Another DNA anniversary, which tells a different story from the textbooks

by Matthew Cobb

60 years ago this week, June 5 – June 11 1953, the 18^th annual Cold Spring Harbor Laboratory Symposium on Quantitative Biology took place on Long Island, New York. The topic was ‘Viruses’, and the papers that were presented were focused around recent discoveries from work on ‘phage (from ‘bacteriophage’), which was becoming a massive research area.

272 scientists crammed into the new lecture hall that had recently been built at Cold Spring Harbor. The site – which is still a major centre of genetic research – is on the north shore of Long Island. It is a marvellous place to study, with the waters of Long Island Sound lapping only a few metres from the entrances to some of the labs, and a beach where evening parties can be had and horseshoe crabs hove up to mate.

There were two stand-out papers given at the meeting, one of them based on research that had been published the year before, and the other that had only just appeared, and had nothing to do with viruses. Together, they changed the way we look at genes and evolution.

The more recent research was presented by a gangly 25 year old, who was dressed in shorts with his shirt hanging out (it can get very hot in Cold Spring Harbor at that time of year):

His name – in case you haven’t twigged – was Jim Watson (whom Jerry spoke to the other day). A few weeks earlier Watson had published two articles in Nature, along with Francis Crick, describing the double helix structure of DNA and its genetical implications. The conference organiser, Max Delbrück, explained that he considered this discovery of such importance that he invited Watson to give a talk and circulated all attendees with copies of Watson & Crick’s first paper, along with those of Maurice Wilkins and Rosalind Franklin, which were published in the same April issue of Nature, and which provided the experimental evidence for Watson and Crick’s theoretical structure.

Watson’s paper (jointly signed by Crick, who was not present) summarises the content of all three papers, and also presented some unpublished data from Maurice Wilkins’ lab. He then went on to discuss the implications of the double helix for gene duplication (if you have one strand, the other strand can be copied from it, so from one molecule it is “straightforward” to get two copies).

Finally, Watson concluded with a brief discussion of mutation, which he correctly concluded involved the substitution of one kind of ‘base’ (A, T, C or G) for another. Looking back over 60 years of scientific discovery, his final section was surprisingly tentative, but quite justified. He first underlined that ‘proof or disproof’ of their structure would have to come from more experiments. No matter how elegant, how much it seemed the double helix must be true, experiments would decide.

And then there is this final sentence:

‘In any case the evidence for both the model and the suggested replication scheme will be strengthened when it can be shown unambiguously that the genetic specificity is carried by DNA alone, and on the molecular side, how the structure could exert a specific influence on the cell.’

The final phrase refers to what genes actually do, which took another decade to begin to realise. But in the opening phrase, Watson still appears to consider that there may be some ‘ambiguity’ about whether ‘genetic specificity’ (he did not use the term ‘information’) resided solely in DNA.

This is striking, because in a series of papers from 1944, Oswald Avery’s group shown that DNA alone carried specificity in pneumococcal bacteria (Watson was well aware of these papers – you can see more about Avery here).  Avery’s finding was not immediately accepted by everyone, partly because most people assumed that DNA was ‘boring’ and that it could not be ‘specific’, unlike proteins. However, in 1952, Al Hershey and Martha Chase had found very similar results to Avery with regard to DNA, in phage. That was the subject of the second key paper presented at the meeting.

Hershey worked at Cold Spring Harbor, and his 1952 paper with his technician, Chase, is now widely seen as convincing everyone that DNA was the genetic material. According to textbooks (which generally misrepresent the experiment), Hershey and Chase’s 1952 experiment provided the decisive proof that sections of the scientific community considered was lacking in Avery’s experiments. Things at the time were not quite so clear, as Watson’s bet-hedging shows.

Even more surprising are the terms used by Al Hershey himself, who presented a paper summarising the results from his group. And from the outset warned his audience of the limits of his knowledge about DNA: ‘Unfortunately I shall not be able to say anything of consequence about its function.’

His results showed that if you made phage (= virus) DNA radioactive, you could show that radioactivity was found in the viral offspring, whereas if you made the virus protein radioactive, very little radioactivity was found in the offspring. This suggested, as he and Chase put it in 1952, that viral proteins had no role in reproduction, while DNA had some role.

But amazingly, despite all his experiments, even in 1953 — even after the double helix—Hershey remained unconvinced that DNA was the sole source of heredity. The conclusion to his 1953 paper summarises three strands of evidence that DNA has a genetic role (I summarise in turn):

1. The amount of DNA in chromosomes is consistent in a species, not in a given kind of tissue

2. DNA can transform bacteria

3. DNA plays some unidentified role in one kind of viral infection.

He then stated:

‘None of these, nor all together, forms a sufficient basis for scientific judgement concerning the genetic function of DNA. The evidence or this statement is that biologists (all of whom, being human, have an opinion) are about equally divided pro and con. My own guess is that DNA will not prove to be a unique determiner of genetic specificity, but that contributions to the question will be made in the future only by persons willing to entertain the contrary view.’ (my italics)

This statement is far stronger than Watson’s bet-hedging. In June 1953, despite Avery, despite his own experiments, Hershey still thought that proteins played a role in heredity. Now that’s a story you don’t get in the textbooks.

This situation continued for some time. Even in the late 1950s, when it was still the case that the genetic role of DNA had not been demonstrated in any multicellular organism,  scientists were regularly presenting the suggestion that ‘all genes are made of DNA’ as a ‘working hypothesis’. No matter how likely it seemed, the proof was not yet there. And that caution – the essence of science, no matter how history might telescope past findings on the basis of current knowledge – is the reason why both Watson and Hershey were still hesitant, even in the summer of 1953.