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Charles Wiessmann and the error rate


Sol Spiegelman's quantitative evolution experiments
Manfred Eigen Scientist
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Let's take his experiment. He has a test tube in which he has the building blocks for nucleic acids, in which he has the right pH conditions, ionic strength conditions, everything are right, and the isolated enzyme. Now all he has to do is to add a few strengths of nucleic acids which then can be replicated by the enzyme using the energy-rich building blocks. Now if he would let this experiment go, you would have soon saturated your test-tube with nucleic acid strengths, so what he is doing, he lets it grow exponentially, let's say by a certain factor, let's say he lets it grow ten times, so that he gives... he adds a certain number of strengths and they replicate now so that he has ten times as many strengths. Then he stops the experiment and takes out one-tenth of that solution, so comes back to the... and puts it into a new glass with such a reaction mixture. Lets it grow a factor 10, stops it, takes out one-tenth. You can go on indefinitely with that. Because you always keep the concentration at the same level, it grows a factor 10 and you take only a tenth out of it. But evolution goes on. During that time you can adapt it to a new purpose, and Spiegelman was the first to do such experiments.

First of all it was a great thing to show that all you need is the enzyme, the replicase, and the template ‒ the nucleic acid ‒ and the building blocks, and can do that in the test tube then.

[Q] But you mentioned he didn't know about the error threshold.

That's right.

[Q] When you did the evolutionary experiments in your laboratory you know of the error threshold. Wasn't it Charles Weissmann who was, so to speak, the...?

Let me... I come back to that. But let me go on with Spiegelman. What he did is really the first to show you can do that with single molecules in the test tube and you get evolution. The first experiment he did was a complete phage Q-beta with his four thousand and some nucleotides, and what happened... the molecule became shorter and shorter and shorter, up to five hundred, so it went down to about a tenth of the length. Why?

[Q] With the same efficiency?

Yes, even with a larger efficiency. Only... you can evolve only the better adapted ones. So if the one... the shorter one grows out of the solution then it must be better than the wild type, otherwise the wild type would have won the competition. Now what happens? This phage is replicated in a test tube and you give the energy-rich building blocks, so the phage doesn't have to infect a cell any more, a coli cell.  So that means it throws away all the information which it would need to infect cells, and it doesn't need... it gets its enzyme, it gets its food, its building blocks, so it throws away everything until it has a shorter nucleic acid which still is recognised by the enzyme and...  If you would make it even shorter than that, then the enzyme... then the efficiency of recognition would be less. But here he got something which is a tenth of the original length and therefore takes much less time to do one, so the speed goes up, and even the speed per nucleotide went up by a factor of three. That was the first experiment... very interesting.

Then he did another experiment. He took a short nucleic acid, which I mentioned... the 216 nucleotides which he called a midi variant... and he added to his solution a selection pressure, in form of a substance which inhibits the replication. In other words there is an interchelating substance which sits in between the bases and hinders the reaction. Now what can evolution do? You can evolve strands which do not get hindered by this substance, so you favour those strands which can cope with the selection pressure, and sure enough he got out a strand which was much better than the wild type, with this... in the presence of this inhibitor. And he even got out a strand which was addicted to ethidium bromide, in other words which worked better in presence of this substance than in absence.

These were quantitative evolution experiments. The mutants he got out were not very efficient, in that the mutants were for error mutants, and that's due to the fact that he was too precise... the short end with that given error rate did not give him efficient way of evolution.

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: Evolution, evolution experiments, nucleic acid, error threshold, Q-beta, wild type, midi variant, interchelating substance, ethidium bromide, quantitative evolution experiments, mutants, error mutants, Escherichia coli, Sol Spiegelman, Charles Weissmann

Duration: 5 minutes, 50 seconds

Date story recorded: July 1997

Date story went live: 24 January 2008