The Human Genome Project - The Birth Of The Human Genome Project

The first meetings to discuss the feasibility of sequencing the human genome were organized by Robert Sinsheimer (1920–), a molecular biologist and chancellor of the University of California, Santa Cruz, and were held on campus in 1985. The idea of sequencing the human genome generated excitement among the many well-known researchers in attendance—they considered the undertaking to be the "Holy Grail" of molecular biology. The following year the U.S. Congress began to consider the feasibility of human genome research. Congress did not, however, decide to fund the project until 1988, after it concluded that the establishment of administrative centers accountable to Congress could effectively manage key aspects of the project, such as databases, sharing of research findings and materials, and cultivation of new technologies. The initial funding from Congress was $17.3 million to the National Institutes of Health (NIH) and $11.8 million to the Department of Energy's (DOE) Office of Health and Environmental Science, with progressive increases over the next few years.

The allocation of these funds incited an impassioned debate. Opponents argued that the financial and human resources devoted to the "big science" of the human genome project would divert research funds from vital scientific and biomedical research and that most of the sequence was of little biological interest and no medical utility. Other detractors warned that the sheer size of the human genome would impede completion of the project within a reasonable time frame without the creation of entirely new research methods and technologies. In the United Kingdom the February 16, 1988, edition of the Guardian described the Human Genome Project (HGP) as "a splendid piece of symbolism and a scientific disaster." In the United States the April 18, 1988, issue of Newsweek offered that "suddenly, science is competing for scarce funding not only against other national needs, but against itself … in the era of federal deficits, a dollar TABLE 7.1
Human genome project funding, 1988–2003[$ millions]
SOURCE: "Human Genome Project Budget," U.S. Department of Energy, Office of Biological and Environmental Research, Human Genome Project,http://www.ornl.gov/sci/techresources/Human_Genome/project/budget.shtml(accessed February 21, 2005)

Fiscal year	Department of Energy	National Institute of Health	U.S. total
1988	10.7	17.2	27.9
1989	18.5	28.2	46.7
1990	27.2	59.5	86.7
1991	47.4	87.4	134.8
1992	59.4	104.8	164.2
1993	63.0	106.1	169.1
1994	63.3	127.0	190.3
1995	68.7	153.8	222.5
1996	73.9	169.3	243.2
1997	77.9	188.9	266.8
1998	85.5	218.3	303.8
1999	89.9	225.7	315.6
2000	88.9	271.7	360.6
2001	86.4	308.4	394.8
2002	90.1	346.7	434.3
2003	64.2	372.8	437
Note: These numbers do not include construction funds, which are a very small part of the budget.

for big science is probably a dollar withheld from small science." The project was launched despite considerable opposition, and most of these concerns were dispelled during the project's early years. Table 7.1 shows the U.S. Human Genome Project budget from fiscal year 1988 through its completion in fiscal year 2003.

In 1988 Congress provided funding to the NIH and the DOE to "coordinate research and technical activities related to the human genome." The NIH also established the Office of Human Genome Research in September 1988. The following year the office was renamed the National Center for Human Genome Research (NCHGR). James Watson served as its enthusiastic champion and director until April 1992. Following his appointment, Watson committed 5% of the project's budget to address ethical, legal, and social issues that arose from the study of the human genome. This ambitious undertaking constituted the largest bioethics program, in terms of funding and human resources, in the world.

The Human Genome Project Information Web site, operated by the DOE, describes the ambitious goals of the HGP when it began in 1990. The overarching HGP goals were to:

• Identify all the approximately 30,000 genes in human DNA
• Determine the sequences of the three billion chemical base pairs in human DNA
• Store HGP findings and other information in databases
• Improve tools for data analysis
• Transfer related technologies to the private sector
• Effectively address the ethical, legal, and social issues that might arise from the project

International genomic research was also underway in England, France, Germany, Japan, and other countries. During 1987 the Italian National Research Council launched a genome research project; the United Kingdom began its project in February 1989. In 1988 an international group of geneticists founded the Human Genome Organization (HUGO) in Switzerland. Many international collaborations had already been forged as individual scientists exchanged information in their quests for genetic links to disease. HUGO developed an international framework to coordinate research projects and prevent wasted resources through duplication, creating a culture of sharing data. In 1990 the European Commission initiated a two-year human genome project. Russia funded its genome research project in the same year.

In 1990 the initial planning stage of the U.S. HGP was completed with the publication of the joint research plan Understanding Our Genetic Inheritance: The HGP, The First Five Years, FY 1991–1995. This initial research plan enumerated the specific research goals and objectives for the first five years of an endeavor that was projected to take fifteen years to complete. During the same year the HGP received the endorsement of the National Academy of Sciences, the National Research Council, the U.S. Department of Agriculture, the DOE, the National Science Foundation, and the Howard Hughes Medical Institute. Just two years into the five-year plan, James Watson resigned from his leadership position with the NCHGR because he vehemently disagreed with NIH decisions about the commercialization, propriety, and legality of patenting human gene sequences. Watson felt that data from the HGP should be in the public domain and freely available to all scientists as well as the public. In April 1993 American geneticist and physician Francis S. Collins (1950–) was named director.

Many prominent researchers sided with Watson against the patenting and commercialization of HGP data. In 1996 scientists at leading research institutions throughout the world agreed to submit their findings and genome sequences to GenBank, a genome database maintained by the NIH. In a resounding and unanimous move, they required the publication of any submitted sequence data on the Internet within twenty-four hours of its receipt by GenBank. This action ensured that gene sequences were in the public domain and could not be patented.

Worming Away

Although sequencing the human genome was the principal objective, the HGP also sought to sequence TABLE 7.2
Model organisms sequenced
SOURCE: "Model Organisms Sequenced," in Genetics, vol. 2, E–I, MacmillanReference USA, Gale Group, 2002

Date sequenceda	Species	Total basesb
7/28/1995	Haemophilis influenzae (bacterium)	1,830,138
10/30/1995	Mycoplasma genitalium (bacterium)	580,073
5/29/1997	Saccharomyces cerevisiae (yeast)	12,069,247
9/5/1997	Escherichia coli (bacterium)	4,639,221
11/20/1997	Bacillus subtillis (bacterium)	4,214,814
12/31/1998	Caenorhabditis elegans (round worm)	97,283,371
		99,167,964c
3/24/2000	Drosophila melanogaster (fruit fly)	˜137,000,000
12/14/2000	Arabidopsis thaliana (mustard plant)	˜115,400,000
1/26/2001	Oryza sativa (rice)	˜430,000,000
2/15/2001	Homo sapiens (human)	˜3,200,000,000
aFirst publication date.
b Data excludes organelles or plasmids. These numbers should not be taken as absolute. Scientists are confirming the sequences; several laboratories were involved in the sequencing of a particular organism and have slightly different numbers; and there are some strain variations.
c The first number was originally published, and the second is a correction as of June 2000.

the genomes of other organisms. These other organisms served as models, enabling researchers to test and refine new methods and technologies that helped identify corresponding genes in the human genome. Table 7.2 is a list of some of the model organisms, including the roundworm, sequenced during the course of the HGP, along with the dates the sequences were published and the number of bases in each.

At England's Cambridge University, geneticist and molecular biologist Sydney Brenner (1927–) was studying the nematode worm Caenorhabditis elegans. By 1989 Brenner and his colleagues had successfully produced a map of the entire Caenorhabditis elegans genome. The map consisted of multiple overlapping fragments of DNA, arranged in the correct order, and Brenner's research team printed the worm's genome on postcard-sized pieces of paper.

Watson felt that the genomes of smaller organisms would not only help to refine research methods and the technology, but also provide valuable sources of comparison once the human genome project was underway. The worm map convinced Watson that Caenorhabditis elegans should be the first multicellular organism to have its complete genome accurately sequenced. When the worm-sequencing project began in 1990, the first automatic sequencing machines had just become available from Applied Biosystems, Inc. The sequencing machines enabled the worm pilot project to meet its objective of sequencing three million bases in three years. Equally important, the worm project demonstrated that the technology could scale up—that is, more machines and more technologists could produce more sequences faster.