Head of Cancer, Ageing and Somatic Mutation, and Senior Group Leader, Wellcome Trust Sanger Institute
By Karen Greendale
It is exciting to think about how we might in the future be able to slow or stop a cell that is genetically predisposed to cancer from actually progressing to cancer.
I was working as a hematologist, looking after patients with leukemia and related diseases. When I moved to the Sanger Institute, I became involved in a number of breast cancer projects looking at the patterns of genetic change in breast cancer tumors. Eventually, when one works with breast cancer, one sees patients who have inherited forms of the disease. Those cancers were sufficiently different from sporadic or non-inherited breast cancer that I became intrigued. It is exciting to think about how we might in the future be able to slow or stop a cell that is genetically predisposed to cancer from actually progressing to cancer.
These are complicated issues that require a multi-disciplinary approach, and that’s what I relish. I enjoy working with people who think differently than I do and who focus on completely different aspects of science, and bringing those different thought processes together.
2. How will preventing BRCA cancers affect children and families?
People who know that they have this genetic predisposition live their lives differently … there is a sense for many people that they are living with uncertainty.
During my work as a clinician and as a scientist, I’ve had many discussions with people who are carriers of these genetic changes, and it’s clear that people who know that they have this genetic predisposition live their lives differently. It’s not necessarily a massive difference and it differs from person to person, but there is a sense for many people that they are living with uncertainty. It’s more proximal to their day-to-day awareness than it is for other people. We all live with uncertainty and do not know what is going to happen to our health in the future, but for someone who knows that they carry a high-risk allele for cancer, it’s there all the time! Any way that we can provide more certainty and ultimately relief from that worry I think will have a huge impact.
Currently many people who are carriers of inherited risk alleles are not found until they are actually affected by cancer and an astute doctor picks up that there is a strong family history. Then they start considering treatment interventions and hopefully initiating cascade screening of the extended family. I think that will change in the future; it’s pretty clear that we will be able to screen people at younger ages before they have that initial cancer. This is a good thing, but it will cause a lot more anxiety, worry and uncertainty. In addition, a young person at risk may be found to have a variant of unknown significance … and we don’t really know how to deal with that.
An important goal is to move toward prevention. If one can prevent cancers in carriers, then more expansive screening programs to identify people at risk becomes a much more attractive proposition.
3. What’s the goal of your research, and how would you explain its scope to a layperson?
My research focuses on the genetics of cancer and in particular on the genetic changes that occur in cancer cells throughout a person’s lifetime. Basically, all cancer is caused by genetic change; some of that genetic change is inherited, such as a mutation in the BRCA1 or BRCA2 gene that is found in every cell of our bodies. But most genetic damage that causes change occurs in cells as we go through life … a particular genetic change will affect the wrong gene in the wrong cell and that will push that cell along a path to cancer. And if in that cell, enough of those specific changes – which we call “drivers” – accumulate, then the cell becomes cancer. We use advances in DNA technology to identify those cancer-causing genetic changes.
My group is interested in identifying the genes that are responsible for causing the cancer, but we also are beginning to understand what processes cause those genetic changes to occur.
We want to identify the timelines and the “pistons” of developing cancer, including how long it takes to develop a cancer from first steps to last, what is the relationship between the primary cancer and the cancer when it spreads to other organs, and so on. These are the kinds of studies that we have been engaged in for the last five years or so. We are beginning to look even earlier in the process, to try to understand what’s happening in normal cells before they become cancerous.
We just launched a large-scale program to look across a range of tissues to try to understand the very first changes that occur in cells and how the cells behave before they become cancerous. Ultimately, by understanding those very first steps, I hope that we will be able to design treatments to hit those cells when they’re at that very early stage.
4. Where were you trained and what was your thesis research?
My clinical training was as a hematologist treating patients with blood cancers; my research started in Cambridge in the UK and it was on the genetics of myeloproliferative disorders. I realized as I was doing my PhD that I was very interested in data and data analysis and the more computational side of science. I arrived in Cambridge just as the Human Genome Project (HGP) was completed, and they were beginning to look at the application of the HGP to diseases such as cancer. And so I started there, fortunately for me, just as the revolution in DNA sequencing technologies was hitting, and so I was lucky enough to do some of the first studies using those new machines to look at cancer genetics and genomes.
The revolution [new DNA sequencing] technologies have brought to our understanding of cancer is probably of the same sort of magnitude as the advances that came with the invention of the microscope.
It was amazing for a relatively junior scientist to be allowed to play with these toys and begin to see things that one couldn’t dream of before … the revolution that those technologies have brought to our understanding of cancer is probably of the same sort of magnitude as the advances that came with the invention of the microscope. Images through the microscope opened up all these new ways of thinking about disease. In much the same way, I think, these genetic technologies have opened up entirely new areas of exploration in cancer research that will keep scientists occupied for decades.
5. What’s your current institution and what is your position in that institution?
My current institution is still the Wellcome Trust Sanger Institute, and my position there is as the “Group Leader and Senior Scientist” in the Cancer Programs. We’re using DNA technologies to begin to study the landscape and the architecture of cancer genomes, and then to understand what that means for how cancers develop, how we can best treat them, and what are the underlying principles by which cancer evolves.
6. Who do you collaborate with on BRCA cancer prevention research?
Much of our cancer sequencing work has been done in collaboration with clinicians around the world; our samples come from Australia, Iceland, Europe, America and Canada. As those samples come in, and we sequence them, we have begun to understand the patterns of genetic changes and to delve into what these genetic changes do in normal cells. And we have also begun to study patterns of changes in tumors across much wider sets of cancers than only breast cancers. We’ve gathered together a collection of about 2,800 whole cancer genomes that span about 25 – 30 different tumor types … and that, again, is an international collaboration. Tumors collected from around the world have contributed to that research, and scientists from many countries have investigated that data set, looking at the patterns of genetic change – the signatures of mutational damage in those tumors. So yes, we collaborate broadly and widely with clinicians and other biologists.
7. How is your research funded?
We are lucky at the Sanger Institute to be very generously funded by the Wellcome Trust, the largest biomedical charity in the UK; most of our funding comes from them. They give a big block grant of money to the Sanger Institute to do the kind of science that they couldn’t fund using conventional funding mechanisms. The more typical funding approach is that a scientist has an idea and applies for research funding to support a specific research project … that doesn’t necessarily do all that you’d want it to do, and doesn’t allow you to dream of a very big project. And so when the HGP came along, that was obviously a very big project and the Wellcome Trust funded the Sanger Institute to get involved and have continued that generous funding in order to allow us to do large scale research that they couldn’t fund using a more conventional approach. So we are very fortunate to have that luxury of generous funding and are able to dream of experiments that we would otherwise not be able to do.
8. What would you like to accomplish in the next five years?
There are lots of possible ways in which genetic mutations might increase the risk for breast cancer … in the next five years, I would like to understand these early dynamics, and to learn whether and how these risk alleles affect the very early stages of cancer development.
I would like to get a decent understanding of the very first stages of cancer development, in the context of hereditary cancer, and to understand how they’re different from the very first stages of cancer development in sporadic cancers. There are several possibilities. It might be simply that if you’re a carrier of an inherited risk allele, that your cells accumulate cellular damage at a higher rate, and therefore they more quickly get to the number of driver mutations that they need to become cancer. Or it might be that most of the cells, in someone who carries a mutation, are perfectly normal, but there’s a population that gets one extra change that somehow unleashes a whole onslaught of changes and drives it toward cancer. Those cells might be rare, but because the person carries the risk allele, they’re not zero, and they will eventually cause problems. It might be that we can’t see any differences at the very early stages, and that all of the risk comes later in tumor development. In this hypothesis, the very early stages look similar to those in a sporadic cancer, but once they get to a certain stage, the risk allele kicks in and has its effect. It might even be that some of these mutations simply increase the numbers of cells that could become cancerous; for example, it’s well known that one of the risk factors for breast cancer is breast size and density, which probably is a metric of the number of breast cells — some of these risk alleles might simply increase the number of cells that could become cancerous. So there are lots of possible ways in which the genetic mutation might increase the risk for breast cancer … in the next five years, I would like to understand these early dynamics, and to learn whether and how these risk alleles affect the very early stages of cancer development.
9. Do you see patients? Are you involved in clinical work as well as research?
No, I’ve hung up my stethoscope. I did that about two years ago. It was a tough decision, because I do enjoy seeing and treating patients. The major reason was that my clinical work was becoming less linked to my research. When I was doing my PhD research, I was working in the same clinical area and many of the questions that I was addressing in my research work were relevant to the patients I was treating. And conversely, I would see patients and they would trigger questions that I could take back to my research. But once I started looking beyond blood cancers in my research, that link became less relevant, and so it was no longer providing that kind of fuel. I was instead getting the fuel for my research questions from talking to carriers of the disease who had questions, and their preoccupations and worries about Hereditary Breast and Ovarian Cancer Syndrome.
10. Why do you think there’s such a dominant emphasis on cancer treatment research and only limited funding for research on cancer prevention?
Yes, this is very much true in the UK as well as in the US. I think that there are three reasons. First, there’s an immediacy to cancer treatment … it demands attention. There’s a patient sitting there in clinic who has a life-threatening condition that demands treatment and demands a focus on treatment-related research. Secondly, I think there’s a sense in which cancer prevention has historically been viewed as a rather dull exercise. The focus of the narrative about cancer prevention has been about changes in lifestyle, because really the only modifiable risk factors that we knew about were smoking, sun exposure, lack of exercise, obesity and so on, and we all know what those interventions should be. Anybody who works in lifestyle intervention knows just how fraught and difficult it is to get people on board with the recommended lifestyle changes. And the third reason is that any study that wants to prove that a cancer prevention strategy works needs to be massive and to run for a long time. And most funding agencies, most funding cycles, even most research careers don’t have the longevity to allow for that kind of study to be done. These all present challenges that must be overcome.
One of the reasons that it’s attractive to study people who have a very high risk of developing cancer due to inherited susceptibilities to cancer is that some of those limitations don’t apply and we can see our way around some of those challenges. The challenges don’t go away, but, the first thing is that there is an immediacy to someone who carries a high penetrance allele. If the cancer risk is very, very high, then I think there’s a similar sort of immediacy as for treatment; it’s an easier proposition to justify funding this research.
The second challenge – which is the focus on potentially modifiable risk factors – is that when we have a specific genetic cause of a cancer, that specific genetic cause will act to cause the cancer through specific biological processes. Now we don’t fully understand all of the process of causation, but whatever it is, it will be a pretty specific mechanism. When you have something that’s specific, then it will be possible to dream of specific solutions. If you had to take chemotherapy every month of your life in order to prevent your cancer, that’s not going to be an attractive thing to do. But if you had a drug that targets a very specific abnormality and it’s fairly benign toward most of the other cells in the body, then that might be more acceptable, and could be a preventive therapy.
The idea that you could come up with a targeted preventive therapy for someone with a genetic predisposition is quite exciting, I think.
And the third challenge – the scale and time that you need to run a prevention study – I can see ways in which looking at a specific genetic abnormality, we can short circuit or shorten that process by using what’s called a surrogate marker. In a cancer prevention study, the best thing that you can demonstrate is a reduction in death rate from that cancer in your treatment arm. In a prevention study, it takes a long time to demonstrate that your intervention impacts the death rate. Yet with specific genetic abnormalities, if we can understand the effect at the biological level in the early stages of cancer, then that can provide a marker of the activity of that process. I can see a world in which we can do much more clever studies that allow us to assess the impact of our intervention at an earlier stage and therefore speed up the process of development and testing.
11. How can the focus on cancer prevention be increased?
I think that we need to develop ways to assess the impact of interventions on cancer development without having to wait for it to become a full-fledged cancer. If we work out ways to assess whether we’re intervening in the biology of the tumor at a much earlier stage, then we can speed up the development cycle. So I think that’s where I would put the focus.
12. How did you first hear about HeritX, and how have you interacted with the organization?
Two years or so ago I had various interactions with Dr. Ralph Scully, one of the scientists working with HeritX; he asked me to meet with Dr. Thomas Bock (Founder of HeritX) at the American Association for Cancer Research, and I had a very interesting meeting with him. He was then formulating the ideas for how this work would come together, and was taking soundings from scientists working on relevant projects, partly to see whether it sounded like lunacy to propose prevention as an idea. In addition, he’d been getting a lot of feedback from carriers and others who had been affected by inherited cancers. He had worked in the pharmaceutical industry and had a sense of how drug development worked – where it worked well and where it didn’t work well. We stayed in touch. The next step, I think, was the Banbury meeting, which brought together a really impressive cast list of scientists … it was so exciting to hear from so many high quality people in this field. And what I took out of that meeting was what an opportunity it was … we knew so much about which genes were involved in driving inherited cancers, yet we knew so little about how they drove cancer.
13. How do you like working with the HeritX team?
I think one of the things that is particularly appealing about the HeritX framework is that it brings together people who are interested in the same questions relating to prevention of inherited cancers.
It established a network of collaborators, including clinicians. Research to understand the first changes in the development of breast cancer will be most usefully accomplished in conjunction with clinicians who are doing, for example, prophylactic surgery on carriers of inherited disease. We will need to build models to look at “What are the clinical predictors of who is going to develop cancer”? We look forward to developing methods in normal tissue to understand how those genetic changes correlate with the predictors and so on. As we move to thinking about preventive agents, it will be useful to share ideas with people who have been involved in drug development, such as Alan Ashworth, for example, who are thinking about those questions in the context of inherited cancers.
It’s refreshing, I think, to work with a collaborative group and I’ve actually relished the discussions around prevention. The idea that is shaping all of the meetings and interactions is this one goal, and all of the scientific discussions we’ve had … they take us into all sorts of interesting areas … we rapidly go down rabbit holes of specifics about the biology … but always Thomas Bock or Joi Morris are there calling us back to the bigger question, and all those rabbit holes do eventually lead back to the primary focus. And that’s refreshing and quite enjoyable!
14. In your view, what is the impact that HeritX is making, and how can HeritX help your work advance faster?
As I said, I like the idea of bringing scientists together around a common theme, and I also like the idea of mobilizing a group of committed people who have experienced this from the other side of the doctor/patient interaction, who’ve been users of the current health system, and who have been impacted by philosophies that have focused on treatment at the expense of prevention. And so I think that the idea that HeritX would mobilize both groups of people is a very powerful one.
In terms of how HeritX can help me and other scientists, the number one thing is funding, as I think research in this area is underfunded. The second thing that HeritX can do very well is to continue to bring together a group of scientists who are working toward a common goal with complementary expertise. So many of the interactions that I’ve most enjoyed thanks to HeritX involve hearing from scientists who are approaching the broad questions from different angles and understanding how their insights might impact my interpretation of the work that I’m doing and then working together to shape the next set of questions that we can address.
I think that the third thing that HeritX can do is to become a focal point for a group of carriers of inherited cancers and their families who can, first, provide some of the raw material that we need to work on – I’m a strong believer that if you want to study a disease process in a human it’s best to study tissues, cells, genes from the sufferers. It’s not to diminish the value of experimental models such as mice, but in the end, whatever we do in experimental model systems, we have to take back to the patients, we have to understand in the patients. So in this context, that’s going to require us to have access to tissue from people who are carriers of BRCA mutations or other cancer predisposition genes. And so I think that a charity like HeritX, that was founded by families, by people that have been touched by inherited cancer, elicits a trust factor that will be quite important in breaking down barriers with the patients.
More importantly, HeritX can help us to push forward on this sort of research, by making sure that the National Institutes of Health and other large funding agencies in the US, the UK and around the world understand that this is a priority for families … so I think that that kind of advocacy will be an important role for HeritX, moving forward.