Less focus on basic science and limited support for discovery research are the two issues the scientific community as well as governments all over the world should be seriously worried about today. Big pharmaceutical companies ignoring the serious threat of microbial resistance to existing antibiotics and not thinking about developing new ones is another dangerous trend that the world is facing at present, says Prof Ada e Yonath.
The Chemistry Nobel Laureate, who was in India in February to deliver the keynote address at the International Conference on Advanced Chemical and Structural Biology – 2019 in Chennai, spoke to Future Medicine at length in an exclusive interview with Editor C H Unnikrishnan. Edited excerpts:
One of the key objectives of your path-breaking work on ribosomes was to help the development of new antibiotics. But, has it really resulted in the introduction of any in the market, especially in a situation where the existing ones are becoming less effective due to bacterial resistance?
There are quite a few in the development stage across the globe, targeting ribosomes. But, in general, it seems that many of the big companies do not think that antibiotics are a profitable business for them. It is very unfortunate, and I wish they would think beyond profit and would take up more such projects and introduce them in the market quicker, considering the urgent need to save human life as antimicrobial resistance is a crucial health issue now.
Why can’t big pharmaceutical companies, who often talk eloquently about philanthropy and social responsibility, work on these novel pathways, including your discovery, to develop new products that help combat this serious issue?
There were several companies that showed interest in developing new products targeting proteins. Nothing much has happened so far as hardly anyone really worked to take it up. I know that the investment that is required to develop new drugs is high and that’s why they found it not profitable. I do not know if there are other reasons as well. One should ask them (the industry).
You have been very vocal about the imminent health crisis that can manifest if there are no new antibiotics developed against multi-drug resistant bugs quickly. Do you think governments and not-for-profit organisations should step in?
I don’t think governments can get into the business of product development and production, though it can facilitate and support research. It is the industry that should take them up. But, as you rightly said, one thing is sure that the crisis of drug resistant bacteria is going to be big in the world if there are no new antibiotics that enter the market soon.
After your path-breaking work on identifying the ribosome structure and crystallising them, are there more research or progressive work on the same happening to take it forward?
Not on the same, but yes, there are many good works happening around. The researchers are thinking in different ways and are exploring new mechanisms to target the ribosome, among others and also to find out different factors that cause natural mutation within the bacteria that gives them resistance. There aren’t anything in the same way, which I know; though we don›t think ours was the best. We are also exploring further.
Multi-drug resistant tuberculosis is a very serious medical challenge in India and also in many other Asian countries. How do we explain the resistance mechanism in tuberculosis, where drugs are not targeting ribosomes?
There are also some tuberculosis drugs targeting ribosomes of late. But, most of the existing drugs target cell walls, cell cycles and checkpoint controls and other pathways. Although we have not focused on tuberculosis as such so far, I think there is scope for exploring new antibiotics for treating drug-resistant tuberculosis, targeting ribosomes.
How do bugs continue to develop resistance to more and more antibiotics?
It is part of the natural survival [mechanism] of organisms. As I said before, there are natural mutations that take place within the living organisms as a process of getting adapted to their living environment and there is constant fight that takes place between one and the other for survival.
Do you think Indian scientists could have achieved more had the government been more supportive and encouraging in research and development here?
I don’t know about the support system in India. So, I can’t comment on that. But I can say that Indian scientists have been doing well in many areas. There is good science done in India, which may not be in antibiotics or new drug development. But it is cleverer in many other areas. Also, there are good Indian scientists outside the country who are brilliant and much more capable than others.
The problem that I really see now everywhere is a lack of support for basic science. Original discoveries should be encouraged by governments and other systems. Basic science that tries to understand what is not understood so far brings real changes in the society and that should be the focus of research.
I know that your best advice to young and aspiring scientists is not to seek advice. Could you elaborate on this?
Because everybody has to develop the way they are. Let the young minds grow with what he or she is really passionate about. It is the self-curiosity that leads one to discover new things and that is the kind of research that the world is looking for and will help it progress. Taking advice is like copying someone else, and it will not work the same way for the other or result in anything new.
Prof Ada E Yonath
Nobel Laureate Prof. Ada E Yonath shared the world’s most coveted prize in chemistry with Dr Thomas Steitz and Prof. Venkataraman Ramakrishnan in 2009. Her pioneering work on ribosomal crystallography helped in the precise identification of the structure and functions of ribosomes and it opened up immense possibilities of targeting ribosomes for developing new antibiotics. The first Israeli woman to win a Nobel Prize, Prof Yonath accepted her postdoctoral positions at Carnegie Mellon University in 1969 and MIT in 1970. She was also group leader with Heinz-Gunter Wittmann at the Max-Planck Institute for Molecular Genetics in Berlin. She was the visiting professor at the University of Chicago in 1977-78 and then headed one of the Max-Planck Institute’s research unit at DESY in Hamburg, Germany in parallel to her research activities at the Weizmann Institute.\
Yonath focuses on the mechanisms underlying protein biosynthesis by ribosomal crystallography, a research line she pioneered over twenty years ago despite considerable skepticism on the part of the international scientific community. Ribosomes translate RNA into protein, and because they have slightly different structures in microbes when compared to eukaryotes such as human cells, they are often a target for antibiotics. In 2000 and 2001, she determined the complete high-resolution structures of both ribosomal subunits and discovered within the otherwise asymmetric ribosome, the universal symmetrical region that provides the framework and navigates the process of polypeptide polymerisation. Consequently, she showed that the ribosome is a ribozyme that places its substrates in stereochemistry suitable for peptide bond formation and for substrate-mediated catalysis. In 1993, she visualised the path taken by the nascent proteins, namely the ribosomal tunnel, and recently revealed the dynamic elements enabling its involvement in elongation arrest, gating, intra-cellular regulation and nascent chain trafficking into their folding space.
Additionally, Yonath elucidated the modes of action of over twenty different antibiotics targeting the ribosome, illuminated mechanisms of drug resistance and synergism, deciphered the structural basis for antibiotic selectivity and showed how it plays a key role in clinical usefulness and therapeutic effectiveness, thus paving the way for structure-based drug design.
For enabling ribosomal crystallography, Yonath introduced a novel technique— cryo bio-crystallography, which became routine in structural biology and allowed intricate projects otherwise considered formidable.
At the Weizmann Institute, Yonath is the incumbent of the Martin S. and Helen Kimmel Professorial Chair. She is also a member of the United States National Academy of Sciences, the American Academy of Arts and Sciences, the Israel Academy of Sciences and Humanities, the European Molecular Organisation and the European Academy of Sciences and Art. In 2014, Prof. Yonath was named a member of the Pontifical Academy of Sciences by Pope Francis. Her other awards and honours include the Israel Prize (2002), Harvey Prize (2002), Massry Prize (2004), Paul Karrer Gold Medal (2004), Horvitz Prize (2005), Wolf Prize in Chemistry (2006), Rothschild Prize in Life Sciences (2006), The EMET Prize for Art, Science and Culture in life sciences (2006), Paul Ehrlich and Ludwig Darmstaeder Prize (2007), Albert Einstein World Award of Science (2008), Wilhelm Exner Medal (2010) and Honorary Doctorates from several universities.