The Human Genome Project - A Decade Of Accomplishments: 1993–2003

When the HGP began in September 1990, its projected completion date was 2005, at a cost of $3 billion for just the U.S. portion of the research. Ever-improving research techniques—including the use of restriction fragment length polymorphisms, the polymerase chain reaction, bacterial and yeast artificial chromosomes, and pulsed-field gel electrophoresis—accelerated the progress of the project and prompted updating the 1990 plan. The new timetable and five-year plan were announced in 1993 in the journal Science, which contended that "priority should be given during the next five years to increasing sequencing capacity by increasing the number of groups oriented toward large-scale production sequencing." The HGP researchers finished the mapping two years earlier than scheduled, and U.S. scientists spent just $2.7 billion.

Although the HGP was truly a collaborative, international effort, the majority of the sequencing work was performed at the Whitehead Institute for Medical Research in Massachusetts, the Baylor College of Medicine in Texas, the University of Washington, the Joint Genome Institute in California, and the Sanger Centre in the United Kingdom. The Sanger Centre opened in 1993 and quickly established itself as a world-class institution, playing a key role in the completion of the yeast genome in 1996, the Caenorhabditis elegans genome in 1998, and the first complete human chromosome, chromosome 22, in 1999. Along with NIH and DOE funding, the HGP was supported by the Wellcome Trust, a charitable foundation in the United Kingdom.

Public and Private Initiatives Compete

In 1993 the NCHGR established a Division of Intramural Research, charged with developing genome technology research of specific diseases. By 1996 eight NIH institutes and centers had also collaborated to create the Center for Inherited Disease Research to study the genetics of complex diseases. In 1997 the NCHGR gained full institute status at NIH, becoming the National Human Genome Research Institute (NHGRI). Francis Collins remained as the director of the new institute. A third five-year plan was announced in 1998 in Science.

The mid-1990s also saw the birth of a privately funded genomics effort led by J. Craig Venter (1946–). Venter had been working in a laboratory at the NIH when he decided to concentrate his sequencing efforts not on the genome itself, but on the gene products—that is, messenger RNAs produced by each cell. In addition to the genes themselves, the genome is composed of a much larger amount of DNA whose function is as yet unknown. This portion of the genome is often referred to as "junk DNA," although it is possible that its true value has not yet been determined. Venter began an ambitious project FIGURE 7.4
IBM SP Supercomputer at Oak Ridge National Laboratory. U.S. Department of Energy Genomics: GTL Program, http://doegenomestolife.org. to sequence lengths of the genome as a way of trying to identify new gene products and to estimate the degree of diversity in gene structure and function. He eventually left the NIH to establish a private, nonprofit organization, The Institute for Genomic Research (TIGR), an organization aimed at collecting and interpreting vast numbers of expressed sequence tags. (Expressed sequence tags are random fragments of complementary DNAs derived from the information in the RNAs, which contain all the information that is actually expressed in a given cell type.) In July 1995 TIGR published the first sequenced genome of the bacteria Haemophilus influenzae. (See Table 7.2.)

In May 1998 Venter announced that he was allying with the Perkins-Elmer Corporation to form a new company that would compete directly with the public effort to sequence the entire human genome by 2001. The new company would become Celera Genomics. Venter planned to take a different approach from the one used by the HGP. Instead of the map-based, gene-by-gene approach taken by the HGP, his firm planned to break the genome into random lengths, and then sequence and reassemble it. This method saved time by eliminating the mapping phase, but it required robust computing capabilities to reassemble the human genome, which includes many repeated sequences. Venter's approach relied on the use of a supercomputer and 300 high-speed automatic sequencers manufactured by the Perkins-Elmer Corporation; it was the precursor to the large-scale genomics studies that have become standard. Figure 7.4 shows an IBM supercomputer used in genomic research at the Oak Ridge National Laboratory; Venter's project used comparable computers.

When the news of the private firm's intention was made public, the Wellcome Trust considered allocating additional resources to the Sanger Centre to accelerate genome sequencing. The competition between public and private initiatives began in earnest. Within one week of the launch of the private initiative, the Wellcome Trust increased its funding to the Sanger Centre in order to step up the production of raw sequence. In response to this increased support, the Sanger Centre revised its objective by aiming to sequence a full one-third of the entire genome rather than just one-sixth. The race between the public and private projects was on, and the milestones of the sequencing project came ever more rapidly.

In the United States Venter's firm energized the publicly funded project and inspired intensified efforts. HGP investigators feared that if their efforts were perceived as slow and inefficient the HGP would lose congressional support and funding. The threat of genomic information ending up solely in the hands of a private firm was simply unacceptable to the researchers. When Celera entered the race to sequence the human genome, it changed the landscape of the field. Celera resolved to offer its data available only to paying customers and planned to patent some sequences before releasing them. Other private companies involved in genetic research that considered individual genes, rather than the entire genome, followed Celera's lead.

The publicly funded HGP released sequence information quickly both to provide the scientific community with timely data that was immediately usable and to place identified sequences beyond the reach of commercial companies wishing to patent them or charge for access to the data. The leadership of the HGP echoed the sentiments that had prompted Watson's resignation. They contended that patenting the human sequence was unethical and delayed the timely application of genomic information to medical disorders.

The international partners in the genome project met in Bermuda in February 1996 at a strategy meeting sponsored by the Wellcome Trust. There they created the "Bermuda principles," a set of conditions that govern access to data, including the standard that sequence information be released into public databases within twenty-four hours. To adhere to this agreement, participating scientists were to deposit base sequences into one of three databases within twenty-four hours of sequencing completion. The data contained in the three databases were exchanged daily. Since these were public databases, access to the stored sequences was free and unrestricted. The agreement was extended to data on other organisms at a meeting later the same year.

The Media Weigh in on Public versus Private
Genome Research

The entry of Celera into the genome sequencing arena and the plan to patent genes were not viewed favorably in the British press. In part the disfavor stemmed from the fact that, unlike the United States, the United Kingdom operates a national health service that provides and pays for health care coverage for all of its citizens. The May 21, 1998, edition of the Telegraph characterized Venter as "the gene genie racing to grab a fast billion," and posed the question: "Could there be a National Health Service broken by the costs of royalty payments, mainly to American biotechnology companies, for diagnostic tests?" This question reflected both the fear and the disapproval of U.S. ventures that favored profits over public access to data to advance scientific knowledge and improve public health.

Some observers, including Francis Collins and other HGP researchers, felt that the entry of Celera into the field had an overall positive influence on the publicly funded effort, in that it inspired healthy competition and stimulated more creative and energetic thinking. Less positive was the picture painted by the media: that the public and private sectors were in an acrimonious race in which the overarching goals of the project—to increase scientific knowledge and to improve human health—had been overlooked.

On November 26, 1999, the billionth base pair of the human genome was entered into the public databases. On December 1, 1999, the publication of the sequence of chromosome 22 was heralded in the press as the "first chapter of the manual of man."

In March 2000 British Prime Minister Tony Blair and U.S. President Bill Clinton entered the human genome debate when they called for all data about human genes to be made freely available to scientists worldwide. Although the statements from Blair and Clinton were intended to end the gene war, the media were not deterred, and the stock prices of biotechnology firms, including Celera, dropped sharply. In the United Kingdom the Guardian cut to the heart of the conflict, asserting "it's U.K. vs. U.S.; public spirit vs. private enterprise. And it's personal."

During the same period, Collins and the other leaders of the public HGP were under pressure from the White House to resolve their differences with Venter and Celera. The issue had polarized politicians along party lines, with Republicans denouncing Democrats for not supporting the U.S. biotechnology industry. Earlier efforts to resolve these differences had failed because Venter refused to release Celera data unconditionally. Since, however, 2000 was an election year, political momentum favored some sort of amicable truce between the public and private initiatives. The result was the joint announcement on June 26, 2000, that both the public and private efforts had completed preliminary working drafts of the human genome. President Clinton and Prime Minister Blair offered their endorsements at press conferences on either side of the Atlantic Ocean.