Issue 266 of SOCIALIST REVIEW Published September 2002 Copyright © Socialist Review

Science

THE GENE MACHINE

Sir John Sulston, former director of the human genome mapping project, talks to John Parrington

Sir John Sulston, whose book The Common Thread, co-authored with Georgina Ferry, is available from Bantam Press for £17.99
Sir John Sulston, whose book The Common Thread, co-authored with Georgina Ferry, is available from Bantam Press for £17.99

We hear a lot nowadays about the genome project initiating a revolution in science, and that we're now living in the post-genomic age. In your book, you say that shouldn't really be called the post-genome age but the post-hype age. What did you mean by that?

In many ways, genomics is simply becoming a posh word for biology. The point about genomics is that one studies the information to make an organism as a whole. Initially, scientists were going after individual genes, because that was all they could do. The evolution of genomics was first of all mapping--getting the individual genome pieces out, assembling them in order to match the linear order of genes along the genome. Then we began sequencing the individual units of DNA.

It's a revolution because it provides people with new, powerful ways of studying ourselves and other organisms. We can now look directly for novel genes likely to be involved in a particular function. It also provides the information for manipulating genomes, for example creating so called transgenic mice, where we deliberately mutate interesting new genes to study their function.

However, it has not really changed the nature of the problems we're after, which is trying to decipher how biological systems work, how development of an embryo occurs, and how the various bits and pieces of an organism function together to make the whole thing function. There is no question though that people do devise their research projects in a different way now that they have access to genome maps and sequences.

One criticism of previous gene-directed approaches is that by focusing on specific genes one misses the global interaction of such genes with other genes (or rather their protein products) within the living cell. An exciting development emerging from genomics is the new technologies, for instance DNA chips or microarrays--glass or silicon chips upon which a robot has spotted thousands of genes from a particular organism. One can now use such chips to survey the global pattern of genes expressed within a living cell or tissue. This could allow us to go beyond what some people have called a reductionist approach. To what extent do such new technologies represent a real shift in the way we do biology?

Here you're using genomics in a positive, constructive way, although it is even more important that your efforts are focused. One exciting application of such technologies is the improved prognosis of breast cancer which involves looking at the coordinated expression of sets of genes. If one set of genes has been turned on, it means a highly malignant tumour and one had better try chemotherapy quickly. If another set is turned on, then there's much less cause for worry. For clinical medicine and researching how things work it can be a valuable tool. But you can't say this is the definitive expression pattern for a cell, as these vary with the environment. What you have done is an experiment which makes use of such an expression pattern.

A curious feature of the human genome, like those of other complex organisms, is that genes represent only a few percent of the genome. An alternative way of identifying new genes is to go directly to the chemical cousin of DNA--RNA--which is how it is actually expressed within each living cell. As RNA is unstable, these can best be collected and studied in the form of their DNA copies--cDNAs. So wasn't it a waste of time to sequence everything in the genome?

Yes, that was exactly the nature of the argument back in 1990 and it was quite heated. But there are two problems with only sequencing cDNAs. Firstly, you won't get all the genes that way. You won't get rare genes only expressed in cell types that are extremely difficult to get hold of. Or those expressed in tiny quantities. So to have any hope of getting the complete gene set, one has to sequence the genome. It's a bit like the tortoise and the hare. The tortoise (being the genome project) plods along more slowly but gets every gene on the way.

Secondly, cDNAs don't include control regions that turn genes on and off in response to hormones, etc. To study the control sequences, you need the complete genomic structure. One exciting new area is comparative genomics. As we line up the human genome with, say, that of the mouse or pufferfish, we can begin to identify important regions. These are the bits that have been conserved in evolution across different species. An important goal will be to compare our genome with that of other primates like chimpanzees. Once we start to look at the differences between ourselves and chimps it'll undoubtedly be the differences in these control sequences we'll be interested in.

It's not widely known that there are many genome projects besides the human one, particularly of organisms used in research or with importance for agriculture. You originally worked on the worm which was the first genome of a complex organism to be sequenced. Was it a revelation to find that so many genes were present and even played similar roles within completely different kinds of organisms?

Oh, undoubtedly. We all expected to find similarities, but as the projects have progressed, the revelation that we share half of our genes with a fly, a worm--or a banana as one colleague has it--is quite an astonishing thing. I like to say it's the fulfilment and proof of Darwinism, which is after all still highly contested in some philosophical and religious quarters. I believe it reinforces the inescapable conclusion that we evolved from single cells. It shows we've inherited the sum total of variation that's been occurring for the last 4 billion years, from the earliest common ancestor.

RNA--DNA'S chemical cousin (above)--and chimps (below)  help us analyse our genes
RNA--DNA'S chemical cousin (above)--and chimps (below) help us analyse our genes

Some people fear that the human genome project stands for a new form of eugenics. Some left wing scientists like Steven Rose and Richard Lewontin say the genome project was from the start linked to a view of human behaviour and society that sees everything determined by our genes. How would you respond to these concerns, and wouldn't you agree that there's something special about humans in the sense that we're not like other animals? For instance, we've progressed from living in caves to sending people into outer space over the space of a hundred thousand years. That's obviously not down to biology, in the sense that we haven't evolved significantly in that time.

Well yes, we've got into a process where cultural evolution has taken over. Let's not forget though, that this sits on top of our genetic characteristics. As far as I'm concerned, the international genome project has never been guided by genetic determinism. With regards to misusing the findings of the genome project, some have compared it to a Pandora's box. It only becomes so if we misuse its findings. If we use them well it becomes a treasure chest. If we don't open the treasure chest, and discuss its use wisely, it's going to be used behind closed doors, for profit, maybe for worse purposes. So there are many reasons for opening the treasure chest, publicly and benignly, and then discussing how we should use the contents. What we really need to do is to move forward on human rights. I believe it's very important to move forward in law, to make sure there is no genetic discrimination. That's one of the main reasons why I'm spending time sitting on the Human Genetics Commission.

A key point you keep returning to in your book is the battle with Celera, the private consortium that began to compete with you on the genome project. How important was this battle?

It was absolutely crucial. The introduction of private enterprise didn't advance the genome project one bit. Conceivably it held us back because we've been distracted by the PR. I never wanted to be a big figure. I never wanted to have to go on television and defend our actions. I did it because otherwise we'd have been steamrollered into oblivion. The property rights of the whole human genome would be in the hands of some American corporation. Celera didn't play a useful role, because their published sequence drew heavily on the framework provided by the public project, and they aren't involved in the completion of the genome project, which will be of most use for scientific research. Now a similar situation, with different players, is happening with the rice genome.

In the final chapter of your book, you talk more broadly about globalisation and the privatisation of the world. Is it true that this is becoming an unstoppable force?

Well, personally I'm not against globalisation. I'm not sure whether anyone is really. It's good if the world becomes smaller and more communicative. However, what's happened is that the globalisation of free market forces directed at short term profit has outrun all the other sorts of globalisation that ought to be going on. I went to a talk at the Royal Society by the incoming director general of the World Trade Organisation. He said quite plainly that the Trade Related Intellectual Property rights agreement signed in 1995 was written by the companies.

Such developments pervert systems that ought to be for the good of all humanity, and pervert it to improve the profits of these transnational corporations. So that's what I'm against. Personally I would not want everything organised centrally by the state. People need to be free to try out their skills. If they make something they can sell to others, that's fine within a uniform system. But the world is very far from uniform. It staggered me to find that money available for health care is approximately 1000 to 1, if one compares the richest nation, the US, with Malawi, one of the poorest. On that kind of playing field there is no possibility of using free market forces to have an equitable outcome. We have got to even up the playing field with the ultimate goal of reducing global inequity.

In the press, you often get portrayed as a child of the 60s, a radical, sandal-wearing individual. What do you think about this and about the so called anti-globalisation movement with its demonstrations in Seattle and Genoa? Are young people right to protest in the way they have been doing?

I describe myself as a child of the 60s, in the sense that I identify with a time when public spending for the common good and liberalism were alive and well. In terms of my portrayal, well you know newspaper editors love these polarisations. So they had Craig Venter of Celera as the son of a marine, and myself as a kind of Red. This extreme portrayal is nonsense but does touch upon an important point, which is to what extent one believes in working for the common good instead of for one's own personal wealth and ambition.

Regarding Seattle and Genoa I think that if people want to protest they must do so. I do not believe in violent protest. Apart from anything else, we're not living under a military regime--it just antagonises the uncommitted middle ground, who are the very people we want to win over. But I understand people's strong feelings about the state of things and I certainly share many of the ideals of the movement, which is that we need to have a fairer world.

chimps help us analyse our genes

What do you think about the prospect of us going to war with Iraq?

Well, I think that would be extremely stupid. America is going through a dreadful phase where the slightest criticism of military endeavour is seen as unpatriotic. Many American liberals and left leaning people are feeling rather muzzled as a consequence.

I think the role of Britain ought to be to stand more firmly with Europe as a voice of caution, because clearly invading Iraq is going to inflame things further.

Scientists are often seen as apolitical people living in ivory towers. Do you think scientists should be public spokespeople? And is there a need for left leaning scientists with a social conscience, committed to making the world a better place?

I believe in being completely honest about what one's doing, and being completely passionate about the things one feels strongly about. So I think it's the duty of all scientists but also all citizens to keep their eyes open. If you come across something, for instance, a crime being committed, or something which you see as wrong, then you should do something about it if you possibly can.

I've come across global inequity directly as a result of my struggle over the genome. I had just assumed that the genome would be a public good and no one would object to that. Having realised that there were some people who wanted to turn it into private profit, I was absolutely horrified. So I began to enquire about what was happening more generally in the world.

DNA is sometimes called the blueprint of life. This is somewhat misleading. Proteins do all the work in a living cell. They are the building blocks of life and also the machines that drive it. The information in DNA is only unlocked when each gene is made into a protein. But this requires the help of an intermediary--DNA's chemical cousin, RNA. Unlike the famous DNA double helix, in which two mirror image strands are twined around each other, RNA usually exists as a single thread.

RNA has been in the headlines recently because of a scientific discovery called RNA interference (RNAi). The technique is being touted as the next big thing for treating cancer and viral infections. RNAi was discovered by accident over a decade ago by US plant biologist Professor Richard Jorgensen. He tried to make purple petunias an even darker hue using genetic engineering but ended up with white plants instead. Serendipitously, he had uncovered an important defence mechanism in nature in which organisms use a double-stranded form of RNA to fight off infection by viruses.

Now scientists have shown that RNAi can work in a human cell. It may be possible in the near future to treat Aids by removing the blood cells from an infected person, engineering them with RNAi to make them immune to the HIV virus and then replacing the resistant cells. Biotechnology companies are already battling for patent rights.

RNAi could be a big medical breakthrough. The technique ought to be very specific in its choice of target, with few side effects as a consequence. There is a need for some caution though. Another technique, gene therapy, was only a few years ago being hyped in the same way. In the rush to test it clinically, some patients died after treatment. It will be important to ensure that there is a proper public debate about the possible risks as well as the benefits of RNAi, rather than the decisions being left to companies most concerned about their share prices.
John Parrington


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