From ‘mad sessions’ to a molecular bio revolution

An exclusive extract from Matthew Cobb's new biography of Francis Crick.

One of the things that made Crick so influential was his ability to see into the heart of a matter and extract general principles and underlying tendencies. That talent was first glimpsed publicly in his work with Watson on DNA, but it really developed with the arrival of Sydney Brenner in Cambridge in 1956. Brenner and Crick rarely worked on joint laboratory projects, or even joint publications (“Every now and again we wrote a paper together,” Sydney told me nonchalantly in 2017).

Instead, every day, except for when one of them was travelling, the pair would talk intensely about anything that interested them. And when they were apart they would write letters, gossiping about science, outlining novel hypotheses and devising potential experiments. There were few hints of personal matters in their correspondence: Crick’s close relationship with Brenner, while deep and productive, was more formal than his lifelong friendship with the mathematician Georg Kreisel. Their collaboration was about exploring and clarifying their ideas, and along the way they produced answers to some of the most crucial issues in biology.

Their discussions involved a freestyle way of examining different aspects of a topic, sometimes raising apparently absurd possibilities. Brenner explained: “The thing we did have was a rule that you could say anything that would come into your head. Now most of these conversations were complete nonsense but every now and then … a half-formed idea could be taken up by the other one and really refined.”

Swapping ideas is one thing, having your ideas subjected to forensic or brutal criticism is another. And yet, for over two decades, that is how Brenner and Crick worked. As Crick put it: “Of course you have to be candid. This is perhaps the most important thing. You have to be candid without being rude. (…) And you must of course try and attack the other person’s ideas because it’s getting rid of the false ideas which is the most important thing in developing the good ones.

Francis was laying out the foundations of a new way of understanding life

This was what Crick had done with Watson earlier in the decade and, to a lesser extent, with Alex Rich in 1955. He would later use a similar approach with Leslie Orgel, Graeme Mitchison, Pat Churchland, Christof Koch and others, but it was in his relationship with Sydney that this method reached its peak. 

For Brenner, this represented “the most important thrill of research, the social interaction, the companionship that comes from two people’s minds playing on each other”. For Crick, “collaborating with Sydney not only made all the difference to my ideas and my few experiments, but it was all such fun. It says much for his tolerance and good temper that there was never an angry word between us. Happy days!”

This frenetic exchange of ideas was not merely some kind of superior scientific banter – it had real consequences for discovery and even for the future of biology. Brenner’s quiet, almost wistful summary of how they worked captures its significance: “I think a lot of the good ideas that we produced were produced in these completely mad sessions.”

Some of the insights that emerged in their early discussions can be found in a lecture given by Crick in September 1957 – a lecture that, according to the journalist and historian Horace Judson, altered the logic of biology. In his talk, Crick presented a new way of thinking about how life works, shaping future research in some of the most thrilling parts of science and making a bold prediction about the appearance of an exciting new discipline that now informs everything we know about evolution. Not bad for a single lecture. The understated title of the talk – ‘Protein Synthesis’ – might suggest something dull, but that would be reckoning without Crick’s uncanny ability to detect connections and reveal deep truths.

The hour-long lecture was given at University College London as part of a symposium on the ‘Biological Replication of Macromolecules’. What Francis actually said that day is unknown – all that survives is the published version of the talk, which was written following long hours of excited discussion with Brenner. At nearly 7,000 words, the printed article could not have been read in 60 minutes, even with Crick’s rapid diction and the fact that he ran overtime. François Jacob sat in the audience, stunned:

“Tall, florid, with long sideburns, Crick looked like the Englishman seen in illustrations to 19th-century books about Phileas Fogg or the English opium eater. He talked incessantly. With evident pleasure and volubly, as if he was afraid he would not have enough time to get everything out. Going over his demonstration again to be sure it was understood. Breaking up his sentences with loud laughter. Setting off again with renewed vigour at a speed I often had trouble keeping up with. (…) Crick was dazzling.”

The opening of the lecture summarised recent work on the biochemical mechanisms of protein synthesis, but Francis soon moved on to the really interesting stuff, some of which had first been outlined in a two-page document he typed up in October 1956. This piece – never circulated – was partly inspired by Sol Spiegelman of the University of Illinois, who in a talk in Baltimore that year had referred to the widespread assumption of the existence of a link between DNA, RNA and protein as a ‘dogma’, because there was little concrete evidence for it. Crick had already referred to this in an April 1956 BBC radio talk.

Riffing on Spiegelman’s ideas in that brief document, Crick had sketched a little diagram showing how genes do what they do. This figure was not included in the printed version of his lecture and he may not have used it when he spoke. The most important point was what Crick called the ‘Central Dogma’: the claim that ‘once information has got into a protein it can’t get out again’. (Crick’s friend French geneticist Jacques Monod later told Francis that this was not in fact a dogma – something that cannot be challenged. Crick admitted that he had got it wrong, explaining: “I used the word in the way I myself thought about it, not as most of the rest of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support.”)

To explain his point, Francis focused on what he called the flow of information between the macromolecules found in cells – DNA, RNA and proteins. This information, he said, was simply the sequence of nucleic acids and the sequence of amino acids that were related to it. This was very different to Watson’s suggestion two years earlier that DNA might be chemically transformed into RNA; Crick’s vision was focused on the movement of that utterly modern, intangible quantity – information – through the synthesis of new macromolecules.

According to Crick, there were four kinds of information transfer: DNA ➞ DNA (DNA replication); DNA ➞ RNA (the first step of protein synthesis); RNA ➞ protein (the second step of protein synthesis); and RNA ➞ RNA (RNA viruses copying themselves). Crick also argued there were two steps for which there was no evidence, but which were possible: DNA ➞ protein (this would mean RNA was not necessarily involved in protein synthesis); and RNA ➞ DNA (structurally possible, but at the time without any conceivable function).

Setting off again with renewed vigour at a speed I often had trouble keeping up with, Crick was dazzling.

Just as striking were the three flows of information that Crick considered to be impossible, due to lack of evidence and lack of a biochemical mechanism. These were protein ➞ protein; protein ➞ RNA; and, most significantly, protein ➞ DNA. (Crick later recognised that infectious proteins – prions – can spread by altering the conformation of otherwise identical protein molecules, but they do not change the amino acid sequence, which was Crick’s definition of information.)

The key point of the Central Dogma was that there was no known biochemical mechanism by which the sequence of a protein could be translated into a nucleic acid; information flowed only in one direction, from nucleic acids to proteins, a fundamental concept that remains true.

There is an important evolutionary implication of Crick’s idea: whatever might happen to an organism’s proteins, those changes will not alter its DNA sequence. Organisms cannot use DNA to transmit characteristics they have acquired during their lifetime to their offspring. Although Crick did not state this, it became a fundamental part of the modern conception of Darwinian evolution. Recent popular interest in epigenetics – the potential transmission of gene regulation mechanisms over a few generations, which never alters the DNA sequence – has done nothing to change this. 

The power of theorising

Crick admitted that the evidence for his Central Dogma hypothesis was negligible, but he defended his approach by pointing out that cosmologists had no qualms about constructing theories without adequate experimental data. That implicit comparison with grand theories of the universe is justified, for Francis was laying out the foundations of a new way of understanding life.

Hundreds of scientists around the world were aware of the experimental data that Crick summarised in his lecture, but he was the only one to think in such a profound way about the implications. That was the power of Crick’s mind, especially when it had been catalysed by that of Brenner during their ‘mad sessions’. In his presentation Crick also outlined some adjacent issues that are also immensely significant. First, he described the ‘adaptor hypothesis’ – the idea that tRNA acts as an adaptor tool that translates the genetic code from messenger RNA (mRNA) into proteins. (He had first developed the idea with Brenner, but it was now supported by the dramatic confirmatory experiments of Mahlon Hoagland and Paul Zamecnik).

Then he explored a fundamental aspect of the link between nucleic acids and proteins: that proteins are intricately folded three-dimensional structures, whereas a DNA sequence is one dimensional. Crick accepted there might be some unknown source of folding information, but emphasised that the “more likely hypothesis” was that “folding is simply a function of the order of the amino acids”. In other words, 3D protein structure is an emergent property of the 1D amino acid sequence, which in turn is a direct product of the nucleic acid sequence. This sequence hypothesis … remains essentially true today.

Finally, he foresaw the development of what is now called phylogenetics – the study of the evolutionary relations of organisms using nucleic acids – which has transformed our understanding of every branch of life, from crustaceans to coronaviruses. Nucleic acid sequencing was still a dream when Crick spoke, but he could see the way things would go: “Biologists should realise that before long we shall have a subject which might be called ‘protein taxonomy’ – the study of the amino acid sequences of the proteins of an organism and the comparison of them between species. It can be argued that these sequences are the most delicate expression possible of the phenotype of an organism and that vast amounts of evolutionary information may be hidden away within them.”

This prediction had an immediate impact: zoologist Charles Sibley of Cornell University wrote enthusiastically to Crick, explaining that he had data from egg white proteins for 370 species of bird. This led to a rapid exchange of letters and what Sibley called a flurry of activity in his laboratory, culminating in the appearance of two papers – a study of proteins from 23 breeds of chicken and a far-reaching paper that encouraged zoologists to use proteins in their studies of systematics. Every part of biology, from the intricate molecular activity of a cell to the broad sweep of billions of years of evolution, was caught up in Crick’s vision.

Matthew Cobb is professor emeritus at the University of Manchester. His book, Crick: A Mind in Motion is published by Profile