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Continuing debate on chromatin


The solenoid structure and developing new technologies
Aaron Klug Scientist
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In 1979, I went to a meeting at Spetsai and came across two Swiss called Thoma, Fritz Thoma and Theo Koller, and they were taking pictures of... pictures of... electron microscope pictures of chromatin. And they were... but they weren't doing things systematically, and so I invited Koller... Fritz Thoma to come to the lab as a visitor. He came at a time when... I've forgotten it was just the time when Jenny Lightfoot, my secretary, came. And I just had some papers on DNA structure rejected by four or five referees and other papers rejected. I know this, that's how I fixed the date. They were... they were papers on DNA structures showing that the DNA structure was sequence dependent, which the referees David Davies, Strathern had all turned down, and JMB, but they couldn't... couldn't bear to have their beautiful DNA helix B form marred by these local variations in structure. I... I... at the time I was quite heavily involved in DNA structure, which is yet another story. And I tell you this... goodness, why do I tell you this.

[Q] The solenoid structure...

Oh, yes, it was... Fritz came, so the... so we did some systematic experiments, we'd already done some before, we repeated them in Cambridge. And it showed without any doubt that to fold up into this 300 angstrom fibre, some of the structures were 300 angstrom fibre, and the... this 300 angstrom fibre was present by electron microscopy in... people had reported these and these very crude preparations fixed us all. There's a lot of work by cell biologists looking at fixed chromosomes and so on, and you could see that the fibres were about 300 angstroms emanating out like loops. And sometimes they were 200, sometimes they were 100, they were... they could be depending upon the state of the... So we believe that 300 angstrom was a natural part of chromatin in the chromosome and so the... the 300 angstrom... so we made... and so, Thoma and Koller showed that you could make the 300 angstrom fibres using magnesium or salt, just in the way that John and I had done it before. But provided you had H1 present, if H1 was absent you found that they meandered across the grid, there was a string of nucleosomes but they weren't... they didn't have any direction, no directionality; so this proved the H1 was present. That paper again, it ran through a lot of trouble with referees people like [Pierre] Chambon and a lot of people working on all this. And they didn't believe it because some people claimed you could fold up without H1. Indeed, you can if you go to very high salt, very high magnesium, you will get a compaction, but it's not the 300 angstrom fibre. So... so that was 1979 and I guess that that together with the nucleosome helped... the Nobel Committee... decide that the structure was basically in outline at least correct. And so the... that's why they put in... so the citation which I said before was protein nucleic acids of biological importance; they didn't say viruses and chromatin.

[Q] Do you ever get the feeling that you had to work rather hard for your Nobel Prize?

 Well, I wasn't working for a Nobel Prize.

[Q] No, I know, but I mean there was a lot of input when you got back, there was an enormous work that they evaluated...

Well, you see, it's different; this is why this whole interview is very different. What we were doing, it wasn't... none of these things were discoveries in the simple straight forward sense, they were explorations. And on the way there you had to... we sort of invented the technology. And that's why I keep referring to the interplay of technology and... And although we call the technology methods, I suppose, and learning to do this. Because, as I said before, and this was, in fact, this proved to be a paradigm, the word was coming into fashion then, a paradigm, for how you do structural molecular biology. In fact I wrote it in my Nobel lecture, that you solve the structure in the outline and the large... large biological assembly by electron microscopy to low resolution. And you fill in the pieces; fill in the sub... protein sub units or even the RNA or DNA by X-ray crystallography of the pieces. And that, in fact, has turned out to be correct, that's the way things are going; except that with X-ray crystallography is now more and more powerful, you can crystallise much large objects. But... but that, in fact, is still the overall and so... this was a kind of payoff for the studies that Hugh... Hugh Huxley and I initiated, combining X-ray as I said, X-ray diffraction and electron microscopy. And indeed, in the early '70s, we ran summer schools, then went for several years ago, and later Hugh backed out and Tony Crowther and I ran the summer schools on these methods. And some of the people you know attended those; so it did have an influence in creating the subject. So I think we... so you had to work hard, yes, because we were developing techniques rather than doing spectacular experiments, which told the story in one go. What Hans Zachau wanted us to do was to crystallise a whole nucleosome, solve it more and go to four angstroms and then say voila, but it doesn't go... it doesn't work like that, you could probably do it now.

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: Fritz Thoma, Theo Koller, Pierre Chambon, Hugh Huxley, Tony Crowther, Hans Zachau

Duration: 6 minutes, 30 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008