The NIH Almanac

Mission

In January 2007, the National Human Genome Research Institute (NHGRI) celebrated its 10th anniversary as an Institute of the National Institutes of Health (NIH), marking a decade that saw genomics emerge as a powerful research tool and looking ahead to an era in which genomics will transform medical care.

NHGRI, established originally as the National Center for Human Genome Research in 1989, led NIH's contribution to the International Human Genome Project. The project, which had as its primary goal the sequencing of the 3 billion DNA letters that make up the human genetic instruction book, 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 technologies 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 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 3 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 expansion of genomic research at academic and other research centers; and the Division of Intramural Research, which is home to the Institute's in-house genetics research laboratories.

Guidance related to NHGRI research programs and grants comes from the National Advisory Council for Human Genome Research, which meets 3 times a year, usually in Bethesda, Maryland. 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.

Important Events in the History of NHGRI and the Human Genome Project

While the Human Genome Project had its conceptual origins in the mid-1980s, the effort to determine the order of all the letters in the human genetic instruction book, or genome, owes much of its success to a series of pioneering genetics discoveries dating back to the early 20th Century. For example, Alfred Sturtevant, Ph.D., created the first gene map for the fruit fly Drosophila in 1911. In 1953, Francis Crick, Ph.D., and James D. Watson, Ph.D., 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, Ph.D., won the 1962 Nobel Prize for physiology or medicine.

In the mid-1970s, Frederick Sanger, Ph.D., developed biochemical techniques to sequence DNA, for which he received a Nobel Prize for 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 2 agencies formalized an agreement by signing a Memorandum of Understanding to "coordinate research and technical activities related to the human genome." James D. Watson, Ph.D., was appointed to lead the NIH component, which was initially 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 5 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% 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, such as the introduction of the "Genetic Information Nondiscrimination Act of 2007" in both houses of the U.S. Congress. 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 2007, ELSI-funded activities included more than 400 research and education projects which have produced hundreds of peer-reviewed journal articles, books, newsletters, Web sites, and broadcast media programs as well as dozens of workshops, conferences, and related activities focused on translating ELSI research into clinical and public health practices.

During its first 5 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, M.D., was appointed acting director of the center. The following year, Francis S. Collins, M.D., Ph.D., 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 8 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 technologies 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 13-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.

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 more than 16,000 human genes was published; and the International Human Genome Sequencing Consortium (IHGSC) made a 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 5-year plan in 1998, again in the journal Science. All 3 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 2 years ahead of previous projections. In addition, researchers would work to finish one-third 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% 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 studying human genome sequence variation, developing technology for functional genomics, completing the genomic sequences of the roundworm Caenorhabditis elegans and the fruit fly 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 3 largest NIH-funded sequencing centers (the Whitehead Institute in Cambridge, Massachusetts, 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, in Walnut Creek, California, were responsible for sequencing 80% 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% 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, 7 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% 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. In October 2004, IHGSC researchers published a scientific description in the journal Nature assessing the quality of the reference version of the finished human genome sequence produced by the Human Genome Project, confirming it has both the high coverage and accuracy needed to perform the most sensitive analyses. For instance, the improved accuracy of the finished human genome sequence, compared with earlier drafts, allowed researchers to lower the estimated number of human genes to 20,000-25,000.

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.

Research Advances and Collaborations

A Vision for the Future of Genomics Research

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 in 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.

In 2003, NHGRI launched a pilot project, called the ENCyclopedia Of DNA Elements (ENCODE), that involves an international consortium of scientists in government, industry, and academia. Initially, research groups worked cooperatively to test a diverse set of existing and novel high-throughput technologies, techniques and strategies for identifying, locating, and fully analyzing all of the functional elements contained in a set of DNA target regions that cover approximately 30 megabases, or about 1%, of the human genome.

In 2007, the ENCODE research consortium published a set of landmark papers in the journals Nature and Genome Research that found the organization, function, and evolution of the human genome to be far more complicated than scientists previously expected. The ENCODE data indicate that beyond genes and their associated proteins, the human genome is an interwoven network in which genes are just 1 of many types of DNA sequences with a functional role to play.

Based on the pilot project's findings and success, NHGRI recently expanded the ENCODE project to begin building a parts list of biologically functional elements across the entire human genome over the next 4 years. NHGRI also began a parallel effort called modENCODE to identify similar functional elements in the fruit fly and roundworm genomes. These model organisms can easily be experimented with to validate the biological relevance of functional elements they share with humans.

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 2 people is 99.9% identical. However, the 0.1% 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, pronounced "snips"). Sets of nearby SNPs on the same chromosome are inherited in blocks. This pattern of SNPs on a block is called a haplotype.

At the project's outset, the consortium set an ambitious goal of creating a human haplotype map, or HapMap, within 3 years. A Nature paper published in October 2005 marked the attainment of that goal with its detailed description of the Phase I HapMap, consisting of more than 1 million markers of genetic variation or SNPs. In 2007, the consortium published a Phase II HapMap in Nature that contains nearly 3 times more markers than the initial version and enables researchers to focus their gene searches even more precisely on specific regions of the genome. The HapMap offers the scientific community an enormous savings, reducing the expense of searching the genome for hereditary factors in common disease by a factor of 10 to 20.

Researchers trying to uncover the genetic risk factors for a wide range of diseases are now using genome-wide association studies (GWAS), a powerful new approach made possible by the HapMap. Since 2005, GWAS research has identified more than 60 common DNA variants associated with risk of disease or related traits—with the pace of discovery rapidly accelerating during 2007

In a related development, the U.S. Department of Health and Human Services launched 2 groundbreaking initiatives: The Genes and Environment Initiative (GEI), a trans-NIH collaboration led administratively by NHGRI; and the Genetic Association Information Network (GAIN), a public-private partnership between NIH, the Foundation for the National Institutes of Health, and major pharmaceutical and biotech companies.

Each study will identify the genetic contributions to health conditions that affect the public health, such as depression and diabetes. Using biological samples already collected in earlier clinical studies, each initiative will comprehensively evaluate the subtle differences between the genomes of approximately 1,000-2,000 normal, healthy volunteers and the genomes of 1,000-2,000 patients with the condition being studied. GAIN launched 6 studies in 2006 focusing on attention deficit hyperactivity disorder (ADHD), psoriasis, schizophrenia, bipolar disorder, depression, and type 1 diabetes. In 2007, GEI selected 8 initial health conditions to target. They include addiction, oral clefts, coronary heart disease, lung cancer, type 2 diabetes, tooth decay, and premature birth. GEI also provided funding as part of its technology development program to more than 30 investigators to devise new ways of monitoring personal environmental exposures that interact with genetic variations and result in human diseases.

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 include: the mouse, the rat, 2 species of puffer fish, 2 species of fruit flies, 2 species of sea squirts, 2 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 a pivotal role in the next stage of genomic research. To aid in interpretation of the human genome, NHGRI has approved plans to sequence a wide variety of other organisms, including the northern white-cheeked gibbon, an elephant shark, freshwater snail, a wasp, as well as several fungi, yeast, and roundworm species. The journal Nature published an analysis of the South American opossum genome sequence in May 2007 and an analysis of 12 fruit fly genomes in November 2007. An analysis of the rhesus macaque monkey genome sequence was published in April 2007 in the journal Science.

NHGRI has recently devoted a portion of its large-scale sequencing capacity to "medical sequencing" projects aimed at identifying the genetic roots of human diseases that have long eluded gene hunters. Three projects announced in 2005 include efforts to identify the genes responsible for dozens of relatively rare, single-gene (autosomal Mendelian) diseases; to sequence all of the genes on the X chromosome from affected individuals to identify those involved in sex-linked diseases; and to survey the range of variants in genes known to contribute to some common diseases.

Also in 2005, NHGRI partnered with the National Cancer Institute to launch a comprehensive effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, especially large-scale genome sequencing. The overall effort, called The Cancer Genome Atlas (TCGA), is a pilot project which will initially target lung, brain (glioblastoma), and ovarian cancer to determine the feasibility of a full-scale effort to systematically explore the universe of genomic changes involved in all types of human cancer.

An international team of scientists, supported in part by NHGRI, recently demonstrated the value of efforts like TCGA, targeting cancer with a systematic approach relying on large-scale sequencing. The team, part of the Tumor Sequencing Project, identified more than 50 genomic changes in lung adenocarcinoma and uncovered a critical gene alteration not previously linked to any form of cancer. Their work was published in Nature in November 2007.

The sequencing centers in NHGRI's Large-Scale Sequencing Research Network will dedicate a significant portion of their pipelines to TCGA. Cancer is now understood to include more than 200 different diseases. In all forms of cancer, genomic changes—often specific to a particular type or stage of cancer—cause disruptions within cellular pathways that result in uncontrolled cell growth. TCGA will delve more deeply into the genetic origins leading to this complex set of diseases and, in doing so, will create new discoveries and tools that will provide the basis for a new generation of cancer therapies, diagnostics, and preventive strategies.

Another of NHGRI's near-term goals is to lower the cost of sequencing a mammalian-sized genome to $100,000, which would enable researchers to sequence the genomes of hundreds or even thousands of people as part of studies to identify genes that contribute to cancer, diabetes, and other common diseases. Ultimately, NHGRI's vision is to cut the cost of whole-genome sequencing to $1,000 or less, which would enable the sequencing of individual genomes as part of medical care. The ability to sequence each person's genome cost-effectively could give rise to more individualized strategies for diagnosing, treating and preventing disease. Such information could enable doctors to tailor therapies to each person's unique genetic profile.

The availability of such gene-sequencing technologies will revolutionize healthcare in the future. In the meantime, NHGRI continues to develop the partnerships and tools necessary to make a difference in today's healthcare setting. For example, in November 2004, NHGRI partnered with the U.S. Surgeon General and other divisions of the Department of Health and Human Services to launch the Family History Initiative.

The Family History Initiative encourages all Americans to learn about their families' health histories as a way of promoting personal health and preventing disease. The centerpiece of this effort is a free, and recently improved, Web-based tool called "My Family Health Portrait" (http://familyhistory.hhs.gov/), which can be used to record common diseases that run in a person's family. The family history can then be printed and taken to a healthcare professional to help determine whether a patient is at higher risk for disease.

Ethical, legal, and social issues continue to occupy a central role in NHGRI's mission. In 2004, NHGRI's ELSI research program announced grants establishing the first Centers of Excellence in ELSI Research, which will bring together investigators from multiple disciplines to address some of the most pressing ethical, legal, and social questions raised by the rapidly expanding fields of genetics and genomics. Two more centers were established in 2007.

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.

Intramural Research Advances

NHGRI's Division of Intramural Research investigators have made numerous discoveries during the last 14 years, including identifying genes involved in type 2 diabetes, Parkinson's disease, hereditary prostate cancer, breast cancer, Pendred syndrome (deafness), tumor suppression, neurological disorders, and developmental disorders. In 2007, NHGRI researchers, working as part of a U.S.-Finnish team searching for genetic variants involved in type 2 diabetes, combined their findings with 2 other international groups of scientists. The groups published simultaneous studies in the journal Science and identified 4 new genetic variants and confirmed the existence of 6 others associated with an increased risk for adult-onset diabetes. NHGRI researchers have also recently identified genetic variants associated with the development of late-onset Alzheimer's disease and the genetic factors involved in how effective a particular antidepressant medication works in patients.

Two efforts involving NHGRI researchers were launched in 2007 with the aim of generating information that will help to integrate genomic tools into clinical settings. The Multiplex Initiative will examine how people who decide to take genetic tests for common conditions, such as coronary heart disease and osteoporosis, interpret and use the results in making their own health care decisions. Ultimately, the insights gained will be used to improve how genetic risk is communicated to patient populations, a key to advancing the concept of personalized medicine. Another NHGRI-led project, known as ClinSeq, will sequence targeted regions of patient's genomes to uncover rare and common genetic variants associated with the cardiovascular disease, coronary artery calcification. Researchers are particularly interested in exploring the technical, medical and genetic counseling issues associated with using genome sequencing in a clinical setting.

Also in 2007, a research team that included NHGRI investigators used a transgenic mouse model to uncover clues that identified a potential treatment of hereditary inclusion body myopathy (HIBM), a rare, degenerative muscle disease. A clinical trial has been launched to test the feasibility of using the treatment for HIBM patients, and preliminary research suggests the treatment may also help patients with certain kidney disorders.

NHGRI Collaborations Across NIH

An additional project featured in NHGRI's vision paper and also appearing prominently in NIH's Roadmap for Medical Research is an initiative called Molecular Libraries. The initiative offers 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. In 2004, as part of the Molecular Libraries initiative, NHGRI's Division of Intramural Research launched the NIH Chemical Genomics Center. In June 2005, an additional 9 centers were funded as part of a nationwide network that will produce innovative chemical "tools" for use in biological research and drug development.

The availability of molecular libraries 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. For instance, NIH researchers used the NIH Chemical Genomics Center's high-throughput screening process to identify 3 new classes of small molecules that may prove useful for treating Gaucher disease, an inherited disorder that disrupts a cell's ability to break down and dispose of certain cellular waste.

NHGRI is also involved with 2 other NIH Roadmap for Medical Research projects initiated in 2007: the Human Microbiome Project and the Epigenomics initiative. Researchers use the term microbiome to refer to the collective genomes of all microorganisms present in or on another organism, such as human. The Human Microbiome Project will begin deciphering the genomes of approximately 1,000 types of bacteria. Researchers will then go on to use new, comprehensive laboratory technologies to characterize the microbial communities present in samples taken from healthy human volunteers. Finally, the project will include a set of demonstration projects designed to examine whether changes in the human microbiome correlate with health and disease.

Epigenetics is an emerging frontier of science that involves the study of changes in the regulation and activation of genes not directly dependent on changes in the gene sequence. The initiative will examine epigenetic changes across the entire genome that contribute to health and disease by regulating the activity of the genetic blueprint. Funding will be provided to establish epigenome mapping centers to develop epigenome maps of a variety of human cells that can be used by the research community and to develop new technologies to aid in epigenome analysis.

NHGRI is also helping to lead the NIH Knockout Mouse Project, launched in 2006. The goal of this program is to build a comprehensive and publicly available resource of knockout mutations in the mouse genome. In knockout mice, specific genes have been intentionally disrupted, or "knocked out." Systematic disruption of each of the 20,000 genes in the mouse genome will allow researchers to determine the role of each gene in normal physiology and development. Even more important, researchers will use knockout mice to develop better models of inherited human diseases such as cancer, heart disease, neurological disorders, diabetes, and obesity.

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	August 1, 2008
Alan E. Guttmacher, M.D. (Acting)	August 1, 2008	Present