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From genetic data to medicine: The promising paradigm? |
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| Before 1977, the idea of sequencing the entire human genome was just wishful thinking. By the 1980s, it was increasingly apparent to many scientists that an understanding of basic biology would be greatly enhanced if the detailed structure of DNA were understood. The Department of Energy (DOE) and the National Institutes of Health (NIH) began the laborious task of decoding and interpreting the human genome chromosome by chromosome. The information was collected and stored at Los Alamos’s Genbank. The task promised to be complex and seemingly endless. But on April 6, 2000, J. Craig Venter reported to a congressional committee that his company had finished analyzing all the necessary pieces of human DNA and would assemble the whole human genome within 3–6 weeks. The interpretation of the 3 billion letters of DNA, however, will require several more years of research.
Venter, president of Celera Genomics, shocked the scientific community in 1998 with the announcement that his new start-up company, formed in partnership with PE Corp., intended to crack the human genome sequence in just 2 years, well ahead of the publicly funded Human Genome Project (HGP). Two years later, he made good on his intentions by announcing the complete analysis of human DNA. This milestone in the history of science and medicine has catapulted Celera to the forefront of medical innovation. On June 26, 2000, Venter announced that Celera had completed the first assembly of the human genome, which had revealed 3.12 billion base pairs (1). An assembled genome is one in which the location and order of the letters of genetic code along the chromosomes are known. At the IBC Drug Discovery Technologies 2000 conference in Boston, Venter commented, “Having the genome complete facilitates the discovery of finding functional targets as well as speeds up the pace of discovery.” Celera is now entering the analysis and annotation phase. The year 2000 was undeniably a landmark for science and medicine. At another IBC Drug Discovery Technologies 2000 conference in Switzerland, Michael Pavia, chief technology officer at Millennium Pharmaceuticals, summed up the genomics landmarks of the year as “a period in which our children and grandchildren will be able to reflect and consider 2000 as the most significant in the past 5000 years of healthcare.” Framework for completing the HGPThe overall goal of genomics is to determine the sequences of all of the chemical base pairs that make up human DNA; store this information in databases (bioinformatics); develop tools for data analysis; and address the ethical, legal, and social issues that may arise from the project. The HGP, albeit controversial at times, has made genomics a living and evolving icon for biotechnology. It has created an interesting paradigm for supporters and opponents alike. Some opponents view the HGP completion as a beginning for Frankenstein science. To supporters, completion of the HGP offers hope to people suffering from this century’s plagues. Regardless of your viewpoint, encoding the 80,000 or so genes needed to make and operate a human being is expected to provide the basis for a new generation of medical treatments that will attack disease at the genetic and cellular levels. The completion of the project will provide more than 100,000 new biological targets, at least 10,000 of which could be used as targets for drugs. In sharp comparison, drugs developed over the past 35 years were aimed at 450 biological targets. And like all new innovation, the completion of the HGP will undoubtedly create lots of bottlenecks for an already strained drug industry. The genesis of HGPThe idea of understanding the human genome was initiated in 1977, when simple and efficient methods for sequencing DNA were under investigation. By 1984, DOE held several meetings to address the problem of detecting extremely low levels of DNA mutations in humans who had been exposed to radiation and other environmental hazards. The actual human genome project began in 1986 as a modest $5.3 million pilot project of DOE to measure DNA damage caused by irradiation and its potential benefits to cancer research (2). It wasn’t until 1988, when DOE and NIH presented their 15-year plan to sequence the human genome before the U.S. Congress, that the HGP was officially born. The public immediately responded with considerable skepticism about the possibility and economical feasibility of the HGP, the value of its results, its impact on the rest of biological research, goal definitions, funding, and potential risks of information abuse. By 1990, the U.S. National Human Genome Research Institute allocated $17.2 million to NIH and $10.7 million to DOE (3). Enhanced, automated sequencers made the process of obtaining the base-by-base (chromosome-by-chromosome) sequencing of DNA easier. With the emergence of new sequencing technology came the realization that completing the human genome was imminent. In contrast to the chromosome-by-chromosome approach pursued by HGP, Celera planned to break the entire genome into small pieces, sequence those pieces all at once with a phalanx of very fast and expensive sequencing machines from PE, and use some of the world’s most powerful supercomputers to assemble the sequenced fragments in the correct order (4). As a dry run before sequencing more complex genomes and to prove to the world that this “shotgun” approach would work, Celera took on the 180-million base genome of the fruit fly, Drosophila melanogaster. Completing Drosophila was the first milestone in genome sequencing; it was a monumental technical feat, and the swiftness with which it was completed was a combined academic and industrial effort. On October 12, 2000, Celera Genomics announced that it had completed sequencing 9.3 billion base pairs of mouse DNA. Celera now has sequenced the 3X-fold coverage gene, which should help researchers make key discoveries. Sequencing the 3X-fold coverage gene ensures 95% representation of the mouse genome. Celera has discovered single-nucleotide polymorphisms (SNPs) among the mouse strains, which it intends to use in a mouse SNP database. Some people have made the analogy that the decoded Drosophila genome sequence is the Rosetta stone of genome sequencing. By comparison, the decoded mouse genome is like the Colossus machine (used to break the Enigma Code in World War II) for deciphering the human genome. Besides Celera’s successes, other landmarks in genomic research have been achieved, most notably, the research of Peter Jenks at the Unité de Pathogénie Bacterienne des Muqueusés in the Institut Pasteur, Paris. Jenks gained considerable advances in an automated DNA sequencing technique, making the sequencing of entire microbial genomes more of a reality in the near future. There is now a frantic rush to sequence a wide range of important microorganisms. The continuing release of data from Jenks’s lab and other projects, combined with advances in bioinformatics and techniques used to investigate pathogenesis, will lead to an unprecedented understanding of microorganisms and how they cause disease (5). The potential impact on drug discovery and deliveryEmerging techniques in genetic testing and manipulation of genes could transform the practice of clinical medicine, from “diagnosis and treatment” to “prediction and prevention” (6). For Big Pharma, genomics will radically change the speed and efficiency with which drugs are brought to market. The growth that these companies have enjoyed will be a thing of the past if they don’t join the revolution. The completion of the human genome is the dawn of a whole new money-making business. Big Pharma “must join the revolution or die” was the warning of Steve Arlington, head of pharmaceutical R&D consulting at Pricewaterhouse Coopers in the United Kingdom, at the IBC Drug Discovery Technologies 2000 conference. Arlington pointed out that genomics has the potential to generate returns three times faster than three of today’s blockbuster drugs, collectively. Arlington speculates that for the top 20 pharmaceutical companies to maintain pace with companies like Celera, they must grow by 7% per year and generate on average an extra $28.9 billion in sales from new products between now and 2005. They must each launch at least 24–34 new products earning $1–1.45 billion apiece during the next 5 years (6). This is 4–6 times the number they currently produce. With these statistics, the large pharmaceutical companies are on a sure course for self-cannibalization if they don’t join the genomics revolution. As the interpretation of the human genome provides a greater understanding of genes as risk factors, and of the gene–environment interaction, there will be changes in the prediction of disease and the development of preventive strategies at individual and population levels. Other ramifications for the healthcare industry include environmental or behavioral interventions directed at genotypically susceptible individuals, in which case it may be preferable to alter the genome itself. Chemoprevention with tamoxifen for those at risk of breast cancer is one example (7). Although the source of much controversy and skepticism, reproductive technologies, such as preimplantation, will also benefit from the interpretation of information from the completed human genome. This information can help to prevent disabling monogenic disorders in newborns. Critical bottlenecks facing genomics researchThe scientific community is targeting 2005 for completing the interpretation of the human genome. Most of the bottlenecks confronting genomics research will stem from issues on how to interpret, use, store, and patent the technology resulting from the new wealth of information. Critical questions facing the HGP are the legal and social implications of decoding the human genome. This is a Pandora’s box for all involved in the genetic screening of embryos. Many people also believe that the proliferation of genetic testing may fuel genetic discrimination at the workplace, in the form of pre-employment screening, or in financial services, such as approval of life insurance and mortgages (8). Although these concerns may seem to be rhetoric, the complexities of biological phenomena may be so great that, even with the available advanced computing technologies, the interactions between genes, and between genes and environment, may defy the power of human analysis. Even though it is far from complete, the human genome is available online to the public. Experts anticipate that the open-source information model used in genomics research will be applied in many areas of science and medicine. They believe that this model will facilitate information exchanges in developing and delivering genetically customized drugs and therapies. This information exchange would ultimately lead to increased profits at the companies licensing their patents, and allow new companies (or divisions within existing firms) to explore new opportunities. The Web site of British magazine The Guardian–The Observer has an excellent pedagogy for understanding the gene patenting process (9). The hope is that as genetic variations and their association with common diseases are better understood, the current range of therapeutic interventions to prevent or treat inherited disorders will increase. References
Marc C. Fitzgerald is assistant editor of Chemical Innovation. |
