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Will the Human Genome Project work?


John Sulston's work on Caenorhabditis elegans
Aaron Klug Scientist
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I did carry some new initiatives. One was I mentioned creating a new Department of Neuroscience, because it seemed to me this is an important coming subject, and we had people doing odd bits there, particularly with an nematode, and particularly with an nematode, and the other thing I think I did, was to... I had this Director's section which I inherited from Sydney [Brenner], and there were all sorts of odd bods in it. One was some neuroscientist. I think I talked about Alzheimer's Disease. There were people who were going to do the... solve the retina, had actually begun. There were also... John Sulston was in the Director's section.

Now, John Sulston was originally a chemist, and he'd come to work on DNA, and so he had an appointment in the Lab which was not that of a group leader, but that of an essential person in the Lab. It was a new category. They were called B appointments and A appointments in the office but not known publicly. So he wasn't entailed to be a research group leader, and so one of the things he did was when Sydney Brenner started the whole nematode, created the whole school, John Sulston was a kind of assistant, a high class sort of lieutenant of Sydney's, originally working on various aspects of DNA and... not DNA sequencing, but DNA sequencing had been carried out by Fred Sanger and Alan Coulson. What he had done was to find out the lineage of the C. elegans there's a whole... one of the profound problems of biology, the C. elegans has only 931, I think that's the number of cells, and everyone is the same. They all have a fixed number of cells, and it was known from the old German work that the embryo of the C. elegans has rather more cells, and how do these number of cells get determined? So the other thing was, was there a lineage? Were there elemental steps where the number of cells could be varied, and so on? It was one of the big problems, and John Sulston spent four years in the dark room observing the growth of C. elegans, this worm, which was already the object of a great deal of research in the Lab. That was Sydney's great contribution for which he got the Nobel Prize later for starting the whole project as an experimental animal.

So then John Sulston went on to start mapping the genome of C. elegans. Now, a map means that you find signposts along the way. So the C. elegans has got, oh, I've forgotten how many million DNA. The human has 3,000 million. C. elegans might be a tenth of that, 30 million or something like that, which still is a large number of genes. And he began to map these, together with Alan Coulson, just a two-man job. They were working on only a two-man job on C. elegans and then Sydney left the Lab and I found John there, John Sulston there. He was in the Director's section. So of course, I had to find out what he was doing, and I inherited him, and he... I could see that he was a very, very, very good experimenter... a very good observer. By this time, he had already observed... he established, by the way, there was a lineage exactly, a perfect lineage, but that during the very stages of the lineage, when certain cells divided, one cell died and the other cell continued. Now this is called apoptosis. It was known there were such processes in higher animals. The word in fact was invented by a man called Curry in Edinburgh, and... but this was a precise... every single cell was accounted for in its origin. He had the complete lineage, just like a family all the way, and he also, because of the anatomy which John White was carrying out... this was part of Sydney's grand plan, because of... John White determined where all these cells were and produced a three dimensional map of the anatomy, but John Sulston did it all by visual observation.

There was a German group developing... working on developing that. They'd automated everything, but you see, if you automate, it's not as... unless you know what you are looking for... but John Sulston noticed that certain cells, what looked like cells, began to sparkle by eye, and what these were, these were the residues of cells, residues of cells which had died in the course of development. This was programmed cell death, which is the right word for apoptosis, and then these disappear after a short while, because they get phagocytosed by their neighbours. They gobble them up, and they leave no trace, and I think that's why the German group, with all their heavy automated equipment, didn't spot this. It was the keen observer and the eye spotted it. So he had done this already, but I'm just going backwards. But he also started... now I'm doing the mapping, the genome with Alan Coulson, and when I became Director, I found them at the stage where they'd made really quite a large map. Other people were trying to make maps of the human genome, a group in France for example, but they were very skilful mappers. I can't explain how they started to map. It's not my work anyway. But then the question of what to do next? Now, Sydney had left, so to speak, a legacy with John that they must go on and now sequence all the expressed mRNA. In other words, look at that part of the genes which produce a protein. I thought it would be a waste, and that one really ought to do the whole genome, because by this time I was working on... I'd been working on transcription, and I realised that the regulation of transcription is far more important, and understanding the development, than just knowing the sequences of all the products, although of course they need to be known as well. So I persuaded John... by this time, John was also being courted by various Americans who wanted to go into this, including a group at Darwin, in Seattle, and so on, and we were in danger of losing him. But I urged him that he should... he and Alan Coulson should start sequencing the whole C. elegans genome. Now it seemed within... so he had started sequencing, developing sequencing, they were still... they weren't all the very automated sequences which Applied Biosystems developed later, but the idea was that he simply start with what there was. It's a very British thing to do. You make the best of what you have, because in the world there was a HUGO, the Human something... I wonder what the U stands for, Genome Organisation, where people like Walter Bodmer, Sydney to some extent, all the leading luminaries went around having meetings about the importance of the human genome and trying to raise money for it.

Born in Lithuania, Aaron Klug (1926-2018) was a British chemist and biophysicist. He was awarded the Nobel Prize in Chemistry in 1982 for developments in electron microscopy and his work on complexes of nucleic acids and proteins. He studied crystallography at the University of Cape Town before moving to England, completing his doctorate in 1953 at Trinity College, Cambridge. In 1981, he was awarded the Louisa Gross Horwitz Prize from Columbia University. His long and influential career led to a knighthood in 1988. He was also elected President of the Royal Society, and served there from 1995-2000.

Listeners: John Finch Ken Holmes

John Finch is a retired member of staff of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. He began research as a PhD student of Rosalind Franklin's at Birkbeck College, London in 1955 studying the structure of small viruses by x-ray diffraction. He came to Cambridge as part of Aaron Klug's team in 1962 and has continued with the structural study of viruses and other nucleoproteins such as chromatin, using both x-rays and electron microscopy.

Kenneth Holmes was born in London in 1934 and attended schools in Chiswick. He obtained his BA at St Johns College, Cambridge. He obtained his PhD at Birkbeck College, London working on the structure of tobacco mosaic virus with Rosalind Franklin and Aaron Klug. After a post-doc at Childrens' Hospital, Boston, where he started to work on muscle structure, he joined to the newly opened Laboratory of Molecular Biology in Cambridge where he stayed for six years. He worked with Aaron Klug on virus structure and with Hugh Huxley on muscle. He then moved to Heidelberg to open the Department of Biophysics at the Max Planck Institute for Medical Research where he remained as director until his retirement. During this time he completed the structure of tobacco mosaic virus and solved the structures of a number of protein molecules including the structure of the muscle protein actin and the actin filament. Recently he has worked on the molecular mechanism of muscle contraction. He also initiated the use of synchrotron radiation as a source for X-ray diffraction and founded the EMBL outstation at DESY Hamburg. He was elected to the Royal Society in 1981 and is a member of a number of scientific academies.

Tags: Applied Biosystems, John Sulston, Fred Sanger, Alan Coulson, John White, Walter Bodmer

Duration: 8 minutes, 14 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008