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Methods for early detection of prion diseases


Autocatalytic proteins in BSE
Manfred Eigen Scientist
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Many people try to invoke nucleic acids because they can't think that anything could amplify autocatalytically without RNA, that simply isn't true. We know proteins which can amplify themselves autocatalytically, there's new work showing that this is possible. But the difference to nucleic acid is now inherent autocatalysis, in other words a very specific protein can be made so that it makes an important bond of itself and therefore can favour its own production. But that doesn't mean that every protein can do that, whereas nucleic acids, they all can act as templates and therefore they are inherently replicative. The same is true for more complex mechanisms. You could think of such mechanisms of protein favouring itself, but in this case that doesn't seem to be necessary because the most surprising finding is that the protein which does the infection is the protein you have in your cells... in your brain cells. So it's a normal substance your organism seems to need. Well, you can make now animals - mice - free of this and they still are alive, so it's not a very critical substance for living, but it seems to be... it will have some function. And the important point is this protein, this sequence... that means this gene, is your own gene, but one thinks that the conformation, the structure of the infectious protein is different from the host form... from the uninfectious host form. So what does it mean, different? Well the host form has lots of alpha helices, the spiral kind of structure, whereas the infectious form, the prion form as one calls it, has much more beta structures, they are strands leaning side by side, and therefore will behave differently in the cell. But one doesn't know what it is: is it just using up your host form and exhausting it, or is it a direct influence of the infectious form? But now you have the problem. Here is... you infect yourself with something which is identical in the primary structure, in the sequence of building blocks, with your own host protein. And this substance apparently manages to transform your form into the infectious form. We know such cases, we have talked about allosteric enzymes yesterday and we have talked about Koschland's mechanism of induced fit, so this would be a type of induced fit.  The protein imposes its form on the other. Also in the Monod model there was this 'all-or-none' transition from one conformation into another conformation. Apparently, that can be triggered. Now you refer to my theoretical paper on prions. I could show that one single subunit cannot do it. At least, what would come out if you would make a autocatalytic mechanism, using only one subunit, would mean that either we all get sick or none of us gets sick. What does it mean, get sick? If you get an infection it's important what is faster. The decomposition of what you get into the body, or the autocatalytic turnover of the other protein? Either one is faster or the other is faster. So, even if you get big infection, if the metabolic decomposition is faster than that it wouldn't harm you or, in the other case, if the autocatalytic conversion's faster everyone would get it. And I could calculate how little is needed for everyone to get it, and that those diseases come spontaneously shows that a very well-known disease like Creutzfeld-Jakob disease, and some others, have the same effect without being caused by an infectious agent, probably they are caused by some genetic defect so that the protein which has formed has a more likely a tendency to get over. But the incidence of those spontaneous diseases is very low. Creutzfeld-Jakob is, I think, one in a million cases, so it would not really be a big medical problem. Of course, who has it they wish we had a way of treating the disease, but it is not as is the BSE and a possible transfer of similar disease to men.

Nobel Prize winning German biophysical chemist, Manfred Eigen (1927-2019), was best known for his work on fast chemical reactions and his development of ways to accurately measure these reactions down to the nearest billionth of a second. He published over 100 papers with topics ranging from hydrogen bridges of nucleic acids to the storage of information in the central nervous system.

Listeners: Ruthild Winkler-Oswatitch

Ruthild Winkler-Oswatitsch is the eldest daughter of the Austrian physicist Klaus Osatitsch, an internationally renowned expert in gas dynamics, and his wife Hedwig Oswatitsch-Klabinus. She was born in the German university town of Göttingen where her father worked at the Kaiser Wilhelm Institute of Aerodynamics under Ludwig Prandtl. After World War II she was educated in Stockholm, Sweden, where her father was then a research scientist and lecturer at the Royal Institute of Technology.

In 1961 Ruthild Winkler-Oswatitsch enrolled in Chemistry at the Technical University of Vienna where she received her PhD in 1969 with a dissertation on "Fast complex reactions of alkali ions with biological membrane carriers". The experimental work for her thesis was carried out at the Max Planck Institute for Physical Chemistry in Göttingen under Manfred Eigen.

From 1971 to the present Ruthild Winkler-Oswatitsch has been working as a research scientist at the Max Planck Institute in Göttingen in the Department of Chemical Kinetics which is headed by Manfred Eigen. Her interest was first focused on an application of relaxation techniques to the study of fast biological reactions. Thereafter, she engaged in theoretical studies on molecular evolution and developed game models for representing the underlying chemical proceses. Together with Manfred Eigen she wrote the widely noted book, "Laws of the Game" (Alfred A. Knopf Inc. 1981 and Princeton University Press, 1993). Her more recent studies were concerned with comparative sequence analysis of nucleic acids in order to find out the age of the genetic code and the time course of the early evolution of life. For the last decade she has been successfully establishing industrial applications in the field of evolutionary biotechnology.

Tags: nucleic acids, RNA, alpha helices, autocatalysis, allosteric enzymes, Bovine spongiform encephalopathy, BSE, Creutzfeldt–Jakob disease, induced fit, Daniel E Koshland Jr, Jacques Lucien Monod

Duration: 6 minutes, 8 seconds

Date story recorded: July 1997

Date story went live: 29 September 2010