Cracking the Code Milestones in the Human Genome Project: genesis to postgenomeRonald J A Trent |  | ||
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The Human Genome Project (HGP) will change medicine and medical research irrevocably. The obvious gains in genetic knowledge from the HGP, together with the advances which will flow into bioinformatics, biotechnology and the potential for novel therapeutic agents, will ensure that the financial investment in the HGP is repaid many times over. The HGP's costs in terms of ethical and social issues remain to be determined, but it is to be hoped that these will not detract from the scientific and medical achievements. How did such an endeavour start, and what path did it follow?
MJA 2000; 173: 591-594 Years 1-5 -
Years 6-10 -
A new era -
References -
Authors' details
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A key player in the formative years of the Human Genome Project (HGP)
was the United States Department of Energy (DOE). The DOE had a long
term research focus on DNA because its early involvement in the World
War II program that produced the atomic bomb had led to an interest in
induced mutations. To understand the link between DNA and induced
mutations, the DOE ultimately needed to characterise individual
differences in DNA sequences. However, at the time, the sequences of
only a few selected genes within the genome were known. Most of the
estimated 40 000 human genes had yet to be discovered,1 and a
considerable proportion of the 3 x 109 base-pairs making up the
human haploid genome did not contain genes (about 30% is repetitive
DNA2). Therefore, vast tracts of
DNA with unknown function remained to be explored.
A concerted effort to sequence the entire human genome within a reasonable time frame required the development of better technology. In addition, no research group was big enough to take on such a mammoth task. Despite the enormous obstacles, the majority of scientific opinion by the end of the 1980s was that sequencing the entire human genome was feasible. However, not all scientists were convinced -- there was considerable apprehension that it was a monumental exercise in data gathering rather than "true" research. There were also fears that the potential huge costs of the HGP would divert funds from more traditional research. Ultimately, the HGP, started in late 1990, was planned to be completed by 2005, and had a budget of US$3 billion. Politically, the HGP promised more than medical benefits -- it promised technological developments that would lead to economic wealth and job creation. David Smith, then Director of the DOE's Human Genome Program, described the HGP as "developing an infrastructure for future research". In reply to concerns about the potential for shrinking research funds in other areas, Smith said that, after the HGP was completed, "individual investigators would do things that they would never be able to do otherwise".3 A final point to note about the HGP is that the term "human" is a misnomer, as parallel work was also planned to sequence the genomes of model organisms, including a mouse, a fruit fly, various microorganisms, a worm, a plant and a fish. This work, called "comparative genomics", was undertaken to facilitate understanding of the human genome, as there are many similarities between human genes and those of other organisms (Box 1). | |||||||||||||||||||||||||||||||
Years 1-5 |
The goals identified for the first five years of the Human Genome
Project are described in Box 2.6 During this time, many
laboratories throughout the world carefully constructed maps of the
genome, and then identified, by DNA sequencing, each base in the
segment they were allotted. The HGP became a truly international
endeavour, with the British and French participating early.
Interestingly, in both countries, substantial funding for
HGP-related activities came from outside the public purses (the
Wellcome Trust, in the UK, and the Muscular Dystrophy Association, in
France). Although the DOE was a key leading player, it was soon
partnered by the National Institutes of Health (NIH). Today, the NIH
is the leading public-sector player in the HGP.
The Human Genome Organisation (HUGO) was formed to coordinate international efforts, as well as to facilitate education and rapid exchange of information. Australia has played a key role in HUGO, with Professor Grant Sutherland, from Adelaide, being one of the presidents of that body; the 1999 Human Genome Meeting (HGM'99) was held in Brisbane. | ||||||||||||||||||||||||||||||
Years 6-10 |
In contrast to the relatively low-key and steady progress made in the
early stages of the HGP, more recent years have been considerably more
turbulent. By 1998, the impressive developments in DNA-sequencing
technology, particularly automation, had brought forward the
timing for specific goals -- it was now believed that the complete
sequence of the human genome would be determined by 2003. The first
success stories of the HGP centred around the completed sequencing of
genomes from model organisms (Box 3). These successes increased the
momentum of the human genome work, as they confirmed that genomes
could be completely sequenced, and that the information obtained had
both scientific value, and potential medical importance.
As the pace quickened towards the 10th year, so did the growing influence of the commercial sector (Box 3). As shown in Box 2, key goals of the HGP were the development of technology (particularly in relation to DNA sequencing), and the transfer of HGP outcomes into the private sector. The HGP represented an ideal venture in which the public and private sectors could cooperate (and compete). Governments and public funding bodies set aside substantial resources to participate in the HGP as part of the intellectual pursuit, but also as a base for economic development or alternative research funding. Developments coming from HGP were meant to be rapidly disseminated to users, an aim which would later come under some pressure. The HGP's goals requiring that DNA sequencing results were to be communicated freely and without delay were, to some extent, at odds with the protection of intellectual property through patenting. In 1991, the NIH was embroiled in an international controversy when it attempted to patent anonymous DNA sequences (those for which no function was known). Following public and international indignation, the NIH withdrew these patents.7 However, apart from the patent issue, free-flowing, publicly available information remained the rule rather than the exception, until the private sector became a major player. A high profile example of commercialisation came in the late 1990s with Celera Genomics, a privately funded organisation sponsored by Applied Biosystems (now PE Biosystems). Celera (company motto, "Speed matters") took on the might of the NIH and the world when it publicly boasted that with its resources (300 of the most modern automated DNA sequencers, and supercomputers second only to those in the US military), and a different strategy for sequencing DNA, it would finish the first draft of the human sequence before the NIH or other countries, and at a much reduced cost of US$200 million.8,9 This challenge had some positive effects, as it focused the cumbersome and slow-moving multicampus, multinational Human Genome Project, but, on the negative side, it once again highlighted that big corporations and big money can get there first, but at a cost -- the availability and access to future databases would no longer be free, at least in the short term. | ||||||||||||||||||||||||||||||
A new era |
In June this year, President Clinton, flanked by Dr Francis Collins of
the NIH and Dr Craig Venter of Celera, announced simultaneously with
the UK's Prime Minister Blair that the first draft of the human DNA
sequence was now complete, having reached this stage with input from
both the public and private sectors. Whether Celera or the
NIH-sponsored initiative won the "race" is less relevant than who
will control access to the databases containing the DNA sequences. At
this stage, Celera appears to hold the upper hand, and is well on its way
to the stated goal of being the definitive source of genomic and
related medical and agricultural information.9 Although the HGP
has officially reached its goals, it is important to note that this is
only the first draft of the DNA sequence, and considerable work
remains to ensure that DNA sequencing errors are removed. This will
take a few more years.
At the end of the HGP, the DNA sequence from the human genome will be deposited in various databases. What will be left is the mammoth task of working out the function of the genes. Hence, the post-genome era has been called functional genomics, which includes proteomics -- the technology and strategies required to determine the function of proteins. How this will be accomplished remains to be determined, but new technologies will be needed. The use of microarrays (a method by which the expression of many thousands of genes can be identified very rapidly with microchips) is an early, promising strategy in functional genomics. Bioinformatics will need to come up with more sophisticated programs by which the function of genes can be predicted. The traditional "wet-lab" approach to research might even give way to a complete "in-silico" (ie, computer) strategy! The first challenge -- sequencing the genome -- has been accomplished. Many more even larger challenges await us as we set out to determine the function of all human genes.10,11 | ||||||||||||||||||||||||||||||
References |
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Authors' details | |||||||||||||||||||||||||||||||
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University of Sydney at the Royal Prince Alfred Hospital, Sydney,
NSW.
Reprints will not be available from the authors. Top right-hand corner is a photo of James Watson (left) and Francis Crick (courtesy of A Barrington Brown, Sciences Source/Photo Researchers). ©MJA 2000
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