Word of honor
The Human Genome Project, like so many 'big science' efforts, made huge claims. But scientists should be careful about promising more than they can deliver, says Philip Ball.
So now the job is finally done: this week Nature publishes a paper1 entitled "Finishing the euchromatic sequence of the human genome". Yes, it's true that the sequence was announced in 20012,3, but actually those were just drafts, and full of holes. Now the gaps have been plugged.
Or have they? The word 'euchromatic' gives it away. Euchromatin is the relatively loose, gel-like portion of human DNA, which is gene-rich and is the most actively transcribed part of the genome. Some of our DNA, however, is more densely packed into heterochromatin, which contains a smaller but by no means negligible number of genes.
The 2001 drafts largely neglected heterochromatin, so that they covered only 70% of the whole genome (didn't they tell you that?). Even the 'completed' sequence announced in 2003 only meant that the euchromatin sequence was 98% finished. Decoding the heterochromatic genome (one-fifth of the whole human genome) could take another five years or more.
In a way all of this is just science's business as usual. A challenge as immense as that faced by the Human Genome Project (HGP) is bound to contain all sorts of loose ends that will be fiddly to tie up. No one could expect the project to wait until all the secrets of heterochromatin have been laid open (something that will require new sequencing techniques) before announcing its success.
In another sense, however, this latest development highlights the dilemma faced by the entire genome-sequencing enterprise. How do you present the work to the public in a way that justifies the immense cost and effort involved without distorting the message?
The HGP is not alone here. Any 'big science' project understandably feels under strong pressure to justify its existence, and there is therefore a great temptation to find a suitably grand and catchy soundbite to convey its quest. We regularly hear, for example, that the enormous particle accelerators of high-energy physicists are built to uncover the 'secrets of creation', which will point the way to a Theory of Everything and thereby let us 'know the mind of God'.
Scientists had better be careful with such imagery, for there are many who are ready to take it literally. I suspect I'm not alone in feeling uneasy at Bill Clinton's words on the day the human genome was unveiled in 2001: "We are learning the language in which God created life. We are gaining ever more awe for the complexity, the beauty, the wonder of God's most divine and sacred gift."
However, we shouldn't feel much better about the comments of James Watson, who was never remotely likely to invoke the divine: "Now we have the instruction book for human life," he said.
Metaphors such as a Theory of Everything and the Book of Life are well intentioned but fundamentally dishonest, because the people who initiate them know that they are misleading.
There is now some frantic back-pedalling going on with respect to the HGP, as geneticists confess that, of course, all the human genome sequence really represents is a list of parts: a dictionary, not a book. (Such a definition is still problematic, as it wrongly implies that once we know the gene sequences we know all about the structures of proteins.) And everyone is now eager to acknowledge that it will take time to transform the genome data into medical benefits, which were the HGP's main selling point.
But the problems run deeper than that. In Kuhnian terms, gene sequencing was firmly within biology's old paradigm. It was safe stuff: we knew exactly how to do it. Unlike the Moon landings, with which it is often compared, there was never any real risk that the HGP would fail to meet its objectives provided that we kept cranking the handle.
In such situations, the temptation is to stick with the business one knows will succeed, rather than facing the difficult questions that really need answering. "I fear that full genome sequences will prove irresistibly seductive, perhaps even deferring the hard wet-lab work required to understand physiology," warned Tom Pollard of the Salk Institute, California, three years ago.
What the gene sequencers kept sotto voce until their project was completed was that the real obstacle to understanding this putative Book of Life was the problem of deducing how genes work together and respond to a changing external environment to generate the dynamic process we call life.
This is the challenge faced by the discipline of systems biology; it not only requires genuine conceptual innovation (as opposed to repetitive and routine methodologies) but is also a problem that no single scientific clan will crack alone. This new-paradigm biology "requires teamwork and putting together different kinds of science", according to Leroy Hood of the Institute for Systems Biology in Washington.
Beyond sequence data
No one can deny that the information in the human genome should be immensely valuable to medicine. It could enable treatment of disease to be customized to an individual's genetic profile; it should help in identifying drug targets and in rational drug design; it could make diagnoses quicker and easier; and it might allow diseases such as cancer to be identified much earlier.
On the other hand, realizing this promise will require far more than the bare sequence data. Again, understanding and preventing disease is likely to depend on a systems-scale view of biology. "There will be enormous scientific and engineering challenges to achieve this vision," Hood and his collaborators said recently4, "far greater than those associated with the Human Genome Project."
What's more, before we join British prime minister Tony Blair in welcoming the human genome sequence as "a revolution in medical science whose implications far surpass even the discovery of antibiotics", let's remember that the principal causes of death in the world are ones that are easily treatable or avoidable. And the wealthiest countries suffer largely from mortalities brought on by tobacco, alcohol, poor diet and lack of exercise. You don't need a Book of Life to cure that.
- International Human Genome Consortium Nature , Nature, 431. 931 - 945 (2004).
- International Human Genome Consortium, Nature, 409. 860 - 921 (2001).
- Venter J. C., et al. Science, 291. 1304 - 1351 (2001).
- Hood L., Heath J. R., Phelps M. E. & Lin B. Science, 306. 640 - 643 (2004).