‘Each Cell has Its Own Autonomy, but It gets Disrupted If Other Processes Fail’

After spending many years searching for plausible explanations for the make and break within DNA, Dr Altaf Bhat, the Coordinator at the Centre for Interdisciplinary Research and Innovations (CIRI) at the University of Kashmir, has his own laboratory where he is trying to find answers for many questions. One question is why the incidence of GI cancers in Kashmir is almost double in comparison to any other place on earth. Read excerpts from Dr Bhat’s interview with Humaira Nabi

KASHMIR LIFE (KL): What are the major goalposts of genetic studies?

DR ALTAF BHAT (DAB): The major goal posts of genetic studies would be to understand how DNA regulates different cellular processes, how the genome regulates cellular identity and how we can use genomic knowledge to address various diseases that are prevalent in the world and also to develop better therapeutic strategies. So in terms of future aspects, I think the aim is to develop personalized medicines based on genomic knowledge and also how genomic variations make an individual susceptible to diseases and how he responds to medicines. This is because every individual would respond to diseases and treatment differently because the genetic make-up is different.

KL: Brief us on your educational process.

DAB: I was born in Punchpora village in Bijbehara (Anantnag). I did my schooling from there and completed my graduation from Government Degree College, Anantnag. Then, I joined the University of Kashmir and completed my Masters in Biochemistry. I moved to Canada where I completed my PhD. In PhD, the main focus of my research was to understand how Epigenetics controls our Physiology. Later, I moved to Harvard University in Boston where I did my post-doctorate. I was there for almost four years and then in 2013, I joined the University of Kashmir as an Assistant Professor. Since 2019, I am heading the newly established Centre for Interdisciplinary Research and Innovations (CIRI) at the University of Kashmir.

KL: What were the major takeaways of your PhD?

DAB: I will not go into the technical details but broadly what we were trying to understand was how DNA repair occurs and how the ends of our chromosomes are protected. DNA gets damaged regularly in the cell by endogenous as well as exogenous agents like UV, and chemicals. Repair of damaged DNA is crucial for the cell and failure to do so will result in the transfer of damaged DNA to the daughter cells which would eventually lead to various diseases. There are set of proteins which are essential to repair this damage.

Since DNA is huge and tightly packaged in the cell, these proteins need to precisely find where the damage is and land there to repair it. I have discovered the signalling cascade that helps these repair proteins to recognise the break in DNA and once the DNA is repaired they are released from the break sites to function elsewhere in the genome. I have also discovered the mechanism of how the ends of our chromosomes are protected and what the proteins necessary for the stability of chromosome ends are.

Dr Altaf Bhat, the Coordinator of the Centre for Interdisciplinary Research and Innovation (CIRI) at the University of Kashmir. KL Image: Bilal Bahadur

KL: Since human bodies carry millions of genes, how is it possible for the repair proteins to take care of a large amount of DNA present in the cell?

DAB: The repair proteins are not retained at the break site indefinitely. They get recruited to the damaged site, repair it and then leave. All these processes are highly regulated and if something goes wrong in this process that would be detrimental to the cell.

KL: Are there methods to induce breaks at specific sites in the genome?

DAB: There are ways to induce breaks in the DNA and study how the repair process works. In small eukaryotes, we use engineered endonucleases which can be cut only at a specific site so we can precisely study the dynamics of the repair process. More recently CRISPR-Cas9 has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other genome editing methods.

KL: Tell us about your postdoctoral research.

DAB: My research focus has been on how epigenetics controls different biological processes. However, during my postdoctoral research at Harvard University, I was trying to understand how and why certain regions of the genome are localised and organised differently within the cell. DNA is not distributed randomly in the cell. It has a definite shape and a particular configuration. That configuration is important for its functioning. During my postdoctoral research, I discovered proteins and epigenetic processes that regulate the positioning of the genome and if we alter the genome configuration, how it affects the function of the cell. This has larger significance because the configuration of the genome in the cell also decides the cellular identity.

KL: Does this mean that the cells are self-regulating? If yes then does it challenge the cephalo-centric life POV?

DAB: It is an established fact that the brain is the centre of the human body. Most of our impulses, and thought processes come from the brain. The architect of the brain is such that it controls each and every organ of the body. At the same time, every cell has its identity and hence works in its own way. But in our body, nothing works in isolation. There is close coordination between different organs and processes. Even though each cell has its own autonomy, but that autonomy will get disrupted if other processes get failed.

KL: Since you completed your post-doctorate, what have you been working on?

DAB: At the University of Kashmir the focus of my laboratory is how epigenetics regulates our genes and how it contributes to various diseases like cancer, diabetes, neurodegenerative diseases and non-alcoholic fatty liver disease (NAFLD).

NAFLD is a global health problem and is one of the most important causes of liver-related mortalities and will probably emerge as the leading cause of end-stage liver disease in the next decade, placing a significant burden on the healthcare system worldwide. Despite being a very common disease, the biology of non-alcoholic fatty liver disease is still not well understood. So one of the focus areas is to understand how epigenetic processes contribute to the pathogenesis of non-alcoholic fatty liver disease  We have discovered an epigenetic factor which plays a very important role in non-alcoholic fatty liver disease. This epigenetic player could emerge as a potential therapeutic target in non-alcoholic fatty liver disease. We will test this discovery in animal models (mice) where we can induce non-alcoholic fatty liver disease and then see whether we can use the identified molecule as a therapeutic target to control the non-alcoholic fatty liver disease.

The other major research area in the laboratory is to understand the biology of Gastrointestinal (GI) cancers in Kashmir.  While the incidence of gastrointestinal cancers in India or around the world is 20-25 per cent,  in Kashmir it is around 50 per cent.  We are trying to find out the reasons, and molecular perturbations for the high prevalence of GI cancers in Kashmir. We are trying to find answers to a set of questions. Are we genetically predisposed? Is it in our genes that makes us more prone to these diseases? Do the epigenetic processes get wrong in our population? These are the questions we are currently addressing.

KL: Why is the interdisciplinary approach the new in-thing in research?

 DAB:  Science for the future can only develop when we adopt an interdisciplinary paradigm of learning. If I, for example, come across a problem, I will always look at it from a biologist’s perspective. I will never look at it from a physicist, chemist or computational biologist’s perspective. Modern science is driven by an interdisciplinary approach which is characterized as a perspective that integrates two or more disciplines into coherent connections thus enabling to make relevant connections and generating meaningful associations. If you have a computational biologist, a physical therapist, and a biologist if they sit together they will have a much broader, comprehensive and holistic approach to addressing a problem. Therefore, to develop impactful science culture, an interdisciplinary approach is very important.

KL: How is the Centre for Interdisciplinary Research & Innovations (CIRI) working on the interdisciplinary approach?

DAB: To uplift the research and academia across the country, the Department of Science and Technology and Department of Biotechnology, the Government of India launched the Ramanujan and Ramalingaswami Fellowships to bring back brilliant Indian scientists and engineers from abroad to take up scientific research positions in Indian universities and research institutions. These fellowships are very selective and are awarded to outstanding scientists by national-level selection committees comprising eminent scientists of the country. The awardees as per DST and DBT guidelines are equivalent to Assistant Professor or Scientist-D level and can supervise PhD students.

To benefit from this national brain-gain initiative, the University of Kashmir established, in 2019, the Centre for Interdisciplinary Research and Innovations (CIRI) housing these fellows with an objective to promote interdisciplinary research and education in line with National Education Policy 2020. It is an initiative to convert brain drain into brain gain and develop the University of Kashmir into a hub of scientific discoveries and innovations.CIRI is serving two purposes: to develop a rich interdisciplinary research ecosystem in the university, to address scientific problems through a multidisciplinary or interdisciplinary approach and also to develop world-class scientific infrastructure so that our young scientists have an access to state-of-the-art research facilities to do quality and impactful scientific research. Over the years several Ramanujan and Ramalingaswami scientists from reputed institutions like Harvard University USA, Max Planck Institute Germany, University of Virginia USA, MRC UK, Laval University Canada and the University of Texas USA are working at CIRI. These young scientists have already made their impact and immensely contributed to the overall upliftment of the university’s research and academic landscape.

KL: How many PhDs should we expect to come out from CIRI in the coming years?

DAB: This year, we have started an interdisciplinary PhD programme and to begin with we are taking around 10 students. In the coming years, we expect to have around 50 PhD students across various disciplines. The good thing about CIRI is that there are no disciplinary boundaries; any science student can apply here for a PhD.

KL: Does CIRI provide scholarships to deserving candidates?

 DAB: There are a number of scholarships provided to research scholars, by the Government of India like CSIR, UGC, ICMR, and JRF. We do provide scholarships to PhD students from our grants. Besides, the University of Kashmir also provides scholarships to the PhD students. With many funding opportunities these days, students can write small research grants which they get fellowships for and also money for research. We encourage our students at CIRI to apply for these grants and help them to develop good and competitive research grant proposals.

KL: How do young scientists rule out redundancy while choosing a topic for their scientific research?

DAB: In science, you do not know who is working on what problem but the originality of your question is very important. While framing a research question one must focus on two things: the question that needs to be answered and the significance of the question. The question could be having local, national or international dimensions. To frame a relevant question, one must read a lot.  Once you have a good understanding of the literature then only you will know about the gaps that need to be addressed.

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