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The National Human Genome Research Institute (NHGRI), established originally as the National Center for Human Genome Research in 1989, led the National Institutes of Health's (NIH's) contribution to the International Human Genome Project. This project, which had as its primary goal the sequencing of the 3 billion base pairs that make up human genome, was successfully completed in April 2003.

NHGRI's mission has evolved over the years to encompass a broad range of studies aimed at understanding the structure and function of the human genome and its role in health and disease. To that end, the institute supports the development of resources and technology that will accelerate genome research and its application to human health. A critical part of NHGRI's mission continues to be the study of the ethical, legal and social implications (ELSI) of genome research. NHGRI also supports the training of investigators, as well as the dissemination of genome information to the public and to health professionals.

NHGRI is organized into three main divisions: the Office of the Director, which provides guidance to scientific programs and oversees the general operation of the institute; the Division of Extramural Research, which supports and administers the role of NIH in genomic research; and the Division of Intramural Research, which is home to the institute's in-house, genetics research laboratories.

Research guidance and final approval of NHGRI grants come from the 15-member National Advisory Council for Human Genome Research, which meets three times a year, usually in Bethesda, Md. Members include representatives from health and science disciplines, public health, social sciences and the general public. Portions of the council meetings are open to the public.

The History of NHGRI and the Human Genome Project

While the Human Genome Project had its ideological origins in the mid-1980s, the effort to determine the order of all the letters in the human genetic instruction book owes much of its success to a series of pioneering genetics discoveries dating back to the early 20 th Century. For example, Alfred Sturtevant created the first gene map for the fruitfly Drosophila in 1911. In 1953, Francis Crick and James D. Watson provided the crucial first step for molecular genome analysis with their description of the double helical structure of the DNA molecule. The two researchers, along with Maurice Wilkins, won the 1962 Nobel Prize for physiology or medicine.

In the mid-1970s, Frederick Sanger developed techniques to sequence DNA, for which he received a Nobel Prize in chemistry in 1980. With the automation of DNA sequencing in the 1980s, the idea of analyzing the entire human genome was first proposed by a few academic biologists.

The U.S. Department of Energy (DOE), seeking data on protecting the genome from the mutagenic (gene-mutating) effects of radiation, established an early version of the genome project in 1987. The following year, Congress funded both NIH and DOE to embark on further exploration of the concept, and the two agencies formalized an agreement by signing a Memorandum of Understanding to "coordinate research and technical activities related to the human genome." James D. Watson was appointed to lead the NIH component, which was dubbed the Office of Human Genome Research. The following year the Office of Human Genome Research evolved into the National Center for Human Genome Research (NCHGR).

Before the Human Genome Project could officially launch in October 1990, Congress asked NIH to develop a strategic plan for the monumental project. NCHGR collaborated with DOE and, in April 1990, published a joint research plan, "Understanding Our Genetic Inheritance: The Human Genome Project, The First Five Years, FY 1991-1995." This plan set out specific goals for the first five years of what was then projected to be a 15-year research effort. If the ultimate goal of sequencing the human genome was to be completed by 2005, it was imperative to construct detailed human genetic maps, to improve physical maps of the human genome and of the genomes of certain model organisms, and to develop better technologies for DNA sequencing and information handling.

The initial plan also set aside 3 percent of the project's budget for the study of the ethical, legal and social implications (ELSI) of genome research so that policy options could be developed to address concerns such as genetic discrimination. Since 1990, the insights gained through ELSI research have informed the development of federal guidelines, regulations and legislation to safeguard against misuse of genetic information, as evidenced by the recent passage of the "Genetic Information Nondiscrimination Act of 2003" by the U.S. Senate. Through the ELSI research program, NHGRI also supports a variety of ethics- and policy-related research studies, workshops and conferences to further explore and address such issues. Between 1990 and 2001, ELSI-funded activities included 235 research and education projects; more than 550 peer-reviewed journal articles, books, newsletters, Web sites and broadcast media programs; and dozens of workshops, conferences and related activities focused on translating ELSI research into clinical and public health practices.

During its first five years, a large part of the work of the Human Genome Project was devoted to developing improved technologies and techniques for accelerating the elucidation of the genome. Advances that helped to speed scientific research and analysis during this time period included: restriction fragment-length polymorphisms, polymerase chain reaction, bacterial and yeast artificial chromosomes, and pulsed-field gel electrophoresis.

NCHGR also went through a number of leadership changes during this time. In 1992, Dr. Watson resigned as director, and Michael Gottesman was appointed acting director of the center. The following year, Francis S. Collins was recruited from the University of Michigan to be the new director.

By 1993, a majority of the goals laid out in the 1990 plan were already on or ahead of schedule. Efforts to construct human genetic maps and physical maps of genomes had been accelerated by technological improvements that could not have been anticipated even a few years earlier. Also, in the period since the original plan was published, leaders of the Human Genome Project had gained a better understanding of what needed to be done to reach the goal of obtaining the human genome sequence.

Consequently, the leaders revised and extended the project's goals to cover the first eight years (through September 1998) with the publication of "A New Five-Year Plan for the United States Human Genome Program" in the journal Science . Among the goals of the new plan were improving technology for rapid genotyping, developing higher resolution physical maps, moving towards a systematic large-scale sequencing strategy, and expanding ELSI goals to contemplate the potential widespread use of genetic testing.

Also in 1993, the NCHGR established a Division of Intramural Research (DIR), in which genome technology is developed and used to study specific diseases. DIR was charged with concentrating its efforts on future applications of genomics. Over the division's 10-year history, NHGRI investigators have developed a variety of research approaches that accelerate the understanding of the molecular basis of disease. These advances include: DNA microarray technologies for large-scale molecular analyses, innovative computer software to study fundamental biological problems, animal models critical to the study of human inherited disorders and the clinical testing of new therapeutic approaches for genetic disease.

NHGRI's intramural investigators have directly been involved in research that has identified genes involved in Parkinson's disease, hereditary prostate cancer, breast cancer, Pendred syndrome (deafness), tumor suppression, neurological disorders, developmental disorders and, most recently, Hutchison-Gilford progeria syndrome, which is the most dramatic form of premature aging.

In 1994, the Human Genome Project's genetic mapping goal was achieved a year ahead of schedule and, in 1995, a physical map of chromosome 22 was published providing researchers with an important tool for finding genes on this chromosome. In 1996, pilot studies were launched that began the process of dramatically improving the technology needed for sequencing human DNA. That same year, the sequence of the first eukaryotic genome, Saccharomyces cerevisiae (brewer's yeast) was completed; a map pinpointing the locations of over 16,00 human genes was published; and the International Human Genome Sequencing Consortium (IHGSC) made an historic decision to place all sequence data of 1 to 2 million bases into public databases within 24 hours for anyone to freely access.

The NCHGR received full institute status at NIH in 1997, being renamed the National Human Genome Research Institute (NHGRI) with Dr. Collins as its director. Having accomplished all major goals in the 1993-98 plan, NHGRI published a third five-year plan in 1998, again in the journal Science . All three plans had a set of interconnected goals that proved pivotal to achieving a completed sequence and maintaining progress to meet ambitious milestones.

Human DNA sequencing would become the major emphasis of the new plan and an audacious timetable was set forth for completing the sequence by April 2003 - more than two years ahead of previous projections. In addition, researchers would work to finish 1/3 of the human sequence during 2001 and publish a "working draft" by the end of the same year. A "working draft," while not as accurate as a finished sequence, would contain 90 percent of the sequence and would provide researchers around the world with a useful tool for bringing important scientific projects to fruition much sooner than having to wait for the finished sequence to be completed. Other important goals included the studying human genome sequence variation, developing technology for functional genomics, completing the genomic sequences of the roundworm Caenorhabditis elegans and the fruitfly Drosophila melanogaster, and starting the sequencing of the mouse genome.

The task of building the "working draft" of the human sequence was delegated to the IHGSC. The three largest NIH-funded sequencing centers (the Whitehead Institute in Cambridge, Mass., Washington University at St. Louis, and Baylor College of Medicine in Houston), along with the Sanger Centre in Hinxton, England, and DOE's Joint Genome Institute, were responsible for sequencing 80 percent of the genome. International partners from France, Germany, Japan and China obtained the remainder of the sequence.

In 1999, the goal of producing a "working draft" seemed very far away, with less than 15 percent of the genome sequenced. If the accelerated goals had not already generated a sense of urgency in the consortium, a decision by the sequencing center leaders at a February meeting in Houston would. At the meeting, the leaders accepted Dr. Collins' challenge to ramp up their efforts to produce a "working draft" by spring of 2000.

By January 2000, the centers were collectively producing 1,000 base pairs a second, 24 hours a day, seven days a week, and 2 billion of the human genome's 3 billion base pairs were sequenced by March. At a White House ceremony hosted by President Bill Clinton in June 2000, Dr. Collins and J. Craig Venter of Celera Genomics, which had carried out its own sequencing strategy, announced that the majority of the human genome had been sequenced.

In February 2001, IHGSC researchers published the sequence and analysis of 90 percent of the human DNA sequence in the journal Nature . A simultaneous publication by Celera Genomics appeared in the journal Science . Surprises accompanying the sequence publication included: the relatively small number of human genes, perhaps as few as 30,000; the complex architecture of human proteins compared to their homologs -- similar genes with the same functions -- in worms and flies; and the lessons to be learned from repeated sequences of DNA.

On April 14, 2003 at a news conference at NIH, the IHGSC announced completion of a finished, reference version of the human genome sequence that has an accuracy of 99.99 percent and covers about 99 percent of the genome's gene-containing regions. When the Human Genome Project was launched in 1990, many in the scientific community were deeply skeptical about whether the project's audacious goals could be achieved, particularly given its hard-charging timeline and relatively tight spending levels. At the outset, the U.S. Congress was told the project would cost about $3 billion in FY 1991 dollars and would be completed by the end of 2005. In actuality, the Human Genome Project was finished two and a half years ahead of schedule and, at $2.7 billion in FY 1991 dollars, significantly under original spending projections.

In late 2001 through 2002, knowing that completion of a finished version of the human genome sequence was imminent, NHGRI gathered the world's leading genome researchers to chart the course of future research at two meetings called Beyond the Beginning: The Future of Genomics I and II . These meetings were supplemented with workshops throughout 2002 to discuss specific areas of genomic research, policy, education and ethics. The ideas and recommendations that arose from these sessions have informed plans for the next stage of genomic research, resulting in a vision document authored by the leadership at NHGRI: A Vision for the Future of Genomics Research , published in April 2003 the journal Nature .

The overarching mission of NHGRI, however, remains the same: to understand the human genome and the role it plays in both health and disease. To that end, NHGRI has embarked on a new set of projects aimed at providing the scientific community with the next generation of tools needed to understand the underlying function and structure of the human genome sequence.

The International HapMap Project, launched in October 2002, is a partnership of scientists and funding agencies from Canada, China, Japan, Nigeria, the United Kingdom and the United States. The purpose of the project is to develop a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals. The DNA sequence of any two people is 99.9 percent identical. However, the 0.1 percent variation among individuals may greatly affect disease risk. Sites in the DNA sequence where individuals differ by a single DNA base are called single nucleotide polymorphisms (SNPs). Sets of nearby SNPs on the same chromosome are inherited in blocks. This pattern of SNPs on a block is a haplotype.

Researchers trying to discover the genes that affect a disease, such as diabetes, will use the set of SNPs from the HapMap to compare a group of people with the disease to a group of people without the disease. Chromosome regions where the two groups differ in their haplotype frequencies might contain genes affecting the disease. The HapMap is expected take about three years to complete.

In 2003, NHGRI launched a pilot project called the ENCyclopedia Of DNA Elements (ENCODE), which will be carried out by an international consortium made up of scientists in government, industry and academia. Initially, research groups will work cooperatively to test efficient, high-throughput methods for identifying, locating and fully analyzing all of the functional elements contained in a set of DNA target regions that covers approximately 30 megabases, or about 1 percent, of the human genome. If the pilot effort proves successful, the project will be expanded to cover the entire genome.

In addition to sequencing the 3 billion letters in the human genetic instruction book, researchers involved in the Human Genome Project sequenced the genomes of a number of important model organisms that are commonly used as surrogates in studying human biology. They were: the mouse, the rat, two species of puffer fish, two species of fruit flies, two species of sea squirts, two species of roundworms, baker's yeast and the bacterium Escherichia coli. By comparing genome sequences from carefully chosen organisms, scientists are able to identify specific DNA sequences that have been conserved throughout the evolution of different species, which is a strong indicator that these sequences reflect functionally important regions of the genome.

Comparative genomics will continue to play an pivotal role in the next stage of genomic research. In 2003, NHGRI-funded researchers were engaged in sequencing a wide variety of other organisms, such as the cow, chicken, chimpanzee, dog and zebrafish. In a paper published in Nature i n August 2003, a team led by NHGRI researchers compared the sequence of the same large genomic region in 13 vertebrate species and demonstrated how such comparisons can reveal functionally important parts of the human genome beyond the genes themselves.

Another project featured in NHGRI's vision paper and also appearing prominently in NIH's new Roadmap for Medical Research is t he initiative called "Molecular Libraries." Molecular libraries will offer public sector biomedical researchers access to small organic molecules that can be used as chemical probes to study cellular pathways in greater depth. It will provide new ways to explore the functions of major components of the cell in health and disease.

The availability of molecular libraries also has the potential to accelerate the development of new agents to detect and treat diseases by providing early stage compounds that encompass a broad range of novel targets and activities. These compounds will help validate new targets for drug therapy more rapidly, as well as enable other researchers in the public and private sectors to take these targets and compounds and move them through the drug-development pipeline.

Ethical, legal and social issues will occupy a central role in NHGRI's mission as medical research and medical practice moves into the genomic era. In 2003, the ELSI research program invited proposals for the development of Centers of Excellence in ELSI research (CEER) that will bring investigators from multiple disciplines together to address new ELSI issues resulting in advances in genetics and genomics.

The completion of the sequence of the human genome in April 2003 represents a major milestone in the history of science. However, the challenges set forth in A Vision for the Future of Genomics Research will likely prove even more significant by advancing the effort to utilize the human genome sequence to benefit humankind. As medical research ventures further into the genome era, NHGRI will remain at the forefront of such research by providing the tools and information needed to understand human health and disease.

Biographical Sketch of NHGRI Director Francis S. Collins, M.D., Ph.D.

Francis S. Collins, M.D., Ph.D., a physician-geneticist noted for his landmark discoveries of disease genes and his leadership of the Human Genome Project, is director of the National Human Genome Research Institute (NHGRI).

With Dr. Collins at the helm, the Human Genome Project attained historic milestones, while consistently running ahead of schedule and under budget. A working draft of the human genome sequence was announced in June 2000, and an initial analysis was published in February 2001. Human Genome Project scientists continued working until a finished sequence of all 3 billion base pairs was achieved in April 2003. The vast trove of data generated by the public sequencing effort is now available to the medical research community without restrictions on access or use.

In addition, Dr. Collins founded a new NIH intramural research program in genome research, which has evolved into one of the nation's premier research units in human genetics in the country. The Collins research laboratory continues to be vigorously active, exploring the molecular genetics of adult-onset diabetes and other disorders.

Dr. Collins received a B.S. from the University of Virginia, a Ph.D. in Physical Chemistry from Yale University and an M.D. from the University of North Carolina. Following a fellowship in Human Genetics at Yale, he joined the faculty at the University of Michigan, where he remained until moving to NIH in 1993.

While at Yale and the University of Michigan, Dr. Collins developed innovative methods of crossing large stretches of DNA to identify disease genes. This gene-hunting approach, which he named "positional cloning," has become a powerful component of modern molecular genetics. In contrast with previous methods for finding genes, positional cloning enabled scientists to identify disease genes without knowing in advance what the functional abnormality underlying the disease might be.

Dr. Collins' research has led to the identification of genes responsible for cystic fibrosis, neurofibromatosis, Huntington's disease, multiple endocrine neoplasia type 1 and the M4 type of adult acute leukemia. Most recently, his lab found the gene that causes Hutchinson-Gilford progeria syndrome, a dramatic form of premature aging .

Dr. Collins' accomplishments have been recognized by numerous awards and honors, including election to the Institute of Medicine and the National Academy of Sciences.

NHGRI Directors

Name In Office From To
James D. Watson 1989 April 10, 1992
Michael Gottesman (Acting) April 10, 1992 April 1993
Francis S. Collins April 1993  
This page was last reviewed on June 21, 2005 .

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