For the last few years, the Nobel Prize in Chemistry has been given for research related to Biology. This year was no exception. The prize, shared by Venkatraman Ramakrishnan, was for mapping ribosomes at the atomic level.
Dr. Ramakrishnan, who trained as a physicist, made a successful transition to Biology, which has now earned him global recognition for Chemistry. This academic switchover was triggered by what he described to the Nobel Prize website as the “wonderful discoveries happening in Biology” and the number of physicists who had successfully moved over to Biology.
In this second email interview to The Hindu, Dr. Ramakrishnan addresses the scientific significance of his work. He says that studying biological phenomena is an exciting area of Chemistry. Excerpts:
Your work was to understand the precision of the pairing mechanism. How did you develop the crystal structure of the small subunits of the ribosome? Is it any different from the crystal structure developed by others?
There were crystals that diffracted to low resolution that were reported originally by a Russian group headed by Marina Garber in which Marat Yusupov and Sergei Trakhanov played major roles. These crystals did not diffract much better for over a decade. We decided to try and improve those crystals.
Was the structure of small subunits attempted before? If yes, how different was yours?
Yes [the Russian group had attempted it earlier]. We made sure that the ribosomes were biochemically pure (homogeneous) and this was key to improving the crystals.
Was the choice of the bacterium (Thermus thermophilus) the secret behind your success, or the process of developing the subunit itself?
I think both are important. The choice of Thermus thermophilus was originally made by the Russian group, and we decided to try that first. When things worked we just stuck to that organism.
Is developing the structure of small subunits different/difficult compared with large subunits?
Well, it’s hard to say. The small subunit is much more flexible and dynamic, and our crystals never diffracted quite as well as the large subunits used by the Yale group [Dr. Thomas Steitz’s group].
Could you, in simple terms, explain the molecular ruler that you identified?
What the ribosome does is to recognise the shape of the base pairs formed between the codon on messenger RNA (i.e. the genetic code specifying an amino acid) and the anticodon on the tRNA that brings the appropriate amino acid. So if the wrong tRNA binds, the base pairs won’t be the normal base pairs and won’t have the right shape.
If the pairing is according to the molecular ruler, then how is that errors do happen? What are the implications of such errors?
Errors happen at a low rate because the free energy difference between the correct and incorrect base pairs is not infinite, so there is a finite probability that the wrong combination will be accepted.
How is your contribution helpful in developing better antibiotics?
Many antibiotics bind to ribosomes. Using these high resolution structures, we and the other laureates have been able to see how they bind to ribosomes precisely, and this in turn allows chemists to design new molecules that would bind to that site but perhaps more specifically or with fewer side effects.
If the atomic structure of ribosome was known only recently, on what basis were antibiotics developed earlier? Were they, unknown to us, targeting the ribosomes?
The antibiotics were discovered in a general screen. Only then was it determined that they bind to ribosomes, but only after the structures was it known exactly how.
Will the understanding of the atomic structure lead to developing more effective antibiotics that attack only the bacteria and not cause any side effects to humans?
Yes, that is the hope.
Is the atomic structure of all bacteria that cause disease in humans mapped? And have any antibiotics developed based on this knowledge?
You cannot have atomic structures for “bacteria.” If you mean ribosomes, then the point is that the important functional sites of bacterial ribosomes are highly conserved, which is why most ribosomal antibiotics are “broad spectrum,” i.e. they will work against a large range of bacteria.
What made you shift your specialisation from Physics to Biology? Did your earlier exposure to physics, in any way, help your work now?
My earlier exposure to physics certainly helped me in the use of biophysical techniques like crystallography, the use of computing, calculations, etc.
The Nobel Prize for Chemistry is increasingly being given for work related to Biology. Your comments.
Ultimately biological phenomena involve molecules, and understanding them involves understanding the underlying Chemistry. In my opinion, this is a particularly exciting area of Chemistry.
Unlike the Prize for Physics given this year, where the industry was equally involved, the Prize for Chemistry has been for work with no contribution by the industry. Your comments.
Well, I think the industry aspect is usually an exception. More often, the prize in all of the sciences goes for basic research, generally conducted in academia. It’s not Chemistry vs. Physics difference.