Venkatraman Ramakrishnan: Investigating a central dogma

I greet him at the Grand Hotel in Stockholm, the hotel where all laureates and their families stay during the Nobel festivities in December. Despite the ongoing Nobel stress he has an aura of calmness and answers all of my questions with thoughtfulness and engagement. 

Venkatraman Ramakrishnan is today a senior scientist and group leader at the Structural Studies Division of the MRC Laboratory of Molecular Biology at Cambridge, in the UK. The Laboratory is home to 11 other Nobel Prize Laureates.

Most of the equipment and infrastructure is shared between departments, there is no hierarchy and the atmosphere is very informal and friendly.

“There is a great history at the LMB and the environment is very stable and supportive. You don’t waste your time doing sort of mundane or routine things. Most of the equipment and infrastructure is shared between departments, there is no hierarchy and the atmosphere is very informal and friendly,” he describes.

Switching fields

Venkatraman Ramakrishnan has just arrived back from the University of Stockholm where he has held a Nobel lecture with the title “Decoding the genetic message: The 3D version”. The central dogma of the translation of the genetic code into proteins has been a subject of his research for many years and was the work he received the Nobel Prize for. But Venkatraman Ramakrishnan began his career in the field of theoretical physics. He earned his BSc in physics from Baroda University in 1971 and his PhD in physics from Ohio University in 1976.

“I was not particularly interested in my PhD work and soon became more interested in biology, so I switched fields,” he says.

At the University of California in San Diego he switched area of interest and conducted research with Dr Mauricio Montal, a membrane biochemist. During a postdoctoral fellowship in 1978, at Yale University with Professor Peter Moore, he first came into contact with the ribosome and worked on a neutron scattering map of the small ribosomal subunit of E. Coli. He then joined the staff at Brookhaven National Laboratory where he began cloning genes for several ribosomal proteins and determining their three-dimensional structures.

In 1995, he became professor of the Department of Biochemistry at the University of Utah. He studied, for example, protein-RNA complexes and the entire 30S subunit. In 1999 he moved to the UK and the MRC Laboratory of Molecular Biology in Cambridge, where he remains today. 

Stressful times

Mapping the structure of the ribosome, the machinery of the cells where the genetic code is translated into proteins, is part of a central dogma in life sciences. It has been complicated and time-consuming due to the large and complex structure of the ribosome. Several researchers have been attracted by this fundamental problem and at the same time, in 1999-2000, the entire structure of the ribosome was published individually by all three Nobel laureates; Venkatraman Ramakrishnan in the UK, Ada Yonath in Israel and Thomas Steitz in the US. Using X-ray crystallography they had all mapped the position of the hundreds of thousands of atoms making up the ribosome.

You could feel the competition and race between our research groups.

“This was definitely the highpoint of our work but it was also a stressful time and you could feel the competition and race between our research groups,” says Venkatraman Ramakrishnan.

He and his colleagues published two papers in Nature. In the first paper they presented the 3 Angstrom structure of the 30S ribosomal subunit. The second paper revealed the structures of the 30S subunit in complex with three antibiotics that target different regions of the subunit. They discussed the structural basis for the action of each of these drugs.

Understanding the ribosome

Venkatraman Ramakrishnan and his colleagues use biochemical, crystallographic and electron microscopy techniques to study the mechanisms of translation by ribosomes. The group has determined the complete atomic structure of the 30S subunit and its complexes with several antibiotics, initiation factor IF1 and cognate and near-cognate tRNA anticodon stem-loops complexed with mRNA in the A site. More recently the group has also determined the high resolution structure of the entire ribosome complexed with mRNA and tRNA. These studies shed light on antibiotic functions and the mechanism of tRNA and mRNA recognition and decoding by the ribosome.

“We have a pretty good idea how antibiotics interact with the ribosome. And it also gave us an idea of why certain mutations would cause resistance and how you might design better antibiotics. One of my co-winners, Thomas Steitz, founded a company in New Haven that is devoted to making new antibiotics based on the structure of the ribosome and they have, actually, new potential drugs in clinical trials. So that’s one of the more satisfying things to come out of it,” says Venkatraman Ramakrishnan.

Another important application of the mapping of the ribosome structure is a better understanding of the origin of life. There is a lot of evidence that the current genetic material, DNA, was preceded by RNA. “The structure of the ribosome shows that RNA contains within itself the ability to sense base-pairing geometry and ensure fidelity,” says Venkatraman Ramakrishnan.

They should care about the answers to fundamental questions and not be afraid to ask questions.

For young scientists Venkatraman Ramakrishnan has two pieces of advice

“They should care about the answers to fundamental questions and not be afraid to ask questions and seek advice because of the risk of feeling ignorant and stupid. They should have a desire to tackle important problems.”

He himself became interested in science early on and was filled with curiosity and an aim to understand the world, he states.