How would you describe your research for a layman, and where it is headed now?
In simple terms, we work on the molecules that make up the information transfer system within living cells. All the sensations we experience depend on nerves connected together to relay signals to the brain. However, before a signal is sent, the nerve cell at the very beginning of that chain must detect light, odours, temperature or other changes in the environment. For example, a photon of light hitting a retinal cell will eventually cause the cell to send an electrical signal to the next nerve cell in the chain. However, a lot happens between photon detection and the electrical output of the retina. There is an elaborate network of chemical reactions that relays information within neurons and this underpins the overall richness of our sensory experience. Our work explores key aspects of such information transfer.
If you imagine signalling molecules as Lego bricks, then much of signalling research in the past was driven by the need to identify the individual bricks and perhaps how two or three bricks could be put together. Now, there is a higher order of questions to be asked; for example, how does one put all of the available Lego bricks together to produce the desired model, such as a train or a car? The technology and approaches to answer such questions in biology are beginning to be available now, and we are working towards asking such questions and interpreting the answers to form a coherent picture of signalling networks.
You studied medicine at St. John's Medical College, Bangalore and are a qualified doctor. What made you decide to plunge into the world of science, do a PhD at NCBS and pick research as a career?
I began studying medicine with no particular goal in mind except for, perhaps the need to pursue a career of some description. While in the 1st year of medical school, I attended a lecture in physiology by Prof. Prakash Shetty, a very charismatic and influential teacher, who would explain the background and history of how discoveries in medicine were made; most unusual in medical school. On that day, he was talking about the endocrine system and explaining the research that led to the discovery of the role of the pancreas in the context of insulin signalling and diabetes. This was probably the first time, in my mind, someone had made a clear distinction between knowledge per se and the way in which this knowledge is arrived at or discovered. I thought this was rather interesting and that was how I got into doing research; it was at that point that my interest in science was born.
Medical school was (and still is) a full-time undertaking that is centred on lectures, practicals and exams (and the need to pass them, that is). Research could only be done after hours in the evening, nights and on weekends. One needed to have the motivation to seek this out and make the time for it, while also pursuing the declared goal of trying to obtain an MBBS degree to become a doctor. As a medical student, most of the research I did took the form of small, specific research projects in Prakash Shetty's lab during the evenings, on weekends and over the holidays. At some level, this was valuable as it helped test my motivation to do research and served as a practical testing ground before making the change towards pursuing a career in basic science.
A couple of years later, while I was still in medical school, I went to TIFR Bombay as a summer student. That was my first contact with an institute purely focussed on research - at a time when NCBS perhaps did not even formally exist. When at TIFR, three people whom I remember very distinctly, positively influenced me to consider applying to TIFR for a Ph.D position - K.S. Krishnan, Veronica Rodrigues, K VijayRaghavan and that is how I ended up coming to NCBS as a graduate student.
Could you tell us a bit about your PhD experience at NCBS?
A very distinctive memory of NCBS is that when we began, we were very small. As students, we were somewhat removed from the difficulties of starting a new institute. The student community was so very tiny and gave one a feeling of cohesiveness. In those days, NCBS was not as grand as it is now, the initial groups shared many things in terms of common space, reagents and resources (we still have a great tradition of shared facilities and resources) and I think it gave us a feeling of working together, even though it was sometimes difficult to manage in a small footprint with a rapidly growing population.
What came after your PhD?
Following my Ph.D, I moved to Cambridge as a post-doctoral fellow to work with Roger Hardie for three years. I then started my own group as a BBSRC (Biotechnology and Biological Sciences Research Council) David Phillips Fellow at Cambridge. Two years later, I moved to the Babraham Institute, where I was a group leader (PI) for about eight years. During this period, my research group transitioned from asking focused questions on visual transduction to a more broad-based analysis of lipid signalling with a cell biology perspective. Six students graduated from my team with Ph.Ds and their excellent work helped to evolve and shape the direction of research that we currently pursue in the lab.
Your recruitment as faculty to NCBS was atypical, in that you already had tenure at the Babraham Institute. What led you to decide to come to back?
I have lived in Bangalore for most of my life (except for my time in Cambridge) and feel very much at home in this city. Of course, it also helps that I have been at NCBS before as a graduate student; I know the science that is done here, and the quality of work. Therefore I could easily imagine doing science in NCBS just as I was used to in Cambridge with the added advantage of being in India.
What differences stand out for you, between NCBS and Cambridge?
Well, there are obviously many differences. Cambridge University is over 800 years old with established traditions that have evolved over time. By contrast, although NCBS is now 25 years old and a well-known institution, it is still relatively young and an experiment in evolution. We are always looking to change and improve. Cambridge is also much larger; NCBS is just about the size of one department in Cambridge University. Another difference, of course, is that Cambridge has a lot of undergraduate students who need to be taught, something we do not have at NCBS.
One other major difference between the two places is that the Ph.D program at NCBS is of much longer duration - five years, as opposed to three in Cambridge, and NCBS places a greater emphasis on course-work. I like the idea that here at NCBS, we have a great opportunity to impart broad, basic training through coursework in addition to a specific research area as part of the graduate program.
What is your approach to doing science?
My philosophy of doing science has evolved from working with and watching some scientifically influential individuals. At multiple stages in my career, Roger Hardie, (co-discoverer of TRP channels), Phill Hawkins and Len Stephens (phosphoinositide signalling) set examples on the importance of careful and detailed analysis, even though the process is time consuming. These days, in science, everybody is under pressure to publish; to produce as many high impact papers as quickly as possible. But it is also important to reflect that discoveries are only made when there is data to support a particular idea. Discoveries do not happen because somebody is coming to the end of their PhD or because the PI needs a paper immediately before tenure proceedings or in time to apply for a big grant. These are key administrative milestones that are necessary, but not sufficient to deliver good science. They are in many ways, artificial deadlines. Science is a difficult business; there is often no linear relationship between input (the time one puts in) and output (the results one gets). This is an idea that is challenging to convey to those beginning a career in science, such as students. However, if people realise that the end results are valuable, then they buy into the idea that good science does take time and application.
In general, I like to wait on observations until we understand them quite well. There is often quite a gulf between making observations and interpreting them and it usually takes a while for a reasonable interpretation to emerge. Although the tools in biology have become much more sophisticated and allow many more things to be done quickly, they also reveal that biological systems are much more complex than we imagined them to be. Thus, if we need to understand the inner workings of systems, the questions we ask must be concurrently deeper and broader. When I began my own group, there was a lot of pressure to produce papers quickly. However, the support of senior colleagues at the institutions where I have worked helped me handle this problem and keep it under control.
Your publication record shows a dedication to quality. Would you like to comment on this? What do you think is the most significant piece of work you have published?
On an average, I find that to produce a high quality paper in my lab, it takes a minimum of 4-5 years of hard work - often from multiple individuals. Since publishing any paper is hard work, I prefer to aim for a complete story containing a significant body of work that makes an important point.
I think one of the most significant papers I have published to date is one that was based on my PhD work carried out in Gaiti Hasan's lab at NCBS in collaboration with Roger Hardie in Cambridge. Rather than revealing a new mechanism, we disproved a long-standing hypothesis. This negative result had a significant impact on our understanding of how calcium influx into cells is not controlled and led to the eventual discovery of the molecular mechanism of calcium influx by other groups. This is an example of where our work which certainly helped to clear up and influence a key area of cell signalling. It is gratifying for my colleagues and me when our peer group is able to comment favourably on the quality and influence of our work.
Are there other ways in which you prioritise quality over quantity?
Yes, the size of one's group is something that influences this issue. I have run my own group for almost fifteen years. During this time the number of people in the lab has grown and when the lab is large, projects sometimes proceed rather inefficiently. This is probably because one is unable to connect individually, on a regular basis, with all of the work that is happening. While having a large lab group can give one the sense that a lot is going on, in reality, it simply gets inefficient beyond a point. For a lab that is large, perhaps composed of ten people or more, a secondary level of daily management is necessary. In a setting like NCBS, this is, for now, likely to be delivered through the most senior PhD students because we are still largely a PhD student based institution. I think this is a good thing for the senior students as well, because this gives them early training on how to sit on the other side (the PI's side) of the table.
Do you think that your training as a doctor helps you add to the quality of your research?
As someone who is trained in clinical medicine, I think it is challenging for basic scientists to relate their research findings at the cellular and molecular level to human physiology; in particular the likely translational impact of their work. Conversely it is also not helpful for clinicians to pursue molecular and cellular projects with a potential translational impact that is overestimated or unrealistic. I think being trained in human physiology is very helpful when working on molecular and cellular mechanisms - ie, training at both levels is incredibly useful.
As a doctor who turned to research, why do you think it is important for clinicians to do basic research?
Broadly there are two reasons why clinical medicine and basic research should intersect. The first is that historically, many practical tools that we now possess for dealing with the needs of human health (diagnostics, therapeutics and vaccines) have arisen from curiosity driven basic science, which focussed on trying to understand natural phenomena. The second, and equally important reason, in my view, is that observations in the clinical setting relating to human health and disease can often generate questions that if answered through research will provide insights into basic biology. For lack of a better phrase, one could think of humans as a next-generation model organism. However, the priorities of these two fields (clinical medicine and basic research) are very different. In clinical medicine, the pressing need of the practitioner is to restore the patient to good health as quickly as possible. In basic science, we would like to seek detailed explanations and have the luxury of time, rigorous experiments and data analysis. The two professions also have vastly different operational styles that add to the logistical difficulties of an inter-disciplinary approach to biomedical science.
These days, there is much discussion and there are perhaps more options in the possible career tracks available for clinicians. Despite this, in India, the numbers of medical students who go on to do research has not increased substantially in recent years. There is a pressing need to introduce research as both an interesting and attractive option targeted at the level of undergraduate medical students when they are most likely to be receptive to this idea. It is valuable that there are structured options now emerging for individuals with backgrounds in clinical medicine to include elements of scientific research in their careers. We also need to take an enlightened view on the logistics of being a clinician-scientist and the administrative problems that arise in this setting. If these challenges can be overcome through better dialog between the two groups, we are likely to see an exciting new interface of science and medicine develop in India. The Wellcome-DBT India Alliance clinician-scientist fellowships are a positive step in this direction.
This article is based on a conversation between Raghu Padinjat and Geoffery Hyde (transcribed by Aathira Perinchery), rounded off with a few questions by Anusha Krishnan.