Doing Science In Kashmir

The lack of infrastructure was the key brain drain factor as researchers would choose better global institutions for doing science. Under an impressive plan to ensure ‘brain gain’, the central government started funding the best researchers with brilliant ideas to return home and this led to the establishment of the Centre for Interdisciplinary Research and Innovations (CIRI) at the University of Kashmir as one of Kashmir’s top two new institutions for science, reports Masood Hussain

Some members of the faculty at the Centre for Interdisciplinary Research and Innovation (CIRI) at the University of Kashmir. KL Image: Bilal Bahadur

It has been a rollercoaster ride for Dr Altaf Bhat. Born in remote Panchpora hamlet in South Kashmir, Bhat studied till his masters in the state-run educational infrastructure where English would mark an entry in sixth class. His life was full of surprises after he moved out as a young biochemist for his PhD in Canada.

Interested in the genetic interplay in the human body, Bhat was always passionate to understand how Epigenetic controls human physiology. Epigenetics is a comparatively newer science that attempts to seek answers to how individual behaviours or the surrounding ecosystem triggers changes that affect the way genes work. The whole idea is how to ensure reversibility, which is possible in such cases, unlike genetic changes dictated by inheritance.

DNA, explains Bhat, does suffer damage owing to a varied set of factors, both endogenous and exogenous. “If quick repairing does not take place, the damaged DNA gets transferred to the daughter cells thus impacting the whole biological process and eventually leading to different diseases,” Bhat said. “There are certain proteins which have the capacity to repair this damage. During my study, I located a set of events which are necessary for the recruitment of these proteins to the repair sites and once the damage is repaired then these factors need to be released.”

In sciences, a PhD is invariably seen as high-end sophisticated training. Real science actually takes off from the post-doctorate level, though there are countless cases in which the bright minds had more high-impact papers to their credit even at the PhD level.

From Canada, Bhat took off for a post-doc at Harvard University in Boston where he spent four years in research. Not moving away from his core focus, Bhat started hunting for answers to an enigma about how and why a certain genome is localized at the periphery while some part of it is present within the nucleus. “We already know that DNA is not present in the cells randomly and follows a definite shape and a particular configuration, which is key to its functioning,” Bhat said. “I studied the mechanism that positions DNA at various parts of the cell and if it is interrupted, how it affects the functioning of different types of cells present in various organs.”

In CIRI

Bhat’s research was in continuation of an intense genetic debate about how cells at their own level retain their identity and autonomy to a level while being part of a larger mechanism where the brain is the ultimate decision-maker.

By 2013, Bhat was back home, now as an Assistant Professor. Since 2019, he is the Coordinator of the newly established Centre for Interdisciplinary Research and Innovations (CIRI) at the University of Kashmir, which is expected to be one of the two new addresses for the high-end cutting-edge science in Kashmir.

The CIRI is the outcome of the Government of India’s major policy intervention on how to ensure brain gain. For the last more than six decades, the better minds would seek spaces in the developing world, apparently because of better infrastructure, advanced research climate and better earnings. The government of India constituted two major fellowships – the Ramanujan Fellowship (piloted by the Science and Engineering Research Board) and the Ramalingaswami Fellowship (Department of Biotechnology) for bright scientists keen to return home as long as they have the best ideas to work on. They are provided with enough funds to pursue their research and after five years, they are adjusted as faculty. Since 2006, when the Ramalingaswami Fellowship was launched, more than 550 biotechnologists have returned home to lay the foundation of a robust biotechnology destination in India.

In the last three years, CIRI has got six scientists under the twin fellowships. They have worked in the best research institutions in the world and are now keen to encourage research. “CIRI serves two things – to develop a rich interdisciplinary research ecosystem in the University of Kashmir, 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 the state-of-the-art technology to do quality scientific research,” Dr Bhat explained. “In the last two years, we have succeeded in securing Rs 40 crore from different funding agencies to address various biomedical problems prevalent in the region and also to develop scientific infrastructure in the institute.”

CIRI is expected to be a major centre in the coming days, Bhat said within a year or so CIRI will be at par with the Harvard or Massachusetts Institute of Technology (MIT) as far as infrastructure goes. This year, CIRI is taking around 10 PhD students. “The university aims to bring around 25 Ramanujan, Ramalingaswami fellows in a year or two so that it gives a push to the interdisciplinary approach,” added Bhat.

Strong Foundations

Setting up of CIRI, however, does not necessarily mean that science was not being done in the University of Kashmir. The departments of biotechnology, biochemistry, and pharmacy are dominating the overall Kashmir science pool as most of the scientists have had their basic education in this chain of departments. While the focus remained on fundamental studies, the research, off late, has taken off.

Mohammad Ashraf Dar was one of the biochemists that the department educated. Hailing from Chanpora in Bejbehara, Ashraf was always fascinated by the proteins as the building blocks, information codes and the workhorses of the cell. Post-masters, he moved to JNU and did his research on plasmodium, the malaria-causing pathogen. “During my research, I discovered a unique protein in the parasite, called DNA gyrase that, we understood, is basically controlling the DNA replication process of the pathogen,” Dr Ashraf said. “Later, we even identified the drug – Acriflavine, that inhibits this Malaria specific gyrase and this discovered led us to a global patent.”

After PhD, Dr Ashraf moved to the prestigious Mayo Clinic’s Biochemistry Department at Rochester. There, he pursued research on understanding chromatin biology. For the next four years in 2011, he joined the University of Virginia as a research associate scientist. “There, I discovered USP46 (ubiquitin-specific protease 46) as a potential drug target in cervical cancer. I elucidated out the molecular mechanism by which human papillomavirus hijacks host’s own protein (USP46) to promote cervical cancer,” Dr Ashraf said. “Synthesising drug molecule against USP46 will open up therapeutic regime against this cancer and will set an alternative route to the much lethal radiation therapy.”

By then, he had enough expertise and exposure to apply for the Ramalingaswami Fellowship, which he got in the first go. Now his laboratory is working on different aspects of ubiquitin, a regulatory protein found in nearly all eukaryotic organisms and is virtually identical across all forms of life – human, yeast, and plant. “We are working on this ubiquitin molecule in different contexts and its relevance to various issues including DNA damage, apoptosis, autophagy and cancer.”

Interesting Struggles

Every one of the scientists who has come with a grant to CIRI has an interesting story of individual struggle and success to his credit. They all have struggled in their lives and now wish to establish the centre as the nucleus of doing science at the University of Kashmir.

Dr Aijaz H Wani is one of them. Hailing from Dakhum, the picnic spot and the last Kashmir village on the road to Kishtwar, Aijaz studied in local state-run schools and did his master’s in biochemistry from the University of Kashmir. For PhD, he joined the National Centre for Biological Sciences at the TATA Institute of Fundamental Research in Bangaluru.

“I opted for Protein Biophysics and wanted to understand why the proteins have essentially to retain a 3D structure to stay relevant and active,” Aijaz said, talking about his PhD. “I found the proteins to be highly dynamic but wanted to understand the factors that determine its 3D shapes and how they are relevant to its functioning.” Using mass spectroscopy, many new things were revealed to Aijaz during the research. He found that sometimes proteins aggregate in situations other than phase segregation, and trigger a degenerative disease like Parkinson’s disease.

When Aijaz moved to Harvard for a post-doctorate, he opted for a ‘quantum jump’ and decided to get into genetics. He had, like many other scientists in different laboratories, one question to seek an answer to: “How does a cell structure barely a few microns size manage to accommodate the DNA that is even two million times longer than it?” Then there were related issues about if the peculiar packaging is disturbed in the cell, and how it exhibits its impact on the human body.

“Using very high-end technology, we could see that proteins play a key role in this packaging and any disruption in it manifests in skeletal deformities,” Aijaz said. “We were working on it when some Japanese scientists came with much clearer answers that it impacts rib cage and many other things.”

The genome eventually fascinated Aijaz so much that he wrote a project that Welcome Trust (UK) and DBT approved and gave him a grant of Rs 3.5 crore for further studies on the same subject in 2017.

“My team of researchers are addressing the same question, the packaging but we are trying to identify other proteins that contribute to this,” Aijaz said. “We have some very good leads and we are working on some molecules and soon we will be out with what we have found.” They are also looking at how certain diseases are linked with the disturbance in the DNA packaging of the cell.

Though it is already known that defective packaging can be inherited and that the genome is not perpetually insulated from the environment it exists within, Aijaz’s team is also trying to see how genome mutations are linked to food habits and other factors that an eco-system offers.

Understanding Genome

At CIRI, there is one scientist who has worked on proteins alone for his entire research career. It is believed that the human body has a set of almost 100 thousand proteins but science knows nothing beyond 20,000. So every laboratory across the globe is in the race to understand the proteins better as these are the workhorses and the building blocks of life. Dr Javaid Yousuf is one of them.

Hailing from Dialgam belt of South Kashmir, Javaid Yousuf studied biotechnology at the University of Jammu and then moved to Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangaluru for his PhD where he worked on Malaria with a focus on finding the similarities and dissimilarities between a particular enzyme that exists in the human body and the Malaria creating Plasmodium. That research project, Yousuf said is still going on in that laboratory and now has reached the drug discovery stage.

His major exposure to advanced science was in the seven years he spent at Max Planck Institute of Biochemistry, Munich, in Germany where he focused on protein chemistry. “The most abundant protein in nature is Rubisco, which forms almost 70 per cent of the total protein in plants, but we did not know how it can be made outside the plants for biotechnological applications,” Yousuf said. “My small contribution was in finding that there are a number of proteins that help in its making and we eventually successfully demonstrated in E. coli the pathway needed for its generation and proper function.”

Besides, he worked on chaperone proteins, which are fundamental to conformational folding or unfolding or modulation of large proteins or macromolecular protein complexes. “These are like go-betweens; they help different protein molecules to get closer to each other and once this task is over, they move out and go for another task,” Dr Yousuf said.

Well trained in mass spectrometry and other protein analysis techniques, Yousuf moved to King Abdullah Research Institute in Riyadh but returned home within a year, as his proposal was accepted by the DBT, India. At CIRI, his team is still working on the chaperons as it is now fully established that these sub-super microscopic king-makers turn into a disaster if even one of the amino acids within them changes. At the same time, his team is studying the immunity and defence response about and around chaperons to diseases in rice with the hope that if they are able to understand the mechanism, it might help manage diseases in various commercial crops.

The Parkinsons Disease

CIRI has a full-fledged team working on the different facts of Parkinson’s disease (PD) by Dr Rafeeq A Mir, another south Kashmir biochemist scientist who has been working on it for more than a decade now. “We do not have clear data available about the incidence of the disease in Jammu and Kashmir but a broad estimation is that in every one lakh population that has crossed the age of 60 years, we must have 250 patients,” Dr Mir said. “The massive use of pesticides must be adding to this number gradually but there is no clear data.” Dr Mir said that the science has already established that PD is genetic in nature in merely ten per cent of the case and in the remaining cases DNA mutations take place because of external factors and pesticide use could be a major contributor. It is, after all, an age-associated brain disorder affecting the function of the nervous system causing uncontrollable movements, shaking etc.

Mir has been working on issues related to PD for a long time now. “In my post-doctorate, I have discovered a breakthrough where we have shown two factors (proteins) work in concert and are crucial for Parkinson’s Disease development,” Dr Mir revealed about his post-doctoral work at Mir later moved to the UK for his post-doctorate at Medical Council UK.

His PhD, at the Indian Institute of Science Education and Research (IISER) Pune, however, was around colorectal cancer, which is caused when cells in the intestine lining or rectum grow abnormally. “In my PhD, I have discovered that SATB1 important molecule required for packaging of DNA inside cells is crucial for colorectal cancer development by promoting cell growth and spreading of cancer cells,” Dr Mir said.

Back home his team is understanding mechanisms underlying PD, especially identifying novel molecular players and epigenetic modulators to locate signalling nexus that may be key in developing the disease. “We employ various biochemical and molecular tools along with in vivo systems to address these questions,” he said.

Molecular Genetics

Interacting with the CIRI scientists gives an impression as if every scientist is working on genetics. Though it is a fact, the larger reality, however, is that everybody has his sub-domain. The 2-meter DNA is so complicated a structure that even after managing to sequence it, science barely knows only a bit of it.

“At one point in time, we were told that the transcription initiation is the most important step in gene expression and once it takes place there is no regulation over the process,” Dr Abdul Wajid Bhat, another biochemist at CIRI said. “But now it is established that the transcription elongation is also very critical because if the chromatin does not restore itself to the original status after the process, the cell is doomed.”

Bhat, a scientist from Dadsara in Tral, did his master’s from the University of Kashmir and moved to the Indian instate of Science Bangalore as a scholar in Molecular Biophysics. He did his PhD from Laval University Quebec in Canada and flew home after his post-doctorate there. In his PhD, he determined a new function of a protein that helps in the process of gene transcription and restoration of chromatin structure, a subject he studied further in his post-doctorate.

“It is a very complicated process and we attempted to identify the factors that play a role in helping chromatin to restore to its original position after the information is expressed /transcribed,” Dr Bhat said. “The bigger mystery in the entire process is how the chromatin retains its integrity after its information is decoded.” The subject, he said, is being investigated by almost every major laboratory across the globe because it is the new thing in genetics.

“My team of researchers is working on the same subject – how genes express, how they decode, what are the complications of the process and which factors help chromatin retain its integrity,” he said. “A defect in this process has dramatic consequences for cellular functions and underlies many diseases.” His laboratory is using budding yeast to study how chromatin organization is established, propagated, maintained, and changed during various cellular processes.

 Chemistry Laboratory

The centre has an impressive infrastructure and within a year it is expecting some of the best machines it requires for research. However, it still is in its infancy. Though biology dominates the scene, scientists have started coming from diverse fields to join for research. Chemist Gulzar Ahmad Bhat is the youngest scientist from Kurhama Ganderbal who joined CIRI after his post-doctorate from Texas.

“I was the first to stabilize monoalkyl phosphates, and consequently produced them in multi-gram quantities. Using these alkyl phosphate ligands later a new family of single crystalline inorganic lamellar copper alkyl phosphates were synthesized to demonstrate how a crystal containing as many as 500 layers can be exfoliated to a single layer nanosheet via a facile and rapid solvent-assisted methodology,” Dr Gulzar said, about his PhD at IIT Mumbai. “Then, I studied the kinetics of exfoliation, which eventually revealed that with an increase in sonication time the thickness of nano-sheets can be reduced. Thus, when sonicated for 40 minutes a true single nanosheet of the thickness of 1.2 nm can be obtained, which matches with the thickness of a single nanosheet, as calculated from single crystal X-ray diffraction data.”

During his post-doc at Texas’s A&M University in the USA, Gulzar worked in the area of utilizing CO2 for making biodegradable plastics in a sustainable manner and developed a strong understanding and training in this new applied field of research. Back home, he is establishing the Inorganic and Polymer Chemistry Lab at CIRI, which eventually will address the capture and utilization of CO2 as a C1 feedstock for making biodegradable polycarbonate polymers in a sustainable manner.

A Future Address

“We hope that more scientists will join in the coming days, “Coordinator, Dr Altaf said. “In a few years’ time, the young scientists will prefer working back home as we will be having the state-of-the-art facility here”.

However, the real profile of CIRI will start building with the distinct papers that will be published by high-impact journals across the globe. Aijaz said that the outcome of the ongoing research will be visible in a year or so as research is going on uninterrupted.

Some members of the faculty of the Centre for Interdisciplinary Research and Innovation (CIRI) at the University of Kashmir with the first batch of research scholars in the 2022 summer. KL Image: Bilal Bahadur

At the same time, the centre is identifying the local issues that it wishes to address. Dr Altaf said the prevalence of the non-alcoholic fatty liver disease is a major challenge within and outside Kashmir. “The biology of non-alcoholic fatty liver disease has not been understood by the scientists yet,” Dr Bhat said, revealing that his laboratory is trying to understand how epigenetic processes get misregulated or how they contribute to it. “We have identified an epigenetic factor which plays a very important role. We have done our experiment with different cell types. In our next phase, we are trying to test this hypothesis in animal models (mice) where we can induce non-alcoholic fatty liver disease and then test whether we can use the identified molecule as a therapeutic target to control it.”

The other major researcher in Dr Bhat’s laboratory is to understand the biology of Gastrointestinal (GI) cancers in Kashmir.  “While the incidence of GI cancer globally is around 20-25 per cent, it is around 50 per cent in Kashmir.”

(Humaira Nabi contributes to the report)

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