Human Genome Project

The genome represents the entire complement of DNA in a cell. The Human Genome Project is the determination of the entire nucleotide sequence of all 3 billion + bases of DNA within the nucleus of a human cell. It is one of the greatest scientific undertakings in the history of mankind. The first draft of the human genome sequence was completed in the year 2001 and published simultaneously in the British journal Nature and the American journal Science.

The data obtained from sequencing the human genome promise to bring unprecedented scientific rewards in the discovery of disease-causing genes, in the design of new drugs, in understanding developmental processes and cancer, and in determining the origin and evolution of the human race. The Human Genome Project has also raised many social and ethical issues with regard to the use of such information.

Origins of the Human Genome Project

One could say that the Human Genome Project really began in 1953, when James Watson and Francis Crick deduced the molecular structure of DNA, the molecule of which the genome is made. (Watson and Crick were awarded the Nobel Prize for this work in 1962.) Since that time, scientists have wanted to know the complete sequence of a gene, and even dreamed that some day it would be possible to determine the complete sequence of all of the genes in any organism, including humans.

The original impetus for the Human Genome Project came almost a decade earlier, however, from the U.S. Department of Energy (DOE) shortly after World War II. The atomic bombs that were dropped on Hiroshima and Nagasaki, Japan, left many survivors who had been exposed to high levels of radiation. The survivors of the bomb were stigmatized in Japan. They were considered poor marriage prospects, because of the potential for carrying mutations, and the rest of Japanese society often ostracized them. In 1946 the famous geneticist and Nobel laureate Hermann J. Muller wrote in the New York Times that "if they could foresee the results [mutations among their descendants] 1,000 years from now …, they might consider themselves more fortunate if the bomb had killed them."

Muller had firsthand experience with the devastating effects of radiation, having studied the biological effects of radiation on the fruit fly Drosophila melanogaster. He predicted similar results would follow from the human exposure to radiation. As a consequence, the Atomic Energy Commission of the DOE set up an Atomic Bomb Casualty Commission in 1947 to address the issue of potential mutations among the survivors. The problem they faced was how to experimentally determine such mutations. At that time there were no suitable methods to study the problem. Indeed, it would be many years before the appropriate technology was available.

During the 1970s molecular biologists developed techniques for the isolation and cloning of individual genes. Paul Berg was the first to create a recombinant DNA molecule in 1972, and within a few years gene cloning became a standard tool of the molecular biologist. Using cloning techniques, scientists could generate large quantities of a single gene, enabling researchers

to study its structure and function. In 1977 Drs. Walter Gilbert and Fred Sanger independently developed methods for the sequencing of DNA, for which they received the 1980 Nobel Prize along with Berg. Sanger's group in England was the first to completely sequence a genome, identifying all 5,386 bases of the bacterial virus φχ174.

Another technological breakthrough occurred in 1985, when the polymerase chain reaction method was developed by Dr. Kary Mullis and colleagues at Cetus Corp. This team devised a method whereby minute samples of DNA can be multiplied a billion-fold for analysis. This technique, which has many applications in diverse fields of biology, is one of the most important scientific breakthroughs in gene analysis. Mullis received the Nobel Prize for this work in 1993.

At this time, however, DNA sequencing was still done by hand. At best, a researcher could manually sequence only a few hundred bases per day. To be able to sequence the human genome, machines would be needed that could sequence a million or more bases per day. In 1986 Leroy Hood developed the first generation of automated DNA sequencers, thereby dramatically increasing the speed with which bases could be sequenced. Thus, by the mid-1980s the stage was set.

With these new techniques, molecular biologists now felt that it might be feasible to sequence the entire human genome. The first serious discussions came in June 1985, when Robert Sinsheimer, chancellor of the University of California at Santa Cruz, called a meeting of leading scientists to discuss the possibility of sequencing the human genome. Sinsheimer was inspired by the success of the Manhattan Project, which was the concerted effort of many physicists to develop atomic weapons during World War II. That project led to rapid development and a massive influx of funding for physicists. Sinsheimer wanted a "Manhattan Project" for molecular biology, to enhance and expand human genome research.

Meanwhile, the DOE continued to be interested in the problem of identifying mutations caused by radiation exposure. Led by associate director Charles DeLisi, the DOE became a strong supporter of the genome-mapping initiative, for it understood that sequencing the entire genome would provide the best way to analyze such mutations. Thus the DOE became the first federal agency to begin funding the Human Genome Project.

Mapping the human genome came to be called the "Holy Grail of Molecular Biology," and many biologists were interested in the project. Most notable among them was Nobel laureate Gilbert who, through his interest, personality, and academic ties, developed enormous enthusiasm for the project. The initial goals set out for the Human Genome Project were threefold: to develop genetic linkage maps; to create a physical map of ordered clones of DNA sequences; and to develop the capacity for large-scale sequencing, because faster and cheaper machines along with other great leaps in technology would be needed to get the job done.

In 1988 the National Institutes of Health (NIH) set up an Office of the Human Genome, and Watson agreed to head the project. It had an estimated budget of approximately $3 billion, and 3 percent of the funding was devoted to the study of the social and ethical issues that would arise from the endeavor. A target date for completion of the project was set for September 30, 2005. By 1990 the Human Genome Project had received the additional endorsement of the National Academy of Sciences, the National Research Council, the DOE, the National Science Foundation, the U.S. Department of Agriculture, and the Howard Hughes Medical Institute. Sequencing of the human genome had now officially begun.

While sequencing the human genome was a primary goal, other sequencing projects were just as important. Many scientists established projects that sought to sequence several organisms of genetic, biochemical, or medical importance (see Table 1). These so-called model organisms, with their smaller genomes, would be useful in testing sequencing methodologies and for providing invaluable information that could be used to identify corresponding genes in the human genome. Sequence databases were established, and computer programs to search these databases were written.

Competition between the Public and Private Sectors

Dr. Craig Venter, a scientist at the NIH, felt that private companies could sequence genomes faster than publicly funded laboratories. For this reason he founded a biotechnology company called the Institute for Genomic Research (TIGR). In 1995 TIGR published the first completely sequenced genome, that of the bacterium Haemophilus influenzae. TIGR was soon joined by other biotechnology companies that competed directly with the publicly funded Human Genome Project.

Among these other biotech firms is Celera Genomics, founded in 1998 by Venter in conjunction with the Perkin-Elmer Corporation, manufacturer of the world's fastest automatic DNA sequencers. Celera's goal was to privately sequence the human genome in direct competition with the public efforts supported by the NIH and DOE and the governments of several foreign countries. Using 300 Perkin-Elmer automatic DNA sequencers along with one of the world's most powerful supercomputers, Celera sequenced the genomes of several model organisms with remarkable speed and, in April 2000, announced that it had a preliminary sequence of the human genome.

In order eventually to make a profit, these biotech companies were patenting DNA sequences and intended ultimately to charge clients, including researchers, for access to their databases. This issue of patenting had already caused controversy. Watson felt strongly that the sequence data flowing from the Human Genome Project should remain within the public domain, freely available to all. Meeting opposition to this view, he stepped down from his position as director of the NIH-sponsored project in 1992 and was succeeded by Francis Collins.

Other researchers shared Watson's view, and in 1996 the international consortium of publicly funded laboratories agreed at a meeting in Bermuda to release all data to GenBank, a genome database maintained by NIH. The agreement reached by these scientists came to be known as "The Bermuda Principles," and it mandated that sequence data would be posted on the Internet within 24 hours of acquisition. Because the information is freely available to the public, the sequences can not be patented. The dispute between Celera Genomics and the International Human Genome Consortium continues, as scientists now begin the task of searching the genome for valuable information.

Progress in the Human Genome Project

Sequencing the human genome has led to some surprising results. For example, we once thought that highly evolved humans would need a great many genes to account for their complexity, and scientists originally estimated the number of human genes to be about 100,000. The draft of the human genome, however, indicates that humans may have only about 30,000 genes, far fewer than originally expected. Indeed, this is only about one-third more than the number of genes found in the lowly roundworm, Caenorhabditis elegans (approximately 20,000 genes), and roughly twice the number of genes in the fruit fly Drosophila melanogaster (approximately 14,000 genes). Subsequent estimates have placed the number of human genes closer to 70,000; the true number is unknown as of mid-2002. Scientists have learned that most of the genome does not code for proteins, but rather contains "junk DNA" of no known function. In fact, only a small percentage of human DNA actually encodes a gene.

The complete human genome consists of twenty-two pairs of chromosomes plus the X and Y sex chromosomes. On December 2, 1999, more than 100 scientists working together in laboratories in the United Kingdom, Japan, the United States, Canada, and Sweden announced the first completely sequenced human chromosome, chromosome 22, the smallest of the autosomes . To assure the accuracy of the sequence data, each segment must be sequenced at least ten times.

Thousands of scientists, working in more than 100 laboratories and 19 different countries around the world, have contributed to the Human Genome Project since its inception. Thanks to the development of later generations of high-speed automatic sequencers and supercomputers to handle the enormous amount of data generated, work on the project progressed well ahead of schedule and well under budget, a rare phenomenon in government-sponsored projects. In 2001 the first draft of the complete human genome was published. However, considerable work remained to be done, particularly in the sequence of regions of repetitive DNA.

Whose Genome Is It?

Although all humans share more than 99.99 percent of their genome sequences, each human is unique. Geneticists estimate that each person carries many mutations, perhaps hundreds or even thousands of them. Therefore, one of the major questions that has arisen in the Human Genome Project is "whose genome is it?" The final catalog of sequences, whenever it is complete, will have to take into account these individual variations, and ultimately there will be a "consensus sequence," but it will represent no one specific individual.

A related issue arises from the distinct differences that scientists anticipate will occur among different populations. Which sequences should be considered "normal," and which ones should be classed as "mutated"? The Human Genome Diversity Project was proposed in 1997 to catalog and study naturally occurring sequence variations among racial and geographic groups. This project never gained much support, however, because of the social and ethical ramifications to such a catalog. On the other hand, a Human Cancer Genome Anatomy Project was initiated to catalog all the genes that are expressed in cancer cells in order to aid in the detection and treatment of cancers. This project enjoyed much more support.

Patenting the Genome

From the outset there has been considerable debate among scientists, politicians, and entrepreneurs as to whether the human gene sequences can or should be patented. Indeed, this debate was the reason that Watson resigned as the first director of the NIH Human Genome Project program in 1992. Watson's position was opposed by many biotechnology companies, which hoped to recover the cost of their genome research and began patenting short segments of sequenced DNA without any idea as to their function. As of 2000, the U.S. Patent and Trademark Office (PTO) changed its policy, and began granting patents only to genes that have been identified, rather than just the random sequenced fragments. The data that flow from genome sequencing will be an invaluable scientific resource, particularly in the area of developing new medical treatments, but its use will be restricted if individual organizations can claim exclusive use rights to large segments of it. It is thus clear that debate on the patenting of genes will continue for years to come.

At present much of data from genome research are available to scientists and other interested parties. The data generated by participants in the Bermuda Principles agreement can be accessed on-line at the National Center for Biotechnology Information (NCBI) Web site, at <www.ncbi.nlm.nih.gov/genome/guide/human>. The International Human Genome Consortium Web site provides a current list of genome sites that offer links to most genome databases at <www.ensembl.org/genome/central>. Information about all the genomes that have been sequenced, as well as information on the sequencing of cancer genes, can be found on the Internet at <http://www.ncbi.nlm.nih.gov>.

Genomics and Proteomics

The Human Genome Project has given rise to new fields of research. One of these is genomics . This new field combines information science with molecular biology. It is resulting in the "mining of the genome" for valuable sequence data.

An even more recent development is the field of proteomics , the study of protein sequences. Research in this field is rapidly expanding, as protein sequences can be predicted from the gene sequence. The folding of the proteins (secondary and tertiary structures) can be predicted by computers, leading to a three-dimensional view of the protein encoded by a particular gene. Proteomics will be the next big challenge for genetics research. Indeed, Celera is already gearing up for massive protein sequencing.

Ethical Issues

From the very beginning of the Human Genome Project, many from both the scientific and public sector have been concerned with ethical issues raised by the research. These issues include preserving the confidentiality of an individual's DNA information and avoiding the stigmatization of individuals who carry certain genes. Some fear that insurers will deny coverage for "preexisting" conditions to people carrying a gene that predisposes them to particular diseases, or that employers might start demanding genetic testing of job applicants.

There are also concerns that prenatal genetic testing could lead to genetic manipulation or a decision to abort based on undesirable traits disclosed by the tests. In addition, some raise concerns that a full knowledge of the human genome could raise profound psychological issues. For example, individuals who know that they carry detrimental genes may find the knowledge to be too great a burden to bear. All of these ethical issues will ultimately have to be addressed by society as a whole.

see also Automated Sequencer; Bioinformatics; Cancer; Cloning Genes; Genome; Genomics; Genomics Industry; Model Organisms; Muller, Hermann; Polymerase Chain Reaction; Polymorphisms; Repetitive DNA Elements; Sequencing DNA; Watson, James; Yeast.

Ralph R. Meyer

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In 2002 Craig Venter announced that Celera had sequenced his personal genome, not a composite as originally claimed.