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Interest in active chromatin and work on Xenopus


What causes Alzheimer's disease?
Aaron Klug Scientist
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I went on working on this, by this time I'd been scientifically interested... And of course, I'd made... I'd already begun to work on it in a way and so the project continued and I was involved with it from... this was till about 1990. There were all sorts of red herrings, one time it was this related to beta amyloid? There were all sorts of people in Australia called Masters and Beyreuther in Germany, do you know Beyreuther? Who got everything... who got things wrong that one time they said it was the same thing the amyloid and the... they were the same. In the meantime, later, Beyreuther together with [Benno] Müller-Hill, Beyreuther and Müller-Hill cloned... but Michel Goedert had also cloned beta amyloid. He didn't publish the sequence and there was a lot of people... I got very much involved in the whole sort of neurological group, I found it fascinating. But so, we did do some other work on trying to understand the relationship of beta amyloid to... to the tau because they're both manifestations and are they related? Now most people believe and still believe that the extra cellular deposit that beta amyloid is what... is the cause of the disease, now cause can mean many things and either in an Aristotelian sense is it the ultimate cause or the proximal cause or the efficient cause. I did quite a lot of reading with Michel who's a... Michel Goedert who is a very well educated European and he had a proper classical education, speaks many languages. Well, I thought that the paired filaments were the efficient cause, they are the cause of cell death. That's what's in the nucleus and they cause their death but other people did experiments to show that if you... by now you could make vast quantities of beta amyloid and you apply them to neuroblastoma cells or different kind of cells which you extract from brain or transform cells sometimes, you can kill the cells. But they had huge quantities and that wasn't the real proof. And then there was another school who believed there was oxidative damage and there's still a controversy about it. I'm still pretty clear that the two things are chemically linked. In 1990 I proposed the link. You see, when the beta amyloid fibres are made, beta amyloid it's actually a breakdown product of what's called a beta amyloid pre-cursor protein which is a cell membrane protein. And this is... so what happens is that there's a cleavage, several sets of cleavages which are part of the normal development but if the cleavage takes place in the wrong place, then you can get these beta amyloid deposits. And it was found there was a genetic link for producing... Alzheimer's disease which was related to one of the enzymes which cuts the beta amyloid... cuts the amyloid pre-cursor protein. Now... so they therefore thought that's... that was the proof of the genetical link. Now what I proposed in 1990 and wrote it in a paper was to say that indeed there is a link but when you chop... when you cut the amyloid pre-cursor protein you have a C-terminal tail which is present inside the cell and this C-terminal tail could be the link. And I wrote it and proposed it, but I couldn't continue it, most of the field still believed in the beta amyloid. But the... in 2001 a group in Texas showed that the C-terminal tail goes into the nucleus and interacts with the protein that's actually likely to be something which is in the gene so that story isn't settled yet but I believe that the beta amyloid is secondary to the production of the disease. It's not actually the main cause. It's highly controversial.

[Q] Can you see what causes phosphorylation?

No, now that's pretty important. People in the Sates showed that the highly phosphorylated... and there are lots of serine proline sites which are seats for phosphorylation. Serine or threanine and there have been lots of studies of all this. It would take several hours to tell this whole story. But Michel Goedert is carrying on with this, but he's mostly... and his wife, who's called Maria Spillantini who came to work on the medical school on the subject and the... but he's also working on Parkinson's disease. So what I did was basically as a result of all this and I was director at the lab, and I later created a new division of neuro science in the lab. When I talk about my directorial activities this met with quite a lot of opposition from certain people in the lab. I might as well say it now, two people that shall be nameless, who were sort of gadflies, they were gadflies with Sydney Brenner and when I spoke about Alzheimer's, or rather I spoke about... I had a note from one of them who said, 'Are we going to turn the lab into a department of applied molecular biology?' Because I'd made a talk at the annual lab talk saying that would be interesting to do, if you can see a potential application in medicine, or biomedicine and why not might as well choose it, on this occasion. Then the Alzheimer's was rather frowned on. These were purists in the lab who thought we should only be working on these very, high important problems and I thought it was pretty important that we, like you know, say the development of the fly or the C-elegans and so on. I thought it was important that if we could see an opportunity to do it, and so I... which I still believe and so this would take another whole hour to describe all the ramifications of all this will still continue. But I didn't do any more on it after 1990 because by this time the zinc finger work also was now beginning to flourish so I had to make a choice. That's my personal scientific career, so that was the Alzheimer's. But we... so we now have a rather good group, small group and we reckoned as part of the Alzheimer community, there's a huge number of people working with Alzheimer's disease as you can imagine because it's... 15% of us are going to get it if we live over 80.

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: Benno Müller-Hill, Michel Goedert, Maria Spillantini

Duration: 7 minutes, 21 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008