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Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
February 27, 1997

Mr. Chairman, it is truly an exciting opportunity to testify before you today, for the first time, as director of the NIH's newest research Institute, the National Human Genome Research Institute (NHGRI). On January 14, after consultation with you and other Congressional leaders, Secretary Shalala signed documents that gave the National Center for Human Genome Research (NCHGR) a new name and new status. We are proud the NCHGR has been recognized for its successful leadership of the Human Genome Project, the accomplishments of its cutting-edge intramural laboratories, and its active policy research programs. As an Institute, NHGRI looks ahead to completing the Human Genome Project and to playing a leading role in 21st-century health science based on understanding the instructions encoded in our DNA.

As in the past, we continue to make remarkable strides toward our goals, and in the process, spin off new ways to approach the study of genetic disease. The genetic maps are complete, the physical maps nearly so, and both are in wide use by the scientific community. The slowest part of a disease-gene hunt nowadays is sorting through all the genes in the target region on a chromosome and determining which one is responsible for the disease. To help solve this, scientists at NHGRI-supported research centers, the National Library of Medicine, and genome centers in England and France, created an on-line map that pinpoints the locations of over 16,000 human genes--about one-fifth of the estimated 80,000 total. With it, the number of mapped human genes has tripled in less than two years; that number will likely double again over the coming year. Taking full advantage of cutting-edge information technology, the electronic map is a mouse click away from on-line references in the medical and research literature, which will aid scientists in linking information about a likely disease gene to its role in cell function.

Human genome maps and technologies are now making the difficult "needle in a haystack" search for genes much easier. As a result, the number of disease genes isolated nearly doubles every year. In 1996, 21 disease genes were isolated using genome maps--almost twice as many as the year before and nearly five times the number isolated the year the genome project began. Among them are genes that contribute significantly to human diseases, including polycystic kidney disease, an adult form of diabetes, and hereditary hemochromatosis (HH).

HH is a common disorder of iron metabolism, affecting about 1 in 400 individuals of Northern European descent. It occurs when both parents contribute a mutated HH gene to their child. About 1 in 10 individuals carries a single mutated HH gene. The major symptoms of HH--liver cirrhosis, heart deterioration, and other organ failures--don't occur until mid-life, and untreated, the disease causes early death. But treatment by simple blood letting allows people with HH to live a normal lifespan. Because HH is so common and easily treatable, it provides an excellent example for offering genetic testing on a large scale to identify people at risk for a disease and enabling them to avoid becoming ill. NHGRI and the Centers for Disease Control and Prevention are planning a workshop this spring to examine the scientific, ethical, social, and medical implications of widespread testing for HH.

The ultimate map of the human genome will spell out all 3 billion letters that make up human DNA. Ongoing projects to sequence the DNA of non-human organisms have provided an opportunity for scientists to practice sequencing genomes much smaller than that of the human, but bigger than anything sequenced before. This past year, an international consortium of scientists finished spelling out the entire genetic code of a species of yeast valuable to biologists and commonly used by bakers and brewers. At 12,057,500 bases, the yeast genome is the largest to be completely deciphered so far and is the most advanced organism yet to be sequenced. Having the entire yeast DNA sequence now paves the way for scientists to study how all the genes in a complex cell similar to human cells function as a system.

With progress in sequencing moving so rapidly, NHGRI has launched pilot studies at six U.S. research centers to explore the feasibility of large-scale sequencing of human DNA--the most technologically challenging phase of the Human Genome Project. This initiative is projected to produce the sequence of about 3 percent of human DNA in the first two years and will help to streamline and cut the cost of DNA sequencing in order to finish the entire human genome by the year 2005.

Using current mapping technology to understand the inheritance of single-gene disorders--the so-called "Mendelian" disorders--is usually relatively straightforward. Current genetic maps are now dense enough to place a disease gene within reach in a matter of weeks. This past year, these maps led NHGRI scientists to a gene associated with Parkinson's disease in a large Italian-American family and to a gene associated with prostate cancer in another study of 91 American and Swedish families. Although these genes have not yet been isolated, "linking" them to specific chromosomes gives scientists the first direct evidence that genes play an important role in these disorders.

But most diseases of modern life--cancer, heart disease, diabetes, arthritis, and a host of neuro-psychiatric disorders--seem to result from the activities of several genes and the interplay between a human body and its environment. NHGRI is supporting several initiatives to make the complex genetic and environmental components of these disorders easier to decipher and understand, and thereby easier to prevent or treat.

In a creative government-university partnership, eight components of the NIH, led by NHGRI, and the Johns Hopkins University School of Medicine, have established a new research center to facilitate analysis of the complex genetics of these common disorders. The new Center for Inherited Disease Research (CIDR) is located on the Johns Hopkins Bayview Medical Center in Baltimore and is expected to be fully operational this spring. Under full capacity, CIDR researchers expect to study six to nine complex disorders per year.

In other studies of complex disorders, NHGRI and the NIH Office of Research on Minority Health are collaborating with scientists at Howard University to study why people of African descent seem to develop adult-onset diabetes and prostate cancer more frequently than do many other population groups. Understanding the genetic basis of an increased risk for these diseases could lead to better strategies to prevent them from causing serious health problems.

Tracking down all the genetic components of a complex disorder requires analysis of the entire genomes of hundreds and perhaps thousands of individuals. For this to be possible, genome maps must be easily adapted to highly automated strategies. In the coming years, NHGRI will begin improvements on the existing maps, which have been so useful in finding single-gene disorders, to increase their usefulness in ferreting out the multiple genes that contribute to so many of today's common disorders.

The impact on the future of biology of knowing the order of all 3 billion human DNA bases has been compared to Mendeleev's establishment of the Periodic Table of the Elements in the 19th century and the advances in chemistry that followed. The complete DNA sequence of the human--the biologic periodic table--will make it possible to define a unique 'signature' for every gene. Rapidly evolving technologies, comparable to those used in the semi-conductor industry, will allow scientists to build detectors that trace hundreds or thousands of these gene signatures in a single experiment. Scientists will use the powerful new tools to reveal the secrets of disease susceptibility, create broad new opportunities for preventive medicine, and provide unprecedented information about the origin and migration of human populations.

One example of this kind of experiment was recently carried out by NHGRI-supported scientists who developed an automated method for determining differences as small as one base pair in comparisons of the entire 16,000 base-pair mitochondrial genome among 10 human volunteers. The scaled-up technique could potentially be used to analyze the entire 3 billion base-pair nuclear genome of the human in a single experiment. NHGRI scientists are using similar technologies to identify the broad range of genes possibly activated during cancer development.

While scientists are discerning the secrets once buried in the human genome, concerns about how the information will be used outside the laboratory call for new public policies about privacy and discrimination. An NHGRI-supported study showed that individuals from families with genetic disorders experience frequent discrimination in health insurance. Some do not even apply because they believe they will be turned down because of their condition.

NHGRI has established productive partnerships among consumers, scientists, and policy makers to help reduce the possibility that genetic information will be used to harm an individual or family members. The Ethical, Legal, and Social Implications (ELSI) Working Group in collaboration with the National Action Plan on Breast Cancer (NAPBC), has created a successful model for policy development through a series of workshops on genetics issues. The first of these resulted in recommendations on genetic information and health insurance that were later incorporated in part into the Health Insurance Portability and Accountability Act of 1996. While it is a laudable first step, the law is not the final solution since it still allows insurers to set exorbitant premium rates for holders of individual policies, which for many consumers amounts to denial of coverage. A second ELSI-NAPBC workshop developed recommendations relating to genetic discrimination in employment. The ELSI-NAPBC team is also interested in addressing privacy issues.

The Task Force on Genetic Testing (TFGT) of the ELSI Working Group has been examining the strengths and weaknesses of current practices and policies for development and delivery of safe and effective genetic tests in the United States and the quality of laboratories providing the tests. Last March, the TFGT released a set of interim principles for public comment. The final principles and recommendations of the task force have just been published in the Federal Register for public comment and will be reported to the Working Group this spring.

In another ELSI project on genetic testing, NHGRI is co-sponsoring a consensus development conference this spring to look at issues related to testing for cystic fibrosis mutations and to determine whether such testing should be a standard part of medical care.

The broad range and critical importance of ELSI issues prompted NHGRI last spring to establish an outside group to evaluate the role of the ELSI Working Group in these functions. To provide the best attention to these important issues, the evaluation committee recommended dividing the Working Group's responsibilities among different committees and at various levels within the government, including a newly established ELSI Research Evaluation Committee to oversee the ELSI grant portfolios at NHGRI and DOE, an NIH-wide process to coordinate the ELSI activities of the various institutes engaged in genetics research, and a federally chartered committee at the DHHS level to formulate public policy resulting from advances in genetics.

As the demand for genetic tests moves from the medical genetics specialty into general practice, it is imperative that health care professionals across disciplines understand the technology and its potential benefits and risks. NHGRI has played a leading role, along with the American Medical Association and the American Nurses Association, in forming the National Coalition for Health Care Professional Education in Genetics. This Coalition brings together leaders in medical professional organizations, consumer groups, government agencies, and industry to develop and implement a national genetics education program for health care professionals. An organizational meeting was held last July, and the first meeting of the full Coalition will be held this spring.