In this, the third of four episodes in Channel 4’s award winning DNA series (first broadcast in 2003), narrator Bernard Hill explores the origins and eventual completion of the Human Genome Project (HGP). Described as the attempt to “catalogue all the genes that carry the instructions to make a human being” (00:00:08), the programme features the majority of the key actors in this scientific and political drama including James Watson, Sir John Sulston, Fred Sanger, Craig Venter, and former US President Bill Clinton. Insofar as the series successfully integrates discussion of the scale and scope of the project in scientific, political and financial terms, it forms an excellent basis for teaching both the science and bioethics of the HGP and large scale sociotechnical projects.
This episode of the Channel 4 series opens with a discussion of the development of DNA fingerprinting technology by Sir Alec Jeffrey’s in the 1980s (00:01:50 to 00:05:23). While DNA fingerprinting has, in itself, become a somewhat controversial technology (at present in its association with the National DNA Database, featured in this BioethicsBytes post, though the programme’s interview with Jefferys highlights many more), Jefferys discovery of single nucleotide polymorphisms – or SNPs – laid one of the key foundations for the HGP. As highly individualised sections of repeated code, SNPs could be used as “page marks” (00:17:29) within the genome and provided a method for the initial ‘mapping’ of the genome: a necessary precursor to the sequencing project.
Reading the pattern
As highlighted in the programme, the first challenge faced in sequencing the human genome was learning how to ‘read’ DNA’s “four letter chemical code” (00:06:31) – a problem that was solved 30 years previously by Fred Sanger working on a virus. DNA: The Human Race describes in detail Sanger’s technique (00:07:03 – 00:10:11), though also highlights how laborious this process was: it took Sanger “four years to work out the virus’s full five thousand letter code” (00:09:08). Since “it was thought that the human genome contained 3 billion letters of undeciphered code” (00:10:17), this meant that using Sanger’s original technique the HGP would take one person roughly “2 and a half million years” (00:10:24) to complete. The second challenge on the road to the human genome was, therefore, accelerating the pace at which sequencing could be done.
Sequencing at speed
This was achieved in a number of ways: first “it was decided to share out the work” (00:17:07) between 16 labs across the globe. The genome was divided using the initial map provided by the SNPs, and when sequencing began in 1992 it was estimated that the completion date would be in 2005. Sir John Sulston, who was put in charge of the UK arm of the sequencing project, likens this to “a divide and rule process, going down from the big, to smaller chunks, to smaller chunks still and then analysing in … detail” (00:18:35). While this distribution of work not only increased the rate at which sequencing could be done, for Sulston it also served a symbolic function within the project: it ensured that the human genome was “shared by everybody” (00:19:02).
However, for some scientists involved in the HGP, simply sharing out the task was not enough to get the speed of sequencing up to an acceptable level. Craig Venter, in particular, developed an alternative approach to sequencing the human genome – the ‘whole genome shotgun’ approach (see 00:19:42 to 00:20:43) – which, when combined with automated sequencing and scanning technology, could “change a genome project from being 10 years to a year” (00:21:10). Venter was advocating a “totally different…molecular biology philosophy” (00:20:37) for the HGP, and – as outlined below – it was this clash of philosophies that lead to the now famous conflicts within the project.
The HGP is also said to mark “the advent of big biology” (00:09:08). The HGP was a project “spanning five continents, consuming billions of dollars and lasting over a decade” (00:01:17), and was the first project in biological science to be conducted on a scale similar to ‘big’ projects in physics (e.g. the LIGO telescope and the LHC at CERN). The programme compares it to “putting a man on the moon” (00:10:36). However, when the prospect of sequencing the human genome was mooted at a meeting in Long Island organised by James Watson, it was seen by some as an essentially technical activity and not as frontier science. There were also concerns that by diverting large sums of money into a large scale sequencing effort, many small science projects would see their funding dry up.
In this sense early support or opposition to sequencing the human genome was not merely a matter of the scientific merits of the project: the allocation of resources within biology became a factor and, in Watson’s bid to congress for the initial $3 billion it was though the project would need, the HGP became more political still. Billed by Watson as a prerequisite for understanding a range of human diseases, including cancer and heart disease, DNA: The Human Race implies that congress’s need for “some positive headlines” (00:15:30) was an important factor in its decision to back the project from the outset in 1990.
‘Reading the Pattern’: Rival Strategies
Another key aspect DNA: The Human Race highlights within the story of the HGP was the interaction between public and private initiatives. While the programme represents this in terms of the rivalry between the public project and that instigated by Craig Venter in the form of Celera Genomics (and to an extent in terms of a personal rivalry between Venter and Sulston), this discussion raises important questions over data-sharing, patenting and the role of venture capital in biology that remain current today.
The programme describes Venter’s highly publicised break from public project in 1998, under the slogan “discovery can’t wait” (00:26:50), and his intention to sell the data derived from sequencing at Celera and render the public project redundant. This contrasted with Sultson’s philosophy (referred to above) and the public project’s preferrence for ‘shared ownership’ of the genome and ‘simultaneous release’ of sequence data to such an extent that the famous ‘race for the genome’ ensued (Sulston highlights succinctly the social and ethical issues implicit in Venter’s approach between 00:27:38 and 00:28:05). Essentially the competition between the public and private projects involved a further injection of cash from Congress into the public project and a ‘retooling’ of machines – bought from Celera.
A similar debate over patenting also took place around the HGP, when Celera – in an attempt to recoup the capital costs of setting up a large scale sequencing facility – announced their intention to file patents on 6,500 genes (see 00:33:42 to 00:34:46).
What is particularly interesting about this conflict between public and privately funded scientists was that it was not resolved within the scientific community. Its resolution and the eventual coming together of the two initiatives was largely achieved within the political sphere: according to one of the political peacemakers, the scientists “were in some way captives of their own communities”, whereas “leaders may think beyond just the rivalries and the competition and seek the middle ground and compromise” (both 00:39:31). This was dramatically demonstrated in the staging of the annocuement of the first complete draft of the human genome in June 2000. Then US President, Bill Clinton, states that having both public and private initiatives present at this event “relived us of the burden of saying who finished first” (00:40:36).
The book of life?
A final aspect of the HGP explored in DNA: The Human Race was the task of assembling the draft and managing the vast quantities of data generated by both public and private sequencing efforts. This included ‘counting’ the genes (see 00:44:16). The programme opens with the statement that “back in the 1980s scientists thought that approximately 100,000 genes controlled all the components of the human body” (00:06:15), however by 2001 it was apparent that “there were far fewer genes…than anyone had anticipated” (00:45:35).
Today it is thought that the human genome is likely to contain less than 30 thousand genes (see the Human Genome Project Information pages for more details), however this discovery was a key finding in the epilogue to the HGP. Sulston’s final description of the sequence generated by the project summarises the questions that remained unanswered simply by compiling the, so called. book of life: he describes the draft published in 200 as “a hieroglyph that we have just dug up in the desert and brushed the sand off a little bit”. The question that continues to preoccupy the scientific community today is: “what does all this mean?” (both quotes from 00:49:23).
Overall, DNA: The Human Race provides an interesting and engaging overview of the main stages in the HGP, highlighting not only the underlying scientific concepts and tools, but also the social, political and economic forces that made it a reality. Readers may also be interested in the following YouTube video from the X PRIZE Foundation which details some of the developments scientists expect to come out of the HGP and current challenges facing today’s sequencing projects (though also gives a flavour of how the power of genetic and genomic information may be marketed).
DNA: Human Race was produced by Windfall films and is supported by an interactive website. This episode was first broadcast on Channel 4 on 22nd March 2003 at 8.00pm. Copies containing clips may be purchased from Windfall films. Alternatively, members of the BUFVC may obtain copies for educational use (TRILT identifier: 001DED2F). All timings contained in this post are approximate and may vary by up to a minute.