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Senate Labor and Human Resources Committee Hearing
on NIH Revitalization, Cancer & Genetics

Statement of Francis S. Collins, M.D., Ph.D.
Director, National Center for Human Genome Research

March 6-7, 1996

The Human Genome Project

The Human Genome Project is a historic 15-year research endeavor with the goal of producing detailed maps of the 23 pairs of human chromosomes and sequencing the 3 billion nucleotide bases that make up the human genome. The primary mission of the project is to develop research tools -- genetic and physical maps, DNA sequence information, and new technology -- to allow researchers to find and analyze genes quickly and efficiently. The project thus far has been successful in meeting or exceeding the goals outlined in its original plan.

Last Fall we celebrated the fifth anniversary of the Human Genome Project with a record of excellent progress toward our goals. The human genetic map has been completed and is much more detailed than was originally contemplated. Recently, a team of scientists published a physical map of the human genome composed of over 15,000 well-ordered markers, and covering approximately 94 percent of the genome. This a major milestone on the way to completing a comprehensive physical map of the human genome. Though original projections were that this map would not be completed until the end of 1998, completion is now expected by early 1997.

The most challenging goal of the Human Genome Project is to sequence the entire 3 billion nucleotides that comprise the human genome. This year we are embarking on this ambitious and exciting phase of the Human Genome Project. When the Human Genome Project started, even the best laboratory could only produce a few hundred thousand basepairs per year. Improvements in DNA sequencing technology and strategy have dramatically reduced the cost of sequencing and increased the efficiency. To further stimulate development of high-capacity DNA sequencing capability, NCHGR solicited applications for pilot projects for large-scale human sequencing and for further improvements in DNA sequencing technology. These applications have now been reviewed by the National Advisory Council for Human Genome Research and we anticipate these projects will get underway in April. As a result, a number of laboratories are now positioned to sequence over 10 million basepairs a year by 1997.

Though we look forward to the first complete DNA sequence of the human genome with great anticipation, we do not have to wait until the end of the project to reap its benefits. Already this information is changing the way biomedical research and the practice of medicine are being conducted. The information, tools and resources generated by the Human Genome Project are quickly disseminated to and utilized by researchers across the United States and throughout the world. All of the information from the Human Genome Project is placed in public electronic databases which are accessed by researchers over 150,000 times each week.

The tools and technology created by the Human Genome Project are being used by scientists to help in their discovery of the genes associated with disease. Already the maps generated by the Project have greatly facilitated the gene discovery. For example, more than 10 years of research were required to isolate the gene for cystic fibrosis in 1989; while the recent isolation of the BRCA2 gene took about two years. When the Human Genome Project is complete, isolating a disease gene of interest will take just a couple of months. In addition to the reductions in time required to find disease genes, there will be significant reductions in cost.

Most of the disease genes isolated so far are so called "single gene" diseases where a misspelling in a single gene is sufficient to cause disease. Many common diseases including diabetes, Alzheimer's, alcoholism and cancer are much more complex and may involve the interactions of many genes as well as environmental factors. Analyzing these complex disease and teasing apart the genetic and environmental components represents a significant challenge and an important scientific opportunity.

Recently there have been many spectacular and far-reaching discoveries of genes associated with cancer, including genes for breast, ovarian and colon cancer. In September 1994, scientists isolated BRCA1, and in December, 1995, scientists isolated BRCA2. These genes are both associated with hereditary breast cancer. Based on studying high-risk families, scientists estimate that a woman who has a BRCA1 alteration has up to a 90 percent lifetime risk of developing breast cancer, and a 40 to 50 percent risk of ovarian cancer. Researchers have found over 100 different alterations in the BRCA1 gene in these high-risk families, and have just begun the complex task of studying the specific risk of cancer associated with each of these mutations.

Scientists have now found one specific common BRCA1 alteration in several unrelated Jewish families with a family history of breast and/or ovarian cancer. These families were all of Ashkenazi, or Eastern European, descent. In September, 1995, NCHGR and NCI scientists published data indicating that this particular alteration in the BRCA1 gene has now been found in about one percent of a group of unselected Ashkenazi Jewish individuals, whose personal and family history of cancer was not known. This surprisingly high frequency suggests that one in a hundred women of Ashkenazi descent may be at high risk of developing breast and/or ovarian cancer. This offers the first evidence that a specific alteration in the gene is present at detectable levels not only in families at high risk for the disease, but also in a specific population group. The NCHGR and the National Cancer Institute are now conducting a study of thousands of Ashkenazi Jewish men and women in the Washington metropolitan area to look at the relationship between this specific alteration and the risk of various cancers.

The recent discovery of the gene for ataxia-telangiectasia will also contribute to our understanding of the relationship between genetic alterations and cancer risk. You may have seen Brad Margus and his family recently on the television news program Turning Point. Two of Brad's four sons have ataxia-telangiectasia (A-T). A-T is a rare but fatal childhood neurological disorder. The discovery of this gene paves the way for more accurate diagnosis in the short term and the potential for effective treatments in the long term for children suffering from A-T. One of the interesting aspects of the A-T gene is the indication that it may play a role in predisposition to certain cancers. Although the disease itself is rare, an estimated 1 percent of the U.S. population are carriers of the altered gene and appear to have a 4- to 5-fold increased risk for various cancers, including breast, lung, stomach, and skin cancer.

Significant progress is also being made to identify the genetic contributions to prostate cancer. Prostate cancer is the most common form of cancer diagnosed in men in the United States, yet little is known about the molecular basis for this disease. Recent studies have shown the familial nature of this disease and studies are underway at NCHGR, in collaboration with Johns Hopkins, to locate the genes involved.

An immediate spin-off of disease-gene discovery is the development of genetic tests which may indicate an individual's risk to develop disease. In the short term, this will allow the design of individual programs of preventive medicine, focusing on life style changes and medical surveillance to reduce the risk of a life-threatening illness. This may be particularly effective for cancer, where early detection is often the best chance for cure.

Our knowledge will continue to grow about the function of these genes as researchers analyze at the molecular level the genetic causes of disease, and associate specific gene alterations with an individual's risk for disease. Eventually, researchers will be able to develop new treatments for many of the diseases that result from malfunctions in our genes. Detailed knowledge of the specific genetic alterations underlying disease and an understanding of their role in cellular processes will allow the design and development of rational drug and gene-based therapies. However, there will often be a substantial lag between our ability to offer a genetic test and the ability of researchers to understand the disease sufficiently well to develop new treatments and therapies.

The Ethical, Legal and Social Implications Program

As an integral part of the Human Genome Project, the NCHGR and the Department of Energy (DOE) have each set aside a portion of their funding to anticipate, analyze and address the ethical, legal and social implications (ELSI) of the new advances in human genetics that human genome research has made possible. The 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 NCHGR ELSI program has focused on several high-priority areas raised by the most immediate potential applications of genome research:

  1. Privacy and fair use of genetic information.
  2. Responsible clinical integration of new genetic technologies.
  3. Ethical issues surrounding the conduct of genetics research.
  4. Professional and public education.

The NCHGR has taken two approaches to address the ELSI goals: 1) a research grant program on which NCHGR spends 5 percent of its annual budget and 2) an interagency working group, the NIH-DOE Joint Working Group on the Ethical, Legal, and Social Implications of Human Genome Research (ELSI Working Group).

Testing and Counseling Initiatives

There are two key initiatives underway at NIH to address some of the crucial questions surrounding genetic testing, especially for cancer susceptibility. To examine issues surrounding the safe integration of genetic testing and counseling for cancer risk into clinical practice, the NCHGR, National Cancer Institute, the National Institute of Nursing Research and the National Institute of Mental Health are supporting clinical research studies on testing and counseling for heritable breast, ovarian and colon cancer risks. These investigators are studying the psychological and social impact of cancer testing on individuals and their family members and are developing recommendations for approaches to genetic testing and counseling for cancer risk.

The investigators in these projects have formed a consortium to pool resources, reduce duplication of effort, and increase coordination of some aspects of the studies. Some of the key aspects the investigators agreed to coordinate include: the use of a core set of evaluation tools to assist in the comparison of results from the studies; the identification of the key elements to be included in all consent forms used in the consortia studies; and a plan to develop specific recommendations for individuals who test positive for BRCA1 mutations. The studies are well underway, and the investigators have developed draft recommendations for how to counsel patients and families who carry a BRCA1 mutation.

A second highly relevant initiative funded by the NIH is the Task Force on Genetic Testing (TFGT). The mission of the Task Force is to examine the strengths and weaknesses of current practices and policies relating to the development and delivery of safe and effective genetic tests and the quality of the laboratories providing the tests. The membership of the Task Force includes representatives from the biotechnology industry, the professional medical and genetics societies, the insurance industry, consumers and the relevant federal agencies involved in the diffusion of new genetic tests. The TFGT was established in April 1995 and is expected to complete its work in early 1997.

The Task Force is concentrating on three areas:

  1. Scientific validation -- developing validation criteria for the sensitivity, specificity, and predictive value of the tests.
  2. Laboratory quality -- addressing the gaps in monitoring the quality of genetic tests.
  3. Education, counseling, and delivery -- providing ways to educate practitioners and consumers about the limitations and capabilities of current test technologies, including their predictive and interpretative value.

The rapid pace with which genes are being discovered and genetic tests are being developed indicates that the findings of the TFGT are urgently needed and will be crucial to the development of sound policies and practices for the introduction of new genetic tests.

Fair Use of Genetic Information

As our knowledge grows about the genetic basis of disease, so too does the potential for discrimination and stigmatization based on the information contained in our genes. Of particular concern is the fear that we will lose our jobs or health insurance because we are shown to be at high risk for a particular disease. Denying individuals health insurance or employment based on genetic information will be an unfortunate deterrent to reaping the benefits of genetics research. Furthermore, we are all at risk for certain diseases, and as gene discoveries and genetic testing advance, we will have the opportunity to learn more about our individual susceptibilities. A health insurance system that uses this information to deny individuals coverage will be unworkable in the long term.

However, there are no federal laws now in place to prevent health insurance companies from using genetic information to deny coverage. Several states are concerned about the use of genetic information and have passed legislation that protects individuals from being denied health insurance based on their genetic status. These state laws prohibit insurers from denying coverage based on genetic test results, and/or prohibit using this information to establish premiums, charge differential rates or limit benefits. A few of these states, including California, Florida and Oregon, integrate protection against discrimination in insurance practices with privacy protections that prohibit insurers from requesting genetic information and from disclosing genetic information without authorization. The federal Employee Retirement Security Act (ERISA) exempts self-funded plans from state insurance laws. Thus, state laws do not provide protection for the many Americans who obtain their health insurance coverage through employer based plans.

The ELSI Working Group has long been involved in discussions about the fair use of genetic information, particularly as it relates to health insurance. In 1993, the ELSI Working Group's Task Force on Genetic Information and Insurance concluded that, "Information about past, present, or future health status, including genetic information, should not be used to deny health insurance coverage." Another important group recently formed is the National Action Plan on Breast Cancer (NAPBC), a public-private partnership established to address the research, education and policy issues in breast cancer. The NAPBC has identified the issue of genetic discrimination and health insurance as a high priority.

Building on their shared concerns, the ELSI Working Group and the NAPBC co-sponsored a workshop on July 11, 1995, to address the issue of genetic discrimination and health insurance. Consumers, researchers, federal and state government representatives and insurance industry representatives came together with the members of these two groups to participate in the one-day session. Based on the information presented at the workshop, the ELSI Working Group and the NAPBC developed and published recommendations for state and federal policy makers to protect against genetic discrimination.

The new advances in human genetics offer the promise that we will find new ways to fight some of the most devastating diseases that Americans suffer from today. We must ensure that our health care policies and practices relating to the introduction of new genetic tests and the subsequent use of genetic information keep pace with these significant new advances.

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Last updated: June 01, 2006