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Letter from Emile Zuckerkandl to Linus Pauling. June 18, 1964.
Zuckerkandl writes to update convey to Pauling the details of recent meetings held at Cold Springs Harbor, New York and Bruges, Belgium. Zuckerkandl describes his presentation of the hemoglobin and evolution data that he and Pauling published in their "Horizons in Biochemistry" paper, and notes certain criticisms raised by Vernon Ingram, among others. Zuckerkandl outlines his response to Ingram's critique, adding that "I was not very impressed with these criticisms." [Published by permission of Emile Zuckerkandl]


REC’D JUN 22 1964

Woods Hole, Mass., June 18 1964

Dear Dr. Pauling :

I much regretted not to be able to wish you good bye as I left Caltech. I was unaware of your plans to go to your ranch and therefore missed you. But I was happy to be able to think and am now happy to say : A bientôt !

After the meetings at Cold spring Harbor we spent a few quiet days here in Woods Hole with my father-in-law and are about to leave for France. I used these days largely to put in shape the manuscript on the paleogenetics of hemoglobins (the talk I have in Bruges) of which I left a copy with you.

In this manuscript and in my presentation I gave our table 1 from “Horizons in Biochemistry” (the approximate time of derivation of different hemoglobin chains from there common ancestor) with slightly revised figures. The order of magnitude of time elapsed between two evolutionarily effective mutations still was 10 Million years. I then proceeded to examine the rate of evolution of cytochrome c and to compare it with the rate of evolution of hemoglobin. I found the two rates to differ only slightly. You may not have at hand the figure that relates to these matters, and I am therefore including another copy of it.

This type of quantitative treatment of the data was criticized at the Bruges meetings by several participants, notably by Ingram, who felt that the uncertainties are still to [sic] great to warrant any quantitative statement in relation to the common ancestors of polypeptide chains.

I was not very impressed with these criticisms. I am however much impressed now to discover that my own paper…implicitly contained a strong criticism of the above treatment of the data. One of the three main sections of the paper is devoted to putting forward and defending the hypothesis that a high degree of morphological similarity between organisms is accompanied by a high degree or similarity of most polypeptides. This is thought to apply not only to contemporary organisms that have changed little in appearance during a given evolutionary span. The most widespread opinion is just opposite. It is thought that two morphologically similar organisms, if separated by many millions of years of evolutionary time, are probably biochemically quite different.

If the proposed hypothesis is correct, it follows that if we compare homologous polypeptide chains from two contemporary forms whereof one is placed low, the other one high on the evolutionary scale, say man and a fish, one of the chains will have undergone a great many changes in amino acid sequence since the time of the common chain-ancestor, the other chain (that of the fish) relatively few. In comparison with their common ancestor, a contemporary fish indeed has changed morphologically much less than man. In such a case, the procedure of halving the number of differences between the two polypeptide chains, in order to arrive at an approximate figure of the number of evolutionarily effective substitutions that occurred in each line of descent, is no more valid.

Consequently it cannot be considered that the graph with the data on cytochrome c represents “the” rate of evolution of cytochrome c. The graph may still have a certain interest: but since it compares man with all other forms, the error introduced by an inequality in the amount of evolutionary change that occurred in each pair of lines of descent since the time of the common ancestor will be the greater, the more distant on the evolutionary scale the other organism is from man. In relation to the human line of descent the apparent rate of evolution of cytochrome will be an underestimate, and with respect to the other line of descent, an overestimate. Perhaps it is possible to devise a factor of correction that would take into account the vertical distance on the evolutionary scale, as known from all available evidence, or any two organisms that are being compared.

It seems to me that our table in “Horizons of Biochemistry” is not critically affected by this discussion, for the following reasons : we used the differences between the horse and human alphachains of hemoglobin as the basis for all other calculations. It may be that the rate of evolution in both the human race and the equine line of descent, since their common point of origin, has not been drastically different. – Moreover we used the figure obtained by the comparison of the sequences of human and equine hemoglobin to calculate the time of common origin of chains, not as they occur in very different animals, but as they occur within one and the same animal. Although the rates of evolution of the different homologous chains found in man alone – the alpha, beta, gamma, delta plus the recently discovered epsilon chain – may even here differ significantly, the chances appear good that this difference in rate of evolution is not too great at least in the case of the two “adult” major component chains, the alpha chain and the beta chain.

I am writing to ask you whether you would like to give me your opinion in relation to these matters. I intend to introduce into my manuscript a discussion along the lines indicated in this letter. But since this discussion is directly related to our “Szent Györgi – paper”, it occurred to me that, in case you would wish to express your ideas on the subject, I might remove this whole chapter from my “Bruges – paper” and reserve it for our “Rutgers – paper”. Either procedure would be fine with me.

Unfortunately my “Bruges”-manuscript is overdue, and I shall have to finish it within the next few days. My address is the following :

Laboratoire de Physico-Chimie Colloldale, Route de Mende, Montpellier, Hérault.

Jane and I are sending you and Mrs. Pauling our affectionate greetings.


P.S. At Cold Spring Harbor a number of people referred to matters that are treated in our article published in the book dedicated to Oparin. People refer to Itano, because he also has described possible consequences of isosemantic substitutions (not so called by him) and has sent a preprint of his paper to numerous investigators. Our paper is ignored, because it has been published in russian [sic] in a russian [sic] book. You once told me that “Evolutionary and Industrial Biochemistry” might be re-edited in English. Do you know what the chances of such an event are? If the_y are low, could our article conceivably be reprinted in English in some american [sic] periodical ?

Handwritten: I’m sorry, I can’t find the figure I meant to include. It must be in a bunk that we shipped over to France directly.

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