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Venkatraman Ramakrishnan won the 2009 Nobel Prize in Chemistry for his work on the structure and function of the ribosome.

Written by The Indian Express |
January 4, 2010 2:12:37 am

Venkatraman Ramakrishnan won the 2009 Nobel Prize in Chemistry for his work on the structure and function of the ribosome. In an interview with The Indian Express Editor-in-Chief Shekhar Gupta on NDTV 24×7’s Walk the Talk,Ramakrishnan speaks of his research,on the value of scientific interdisciplinarity,and of his ongoing attempt to learn Spanish

•Shekhar Gupta: I am at Bangalore’s Indian Institute of Science and my guest this week is Venkatraman Ramakrishnan,Nobel Laureate for Chemistry,also a physicist and a biologist. Welcome to Walk the Talk.

Venkatraman Ramakrishnan: Though I have to say,no physicist would consider me a physicist today.

•Shekhar Gupta: That’s the problem with the business of science now,you don’t know who’s who.

Venkatraman Ramakrishnan: That’s true. As Balram,director of Indian Institute of Science said in an editorial,the boundaries between the sciences are becoming more fluid.

•Shekhar Gupta: So boundaries are breaking up?

Venkatraman Ramakrishnan: Techniques from one discipline are being routinely applied to other disciplines and I have to say that biology is at the receiving end of a lot of this.

•Shekhar Gupta: You should know how one thing leads to another and how people find their calling —you are the father of a brilliant musician and even the father-in-law of one.

Venkatraman Ramakrishnan: My son was a physics undergrad but his love was always the cello. I think he treated physics as hobby. He’s a happy musician,I hope.

•Shekhar Gupta: Science is a good beginning. I’m happy to say that about myself — I’m from a generation of musicians forced to study science.

Venkatraman Ramakrishnan: My feeling is that even if you are not a scientist you really should have a certain minimum education in science because we live in a highly technical society. How do you know that the right decisions are being made by your government or people around you? We talk about pollution or global warming. How can you even judge if these things are meaningful or not? If you have a fundamental background in science even at the high school level,it does help you come to grips with the problem instead of taking someone’s word for it.

•Shekhar Gupta: By the same logic,you also need a background in liberal arts and humanities. Because a lot of kids in India go to IIT straight from school and spend a lifetime in science.

Venkatraman Ramakrishnan: I grew up in the Indian system and I unfortunately had to choose between humanities and science in high school. I’m making up for it. I’m learning Spanish — I’ve to take an exam in January.

•Shekhar Gupta: I took my last exam 33 years ago. My regular nightmare around May is that I come prepared for a botany paper and it’s a zoology paper!

Venkatraman Ramakrishnan: When I got this Nobel Prize,they had a student from the school where I study Spanish interview me for their paper. And they said,“Hills Road 6 form student wins Nobel Prize.”

•Shekhar Gupta: Tell us about your journey in science — you started off as a physicist.

Venkatraman Ramakrishnan: I originally thought I might go to medical school. And I got admitted to the Baroda Medical College ,but I also appeared for the National Science Talent exam. That was at the encouragement of my mother. I made a deal with my father — that if I got the scholarship,then you shouldn’t force me to do anything. He wanted me to be a doctor. I got the scholarship,and while he was away,I transferred my admission from medical college to study physics. The clerk thought I’d made a mistake,and I actually meant the other way round.

•Shekhar Gupta: For our generation,the first choice was medicine. Next was engineering. If you failed in both,you went for the IAS.

Venkatraman Ramakrishnan: One thing that motivated me was that a group of professors,some of whom had come back from the US,had completely modernised the curriculum. 30 years later,my son studied basically the same curriculum at Harvard. So that was a motivation for me to go into physics. Somewhere along the line I realised that I was not going to be a good physicist. I would just be doing some boring calculations and not have any real insight. I believe physics is on a difficult plane,because to make truly fundamental breakthroughs in physics is very hard now. At the same time,molecular biology was blossoming. It seemed every week there was an important discovery being made.

•Shekhar Gupta: You talked about reading the Scientific American and seeing breakthroughs all the time…

Venkatraman Ramakrishnan: When I read the Scientific American,it was often the biology breakthroughs that were leaping out of the magazine. I thought lots of physicists,Francis Crick for one,have made the transition from physics to biology. And so I thought,why not?

•Shekhar Gupta: Francis Crick made the transition very much to the area where you moved.

Venkatraman Ramakrishnan: He started off as a structural biologist,then became a very general molecular biologist and later a neurobiologist. But he was really a genius,a class by himself.

•Shekhar Gupta: So are you,but you don’t have to say that.

Venkatraman Ramakrishnan: I mean that very seriously. I think people mistake the Nobel as a prize for being exceptionally intelligent. I think that’s a false impression people have. Most Nobel laureates are people who have done important work but they are not themselves that special. They are people who’ve had the luck to stumble on to something. Some of them have had the combination of persistence and research. But people like Crick really were in a different class.

•Shekhar Gupta: Was it like an ‘a-ha’ moment when you decided to make the switch?

Venkatraman Ramakrishnan: I think my a-ha moment came when I was writing my thesis,actually slightly before. And I realised — what next? I just couldn’t see continuing on as a physicist. And then rather doing a post-doc in biology,I decided to go to graduate school and start essentially all over again with the option of getting a second Ph.D. I even took undergraduate courses in biology. Here I was,with a Ph.D. in physics doing undergraduate courses.

•Shekhar Gupta: There is performance pressure in academia as well.

Venkatraman Ramakrishnan: I think,in America ,there is the idea of starting all over again — having second,or even third chances at life.

•Shekhar Gupta: You actually took undergrad courses?

Venkatraman Ramakrishnan: I was registered as a graduate student but since I didn’t know any basic biochemistry or genetics,I had to start at a lower level. So in the first year,I actually took undergraduate courses. And once I’d acquired a broad background — I did a year in research in biology — but then I realised I didn’t actually need a second Ph.D. I decided to do a postdoctoral fellowship at Yale with Peter Moore,who’s a very famous ribosome scientist,which is how I got into my field in 1978.

•Shekhar Gupta: One of the wonderful things about doing this show is that there is an opportunity to be educated by the finest teachers in the world. We’ve had the privilege to have Dr Baltimore to tell us be patient to try and understand biotechnology,we’ve had Elizabeth Blackburn tell us about aging. So from aging to DNA,to now RNA,we learn about this magical trinity. Tell us about the linkages and connections,the breakthroughs and why we need to be patient.

Venkatraman Ramakrishnan: Let me start off with the ribosome and what it is. If you think of DNA,you can think of it as an archive of information. Ribosome is the machine that takes the information in our genes and makes proteins,using the instructions in our genes. The analogy people draw is that if we have a tape with music stored on it. The tape consists of instructions on how to reproduce that music — it can be stored in different ways,it can be stored digitally or in analog ways to clear a set of instructions. But to convert that set of instructions,you need a tape — like a tape recorder or a machine player. You can think of genes as containing information to make proteins,and what the ribosome does is take that information. You can think of DNA as an archival storage form,and RNA as a working copy. It takes the working copy,in the form of what is called messenger RNA,because it contains the genetic message.

•Shekhar Gupta: Why is that important?

Venkatraman Ramakrishnan: It’s important because everything in this cell is done by proteins. We are,of course,discovering more functions for RNA. It is still true that the bulk of the functions is carried out by proteins. Oxygen in your blood is carried by a protein,light in your eye is sensed by a protein. When you have an infection,the antibodies you make are proteins. Your skin is basically collagen,which is protein.

•Shekhar Gupta: Antibiotics have to go through proteins…

Venkatraman Ramakrishnan: Antibiotics can work in many different ways. One other way of looking at the ribosome’s importance is that virtually everything in the cell was made by the ribosome,or by enzymes,which themselves are made by the ribosome. It’s really responsible for the way a cell is constructed,and that’s true for all life forms,including viruses. That’s why it is of fundamental importance.

The question you asked about antibiotics — because a ribosome is so ancient,the ribosome of human and bacteria are slightly different. About half of known antibiotics work by targeting the bacterial ribosome,while not binding so well to the human ribosome. When they bind to the bacterial ribosome,they do so at critical sites in the bacterial ribosome and they stop it from working. If a bacteria cannot make protein,it dies,just like if we weren’t able to make protein,we would die too. It’s the basis of antibiotic function.

The ribosome was discovered in the 50’s,and it has been known for a very long time. But to understand how it works,you needed to know its detailed structure. Because if you don’t know how a machine works in detail,such as a car engine,then you wouldn’t really understand how motor works. We needed a high-resolution structure,and that’s what the three awardees of the Nobel Prize did this year which was to determine the atomic structure of the ribosome. We each did one of the sub-units,and then eventually of the entire ribosome.

•Shekhar Gupta: Between the three of you,you did about thirty models.

Venkatraman Ramakrishnan: We’ve solved many structures,but the real key was the atomic structures of the large and small sub-units of the ribosome. All ribosomes consist of two sub-units,which sort of move,relative to each other during the process. We did atomic structures of the sub-units in the year 2000,and that really paved the way for everything that came later.

•Shekhar Gupta: What is your common connection with antibiotics — the three of you? How much of it was collaboration,and how much was it competition?

Venkatraman Ramakrishnan: Once you got the atomic structure,then it was relatively easy to bind the ribosome with these antibiotics and re-determine the structure. Once you have the basic structure,to get the antibiotic structure is quite routine. Once the three of us had our structures of the ribosome components,then we quickly determined the structures with antibiotics. That enabled us,for the first time in 50 years,since tetracycline had been discovered…

•Shekhar Gupta: It has been available over the counter in India for over 50 years — people pop it like cough syrup…

Venkatraman Ramakrishnan: It’s a bad practice,which if you want,I can discuss later. It was possible to determine how these antibiotics bound,and that allowed us to understand how antibiotics blocked ribosome function. It also allows people now how to design better antibiotics,you can see how natural antibiotic is binding in a particular site. You might say,well,we could fill up this vacant space around this antibiotic binding region and say,well,can we design a better molecule? In fact,Thomas Steitz started a company,for which I’m also a consultant. I’m on their scientific advisory board. And they are actually designing new antibiotics,based on these ribosome structures

•Shekhar Gupta: Let’s go back to what you said just now. Why is it so bad to pop an antibiotic over the counter? We know it can make a bacteria more resistant.

Venkatraman Ramakrishnan: Just because you have a fever or a running nose doesn’t mean that you have a bacterial infection. Many infections are viral. If you have a flu,you have a viral infection. So these antibiotics will be of no use,when you have a viral infection like a flu. At the first sign of something like that,and in India it’s especially bad,you ask for tetracycline and they give it to you. The way they do it is that they have some phony doctor on their books who will sign up at some point in time. This leads to overuse of antibiotics,and this causes resistance,where the bacteria becomes resistant to antibiotics. And also,they don’t follow the whole course — as soon as they feel better,they stop taking the antibiotic which also leads to resistance.

I know from working in this company how difficult it is to make a new drug — it takes over a billion dollars. If you make existing antibiotics useless,you’re certainly destroying an extremely valuable commodity. I think people should be very careful.

•Shekhar Gupta: All you great scientists who have been focused on molecular biology,where has it taken us in our understanding of big diseases such as cancer and HIV,the big challenges?

Venkatraman Ramakrishnan: I’m not an expert on either cancer or HIV. But if you look at the progress in the treatment of cancer,you realise that life expectancy and the prognosis of cancer is dramatically different from 10 years ago. (Some lines of treatment) are a complete offshoot of molecular biology,which depends on a technology which was actually developed in my institute. It involves making an antibody that very specifically targets a protein on B-cells,and it ends up specifically killing these cells that are responsible for the lymphoma. That kind of technology will only be available with advances in molecular biology. The time from a basic discovery to an application can be decades,sometimes centuries. Newton discovered the laws of mechanics,but we only had rocketry which used those laws in the 20 th century.

•Shekhar Gupta: I’ve been reading about your irritation,if I may say so,with India embracing you and declaring your Nobel as an Indian triumph. I liked your comment,when you said it’s not like cricket and our man winning.

Venkatraman Ramakrishnan: First of all,science is a highly international enterprise. For instance, my lab has a person from Malaysia ,two people from China ,one from Germany ,one was a Canadian,one American… That’s the make-up of any lab that’s at the forefront of things. Science is international. For example,a discovery made in country X can be quickly exploited in country Y. Information flows quickly,especially in the age of the Internet. Getting back to this whole thing about claiming somebody,I have made it very clear that I grew up in India and I’m very grateful,especially to my teachers. But I’m fundamentally not a nationalist,I have to be honest about that. Because nationalism leads to jingoism and all sorts of problems.

•Shekhar Gupta: Last 30 years have seen decline of nationalism in developed societies. There is more passion supporting your club than supporting your country.

Venkatraman Ramakrishnan: That’s always been true of science. Scientists have been the least nationalistic of people — they have always been global in their outlook. They’ve been willing to move,even in the 19th century. On the other hand,if Indians feel proud that someone who grew up in India ,who got their B.Sc in India has gone on and done well — I think that’s perfectly understandable.

•Shekhar Gupta: And your other comment,that if India has to achieve more,it has to build genuine meritocracy in its institutions.

Venkatraman Ramakrishnan: It was a reporter from your newspaper who asked me,why is it that Indians who go to the US do so well,and why aren’t we doing so well? I think part of the problem is money. America is a very rich country — it has far more resources and that’s part of the thing. But America attracts people from all over the world,and these people go on to top positions. They become presidents,CEOs,they are heads of departments,hospitals,they become Nobel laureates.

I think its because in America ,people don’t care what your background is. What’s your family background,which country are you from? In some cases,even where were you educated? I would be lying if I said it didn’t matter if you were from Harvard or some unknown state school. But it plays less of a role than in other countries. Primary thing they want to know is — what have you done recently and what can you do for us? And that’s a very healthy attitude,and that meritocratic attitude is responsible for America’s role as much as anything else.

•Shekhar Gupta: In India ,I say in some of my cynical moments,that it is important for your parents to have done very well.

Venkatraman Ramakrishnan: If you get beyond that and become a true meritocracy,it would be a step ahead.

•Shekhar Gupta: We have a minister who is trying to set up new great institutions,scale up institutions. Do you have any advice for him?

Venkatraman Ramakrishnan: I can’t give any advice,but I’ll tell you one promising thing I’ve seen. New institutes are being opened up that combine undergraduate education with research and they are more widespread.

•Shekhar Gupta: There is massive expansion of higher education,especially in science.

Venkatraman Ramakrishnan: That’s a very good sign. That’s a sign that research and science education is being taken seriously. The hope is that these kinds of institutions will be more insulated from local politics that often plagues universities. That’s a good sign.

•Shekhar Gupta: Even in IIT,JNU,the finest schools in India will not allow the mobility across disciplines that you’ve enjoyed.

Venkatraman Ramakrishnan: People are in favour of creating more fluidity between institutions,people are in favour of change. When I went to the US in 1971,virtually no one who could stay on came back to India . Whereas now,there are scientists choosing to come back. And they’ll come back with their own ideas of how things should be.

•Shekhar Gupta: In the scientific community,this is widely seen as the decade of biology. What will the next decade be like? Will biology continue to rule for another couple of decades?

Venkatraman Ramakrishnan: If you look at the early half of the 20th century,that was probably physics. And then,chemistry and biology. I think biology is going to be very exciting for the next few decades to come. For example,we still don’t know anything about the organisation of the brain. If I ask you,how do you remember a telephone number,it leads to all sorts of complex questions. There’s all this business of generating gnomic data,but we still don’t know how to use the data.

•Shekhar Gupta: I read somewhere you said the great excitement comes from solving a mystery.

Venkatraman Ramakrishnan: That’s what it comes down to in its essence,that we’re basically puzzle solvers. But the puzzle has to be important,it can’t be some trivial thing. It has to be some deep problem that interests you.

Transcribed by Vaibhav Vats.

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