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 Table 1.

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.