From Chidambaram to Cambridge: a life in science

V. Ramakrishnan MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

---

In this charmingly narrated autobiographical essay written for the Nobel Foundation, 2009 Chemistry Laureate Venkatraman Ramakrishnan recalls his Indian roots, the shaping role of his exceptional parents and teachers, the affective care he received from his grandmother and aunt, the twists and turns of his scientific career — and how he came to his lifelong interest in ribosomes. Part I of the excerpted essay:

---

— PHOTO COURTESY: V. RAMAKRISHNAN

GRADUATE STUDENT:A 1975 picture of V. Ramakrishnan. “I often joke,” the Nobel laureate says, “that if I had graduate students like me, I'd fire them!”.

Childhood

I was born in 1952 in Chidambaram, an ancient temple town in Tamil Nadu best known for its temple of Nataraja, the lord of dance. When I was born, my father, C.V. Ramakrishnan, was away on a postdoctoral fellowship in Madison, Wisconsin, with the famous enzymologist David Green. Because he came from a poor family, he did not think that he could support my mother and me on his postdoctoral income, so he went alone. I often joke that but for this, I would have been born in Madison and could have gone on to become President of the United States. In fact, I first saw him when I was about six months old. My mother, R. Rajalakshmi, taught at Annamalai University in Chidambaram, and during the day, I was well cared for by aunts and grandparents in the usual way of an extended Indian family. When I was about a year and a half, my father left again, this time with my mother, to go to Ottawa on a National Research Council fellowship. They returned a little over a year later, and during their absence I was brought up by my grandmother and my aunt Gomathi, to whom I remain close to this day.

At the age of three, my parents moved to Baroda (now appropriately called by its Gujarati name of Vadodara, which refers to the abundance of banyan trees that the city used to have), where my father was appointed at an unusually young age to head a new department of biochemistry at the Maharaja Sayajirao (M.S.) University of Baroda. When he started the department, there was just some empty lab space with no equipment or people. He managed to acquire a low-speed table-top centrifuge, and would get blocks of ice from a nearby ice factory, crush them, and place them around the centrifuge so that his samples would remain cold during enzyme purification .

With this setup he managed to publish two papers in Nature in quick succession.

Within a few years, the department was well established in both teaching and research, and equipped with instruments, a cold room and an animal house.

Unusually for an Indian man of his generation, my father, being aware of my mother's intellectual abilities, encouraged her to go abroad by herself to obtain a Ph.D. She obtained a fellowship in McGill University to do a Ph.D. in psychology.

Probably because she felt guilty about leaving my father and me behind, she finished her Ph.D. in under 18 months, which must be something of a record. When she returned, she could not find a suitable position in the Psychology Department in Baroda. Instead she used her analytical skills to help my father in his research, working initially as a CSIR pool officer, which was a temporary scheme by the Government of India to support scientists returning from abroad. This was the beginning of a lifelong collaboration in their work. My childhood and adolescence were filled with visiting scientists from both India and abroad, many of whom would stay with us. A life of science struck me as being both interesting and particularly international in its character.

My move to Baroda was something of a culture shock initially because until the age of three I only spoke Tamil, a language that I unfortunately no longer speak well. One of my earliest memories is of standing in a playground not being able to understand a word of the Gujarati the children were speaking. This feeling of being an outsider has remained with me for much of my life, as my career has taken me to various countries. Because my parents did not speak Gujarati either, they enrolled me in what was then the only English language school in town, the Convent of Jesus and Mary School, which was located next to a large military base.

Shortly after my sister Lalita was born in 1959, my family went to Adelaide, Australia in 1960-61. I remember the year in Adelaide as one of the most carefree years of my childhood, and returned with an Australian accent that my former schoolmates could hardly understand.

The rest of my schooling was at the Convent School. By that time, there were other English schools in Baroda, and the nuns who ran the school decided to convert it to a girls' school and no longer admit boys. They allowed those boys who had enrolled to stay on, but by attrition, our class kept losing boys, so there was a roughly four to one ratio of girls to boys when I graduated. Perhaps because of this and the fact that my mother and sister both went into science, I have felt perfectly comfortable among women even when I am the only male present, and there have been times when my lab has consisted almost entirely of women .

During the 7th – 9th grades, I dropped from being at or near the top of my class to being in the bottom third. Rather than studying, I spent my time playing and reading novels and other extracurricular books. Luckily, in my last two years I had a dedicated science and mathematics teacher, T.C. Patel, who made those subjects come alive. A strict disciplinarian, he nevertheless had a twinkle in his eye as he would expose us to clever ideas and difficult problems. This sparked my interest in my studies again, and I graduated second in my class overall despite the fact that I did very poorly in Hindi, a language that I never managed to learn well.

Choosing basic science

By the time they finished high school, students in India were separated, as they are in England but not in America, into those who are going into science, medicine or engineering, and those who plan to study the arts or humanities. Although I liked literature and did well in my English class, studying English was never really an option I considered seriously, especially given the scientific environment in which I grew up. Additionally, the cultural climate in India makes it difficult for good students to choose to study the humanities unless they are particularly strong willed, because parents are too often opposed to what they see as a risky career choice.

Accordingly, I enrolled in the pre-science course at my local university, the M.S. University of Baroda. This was a one-year preparatory course before students chose to go into medicine, engineering or basic science. The pre-science course had an excellent curriculum in both physics and mathematics, largely due to forward thinking faculty in those departments. However, the teaching of botany and zoology was very old-fashioned and involved memorisation of lots of facts in a relatively unconnected and tedious way. As a result, I was not particularly interested in the life sciences at that stage.

A critical decision that students have to make after their pre-science year is whether to go into medicine or engineering. Generally, those students who did not get accepted into either of these went into basic sciences as a last resort. My mother however had just become aware of the National Science Talent Search Scholarship by the Government of India, which was modelled after the Westinghouse (now Intel) Science Talent scholarships in the USA. A condition was that the recipient had to major in a basic science. She encouraged me to take the scholarship exam, and arranged for me to do the required research project with a colleague of hers in the Biochemistry Department on quantifying the amount of nitrogen fixation by leguminous plants, which was somewhat ironic given my general apathy towards biology courses.

PHOTO COURTESY: V. RAMAKRISHNAN

VENKI'S PARENTS: C.V. Ramakrishnan and R. Rajalakshmi on their way to Ottawa.

At the end of the year, I also took national entrance exams for the famous Indian Institutes of Technology (IITs) and for the Christian Medical College in Vellore, one of the finest medical schools in India, but which had a very small quota for males since it was founded to train female doctors. I did not do well enough to qualify for admission to either institution. However, as a result of doing well in my university exams, I was offered admission to study medicine in Baroda. In the meantime, however, I was offered the National Science Talent Scholarship.

I had made an agreement with my father, who wanted me to study medicine, that if I was awarded this scholarship I could choose to study basic science. That decided, there was the further question of where to do my undergraduate studies. I briefly considered going to Madras, which would have reconnected me with my Tamil roots, but a faculty member in the physics department in Baroda, S.K. Shah, told me about a brand new curriculum they were introducing for their undergraduate course. It began with the Berkeley Physics Course, and was supplemented by the Feynman Lectures on Physics before moving on to more specialised areas. I therefore decided to enrol in the B.Sc course in physics in Baroda, my hometown. Since I was only 16 when I began this course, I sensed that my parents, especially my father, were relieved that I was not leaving home at an age when they felt I was not sufficiently mature emotionally.

My teachers in physics, especially S.K. Shah and H.S. Desai, were very excited to be teaching the new curriculum for the first time, and their enthusiasm was infectious. I also had several excellent mathematics teachers, including the scholarly S.D. Manerikar, who discarded our exam-oriented Indian textbooks and taught us from books like Hardy's “A course of pure mathematics” and Courant's textbooks of calculus. It was during this time that I first met Sudhir Trivedi, who has gone on to a successful career in applied physics in the USA and become a lifelong family friend.

When we had a boring class, we would often skip it. Once he and I sat near an open window and decided to jump out of it as soon as attendance was taken to go off and have tea and snacks at a nearby restaurant. His jump created a loud thud so I could not follow because the professor was staring directly at me.

Towards the end of my undergraduate studies I had to decide where to go to graduate school. The normal route for science students was to do a master's at some university in India before thinking of going abroad. As a Science Talent Scholar who was doing well, I would have been accepted almost anywhere. However, my parents were doing a short sabbatical at the University of Illinois in Urbana at this time, so it was tempting to spend the summer with them and go on to graduate school in the United States. By the time I applied, it was too late to take the GRE and without it almost no universities would consider my application.

At about this time, my chairman N.S. Pandya brought to my attention a letter from the physics department at Ohio University, which said they were looking for qualified students for their graduate programme. I wrote them a letter of inquiry and soon afterwards was accepted with a fellowship. I was living alone when the acceptance arrived, and was absolutely thrilled to be going to graduate school in the USA, a land I associated with many of the great scientists whose textbooks I had studied, including Feynman, Purcell and others. I arrived in America a month after my 19th birthday.

Graduate school in the USA

When I got to graduate school in Ohio, I was surprised to see that over half of our class consisted of foreigners, many of them from India. I passed the obligatory comprehensive exam after two years of coursework, and then chose to work in solidstate theory with Tomoyasu Tanaka. For my proposal, I had considered doing some theoretical work on biological systems, but since neither he nor I knew any biology, this did not go anywhere. The problem I took on was to look at ferroelectric phase transitions in potassium dihydrogen phosphate. This was a particularly difficult time for me, since I had no feel for the problem or even what the basic questions we were trying to understand were. It was the first time in many years that I felt I had chosen the wrong field.

The result was that I felt so frustrated that I withdrew from my thesis work and spent an inordinate amount of time on extracurricular activities. I went hiking and hopped on freight trains with my good friend and classmate Sudhir Kaicker, learned about western classical music from another friend, Anthony Grimaldi, played on the chess team, read literature, and went to concerts. In short, I did everything except make progress on my work. Tomoyasu was far too kind and patient, but even he would get worried every few months and ask how I was getting on. I was too embarrassed to tell him that I wasn't getting on at all! I often joke that if I had graduate students like me, I'd fire them!

It was during this time that I met Vera Rosenberry, who was majoring in painting and was introduced to me by mutual friends because, unusually for the early 1970s in Ohio, we were both vegetarian. After an intermittent courtship that lasted only 11 months in total, we were married in 1975. She has been my companion and friend ever since, and has not only done most of the work of raising our children but uprooted herself many times to move with me all over the USA and to England. The emotional support and stable home environment she provided has been invaluable to me and my work. During that time, in addition to painting, she also became a children's book writer and illustrator, and has published over 30 books.

After my marriage at the age of 23, I was suddenly no longer alone but had a wife and a five-year-old stepdaughter, Tanya Kapka. This sudden change in my responsibilities made me realise that I had to get on with my career. I produced a passable thesis in the next year and obtained a Ph.D. in physics in 1976 just a month before our son Raman was born. But by that time I had already decided I was going to switch to biology.

Transition to biology

Since I hardly knew any biology, I felt I needed formal training of some sort. When three schools accepted me into their graduate programme, I chose to go to the University of California, San Diego (UCSD). My first year [there] was tremendously exciting. For the first time in my life, I was at a university that was at the forefront of international research.

In my second year, however, I read an article in Scientific American by Don Engelman and Peter Moore about their ribosome work, and became interested in it. I therefore wrote to Don Engelman, who wrote back and said that he and Peter had a position open on their ribosome project. Peter arranged to meet me in San Diego in early 1978 and offered me a postdoctoral position soon afterwards. Thus began my lifelong interest in ribosomes. — © Nobel Foundation

_____________________________________________

From Chidambaram to Cambridge: solving the 30S subunit structure of the ribosome

---

In this concluding excerpt from his autobiographical essay written for the Nobel Foundation, 2009 Chemistry Laureate Venkatraman Ramakrishnan relives his experience of staking all on “one risky project” when, in 1999, he took a hefty salary cut and moved to the MRC Laboratory of Molecular Biology, Cambridge, U.K. Reasoning that “the structure of the ribosome was the most important goal in my field,” he decided to focus entirely on the 30S subunit. The rest, including the Nobel and the Padma Vibhushan, is history.

---

— PHOTO: AFP

RIBOSOME MOMENT: Venkatraman Ramakrishnan receives the Nobel Prize in Chemistry from King Carl XVI Gustaf of Sweden on December 10, 2009.

Starting an independent career

My first experiment [at Brookhaven National Laboratory] was on ribosomes, in which I tried to settle an emerging controversy about whether the proteins and RNA in the 30S subunit were asymmetrically distributed. This resulted in my first independent paper being a single author paper in Science. Since this was a decade before the internet, I wrote a letter to my father in India when it was accepted, and about a month later received his reply saying that he was glad I had made a good start, and that if I continued to work hard, I might some day even have a paper in Nature.

[Dr. Ramakrishnan went on to do a sabbatical at the MRC Laboratory in Molecular Biology at Cambridge, England in late August 1991 to learn crystallography, as he felt that was how he could answer the really important questions in his field. Having learnt the nuts and bolts of how to solve a structure, he returned to the U.S. and moved to the Biochemistry department of the University of Utah.]

Starting work on the 30S subunit at Utah

Even before coming to Utah, I had ideas of solving the structure of the ribosome, beginning with its small or 30S subunit. My first task was to convince someone in the lab that this was a worthwhile project.

The project really took off when the graduate students came on board. [Bil Clemons, John McCutcheon, Brian Wimberly and Joanna May joined the team.]

As soon as we started, my insecurities about funding again set in. I could just imagine writing a grant application to NIH saying that we had no good crystals of the 30S subunit but had some ideas about how to get them, and that although a group had been working on good crystals of the 50S subunit for almost a decade, we had some ideas for how to solve our structure if we got good crystals. Having served on study sections myself, I could just imagine the peals of laughter that would go around the table as my application was considered.

On the other hand, I knew that the LMB, where I had done my sabbatical, had a longstanding tradition of supporting exactly this kind of difficult but fundamentally important project. Apart from funding issues, I felt I would have access to world leaders in crystallographic methodology who could help me if I ran into technical problems.

So I wrote again to Richard Henderson, who by that time had also become the director of the LMB, and we agreed that I would visit on my way to a ribosome meeting in Sweden. After my talk on ribosomal proteins, Richard and Tony Crowther (who was joint head of the division with Richard) chatted with me for a couple of hours on the “ribosome problem.” They were interested in my ideas, what the competition was likely to be, what approaches had failed, what resolution one would have to reach to achieve a significant breakthrough in understanding and how long that was likely to take. The conversation was unlike any other job interview. There was no discussion of space, salary or equipment, just about science and ideas.

At the time, I had no crystals; nevertheless Richard wrote shortly after my visit saying they were interested in supporting me, and would let me know when they would have the additional space to accommodate me. A few months later, Richard wrote again to say that indeed the space had materialised.

I suddenly had to make what was one of the hardest decisions of my life: whether to gamble everything on going to the LMB and work exclusively on this project, which would involve taking a large salary cut and leaving our families (including our grown children) in the USA, or to continue working in Utah, where I would probably have to hedge my bets by working on safer projects simultaneously. In the end, I decided that the structure of the ribosome was the most important goal in my field, the time was ripe for an attack on it, and it would be a mistake to be distracted from it by other projects because there was only a narrow window of opportunity before other groups entered the field that had so long been dominated by just one person, Ada Yonath.

Most people thought that it would be insane to move to England staking all on this one risky project. Vera and I finally decided to leave Utah where we were very happy, take a 40 per cent salary cut and move to the LMB.

With the decision to move to the LMB made, I decided to focus entirely on the 30S subunit. Within a few months we had crystals, and a few months later, we had cracked the problem of getting them to diffract well. This was largely due to John and Bil's willingness to try completely new approaches to purifying the 30S subunit and to their sheer dedication and hard work.

Work at the MRC Laboratory of Molecular Biology

I moved to Cambridge in April of 1999, while Brian, Bil and Joanna stayed behind. The result was that I was able to make use of the LMB's computing resources to try several phasing runs in parallel, and send the maps to Utah. Because of the seven-hour time difference, we may have been the only group that actually speeded up to some extent as a result of a move.

So only a few months after my move to Cambridge, we had made a major breakthrough in tracing [the entire central domain of the 30S subunit.] When I revealed our findings at the triennial ribosome meeting in Denmark in June, I could sense the shock in the audience, especially since virtually none of them knew we were working on the problem. Soon afterwards, our work was published in Nature in August 1999 with much fanfare.

By this time, Brian and Bil had moved from Utah, and we needed to focus on getting to high resolution.

Solving the 300S subunit structure

Getting to the high-resolution structure of the 30S subunit was beset with problems, which are described in the Nobel lecture. This was a particularly stressful time for me and my lab members. The Yale group of Tom Steitz, Peter Moore and their colleagues was making steady progress with their structure of the 50S subunit. More significantly for us, soon after we had decided to focus on the 30S subunit in Utah, I had found out that Ada Yonath, who had first crystallised the 50S subunit and had been working on determining its structure for over a decade, had now essentially switched to determining the 30S subunit structure using crystals obtained by a slightly different route. So instead of having a quiet niche to myself, we were in a flat-out race.

Given the competition, we wanted to ensure that our data collection at the [Advanced Photon Source (APS) in Argonne in February 2000] was a success, since it was not clear that we could avoid being scooped if that trip failed. [Team members] froze over a 1000 crystals in the cold room while listening to Johnny Cash on a mini stereo system. Four of us worked in 12 hour shifts using a large spreadsheet that told us which crystals we had to look at next. Ditlev used his computing skills to streamline our data collection and analysis procedures. We calculated an anomalous difference Fourier map while still at the beam line, and when I saw the large number of strong peaks for our best derivative, much to Rob's amusement, I started dancing around the office saying, “We're going to be famous!”

The maps from the improved data were stunning, and we were on our way to building the structure. With five of us working long hours, were able to build a complete atomic model for the subunit within weeks. Even before we had finished, Andrew Carter had crystallised the subunit with three different antibiotics, and seeing them directly in difference Fourier maps was another great highlight.

The structure of the 30S subunit led to a number of follow-up studies on antibiotics and ligand binding. The most important of these, largely carried out by James Ogle, led to understanding how the ribosome ensures the accuracy of translation during decoding of the genetic message. Our studies on decoding continue to this day in the context of the whole ribosome.

The politics of scientific recognition

People go into science out of curiosity, not to win an award. But scientists are human, and have ambitions. Even the best scientists are often insecure and feel the need for recognition. Our ribosome work led to lots of invitations to give seminars and speak at conferences. It resulted in my election to the Royal Society and the U.S. National Academy of Sciences and also led me to receive a prestigious European prize, the 2007 Louis-Jeantet prize for medicine. Thus in both my scientific efforts and the recognition for it, I had succeeded beyond my wildest dreams.

Although few scientists are foolish enough to enter a field to win a Nobel Prize, ever since the 30S subunit had been solved, people would regularly bring up “the Prize” in conversations whenever I went to conferences or give seminars. It was clear to me that the ribosome was at least as important as other structures that had been awarded the Nobel Prize. But there were many more than three people who had contributed to the ribosome, even if one only counted principal investigators, which itself is a fictional view of the way modern science is done.

While we were solving the structure of the 30S subunit, I had mostly refused to be distracted by going to meetings to speak about our work. So it was something of a shock when only a couple of months after the atomic structures of the subunits came out, a prize in the USA was awarded to just one aspect of the ribosome, peptidyl transferase. It seemed to me that instead of waiting for the impact of the ribosome work to become clear and then thinking hard about what had really made a difference to the field, the committee had hurriedly decided on which three people they wanted to honour and then written a citation around them that would exclude the others. Richard Henderson, my director, suggested that I should accept more invitations to meetings and talks to get our story known if only to get proper recognition for our work, regardless of prizes.

Deep down, I felt that the scientific event that transformed the field more than anything else was the determination of the atomic structures of the ribosomal subunits and the functional studies that followed as a result, to which we had made a major contribution. However, international prizes for work on ribosomes always seemed to go to other people. So over the years, I had gradually come to accept that I would probably not get a major international prize for the ribosome, least of all the Nobel Prize. Once I had accepted that, I felt liberated and happier, but I have to confess that I felt some trepidation each October. Every time I learned the Nobel Prize was for something other than the ribosome, I would be relieved because it was a postponement of what I felt would be the inevitable disappointment. As the years went by, it seemed to me and many other scientists that there would never be a Nobel Prize for the ribosome because the problem of choosing three people out of all the contributors appeared insurmountable.

The Nobel Prize and its immediate aftermath

On October 5, 2009, the Nobel Prize for Physiology and Medicine went for work on telomerase. Since the Chemistry prize had been awarded for biological work the previous year, I was confident that it would not be awarded for the ribosome that year.

On the morning of October 7, I was halfway to work when my bicycle developed a flat tire. As a result, I came in quite late and somewhat irritated, and had completely forgotten that it was the day the Chemistry Prize was going to be announced. So when the phone rang soon afterwards and a voice said it was an important call from the Royal Swedish Academy of Sciences, I immediately suspected it was a prank orchestrated by one of my friends like Rick Wobbe or Chris Hill, who like practical jokes. When Gunnar Öquist came on the line and started talking to me, at first I simply refused to believe him and even complimented him on his Swedish accent. Finally, after he was done, I asked if I could speak to one of the committee members, Måns Ehrenberg, whom I knew personally. When I heard his voice, it was with a shock that I realised it was true, a feeling that was reinforced when Anders Liljas and Gunnar von Heijne also came on the line to congratulate me.

Two members of my lab, Martin Schmeing and Rebecca Voorhees, had desks just outside the open door to my office and had overheard my end of the entire conversation. They did not share my scepticism and could hardly contain themselves. By the time I got off the phone, they were jumping up and down, and Martin popped open a bottle of champagne he had been saving to celebrate the publication of a paper that had just been accepted in Science. In the intervening minutes between the phone call and the public announcement, I was unable to get hold of Vera, because she was taking a walk with Tanya and does not use a mobile phone. It was 2 a.m. in Seattle and 5 a.m. in New York, so I did not want to wake up my father, sister, or Raman. Unfortunately, the press was not so considerate.

It was not until I saw the public announcement on the Nobel website that it fully sank in. Within a few minutes, the phone rang and did not stop ringing for two days. My colleagues at the LMB, many of whom had supported me when I had nothing but an idea, were delighted. They organised the customary drinks celebration in the canteen, for which Mike Fuller bought and served the champagne as he had for all the previous Nobel Prizes awarded to scientists here. After the celebration, Vera and I walked my bicycle home in the rain.

It was touching to get congratulatory messages from old friends and scientific colleagues around the world. I was especially moved by messages from colleagues in the ribosome community, including my mentor Peter Moore and Joachim Frank, both great scientists who had made major contributions to the field and were justifiably contenders for the prize themselves. Peter was particularly (and typically) gracious, and seemed proud that his protégé had done so well. Much was made of my prize in India, and I found myself the subject of an entire nation's celebration. I was taken aback by the flood of emails from complete strangers in India, and when they continued unabated for several days, I overreacted to what I felt was an intrusion on my ability to carry out my work. This angered many people there and a clarification I made only partly mollified them.

The Nobel week in Stockholm in December was surreal and memorable. After Sweden, I went on my usual annual visit to India, but this time with some trepidation because I did not know what the reaction to me would be given the email controversy. I need not have worried, because I was overwhelmed by the warmth and affection from both members of the public and my scientific colleagues there. I was honoured that the Government of India decided to bestow upon me their second highest civilian award, the Padma Vibhushan. I have come to realise that I have inadvertently become a source of inspiration and hope for people in India simply by the fact that I grew up there and went to my local university, but could nevertheless go on to do well internationally.

On my return to Cambridge in early January, things slowly began returning to normal after the euphoria of the autumn. I began to realise that the Nobel Prize could be seen not just as an affirmation of my past work but also as an encouragement to continue to work on interesting problems. Certainly, it seems to have fired up people in my laboratory, and I look forward to the struggles ahead as we try to answer some of the hard questions in our field and beyond. Looking back on my life so far, I feel a deep sense of gratitude for having been able to lead such a rich life both intellectually and personally. — © Nobel Foundation

( This is the concluding excerpt from an autobiographical essay by 2009 Nobel Prize winner for Chemistry V. Ramakrishnan, made available exclusively to The Hindu . The entire essay is now available at The Hindu website and will be published by the Nobel Foundation in a few months.)

(The Hindu, Opinion, 08 and09 of April,2010)

____________________________