First and Phoremost: An Interview with Professor Ashok Venkitaraman

Professor Venkitaraman is Director of the MRC Cancer Unit in Cambridge and a Fellow of Pembroke. Since 1998, he has been Ursula Zoellner Professor of Cancer Research at Cambridge University. His work provided the basis for a new spin-out company, PhoreMost, which aims to develop drugs that target molecules previously thought to be ‘undruggable’, and provide new treatments for diseases such as cancer.

Could you tell us a bit about your career path and what has motivated you along the way?

I trained at the Christian Medical College in Vellore, India. It was a rather unusual place since it exposed us not only to the science of medicine but also to primary healthcare in a developing country. As students we spent a month each year living and working in an Indian village. This was a very formative learning experience for me, and I soon realized how many major health problems were socio-economic rather than medical in their origins, arising for instance from lack of clean drinking water, and so on. At the same time, during my undergraduate studies I had the opportunity to research with Professor Jacob John at the Christian Medical College Hospital how humans acquire immunity against viral infections. This made me wonder if a career in medical research might help me make a more lasting impact than I might as a practitioner. This led to my PhD in infectious diseases at University College London with Sir Marc Feldmann, where I began to think about how the immune system recognizes diverse pathogens, and subsequently to my postdoctoral work on the same topic with Professor Michael Neuberger at the MRC Laboratory of Molecular Biology (LMB) in Cambridge. I began my independent research on this problem as a faculty member at the MRC LMB, studying how cells in the immune system rearrange their genomes to enable the recognition of a vast array of pathogens.

What does your research focus on mainly?

My interest in genome rearrangement in the immune system led to an opportunistic change of research focus when the “breast cancer genes” BRCA1 and BRCA2 were first identified. Humans who inherit mutations affecting these genes have a very high risk of developing cancers (not only of the breast but also of the ovary, pancreas, prostate and other organs). Various clues led me to ask if BRCA2 might act to prevent the abnormal genome rearrangements that are typical of cancer cells. Work in my laboratory by K.J. Patel (then a postdoc) and Veronica Yu (then a PhD student), and assisted by our Cambridge colleagues Bruce Ponder and Martin Evans, quickly showed that this was indeed the case. The notion that a gene inactivated in common types of cancer was normally involved in preventing abnormal gene rearrangements was an exciting revelation to us, since at the time the role of genome instability in carcinogenesis was unclear. A major focus of my research since then has been to better understand how BRCA2 works, and how its inactivation predisposes to cancer. This (still continuing!) journey has led my lab to span a number of disciplines, ranging from molecular cell biology to biophysics to structural biology to preclinical and clinical studies. It has led us from better understanding familial cancer genes like BRCA2 to other genes that are sporadically altered in many human cancers.

Our early attempts to translate this new knowledge concerning the genetic basis of cancer to better cancer treatments led me to confront a second – primarily technological – hurdle. Biological systems are very complex, with cellular behaviours arising from vast interacting networks of protein molecules that are encoded by genes. So subtle changes in genes have profound effects on proteins, which in turn have significant corollaries for cellular behaviour that lead to disease. The effects of genetic changes associated with disease are not easy to predict. How do you find the best molecular targets for new medicines? We need new technologies that might enable us to do this, a second and more recent focus of work in my lab.

How does your work relate to PhoreMost, the new drug discovery company which you co-founded?

Genes can be likened to “tapes” that hold the information which encodes protein molecules, which interact with one another to execute cellular behaviours. Protein molecules fold into complex 3D shapes that enable these interactions and functions. My lab developed a technology (which we call ‘protein interference’) that can directly interrogate protein shapes within cells, and test if blocking or changing these shapes can reverse the cellular defects associated with diseases like cancer. This technology enables us to scan diseased cells in an unbiased way for protein shapes that represent new targets for the development of drugs. The University has spun out this technology to a new company, PhoreMost. Dr Chris Torrance, who co-founded PhoreMost, is an experienced scientific entrepreneur who leads the company; my major role now is as a scientific consultant.

What does a typical day look like for you?

I’m fortunate in that about 70% of my time is still spent on research. About 10-15% is taken up with the running of the MRC Cancer Unit – we have around 150 staff and students working in the institute. I’m involved with a number of other activities in the Clinical School, within the University and of course at Pembroke College, including the Fellowship Committee.

You became a Fellow of Pembroke College in 2007. What attracted you to Pembroke, and what are your impressions of Pembroke as a research environment?

I find Pembroke to be a warm, collegial and relatively unstuffy place fully of friendly people, from the Porters and College staff to the students and the Fellowship. Truly a Society! The College’s physical beauty is another major attraction – I know of few places with such a harmonious diversity of structures and vistas. Last but not least, I enjoy being around colleagues from so many different disciplines, ranging from arts and humanities to medicine and other sciences. I’m an experimentalist, and so I cannot perform my own research at Pembroke. Having the opportunity to interact with colleagues at Pembroke, however, has provided several important conceptual insights, which I wouldn’t have had from talking to people in my own field. To give one important example, my long-standing interactions with Professor Mike Payne from Physics have influenced my thinking about approaches to modulate protein structure and function for drug discovery.