The LMB Governing Board, October 1967. Left to right: Hugh Huxley, John Kendrew, Max Perutz, Francis Crick, Fred Sanger, Sydney Brenner. (From the website of the MRC Laboratory of Molecular Biology)
I recently had the privilege of speaking with Professor Sydney Brenner, a professor of Genetic medicine at the University of Cambridge and Nobel Laureate in Physiology or Medicine in 2002. I had originally intended to ask him about Professor Frederick Sanger, the two-time Nobel Prize winner famous for his discovery of the structure of proteins and his development of DNA sequencing methods, who passed away in November. I wanted to do the classic tribute by exploring his scientific contributions and getting a first hand account of what it was like to work with him at Cambridge’s Medical Research Council’s (MRC) Laboratory for Molecular Biology (LMB) and at King’s College where they were both fellows. What transpired instead was a fascinating account of the LMB’s quest to unlock the genetic code and a critical commentary on why our current scientific research environment makes this kind of breakthrough unlikely today.
LMB at Cambridge. Original LMB
It is difficult to exaggerate the significance of Professor Brenner and his colleagues’ contributions to biology. Brenner won the Nobel Prize for establishing Caenorhabditis elegans, a type of roundworm, as the model organism for cellular and developmental biological research, which led to discoveries in organ development and programmed cell death. He made his breakthroughs at the LMB, where beginning in the 1950s, an extraordinary number of successive innovations elucidated our understanding of the genetic code. This code is the process by which cells in our body translate information stored in our DNA into proteins, vital molecules important to the structure and functioning of cells. It was here that James Watson and Francis Crick discovered the double-helical structure of DNA. Brenner was one of the first scientists to see this ground-breaking model, driving from Oxford, where he was working at the time in the Department of Chemistry, to Cambridge to witness this breakthrough. This young group of scientists, considered renegades at the time, made a series of successive revolutionary discoveries that ultimately led to the creation of a new field called molecular biology.
To begin our interview, I asked Professor Brenner to speak about Professor Sanger and what led him to his Nobel Prize winning discoveries.
Sydney Brenner: Fred realized very early on that if we could sequence DNA, we would have direct contact with the genes. The problem was that you couldn’t get hold of genes in any way. You couldn’t purify what was a gene. That is why right from the start in 1954, we decided we would do this by using Fred’s method of sequencing proteins, which he had achieved [proteins are derived from the information held in DNA]. You have to realise it was only on a small scale. I think there were only forty-five amino acids [the building blocks of proteins] that were in insulin. We thought even scaling that up for proteins would be difficult. But finally DNA sequencing was invented. Then it became clear that we could directly approach the gene, and it produced a completely new period in science.
He was interested in the method and interested in getting the methods to work. I was really clear in my own mind that what he did in DNA sequencing, even at the time, would cause a revolution in the subject, which it did. And of course we immediately, as fast as possible, began to use these methods in our own research.
ED: This foundational research ushered in a new era of biological science. It has formed the basis of nearly all subsequent discoveries in the field, from understanding the mechanisms of diseases, to the development of new drugs for diseases such as cancer. Imagining the creative energy that drove these discoveries was truly inspirational. I asked Professor Brenner what it felt like to be part of this scientific adventure.
SB: I think it’s really hard to communicate that because I lived through the entire period from its very beginning, and it took on different forms as matters progressed. So it was, of course, wonderful. That’s what I tell students. The way to succeed is to get born at the right time and in the right place. If you can do that then you are bound to succeed. You have to be receptive and have some talent as well.
ED: Today, the structure of DNA and how genetic information is translated into proteins are established scientific canon. Brenner joked that he “knew that molecular biology was doomed to success when [he] heard two students speaking in a bus once and asking whether they would get the genetic code in the examination. It had become an academic subject.” But in the 1950s, the hypotheses generated at the LMB were dismissed as inconceivable nonsense.
SB: To have seen the development of a subject, which was looked upon with disdain by the establishment from the very start, actually become the basis of our whole approach to biology today. That is something that was worth living for.
I remember Francis Crick gave a lecture in 1958, in which he discussed the adapter hypothesis at the time. He proposed that there were twenty enzymes, which linked amino acids to twenty different molecules of RNA, which we call adapters. It was these adapters that lined up the amino acids. The adapter hypothesis was conceived I think as early as 1954 and of course it was to explain these two languages:
DNA, the language of information, and
proteins, the language of work.
Of course that was a paradox, because how did you get one without the other? That was solved by discovering that a molecule from RNA could actually have function. So this information on RNA, which happened much later really, solved that problem as far as origins were concerned.
ED: (Professor Brenner was far too modest here, as it was he who discovered RNA’s critical role in this translation from gene to protein.)
SB: So he [Crick] gave the lecture and biochemists stood up in the audience and said this is completely ridiculous, because if there were twenty enzymes, we biochemists would have already discovered them. To them, the fact that they still hadn’t went to show that this was nonsense. Little did the man know that at that very moment scientists were in the process of finding the very first of these enzymes, which today we know are the enzymes that combined amino acids with transfer RNA. And so you really had to say that the message kept its purity all the way through.
What people don’t realise is that at the beginning, it was just a handful of people who saw the light, if I can put it that way. So it was like belonging to an evangelical sect, because there were so few of us, and all the others sort of thought that there was something wrong with us.
They weren’t willing to believe. Of course they just said, well, what you’re trying to do is impossible. That’s what they said about crystallography of large molecules. They just said it’s hopeless. It’s a hopeless task. And so what we were trying to do with the chemistry of proteins and nucleic acids looked hopeless for a long time. Partly because they didn’t understand how they were built, which I think we molecular biologists had the first insight into, and partly because they just thought they were amorphous blobs and would never be able to be analysed.
I remember when going to London to talk at meetings, people used to ask me what am I going to do in London, and I used to tell them I’m going to preach to the heathens. We viewed most of everybody else as not doing the right science. Like one says, the young Turks will become old Greeks. That’s the trouble with life. I think molecular biology was marvellous because every time you thought it was over and it was just going to be boring, something new happened. It was happening every day.
So I don’t know if you can ride on the crest of a wave; you can ride on it, I believe, forever. I think that being in science is the most incredible experience to have, and I now spend quite a lot of my time trying to help the younger people in science to enjoy it and not to feel that they are part of some gigantic machine, which a lot of people feel today.
ED: I asked him what inspired them to maintain their faith and pursue these revolutionary ideas in the face of such doubt and opposition.
SB: Once you saw the light you were just certain that you had to be right, that it was the right way to do it and the right answer. And of course our faith, if you like, has been borne out.
I think it would have been difficult to keep going without the strong support we had from the Medical Research Council. I think they took a big gamble when they founded that little unit in the Cavendish. I think all the early people they had were amazing. There were amazing personalities amongst them.
This was not your usual university department, but a rather flamboyant and very exceptional group that was meant to get together. An important thing for us was that with the changes in America then, from the late fifties almost to the present day, there was an enormous stream of talent and American postdoctoral fellows that came to our lab to work with us. But the important thing was that they went back. Many of them are now leaders of American molecular biology, who are alumni of the old MRC.
ED: The 1950s to 1960s at the LMB was a renaissance of biological discovery, when a group of young, intrepid scientists made fundamental advances that overturned conventional thinking. The atmosphere and camaraderie reminded me of another esteemed group of friends at King’s College – the Bloomsbury Group, whose members included Virginia Woolf, John Maynard Keynes, E.M. Forester, and many others. Coming from diverse intellectual backgrounds, these friends shared ideas and attitudes, which inspired their writing and research. Perhaps there was something about the nature of the Cambridge college systems that allowed for such revolutionary creativity?
SB: In most places in the world, you live your social life and your ordinary life in the lab. You don’t know anybody else. Sometimes you don’t even know other people in the same building, these things become so large.
The wonderful thing about the college system is that it’s broken up again into a whole different unit. And in these, you can meet and talk to, and be influenced by and influence people, not only from other scientific disciplines, but from other disciplines. So for me, and I think for many others as well, that was a really important part of intellectual life. That’s why I think people in the college have to work to keep that going.
Cambridge is still unique in that you can get a PhD in a field in which you have no undergraduate training. So I think that structure in Cambridge really needs to be retained, although I see so often that rules are being invented all the time. In America you’ve got to have credits from a large number of courses before you can do a PhD. That’s very good for training a very good average scientific work professional. But that training doesn’t allow people the kind of room to expand their own creativity. But expanding your own creativity doesn’t suit everybody. For the exceptional students, the ones who can and probably will make a mark, they will still need institutions free from regulation.
ED: I was excited to hear that we had a mutual appreciation of the college system, and its ability to inspire interdisciplinary work and research. Brenner himself was a biochemist also trained in medicine, and Sanger was a chemist who was more interested in chemistry than biology.
SB: I’m not sure whether Fred was really interested in the biological problems, but I think the methods he developed, he was interested in achieving the possibility of finding out the chemistry of all these important molecules from the very earliest.
ED: Professor Brenner noted that these scientific discoveries required a new way of approaching old problems, which resist traditional disciplinary thinking.
SB: The thing is to have no discipline at all. Biology got its main success by the importation of physicists that came into the field not knowing any biology and I think today that’s very important.
I strongly believe that the only way to encourage innovation is to give it to the young. The young have a great advantage in that they are ignorant. Because I think ignorance in science is very important. If you’re like me and you know too much you can’t try new things. I always work in fields of which I’m totally ignorant.
ED: But he felt that young people today face immense challenges as well, which hinder their ability to creatively innovate.
SB: Today the Americans have developed a new culture in science based on the slavery of graduate students. Now graduate students of American institutions are afraid. He just performs. He’s got to perform. The post-doc is an indentured labourer. We now have labs that don’t work in the same way as the early labs where people were independent, where they could have their own ideas and could pursue them.
The most important thing today is for young people to take responsibility, to actually know how to formulate an idea and how to work on it. Not to buy into the so-called apprenticeship. I think you can only foster that by having sort of deviant studies. That is, you go on and do something really different. Then I think you will be able to foster it.
But today there is no way to do this without money. That’s the difficulty. In order to do science you have to have it supported. The supporters now, the bureaucrats of science, do not wish to take any risks. So in order to get it supported, they want to know from the start that it will work. This means you have to have preliminary information, which means that you are bound to follow the straight and narrow.
There’s no exploration any more except in a very few places. You know like someone going off to study Neanderthal bones. Can you see this happening anywhere else? No, you see, because he would need to do something that’s important to advance the aims of the people who fund science.
I think I’ve often divided people into two classes: Catholics and Methodists. Catholics are people who sit on committees and devise huge schemes in order to try to change things, but nothing’s happened. Nothing happens because the committee is a regression to the mean, and the mean is mediocre. Now what you’ve got to do is good works in your own parish. That’s a Methodist.
ED: His faith in young, naïve (in the most positive sense) scientists is so strong that he has dedicated his later career to fostering their talent against these negative forces.
SB: I am fortunate enough to be able to do this because in Singapore I actually have started two labs and am about to start a third, which are only for young people. These are young Singaporeans who have all been sent abroad to get their PhDs at places like Cambridge, Stanford, and Berkeley. They return back and rather than work five years as a post-doc for some other person, I’ve got a lab where they can work for themselves. They’re not working for me and I’ve told them that.
But what is interesting is that very few accept that challenge, providing what I think is a good standard deviation from the mean. Exceptional people, the ones who have the initiative, have gone out and got their own funding. I think these are clearly going to be the winners. The eldest is thirty-two.
They can have some money, and of course they’ve got to accept the responsibility of execution. I help them in the sense that I oblige them and help them find things, and I can also guide them and so on. We discuss things a lot because I’ve never believed in these group meetings, which seems to be the bane of American life; the head of the lab trying to find out what’s going on in his lab. Instead, I work with people one on one, like the Cambridge tutorial. Now we just have seminars and group meetings and so on.
So I think you’ve got to try to do something like that for the young people and if you can then I think you will create. That’s the way to change the future. Because if these people are successful then they will be running science in twenty years’ time.
ED: Our discussion made me think about what we consider markers of success today. It reminded me of a paragraph in Professor Brenner’s tribute to Professor Sanger in Science:
“A Fred Sanger would not survive today’s world of science. With continuous reporting and appraisals, some committee would note that he published little of import between insulin in 1952 and his first paper on RNA sequencing in 1967 with another long gap until DNA sequencing in 1977. He would be labelled as unproductive, and his modest personal support would be denied. We no longer have a culture that allows individuals to embark on long-term—and what would be considered today extremely risky—projects.”
I found this particularly striking given that another recent Nobel prize winner, Peter Higgs, who identified the particle that bears his name, the Higgs boson, similarly remarked in an interview with the Guardian that, “he doubts a similar breakthrough could be achieved in today’s academic culture, because of the expectations on academics to collaborate and keep churning out papers. He said that: ‘it’s difficult to imagine how I would ever have enough peace and quiet in the present sort of climate to do what I did in 1964.’”
