With the sequencing of the entire human genome coming closer by the day, the implications resulting from the exploitation of this information are becoming clearer. Intellectual property claims play an important role in the race between private and public sequencing efforts. While pharmaceutical companies are eager to use the generated knowledge to optimize drug development strategies, these will most likely neglect the intrests of developing countries.

The human genome is composed of approximately 3 billion base pairs the sequence of which is estimated to encode for about 100,000 genes. The Human Genome Project (HGP) is a global initiative to map and sequence the human genome. It was initiated by two US public institutions, the Department of Energy (DOE) and the National Institutes of Health (NIH), which formalized their efforts in 1988. After the first joint five-year plan had been written and a memorandum of understanding had been signed between the two organizations, the DOE-NIH US Human Genome Project officially began in October 1990 (see also the article in Monitor no. 25).
Since then, at least 18 countries have established human genome research programmes. Some of the larger programmes are in industrialized countries such as Australia, Canada, France, Germany, Japan, and the United Kingdom. Some developing countries such as Brazil, China and Mexico are participating through studies of molecular biology techniques for genome research and of model organisms that are particularly interesting to their regions.
The coordination among the different scientific groups worldwide is provided by the Human Genome Organisation (HUGO). HUGO was established in 1989 by a group of the world’s leading genome scientists and entails three dimensions of coordination:

•	international;
•	interdisciplinary, among scientists working on genetic mapping and those working on physical mapping;
•	interspecies among scientists working on the genomes of various model organisms.

Although many industrialized countries have come up with their own national human genome sequencing activities, the efforts by the public US research institutions are still the most advanced and receive the largest funding. From 1988 to 1999, the funding for the US human genome project totalled about US$ 2.2 billion, of which two third was provided by the NIH and one third by the DOE.
During the course of the project, technological developments and increasing experience with large-scale sequencing have led to an adjustment of the schedule. For instance, over the last four years the time to sequence DNA has dropped by a factor of 100, while the cost has decreased from several US dollars to determine a single base pair to US$ 1 per 500 base pairs. In September 1999, international leaders of the HGP confirmed a plan to complete a rough draft of the human genome by early 2000, a year ahead of earlier announcements. This draft will provide a framework of sequence across about 90 per cent of the human genome. Remaining gaps will be closed and accuracy improved over the following years to achieve a complete, accurate human DNA reference sequence by 2003, 2 years sooner than previously predicted. NIH and DOE expect to contribute 60 to 70 per cent of this sequence, with the remainder coming from the efforts of the Sanger Centre (UK) and other international partners. As a first milestone, the DNA sequence of the chromosome 22, the smallest chromosome apart from the male Y chromosome, was published in December 1999 in Nature.

Public and private sequencing competition
Public research effort was challenged by Craig Venter, a former NIH researcher who set up his own, privately funded genomics company The Institute for Genomic Research (TIGR, USA) in 1992. In May 1998, TIGR announced to cooperate with the analytical tool manufacturer Perkin-Elmer (USA) on a joint venture called Celera Genomics. Celera was established to sequence the entire human genome in only three years for US$ 200 million, a fraction of the expenses of the public research efforts. To meet this ambitious goal, Celera employs a ‘shotgun approach’, which involves randomly sequencing fragments from a genome that has been broken into short stretches. This strategy is based on pure sequencing power provided by high-speed automated sequencers in combination with elaborate bioinformatics tools. Critics contend that when the data are assembled into a sequence it contains gaps and is not very accurate.
In contrast, the HGP has a map-based approach and systematically sequences libraries of ordered bacterial artificial chromosomes (BACs, see glossary in this issue). Yet also the HGP’s new goal of a working draft by early 2000 will be attained using a shotgun style approach. The remaining gaps will be filled during the more labour-intensive second phase.

Property rights on the human genome
The competition between Celera and the HGP is only in part driven by these scientific arguments. More important is the question regarding the proprietary status of the data generated, and in this sense Celera’s shotgun approach becomes more rational. It aims at the detection of expressed sequence tags (ESTs) to identify genes that have the potential for further drug development, and only if they do further sequencing will be applied. As such, it tries to pick the ‘crown jewels’ out of the genome. Venter, who left TIGR to head Celera, explained that his new sequencing company would patent no more than 300 human genes, while the rest of the data would be made freely available in the public domain. But in October 1999, it turned out that Celera has in fact filed preliminary patent applications on about 6,500 gene sequences, fuelling the fear that the future of medical research will be hampered by an individual company’s claim. Since 1995, US patent law has allowed ‘provisional’ applications that establish the date of a discovery and give inventors the possibility to submit a detailed and more expensive application within one year. Celera announced that it would continue to file provisional patent applications, possibly totalling 20,000 to 30,000 by the time all genes are mapped. However, Venter states that most of these claims will be abandoned if it turns out that a sequence is of no medical use. As a result, full patent applications would indeed be filed only for a few hundreds sequences.
Another strategy of Celera to commercially exploit its genomics knowledge is to grant pharmaceutical companies licences to use the sequencing data bases. For instance, in November 1999, Pfizer (USA) subscribed to all of Celera’s databases to have access to a large number of novel drug target genes derived from Celera’s sequencing of the human genome.
While it seems that Celera is becoming the focal point of public discontent on the issue of privatization of genetic information, other companies are by no means less active in this field. Another company that pursues an aggressive strategy towards Intellectual Property Rights (IPR) on the human genome is the US company Human Genome Sciences Inc. (HGSI). As of October 1999, HGSI has filed patents for over 6,450 full-length human gene sequences, complete with information on protein expression, biological activity and potential medical use.
Concern arose that decoding the human genome will not render full medical benefit if genetic information can be exploited by private companies for profit. This has led to negotiations between UK and US government officials on an agreement to prevent patenting of the human genome. At present, patent systems both in the USA and Europe in principle allow for such patents and the US Patent and Trademark Office (PTO) has already granted over 1,500 patents on human DNA.

Pharma giants team up against genomics companies
The advent of pharmacogenomics (see box) makes it especially interesting for pharmaceutical companies to have access to genetic data for drug development. This has recently been emphasized by the announcement of an unprecedented collaboration of pharmaceutical companies such as Bayer (Germany), SmithKline Beecham (USA), and Hoffmann-La Roche (Switzerland), which are normally in fierce competition. In April 1999, the Wellcome Trust (UK), a leading medical research charity, and a group of multinational pharmaceutical companies decided to join forces with five of the world’s leading gene mapping institutes to set up The SNP Consortium, Ltd. (TSC). This consortium intends to release its knowledge on Single nucleotide polymorphisms (SNPs) jointly into the public domain, for instance on the internet, ensuring that it cannot be patented by other parties.
SNPs are point mutations of the DNA sequence, which are the most common type of genetic variation. They are expected to be responsible for a large part of the genetic differences among human beings. Drug companies also see this information as decisive for the future of drug development, allowing drugs to be made more appropriate to the patients’ genetic predisposition.
The aim of the two-year research programme is to identify 300,000 SNPs and to map 170,000 of them. This work will be performed at four major centres for molecular genetics, including the Stanford Human Genome Center (USA) and the Sanger Centre, and all the data from the Consortium-sponsored research will be stored and accessed in databases maintained by the Cold Spring Harbor Laboratory (USA). The two-year budget for the current TSC programme is US$ 47 million. Of this amount, the Wellcome Trust will contribute US$ 14 million while each of the eleven TSC corporate members will provide a total of US$ 3 million over the two-year membership term.
Pharmaceutical companies feel urged to collaborate because they are aware of the increasing expertise that smaller biotechnology and genomics firms have gained in unravelling genetic information for which they have claimed intellectual property rights. The pharmaceutical industry’s fear is that these companies could either withhold or charge high fees for access to such proprietary information needed for the development of lucrative medicines.
Yet also in this case, the distinctions between private and public domain are not clear cut. For instance, the pharmaceutical multinational Merck (USA) has not joined TSC, but has released all of its several hundred thousands ESTs into the public domain. On the other hand, Pfizer follows a parallel strategy: it pays Celera to get access to proprietary data, but at the same time generates information for the public domain within TSC.

Genetic information and drug development Why do some individuals react to particular drugs while others do not? The differences in reactions are mainly caused by mutations in the respective enzymes responsible for the metabolization of the given drug. As a result, the degradation of the active substance can lead to harmful by-products, or the drug might not have an effect at all. • Pharmacogenetics Pharmacogenetics has dealt with this question for more than 40 years. Based on classical genetics, pharmacogenetics has studied the inheritance of reactions to different drugs. This approach might be used to find a suitable drug for a patient, but it had little impact on the development of new drugs.  • Pharmacogenomics Pharmacogenomics is a new field of science. Instead of starting of from existing drugs, it tries to make use of information on human DNA sequences for the development of new drugs. The expectations are twofold; first that pharmacogenomics will render the search for new potent substances more effective and second that it will help to find more molecular targets for drugs in the human body. It is estimated that between 1940 and 1995 the entire pharmaceutical production was based on only 400 to 500 molecular targets. With the increasing knowledge of the human DNA sequence, databases of individual drug development companies now easily contain several tens of thousands of potential targets for drug actions.

Linking genotype and phenotype
Even though a lot of money and work is allocated to the HGP, having the ‘pure’ genetic information is not enough. Only if the genetic variation is linked with the effect on the phenotype it is possible to investigate, for instance, how certain mutations might cause a disease.
One initiative towards this end is the Human Genome Diversity Project (HGDP). In contrast to the efforts of the HGP to sequence a Euro-American set of chromosomes, the HGDP claimed to offer a broader view on the variations of the human genome worldwide. The initial idea was to collect DNA samples from about 500 genetically distinct populations. With data on specific DNA sequences and their distribution over the world, it should also be possible to answer questions about the migration of early humans. But the most important reason was that isolated populations are in most cases genetically more homogenous. In addition, such indigenous groups are often genetically distinct groups in which particular diseases may hence be more abundant. Therefore it might be easier to detect and isolate a gene responsible for the disease from such an isolated group than from heterogeneous groups.
In the early 1990s, the HGDP was initially estimated to carry out its work for 5 years and to cost about US$ 25 million worldwide. It was supposed to be funded independently for each region, mostly by public institutions. In 1995, a US patent was granted to the NIH on a cell line containing unmodified DNA of an indigenous man of the Hagahai people. Indigenous groups contended that the taking of blood and tissue sample for scientific research as well as for commercial use and for the patenting of genes, claiming this to be theft and a continuation of colonization. The worldwide protests urged the NIH to drop the patent claim, but the damage to the project’s image was severe. As a result, even though the HGDP and the NIH have developed a ‘model ethical protocol’, funds have not so far been granted to the Project’s North American Committee. Due to these funding restrictions, the HGDP research activities have mostly come to a halt.
Another project on disease-related genes is currently being carried out in Iceland. In December 1998, the parliament approved a bill by which the Icelandic company deCODE genetics gained a licence for the next twelve years to build up and exclusively use a national database. This database will include not only the genetic data of all 270,000 Icelanders, but also their medical records. The bill provides that medical data are automatically transferred to the central database after every treatment as long as the patient does not declare dissent. Furthermore, the database contains medical information on deceased persons as well as genealogical data on some 700,000 Icelanders. The combination of a small isolated population with a high standard of technology and large-scale medical as well as genealogical data makes Iceland an ideal place for such research. Under these circumstances, it is more likely to generate valuable information for drug development than, for instance, by trying to prospect genes from remote indigenous communities in isolated sampling expeditions.
The value of the database for drug development attracted the Swiss pharmaceutical company Hoffman-LaRoche to sign a contract with deCODE genetics. The Swiss pharma giant agreed to pay up to US$ 200 million for information deCODE genetics will provide on the genetic causes of twelve common diseases, such as diabetes and Alzheimer’s disease. Drugs derived thereof will be given to the Icelandic population free of charge.
The bill and the treaty with Hoffman-LaRoche are criticized for several reasons. While some Icelanders are concerned about the abuse of their private medical data, others do not want to be used as resource for commercial research. Furthermore, the promise of the free use in Iceland of drugs that may be developed based on the Icelanders’ genetic material is not so much perceived as a gift but as a large-scale medical trial.

Genomics and the future
As the finalization of the first complete sequence of a human genome comes within reach, questions about the use of such scientific progress become more urgent. Of course, not even the most pronounced advocates of genomics would claim that the causes of disease are all ‘in our genes’. The interaction of genetic and environmental effects is widely acknowledged. Scientific progress strongly depends on resource allocation and therefore human genomics will certainly make a contribution to our understanding of disease and the development of new medical treatment. On the other hand, non-genetic aspects of diseases might easily drop out of sight.
It seems today that in the industrialized world pharmaceutical research and development (R&D) has fully embraced a drug development approach based on genomics. If this is successful, the pharmaceutical industry would increasingly shift from selling substances towards selling information. Drugs would no longer be based on the biology of an average patient, but tailor-made towards the individual’s genetic preconditions. With smaller target groups, the investments would have to be earned back not so much by substance production and retailing, but by offering service and information. On the other hand, genomics progress could also lead to an improvement of general medicines, making them more effective for a larger part of the population.
The benefits, both to the companies and to the consumers, are still to a large extent speculative. The enthusiasm about the technological potential of genomics will not stop pharmaceutical companies from dropping this strategy if it does not help to develop commercially successful products and services.
With the increase in added value by genetic information the distinction between drug development for industrialized and for developing countries will widen. Genomics research in industrialized countries will continue to focus on diseases in affluent societies. Nevertheless, the increasing amount of information becoming available, such as on the genomes of microorganisms and pathogens, as a side effect also creates new possibilities for drug research for developing countries. To date, all developments of vaccinations against malaria, or Human Immunodeficiency Virus (HIV) make use of modern molecular biology and genetic techniques. One approach towards this end is being taken by the Medicines for Malaria Venture (MMV). To create incentives for the development of drugs that specifically address developing countries’ needs, new initiatives, such as ‘not-for-profit virtual drug companies’ under the umbrella of the World Health Organization (WHO), are trying to bring together public sector and drug companies. It remains to be seen to what extent such initiatives can generate the transfer of knowledge and resources that are needed to tackle the health problems in developing countries.
Genomic research certainly will have an impact on humanity. However, for the largest part of the world population it is not any genetic predisposition that decides their fate but the access to food, land, water and basic medical care.
Volker Lehmann & Antje Lorch

Editors Biotechnology and Development Monitor

Sources
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Housman, D. and Ledley, F.D. (1998), "Why pharmacogenomics? Why now?" Nature Biotechnology, October, Volume 16, Supplement, pp. 2-3.

National Human Genome Research Institute (1998), New Goals for the U. S. Human Genome Project: 1998-2003. http://www.nhgri.nih.gov/98plan/

Planqué, K. (1999), "Genoom, transcriptoom, proteoom: sequentie en consequentie." Technieuws, 37, no. 4, June, pp. 20-40.

http://www.ornl.gov/TechResources/Human_Genome/home.html