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Dr Robin Hesketh

Dr Robin Hesketh is a senior lecturer in the Department of Biochemistry at the University of Cambridge.  For over 30 years he has worked as a research scientist on the subject of cancer.  He is the author of many papers and books on the subject including the authoritative textbook ‘Introduction to Cancer Biology’.  In a first for a comedy event, he had blood taken on stage as part of the 2014 Christmas Ghosts shows.

People have been trying to inhibit the growth of cancer tumours for a very, very long time.

On becoming interested in science

I suspect like a lot of scientists, you could consider [it] to be an interest in science because, like most small boys, I was interested in anything mechanical. My family are from farming stock so quiet a lot of my time, especially in the summer holidays…I was actually brought up on farms and made to work very hard, I have to say, but nevertheless I learned to drive at a very young age on a Fordson Major tractor and learned a lot about more about things mechanical.  From that very early stage was an interest in mechanical things and science, greenly I suppose you could say, because you learn without thinking about it about animals and animal husbandry, and you're probably looking at the only person in the whole of Cambridge University who has actually turned a field of hay with a team of horses, so in those days we were quite backward up in West Cumberland.  We did actually have a Fordson Major, as I mentioned, but we still did a lot of the work with horses and I learned to drive a team of horses when I was 9, 10, 11, and that kind of fuelled a real interest in things scientific and I ended up…as a consequence of that interest went to university actually to read engineering, not because I knew anything about engineering but simply because I thought it’d oddly be quite good, it would enable me to do the sorts of things I liked doing, playing with things and making things and blowing myself up from time to time, which I certainly did.  It wasn't a terribly shrewd or calculated decision,, I have to say, but it kind of turned out alright in the end.

On moving into biochemistry

Well it happened step (by step) wise and, as quite often happens, fuelled by a hefty chunk of luck. After I graduated I knew that I still wanted to go on being a small boy, basically, which meant doing a PhD and I was incredibly fortunate, I got taken on by a group working on material science, so they were really interesting, and that was the dielectric properties of liquids, so it was very much actually a hands on PhD and I loved that because I carried on making things, so it’s like the whole of research, you actually get paid to behave like a schoolboy, it was fantastic.  But the problem came after that when I actually went to America to do a post-doc and I realised I didn't want to go on working in that field and I had a short stint as a computer programmer, believe it or not, working for a company in North America and that decided me that, well, not that I didn't really want to do it but that I simply wasn't cut out for computer programming.  It’s very interesting, but nevertheless.  And eventually I came back to England and I didn't really know what I wanted to do.  I actually did a short stint of teaching in a secondary school which was extremely interesting and scarred me for life, as you might say, but very, very instructive. 

And I was very, very fortunate because I was just at the end of a period where very strange things happened, and one of them was that the National Institute for Medical Research advertised for somebody who was a physicist to do something completely non-specified and I applied for this job and to my very considerable surprise I got it, and it simply wouldn't happen today.  And that was the real major change in my life because it meant I had to start learning about biology first of all, but the really important thing was that I discovered that it was just so absolutely riveting that it left everything else that I’d done before in the shade.  So I worked incredibly hard to catch up and learn some basic biology, which fortunately is not too difficult if you come from a hard science background.  So it was a lot of flukes and luck, basically. 

And if we’re on the subject of people who shape you and influences that shape your career, the director of the National Institute of Medical Research who hired me was Sir Peter Medawar who is now long deceased but is really a legendary figure in science, he was of course a Nobel prize winner for his work in immunology, but he was certainly one of the greatest science communicators that have ever been and he was a phenomenal figure and an extraordinary polymath and for some reason or other, he took me on and I’ve been forever grateful to him for that, forever grateful to him for letting me do some work in his immunology lab with his second-in-command John Humphrey, who's another amazing character.  Peter Medawar was a fantastic example to young scientists because when I joined the National Institute of Medical Research it was before he was stricken with a stroke a few years later, and I can remember him in the days when he used to allocate two days a week to running the National Institute of Medical Research as director and everything else that he did as an external propagator of science, and the rest of the time he worked in the lab.  And my most vivid memory of Medawar, his office was on the ground floor and the immunology lab was on the first floor, more or less above, and his regular practice was to come out of his office, turn right, take the stairs three at a time and bound into the lab and this was a bloke who had achieved, I guess you could say, everything it is possible to achieve in science, and I simply cannot think of a more motivating individual for young scientists.

On current research projects 

Well, I guess it’s worth making the point that people have been trying to inhibit the growth of cancer tumours for a very, very long time, but if you restrict your thinking about that to the modern era, lets say the last sort of 30-odd years or so, a huge amount of the effort has gone into coming up with drugs that interact with targets in or on the tumour cells themselves and block them.  And, broadly speaking, this has been extremely unsatisfactory and unsuccessful, notwithstanding the fact that some of these drugs are in fact in clinical use, but by and large their effects are very limited even when they exert a beneficial effect at all.  About 20 years ago a very clever guy who’s just recently died called Judah Folkman, he came up with notion that it might be worth people thinking about an alternative approach, and this arose from the evidence that he had that is now widely accepted that to grow, tumours need to establish their own blood supply, so they are a normal growth in the body but like every other cell in the body they need nutrients, they need oxygen and they need a way to get rid of their waste. 

The long and short of all of this is the model whereby tumour cells, once they actually kick off and start growing beyond a certain very small size, up to which state they are called dormant tumours, have to recruit host blood vessels and what Folkman argued - and a lot of people since have thought the same - was that those would be very good targets to inhibit if you're trying to target tumour growth, because the cells of the blood vessels are normal tissue in the host and what that means is they should be genetically stable, so the genetic instability that characterises tumour cells and is the bugbear of therapy in the sense that the cells are primed, if you like, to come up with strategies for short circuiting any kind of inhibitor that you care to throw at them and they're generally very good at doing that.  Maybe this wouldn't work with tumour vasculature and so he and a considerable amount of other people have done a lot of work developing particular inhibitors of the major pathway that turns on this process of new vessel growth called angiogenesis, and the most potent growth factor in doing that is a thing called VEGEF, vascular endothelial growth factor.

And that work has met with some success, to the extent that there is a drug in clinical use that has FDA approval, but it’s been a pretty rocky road and really, rather like many other great white hopes of cancer therapy, it really hasn't worked out as we hoped and the way that we thought.  Nevertheless, a lot of work is still going into blocking blood vessel growth and we’ve been trying to do it by an alternative strategy which is to disrupt the signalling pathways in the endothelial cells in a very specific way by using viruses, so essentially we make an artificial construct, stick it into a virus to give us infectivity, we design the construct so that it is only turned on in endothelial cells by putting the appropriate promoter in and then the inhibitor strategy is either to have a cytotoxic gene as part of the construct or alternately to have a mutated version of one of the key concepts that are involved in signalling angiogenesis.  And it sounds really quite ingenious and I suppose it is, and we’ve done a lot of work on that, so have other people.  But I have to say that if I’m really honest about it, we've not published very much on that and the reason for that is, like a lot of other cancer therapies in development, we can show data that shows that you can set a tumour growing in mice and the tumour grows and grows, and then you treat with a virus and it stops growing or it even regresses or whatever, but the problem is that if you carry on those experiments for longer than about 30-odd days, what  almost invariably happens is that the tumours overcome the inhibitor and they carry on growing in the end in a perfectly normal fashion, an uninhibited fashion.  So we’ve learned an awful lot, it’s a very interesting field, I think it still has some way to go but at the moment it’s still in the same category as many other cancer therapies, the kind of…nice try, but no cigar.

The optimistic way of looking at it might be, well, with that method of delivery, of course its not 100% efficient, so you hit a limited number of the cells of the endothelium and if the tumour’s not going full steam ahead, that’s to say its relatively small, then at that stage that may be to say that it’s very effective, it’s like having a bit of a headache and taking an aspirin.  But if you've got a migraine, thats not going to do you any good, in other words, if the tumour has got to the stage of being really quite well-developed in size, with really quite well-developed vasculature, which is of course is the situation which you are trying to counter in the clinic very often, then maybe because your targeting efficiency isn't great or for other reasons it simply doesn't work, and it may well be for other reasons, it may well be that you can come up with these very clever ways of targeting a signalling pathway, for instance.  But the tumour cells, or in this case even the endothelial cell, says well, to hell with that, we’ll just use another signalling pathway, it’s not a tumour cell, it doesn't have a highly mutated genome, but that doesn't alter the fact that it’s got a lot of strings to its bow, in terms of signalling pathways that it can call on, so it’s this kind of…in tumour cells it’s this genetic flexibility but even in ordinary cells theres a flexibility in terms of what the cell can do, it’s why a lot of drugs in the end don’t work because you ramp up the concentration of the drug and eventually the cell just makes more and more of the target to overcome the drug and you reach the stage where you can’t go on any longer, so maybe it’s something like that and we need to be more clever about our targeting strategies.  I think that’s one thing that could improve the efficiency of target, that’s to say the proportion of the target cells that you hit and the dose that you hit them with, but we’re still at the stage of trying to overcome those problems; it’s very frustrating, but that’s science.

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