Ron Vale, vice-president of Howard Hughes Medical Institute, is a biologist who uncovered fundamental insights into the functioning of molecular motors in cells. He spoke to The Hindu about drug discovery, the importance of basic-science research and the lessons from COVID-19 for scientific practice. Edited excerpts:
I read that your mother was an actress and your father a novelist. How did you end up being a scientist?
I grew up in Hollywood. But my interest in science was really triggered by museums. My parents took me to museums and there were wonderful ones in Los Angeles. I loved seeing the dinosaur (exhibits). I’d say they stoked my sense of wonder and curiosity about the natural world. I think as children, adults and even scientists it’s important to constantly stay curious.
Did you have a role model in school who piqued your interest in science?
I’d say in school my classes in science were not so interesting. There was a lot of memorisation but I did a science fair project in high school and went way beyond what was expected. It was about biological clocks (circadian rhythms). My project was about the movement of the leaves of the bean plant. The leaves turn towards the sun in the morning and droop down at night. However, this is not just triggered by sunlight. The bean plant will do maintain this pattern even in continuous light or, for a while, in continuous dark. When I read about this, I was fascinated by how plants and animals could ‘tell time.’ In my experiment I was trying to determine the extent to which I could influence the plant’s circadian rhythm by changing the light-dark cycles. However, it was not a teacher, but a general guidance counsellor in my school who noticed my deep interest in the project and she called up the University to ask if there was a way I could continue working on this problem. This was something I would never do on my own.
That’s interesting because your scientific career deals with movement in biological systems and how microscopic particles move about in the cell?
Indeed. So much of life is about movement. My training after high school gravitated towards smaller and smaller things. I became interested in cell biology and the biochemistry that goes on inside it. I was trained as a biochemist, cell biologist and neuroscientist and I became interested in movement in nerve cells and trying to understand the molecular machinery responsible for that movement.
What knowledge existed about such transport within cells when you started out as a scientist?
It was reasonably unexplored territory. There were some ideas about how when nerves regenerate, they move material. Nerve cells are very unusual because they are microscopic but their dimensions are extraordinarily long. For instance, a motor neuron in your leg is a single cell but the starting point of that cell is in the spinal cord. All the cell machinery is in the cell body. But that cell extends as a very long tube, nearly a metre, and till your toe. However, material necessary for the cell has to be shipped all the way to the end of the cell. While electrical conductance is very fast, it would take two days for material from the cell to reach the end of your foot. If you imagine the cell body to be as big as a room, the end of nerve would extend all the way from Mumbai to Pune. There were many theories as to how this travel happened. When I got into these questions in the 1980s, it became possible to watch this transport happen directly thanks to advances in microscopy techniques. We were able to see very, very small membrane vesicles which are the carriers of a lot of these materials. The carriers are what a lot of these motor proteins bind to. If you think of a lorry, it has a motor in front and transport-container behind. My contribution at the time was being able to take this machinery outside of the living cell and get it to work outside, in a test tube, and see the transport system work. My training as a biochemist helped me sort through the nearly 15,000 components of a cell and find out which are the most essential ones for certain processes.
And this is how you discovered kinesin…
Yes. It is the essential engine in the cell. It has a chemical fuel (adenosine tryphosphate) that it converts into motion and even generate force that can be used to move things. A similar molecular motor exists in muscles called myosin. Today we know that there are many genes for molecular motors. Humans have about 80 different motor genes and there are 45 different kinesin motors, because there are many different kinds of motor needs. Kinesin is found in liver cells, skin cells, nerve cells. Some kinesins are found only in nerve cells. Some are extremely specialized for instance dedicated to DNA replication.
How do you use this knowledge about kinesins and movement to make drugs and improve therapy?
I co-founded a company (Cytokinetics) in 1997 to look if we could make drugs using these properties of molecular motors and change their activity for certain diseases. This approach has worked successfully for certain myosin, particularly for the heart. That company started making drugs that either activate cardiac myosin and make it generate more force. The FDA (US Food and Drug Administration) is expected to evaluate for its use in treating heart failure. There are mutations in myosin that cause an enlargement of the heart and often cause even sudden death in athletes. There are drugs to regulate the myosin activity to prevent this. There are other diseases of kinesins that show up as neurological diseases often in children. Currently there are no drugs to treat them and I’m interested in the possibility of working on them.
Can we use gene editing to change kinesin to have them behave differently?
It’s a bit in the future. It’s not that easy to edit genes controlling neurons or several types of cells in the body. But it’s not beyond the realm of possibility. There are ideas to use molecular motors for delivering drugs to various parts of the body.
You have done a lot of work in science outreach. What led you in this direction?
Through the years, I’ve realised that many aren’t able to access information on science. Particularly, it was in India during a trip in 2006 that I was struck by how many didn’t have access to scientists and that led me to initiate –following that trip – ibiology. We have now about 800 science videos. I have a very interesting project now with TNQ, called ‘explorers guide to biology’ and its goal too is to democratise science but now more at the undergraduate level. College level textbooks in the U.S. are very expensive, and I’d imagine in India too. That seems wrong and that kind of knowledge should be free. We have a responsibility to make science interesting and accessible. The way we teach biology is like a sea of memorisation. Through this project we are trying to teach students about how knowledge in science is arrived at. We use a story telling approach. Our current textbooks are written in a dull way and we aim to make them more interesting. We have a lot of videos – long and short –and it’s a web interface. In the future we’ll increase the number of short videos (given how communication trends are moving) however we can’t totally lose the battle against reading (text). If we don’t ask students to read and build their attention span for it, then we are going to encounter a big problem. You can make written text more interesting and beautiful. We have for instance Jennifer Doudna (co-winner of the Nobel Prize in Chemistry for discovering gene-editing tool CRISPR) writing about her discovery of CRISPR. This gives students an insight into the processes and failures in the process of scientific discovery.
There are a lot of steps to make science more accessible but it looks like being able to do cutting edge science is becoming more expensive and it’s harder than ever for many scientists to access funding, tenure…
A lot of people jump on the same problem and then it become a sort of arms race on who has more money, more people. But there are a lot of interesting problems in biology and unexplored and you have to be courageous enough to identify and find your own path. My sense of India, atleast it was in the past and I hope it will be in the future too, is that there is a greater tolerance for people wanting to pursue their own independent line of research. That’s important to nurture. It’s important to remember that a field that seems like a backwater can suddenly become the hottest and extremely cutting edge. Look at the covid vaccines, particularly mRNA. The research started decades ago.
How has covid affected the practice of science?
COVID-19 has taught us that science should be global and the problems facing the world right now are not isolated to individual nations. There’s a lot of science behind paywalls and lot of times scientists hold on to their data for very long. We need to improve communication and sharing. To be ready for a problem like Covid we need a lot of basic research and tons of advance planning. I think in many ways we missed the narrative around Covid. What would we have done without science? Vaccines and tests were developed with a year and a half. That’s incredible. I don’t think that story has been told very well. The story became about politics, mistrust. There was a vacuum and other narratives took over. I expected a revival of interest in science and basic research but I think we saw a 180-degree flip and greater mistrust in science. We really need to think about a new kind of engagement between the scientific community and society.
