Exploring new territory
Vishva Dixit is Vice President of Physiological Chemistry at Genentech. In the 1990s, Dr. Dixit and colleagues made a series of discoveries at the University of Michigan that helped define the molecular events of programmed cell death. More recently, he has been looking at the links between molecular signaling, cancer and inflammation. At The 5th EMBO Meeting in Amsterdam, The Netherlands, he talked to Barry Whyte about his career in academic and industrial research.
Let's go back to your formative years in Kenya. What influence did they have on you as a scientist?
We lived in a small town in Kenya. My parents were both physicians. They were in general practice and they ran a small clinic. It was incredibly busy. They would see very sick individuals. Many of them had infectious disease but they were effectively treated with antibiotics. And that always had an impression on me – the good work my parents were doing, and the ability of essentially reviving someone at death's door.
Did you think about medicine first as a career or science or a combination of both?
Well I would say it was a combination. My parents had bought me this series of books from Time Life on scientists and their work and that influenced me. I thought it would be fascinating to be a discoverer, an explorer, and that captivated my imagination.
What made you leave Kenya and go to the United States?
Well it was really about opportunities. I had finished medical school in Kenya. I had completed my internship and I wanted to do biomedical research. Unfortunately the facilities were not adequate for that. And that meant either going to Europe or the United States. My brother and sister had already settled in the United States so that made it easier.
What was the first research project you worked on there?
In the States I did a residency in pathology at Washington University in St. Louis. As part of that residency training I did my research with Bill Frazier in the Department of Biochemistry and we worked on thrombospondin, a protein involved in platelet aggregation.
And then you switched to cell death?
When I worked with Bill in St Louis the work on thrombospondin and extracellular matrix biology went reasonably well. I took a lot of that work with me to the University of Michigan. I started out as an assistant professor and my first grants were based on that work. We published papers.
But it became evident to me that we were not the front-runners in the field. We were doing good work but we were not dominant, not painting on a larger canvas. I decided to throw caution to the winds and do something totally new. This was very risky since as an assistant professor in the United States you are not tenured. But you know nothing ventured, nothing gained.
And your discoveries in programmed cell death that took place in the 1990s?
The problem was how does one study cell death biochemically. You could induce cell death in many ways, but none at the time were biochemically amenable. What happened was that Shigekazu Nagata and Dave Goeddel had described members of the tumour necrosis factor receptor family – TNF receptor and FAS. If you engaged these receptors you got cell death. Now that was a biochemical handle. You could take a receptor and ask what was downstream as a way of illuminating the death pathway.
The results were really surprising? People were looking for ion channels, phosphorylation events.
I would say that probably the most important result was the realization that there was a protease involved. We came around to that in a very convoluted manner, but finally nailed it by using a virally encoded inhibitor of caspases.
This was a classic inhibitor experiment?
We could engage the death pathway by stimulating these receptors but what was downstream was a complete mystery. Around that time Bob Horowitz's team had identified Ced3 as a protease that was a component of the death pathway in the worm and this made us wonder whether an equivalent activity could exist in mammals, one responsible for death receptor-induced cell death. The use of a virally encoded caspase inhibitor was the key that unlocked a Pandora's box of riches.
And then you moved to Genentech in 1997?
It was really at the tail end of the heyday of apoptosis research that I moved to Genentech. I had exciting new responsibilities – at that time to form and run an oncology programme.
We hear a lot about the research culture of Genentech. It's very much a research driven environment. Can you tell us about the culture?
Research is given a very high premium. It's a very data driven organization and a very flat organization.
There clearly must be pressure to develop drugs. So how "free" is the research?
Yes, there are enormous pressures to develop drugs. At the end of the day that is what we are about. Making medicines is a highly competitive arena and we have to succeed in that. Our model for being a successful pharmaceutical company is just different. I won't say it is better or worse – it is just different. We believe a significant proportion of our resources should go to fundamental research.
Do you think it is a privilege to be a scientist? How do you see this?
I think it is an enormous privilege. It is essentially being paid to pursue one's hobby and it's an activity that you only find in enlightened societies. I think the quest for knowledge is a common human trait. We all want to know the unknown, but it's only in certain countries where one is afforded the luxury of being able to pursue curiosity.
And what advice would you give to a young scientist interested in working in industry or a university environment?
I would say that in the pharmaceutical industry it is very important to be a team player. You have to be able to play well with others in the sandbox.
You have to realize that the creation of a drug is nothing short of a miracle and it requires the efforts of lots of people.
Are you excited by the future, for your science and science in general?
I think there is so much more to explore, so much more to find out – in terms of the pharmaceutical industry, in terms of medicines and human biology.