Interview transcript

Professor Aaron Klug, welcome to Stockholm and to this Nobel interview. You are one of more than 20 Nobel Prize winners that have done a big part of the research work in Cambridge.

Aaron Klug: Yes.

Can you tell us about your first years there?

Aaron Klug: Well, I came to Cambridge as a graduate student from South Africa.

When was it?

Aaron Klug: In 1949. And I thought originally I would do a Part II, which is the last year of the undergraduate, but my tutor, supervisor it was called, said I knew enough and I might as well start research, which I did. I should explain there was a fair amount of freedom which was rather important. And actually I had to find a supervisor. And indeed it wasn’t a very good choice of supervisor in some sense because my PhD was on a problem in solid state physics – my PhD is in physics – which didn’t lead anywhere directly, but it gave me the chance of learning a great deal of things which later turned out to be very useful, although I didn’t know it. In fact it was a preparation for things to come, without my knowing it; it wasn’t planned in any way.

No – for things that you did later in molecular biology.

Aaron Klug: Yes. I used some of the concepts for material science and I learned to do computing. I learned physical chemistry. And I had a good deal of freedom, which was the right way. I was in no sense somebody’s research student as the way that things are now, you know, working closely under supervision. I saw my supervisor once a month which was very typical in Cambridge at the time and less typical now.

You’re still there?

Aaron Klug: I’m still there, yes.

Or back there?

Aaron Klug: Back there, because I did go to London after Cambridge for some years. I was in London for nearly eight years and that was quite useful too, because I met different kinds of people. It’s a broadening experience. And I met Rosalind Franklin there.

When you came to London?

Aaron Klug: Yes, and that determined really my scientific career, because up to then I hadn’t had a firm idea of what I wanted to do. I wanted to work on the structure of matter by logic or inorganic. In fact I wanted to work with the problems in solid state physics, which I found quite fascinating. I’m interested in how things are made and constructed.

So I wasn’t totally green when I came to work on viruses. And I wasn’t scared. Because most physicists can’t bear to touch wet, messy things, you see …

But I did know some biology because I’d been a medical student in South Africa before – well pre-medical – so I’d done physiology, biochemistry, things of that sort. So I wasn’t totally green when I came to work on viruses. And I wasn’t scared. Because most physicists can’t bear to touch wet, messy things, you see, but I didn’t mind mincing up a plant when I worked on plant viruses and doing a bit of chemistry and things like that. So in a sense it was quite a long preparation, but it turned out to be very good in the end – but totally unplanned.

I see. So you moved to London and then worked together with Rosalind Franklin?

Aaron Klug: Yes I did. She died while I was there. I met her in 1954 and she died in 1958. But during a few short years together with two or her researchers we worked out the general structure of tobacco mosaic virus and after she died I went on with the three dimensional structure – because it’s not an ordinary crystal; you have to develop new analytical methods for dealing with it. And I can do some mathematics. But I have always kept close to experimental work.

As a physics student?

Aaron Klug: Yes, well some of the mathematics was reasonably sophisticated but it wasn’t pure mathematics; it was applicable mathematics they call it. And then after I worked with her – before she died I decided I must have a problem of my own – I began working on the structure of spherical viruses and we studied plant viruses because they’re easy to handle. Later I worked out the structure of polio virus – that was after she died. So that was a useful contact. But I didn’t go there with the object of working with her – again a chance contact.

We’ll come back to viruses, but I know that you have written an article on Rosalind Franklin and she is quite known for her role, or the denial of her role, in the discovery of the double helix of DNA. Can you say some words about that?

Aaron Klug: She did the basic experimental work which supplied Watson and Crick with key information, some known to her and others unknown to her. And she was a very single minded person, but she had no collaborator. She didn’t get on well with Wilkins.

And Wilkins …?

Aaron Klug: Wilkins was the man who got the Nobel Prize with Watson and Crick. He had started the work on DNA, so in that sense he was justified, but later he gave up the problem and began to work on complexes of DNA in sperm, you see, because nobody knew at that time that the DNA would carry the secret of its action with structure which was very unusual then in science. But she, being a very systematic and very good physical chemist, which is what she was, she was able to sort out two different forms of DNA.

Up to then everybody had been working on mixtures and that had made it possible to get very good x-ray diffraction photographs of the two forms. And she developed methods – improved the x-ray method, again as another crystal in the ordinary sense. So if she had continued to live and if Watson and Crick hadn’t intervened she would have got the structure out but it would have come out in a less dramatic way. It would have come out in stages. I have no question about it and that’s what I’ve written about it in two articles – one in ’68 and one in ’74. But I did learn from her. I think the main thing I learnt was to be single minded.   I tended to do different things because I was interested in a curious amount then rather than being dedicated to a particular target.

But for a while you got dedicated in viruses.

Aaron Klug: Oh yes, yes, but I immediately moved and started to develop electro microscopic methods for it and it was those microscope methods which led to the x-ray CAT scanner, which you may not know about.

Yes, used in medicine.

Aaron Klug: Yes. There was a Nobel Prize given for it and some people think I should have got it together with Hounsfield and Cormack, because I developed the whole technique of doing an objective reconstruction in the context of electron microscopy, because with an electron microscope, as I showed, everything in the line of view is projected and so I showed how you could take a specimen – viruses again – and tilt the specimen through various angles, or tilt the beam through various angles and from the two dimensional images you can make what we call the three dimensional image reconstruction. And six months later Hounsfield took out a patent and persuaded EMI to build it. But it doesn’t matter. In the long run I got it for what they call crystallographic electron microscopy. It’s not a good term. It should be Fourier electron microscopy, but there you are. That was three years later. So I’ve tended to do new things every five or ten years. I couldn’t be like Max Perutz and spend 40 years working on haemoglobin.

I see. Molecular biology in some sense started in these years.

That’s what we find all the time. Full of surprises. New mechanisms which you can’t imagine …

Aaron Klug: Yes it did, yes. And I was one of the band, because what I worked on, together with Hugh Huxley – he worked on the structure of the muscle and the mechanism action of the muscle and I worked on viruses – and these are the assemblies of protein molecules. And at that time we never thought we could ever describe them in atomic details. It wasn’t our aim. Our aim was to sketch the outline of the architecture of the viruses, how they were made of protein sub-units and DNA or RNA, and also work out the chemistry of their assembly, which we succeeded in doing. But of course as methods got more powerful – some of which I helped develop – we were able to solve the structure in atomic detail.

And one of the structures I solved in tobacco mosaic virus was a key to its assembly, because the virus doesn’t assemble in any simple fashion, it assembles in a way which has no counterpart in the ordinary macroscopic world. It’s full of surprises in fact. That’s what we find all the time. Full of surprises. New mechanisms which you can’t imagine – well, you imagine them just near the end, but you can’t imagine them before you start.

Why was it so interesting to get this structure?

Aaron Klug: It was there. Also, it became a test object, in the sense that some of the methods of working out large assemblies, which is what we pioneered – because you must remember that at the time, when I started on it, nobody had even solved the structure of a single protein; Perutz and Kendrew only did that in … 1962 they got the Nobel Prize. It came out in 1958 whereas I started working on viruses in 1954. And it was a time when people didn’t believe that Perutz and Kendrew could solve the structure of a protein, let alone a virus. We took risks in some sense, although I didn’t think of it at the time.

But as we said much has happened since then. And during the course of your career, what do you consider is the most significant discovery in molecular biology?

Aaron Klug: I think the structure of chromatin which is a material of which chromosomes were made. And I began that after work on transfer RNA, which also are quite a major achievement. That was also done by Alex Rich. We competed with him. But the chromatin – and I would think another major achievement has been work I’ve done since my Nobel Prize when I discovered a new class of proteins which are involved in switching genes on and off. They’re called zinc fingers and they work in a modular fashion. Each of the fingers, which includes zinc, recognises three base pairs of DNA so it’s a modular system, a combinatorial system and after we began to understand how it worked and the fingers are flexibly connected so they can attach themselves and recognise the sequence of DNA.

And we’ve now used this to engineer artificial transcription factors which can switch genes on and off and there are now a couple of companies in the world developing it. I think that’s quite a major achievement and I’m still working on it. I’m trying to improve the specificity, because you have to be sure when you target DNA that you have to hit the right target and not hit something closely similar. In a human genome of 3,000,000,000 bases, if you have a run of DNA, a certain sequence, you might well have something very similar elsewhere and you want to be sure you get the right one. So you spend a lot of time trying to develop specific recognition.

You moved back to Cambridge and started to work in a new MRC laboratory for molecular biology. You’re now a director of this.

Aaron Klug: I was until a few years ago. I was director from 1986 to 1996.

So you were the director of the laboratory and it was very famous for the work that has been done there.

Aaron Klug: Since my time we’ve had very good people there and we continue to get good people.

How come you manage to have this …

What one needs are resources; of course a good laboratory … we weren’t all that well equipped …

Aaron Klug: I regarded my job, and my predecessors, to encourage young people who are good, who are chosen, to have the opportunities that I had when I went to the MRC, which meant freedom to work for quite a long time on problems without having to publish a great deal while you were developing techniques. What one needs are resources; of course a good laboratory … we weren’t all that well equipped … we had to apply for money and so on. But the MRC lab, the key is that they’re in it for the long term; they don’t work by three year projects or five year projects.

So in some way you’re saying that the competition is not so important, at least in the beginning.

Aaron Klug: Well, because in the beginning we’re not, because on the whole we start new things so there’s nobody else. But then – let me give you an example – almost everything I’ve worked on, after I started other people moved in and did all sorts of useful work, but by then I’d moved on to something else, because people jump in when they see something good and spoil the fun really, because that’s the fun of research. So for example in the zinc fingers, which I discovered and spent many years on it, when people began to realise the power of this design of zinc fingers, because there’s no other transcription factor which had this property, I worked on it but it’s now got to the stage where it’s technology rather than science and that’s why it’s spun out into companies.

My last question then – where are you going to jump over to now?

Aaron Klug: Well I’m not going to live forever. Some years ago I started a group on Alzheimer’s disease. I started out in a managerial capacity but I got involved in the science and I cover quite a wide range in these methods and so we showed that there was a molecule called tau which aggregated in an abnormal form and killed the cells and that wasn’t known before. And so that has been quite useful. And I still keep a foot in that, together with my colleagues. I don’t work in it myself but I’ve done a few useful things there. I can’t say, but mostly I’m thinking about gene regulation, how to regulate gene expression, which is an immediate problem in molecular biology. Because if you can intervene in gene expression you can actually follow a biological pathway and develop a central pathway, or in the case of a disease. We have used zinc fingers to reduce the herpes simplex virus by a factor of ten, using zinc fingers to attack the gene of the virus. That’s done not so much to cure the disease but to be able to see what you can do. This is what I’m doing now. That’s my main interest.

So if a youngster would come into your laboratory then you would advise her or him to start …

Aaron Klug: Well I’d advise them – they can work on this. But my best student has now left, I’m not taking on any more students – I take post-docs, and he did some very nice work and proved the power of the method. But I said he should go and do something else because the cream of the problem has been taken off in a sense and since there are at least two companies doing it they can put on huge resources. Some of the work is after all humdrum; you have to try many alternatives, so this is better done by a large group. You must understand, in Cambridge our groups are very small. I’ve never had more than four or five people working.

So you make the basic research and then leave the development.

Aaron Klug: Yes, but the point about our lab in Cambridge is that because there’s quite a spectrum of talent you can make loose associations with others and you can learn from others, learn in two senses: one, they can give you information; one is watching how they go about something. So although you don’t have a ticket in a field – I had no ticket in neuroscience.

You can talk to a neuroscientist.

Aaron Klug: Well, yes, and you have some basic biological knowledge and so on. But I think the key thing about the lab is the fact that you’re encouraged to tackle important problems but not so difficult that you’re not going to solve them. It’s been said by Medawar that science is the art of the soluble.

Now we must conclude the interview. Thank you very much for taking your time.

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