by REgulator) gene. This “master gene” coordinates the work Biotechnology Pärt Peterson, is to gain better insight into how the immune of other genes and is to a large extent responsible for the system prevents the onset of autoimmune diseases. prevention of autoimmune diseases. Association The immune system protects us against microbes The research, launched at the University of Tartu, will by special cells, T lymphocytes. Some of them are able to focus on the AIRE gene’s functions and regulations. For Pärt In February 2003, sixteen react with the body’s own proteins, thereby causing autoim- Peterson, one of the discoverers of the AIRE gene in 1997, Estonian biotechnology-related mune diseases (e.g. multiple sclerosis, diabetes). The reason the research follows his former research at the Institute of organisations established behind the development of most autoimmune diseases is Medical Technology at Tampere University. a non-profit organisation not known yet. – the Estonian Biotechnology Association. The Estonian Andres Merits Biotechnology Association is a viruses. The SFV is comparatively similar, for example, to the Born in 1967, a graduate of Moscow State University, body of companies and organi- PhD from Moscow State University, work experience from the Sindbis fever virus, quite common in Finland, and also to Institute of Chemical and Biological Physics, Tallinn Technical several dangerous tropical alphaviruses (Venezuelan equine sations dedicated to the develop- University, Helsinki University. encephalitis virus, Ross River virus). ment and prosperity of the To a smaller extent the human hepatitis C virus is also Estonian biotechnology industry A three-member research team, financed by the Wellcome studied. Although this virus is not directly related to the and research. All of the country’s SFV, there are some similar characteristics which make Trust, is interested in the Semliki Forest virus (SFV). The SFV largest and most influential is an alphavirus, discovered in Africa in 1942. It infects ani- simultaneous studies reasonable. mals and insects and in general does not pose any danger The research project at the University of Tartu will research institutions and compa- to humans. The virus has been extensively studied and is enable Andres Merits to test several hypotheses that nies stand behind the organiza- used in laboratories. he has put forward during his five years of research on tion. The Estonian Biotechnology The SFV is of special interest as a model virus, enabling the SFV. Association will work actively researchers to obtain more knowledge about the alpha-type to improve the conditions for biotech research and develop- Tõnis Timmusk ment to encourage balanced Born in 1959, a graduate of the University of Tartu, PhD from the and maintenance in vertebrates, for instance. Neurotrophins biotech business development Karolinska Institute. Work experience from Helsinki and Uppsala also have high therapeutic potential in the treatment of sev- throughout Estonia. It is the peak eral neurological diseases such as Alzheimer’s or Huntington’s Universities and the Karolinska Institute. body for Estonian biotechnology disease, as well as neural tumours and epilepsy. The research targets of the three-member team, led by Tõnis Tõnis Timmusk has studied neural genes for more than and provides a ‘platform’ which Timmusk, are neural genes. Studies of the regulation of their ten years. His research has been essential for understand- brings together all the relevant expression have fundamental importance for understand- ing pathogenetic processes, such as the mechanism of players involved in the Estonian ing nerve cells and the nervous system alike. The main task Huntington’s disease. biosciences community. of the planned research is to investigate the regulation of The research, financed by the Wellcome Trust, is neurotrophin gene expressions in the nervous system. targeted on molecular mechanisms controlling the Neurotrophins are secreted proteins responsible for the expression of the BDNF and NGF genes, which regulate The main aim of the Estonian maintenance of nerve cells. Very little is known about the tissue- and cell-specific expression of the BDNF and NGF Biotechnology Association is to molecular mechanisms regulating neurotrophin genes. genes. The research will also provide insight into how further partnership between the Neurotrophins NGF, BDNF, NT-3 and NT-4 are a protein the expression of the BDNF and NGF genes is affected public sector and non-govern- by neural activity. family, playing an essential role in nerve cell differentiation mental organisations to discuss matters concerning the develop- Priit Kogerman tiation into certain types of cells. The pathways are important ment of Estonian biotechnology Born in 1967, a graduate of the University of Tartu, PhD from Case both for cancerous and normal development. In this pathway and actively participate in the the signal is released by the growth factors of the Hedgehog Western Reserve University, work experience from Helsinki University, process of drafting legislation Case Western Reserve University, the Karolinska Institute, Tallinn family. Binding to its receptor, the Hedgehog releases a signal Technical University, the Institute of Chemical and Biological Physics. transduction pathway into the nucleus, where transcription regulating the field. Another factors of the GLI family switch some genes on and others goal is to develop and ease com- The research targets of the three-member research team, off, resulting in uncontrollable cell division. munication between members financed by the Wellcome Trust, are the genes that contrib- The aim of The Wellcome Trust-financed project is to and with the outside world. ute to the development of cancer. explore how the GLI3 transcription factor (“gene-switch”) It is known that these genes also affect the normal growth switches off its target genes. There are three GLI genes in and differentiation of cells, especially during embryonic devel- humans (and other mammals). All of them are able to switch opment. This means that cancer can be regarded as inappro- genes on and off, but the most powerful off switch is the GLI3. priate activation of embryonic programs in an adult body. Priit Kogerman has been studying the Hedgehog path- More specifically, the research focuses on the signal way with special attention focused on the “gene switches” transduction pathways which give cells instructions from the of the GLI family since 1997. The team hopes to find new outer environment, resulting either in cell division or differen- ways to inhibit cancerous growth. AWARDS: THE SENIOR RESEARCH FELLOWSHIP

BIOTECH ESTONIA 5 BIOTECHNOLOGY

Estonian biotechnology is still at an embryonic stage, but the ingredients for its future success are already in place. Biotechnology has simply become too important to ignore. Estonia has a century-long tradition in molecular biology. OVERVIEW: Biotechnology in Estonia

Gene Forum There are altogether 15 research Knowledge-based Estonia institutions and about 1700 people In December 2001, the Estonian parlia- The annual Gene Forum involved in the fields of medicine, biol- ment passed a strategy paper on research conference hosted by the Estonian Genome ogy and chemistry (300 in biotechnology). and development for the years 2002 to 2006. Foundation is the biggest Each year, ca 700 students will graduate in In the end, at the highest possible political biotech event in the the abovementioned fields from univer- level, it was declared that the future Estonia Baltic region. sities and an additional 700 from voca- would be a knowledge-based society. Held for the fourth year the event tional schools. During the period of 1997 The strategy specifies the objectives, has won international recogni- to 2002, about 300 PhD’s and MD’s were opportunities and principles of R&D and tion among the professionals and awarded in these fields. it serves as a basis for developing R&D in organizations involved in the field The first biotech companies in Estonia Estonia, by establishing the framework and of gene and biotechnology. The were established even before regain- the scope of public sector support measures event brings together experts from Europe and other parts of ing independence in 1991. During the until 2006. Strategic objectives include renew- the world for discussing progress last dozen years, there have been wide- al of the knowledge base and increased com- in the field of biotechnology and, in spread changes in Estonian science. The petitiveness of businesses. Among the three particular, human genetics, popula- enforced isolation of half a century has priority areas are biomedicine and material tion and community genetics and ended. Today, a few years later, fostered technologies (besides user-friendly IT). pharmacogenomics. by the country’s successful reforms and Through this initiative, Estonia’s budget The keynote speaker for the 4th Annual International Gene change in orientation, biological research for R&D will be increased from 0.76% (1999) Forum 2003 “50 Years of the is thriving again. to 1.5% of gross domestic product by the year Double Helix” is Professor Rolf 2006. While it will be still far behind the EU M. Zinkernagel (Nobel Prize in Positively transforming average (1.9% in 2000), it means doubling Medicine, 1996) from the Institute According to a recent evaluation report of in just 5 years. In addition the relationship of Experimental Immunology, an international expert group1, Estonian between public and private sector R&D Zurich, Switzerland. The forum will take place in Tartu (September research in the field of genetics, physiol- expenditures is expected to change from 12-13, 2003), a city rich in academic ogy, microbiology and molecular biology 80/20 (1999) to 35/65. and historical traditions. is performing quite well, especially con- The Gene Forum is an inter- sidering the limited resources currently SPINNO and Competence national event with a top-level available for most of the research units. Centre programme conference, investor forum and This is largely due to the traditions, human As several other countries exhibition and will open windows to the latest innovations and issues resources and enthusiasm that survived around the globe Estonia is in the field. Plenary debates, work- during the difficult periods in the past. betting on high-tech. During shops and the exhibition will focus In recent years, a certain political the last couple of years, sev- on interesting themes such as consensus has been achieved in Estonia eral new companies have genomics and genetics of complex about research and development (R&D). been launched in the diseases, population genetics and In addition to favourable economic condi- field of biotechnol- biobanks, pharmacogenomics and business, biopartnership, bioethics tions, R&D and innovation is considered ogy. Most of them and genetics. to be the locomotive behind long-term are still small, both economic growth. Several initiatives have in market capitaliza- Further information and been launched to enhance the country’s tion and the number registration is available at science base. of employees. www.geneforum.ee. 1 Research Evaluation on Genetics, Physiology, Microbiology and Molecular Biology http://www.ekak.archimedes.ee/eval/genetics-physiology.htm

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Origins of Biotech OVERVIEW: Biotechnology in Estonia in Estonia

Estonia has, perhaps surprisingly, Given the fact that most firms are not One of the reasons for starting research always been among the leaders able to invest sufficiently on their own, in Estonia is still the comparative advan- in this field. Karl Ernst von Baer (1792–1876), the naturalist and the government has established, through tage of cost effectiveness. Perhaps this was embryologist, one of the founders Enterprise Estonia, several general instru- also one of the reasons why the Finnish of the modern science of develop- ments that support R&D and innovation, Company FIT Biotech recently transferred ment, who ranked among the most and therefore contribute to the competi- part of its research activities to Tartu, influential scientists of his day, was tiveness of Estonian enterprises and indus- Estonia. There have been indications that born in Estonia. His discovery of the try. However, there are no sector-specific this move might not be the last. mammalian egg and his recogni- tion of the formation of germ lay- instruments for biotechnology. ers out of which embryonic organs Programmes such as SPINNO or the Future developments develop laid the basics of modern envisaged Competence Centre programme There are several reasons why Estonia’s embryology. will not show immediate success, but take biotech business should enjoy a boost Genomic studies in Estonia time to develop. For more “advanced” in the coming years. First, the political were launched as early as the investments venture capital is an impor- circumstances – Estonia is expected to 1960’s by a few visionary scien- tists, such as Prof. Artur Lind and, tant issue. Currently, the financial markets become a full member of the EU in May against all odds, the discipline in Estonia are characterised by a limited 2004. Even now, it is a full member of took off in the 1970’s, when first- amount of available venture capital. This is European R&D programmes. generation molecular biologists especially the case for early stage and high- Second, an important factor is the were educated in the University risk investments. There is a clear need for favourable government policy and public of Tartu (including Prof. Andres a government-supported venture capital support. One of the three most favoured Metspalu, Prof. Richard Villems, Prof. Mart Saarma). fund that could provide seed money. areas for the coming years will be biotech- nology (biomedicine and material science). Europe’s freest market Estonians have been open-minded when it The guaranteed financial stability of the comes to genetic engineering, GMO’s and Estonian kroon being pegged to the euro other biotechnology issues. and liberal economic policy have Third, implementation of the Estonian been the key to Estonia’s suc- Genome Project will create a necessity for cess as a highly attractive setting up new biotech companies and it

location for foreign inves- could also repatriate Estonian scientists After the opening of the Laboratory Prof. Artur tors. In addition to this, all now working abroad, reversing the brain of Molecular Genetics in 1984, the Lind, the visionary corporate investments are drain trend of recent years. National Institute of Chemical scientist, in exempted from corporate Hopefully the ongoing research in Physics and Biophysics in Tallinn the 1960’s. tax and foreigners have the right Estonian universities, research insti- became one of the leading institu- to purchase land in Estonia. In tutes and companies is generating a tions in the field of biotechnology. In 1986 the Estonian Biocentre was addition to the tax and legal solid knowledge base and increasing established to promote research environment clearly sup- networking among researchers, which and development of gene and cell porting entrepreneurship, further increases Estonian intellectual technologies in Estonia. Since then, investments and innovation, and material prosperity and improves its the discipline has flourished and at there is also a sufficient and international competitiveness, visibility the moment there are hundreds of well-educated labor pool and esteem. ■ people doing research or studying according to various curricula in the in Estonia. By Rain Eensaar broad field of life sciences.

Karl Ernst von Baer (1792–1876), one of the founders of the modern science of development, was born in Estonia.

BIOTECH ESTONIA 7

ANDRES RÕHU BIOTECHNOLOGY

English teacher Kristiina Kenn has suffered from unbelievably numerous diseases during her young life. Why such a young person is so ill is a question the doctors are not able to answer yet. Distressed by her health problems, she made a conscious decision and joined the Estonian Genome Project.

LAURI KULPSOO Estonia’s gene database – a “crazy idea” becomes a reality

he sincerely believes in the would-be data- an example and a former agricultural country base of the Gene Bank that would enable decided to change direction, contributing to the diseases to be diagnosed more accurately development of modern technologies. Mart Laar, Sand make treatments more effective. “If not me the former prime minister (1999-2002), recalls the then my children would surely profit from this,” Genome Project as the first response to his appeal says the mother of two. to scientists and businessmen “to bring crazy new Kenn is one of the thousands of gene donors ideas to the prime minister.” whose DNA, extracted from blood samples, is Enormous preparatory work took a couple preserved in nitrogen at -186ºC in the storage of years, resulting in an initial blueprint for the facility for future medical use. Every week brings project. Legislation was also prepared. After the in hundreds of new blood samples. The target that Human Genes Research Act entered into force in the Estonian Genome Project Foundation (EGPF) 2001, the government of the republic founded the hopes to encourage to join the project in the near EGPF, which is responsible for the creation and future is 1 million from Estonia’s population of maintenance of the Gene Bank. approximately 1.4 million. Although the first three million came from the government (192,300 EUR) as well as sup- By support port in the form of a loan from the Estonian of the Government Technology Agency, it was clear that the budget It was only four years ago when a group of out- of a small country could not meet the demands standing researchers convinced the Estonian of the project. Today, only the Ethics Committee government of the project’s necessity. The of the EGPF, independent in its decisions, is state- Finnish neighbours’ successful Nokia served as financed.

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The investor has huge obligations health risks better than a family doctor? By now, To finance the project, public limited company the pilot project has come to an end in three coun- EGeen Ltd. founded. The investments have been ties and the project is gradually expanding all over incorporated through the EGeen International the country. The data is also collected according Corporation, located in California. EGeen Ltd. to the patient groups. Hypertension and diabetes possesses a 25-year-licence for using the anony- (II type), topical at the moment, will be followed mous data of the Gene Bank. Therefore it has huge by heart, cardiovascular and neurodegenerative obligations to the EGPF and also a good chance to diseases, e.g. Alzheimer’s disease in the future. attract drug manufacturers as potential clients. The doctors have to do most of the work but in Even today EGeen has several orders, e.g. bio- the future IT will take over. It is logical as the end technology company Prediction Sciences in San product of the project is information. Software, cre- LAURI KULPSOO Diego is interested in research on depression and ated specially for the project by the help of three hypertension. Despite the fact that at the present companies, is Estonia’s secret weapon. The system moment the investment contracts secure only 4.25 for collecting data is ready but it is up to the software million US dollars, the management of EGeen is to analyse and draw the conclusions in the future. not worried as the data collection is progressing, adding value to the database. Consistent interest The EGPF started thorough preparation work Being one of the first of its kind, the Estonian in 2001-2002. During this period, laboratory and Genome Project has been constantly attracting information systems were built and the first fam- the interest of the already existing and newly bud- ily doctors (GP) received intense training. Within ding gene banks. Every week brings guests from the framework of the ISO quality management all parts of the world to the EGPF, located in Tartu system extremely precise procedural instructions (100,000 inhabitants). Several countries have used were worked out so that the employees jokingly say the Estonian Human Genes Research Act and a that they have rules for every fit of cough. donor questionnaire as a model. The media has been interested in the course of Project focus events. Francis Collins, director of the US National The system where the data from gene donors is col- Human Genome Research Institute, finds noth- lected mostly by family doctors has justified itself. ing surprising in the fact that Estonians have been After all – who would know a person’s illnesses and mentioned alongside the UK Biobank and the

LONGTERM POPULATION BASED RESEARCH DECODE GENETICS of Iceland provided deCode The aim is to understand the combined effect of genes, Reikjavik, Iceland Genetics firm the sole right to life style and environmental factors on public health 1998 – utilize and sell the database Plans to collect data from THE UK BIOBANK No feedback federal grants, non-profit 270,000 inhabitants of GENOMEUTWIN 2004– Financing:non-profit corpo- organization Marshfield Iceland Helsinki, Finnish National Plans to collect data from ration IPEG (Institute of Medical Research Ca 80,000 blood samples Public Health Institute 500,000 donors (aged 45–69 ) Population and Genomics) Foundation have been obtained, on 1990 – No feedback this basis classical genetic Plans to collect data from Financing: Medical Research MARSHFIELD CLINICS ESTONIAN research into genealogy is 800,000 twins, presently 30,000 Council, Wellcome Trust, PERSONALIZED MEDICINE GENOME PROJECT performed with the aim have been included in the Department of Health RESEARCH PROJECT Tartu, Estonia of identifying gene-disease study. Twins from Denmark, Wisconsin, USA 2002 – relationships Finland, Norway, Italy, Sweden CARTAGENE 2002 – Plans to collect data Feedback and the Netherlands are under Quebec, Canada Plans to collect data from from 1 million gene donors Financing:US investigation. 2003 – 40,000 gene donors (older than 18) Pharmaceutical Concern No feedback Plans to collect data from No feedback Feedback Hoffmann-La Roche Financing: The Commission 50,000 donors (aged 25–74) Financing: state and Financing: EGeen Peculiarity: the Government of the European Union

BIOTECH ESTONIA 9 BIOTECHNOLOGY

The head of the Laboratory, Dagni Krinka, shows the storage facility where DNA is preserved in nitrogen at -186ºC.

PM/SCANPIX BALTICS

Marshfield Clinic Project in his visionary article Research Act, forbidding any misuse of the per- in the prestigious journal Nature. While discussing sonalized information in Estonia, the critics’ worst the future of biotechnology with his co-authors in scenarios foresee a leakage of data to, e.g. insurance this paper, they stressed the importance of creat- companies or employers. ing such databases. To him the projects mentioned The EGPF has paid great attention to security Some critics have men- above seem to follow the right direction: all three demands. A family doctor has to obtain permission tioned patient`s stress caused by learning have been publicly discussed, and would look at a from the Data Protection Inspectorate to process negative information. In cross-section of the population rather than focus the delicate personal data. The data in cryptic form reality the gene donor is the one who decides if on the specific diseases. arrives from a family doctor to the server of the he wants any feedback The problem with the existing large databases is Gene Bank from where it moves on to the coding in the future or not. If he wants to “quit” the that they are relatively incomparable – to analyse the centre. There the personal data is separated from project, the code which enables to relate data majority of so-called “common” diseases, data from a the donor questionnaires and replaced with a 16- with the person, will be large number of people is needed. The harmonization digit code. Only three employees have the right to destroyed. of principles would provide a possibility to combine enter the centre. This secured room resembles the data from different databases. This was the idea of the one in the film “Mission Impossible” from where four most influential genome projects in the world no wires run out and where the work is done under – the Estonian Genome Project, the UK Biobank, the vigilant eyes of a camera. CARTaGENE, and Genomeutwin – when they Such a scheme ensures anonymity of the data- founded an international consortium called the Public base. Only the gene donor and by his consent his Population Project in Genomics in July 2003. doctor has access to his personal data kept in the Gene Bank. Some critics have mentioned patient Special attention to security measures stress, which can be caused by learning negative Although the overall attitude towards the project in information. In reality the gene donor is the one Estonia is positive, there are also doubts. The confi- who decides whether he wants any feedback in dentiality of the data is the source of most worries, the future or not. If he wants to “quit” the project, as it is everywhere in the world where analogous the code that enables the data to be related to the projects are under way. Despite the Humans Genes person will be destroyed. In certain cases the gene

10 BIOTECH ESTONIA BIOTECHNOLOGY

Gene database: ESTONIAN GENOME PROJECT EGeen origin and usage > Collects and preserves data Have twenty-five year exclusive license for com- mercial use of all data emerging from the Estonian Donor Family Database of the Doctor Gene Bank Genome Project (EGP) > Has the > Financing investor >Takes a Coding right for free relationship blood sample centre inquiries > Bioinformatics > Fills out Separation of DNA > Genotyping the donor in the laboratory > Processes questionnaire anonymous data Storage facilities Advising Biotechnology and Research institutions pharmacy firms > Commercial research and > Are able to use the data free for project patnership non-commercial purposes donor also has the right to demand that his or her about 1.5 hours a day to a donor, for which she is personal data be deleted from the database. paid up to 32 EUR per person. Despite the time- Although according to the Estonian legislation consuming procedure she is convinced that she one has the right to participate when 7 years old, is doing the right thing. She sums up her present the leaders of the Genome Foundation decided not possibilities as a doctor, saying, “The only thing I to invite participation before one reaches 18 years can do for a patient suffering from diabetes is to in order to assure that a potential donor is fully write out a prescription to alleviate his/her illness. aware of the impact of his decision. This contradic- This is not really treatment.” tion between the youth’s right to make their own What can be done with the help of such a decisions and the act presently in force serves as huge amount of data, which the project promises? a good example of the problems that need to be Hopefully all those things that seem like miracles at addressed by the Ethics Committee of the EGPF. present: determine disease-carrying genes, provide accurate diagnoses based on the patient’s gene map, The future of the gene database find an appropriate drug for the patient’s genotype, A family doctor is the link between the EGPF and correct or even replace a disease-causing gene... a potential gene donor. His/her task is to introduce In the more distant future, we might not be talking the project to the people and provide feedback for so much about treatment of the diseases but about those who participate in it. There are many ques- their prevention. Or, as the founding farther of the tions that need to be answered, among them also Estonian Genome Project, Professor of Biotechnology funny ones, such as “Will I lose my genes forever at the University of Tartu Andres Metspalu, puts it, by becoming a gene donor?” “Similarly to our present understanding that wearing First a potential donor has to sign a Gene Donor a helmet when driving a motorcycle is a precaution- Consent Form and only then the family doctor, hand ary measure and driving without it would be unthink- in hand with the donor, will electronically fill in a able, there will be a time in the future when we have health questionnaire and take a blood sample. to take a pill before a meal to keep our body in better One of about 100 family doctors who have working condition.” ■ joined the project so far, Vivian Alles, dedicates By Õnne Pärl

BIOTECH ESTONIA 11 BIOTECHNOLOGY Former University Lab Developed into Spin-off Company The aim of the Quattromed company, which has the addition, negotiations have started with potential largest turnover in the field of biotechnology in Estonia, is European partners in light of Estonia’s assumable to offer high-quality laboratory diagnostics to the medical accession to the EU. sector and molecular-biological tools to scientists for Quattromed is also active in another field as performing gene and protein research. it offers a diversified portfolio of products and services to research laboratories dealing with functional genomics and functional proteomics all over the world. Any entrepreneur would dream of found- These products, discovered in the University of ing a company just the way Quattromed was Tartu, are based on the unique properties of the born. There was a clear demand for the service regulatory protein (E2) and its opponent antibody even before the company was set up. Medical staff of the bovine papilloma virus. These antibodies were frequent visitors to the lab, always asking for form a strong and very persistent bond with pro- molecular diagnostic services. Four researchers tein parts from the papilloma virus. took to the task in 1999. The product is a tool for studying the properties By now, the methods of molecular diagnostics of protein: an E2 Tag is attached to the protein under that we offer have been positively accepted by many study and by means of antibodies from the tool kit Estonian doctors because of their speed, accuracy the labelled protein is caught. Quattromed has and acceptable price. This has enabled researchers worked out the whole product family on the basis of to increase the number of hard-to-detect diagnos- regulatory proteins and antibodies. Next generation able infections by usual methods to up to 16. In products will reach the market in autumn 2003. Asper Biotech partners are world famous research institutes In four years, Asper Biotech has grown from a small company producing Genorama detectors for gene analysis into a full-service firm.

“Detector sales is now a side activity,” says the manager Indrek Kask. The clients will pur- chase them only after becoming convinced of their user-friendliness. The main client target group of Asper Biotech ASPER BIOTECH is academic institutions, e.g. universities and insti- Asper’s services are certified to be in accordance with ISO quality standards. tutes with versatile demands. The present as well as potential clients are mostly in the US. This is Columbia and Stanford Universities and Baylor why it is essential to be able to demonstrate the Medical College. fruits of previous experience. Just advertising The company is presently using a US-based on the back cover of an expensive journal is not retailer, though the option of establishing a enough. Asper Biotech has succeeded in finding daughter company there in the future cannot collaboration partners from world famous US be excluded. There are no plans to move outside research and educational institutions such as Estonia as a number of important clients are in

12 BIOTECH ESTONIA BIOTECHNOLOGY Former University Lab Developed into Spin-off Company Marketing was difficult at first as there were many plan for a research experiment is worked out offers and competition was tough. Fermentas, a along with the client. Quattromed has experience Lithuanian company with experience from the with a number of Finnish and Swedish compa- Soviet period and representations in more than 50 nies. Presently, joint projects are under way with countries, became the first retailer, though by now Canadians, Italians and Germans. Quattromed has established a distribution network of Tiit Talpsep, the development manager of special sales companies everywhere in the world. Quattromed, confesses that in the end the pat- The home page in English has contributed ented technology will be sold and in order to get to increasing sales. Abcam, a retailer from Great the best price possible, the whole product family Britain, contacted Quattromed after seeing its will be completed to perfection and its trademark home page and now does most of the marketing. promoted. A certain proportion of the clients require a serv- Quattromed, located in Tartu, currently has 22 ice in addition to the product, thus the first research employees, most of them graduates from Tartu experiments offered by the company became a new Medical College and the University of Tartu. marketing niche and the sales of services have con- Collaboration with top Estonian academic R&D tributed to multiplication of turnover. centres is active. If retailers can be used for marketing laboratory Tiit Talpsep, who has some experience from products, then in case of specific services personal Scandinavia, is pleased with the level of biotechnol- contact is the only way. Thorough negotiations ogy in the University of Tartu, saying, “It is even take a lot of time before concluding a collabora- better than in the Northern European universities tion agreement. During these talks, however, the as here students get more hands-on training.” ■ Asper Biotech partners are world famous research institutes Europe. Another reason for keeping the company Competition for producing detectors for gene in Tartu is the advanced level of biotechnology analysis is extremely tough in the world. One of the at the University of Tartu and the presence of a competitive arguments offered by Asper Biotech is high-quality labour force. Asper Biotech employs flexibility: their technology enables users to per- 25 people, most of them biologists. Therefore, there form versatile research, e.g. it is possible to carry is enough space for growth. out research on genetic material from humans, in Asper Biotech was founded in 1999. The scien- addition to animals and plants. tific idea of the detector was offered by the found- Secondly, a distinction from major rivals is that ing father of the Estonian Genome Project, Andres Asper Biotech never offers standard solutions. The Metspalu, Professor at the University of Tartu. company adjusts precisely to clients’ needs. Sound Collaboration with the Estla company, founded scientific support is another bonus offered. As a result, by laser-producing physicists in Tartu, started almost detectors for gene analysis have been marketed in immediately. The future plans include development France and South Korea in addition to in the US. of second-generation Genorama detectors. According to the evaluation by Deloitte & Touche in October 2002 (the study included 12,000 compa- Microarray production for DNA analysis. nies), Asper Biotech belongs to the 50 most rapidly developing technology companies in Central Europe. The company’s turnover increased by 1550% in just three years. ■ Stories by Tiit Efert

BIOTECH ESTONIA 13

ASPER BIOTECH INTERVIEW

A NEW HIV VACCINE HAS BEEN SUCCESSFUL IN CLINICAL TRIALS

Professor Mart Ustav is going There is no effective HIV vaccine in the through extremely exciting times. world at present. What makes you think that The HIV vaccine developed by him is your vaccine is going to be successful? The design of our vaccine is based on a new entering the second phase of clinical The number of concept. Earlier experiments used the envelope HIV-positive people trials in Finland. It will be closely in the world is 45 protein of HIV produced for example in yeast as mln, 25 mln have monitored by the global International an immunogen. The problem is that the structure died. The disease began to spread in Aids Vaccine Initiative (IAVI), the aim of the protein obtained this way is different from the 1980’s, and soon the one within the envelope of the virus. Therefore, attempts to find of which is to find the best candidate counteracting drugs although the body triggers an immune response, it followed. Today, for HIV vaccine production. does not have the power to neutralize the virus. we have Fuzeon, produced by Swiss We have developed a different approach in our Roche Holding, vaccine, inducing a cellular immune response. The which prolongs the lifespan of patients The first phase of the clinical trial was success- immune system and especially cell-mediate immu- as it prevents the spread of the virus ful. Even a dose a thousand times smaller than nity resemble a guard who has to ensure that all in the human body. the conventional amount produced the cells of the body are normal. The Unfortunately, the drug does not an anti-viral immune response in The task of the vaccine antigen presenting system in each cell remove the virus four out of five subjects. If all goes is to teach the immune provides a sort of warranty for the from the body and its price is extremely well, this vaccine might become the system to effectively immune system, which guarantees high (19,000 EUR first remedy to stop the spread of recognize cells infected that there are no foreign proteins per year). No vaccine able the disease, often called the plague by the virus and quickly in it. However, if the cell becomes to cope with HIV of the 20th century. infected with the virus, this antigen has been developed destroy them. so far. presentation system lets us know: I Professor Ustav, is this HIV have become infected. vaccine that the Estonian team is working Killer cells of the immune system (cytotoxic on really something unprecedented? T-lymphocytes) with the help of other cells bind Indeed, we have achieved results that could be of to the cells infected by the virus, “drill” holes into great importance for the creation of an anti-HIV them and end the cell’s life. Thus the task of the vaccine. Even by administering it only once, the vaccine is to teach the immune system to effectively 4 antigens designed by us are able to trigger an recognize cells infected with the virus and quickly immune response that recognizes most common destroy them, so that if a person is infected with strains of HIV.

14 BIOTECH ESTONIA INTERVIEW

Professor of microbiology and virology at the University of Tartu, head of the Tartu laboratory of vaccine design and development of FIT Biotech Oyj Plc, Mart Ustav.

help of the vaccine, an adequate defence against the virus should be guaranteed. We determined the sequences of the virus proteins that are The vaccine able to cover the whole variety of the HIV developed by FIT family. In 99% of the cases the immune Biotech is based on response should be able to recognize HIV a novel concept – it – this is why we can say our vaccine may teaches the immune system to fight the work. infected cells

How did the process of is cheap – according to developing the vaccine begin? estimates a dose In 1992, we launched an applied would cost ca research project with the aim of work- 10-20 EUR ing out new methods for gene therapy

and vaccination at the Institute of small dosage – PM/SCANPIX BALTICS Molecular and Cell Biology of the only 1 μg produced University of Tartu. We made use of a positive effect, it HIV, the immune system is immediately ready to the knowledge obtained from previous is a thousand times less than common destroy the infected cells. research on the multiplication mecha- doses in clinical vac- nisms of the papillomavirus (a widely cine trials HIV is known to mutate very quickly, spread virus causing benign tumors). 2 aspects: how can a vaccine recognize it? Papillomaviruses are special because in prophylactic (is In every replication cycle of HIV new mutant case of the onset of an infection these administered to viruses are produced, all of which may have the viruses remain in the nucleus of the host non-infected people ability to multiply and to destroy the normal activ- cell as a genetic element outside the chro- to induce protection against the virus), ity of the human immune system. This is why it mosome. We developed vectors for gene therapeutic (is is necessary to keep the immune system alert and therapy and gene vaccination that could be administered to HIV- ready to fight the mutating virus. Otherwise we end used in various cells. infected patients to up in danger: the body is always a step behind in prevent AIDS) recognizing the mutated virus. What are vectors? One of the main tasks in creating the vaccine A vector, i.e. gene carrier is used to deliver a desired was the analysis of the database, i.e. elucidating how gene to a specific location in the body. We insert the sequence of virus proteins can alter the body. a gene into a papilloma vector and introduce it In collaboration with the Chair of Evolutionary into human cells, for instance. An advantage of the Biology of the University of Tartu we were able to papilloma vector is that it remains outside the chro- design such antigens, which represent the whole mosome in the cell nucleus. Thus, it does not alter “spectrum” of the viral protein variations. If the the human genome. A therapeutic gene, however, immune system is taught to recognize them by the has the same effect in the cell as the virus.

BIOTECH ESTONIA 15 INTERVIEW

How are the papilloma vector and a gene-carrying vector and a gene that encodes the HIV vaccine related? immunodominant regions of the proteins of Our vector system seemed to be a suitable appli- HIV. cation to Professor Kai Krohn from Tampere University, who was looking for a new technology What kind of trials does the vaccine have to pass? for creating an HIV vaccine. In order to finance At present, we have successfully completed the the project (Estonian resources were insufficient to first stage of the clinical trials, proving that the continue the project), we had to look at the whole vector is not harmful to the human body and acts project from the commercial aspect and come in the way a vaccine is expected to. The vaccine up with a business plan. We needed a laboratory, has to pass several other stages of clinical trials organised clinical trials and production. with human patients, and before moving on to the next stage the previous has to be approved by the Why was the project transferred into the Finnish State Agency of Medicines. Although the Finnish biotechnology firm FIT Biotech? vaccine has been developed in Estonia, the patent An investment needed for producing the vaccine is belongs to FIT Biotech, which has financed all the about 1–5 billion EEK and the development proc- development activities. ess takes at least 7 years. Clinical trials make the vaccine expensive, because on average up to12,000 When can we hope to see the EUR is spent per patient. Every sample taken from vaccine on the market? an infected patient involves a biohazard, as this 50 When we have successfully completed the clinical ml of blood may be highly contagious. trials on human patients, hopefully in 2006, we FIT Biotech (financed, e.g. by the SITRA and could really have promise for the vaccine’s pro- TEKES public investment funds, controlled by duction. In every state, however, it is obligatory to the Finnish state and private investors) provided apply for permission from the National Agency money for setting up a development laboratory of Medicines to market the vaccine. Therefore it with 11 researchers in Tartu. The research team is difficult to predict when exactly the vaccine will designed completely new vectors and developed reach the market. ■ a new concept for antigens. The vaccine combines By Õnne Pärl

I STAGE The following questions The development of the vaccine had to be answered: 1. Is the developed vaccine A single protein of the virus is not able to virus. The trial includes both HIV-infected dangerous to people infected with HIV? trigger the protective immune response. and non-infected subjects. In case of a In 2001-2002, FIT Biotech tested the The vaccine has to be developed from positive result the last stage follows. vaccine on 15 HIV-positive Finns an artificial antigen, representing all the 2. Is the developed vaccine proteins of the virus. In order to cope dangerous to non-infected people? with the question of variety, 4 antigens III STAGE In 2002-2003, vaccine injections were were designed. The final vaccine consists FIT Biotech tests the vaccine, given to 24 medical and police academy of 4 antigens and a vector. made up of 4 antigens able to students in Finland who did not have trigger an immune response that would the virus. The trial tested the vaccine recognize the whole HIV family. In case containing only a single protein of the II STAGE an immune response occurs both in HIV- virus. The first stage proved that the vec- FIT Biotech tests the vaccine infected and non-infected subjects, the tor was not harmful to the human body containing a single antigen, rep- vaccine is ready. and it acted appropriately. resenting all the proteins of one certain

16 BIOTECH ESTONIA ECONOMY Skills improve more quickly than the cost of labor

Elcoteq is the first large Finnish com- pany to seriously consider moving its central offices abroad, possibly to Estonia.

PM/SCANPIX BALTICS INDEX OF ECONOMIC FREEDOM RANKING 2003 Because of the crazy working speed and ten employees, and today the number of work- 1. Hong Kong4 huge quantities of components characteris- ers reaches 2000. Another eloquent fact is that it 2. Singapore tic of the electronics industry, the components was back in 1997 when the first mobile phone was 5. Ireland 6. Denmark meant for the Tallinn factory of the worldwide produced in Tallinn from the beginning to the end 6. Estonia Elcoteq Network company from the Finnish – the Ericsson GA 628 came out. High quality is 6. USA 9. United Kingdom central warehouse sometimes ended up in some guaranteed both by cutting edge technology and 11. Finland other country. To sustain the production process, quality management. Elcoteq Tallinn won the first 11. Sweden 19. Germany the managers in Tallinn performed miracles, e.g. Estonian quality competition in 2002. 27. Norway 29. Lithuania ordering a plane to deliver the necessary missing A new unit of the NPI company (New Product 33. Latvia details from Finland. Introduction) is also located in Tallinn. Similar cen- 35. Czech Republic 35. Japan To improve the situation, the Elcoteq Network tres are in China, Finland, the USA, Mexico, Russia 44. Hungary allowed the Estonian logistics specialists to act and Germany. The centres have a big responsibility 66. Poland 135. Russia independently. Now, the necessary components to help to develop their clients’ novel ideas into Source: Wall Street Journal, arrive in Tallinn from all over the world, reducing products manufactured by Elcoteq factories. The Heritage Foundation the number of factory standstills and guarantee- Up to now, the Elcoteq Network has been sat- ing a sufficient number of components in stock. isfied with the Estonian economic environment. Finished products bearing the Ericsson and Nokia According to Lasse Kurkilahti, the president of trademarks are shipped from Tallinn to different the company, the situation on the Estonian labour destinations all over the world. market is good and one can be pleased with the The importance of the Estonian unit of the competitive ability and the price level in general. Elcoteq Network company has grown from In 2002, the average salary in Estonia was a bit year to year. In 1992, it began in Tallinn with less than 400 EUR. The difference in comparison continues on next page

BIOTECH ESTONIA 17 ECONOMY

continues from previous page with the European average is remark- able. According to Eurostat the average wage per hour in the EU in 2000 was Estonian programmers offer services all over Europe approximately 8 times higher than in the Estonian industrial and services sec- tor. The Estonians, however, are worried that the continuous increase of wages When the head of SEB IT Partner, Peeter Klanberg, was looking could harm Estonia’s competitiveness. for new employees, the requirement was not only fluency in pro- A study by the Ministry of Economic gramming languages but also readiness to leave Estonia for another Affairs and Communications reveals destination for up to half a year on extremely short notice. The company that the share of the labour cost in dealing with IT development is working out novel IT solutions for the the GDP has not decreased but rather Skandinaviska Enskilda Banken (SEB). increased. Therefore, we cannot speak The first large investment into Eastern European banking for the SEB about the deterioration of the state’s was the purchase of the Union Bank of Estonia (EÜP) in 1998. Two years competitiveness. The analysts confirm later, the heads of the Swedish megabank were brave enough to agree to that a sharp increase in salaries cannot the proposal by the IT unit of the EÜP to set up a new SEB IT develop- be expected: one of the reasons is the ment center in Estonia. The new establishment became known as SEB weakness of local trade unions. IT Partner Estonia. Other factors compensating the The first task was the creation of an internet-based environment for the increase of the labour cost are the sta- Gyllenberg Investment Bank from the SEB group. Presently, the consultants bility of the economic environment, are able to use the bank’s data both at home and at clients’ locations. low level of corruption and minimal Another more complicated task followed: the creation of the trading centre state intervention in the business for major clients of the SEB. This meant establishing an efficient and secure

activities of a company. Corporate tax The Tiger Tour travels from town to town each year: the organizers set up hundreds of computers has been abolished for legal persons, in a huge tent connected to the Internet, and invite the local residents to use them. and for private persons income tax is 26% (proportional system). Paul Oberschneider, who has estab- lished the largest Estonian real estate company Ober-Haus, which by now has expanded to other Baltic countries and Central Europe, has called Estonia one of the most investor-friendly coun- tries. “It is important for the investor to communicate in his own native lan- guage, and it is also essential to have clear and stable laws,” says US citizen Oberschneider. This is one of the reasons why the analysts from the prestigious economic journal The Economist have faith in Estonia. A recent study carried out by them shows that the Estonian living standard will catch up to that of the EU in only 31 years. ■

18 BIOTECH ESTONIA

PM/SCANPIX BALTICS ECONOMY

Estonian programmers offer services all over Europe

environment which would enable major enterprises New Estonian applications for e-business as well as NETWORK READINESS to carry out their own financial transactions. m-business caught the interest of Sony employees, INDEX 20022003 As early as 2001, the company had earned who decided to visit the CeBIT fair in Estonia this 1. Finland 300,000 EUR profit and thus covered its investment year to gain firsthand experience. 4. Sweden expenditures almost fourfold. The emergence of this Due to the economic situation the spread of 7. UK 8. Denmark unit enhanced inside competition in IT develop- home computers is not comparable to that in the 10. Germany ment as Estonians are competing with an analogical EU. The Tiger Leap project (supplying schools 17. Norway 24. Estonia unit in Stockholm, and, owing to that, the SEB has with computers), however, has already had a posi- 28. Czech Republic 30. Hungary been able to cut IT costs by 64,000 EUR. tive effect. Young Estonians are not different from 33. Slovenia Increasingly more and more orders from their peers in the three well-known IT countries 38. Latvia 39. Poland Western European companies are met by Estonian (Finland, Sweden and the US) as far as intensity of 40. Slovak Republic IT companies: Trigger Software, for example, has computer usage and its popularity are concerned. 46. Lithuania programmed the Everyday.com portal used At present, another major project (Look@World) Source: World Economic Forum throughout Europe, for Tele2 as well as the WAP is under way, supported by private com- portal Geisha, enabling paid content service in a panies. In two years, 100,000 people WAP environment to be offered. In addition to with no previous experience will learn more favourable prices (often half to a third as elementary skills needed for computer LARGER FOREIGN INVESTMENTS AND expensive as the Western European average) usage. INVESTORS IN ESTONIA: the terms of delivering orders can be The Estonian educational system I shorter in Estonia. Wi-Fi and paying has caught up with the new require- Galvex (US private persons) for purchases by FSS Plywood (UPM Estonian programmers have con- ments. In addition to public establish- Kymmene) siderable experience, especially in e- mobile phone are the ments of higher education, Estonia Horizon Pulp & Paper (Tolaram Group) banking and mobile phone services. hot topics of the day. has an IT College with internationally Elcoteq Eesti (Elcoteq The New York Times printed an article accredited curricula. Western European Network)

on how in a country with 1.4 million inhabitants, companies have become increasingly interested in T more than 700,000 use internet banking. Estonia recruiting the IT graduates. A Finnish company Eesti Telekom (Telia,Sonera) Radiolinja Eesti (Radiolinja) is in second place in the world in internet banking from Turku has calculated that they would save Tele2 Eesti (Tele2) developments and eighth place in practical applica- 2000 EUR per employee a month provided they T tion of e-services. In Tallinn, the capital of Estonia, moved to Estonia. ESCO (Tschudi & Eitzen) Estonian Air (Maersk Air) half of the turnover produced by car parking lots “We have not run out of good programmers Eesti Raudtee (Rail World) is provided by mobile phone payments. No wonder yet,” says the head of SEB IT Partner, Peeter C the largest mobile operator in Estonia, EMT, initi- Klanberg. “Our company prepared an interbank EMV (Skanska) ated a pilot project for the same purpose in Oslo, transaction system for the Estonian Bank (Eesti Norway. Pank) after a well-known major French group did The hot topic of the day is the digital signature. not succeed in creating a system able to perform The head of Estonia’s largest telephone company 500,000 transactions an hour without fail. After provides a good example: while in France, he was serious consideration, we undertook the task, and able to sign a collaboration project with Tallinn as a result created a system that works five times Technical University. faster than what the French offered.” ■

BIOTECH ESTONIA 19 ECONOMY Scandinavian quality at a low Baltic price

Stephania Belmondo and Bente Skari are Before launching the factory in 2000, the only considered by local people in Otepää, a small person with any experience in modern plywood town in Southern Estonia, as their own. The town production technology was the present head of is the skiing capital of Estonia where several of the the factory, Kaido Kukk. Thus, 25 people were world’s best skiers go through their preparation sent to Finland to pick up the secrets of the periods and participate in competitions. Otepää is trade. When back, they trained others in turn also the starting place of the Tartu Marathon, a long- and today the number of employees in Otepää distance skiing event in the Worldloppet series. In reaches 140. some mysterious way snow could be found in local UPM-Kymmene sells plywood produced forests even when grass is emerging elsewhere. in Otepää under the WISA trademark all over The same forests provide lumber for the FSS Europe. Kaido Kukk confirms that there have Plywood Factory, situated in Otepää. The factory, been no complaints as to quality up to now. The LONGTERM FOREIGN belonging to the Finnish Forestry Trust UPM- employees have to work hard, because – as he puts CURRENCY RATINGS FOR ESTONIA DEC. 4, 2002 Kymmene, turns thin layers of decorative wood it – the owners want Scandinavian quality at a low from soaked birch to logs that are then glued Baltic price. Fitch IBCA: A-; Outlook stable together to become plywood. Good quality birch Plywood is one of those foreign investments Standard & Poors: plywood is in high demand and increasingly used that have caused debate in Estonia. There is a A-; Outlook stable Moody`s: in construction work as well as in building ships, fear that locals will remain only low-paid sub- A1; Outlook stable trailers and railway coaches. contractors while expensive end products will be Source: Trigon Capital Although most of the production process in produced by the Western European factories. Yet, Otepää is automatically controlled, plywood produc- the same plywood is used by the Estonian compa- tion still requires some extent of handwork where nies to produce refrigerator trucks and parts for a sharp eye and quick decisions are vital, e.g. while Mercedes-Benz luggage vans. The plywood has assorting plywood according to its quality. That is why also been successfully used in furnishing projects great attention is paid to employee qualifications. in Italy and Austria.

INTERVIEW Foreign investors` second round in Estonia Foreign investors are having a new round in Estonia. According to Andrus Viirg, the head of the state agency responsible for attracting foreign investments, accession to the European Union has also made Estonia alluring for Southern Europe.

The head of the >> How big a loss for Estonia was the decision >> Is it true that 65-70% of foreign investors Agency of Foreign Investments, by BMW to establish a new factory in Germany give up the idea because of the absence of any Mr. Andrus Viirg, instead of Estonia? state-offered privileges? the former head of I would not call it a loss, but perhaps our utopian Yes and no. It is true that, differently from us, most the Estonian Unit dream. There is no car industry tradition in Estonia Eastern European countries offer tax reductions of the World Bank. and finding 2000-3000 skilled workers would have and even financial support for new jobs cre- been extremely difficult. Estonia, however, is a ated. One of the decisive factors for choosing wonderful place for investments requiring less East Germany for the location of the BMW labor force. The Estonian steel producer Galvex, factory mentioned above was huge privileges for instance, employs 120 people. demanded.

20 BIOTECH ESTONIA ECONOMY Scandinavian quality at a low Baltic price

The company itself is becoming more interested in producing more sophisticated items that will pro- vide added value. A licence allowing plywood to be produced for liquid gas tankers has been applied for. This is exclusive production and according to a new standard the licence will be the second one in the world. The tankers transport liquid gas in containers at a very low temperature (-162 ºC) WORLD under very high pressure. Plywood parts are used COMPETITIVENESS RANKING 2003 Plywood to produce insulation for containers. POPULATION LESS produced in THAN 20 MLN Otepää under The recent decade in the Estonian the WISA forest industry has been characterized trademark is 1. Finland well-known all by a continuous decrease in round 2. Singapore over Europe. 3. Denmark lumber exports and an increase in 7. Sweden sales of more valuable lumber. In the middle of the 12. Norway 17. Estonia 1990’s, 70% of exported lumber consisted of raw 21. Czech Pepublic materials, but in 2000 the percentage decreased 23. Hungary 27. Slovak Republic to 50% and is even lower now. In 2002, Estonian 28. Slovenia

Source: IMD World companies exported lumber and lumber products Competitiveness Yearbook 2003 for 860 mln EUR, furniture and wooden houses contributing the most. The demand is carefully monitored by the FSS Plywood Factory: if demand increases, a new building is constructed and another production PM/SCANPIX BALTICS line added. ■ Stories by Taivo Paju

>> What are the bonuses offered to foreign have shown noticeable interest lately, and this is our real estate developers have understood investors in Estonia? There are no specific a new trend. I believe that due to our forthcom- the importance of industrial real estate. The bonuses. Our best competitive advantage is ing accession to the EU investors from Germany, same holds true for foreign developers who equality. If an enterprise has been registered in France and Great Britain will feel encouraged to have become interested in setting up industrial Estonia then the source of the capital it is based show interest in this region. After all, we could facilities with the basic structures in order to rent on is of no importance. The same transparent tax be the last region characterized by the European them out in Estonia. system is valid for everybody (income tax rate is tradition of risk-taking and business mentality, 26% for both a private person and a company providing at the same time the huge Russian >> How pleased are foreign investors with and reinvested profit is tax-free). All companies market and St. Petersburg behind our border. Estonian skilled labor? can apply for state support for the development Every undertaking is different, of course. Estonia of their entrepreneurship. >> The companies have been privatised, so did not have a plant like Elcoteq before. All com- what kind of investments are you expecting? panies have educated their employees and the >> Which countries are presently the biggest Transpositions and mergers will play an ever- feedback given by them has been very good. Our foreign investors in Estonia? Almost 70% of all increasing role. There will be a few Greenfield employees have been characterized by the ability investments come from Sweden and Finland. We investments, though there are few lucky excep- to learn and pick up new skills quickly. ■ do not have large-scale investments from Germany tions, e.g. Norwegian Larvik Cell is going to More information about investment or Great Britain. Spain, Greece and Italy, however, establish a cellulose plant in Kunda. By now, opportunities in Estonia www.investinestonia.com

BIOTECH ESTONIA 21 PHENOMENA

There are not many companies whose trademark coincides with the country’s name. One such rarity is the Estonia Piano Factory in Tallinn, which has been in operation for more than 100 years and has found its way to the top, being now among the leading piano manufacturers.

lthough the piano building school was established in Estonia back at the end of the 19th century, production didn’t boom Auntil half a century ago. The beginning was quite unexpected – every Republic of the Soviet Union had to produce a present for the jubilee of the great leader, Stalin. Soviet Estonia, subject to a supreme power, decided to present a grand piano. Stalin liked the instrument so much that he The Estonia Piano Factory focuses on mahogany pianos. insisted on establishing a grand piano factory in Estonia, which could supply the whole Soviet Estonia’s playground is an instrument labelled as Union. Since then, Estonia has provided pianos “expensive” or “reasonable.” The Estonia Piano for quite a large music market. Factory strikes with a historically rare approach: Today’s Estonia Piano Factory is associated most of the manufacturers have started by launch- with another world power – the United States of ing cheaper vertical pianos and baby grand pianos. America. More than 80% of production is exported Having gained ground with these product groups to the US. The country also offers the best future they aim at parlour grand pianos, ending up with prospects, says one of the company owners, Indrek concert grand pianos. The Estonia Piano Factory Laul, who is planning to increase the share of US started with handcrafting concert and parlour exports to up to 90%. grand pianos, and expanded the line with studio grand pianos. All models are handcrafted in Tallinn. Only the Italian Fazioli factory started at the beginning

Indrek Laul, the of the 1980’s in a similar way. At present, Estonia head of the com- Grand Pianos are promoted as “a professional’s pany, and super- model Carmen choice.” Market development takes time and a Kass in the Vaal art celebrated expert is the best reference, for a piano gallery, Tallinn. is a luxury – it has been a luxury since its birth. The best sales strategy is personal selling. On that market clients choose products and, vice versa, products choose clients. Estonia’s client

22 BIOTECH ESTONIA PHENOMENA

Grand piano Estonia – sales hit in USA

is a dealer: the factory has 12 major and almost Russia and Europe and delivers pianos for the US. 30 minor dealers. Consequently the sales strategy As most of the production is sold to a wholesale emphasises the need for expedient dealers. dealer from the US, the factory’s marketing costs The piano business assumes that a dealer must are reduced. be personally interested in the manufacturer; In 2000, Musictown USA issued a run-down, to put it another way, one must understand the which gave Estonia higher credit than many spirit of the product in order to sell it. It helps known trademarks. Larry Fine argues in his best- to arouse interest if a celebrity seller from last year “The Piano Book” plays music on the instrument A Soviet instrument, that Estonia’s grand piano has had a or values it highly – the proc- which in 1993 belonged to sharp rise compared to the year 1993 ess is called celebrity promotion. the lowest category, is now – a Soviet instrument, which in 1993 This is why the factory has given on the competitive level with belonged to the lowest category, is gifts to supermodel Carmen the best German trademarks now on a competitive level with the Kass, schools, churches and other such as Sauter and Seiler. best German trademarks such as institutions. And last but not least, Sauter and Seiler. Many influential Juilliard School graduate Indrek Laul himself serves registered piano technicians of the US participated as a means of promotion. It can be compared to in the evaluation. Mika Häkkinen selling rally cars constructed in The long-term development plan of the Estonia his company. Piano Factory can be characterized by the words Thus, the marketing budget priorities of the “concentration” and “focus.” “The more we focus, the Estonia Piano Factory are explicit: a lot of atten- better the results whether regarding sales, production, tion is paid to promotional events. “One baby grand personnel or finances. Today, only Fazioli and Estonia piano (16.000 dollars) was presented to the Detroit do not produce vertical pianos,” explains Laul. Orchestra, the conductor of which, Maestro Neeme At the same time, the factory is reducing its Järvi, is of Estonian descent,” says Indrek Laul. activity on the markets of South America, Asia, The factory, situated in Tallinn, is mainly a Canada, some European countries and even some manufacturing unit. The marketing problems are states of the US. The emphasis is on the American targeted mainly in the US – a wholesale merchant, metropolises. Why? “It’s more efficient in regard to the Estonia Piano Factory (New York State), deals sales and production,” explains Laul. ■ with the marketing issues. The sales department By Andres Aarma in Tallinn mainly addresses orders from Estonia, Reviewed from Tallinn Airport magazine

BIOTECH ESTONIA 23 CULTURE

900 Old Believers preserve their traditions and culture

he Eastern shore of the fifth largest lake in The road that passes through the villages is narrow. Europe, Lake Peipsi, belongs to Russia and The main means of transport is the bicycle, or peo- the Western shore to Estonia. Forty kilom- ple just walk. 50-year-old bicycles are still in use. Teters to the northeast of Tartu lies the Peipsiääre The Old Believers are quite reserved and intro- district. This local government unit includes three verted. They pray frequently and are not keen on villages on the lake shore populated mainly by inviting strangers into their homes. Their little Russian Old Believers. houses smell of onions and candle wax - manu- The Old Believers ended up in Estonia after factured candles are never used; preference is given the church reform (1653-1656) instigated by to candles made of real beeswax. Patriarch Nikon. In Russia they were forced to “Every room in the house must have an icon,” adapt to changes in Orthodox rituals and accept says Feodosia Filippova. The Filippov family has new liturgical texts. A greater majority submitted built themselves a new spacious home, as the old to being re-baptized, but some fled to neighbor- one was just too small for the whole family. The ing countries - Latvia and Estonia. Their biggest house might be new, but the spirit of the Old concentration in the world is to be found in the Believers has been preserved. The head of the Peipsiääre district, in the villages of Varnja, Kasepää family, Vladimir Filippov, is one of the biggest and Kolkja. Of the 1014 inhabitants in the district employers in the district, being the owner of the almost 900 are Old Believers. Peipsi Kalamees fishing company. The three villages lie on a narrow, almost 12 Lake Peipsi is abundant with fish. According km-long strip on the lakeshore. Low wooden to scientists, the annual replenishment of the fish houses and garden plots are close together. Direct supply in Lake Peipsi is 24 kg per hectare of the access to the lake is important for the people liv- lake’s surface. There are only two private companies ing in beachfront houses. Unfortunately, not all the in the Peipsiääre district, both of them headed by families can afford to have their own boat, as regis- local men. tration and technical inspection is quite expensive 60% of the inhabitants of the district are nowadays. A boat is usually shared by a number of pensioners. They manage quite well, however, families, who take turns fishing. by growing vegetables and selling the produce to Each house consists of two parts – living quar- wholesalers. During the Soviet period, the villages ters with a low onion-drying oven, and adjoining supplied the Leningrad (St. Petersburg) markets rooms for storing fishing equipment and drying with onions and cucumbers. fish. Many houses have an oven for smoking fish The wild nature along the shore is unpolluted located between the house and the lake. – there is no industry or any other source of pollu-

24 BIOTECH ESTONIA CULTURE

900 Old Believers preserve their traditions and culture

PM/SCANPIX BALTICS

tion nearby. In this clean environment the famous The names the Old Believers give their children Old Believers sing their own chorals during Peipsi shore onion has been grown for many centu- are also unique – for example, Pulheria, Jevstolia church festivals. ries, using the same methods. Local onion beds are or Prokudija. The child is always baptized on their specific: they are always tilled by hand, and the soil patron saint’s name day. In summer, they go out is piled into to meter-wide beds by special shovels. onto the lake by boat and dip the child three times Between the beds are ditches, half a meter wide into the water. In colder months, a three-legged and deep as well. Such beds hold water for a long vessel is used for baptizing. After the procedure, time, and any additional water from downpours is boys receive a boy’s cross to be worn around his collected in the ditches. neck, and girls are given a girl’s cross. Men and Four Old Believer churches have survived in the women also wear different crosses. Peipsiääre district and they are all active. During The favorite sightseeing spots are old churches, church festivals, the congregation enters the church and also the Old Believers’ Museum. Museum at dawn. The Old Believers have distinct traditions, director Niina Baranina has collected significant church festivals and their own chorals. The old local history exhibits from the surrounding vil- script has also been preserved, although now only lages. Next to the museum is the only onion and very few are able to read it. The Old Believers live fish restaurant in Estonia, where fish dinners are according to their own calendar. Their New Year prepared according to special Old Believer recipes. is particularly unusual – on January 13 they cel- The fish offered is, of course, from Lake Peipsi and ebrate the Old Year, and on January 14 the New the onions are from the local village. ■ Year itself. Reviewed from In Time magazine by Hannes Tamme

BIOTECH ESTONIA 25 CONTACT

Estonian Biotechnology companies and research institutes

Company Name: Address: CEO/contact: www / e-mail Tel: / Fax Profile: Lunini 24, Tambet www.appliedphenomics.ee +372 52 73 465 Target validation using well-characterized set Applied Phenomics LLC. Tartu 50406 Teesalu [email protected] +372 7 426 87 of human tissue specimens. Custom mutation detection and SNP genotyping services Oru 3, www.asperbio.com +372 7 441 556 Indrek Kask and products for association studies and haplotyping projects Asper Biotech AS Tartu 51014 [email protected] +372 7 442 343 based on APEX technology.

Poska 4-27, www.bestenbalt.com +372 50 25 559 Proteomics-related services including production, Bestenbalt LLC Tallinn 10147 [email protected] +372 6 013 861 purification and identification. Akadeemia tee www.bimkemi.ee +372 6 654 248 Environmental biotechnology, specialty chemistry and and equip- 21G-320, Maris Liiders BimKemi Eesti AS [email protected] +372 6 654 248 ment construction. Tallinn 12618 Methods and software for large-scale SNP genotyping, Oru 3, Andrus www.biodata.ee +372 50 91 007 fully automated systems for automatic processing and BioData OÜ Tartu 51014 Kaldalu [email protected] +372 7 442 343 analysis of large datasets. Sakala 17, Tallinn www.celecure.com +372 6 512 670 Discovery and preclinical development of next generation Rainer Nõlvak Celecure AS 10141 [email protected] +372 6 512 671 tumour cell specific therapeutic compounds against cancer. Analysis of disease and drug response data Vallikraavi 2, www.egeeninc.com +372 7 440 455 Piret Roos in association with DNA and biomarker profiles emerging EGeen AS Tartu 51003 [email protected] +372 7 440 456 from the Estonian Genome Project (EGP). Nooruse 9, www.fitbiotech.com Fit Biotech Mart Ustav DNA vaccination, and immuno- and gene therapies. Oyi Plc Estonia Tartu 50411 [email protected] Riia 185, +372 51 05 079 Raivo Uibo [email protected] Novel immunodiagnostic devices for human diseases. Immunotron OÜ Tartu 51014 +372 7 383 041 Custom antibody services and peptide synthesis, www.inbio.ee +372 6 397 974 Sakala 17, Tallinn Tarmo Kivi research in the field of cell-membrane penetrating antibody InBio OÜ [email protected] +372 6 397 974 technologies and diagnostic and therapeutic intrabodies. Akadeemia tee 15/1, www.kevelt.ee +372 6 204 390 Ivar Järving Prostaglandin synthesis. Kevelt AS Tallinn 12618 [email protected] +372 6 703 683

Kungla 40, Aavo-Valdur www.labas.ee +372 7 428 009 Production, purification and labeling of mono- and LabAs AS Tartu 50403 Mikelsaar [email protected] +372 7 428 940 polyclonal (mouse, goat, rabbit, chicken) antibodies.

Vilmsi 28-1, www.labema.ee +372 6 419 496 Maja Riskala Products for microbiology and clinical diagnostics. Labema Eesti OÜ Tallinn 10126 [email protected] +372 6 419 497

Riia 185, www.naxolab.com +372 7 428 001 Indrek Toots Enzymes, reagents and Smart Mix buffers. Naxo OÜ Tartu 51014 [email protected] +372 7 477 131 www.ut.ee/innovation/ Ravila 19, +372 7 374 378 Ülo Puurand technologies/geen_analyys.htm A novel method for genome analysis. OÜ IasGen Tartu 50411 +372 7 374 372 [email protected] www.eau.ee/~agt/mustikas/ Specific micropropagation protocols for different Sillapää, Räpina Hedi mikrotaim.html +372 51 32 091 plant species, initiation of plant tissue cultures, micropropagated OÜ Mikrotaim vald 64507 Kaldmäe [email protected] plant material, consulting production labs etc. Manufacturing of fine chemicals and developing of chemical Akadeemia tee 15, www.prosyntest.com +372 6 204 398 Kaarel Siirde processes and new synthetic procedures as well as manufacturing ProSyntest AS Tallinn 12618 [email protected] +372 6 547 520 pharmaceutical active ingredients and advanced intermediates. Medical diagnostics services, FIUO products of gene-expression Nooruse 9, www.quattromed.com +372 7 380 276 analyse systems, research in the fields of gene therapy and gene Erki Mölder Quattromed AS Tartu 50411 [email protected] +372 7 380 284 vaccination (replicating vectors of human papilloma and herpes viruses against cancer). CONTACT

Estonian Biotechnology companies and research institutes

Company Name: Address: CEO/contact: www/e-mail Tel:/Fax Profile: Pikk 14, www.sbd.ee +372 7 402 079 Agu Artma Production of high-quality thermostable DNA polymerase. Solis BioDyne OÜ Tartu 51013 [email protected] +372 7 402 079 Koorti 37, Toonika www.hot.ee/torrosen +372 7 375 167 A spin-off company commercialising TorroSen OÜ Tartu 51011 Rinken [email protected] +372 7 375 264 the new technology of biosensors. PO Box 229, Tartu www.visgenyx.com +372 51 55 431 Transgenic animals for gene polymorphism studies, Indrek Toots Visgenyx Ltd. 50002 [email protected] +372 7 477 131 original disease models and biopharmaceutical production. RESEARCH Ülikooli 18, www.ut.ee +372 7 375 100 Jaak Aaviksoo University of Tartu Tartu 50090 [email protected] +372 7 375 440 Ehitajate tee 5, Andres www.ttu.ee +372 6 202 002 Tallinn Technical University Tallinn 19086 Keevallik [email protected] +372 6 202 020

Kreutzwaldi 64, www.eau.ee +372 7 313 001 Estonian Agricultural Alar Karis University Tartu 51014 [email protected] +372 7 313 068 National Institute of Akadeemia tee 23, www.kbfi.ee +372 6 398 300 Ago Samoson Chemical Physics and Tallinn 12618 [email protected] +372 6 703 662 Biophysics Riia 23, Richard www.ebc.ee +372 7 375 064 Estonian Biocentre Tartu 51010 Villems [email protected] +372 7 420 194 Tallinn Technical Ehitajate tee 5, www.ttu.ee/biogen/ +372 6 298 339 Riin Ehin University Center for Bio- Tallinn [email protected] +372 6 398 382 and Gene Technology Institute of Molecular Riia 23, Juhan www.tymri.ut.ee +372 7 375 037 and Cell Biology Tartu 51010 Sedman [email protected] +372 7 420 286 Centre of Excellence Riia 23, Richard www.tymri.ut.ee/TK +372 7 375 028 for Gene and Environmental Tartu 51010 Villems [email protected] +372 7 420 286 Technologies Centre of Excellence Ravila 19, +372 7 374 231 Raivo Uibo [email protected] for Molecular and Tartu 51014 +372 7 374 232 Clinical Medicine OTHER Organizing, coordinating and promoting R&D activities, training Riia 23, www.genomics.ee +372 56 621 301 Estonian Genome Maris Väli and promotional activities in the field of gene and biotechnology. Tartu 51010 [email protected] +372 7 420 286 Foundation Regional Branch Office of the European Federation of Biotechnology. A non-profit foundation founded by the Government Vallikraavi 2, www.geenivaramu.ee +372 7 440 420 Estonian Genome Project Krista Kruuv of the Republic of Estonia for the preparation and implementation Tartu 51003 [email protected] +372 7 440 421 Foundation of the Estonian Genome Project. Tiigi 61b, www.biotech.city.ee Aims to further partnership between the public sector and non- Estonian Biotechnology Jaanus Pikani Association Tartu 50410 [email protected] governmental organisations and develop Estonian biotechnology. Infrastructure and related services for biotechnological Riia 185, www.biopark.ee +372 7 383 053 Andrus Tasa development activities and entrepreneurship to Estonian Tartu Biotechnology Park Tartu 51014 [email protected] +372 7 383 041 and foreign biotechnology companies. Soola 8, www.quintiles.com +372 7 371 150 Clinical studies, capturing the high quality data collection, Katrin Otsalt Quintiles Estonia OÜ Tartu 51013 [email protected] +372 7 371 151 management, finalising the data-report; Post-Marketing studies ��������������� ������ �������������� ���������� ��������������� ����������������� ������� ������� ������������������� ���� ���������������� ������ ��������������� ������ ���������������������� ���� �������������������� ����� ������������������������� ��������� ��������������� ������� ���������������� ������� ���������������������

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