What first sparked your interest in immunology, and how did that shape the direction of your career?
It was Susumu Tonegawa’s revolutionary (and Nobel prize-winning) finding that we create diversity in our immune system by shuffling our genes. Imagine a pack of cards: you have 52 options, but if each option requires a combination of three cards, then you have 22,100 options. This is exactly how diversity is generated in the immune system (using gene segments instead of cards), but shuffling genes seemed heretical at a time when genome integrity was considered sacrosanct. I was stunned by the work and decided I wanted to train with Susumu, leaving to join his lab at M.I.T. at the end of February 1982.
What has been the focus of your research?
My initial focus at M.I.T. was how the mechanism of gene shuffling might go awry and create chromosome translocations that activate so-called oncogenes that cause lymphoma. The work went very well, with our identification of a novel mechanism of lymphomagenesis, which in hindsight seems obvious! I was offered a job at Yale, which I accepted, but I delayed moving because Susumu had asked me to stay on for one more year at M.I.T. In that time, something really remarkable happened: we identified a gene, which we called T cell receptor gamma, that was unanticipated and not attributable to any known immune cell type.
This in turn led to the discovery of gamma delta T cells which comprised a third and wholly unanticipated lineage of immune cells with diverse receptors. I was convinced to study them when it became clear that these cells have been conserved in almost all jawed vertebrates: evolutionary conservation is a sure sign of biological significance. And, in the decades since, we have demonstrated that gamma delta T cells have a completely unique biology that is seemingly well suited to targeting tumour cells. We have continued to focus on the basic biology of the cells but in parallel set up biotech companies, subsequently acquired by ‘Big Pharma’, to promote the movement of our knowledge into the clinic.
In 2003, you set up and led the Division of Immunology, Infection and Inflammatory Diseases (DIIID) at King’s. What were your motivations for setting up, and hopes for, the DIIID?
Before the DIIID and the other Divisions were created, the School of Medicine was organised in a very old-fashioned and siloed way, which prevented those with shared research interests and even shared clinical modalities from collaborating and sharing perspectives. The re-organisation, which was proposed by the then Dean, Professor Gwyn Williams, Professor Alan McGregor and me, worked extremely well. I believe that these refreshed ways of interacting and intersecting provided a useful foundation for the subsequent creation of our current Schools. Established organisational structures always benefit from a fresh perspective, and it is a credit to the College that Gwyn, Alan and I were allowed to do things differently in 2003.
Looking back over the past 27 years, what moments or achievements stand out most strongly to you from your time at King’s?
I believe unequivocally that basic, curiosity-driven enquiry drives everything of value in science. The most transformative insights come from the most unexpected observations, and those are seldom made when research is over-prescribed. From around 2004, King’s strategic focus was more on its clinical strengths, and that direction impacted its research strategy. While we forged greater alignment between our research and our clinical strengths, I’m glad that now the amazing technological breakthroughs that characterise biomedical research are being used to power basic, curiosity-driven enquiry. It’s much more impactful I think to find ways to apply wholly unexpected findings than it is to try to address a clinical problem with known and predictable approaches.
Is there a discovery or project you’re particularly proud of?
I am very proud of the contribution that our team has made toward placing gamma delta T cells into the mainstream of immunology, particularly through our identification of molecules that mediate their information flow to and from our tissues, e.g. gut and skin. In almost every case, the findings were unexpected and the molecules identified were largely unknown. Now defects in those molecules are linked with susceptibilities to several conditions, including inflammatory bowel disease. This is a new frontier that we are proud of defining.
Over the past few decades, what developments in immunology do you think have been the most transformative?
Wow: immunology has completely transformed over the past 27 years, and in turn this has completely transformed the ways that we think about biology and disease. When we published in 2001 that gamma delta T cells were part of a cancer surveillance machinery, the whole notion of cancer immunosurveillance was mostly derided. But, since then, our colleagues and collaborators in global academia have gone on to prove the veracity of cancer immunosurveillance and the consequent application of immunotherapy in settings such as melanoma, lung cancer, and some lymphomas has saved an extraordinary number of lives. Indeed, it has become standard practice.
This development was closely intertwined with the growing realisation that immune cells, particularly B and T lymphocytes, were not all as we had imagined them to be. Whereas the textbook view had been that they circulated in our bodies, simply waiting to pounce upon some forms of recognisable infections, today’s view is of a highly integrated system where many lymphocytes sit, day-to-day within tissues where they seemingly contribute to functions as basic as the maintenance of body barrier integrity. The biological and therapeutic implications of this revised perspective are profound.
How do you think immunology research will change in the next decade?
It is clear that almost every aspect of pathophysiology has an immunological component, so there is a desperate demand from across the spectrum of disciplines to better understand B cells and T cells. So, immunology will move from a specialist area to one of more integrated pursuit. This will offer immunotherapeutic options in situations where those were not previously considered.
Another change will be in the increasing use of computational tools (AI, but not limited to AI) to predict how immune cells interact with and respond to the environments in which they find themselves, be they tumours or inflamed or infectious lesions. As those models show heightened predictive accuracy, we will be better able to engineer immune cells for use as therapies for a whole spectrum of autoimmune disease and cancers.
What advice would you give to researchers who are at the start of their careers?
To recognise that the pursuit of science is a privilege and privileges need to be earned and re-earned. Work hard and focus, but do not shut yourself off from the many brilliant and equally motivated people around you. Be aware of what they’re doing; find it energising; question it; and they will do the same for you. In science, anyone’s success is everyone’s success: love your department and strive to make it a world-leading community. Why not?
What have you enjoyed most about your time at King’s?
The extraordinary freedom that the College allowed me to pursue my own convictions and curiosity. This was primarily in my research, but also in helping bring people together in better organisational units. Beyond the Peter Gorer Dept of Immunobiology (1999) and DIIID (2003), we facilitated the creation of the Centre for the Molecular and Cell Biology of Inflammation (CMCBI, 2007) that in 2016 we morphed into the Centre for Inflammation Biology and Cancer Immunology (CIBCI). I think that each of these steps was motivating and empowered people. And people are the key ingredient: I’ve been so impressed at the lengths to which so many in the College have gone to in order to continually raise the standards of our recruitment at every level. As a consequence, we now sit within a community of brilliant scholarship that is broader and deeper than I ever remember it being.
What are you looking forward to in retirement? Do you have plans to explore any new projects or passions?
I’ll take some rest because 41 years of running one and then two labs has been tiring! But I’ll quickly regroup and enjoy taking on another challenge, possibly in relation to the obstacles that still hamper the movement of brilliant science into the clinic. Additionally, I’m very interested in public engagement with science, for which I may now have more time.