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What causes Alzheimer's disease?


Starting to work on Alzheimer's disease
Aaron Klug Scientist
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In 1986 I became director of the lab after Sydney... after Sydney Brenner and I had to take stock of what was in the lab. I discovered that a group of four people, whom Sydney had got in, as he called it, to solve the retina, one of them was a man called Michel Goedert now didn't know he was in the lab because Sydney had him in one corner and there were three others and they were going to solve the retina, it's a major problem in biology had Rogers and several others, and I don't remember their names and I wondered what to do with them, they were in a section called the director's section. Sydney had set up as well as the department, a thing called the director's section where various... he pursued some of his own interests as distinct from... from the cell biology division of which he had been the head.

[Q] The retina business has fizzled out?

No it hadn't... well, they were left dangling, they didn't know what to do. I was at a meeting in... I think it was an EMBO meeting and I saw they were handing out papers on brain and I started to look... papers on brain research and I saw a paper by Michel Goedert, MRC laboratory of molecular biology... on nerve growth factor which involved and... so I thought, 'Who the hell is he?' And I discovered he was one of Sydney's four retinologists and he was dangling, they didn't know what to do. Sydney had gone and no one had made any great start on it. So I said to him, 'Well, would you like to work on Alzheimer's?', and he was trained, he had done work in neurochemistry, his PhD was with Les Iversen in the MRC group, he was actually from Luxembourg and he had a degree in Switzerland in medicine, Basle, and had some training on neuroscience. And here he was, that's why Sydney recruited him, and the retina had just... had stopped. There was nothing... nothing had really been accomplished, not even really properly started, so I said well, we must clone this. So I went to talk to people to find out what was... Eric Barnard... there was in our neuro chemical unit, MRC, and I went to see Eric Barnard and I thought they I would... knew how to clone DNA, and how to make libraries, but turned out they didn't. So Michel said that he would do it, he would learn it. He was very good and he learnt it. So what he did was to... we had to first of all determine the protein sequence and so I enlisted... you know this was the time when I enlisted, I was doing it in a managerial way you see, so I could enlist people to do this. So John Walker at that time was in the PNAC as it was called, protein nucleic acid chemistry and he ran the protein sequencing so I enlisted him and so what we did was to get bits of the... we were purifying the protein and Wischik started chopping them up under our instructions, by proteases to find fragments, peptides and they were sequenced by John Walker and so we had our peptide and then once you have an amino acid sequence you can make a nucleotide sequence and then you can clone the gene. And Goedert cloned with the gene, Tony Crowther and Wischik had already published a couple of papers on the structure neither was a paired filament, they were twisted filament we knew the periodicity and now we were finding what it was made of and cloning the gene you got a sequence out that turned out to be a microtubular associated protein called tau, t-a-u, which had been cloned by Mark Kirschner who is a very distinguished cell biologist at Berkley and this was none other than tau. This was a natural protein but unnaturally aggregated into these paired helical filaments. This was the disease, it was a neuro degenerative disease caused by abnormal aggregation of a normal cell component. So later it was shown, we didn't know this at the time, that it was actually highly phosphorylated as distinct from the low phosphorylation you find in the foetal brain and also in the adult brain, phosphorylation state changes over the development, but we didn't know this at the time. But clearly it was tau and so this was the... and before that there had been at least half a dozen candidates for... possible candidates for the protein in which the paired filaments were made, actin was one of them, is was... this is because people, mostly neurologists and people really didn't know how to do practical biochemistry, they were trying to get bits and pieces, they're trying to break up the cells and so on, hippocampus cells, they didn't know how to extract the protein but they tried to create fragments out of it and this clearly showed that this was the main component. In fact, once we purified it was the only component, so we published a series of three papers in 1988 in PNAS which told the whole story of the structure, the cloning and the sequence.

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: Ken Holmes John Finch

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.

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.

Tags: Sydney Brenner, Michel Goedert, Les Iversen, John Walker, Mark Kirschner

Duration: 5 minutes, 55 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008