‘I had no confidence of success’ says Wellcome Sanger Institute director and cancer genetics pioneer Prof Sir Mike Stratton
The inaugural winner of the In Search of Wonder Lifetime Achievement Award, sponsored by JDJ Creative, at the Cambridge Independent Science and Technology Awards 2022, Prof Sir Mike Stratton is a cancer genetics pioneer, director of the Wellcome Sanger Institute and CEO of the Wellcome Genome Campus. In this exclusive two-part interview with him, editor Paul Brackley discusses his extraordinary career.
Professor Sir Mike Stratton has made huge contributions to our understanding of the genetics of cancer, but he didn’t begin his career as a researcher – and he had no confidence he would succeed as one.
He admits, as we discuss his work, there were moments when he faced repeated rejection, despair and uncertainty over how to proceed.
Through it all, however, shined a belief in the extraordinary power of science.
“I was always interested in biology at school and I thought I’d like to find out more about the natural world,” he says. “I did medicine, not necessarily because I had a particular vocation for medicine, but in my family that was the thing that one did if one had some inclination in biological sciences.
“I qualified but, working as a doctor and specialising, the thing that was in my mind the whole time was what research I was going to do.
“So, some way or other, I was configured as a researcher right from the beginning, but I had no confidence at all of success – none.
“I remember many times confronting myself and thinking, this is something within you, and you’ve got to do it. Who knows? If it isn’t a success, at least you will have tried. That was very much my perspective quite a few times during the first decade, or even more, of my scientific career.”
The prospect of failure may seem hard to imagine now, as we look back on Sir Mike’s career, which has taken him to director of the world-renowned Wellcome Sanger Institute and CEO of the Wellcome Genome Campus on which it lies – positions he will relinquish this year after announcing his intention to stand down after 12 years in the roles.
It could all have been very different if he had not followed his instinct.
“In the very early 80s, as a junior doctor I specialised in pathology –looking down microscopes at cancers and other diseases. I knew if I was going to do some research, I had better start doing some,” he recalls.
“When I was very close to qualification, and having done internships, I failed to get the next step up, beyond an internship. I applied to many, and couldn’t get one. There were always other people ahead of me.
“I went to a professor of neuropathology, and I just said, ‘look, can I just do some research for six months? You don’t have to pay me. I’ll live off my wife and I’ll just come and do some research’.
“So he said yes, but he found me some money to keep me going for those six months: I messed around with cells and tissue culture. That was my first hands-on research experience, and I was very excited by it. Looking back on it, the experiments weren’t that interesting. Nevertheless, I was excited, which was the important bit.”
Sir Mike, who studied medicine at Oxford and completed clinical training at Guy’s, qualified as a histopathologist in London.
For his PhD studies at the Institute of Cancer Research in London, he focused on the molecular biology of cancer.
“At that time, there were these transformative advances in molecular biology and DNA technology, of which the key one for me, which still looms incredibly large in my mind and is the seed of everything I have ever done, was the discovery by three or four different groups that a change of one letter of code, in one gene – so a mutation of one base, causing one amino acid change – in a cell, could convert that cell from being a normal cell into a cancer cell.
“To me that was an extraordinary insight, both in its potential implications biologically and its potential implications for medicine. I was captured by the sheer simplicity of it. In the end, that is one of the great joys of science: reducing the natural world to these very simple processes.
“It led me to think, here is one mutation in one gene, and if it’s doing this, how many other genes behave similarly and how could we use that information?”
Without ever practising, Sir Mike was offered the chance to start his own research group at the Institute of Cancer Research, working with epidemiologists and scientists working on breast cancer susceptibility.
“It was well known at that time that there were women who were at an elevated risk of breast cancer, that breast cancer often ran in their families, that they got breast cancer at an early age and it was often associated with ovarian cancer,” explains Sir Mike.
“The cautious interpretation was that these women were carrying a bad, inherited gene.
“At the moment I started to lead my own group there, the first major discovery in this field was made by Mary-Claire King in Berkeley, California, who by genetic linkage analysis of these families had worked out that there was a gene on chromosome 17 that presumably had a mutation and different mutations in these families were the cause of the familial breast cancers in some. This was a big shift in the field.
“I had just started my group, I was very green. I didn’t really know what to do. I was still working my way into things and most of the field decided to follow that observation. There were so many people doing that, I couldn’t quite see what we could contribute.”
The gene, isolated on chromosome 17, was given the name BRCA1.
“It wasn’t a very inspired idea, but we thought, well maybe there’s another gene, and if there was, we would call it BRCA2.
“It was a natural extension but there were many wise minds who said ‘I wouldn’t count on that and if you put a lot of effort into that then you could end up finding nothing’. I listened to that but in the end I was thinking, what can we do that would add something substantial to this field?
“I put the whole of my very young group – all of us were new to running things – to investigating whether there was a second breast cancer gene. We started collecting families which looked, on the basis of the analysis we did, like they may not be linked to BRCA1. But again those wise old heads told us ‘there could be all sorts of reasons so be cautious and don’t get too hooked on your own idea’.
“The transformation was just a moment – worrying and gnawing at the problem one afternoon. These families that we were getting had three, four, five cases of breast cancer, but for the purposes of research they were not very big families.
“What we really needed was some big families with lots of cases of breast cancer that could convince us, unambiguously, that there was a second gene.”
Sir Mike contacted all the oncologists he could in Dublin, hoping that they would know if larger families in Ireland had multiple cases. One oncologist wrote back with just such a family and analysis suggested BRCA1 was probably not to blame for their cases.
“We put everything into the further investigation of this family in Dublin, with us doing the analysis in London, and this took us two years,” he recalls.
“The family pedigree was huge. Hundreds of people. It became clear that unambiguously it was not due to the first gene and was very likely to be due to a different gene. We started to look around the whole genome for where this gene might be.
“You have DNA markers around the genome and you see whether this marker is on chromosome 12 or 22 or the X chromosome. We went around the whole genome – 200, 250 markers – and we didn’t find anything. So this was a moment of despair. There are plenty of those in science. Also it was a test of leadership.
“There I was, facing my very own group looking up at me saying, what are we going to do now? I didn’t have a very good answer. All I could say was, ‘let’s try and do it all again’. It was a year or two later, the actual DNA markers themselves were better, easier to read, easier to interpret. And the family had extended itself.
“We went around again. I will always remember the afternoon when post-doc Richard Wooster came in waving an X-ray film with bands. I came into work that day, not knowing at all where the second breast cancer gene was and I went home in the evening knowing absolutely sure where it was. It was so unambiguous.
“That’s an example of the nature of discovery in science. It was a moment of epiphany.
“We knew where it was, which was the beginning of the process of isolating and identifying the gene itself. A year or a year and a half later against the odds we did succeed. That led to the identification of BRCA2 and the impact of that was very quick.
“There were many families throughout the UK for whom we were able to find the mutations in their genes. I remember a young woman in one of these families that we had been working with for years who wanted to bring up her family and did not want to get breast cancer, and so she was on for a prophylactic mastectomy.
“We were able just to say to hang on and we were able to find the mutation BRAC2 in her family but she wasn’t carrying it. So she did not need to have a prophylactic mastectomy.
“That gives you a sense of the impact of genetics. Science is an extraordinarily powerful thing. All of this is a work of human imagination.”
The team, with the ICR, confirmed BRCA2 to be on chromosome 13.
“The next stage was to identify the gene. And that meant bringing in a whole range of technologies,” says Sir Mike. “We contacted the then Sanger Centre in 1994. It had been in existence for two years. And David Bentley, head of human genetics here, was very happy to help us. They were instrumental in helping us to succeed in identifying the gene in 1995.
“I came up to Sanger, and I could see the scale of things that were being done there, and the different way of doing science – big team science, with a lot of data, a lot of computational work. That was a type of science and a way of doing science, cultural science, that really didn’t exist anywhere else.”
The discovery of the BRCA2 gene allowed families with a history of breast, ovarian and prostate cancer to be assessed for future risk, meaning they can be preventative treatment or closely monitored. A decade later it enabled the development of a therapy targeted at BRCA-associated cancers.
After identifying BRCA2, Sir Mike considered where to take the research next and it led to him proposing the Cancer Genome Project.
“Having had that contact with Sanger, and seeing how the human genome was rolling off the sequencers at Sanger, it seemed intuitive, and obvious to us, that actually that human genome was going to be a normal template against which we could sequence cancer genomes, to find the mutations in them,” he recalls. “We just needed to hammer the whole genome and go through it systematically and we would find everything that was there.
“That was the thinking that we had, myself and two colleagues. In 1998, I started to put this to Wellcome.
“All cancers, we believe, are due to abnormalities of DNA. Abnormalities that we acquire during the course of a lifetime in the cells of our body. That’s a pretty good use of the human genome but also of an organisation like Sanger, because this was going to be large-scale science.
“They were generally very enthusiastic. They gave us a big grant which allowed us to start the Cancer Genome Project on April 1, 2000, which was two months before the draft human genome was announced to the world. We got in there early,” recalls Sir Mike, who joined Sanger Institute that year.
They were reliant on “laborious” technologies – elaborations of the sequencing technique invented by Fred Sanger, but important discoveries were made, including in 2002 that mutations in the BRAF gene were involved in 60 per cent of malignant melanomas.
“In terms of that grand vision, of having the whole genome sequence of many, many cancers, that was not doable using those technologies,” Sir Mike says.
“We did what we could but, towards the middle of the 2000s, the company Solexa in the Cambridge area was developing a step forward from Fred Sanger’s technology.
“That company was bought by Illumina and in 2007 the first machines became available.
“This is where Sanger is great because it’s a very strategic organisation,” notes Sir Mike, who became deputy director that year. “We could see that this was a sequencing technology that would go much faster so we invested at scale in that and that allowed us to do things in human genetics, and in the genomes of infectious disease microorganisms but also in cancer.
“We were then on a trajectory to sequencing whole cancer genomes and indeed we produced the first two whole cancer genomes in 2009.”
Sir Mike led this collaboration, known as the International Cancer Genome Consortium – which continues today – as it contributed full catalogues of the mutations in small-cell lung cancer and malignant melanoma.
“Each of those two was a paper in Nature. We found every type of mutation,” he explains. “You can find a change of one letter of code to another, you can find a deletion of a piece, you can find rearranging of pieces of DNA, you can find increases of numbers of whole chromosomes, all of those things – that’s the full repertoire of mutations that cancers undergo. That was transformative in our vision.
“We needed further shifts in the speed of the technology and the cost in order to fulfil the vision of doing hundreds or maybe thousands of those cancer genomes.”
Sir Mike’s work also identified other genes implicated in some breast cancers such as CHEK2, ATM and PALB2, along with others involved in the development of skin, testicular, colorectal and thyroid cancers, Wilms tumour and Peutz–Jeghers syndrome.
Made a fellow of the Royal Society in 2008, he became director of the Wellcome Trust Sanger Institute in 2010 and was awarded a knighthood in the 2013 Queen’s Birthday Honours for his services to medical sciences.
Meanwhile, next-generation sequencing was transforming what was possible.
“To sequence a human genome now is more or less about a millionth of the cost that it took to sequence the reference human genome up to the year 2000,” notes Sir Mike. “It is an extraordinary, amazing change in technology, which has been behind everything. It’s been behind cancer genomes, it’s behind the recent sequencing of the Biobank in germline human genomes. It’s behind what we did with sequencing two million coronavirus genomes in the last year.”
The Wellcome Sanger Institute played a key role in the UK’s response to Covid-19, as a funder and partner in the Covid-19 Genomics UK (COG-UK) Consortium, providing large-scale, high-throughput genome sequencing and analysis of the virus and its mutations.
The extraordinary power of modern sequencing is increasingly being brought to bear in other finds of healthcare too, helping to enable the era of personalised medicine.
So how will the technology develop next?
“I find it a little difficult to predict,” acknowledges Sir Mike. “We would like, certainly, a similar sort of million-fold reduction in cost over the next 20 years. Then we could be sequencing a significant number of cancers that are happening in real time and a significant proportion of the world’s population.
“I think there are some uncertainties as to whether we are going to get that sort of extraordinary reduction in cost. There will be some, but a million-fold? I’m not so sure.”
Today’s sequencing technology is already helping us understand the genetic make-up of not just human beings, but the fauna and flora around us. Such data gives us insights into evolution, enables the development of new biotechnology and aids efforts to conserve biodiversity.
The Sanger Institute’s Darwin Tree of Life project aims to sequence the 70,000 known species present in the UK, as part of the wider ambition to sequence all life on Earth.
“We are doing this to demonstrate that it can be done, at this sort of scale. It’s also required a shift in the technology, where the sequence reads are much longer. It’s pretty amazing to watch as you put the DNA into the sequencer and the sequencer spits out its long sequences. In a computer those are assembled together and it’s the long read that allows them to be assembled – end-to-end chromosome sequences of new species.”
Sir Mike believes there is huge value in understanding all the species on the planet.
“We don’t know the real number of species of life on Earth but there’s probably a couple of million and there could be a lot more than that. That’s a big trajectory but actually it is something that humanity should embrace. We should know we are custodians of the world and if we don’t hurry up we will ruin it.
“We need to look after it and knowing every species of life on Earth is a pretty good task to set ourselves,” he concludes.
Now read part two of our exclusive interview with Prof Sir Mike Stratton, exploring the plans to treble the size of the Wellcome Genome Campus.