William Loob

September 1, 1999

12 Min Read
Genome Research Probes for Secrets of Human DNA

Medical Device & Diagnostic Industry Magazine
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An MD&DI September 1999 Column


William Loob

Less than a decade since its official beginning, the Human Genome Project (HGP) has significantly altered the way medical science will progress in the future. The genes that cause a number of serious hereditary diseases have been identified, leading to the development of genetic tests that could predict predisposition to disease prenatally; gene therapy trials have begun to test methods for fixing genetic flaws directly; and pharmaceutical companies have started to use genetic information as a guide to discovering new and more-effective drugs.

In its infancy, the goals of the HGP were viewed by some as overly ambitious. With approximately 3 billion base pairs of DNA coiled up in the full set of human chromosomes, skeptics argued that the analytical techniques and the methodology of genetic research were too slow and labor-intensive to achieve the goal of determining the proper sequence of the entire genome. But the technology available to HGP researchers advanced steadily, and the project now includes the vast resources of an unprecedented number of academic, government, and commercial institutions working in collaboration.

The HGP is accelerating the development of diagnostics and drugs.

Backed by government funding and using many different investigative strategies, the HGP centers began making steady progress toward decoding the fundamental instructions for building a human being. Recent developments in sequencing technology now promise to accelerate the pace of work by an order of magnitude or more. In addition, use of the latest technologies has reduced the research cost dramatically. When the HGP began in 1990, the cost was $10 per DNA base. The current figure is approximately 50 cents per base.

The agencies principally involved in managing the project in the United States, the Department of Energy (DOE) and the National Institutes of Health (NIH), now have compiled a database of high-quality DNA sequences that represents more than 10% of the entire human genome. The research effort has been so successful thus far that DOE and NIH recently revised their original target date for completing the project from 2005 to 2003.

The increased capabilities of the latest sequencing technologies has started a race to determine who can decode the entire sequence and become the first to build a complete map of the human genome. On one side is the public sector, an international collaboration of government laboratories and academic research institutions striving to build a complete guide to the human genetic makeup as a publicly accessible information resource. The incentive for competitors from the private sector is the commercial potential of owning a database that pharmaceutical and diagnostics firms would find useful in conducting research and in developing new kinds of products specifically for populations with a specific genetic makeup.


The prospect of using findings from genomics research to further knowledge of our own biology and to develop more-effective medical products has generated great enthusiasm in the scientific community and in industry. There was equal concern, however, regarding the social implications of genetic technology and its uses. The much-publicized early applications of genetic technology in medicine—genetic testing and gene therapy—spawned public controversy. There was significant public concern over protecting the privacy of personal genetic information and over potential uses of that information.

The DOE's Human Genome Project could be completed as early as 2003.

Though early discussions of genetic ethics focused primarily on aspects that would affect laboratory diagnostics directly, the issues of greater economic significance centered on gray areas in corporate law rather than general issues of personal privacy. Private-sector research on the human genome is largely geared toward patenting the information gained from the work to protect private investments. Ultimately, the prospects for using the knowledge gained from genomics has many avenues of commercial interest that extend far beyond genetic testing for heritable diseases and gene therapy applications.

According to a number of companies participating in the most fundamental work involved in sequencing DNA, the apprehensions of the general public about genomics research is largely irrelevant. Paul Gilman, director of policy planning at Celera Genomics (Rockville, MD), notes that the main business objective in large-scale sequencing is to acquire information about strings of DNA that can guide further research. The firm last year announced its plan to complete a map of the human genome. "The principle focus of our business is providing information about the human genome to other companies that can make products," he says.

Although Gilman acknowledges that Celera does follow debates about the privacy of patient records and efforts to reform FDA rules to facilitate the drug-approval process, he adds that the ethical dimensions fall to areas largely outside sequencing activity. The ethical issues that surround the HGP can affect the potential value of Celera's database, he explains, "but the downstream issues related to the use of that information does not affect our business directly."

Incyte Pharmaceuticals (Palo Alto, CA) is another firm that has declared plans to map the genome. The company's effort to expand its genomics database is currently focused on completing "most of the pharmaceutically relevant genes." Incyte's position on these issues suggests a degree of optimism about the future of drug development based on genetic research regardless of ethical quandries. Although public concern regarding the ethical use of genetic information could hinder progress toward new technologies, the potential gains from discovering novel biological agents keyed to specific genetic factors almost ensure that major corporations involved in developing drugs and in vitro diagnostics will stay in the game. Such incentives have been responsible for the formation of many new bio-technology enterprises in the last decade.


Once the major work of mapping the genome is complete, research will shift to characterizing the differences between the normal genetic sequences and variations that seem to affect disease processes. To get more information about the way we work from the basic map that the HGP provides, many investigations will focus on intense study of single nucleotide polymorphisms (SNPs), or variations of a single DNA base in the long sections of DNA that remain stable in the genome.

Experts in molecular genetics expect to find that such minor variations in the DNA sequence can account for clinically significant differences. The way in which these variations affect the structure and function of the protein that is built from the information in the gene can unlock clues to variability in human ailments. The information can also yield clues to designing proteins that can facilitate drug manufacturing processes, which can present difficulties with current technology.

In the interest of pooling resources to speed the process of discovery, many major corporations involved in the development of biomedical products have formed partnerships. Most of the partnerships are based on agreements to collaborate on a limited region of DNA thought to be associated with specific diseases. In April of this year, however, a large group of companies and academic centers formed an alliance, called The SNP Consortium, to create a public database of SNPs. The database will be used to identify the genes that could serve as markers for various diseases and the gene variations that can account for differences in the way people react to certain drugs. The activities of the consortium entail a two-year collaboration between ten pharmaceutical companies, five academic biomedical research centers, and one nonprofit medical research foundation. The major goals of the consortium are to identify genes involved in disease, develop diagnostic tests, and find ways to predict responses to drug therapy.

Though the SNP map will be freely accessible to the public, the members of the consortium will most certainly be among those who benefit from the research. Bayer Diagnostics (Tarrytown, NY), for example, as one of the consortium members, will be in a position not only to begin identifying potential candidates for new clinical diagnostic products but also possible drug targets for other Bayer business units involved in pharmaceuticals. William Wallen, PhD, senior vice president for research and development of Bayer Diagnostics, stated that the SNP map will help guide investigators to discover genes involved in human disease processes, but Wallen also placed his comments in a broader context than clinical diagnostics. "This important work will provide the foundation for the future development of many new therapies leading to an overall improvement in the health of mankind."


Understanding how subtle genetic variations can affect individual responses to specific drugs could help clinical laboratory scientists predict which patients are at greater risk of suffering side effects from certain drugs. Researchers involved in the budding field of pharmacogenetics suggest that this approach to will lead to new diagnostic tests that will allow physicians to design personalized drug therapies for their patients. Development of in vitro diagnostics that can characterize an individual patient's probable response to drug therapy could also define a new role for the clinical laboratory.

One recent example of such a development in pharmacogenetics is the discovery of two genes associated with hepatotoxic responses to the asthma drug Zyflo. The discovery resulted from a collaboration between a U.S. drug manufacturer, Abbott Laboratories (Abbott Park, IL), and a French genomics firm, Genset (Paris). The two firms entered into a partnership two years earlier to work toward an understanding of how genetic variations in patients determine individual responses to the drug. Clinical trials on Zyflo had revealed that about 4% of patients treated with the drug developed elevated ALT enzyme levels, which indicated a potential for liver damage. The affected patients consequently needed regular liver function testing while undergoing treatment. "This is a first step in the direction of a systematic screen that could serve to specifically exclude from treatment patients with marked susceptibility to side effects and lead to a significant decrease in the incidence of adverse events," explains Pascal Brandys, Genset's CEO.

Many gene discovery firms and pharmaceutical companies have formed similar alliances to exploit the growing databases of genetic information in reaching a fuller understanding of the actual mechanisms of drug action at the molecular level. These discoveries could lead to the development of screening tests to identify patients at risk for adverse side effects. They also open up the possibility of personalizing drug treatment. The American Association of Clinical Chemistry (AACC) held a conference devoted entirely to pharmacogenetics in November 1998, and this field of laboratory medicine shows signs of developing quickly. Among the promising areas of current research are discoveries in oncology, cardiology, neurology, and environmental medicine. Some observers predict that diseases may eventually be subdivided according to a patient's genetic factors that affect potential disease progression and response to therapy.

As research technologies begin to close the gap between diagnostics and drugs, business developments will also focus on developing complementary products to provide precise diagnostic information about a patient so physicians can prescribe better, more-efficient therapies. Vysis (Downers Grove, IL) recently announced a collaborative research and development project with Eos Biotechnology (South San Francisco, CA) that will make use of the tools of genomics to identify new diagnostics and drugs for breast cancer. Eos will provide samples of potential targets for breast cancer drugs that have been identified by DNA array technology. Vysis's role in the research will be to validate the panel of cancer-specific genes with its proprietary genetic tests and microarray technology. Eos will retain rights to drugs developed as a result of the collaboration, while Vysis plans to develop and market diagnostic products.

Michael Shi, MD, PhD, senior research associate for Parke-Davis Pharmaceutical Research (Morris Plains, NJ), told attendees of the AACC pharmacogenetics conference that high-throughput technologies for analyzing DNA sequences could soon find useful applications directly in the clinical setting. Chips that fix thousands of oligonucleotide probes into an ordered array can be used to identify multiple DNA polymorphisms in clinical specimens, he said. "In one reaction you can actually monitor all these polymorphisms. This technology could become a powerful tool for clinical diagnosis." The ability of DNA microarrays to detect multiple diagnostic markers from a single sample could speed up difficult diagnoses.


The proposal to create a map of the entire human genome has sparked research interest around the world, and a number of countries have joined in on the project. Major players in the international research effort include France, Germany, Great Britain, and Japan. Most of the institutions involved in this global effort have entered into the project in a collaborative spirit, often forming partnerships with scientists working in the United States. However, these countries are also realizing the commercial boost that can come to their national economies from protecting the results of their biotechnology research.

Germany's research community earlier this year called for more government spending to support a unified national effort to develop a genome map of its own and to promote the further development of its biotechnology industries. A central issue for proponents of a German HGP initiative is to clear the way for patenting genetic discoveries, which has been an obstacle for private firms seeking to protect the commercial value of their research investments. The French government has also stepped up spending on genome research and French biotechnology companies have shown a commitment to developing new products based on the results of their research efforts.

The field is still dominated by international collaborations, and the interests of genomics research seem not to be restricted by political borders. Clearly the United States, as the early originator of a research project with such far-reaching goals, maintains the lead in genomics research, and U.S. firms are now in a good position to begin trading in products developed from this work.


Though the technological advances of recent years support an optimistic view that the project is ahead of its original timetable, achieving the primary goal of mapping the genome is only the beginning of research that will eventually yield new products for the medical community. The task of cataloging the significant variations in gene sequences, then finding their significance in treating various diseases, is a major task that will keep researchers busy for decades.

If the real progress toward better drugs and diagnostics is just starting, however, the situation looks good for the industry as a whole. Progress in the basic research objectives is steady, and the portion of the genome that has been mapped to a high resolution has already resulted in new technologies, new drugs, and new diagnostic tests. If the accelerated pace of research in recent years is any indication, medical manufacturing should be well on its way to exploiting the riches of the research by the completion of the HGP's main objective in 2003.

William Loob is a medical writer living in Brooklyn, NY.

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