Science, society and drug design
Biochemist Professor Sir Thomas Blundell has been elected to local council, designed cancer drugs and advised Prime Ministers on public research, bringing a bit of a revolution to each role
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Sir Thomas Blundell, a professor from the University of Cambridge, is one of the people who first discovered what insulin looks like – a medical breakthrough in the 1960s for diabetes patients everywhere. His previous work also contributed significantly to understanding how to stop the progression of HIV to AIDS, and to developing new drugs for cancer treatment. As a scientist he’s been everywhere – even advising the late British prime minister Margaret Thatcher in the 80s.
Professor Sir Thomas Blundell was recently at the University of Melbourne presenting the 2019 Grimwade Visiting Fellow Oration, titled “Science, Society and Spinouts: From Genomes and Structural Biology to Drug Discovery.” He sat down to chat with our reporter Dr Andi Horvath, who reckons he’s a bit of a renaissance man...
When you meet people in the public and they ask you what do you do, like at a barbecue, what do you say?
I say usually that I make medicines, because I do basic science which is underpinning the ways we make new drugs for cancer and also for tuberculosis, but I am a basic scientist and I think it's beautiful, but I've also been lucky that I've been able to create companies and the medicines I've made are on the market for cancer.
I want to delve deeper into the world of the molecules because that's where you do your work. Your speciality is protein assemblies, you look at the way DNA repairs itself, and this is all happening at the level of the cell, at the level of molecules and, of course, proteins. So you’ve buried yourself into what they call structural biology.
The first thing is, I can't see it with light so I have to use a different kind of way of looking at things, and it turns out that if I use X-rays with very short wavelength, I can see these very tiny molecules. I can also use other methods like electron microscopy and I can begin to see the individual molecules. I was one of those who, in the 1960s, discovered what insulin looks like, what these very complicated molecules - which are of very great importance in keeping, in this case, diabetics alive.
You're looking at this invisible world where all the action is. Tell us about the different roles of some of these molecules in our cells that are responsible for basic functions.
I've worked on two kinds of molecules. One kind is what we would call a catalyst. It will change something to something which is active. That kind of molecule we find, for example, in HIV. In HIV, it's a very small genome. It has around 10 products which form the virus. One of the key components is what we might consider a pair of scissors. So we have a long chain and the scissors cut things up. So one thing that I did in the '80s was to describe these pair of scissors and then suggest how we might stop them working, so that somebody who was infected with the virus would not get HIV AIDS. So that's one kind of thing, I'm stopping the catalysts to work, but the other kind of target that I work with is really about signalling.
So I worked on insulin. Insulin is a hormone and it signals, it controls blood pressure. I wanted to understand that and, of course, many people have to take insulin if they are diabetics to keep insulin levels correct. So I wanted to see whether I could modify it a little bit so that people with diabetes didn't have to take it so often, and so the insulin that they took, say, once a day would be long-lasting. So two different kinds of design problems, both to treat diseases, one an infection and the other disease really quite often genetic.
Professor, is there a project that you worked on - and you've worked on many, your reputation precedes you - is there one that particularly surprised you, that you thought, wow, nature is very interesting?
Surprised me? Of course, I always assume something I'm going to learn from every project I do. I guess - surprised me, it was really the second thing I did, because I was working on insulin, as I said, in the 1960s. Insulin puts blood sugar levels down, but there's a yin and yang of blood pressure and there's another hormone called glucagon that put it up. What I was very surprised to find was that although insulin was kind of pre-formed - it had a shape - the glucagon had no shape until it found its receptor, its target. It turns out that what we discovered in the '60s and '70s were the two different ways that these peptide factors that control most aspects of you and me - they are regulators, they are signallers - those two models are quite general. So I was surprised that nature didn't pre-form everything, that it assembled when it interacted. That was a real surprise.
A lot of this basic research ends up eventually at the clinical end, where you have patients who are now surviving or leading a better life and having better health. Have you met some of the people whose lives you’ve changed?
I have done. Of course, I have two cancer medicines that are being sold all over the world, and that came out of my company, but some time ago I was lecturing at a meeting and Bill Gates heard about me. He came to my company and asked that we started working on tuberculosis, and tuberculosis, of course, is a very different disease, it's an infection, and my company is a cancer company. So what we did was to say, we'll try and help you with the new method we've invented. It's getting drugs to work, but in tuberculosis, you're not really going to be able to sell your drugs, and so we have to do it differently because most people with tuberculosis are in developing countries. You have to do it in a different way.
So we did it in my laboratory and we made quite a lot of progress, but then another thing happened, and that was that I didn't realise that leprosy was very closely related, as it happens, to tuberculosis. I was lecturing in the United States, I had 1000 people around me, I was on the pedestal and at the end of my lecture I answered questions. I was a little bit nervous because I didn't know as much about the whole area of mycobacteria, and I looked down from the pedestal and there were very serious people at the bottom of the steps. I walked down rather slowly, nervously, and one guy pushed the other one forward and he said, he's going to work in your laboratory from tomorrow. I said, who are you, who's he and what's he going to do? He said, we are from the American Leprosy Mission, and we want you to use your techniques in leprosy.
So after three years of working in this area, just two weeks ago, I went to the International Congress of Leprosy, and there it was very different. There were leprosy patients, carers, medical doctors, clinicians who were scientists, and basic scientists. So I think this is the first time - very different from cancer - where I was with 1500 people, I got on the pedestal and gave a talk, but in my audience were patients, carers, medical doctors, that's not so usual, but it was a wonderful experience.
I want to hear the stories about your cancer drugs, how it started and how it led on this journey to be a drug.
The cancer drugs came because during the 1980s, the Institute of Cancer research said to me, what you're working on are very complex, what we call multicomponent, multi-protein systems, and many of the things in cancer that happen - and, of course, you get mutations occurring randomly - affects these systems. So we wanted you to work with us, and we'll fund a cancer unit for you.
So I set up that unit. I was very happy developing rather basic ideas, and then two things happened. The first one was that I was advising our Prime Minister, Margaret Thatcher. You may have heard of her. I'm a left-wing socialist, by the way, but I worked with Margaret Thatcher in No. 10 for three years. She wanted me to go and reorganise research, so I had to stop a lot of my basic research - not all of it - and go and organise public research.
After six years, I finished doing that and I thought, why don't I form a company and do it in the company? Because with two or three people, I can't do too much. So with a very brilliant student who studied with me in the 1980s - so we're now in 1999, so 15 years later or so - we went to another student of mine and said, we want to use the ideas we've been thinking about in an academic way to form a company.
This entrepreneurial person who ran a company for funding early discoveries, he was very sceptical. He said, Tom, I'll give you some money, but a small amount just for a year, because I'm pretty sure what you're going to do is not going to work. So you may think it's a lot of money, I got half a million dollars.
Then, after one year, everything worked, so I then moved the company from my laboratory in the University of Cambridge. My colleague joined us and we set up a new company on the Science Park. From just a few people, we got 150 people. We developed the ideas of targeting some of the molecules I'd been working on academically, and with a huge investment from the venture capital and then collaboration with a large company, I eventually - and it took me a long time, actually 1999 to 2017, 18 years before my first drug got on the market, 2017, and it's for breast cancer.
Then we have a number in clinical trials, but this year I got another one on the market and that's for urethral carcinoma, so another kind of cancer. So after that basic idea, a small amount of money but quite a long time, I've now got cancer medicines being made available to anybody, and they're selling in the United States, in Europe and throughout the world.
You're an extraordinary problem solver in the world of what's happening down in the cell and what's happening down at the levels of proteins and molecules. What's the secret to your success?
I was always interested in doing a range of different things. I came from a family where my grandfather was a very gifted artist and musician. However, my parents left school when they were 14 and 15 and they had no vision of what I could do, but they had confidence in me. So I was the first person anywhere in the family to stay at school beyond the age of 15, and that inspiration from my parents' encouragement allowed me to think much more broadly than maybe others.
So I was already running a jazz group, I was already well used to organising things. I won a scholarship to Oxford and I soon became Chairman of the biggest club in the University of Oxford for undergraduates, and that was called the Joint Action Against Racial Intolerance. I was interested in that because my mother had encouraged people from over the world to come and stay in our house, even though she left school at 14.
So I had this vision that I could help, and then I realised that in Oxford, we had a big motor industry, Pressed Steel, and people were coming from Bengal, India, and they were coming from the West Indies, and they were having problems. So I then moved outside the University and set up a new organisation, and from that eventually I got elected to the City Council, and so I ended up running a large part of the City of Oxford, at the same time as doing my science. So I'm a little bit unusual because I've ended up doing things in politics, things in music and things in my basic science, and that then, of course, led me to advise prime ministers and to run organisations and found companies.
You're a broad thinker and a Renaissance man of sorts.
Professor Blundell, what advice do you give to your students?
My students come to a laboratory which is, I think, quite unusual. First, it is multidisciplinary. I've been in a Physics Department, a Chemistry Department, I've been head of all biology and preclinical work in Cambridge. So first, multidisciplined. Secondly, I worked with one of the most famous woman scientists in the world, Dorothy Hodgkin. She was a Nobel prize winner in the 1960s, and she taught me that you have to have gender balance and that women can be incredible scientists. So the second thing I tell my students, and they can see it in my lab, is you’ve got to be gender diverse. Then thirdly - I learnt from Dorothy Hodgkin, as well, so I tell my students - is that you can find scientists everywhere in the world. So when my laboratory was bigger - I should been retired for 10 years, you must understand. The University thinks that older people ought to have smaller labs, even if they're more productive than other people. I call it ageism.
Anyway, what I discovered was that in my laboratory 10 years ago, we could speak 33 languages. Last Saturday, I had another party for my team now. It's smaller. We did the same thing. Each of us talked to somebody else in one language, but they translated it into English, and then speak to somebody in a second language, and we could do 22 languages. So we're smaller now, but still, we're diverse. So the third message is, you can learn from everybody in the world and you can bring them together. So these three messages, I think. Gender balance, interdisciplinarity and worldwide participation.
You're ahead of your time. You were always ahead of your time, by the sounds of things.
You could say that.
Professor, what do you want us to think about next time we're going to the doctor or taking some drugs?
I'd like you to think, next time you go to a medical doctor in Europe, in Australia, in the United States, how lucky you are to have access to some of the medicines that we have been - my colleagues, of course, many people - making, because the real challenge is not just to make the drug which costs a lot of money, but to make sure that it's available not just to the rich, but to the world in general. So I'd like you to remember next time you have a drug which in Australia, in England, in the UK, you can get, that we need to make them available to everyone in the world.
Professor Thomas Blundell, thank you.
Thank you very much.
Thank you to Professor Sir Thomas Blundell from the University of Cambridge. And thanks to our reporter Dr Andi Horvath.
Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on September 26, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2019, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.
Now a professor of biochemistry at the University of Cambridge, in 1969 Sir Thomas Blundell was one of the first people to see what the hormone insulin looked like. As part of the team led by Nobel Prize winner Dorothy Hodgkin, it was a medical breakthrough for diabetes patients everywhere.
“I was always interested in doing a range of different things,” Professor Blundell says.
“I came from a family where my grandfather was a very gifted artist and musician. And although my parents left school when they were 14 and 15, they always encouraged me to think more broadly.”
“So I may be a little bit unusual because I’ve ended up doing things in politics, music and science, and that of course led me to advise prime ministers and to run organisations and found companies.”
Professor Blundell’s research has focussed on understanding the structure and function of molecules for targets to improve drug design.
“By using X-rays with very short wavelength, I can see these very tiny molecules. Add in other methods like electron microscopy and the individual molecules can be revealed.
His work has contributed significantly to stopping the progression of HIV into AIDS and to developing new drugs for cancer treatment in both his academic career and through a spinoff company he initially founded with two former students.
“In Europe, Australia and the United States, we are lucky, we have access to medicines that research has developed, but the real challenge is to make sure that it’s available not just to the rich, but to the world in general.”
Episode recorded: September 26, 2019.
Interviewer: Dr Andi Horvath.
Producer, audio engineer and editor: Chris Hatzis.
Co-production: Silvi Vann-Wall and Dr Andi Horvath.
Banner: Getty Images