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Work on Alzheimer's disease: Trying to extract brains


Work on Alzheimer's disease: Getting interested
Aaron Klug Scientist
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I was head of structural studies at the time, Hugh [Huxley] and I were joint heads of structural studies, and after my Nobel Prize, about a year later, in about 1983 or '84, maybe later, Martin Roth, Sir Martin Roth, a professor of psychiatry came to see me and he said, 'Can you do something about Alzheimer's disease?' Well I'd heard of Alzheimer's disease and I thought it was a disease of the elderly. I'd read about it of course, it's about a 5% chance above the age of 65, but over 85 its 15%, it's serious. And moreover, my own mother, living in Durban, showed symptoms of Alzheimer's, so I felt duty bound to try to do something about it.

So I read about it and I read that it wasn't general degeneration of the brain, it was very specific. Certain parts of the brain degenerated first. They were the hippocampus which is involved in short term associations and also in short term memory, but it's mostly it's associations it's involved with. And the first neuropathological lesions are showing there. Now the neuropathological lesions are of two types that are found in post-mortem brains of people with Alzheimer's disease and there were studies going on in Cambridge, because Roth had come down from Newcastle and he had shown that there were basically two kinds of lesions, one were extra-cellular deposits called amyloid deposits, now amyloid is a very general term, there are many different proteins that can... misfold to form amyloids so it's really a tinctorial term because amyloid is defined, histologically, it's something which have add various dyes including primulin, it has apple green biofringence and red absorption primulin and there are other dyes as well, so it's... but nothing was known about amyloid structures. So I decided, I said, 'Well, I think we'll work on this', we'd had some experience, you know, of extracting chromatin and quite a lot of experience of what you might call crude biochemistry, setting up a problem and the question is how do you turn a disease into... a clinical problem into a biochemical or molecular biological problem. Well, the obvious things was to get this stuff out of the brain, get some of these lesions... and other people worked on amyloid fibers but I came to a conclusion that because they were extra cellular they may be not as directly involved as the intracellular tangles, this was the second lesion. Intracellular tangles as they were called consisted of filaments which from electron microscope studies of sections of post mortem brains, appeared to be filamentous and they appear to consist of two chains and a man called Kidd had called them paired helical filaments. These were inside the cell. So I thought, so I had to make a decision and from reading the literature and talking to people, I thought that we should go for this and I thought we should get them out, get them out of a brain, nobody ever extracted these things, so I said to Roth well we would do it but you have to send somebody along who knows how to work with brains. So he sent along a man called Claude Wischik who was a medical doctor and so we said we must get these tangles out of the brain and purify them but how do you... you know they're not enzymatic, it's just a structure so what I thought we would do is plan to take them out, try to find a chemical label or an antibody to label then and then as we would follow the process of extraction by the label at the same time we could look in an electron microscope to see what these filaments looked like. That was actually... in fact that was the plan of action and it worked. Some of the so-called experts had never got as far as... they were cross linking things inside the cell and trying to do things but the main thing is to get the stuff out, it's sort of obvious. So I started out in the managerial way and got Claude Wischik to come to the lab, Sydney opposed it, Sydney Brenner, he thought it was too far a diversion from the lab... and also he used to make fun of Martin Roth because he was quite an interesting figure, a fellow of Trinity, lots of stories and... old-fashioned type of professor, you see. But he had done very important work, counting the number of... correlating the extent of a disease with a number of fibrillary tangles and also the amount of extra cellular amyloid deposits. And of course, he was a great man... he was later elected FRS, which pleased him no end.

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: Hugh Huxley, Martin Roth, Claude Wischik, Sydney Brenner

Duration: 5 minutes, 33 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008