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Experimenting with zinc finger constructs


Trying to improve the zinc finger constructs
Aaron Klug Scientist
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That paper simulated, and this is part of the story, simulated... a man in the States called Edward Lanphier who was a business development officer at one of the biotech companies, to set up a zinc finger company, you see they don't lose any time, these Americans. And he invited Yen Choo and myself to join the scientific advisory board. And I didn't know who he was. He wasn't a respected scientist, he was a... he had a degree in biology and so we rather pooh-hooh'd the idea you see. We underestimated him and I'll come to that later in the story as they figure prominently later. So we decided after that the next step would be to try to improve the affinity... improve the affinity and the specificity of our zinc finger constructs and there were two ways that you could do that. One was to change our phage display methods so we could take into account this... cross-contact interaction figure from position two to the second strand. And that required quite a bit of fancy engineering and this was solved by a student of mine called Mark Isalan, very bright fellow, top of the biochemistry class in his year, who came to... applied to me to work on zinc fingers because they'd got around. And he succeeded in doing that and the second thing we did was to try to extend the three fingers to six fingers and eventually to nine fingers. Now, other people had tried to do this and a group at the Scripps who had now jumped in, there were people all round the world now jumping into this, they spoil all the fun I must say, as you well know from your own experience. And of course, some people say a bit of competition is healthy but it is galling sometimes when they... it would be okay if they contributed to the subject, mostly they create a lot of noise, a lot of extraneous noise and diversion and you have to sort out the good stuff from the stuff which is rotten, as I said yesterday. You have to police the subject, you haven't got time to police and answer every bit of nonsense that's published, but there are some good papers in the field, of course I mustn't be too damning in all this there are some good...

[Q] Your scientific inquisition?

Not an inquisition. Well, because you know they make it difficult because people can't see what's being achieved because of this clutter. There's a lot of extraneous clutter. And you know very well how examples of molecular biology or any branch of science where this happens. So we decide to do this and I. Marcus and I recruited a man called Michael Moore.

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: Edward Lanphier, Yen Choo, Mark Isalan, Michael Moore

Duration: 3 minutes, 10 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008