Venkatraman Ramakrishnan, Born in Chidambaram in 1952, Published an Atomic Model of the Ribosome's 30S Subunit in 2000 and Shared the 2009 Nobel Prize in Chemistry

On 7 October 2009 the Royal Swedish Academy of Sciences announced that the Nobel Prize in Chemistry would go jointly to Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology in Cambridge, Thomas Steitz of Yale University and Ada Yonath of the Weizmann Institute of Science in Israel, “for studies of the structure and function of the ribosome”. The Nobel Foundation lists Ramakrishnan as born in 1952 in Chidambaram, Tamil Nadu, with a PhD in physics from Ohio University in 1976, and as a US citizen at the time of the award.

Each laureate took one third of the SEK 10 million prize money. Tuput’s review of the science prizes of 2016 to 2026 finds no India-born winner in chemistry, physics or medicine since Ramakrishnan.

What a ribosome does, and why it took crystals to see it

Every cell holds tens of thousands of ribosomes, each about 25 nanometres across. The Nobel committee’s popular account calls the ribosome the cell’s protein factory: it reads a messenger RNA copy of a gene and builds the matching protein, a step scientists call translation. Scientists worked out the three-letter code it reads in the 1960s, a story told in tuput’s piece on Har Gobind Khorana and the genetic code.

A bacterial ribosome has two parts, a small subunit called 30S and a large one called 50S. To see where every atom sits, the three laureates used X-ray crystallography. Scientists fire X-rays at a crystal, record how the beams scatter, and work back to the positions of the atoms. Crystals have to be nearly perfect, and the Academy notes that the bigger the molecule, the harder one is to grow.

Yonath began trying to crystallise ribosomes at the end of the 1970s, when most people thought it was impossible, and by 1980 she had grown first crystals of a large subunit. Steitz solved a mathematical obstacle called the phase problem, using electron microscope images from Joachim Frank, and in 1998 published a large-subunit structure at 9 angstroms, too blurry to show single atoms. Between August and September 2000 all three laureates published structures sharp enough to place atoms.

A physicist from Baroda who turned to biology

Ramakrishnan’s own Nobel autobiography says he was born in Chidambaram, a temple town best known for its temple of Nataraja. His father, C. V. Ramakrishnan, was a biochemist appointed to head a new biochemistry department at the Maharaja Sayajirao University of Baroda, now Vadodara. When he was three the family moved there, and until then he spoke only Tamil. Ramakrishnan’s mother, R. Rajalakshmi, taught at Annamalai University and later earned a PhD in psychology at McGill University.

At 16 he began a B.Sc. in physics at the Baroda university. His mother had learned of the Government of India’s National Science Talent Search Scholarship, which required the recipient to major in a basic science, and he won it. A month after his 19th birthday he left for Ohio University, and he completed his physics PhD in 1976. By then he had decided to switch to biology.

Biology courses at the University of California, San Diego, came next, and then he read a Scientific American article on ribosome work by Don Engelman and Peter Moore. Moore met him in San Diego in early 1978 and soon offered him a postdoctoral place at Yale. “Thus began my lifelong interest in ribosomes,” he writes. Brookhaven National Laboratory hired him in 1983. The autumn of 1988 found him on the first Cold Spring Harbor course on crystallography, and from late August 1991 he spent a sabbatical at the Laboratory of Molecular Biology in Cambridge.

Utah was where he chose to go after the 30S subunit with graduate students Bil Clemons and John McCutcheon, later joined by Brian Wimberly. He moved to Cambridge in April 1999, while part of the team stayed in Utah for a time.

From a 1999 map to the September 2000 structure

The first result came in Nature on 26 August 1999. At a resolution of 5.5 angstroms the team could see the phosphate backbone of the ribosomal RNA and the spiral helices of proteins, and it placed all seven small-subunit proteins of known structure in the map. When he presented the work at a ribosome meeting in Denmark in June 1999, he writes, he could sense shock in the audience, since almost nobody knew his group was working on the problem.

Higher resolution needed more intense X-rays. The team won beam time at the Advanced Photon Source in Argonne, Illinois, for late February 2000 and worked there in 12-hour shifts. He recalls seeing strong signals in the map while still at the beamline and saying, “We’re going to be famous!” With five people building the model, the complete atomic structure of the subunit was in place within weeks.

Three groups were close together. The Steitz and Moore team at Yale published the large subunit from the Dead Sea microbe Haloarcula marismortui in Science on 11 August 2000, at 2.4 angstroms, with 2,833 of its 3,045 nucleotides and 27 of its 31 proteins placed. Yonath’s group published a 3.3 angstrom structure of the 30S subunit from Thermus thermophilus in Cell on 1 September 2000, reporting that 96 per cent of its nucleotides were traced. Ramakrishnan’s team published the same subunit, from the same bacterium, in Nature on 21 September 2000. That model was refined to 3 angstroms and included all the RNA and proteins present.

Three antibiotics, then three more, on one structure

A second Nature paper appeared the same day. This one showed the 30S subunit with three antibiotics, paromomycin, streptomycin and spectinomycin, bound at once. His Nobel lecture adds that tetracycline, pactamycin and hygromycin B followed soon after, and that these were the first detailed structures of antibiotics bound to entire ribosomal subunits.

The Nobel committee says many antibiotics work by blocking the ribosomes of bacteria while leaving human ribosomes alone, and that some block the tunnel through which a new protein leaves, some stop peptide bonds from forming, and some corrupt the reading of the code. The committee states that the laureates’ three-dimensional models are used by scientists developing new antibiotics. When it wrote its popular account in 2009, it said several companies were using the structures and that some candidate drugs were in clinical tests.

The World Health Organization’s fact sheet estimates that bacterial antimicrobial resistance was associated with more than 4.7 million deaths worldwide in 2021 and says too few new antibiotics are being developed to replace those that no longer work.

The ruler that double-checks every letter

The structure also explained a long-standing puzzle, because a ribosome picks the wrong amino acid only about once in 100,000. The Academy’s account says Ramakrishnan’s structures of the small subunit revealed a kind of molecular ruler: nucleotides in the subunit’s RNA measure the distance between the messenger RNA codon and the matching transfer RNA, and if the spacing is wrong, the transfer RNA falls off. The check runs twice.

A follow-up paper in Science on 4 May 2001, from the same laboratory, solved the 30S subunit with messenger RNA and the correct transfer RNA in place, at 3.1 to 3.3 angstroms. Three RNA bases, A1492, A1493 and G530, sense the shape of the pairing between codon and anticodon, the paper reports, and paromomycin makes the subunit accept some transfer RNAs that do not quite match.

Who shares the credit

In the Academy’s popular account Yonath is the pioneer of ribosome crystallography and Steitz solved the phase problem. Ramakrishnan’s lecture says the Yonath group’s 2000 structure of the 30S subunit had a number of discrepancies with his own, detailed in a 2002 paper, but that her group’s 2001 structure, at 3.2 angstroms, agreed well with the original. His autobiography says that many more than three people contributed to the ribosome work, and that for years he did not expect a Nobel because choosing three seemed impossible.

Honours in Britain and India

Before the Nobel, he had received the 2007 Louis-Jeantet Prize for medicine and been elected to the Royal Society and the US National Academy of Sciences. The Indian National Science Academy elected him a foreign fellow in 2008. His first trip to India in 13 years came in early 2002, when he gave the first G. N. Ramachandran Memorial Lecture in Chennai and spent a day at the Indian Institute of Science in Bangalore, where he later held a visiting professorship named for Ramachandran.

On 8 December 2009 he gave his Nobel lecture at Stockholm University. The Gazette of India of 31 March 2010 lists “Dr. Venkatraman Ramakrishnan, Science and Engineering, UK” among the Padma Vibhushan awards. He describes the Padma Vibhushan as the Government of India’s second highest civilian award, and writes that people in India had warmly welcomed him, seeing in his path from a local university to international science a source of inspiration.

The Royal Society and the University of Cambridge both report that he was awarded a knighthood in 2012. The Royal Society confirmed him in 2015 as its next president, to take office on 1 December 2015.

The memoir and the work now

His memoir, Gene Machine, was published by Basic Books in the United States on 6 November 2018. Its publisher calls it an insider account of the race for the ribosome’s structure. The MRC Laboratory of Molecular Biology lists him as an emeritus research leader whose recent work uses electron cryomicroscopy to study how cells with a nucleus start translation, and who has also studied translation from circular RNAs, including their use in RNA therapeutics. The same page lists a second book for general readers, Why We Die, from 2024.