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I can't seem to find anything on my own. Surely there were experiments performed (possibly using bacteriophages) that managed to come to this conclusion?

Specifically I'm interested in anything pre-Hershey/Chase.

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  • $\begingroup$ do you want primary literature or just something that talks about the historical aspects? have you tried google? $\endgroup$ – Vance L Albaugh Nov 14 '16 at 1:29
  • $\begingroup$ @VanceLAlbaugh I have tried google, I have also searched my schools' library/journal database (and looked at the genomics shelves in person). I would appreciate primary literature or a historical piece that references primary literatures/goes into more detail than "...molecular geneticists felt that proteins had to be the primary carriers of genetic information because they could be much more differentiated than the 4-base DNA molecule" and the "1 enzyme 1 gene" hypothesis. $\endgroup$ – Antecedent Nov 14 '16 at 2:18
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    $\begingroup$ This is a wild guess, but have you looked at Schrödinger's What is Life? It's not a primary report on experimental results, but might have useful refs. $\endgroup$ – Ben Bolker Nov 14 '16 at 15:45
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It’s difficult to be convincing with a negative answer, but I venture that the answer to your question is that the idea that protein was the genetic material was not supported by any experiments, but was a supposition based on the conventional wisdom that proteins were more complex and therefore more suited to the job.

I suggest that you should be thinking earlier than bacteriophage and Hershey and Chase. Bacteriophages only came into genetic research after the war, and the Hershey/Chase experiment (1952) was only a rigorous confirmation of the conclusion of Avery et al. in 1944 (mentioned in this Scitable article). The system that Avery et al. used (bacterial transformation) went back to Griffiths in 1928 and must have been the first that allowed any sort of experimentation in this area. And I think it was more a question of working out what was happening than devising an experiment to distinguish between protein and DNA as the genetic material.

To my mind this illustrates something about how science progresses. It is often dependent on advances in technology and changes in the conceptual framework in which scientists work. (Sometimes — e.g. Mitchell’s Hypothesis — it needs the experimental results to change that conceptual framework.) Coming back to the Hershey/Chase experiment, this was performed when the balance of scientific thought had already changed to DNA as the genetic material.

Footnote: It’s earlier than you think

I generated the Google ngram below to put the term you use, ‘molecular genetics’ into historical perspective.

Google ngram of terms molecular biology and molecular genetics

This shows that the term ‘molecular genetics’ was hardly in use at the time of the Hershey–Chase experiment and Watson and Crick’s postulate of the structure of DNA in the early 1950s. I think that this reflects the fact that the concept was not current. The more popular term, ‘molecular biology’ gained currency on the basis of the structural work on DNA and proteins, and the name of the journal in which much of the work was published (Journal of Molecular Biology). The question is assuming a state of science that did not actually exist before the 1950s.

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I am relying heavily on Morange's book (quoted below) for what follows.

As pointed out by David, the definitive experiment showing that nucleic acid, rather than protein, is the carrier of genetic information is that of Avery, MacLeod and McCarthy (1944). Their conclusion that DNA is the 'transforming principle' was, however, very reluctantly accepted by the scientific community, in particular by the biochemists (see Cobb, 2014), and it was not until the famous 'Waring blender' experiment of Hershey and Chase (1953), and beyond, that it was accepted that DNA is the hereditary material.

So, to attempt to answer your question, what was the evidence for proteins (in particular enzymes) being the hereditary material?

  1. It was known that proteins are one of the two components of chromosomes (Morange, p 35)

  2. The tetranucleotide hypothesis of Levene, published about 1910, held that DNA was made of a monotonic, tetranucleotide repeating unit, and this gave rise to the idea that DNA had only a non-specific structural rule in the chromosome (Morange, p 34).

  3. By the 1930's, several enzymes (including urease) had been crystallized by Northrop and Sumner and it was unequivocally established that enzymes are proteins and are macromolecular, thus ushering in the great era of enzymology. Compared to the dynamic world of enzymology, DNA was considered boring.

  4. In 1935, Wendell M. Stanley had isolated TMV virus as "a crystalline protein possessing the properties of Tobacco Mosaic Virus" and had published the results in Science. Crystallization (wrongly) implied purity and it probably understandable that such a high profile result lent weight to hypothesis that genes and proteins are intimately connected. This result was criticized, however. Bawden & Pirie (1938) in the UK repeated the experiment but (unlike Stanley) found 6% RNA in the final product (Morange, p 65).

  5. Beedle and Tatum (1941) had published the 'one gene one enzyme' hypothesis and (to again quote Morange) [p 35] this "had reinforced the more or less conscious identification of genes with enzymes and proteins". The idea that enzymes must be important in hereditary was further reinforced by the work of Garrod on inborn errors of metabolism, which also associated enzymes (specifically, the lack of them) with hereditary factors (Fruton, p431)

  6. Avery's work was sharply criticized in some quarters, most notably by Alfred E. Mirsky, who pointed out that trace contamination by proteins could not be ruled out as an explanation. A great account of the controversy with Mirsky and of the reasons why Avery's work was only slowly accepted is given by Cobb, 2014 [pdf]. One interesting stat from this paper: Hershley and Chase did not quote any of Avery's papers and Hershey is quoted as saying that “I wasn’t too impressed by the results myself” (Cobb,2014). This despite the fact that the DNA preparation of Hershey and Chase contained maybe 20% protein, but that of Avery and colleagues contained less than 0.2% (Cobb,2014). A key paper in the controversy (by Mirksy) may be found here [pdf]

J.B.S Haldane stated (in 1942) that "the size of a gene is roughly that of a protein molecule and it is very probable that genes are proteins" (quoted by Fruton, p 430).

So the biochemists, it would seem, felt that proteins were the 'holy grail' of hereditary, and this attitude prevailed in some quarters long after Watson and Crick. Morange (p 232) points out that Arthur Kornberg discovered DNA polymerase in 1958 and was (jointly) awarded the Nobel prize in 1959. Watson and Crick, whose seminal paper on DNA was published in 1953, were not so honored until 1962. That is an interesting, and perhaps very revealing, point.

And speaking of Nobel prizes, Avery did not get one (he died in 1955), perhaps in part due to the controversy with Mirsky (see Cobb). Erwin Chargaff - he of the A/T and G/C ratios - (who accepted Avery's work as of fundamental at a very early stage) is quoted as saying that Avery's work deserved two Nobel prizes. And, of course, Chargaff himself did not get one, which he surely deserved. As well as the famous ratios, Chargaff was one of the first to suggest that "Differences in the proportions or the sequence of the several nucleotides forming the nucleic acid chain also could be responsible for specific effects" (see Cobb).

Fruton (pp 416-417) quotes Francis Crick as saying about the reception of the double helix. "The reaction of many biochemists, including Joseph Fruton, ranged from coolness to muted hostility. They had long considered the biology of the gene to be based on proteins, not nucleic acids, and thought the problem far too difficult to tackle in the immediate future. It did not help that the structure had been put forward by two people who were not obviously card-carrying biochemists". Fruton (p 417) rejects this view and points out that in their classic text book (with Sofia Simmonds) the Watson and Crick structure for DNA was readily accepted, and concludes (p 417) that "I can only surmise that Francis, who showed me much kindness during my stay in Cambridge during 1962 - 1963, may have accepted too readily some idle gossip".

All this and more may be found not only in Fruton and Morange, but also in Judson's great book The Eight Day of Creation (which I don't have to hand at the moment).

Edit

After replying to David's comment, I dug out some further quotes by Sydney Brenner from Biochemistry Strikes Back which are also (somewhat) relevant.

"In years gone by, biochemists viewed most of the rest of biology as a descriptive science and from the even loftier standpoint of physics, Rutherford dismissed it as stamp collecting.

The early days of molecular biology were marked by what seemed to many to be an arrogant cleavage of the new science from biochemistry. People like myself, whose application for admission to the Cambridge Department of Biochemistry was ignored and who did not even receive the attention of a rejection letter, often expressed exaggerated views of our relationship to biochemistry. However, out argument was not concerned with the methods of biochemistry but only with their blindness in ignoring the new field of the chemistry of information". (Brenner, 2000)

(He goes on to say: "I once made the remark that two things disappeared in 1990: one was communism and the other biochemistry and that only one should be allowed back. Of course biochemistry never really went away but continued to flourish in the thousands of unread pages of biochemical journals") (Brenner, 2000) .

Some great references:

Cobb, M (2014) Oswald Avery, DNA, and the transformation of biology Current Biology, Volume 24, pR55–R60 free pdf

Fruton, J. S. (1999) Proteins, Enzymes, Genes. The Interplay of Chemistry and Biology. Yale University Press.

Judson, H. F. (1996) The Eight Day of Creation. Makers of the Revolution in Biology (25th anniversary edn). Cold Spring Harbor Press.

Morange, Michel (1998) A History of Molecular Biology (translated by Matthew Cobb). Harvard University Press

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  • $\begingroup$ A much more complete answer than my tentative contribution. $\endgroup$ – David Mar 21 '17 at 14:42

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