The Human Genome Project: a new reality

In June 1985, as dusk encroached on the second millennium, meetings aimed at outlining the practical task of sequencing the human genome began at the University of California, Santa Cruz. The scientific and technological conditions of the 1980s had become a catalyst for these discussions. DNA cloning and Fred Sanger's sequencing methods, developed in the mid- to late 1970s, were being exploited by scientists who felt that sequencing the human genome seemed possible at an experimental level. Crucially, researchers were, at the same time, beginning to apply computing solutions to genetics and DNA sequencing, developing methods that would make feasible the task of generating and handling genetic data globally.

This grand, new concept - a "Human Genome Project" - had strong supporters, who argued that deciphering the human genome would lead to new understanding and benefits for human health as well as and determined detractors, who feared such a project would provide a product that would bear little explanatory power for humans - perhaps merely a meaningless string of letters. Even before the Human Genome Project began in earnest, some commentators feared that this project had "engendered a controversy... that involves personalities and politics." [2]

The personalities, the politics and the controversy were only just emerging.

[Morag Lewis, Genome Research Limited]

The Human Genome Project launched in 1990, through funding from the US National Institutes of Health (NIH) and Department of Energy, whose labs joined with international collaborators and resolved to sequence 95% of the DNA in human cells in just 15 years. Meanwhile in the UK, John Sulston and his colleagues at the MRC's Laboratory of Molecular Biology in Cambridge, had, for several years, been working at mapping the genome of the nematode worm and had resolved that sequencing the entire genome of the worm was finally feasible.

As the Human Genome Project was progressing in the US, in the UK the MRC approached the Wellcome Trust suggesting they form a new partnership to fund John's proposed worm sequencing, as a pilot for the Human Genome Project. From here things soon snowballed: the Wellcome Trust suggested that a much larger sequencing effort, to bolster the Human Genome Project should be embarked upon in the UK and appointed one of their senior administrators, Michael Morgan, to look into the viability of such a sequencing initiative. Eventually, in 1992, John Sulston submitted a grant application for an enormous £40-50 million to fund a new centre - the Sanger Centre - which was to form the British arm of the Human Genome Project's sequencing efforts.

In 1993 - with funding from the Wellcome Trust and MRC - the Sanger Centre was officially opened. One scientist recalls being struck by the scale of the task that lay ahead, on arriving at the Institute in 1993 Simon Gregory reflects: "it was just a huge lab, a huge empty lab, with boxes and boxes of equipment. It was all very exciting."

By the end of that year 87 scientists were working at the Sanger Centre, under the leadership of John Sulston, beginning to map and sequence the human genome.

The global sequencing effort

To sequence the human genome as accurately as possible, researchers developed the 'hierarchical shotgun' method. Researchers agreed that this was the best way to achieve the Human Genome Project's target of 95% coverage of the human genome by 2005.

[Morag Lewis, Genome Research Limited]

The first challenge was to create a map of the human genome - a set of index marks on the genome code, used to position the sequences of letters of code that would come later.

Researchers essentially broke many copies of the genome into fragments, each around 150,000 letters of code (or base-pairs) long. They inserted the fragments into a bacterial artificial chromosome that could be grown in E. coli bacteria which divided, thereby replicating the DNA samples to create a stable resource - a 'library' of DNA clones. Where the cloned fragments came from or which overlapped was not known at this point.

[Morag Lewis, Genome Research Limited]

Using special enzymes, researchers could cut the individual clones into diagnostic 'fingerprint' of fragments defined by each clone's sequence. They could then search among millions of fingerprints for shared fragments that would reveal overlaps among the clones. Researchers then assembled the clones into longer contiguous regions and mapped these onto the human chromosomes. The result: a physical human genome map that would be crucial for the sequencing efforts.

To generate sequence of the individual bases that make up the genome, scientists needed to break the cloned fragments into smaller, more manageable, chunks, each around 1000 to 2000 base-pairs long. Researchers sequenced these fragments of human DNA using the shotgun method developed by Fred Sanger and his colleagues a dozen years before. Much as in mapping, researchers used overlaps, this time in the letters of genetic code itself, to reassemble the short stretches of determined sequence. Assembling the sequence from many short segments of sequence was a hugely intense compute task that depended on emerging technology and software to succeed.

Gradually labs around the world began producing DNA sequence. By 1994, the Sanger Institute had produced its first 100,000 bases of human DNA sequence. Remarkably, researchers at the Institute had already produced ten times that amount from the nematode worm genome. The worm project was a trailblazer- its methods, practices, collaborations and ethos would be integral to the development the social mores that would later lead to the successful completion of the Human Genome Project.

As the human sequence data was pouring out from centres across the globe, researchers were afforded glimpses of the kind of power that the human genome sequence might have for medical advance. In 1995, researchers from the Sanger Centre, with international collaborators, located the BRCA2gene, associated with increased risk of breast cancer. Elsewhere, as early as 1993, a US team had located the MSH2 gene, which increases the risk of colon cancer for carriers. In Canada, researchers found five variants on the FAD gene, which together confer an almost 100 per cent risk of developing Alzheimer's disease.

SOURCE

http://www.sanger.ac.uk/about/history/hgp/