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A chance meeting with Francis Crick in Mainz


Nature finds a way not to calculate everything in detail
Manfred Eigen Scientist
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In the first round, the experiment was a very simple one. We took a selection pressure... another enzyme, which degrades... which chops down the nucleic acid.  And this enzyme, so-called Ribonuclease T1, chops always at a G. It does not chop at other letters... I mentioned four letters, A, U, G, and C. Always chops at a G. So the system can evolve by simply hiding its Gs. So that the enzyme can't find it any more. And it can hide the Gs either by putting them into a base pair with a C, or by substituting the G by another letter, or by folding the molecule so that the enzyme doesn't have access. Well, Günther Strunk did this experiment. It took 70 minutes.  After 70 minutes we had a strain which was completely inert towards this enzyme. So it works wonderfully. This was an experiment which went on the way we thought of. And now comes the true experiment. We try to place a problem in such a way that we don't see an easy solution for it. And he did the experiment... nature found immediately, took again 70 minutes, found the solution.

What was the experiment? We took another ribonuclease, Ribonuclease A, and that chops at a pyrimidine. Now I told you before that in nucleic acids you have always a plus and a minus strand, a positive and a negative, and wherever you have a pyrimidine in the positive you have the purine in the negative. So it wouldn't help now to substitute the pyrimidines, or hide the pyrimidines or place them into base pairs, it would be just the wrong for the negative strand. Whatever you do for one strand is wrong for the other, and vice versa. So we said there shouldn't be any solution, but what will the system do? Well, before making big theories about it we did the experiment, and after 70 minutes we had a strand completely inert against this Ribonuclease A. So what happened?

Something like that happens, you do sequence analysis, you look at your product before and after the evolution. And we found something which we couldn't understand. Before the initial product had many, I think 30, positions at which the enzyme could cut and so no wonder that everything died out when you add the enzyme to the wild type, in both the plus and the minus strand. The final product which came out of evolution had in the plus strand no 'cut-able' region, everything substituted by purines, but all the vulnerable regions were now in the minus strand. How come? I mean, how can the system duplicate? The minus strand is necessary as an intermediate because minus makes plus and plus makes minus, so if you destroy one, the system is out. Well, we couldn't understand so we found out, let's do kinetic measurements, let's measure the rates by which it... and then we found a surprise. In the wild type, in the initial product, both strands replicate with the same rate; plus makes minus, minus makes plus.  Both with the same rate. That is in all wild types the optimal condition, and surely our system had adapted to it. Now the evolution product, there's a minus strand... is hundred times better than the plus strand. In other words the minus strand makes hundred times more plus strands than the plus strand makes minus strands. What is the result? You have hundred times more plus strand of the inefficient strand and hundred times less of the very efficient one, that's in daily life not very different. This really happened.

Now what does it mean? It makes hundred times more than the other. Well it means that the replicating enzyme binds a hundred times better to one strand than to the other. And now you see what happens; the efficient strand, which is present in low concentration, is always covered by the enzyme which does the replication. But the other, the inefficient strand which is present in large amount, cannot be covered and is vulnerable, so it got completely substituted. All the vulnerable strands got cut out and replaced by other strands. So within these 70 minutes of the experiments, two goals were reached. First of all in one strand all vulnerable regions were removed and secondly, in the other strand, it was made a hundred times better, more efficient, for the replicating enzyme than the other, so two independent goals. No one of us could have guessed this... could have calculated this. And you see, that's evolution, it's complexity in nature.  Nature finds a way not to calculate everything in detail, it simply replaces it by a number, namely that is fitness. And that's why it gets selected.

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: RNase T1, Ribonuclease T1, nucleic acid, Ribonuclease A, RNase A, pyrimidine, purine, base pairs, Günther Strunk

Duration: 5 minutes, 54 seconds

Date story recorded: July 1997

Date story went live: 24 January 2008