Senate Committee on Labor and Human Resources
Advances in Genetics Research and Technologies: Challenges for Public Policy
Statement of Francis S. Collins, M.D., Ph.D.
Director, National Center for Human Genome Research
July 25, 1996
Madam Chairwoman and members of the Subcommittee, I am pleased to appear before you today to discuss advances in genetic analysis technology, the biomedical opportunities it presents, and the public policy challenges it poses. Genetic analysis is important to biomedical research because nearly every disease has a genetic component, and understanding disease at the genetic level in many instances gives us the best hope for preventing, treating or curing it.
Technology development in genetic analysis has received a tremendous boost from the Human Genome Project (HGP), the international research program launched six years ago to develop technologies that make finding genes easier, faster, and cheaper. The National Center for Human Genome Research (NCHGR), part of the National Institutes of Health (NIH), and the U.S. Department of Energy (DOE) carry out the HGP in the United States. One of the goals of the HGP is to produce new technologies for the characterization of large amounts of DNA, specifically, all 23 pairs of human chromosomes and the 3 billion nucleotide bases that make up the human genome. Analysis of the genomes of several important model organisms are also included in the project's goals.
Briefly, the products of the HGP include genetic maps with closely spaced molecular markers throughout the human genome, physical maps consisting of sets of contiguous, cloned DNA spanning the entirety of each human chromosome, computer methods for easy data storage, retrieval, and manipulation, and ultimately, the complete nucleotide sequence of the human genome. The project thus far has been successful in meeting or exceeding the goals outlined in its original plan.
The HGP has been successful so far for several reasons. It was thoughtfully planned, focused on the development and application of new technology to significantly reduce the costs and vastly increase productivity, and recognized the need for a new kind of laboratory organization.
Last October, the HGP completed its fifth year with a record of excellent progress toward its goals. Its first goal, creating a detailed genetic map for the human genome, has been accomplished. Recently, a team of U. S. investigators published a physical map of the human genome composed of over 15,000 well-ordered markers; this represents a major milestone on the way to the next goal -- a comprehensive physical map of the human genome. Though original projections were that this map would not be finished until the end of 1998, completion is now expected in 1997. Already, over 95 percent of the human genome is represented in ordered sets of cloned DNA fragments.
These accomplishments have set the stage for the project's ultimate goal, sequencing all the DNA in the human genome by 2005. To accomplish this goal, the NCHGR has increased its investment in the development of new technology for DNA sequencing, concentrating on miniaturization and automation of current techniques. This approach has focused on improving speed and lowering cost. Progress in these projects has been remarkable as several laboratories have obtained at least 1 million base pairs of DNA sequence at a cost of about 50 cents per base pair. This represents a dramatic reduction in the cost of DNA sequencing from $5 to $10 per base pair when the Human Genome Project began.
This year, the NCHGR expanded its investment in DNA sequencing research. Pilot projects were initiated to address and resolve issues that will be confronted in large-scale sequencing of human DNA. These pilot projects are expected to generate between 50 and 100 million base pairs of human DNA sequence by 1998 and, in doing so, will develop and test the methods that will be used in the determination of the complete human DNA sequence.
With the prospect of completing the human DNA sequence early in the next century, we are eager to begin the translation and interpretation of this information. The HGP is producing detailed information about the chemical structure and organization of human DNA -- the order (sequence) of its three billion bases and the location of the approximately 100,000 genes it contains. However, the structural information that will result from the Project is only the beginning of biological interpretation. We will still face the challenge of understanding what the "instructions" encoded in human DNA mean; in other words, how the genes actually function. As Science magazine noted "To transform a single fertilized egg cell into an adult human body and then keeping that body alive and healthy ... requires some 100,000 genes, each adjusting its activity to precise degrees and at precise times and locations. Thanks in part to the Human Genome Project ... [scientists have assembled] ... vast amounts of raw material [emphasis added] about that intricate genetic machinery" [vol. 270, p. 368, 1995]. In less scientific terms, having a complete dictionary of the English language at hand is necessary, but not sufficient, for understanding Shakespeare's plays.
In biology, structure determines function. In general, the chemical structure and molecular shape of the DNA, RNA, proteins and other molecules that comprise our cells determines how these complex molecules work. For the most part, however, we have only superficial knowledge of how most of the molecules work together to form the complex, organized systems called cells, tissues and organs. If we understood how our genes and their biological products functioned normally, we would gain great insight into what happens when such normal function is disrupted or goes awry, which is what we call disease. We would then be able to take a truly knowledge-based approach to developing therapies and preventative strategies to reduce the disease burden on the American population.
As examples of how progress in genome technology is transforming our understanding of biology and medicine, let us consider three recent advances. One of these is "spectral karyotyping," a powerful new way to visualize the full set of human chromosomes, or karyotype, in a rainbow of colors. NCHGR scientist Thomas Ried and his coworkers applied spectral imaging, a technology used in remote sensing devices, to chromosomes isolated from cells. This exciting new technique translates computer-gathered light waves into a full-color palette and assigns each chromosome its own distinct hue. With all 23 pairs of human chromosomes identified by a different color, scientists can more easily examine the entire group of chromosomes for changes that could lead to disease, such as missing or extra pieces, or parts from different chromosomes that have swapped places. Dr. Ried and his coworkers have identified structural abnormalities in chromosomes from several different samples obtained from diagnostic laboratories, and demonstrated the value of the technique in identifying a breast cancer cell with a large number of broken and rearranged chromosomes and extra genetic material.
The power of the current whole-chromosome diagnostic techniques is limited because the methods rely on chemical stains that reveal only shades of gray. Pieces exchanged from one chromosome to another -- a process called "translocation" that is often associated with disease -- cannot easily be detected. And in diseased cells containing several badly distorted chromosomes, tracking the multiplication or exchange of genetic material is often impossible with conventional black-and-white banding.
In addition to its role in identifying chromosome changes related to the progression of disease, spectral karyotyping may be valuable in comparing genomes from different species to determine how genetic composition evolved over hundreds of thousands of years.
Another very exciting new technology is the DNA "chip," which takes a lead from semi-conductor science. A number of investigators in both the academic setting and in the biotechnology industry have been working to develop miniature devices that will allow hundreds, thousands, or millions of DNA assays to be carried out on a device smaller than a credit card.
One approach uses robots to produce arrays of hundreds or thousands of microscopic spots of DNA that represent genes on a "DNA array chip." All cells of an organism contain the same genes, but the pattern of genes being turned on or off is critical to the health of that tissue. Using this technology, one research team led by Pat Brown of Stanford, spotted samples representing 45 different genes from a small flowering plant (Arabidopsis thaliana) onto a microscope slide measuring just 1.5 inches by 2.5 inches. They then used this array to compare the activity of those genes in leaf and root tissue of the plant, finding that the activity of 27 of the 45 genes differed between those two tissues. This experiment shows that this technique has the potential to be a very sensitive and accurate way to identify specific genes that are turned on in any particular tissue, either healthy or diseased, or in any particular developmental stage.
Looking into the future, we can imagine the wealth of knowledge that can be gained from a gene expression chip consisting of 100,000 spots representing every human gene. Researchers are already laying the groundwork for using such technology to characterize the differential expression of genes in different tumor types, which would allow us to develop much more precise diagnostic criteria for different cancers and more individualized and effective treatments.
This chip sequencing technology will also have applications in human genetic testing. As the DNA sequence of more and more human genes becomes known, the chip will be used to scan for mutations in many genes at one time. This technology will also simplify testing in cases where many different mutations in a single gene can cause disease, such as breast cancer susceptibility genes like BRCA1 or the cystic fibrosis gene.
Virtually all of us are predisposed by our inheritance to at least one illness -- cancer, heart disease, diabetes to list a few. We are striving to learn more about the complex gene interactions that confer disposition to these common diseases. To accomplish this goal, the Center for Inherited Disease Research (CIDR) is now being established through an inter-institute agreement among eight NIH Institutes or Centers (IC) with the NCHGR serving as the lead. CIDR's main objective is the establishment of a facility dedicated to providing the research community with the physical and informatics infrastructure to successfully map the genes responsible for complex diseases. This marks a transition from "one gene-one disease" research into the study of gene-gene and gene-environment interactions. CIDR will use genetic and statistical tools to analyze large numbers of samples and locate genes that contribute to the inheritance of complex traits in humans. CIDR will accept proposals for access to its resources from all researchers including NIH intramural scientists, NIH grantees, and researchers with non-NIH support. Grantees of the NIH Institutes participating in CIDR will receive a substantial discount in costs. We anticipate that CIDR will be operational in the Spring of 1997, and will rapidly expand the development of complex disease diagnostic technologies and the discovery of genes for common illnesses.
Already as a result of the Human Genome Project, new disease genes are discovered almost weekly. Once a disease gene is identified it is often only a matter of months before a diagnostic test can be made available. In some instances the development of accurate diagnostic technologies can be potentially life-saving.
An exciting example is the potential development of a genetic test for hereditary hemochromatosis (HH). It is a common recessive disease where 1 in 10 Northern Europeans are carriers of the trait, and 1 in 400 have the disease. It is caused by a defect in iron metabolism that results in the accumulation of iron in various organs in the body. The symptoms reflect the system affected; the most common symptoms are abnormalities in liver function, diabetes and arthritis. Therapy is simple and highly effective: periodic bloodletting to reduce the level of iron in the body. Early treatment can prevent the clinical manifestations of the disease. Currently, however, HH can masquerade as other diseases and is frequently misdiagnosed, preventing prompt treatment and leading to needless deaths.
Now that the gene has been identified, it is likely a genetic test could be available soon. The availability of such a test could significantly reduce the health impact of HH. This example illustrates the far-reaching beneficial effects of genetic research on public health.
This year also marks the potential commercial availability of tests for identifying mutations in the BRCA1 and BRCA2 genes that predispose individuals to breast cancer, the HNPCC genes that predispose individuals to colon cancer, and the apolipoprotein E gene that plays a role in the inherited form of Alzheimer's disease. However, unlike HH no simple effective treatments are now available for these genetic disorders. Predictive genetic testing of healthy individuals in the face of poor or uncertain preventative or therapeutic interventions, raises many questions about benefits and risks. The individual undergoing genetic testing, as well as their health care provider, needs to understand the relationship between genetic mutations and the development of disease, and the evaluation of prevention or treatment options to determine effectiveness. Additionally, the safety and efficacy of these new predictive tests must be addressed to ensure a level of quality and reliability. Until the scientific knowledge is sufficient to ensure that the benefits exceed the risks, many observers feel the clinical use of mutation testing is premature outside of a research setting.
But as our technology grows in genetic testing, more information will be made available to concerned individuals about their potential for developing certain conditions. While potentially providing enormous benefit by allowing individualized programs of preventive medicine, the availability of this genetic information raises questions about the potential for discrimination and stigmatization based on the information contained in our genes. Of particular concern is the fear of losing jobs or health insurance because of a genetic predisposition to a particular disease. For example, a woman with a positive family history who tests positive for BRCA1 has an estimated 85 percent likelihood of developing breast cancer, and a 50 percent risk of ovarian cancer. Fighting those risks with intensive surveillance or surgery, without health insurance, would for many individuals result in economic ruin and probable tragedy.
As an integral part of the Human Genome Project, the NCHGR and the DOE have each set aside a portion of their funding to anticipate, analyze and address the ethical, legal, and social implications (ELSI) of the Project's new advances in human genetics. The current goals of the ELSI program are to improve the understanding of these issues through research and education, to stimulate informed public discussion, and to develop policy options intended to ensure that genetic information is used for the benefit of individuals and society. The ELSI program is focusing on several high-priority areas raised by the most immediate potential applications of new genetic technologies: privacy and fair use of genetic information; responsible clinical integration of new genetic technologies; ethical issues surrounding the conduct of genetics research; and, professional and public education about these issues.
Two key initiatives are underway to address crucial questions surrounding genetic testing, especially for cancer susceptibility. NCHGR and several other NIH Institutes are co-sponsoring a Cancer Genetics Studies Consortium, focusing on the psychological and social impact of cancer testing on individuals and their family members. Recommendations for approaches to genetic testing and counseling for cancer risk are being developed. The studies are well underway, and the investigators have developed draft recommendations for the optimal medical management of patients and families who carry mutations in the major genes for heritable breast cancer, BRCA1 and BRCA2 and the HNPCC colon cancer genes.
A second NCHGR initiative on testing, the Task Force on Genetic Testing (TFGT), was established by the ELSI Working Group to examine the development and delivery of safe and effective genetic tests and the quality of the laboratories providing the tests. The Task Force includes representatives from the biotechnology industry, professional medical and genetics societies, the insurance industry, consumers and federal agencies. In light of the rapid pace of disease-gene discovery and genetic test development, the findings of the TFGT will be crucial to the development of sound policies and practices for the introduction of new genetic tests. The group has now issued draft principles and expects to complete its work in early 1997.
Genetics research may result in the discovery of information that is powerful and potentially predictive. In addition, such information may have familial implications. While in many cases such information will be beneficial to patients and their families, there is also potential for misinterpretation or misuse. In order to assure that the Nation benefits from the fruits of genetic research, safeguards must be in place to protect individual privacy and prevent insurance and employment discrimination. In addition, the scientific validity and efficacy of the genetic tests need to be addressed. I look forward to continuing to work closely with the Congress to develop sound policies to ensure that the Human Genome Project and new genetic testing information is used to benefit, not harm, the American people.
This concludes my remarks. I would be pleased to answer any questions you may have.
Last Reviewed: March 16, 2012