Musings of a woman bioscientist: Interview with Dr Shilpee Dutt

Dr Shilpee Dutt, winner of this year’s Janaki Ammal – National Woman Bioscientist Award for the young category, is a Principal Investigator at Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Mumbai. In this interview, she briefly discusses the research by Shilpee Lab and her journey so far. 

The National Women Bioscientist Award is conferred by the Department of Biotechnology, Government of India, in recognition of the contribution of women scientists in the country who are working in biology and biotechnology. The young category award is given to women scientists below 45 years of age who have contributed significantly towards unravelling challenges in various areas of biosciences and biotechnology.

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Dr Shilpee Dutt and her lab at ACTREC, Mumbai

1. How do you feel winning the Janaki Ammal – National Woman Bioscientist award?

I feel really happy that our research at ACTREC, Navi Mumbai, has been recognized at a national level. It is a teamwork and I am privileged to have students who have made this work possible. This achievement gives a lot of confidence and boost to strive for better.

2. Could you please explain your research?

Resistance to therapy is a longstanding problem in cancer therapeutics and is the major cause of cancer-related deaths. In our lab, we are trying to understand the molecular basis of therapy resistance in cancer with a focus on Glioblastoma (Brain tumours) and Leukemia (Blood cancer). Over the last 8 years, using genetic, molecular biology, biochemical approaches and mouse-xenograft models combined with studies in human patient samples, we have identified that tumour cells are very heterogeneous. We have shown that more than 95% of tumour cells die upon radiation and chemotherapy, but a small set of cells that we call ‘residual resistant’ cells survive and give rise to relapse tumour. We have also identified certain molecules that are responsible for the survival of residual cells thus providing critical information necessary for therapeutic interventions in Glioblastoma and Leukemia.

3. When was the first time you got interested in science?

Although I was always interested in science, it was my research experience at Dr Subrata Sinha’s lab (AIIMS, Delhi) for my M.Sc dissertation that I first realized research was so interesting and something I would want to pursue for the rest of my life.

4. What were the challenges you faced growing up as a girl interested in pursuing science?

There were no challenges growing up as a girl interested in pursuing science. My parents always encouraged me to do what I wanted to do. In fact, I was given a lot of freedom to think on my own and make my own decisions. The way I was brought up has moulded my personality into how it is today.

5. What was the happiest moment in your career so far?

I think the happiest moment was when I started my own lab at ACTREC. This provided me with the opportunity to ask and answer the scientific questions that I was interested in. Setting up your own lab has a lot of challenges and is quite an experience, but I must say I enjoyed every bit of it. I think there cannot be anything better than having your own lab.

6. What was the toughest or saddest moment in your career?

As a researcher, there are always moments when one feels disappointed with the experiments not working, but these are short-lived and they actually provide you with a challenge to start over again, learn from the mistakes and do better.

7. What were the struggles you faced as a woman in science?

Fortunately, I have not faced any gender bias in my scientific career. However, I know everyone is not as privileged. We know that there are fewer women in leadership positions in science as compared to men. It is important that female scientists are promoted to leadership positions. That would provide role models for young researchers and inspire them to take the same path. Providing support systems like campus child-care facilities would help women scientists to balance work and family.

8. Did you find yourself at an advantage anytime being a woman in science?

Not really

9. What is your favourite thing to do when not in the lab?

Reading (fiction), listening to music and watching movies

10. Any advice for those aspiring to pursue a career in scientific research?

Having a research experience like summer training/internship before you apply for a PhD program would help you realize how much you love doing research. Research could be slow and demanding at times, so unless you are passionate about your science you can easily give up. I would suggest pursuing scientific research only if you enjoy both the ups and downs of it.

 

Musings of a woman bioscientist: Interview with Dr Kavita Babu

Dr Kavita Babu, winner of this year’s Janaki Ammal – National Woman Bioscientist Award for the young category, is an Associate Professor at Centre for Neuroscience, Indian Institute of Science (IISc), Bengaluru. Before joining IISc, she worked at the Indian Institute of Science Education and Research (IISER), Mohali. In this interview, she briefly discusses the research by Babu Lab, her journey so far and the principles that drive her. 

The National Women Bioscientist Award is conferred by the Department of Biotechnology, Government of India, in recognition of the contribution of women scientists in the country who are working in biology and biotechnology. The young category award is given to women scientists below 45 years of age who have contributed significantly towards unravelling challenges in various areas of biosciences and biotechnology.

                  Kavita Babu     Babu lab IISER

                                    Dr Kavita Babu and her lab at IISER Mohali

1. How do you feel winning the Janaki Ammal  National Woman Bioscientist award?

It feels good to get an appreciation for our science. The Janaki Ammal – National Woman Bioscientist award was possible because of the work performed by our lab members: postdoctoral fellows, graduate students and undergraduates at IISER Mohali where I set up my lab and spent more than seven and a half years. I have now started setting up my lab at the Centre for Neuroscience, IISc where I have spent the last six months and am currently on lien from IISER Mohali.

2. Could you please explain the research that led you to win this award?

Normal movement occurs when neurons from our brain can “talk” to muscles in our body. The interaction between neurons and muscles occurs at sites called neuromuscular junctions. These regions are sites where the neuron sends a chemical (neurotransmitter) that binds to a class of proteins present on the muscle (called receptors). The activation of these receptors by the neurotransmitters causes contraction or relaxation of muscles and hence movement. We study how surface proteins at the neuromuscular junction affect their functioning. Our work uses a simple non-hazardous worm (C. elegans) to study these proteins. Although we study a small worm, the proteins in these animals are similar to those found in you or me.

Research in our lab has identified proteins that are required for normal neurotransmitter release as well as receptor maintenance. These proteins although found in worms, have counterparts in humans that may be functioning in a similar manner.

3. When did you first decide to become a scientist?

I think I had decided during my undergraduate years that I would become a scientist. During my undergraduate education, I did summer internships at laboratories in TIFR, Bombay and IISc, Bangalore. Those summers convinced me that working in a lab was something I wanted to pursue.

4. What was the best moment of your career so far?

Being able to grow worms for multiple weeks and starting to perform experiments with them was a great moment. It had taken a long time for me to set up a worm lab and it was a great feeling to know that we would soon be able to start performing our experiments in full swing. I am also hoping that this moment will happen fairly soon here at the centre for Neuroscience, IISc where I am currently setting up my lab.

5. What was the greatest struggle in your career so far?

I think struggles and good moments are part of everyday life for many careers. I try to avoid dwelling into past struggles as there are so many present ones that need my attention.

6. What were the struggles you faced as a woman in science?

I think many of the struggles one faces initially while setting up a lab are the same whether you are a man or a woman in science. I try and deal with them by being very organized and fairly prompt with getting things done and avoiding worrying too much about what I can’t change. Although I realise that there are inequalities between how men and women scientists may be treated, I feel that if there is nothing I can do about it, I should just get my work done and carry on instead of worrying too much about these inequalities. Having said that it is clear that there are very few women in professorial positions in most STEM subjects and one hopes that this will change soon. The way forward would be to advocate for more women scientists as this is something that may be more difficult for some women scientists to do for themselves. All things considered, I feel that I have been fortunate in my circumstances and education to be in my current position.

7. Was there any time you were in a privileged position as a woman in science?

I don’t think so.

8. What is your favourite thing to do when not in the lab?

Watching crime and food shows, reading and walking.

9. Any advice for those who wish to pursue a career in science?

Believe in yourself. Do a lot of research on whatever career you want to pursue, there are lots of small things that you won’t know unless you talk to people. Talk to lots and lots of people pursuing careers that you are interested in. However, in the end, make your own decisions on what to pursue based on your strengths, interests and understanding of what the career you want to pursue entails. It helps to go with something that you are passionate about, but there are pros and cons to most decisions, and it helps to think through those carefully while making your final decision. But again, I know a lot of people who have made decisions in an instant and are very happy with the outcome.

A viral conversation: Interview with Dr G Arun Kumar

Dr G. Arun Kumar, currently heading Manipal Institute of Virology (MIV) under Manipal Academy of Higher Education (MAHE), is a renowned Indian microbiologist and virologist. He also heads the Regional Reference Laboratory for Influenza viruses established by Ministry of Health and Family Welfare, Government of India at Manipal and the ICMR Virology Network Laboratory (Grade-1) at Manipal. He is the pioneering scientist, who established the virology facility in Manipal with the support of the University and the Government. His research interests include viral diseases, epidemiology and diagnostic virology and public health response during infectious disease outbreaks. He led the team that was instrumental in containing the first Nipah Virus outbreak in South India. He is an expert member of several national and international committees pertinent to public health. 

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Dr G. Arun Kumar at Manipal Institute of Virology

How did you come to join Manipal Academy of Higher Education and how was the virology facility set up there?

I came to Manipal in 1994 to pursue MSc in Medical Microbiology after my BSc in Medical Laboratory Technology from Trivandrum Medical College. It was within a year since Manipal had become a deemed university. As soon as I finished MSc, I received the CSIR-JRF fellowship and went to the All India Institute of Medical Sciences (AIIMS), Delhi, to pursue my PhD in Virology.

About six months into AIIMS, as I was preparing to register for PhD there, my Professor from Manipal, Dr P G Shivananda MD, PhD., wrote to me asking me to join them. It was a difficult decision to take as Manipal did not have a virology lab at that time. The risk-benefit analysis showed that it was risky to move to Manipal. But my professor was insistent and promised me to provide a small facility for virology. I also discussed these things with my guide Dr Pradeep Seth, MD at AIIMS, New Delhi, and he also suggested taking up Manipal’s offer. I then thought that moving to Manipal was a challenge I had to take up – to initiate something that would have a lasting impact not only on me but also on the institution.

So, I joined Manipal as a lecturer in Nov 1997. I wrote a proposal to Prof. M. S. Valliathan, the then Vice-Chancellor of MAHE, through my professor, Dr P G Shivananda, to establish a virology laboratory. After a year, INR 500,000 was granted to set up a virology facility. That is how the virology lab was set up in Manipal and I came to be associated with it.

How did this facility grow to be an internationally renowned institute?

In May 1999, we set up a small lab with viral serology, tissue culture and virus isolation facility and started working on some clinically relevant viruses. We started the work with Respiratory Syncytial Virus (RSV) as I had worked on it in AIIMS and was familiar with it. I also started my PhD on RSV and completed it in 2002. By then we were actively working on 4 to 5 viruses and were providing diagnostics for it. This was also the time when we started attending conferences and people started noticing our work.

In 2003, there was a huge outbreak of SARS in Hong Kong. Government of India started looking at developing the capacity to detect and fight this virus. A review committee emphasized the requirement for more virology labs in India. The government also wanted to prepare the country for Avian Influenza (bird flu) Virus. Fortunately for us, without our knowledge, our facility was identified as a potential lab to be supported to work on these programs.

In 2007, we got a letter from the Indian Council of Medical Research (ICMR) asking if we were willing to develop the lab to a state-level virus diagnostic and research laboratory (VRDL). Following an expert site visit and a detailed project proposal review in 2010, they sanctioned a grant of INR 5 crore for a period of five years.  Meanwhile National Centre for Diseases Control (NCDC), Delhi had included our lab under the network of regional influenza laboratories.  This enabled our facility to be notified as a reference laboratory for influenza A H1N1 when the pandemic influenza arrived in India in 2009. The ICMR- VRDL facility was established in March 2010. Subsequently, realizing the potential of the lab, MAHE elevated it as a University department – Manipal Centre for Viral Research (MCVR). Now I had to report directly to the Pro-Vice-Chancellor of the university. This removed many hurdles and facilitated a faster decision-making process. We also moved into a new building with the support of the university. In this way, we grew in close association with the State and Central Health Services in India in the area of disease surveillance

In 2013, we had another quantum leap when we received a foreign grant from the Centre for Disease Control (CDC), USA as part of the global health security agenda (GHSA). We were awarded a sum of USD 250,000 to study emerging pathogens in the human-animal interface. We started the study in Shimoga, Karnataka. It progressed well and we received an upgrade of the award in 2015 to carry out the study in ten states in India. With that our funding had increased and our capacity grew tremendously. This enabled us to become a centre for excellence in disease surveillance and outbreak investigations.

In this way, we grew with the support of the university and the Government of India. We received several grants from the government and the university provided us with the infrastructural support. Manipal provided enormous support, space and freedom to grow and implement some of the dreams I had. The support has continued and now we have been elevated as independent institute – Manipal Institute of Virology (MIV) – under the university with higher containment labs and facilities.

MCVR (now MIV) did an excellent job in checking the Nipah virus outbreak. How did you go about detecting this rare virus?

Since 2009, we have been working very closely with Kerala on the detection of Pandemic Influenza. Besides the Influenza virus, we would also run diagnostic tests for other viruses in many cases. Gradually, many doctors of Kerala gained confidence in our viral detection tests and we developed a close relationship with the doctors. Baby Memorial Hospital at Calicut was one of the hospitals we had been closely working with.

In May 2018, a patient with symptoms of Encephalitis came to Dr Anoop Kumar at Baby Memorial Hospital. His brother had died with a similar illness 12 days earlier and two others in his family were also sick. This cluster of brain fever in a family raised an alarm. There were two possibilities viz., (i) Serial Poisoning (ii) An infection. When Dr Anoop called me around lunchtime on May 17, 2018, and explained the case, I sensed that it was a serious case. I directed him to collect multiple clinical samples and asked him to send it across quickly by hand. In a usual case, the samples are collected through a nodal officer at the district and are sent as a batch by train either daily or on alternate days.

In our primary investigation of this sample, in addition to the test for common Encephalitis agents like Herpes Simplex Virus and Japanese Encephalitis Virus, we tested for Nipah Virus as well. In the usual case of Encephalitis from Kerala of Karnataka, we would never consider testing for Nipah in the first set. But we considered it because of our understanding of Nipah epidemiology and knew that Nipah presents as a family cluster of encephalitis. Nipah virus testing was not new for us. In our fever study program in Assam and Tripura, we had tested samples for Nipah in the border areas close to Bangladesh (Bangladesh has been reporting Nipah cases every year since 2001) but didn’t detect any. That is why we considered it in our primary investigation and it turned out that the patient was positive for Nipah. But since this was from a different region, we were sceptical. We wanted to be sure. So we tested for about 30 other agents and by evening we were sure that it was Nipah only.

How did you tackle the situation when you realized that you were dealing with this deadly virus? What were the measures you took to rise to this public health challenge?

By the evening of May 17, 2018, we knew that we were dealing with Nipah. But you cannot announce it right away as it would have implications on national and international mobility. We also had to be absolutely sure of the agent. But the information had to be conveyed quickly to contain the virus and avoid transmission.

So immediately we sent the samples to National Institute of Virology (NIV), Pune, for a reconfirmation. In the meantime, we alerted the central and the state government authorities about the virus without naming it and urged the hospitals to isolate people who had come in contact with the patient.

Kerala responded to this situation in a very positive way. The health department instructed the hospitals about isolation procedures and patient care. The healthcare workers were pro-active, and the public also responded well.

The Hon. Health Minister of Kerala Smt. KK Shailaja teacher asked me to join them on the field as very little was known about this outbreak and had to be investigated. When we got there, we realized that there were several undiagnosed deaths in the medical college that week. Fortunately, the samples were preserved for few cases at least and they turned out to be positive for Nipah.

But these cases had no obvious connection to the first patient or the family. This was frightening. By this time the public and the government were growing restless and wanted to know what was happening. If these cases were not linked to the first cluster, we would have to consider the case of a biothreat. But Nipah is a difficult agent and is usually not used as a bioweapon. We launched a thorough epidemiological and virological investigation and traced those who had come in contact with the initial patients, isolated them and put them under surveillance. The health department of Kerala had already started isolation procedures on the night on May 18.

We then went into a detailed investigation of the first case, twelve days before the reported death. The patient was hospitalized in the Taluk hospital for one day and in the Medical College Hospital for another day. The Taluk hospital had already been evacuated, but the staff recreated the scene of the original patient in the ward. He had cough, vomiting, and irritability. His father and brother had attended to him and there were some deaths from the same ward because of human to human transmission. Nine cases were thus linked to this hospital.

When we tried to trace the other cases, we found an intriguing association with the radiology corridor of the Calicut medical college. Investigations revealed that the index case when admitted to Calicut medical college was subjected to a CT scanning on 5 May and most of the cases had exposure to index case that day. The index case was moved around the CT scan room and in the corridor for about four hours since it was difficult to get his scan due to his altered sensorium and irritability. CCTV footages helped trace this exposure.  Once this link was established, we were relieved. Health department identified all contacts of these people and isolated all symptomatic cases and the situation came under control.

After this, the health department called for a meeting with News Editors and discussed the situation. We made them aware that Nipah is transmitted by droplets, where the person had to be within one-meter vicinity of the patient for it to be transmitted and not by aerosol (Airborne). At the start of the meeting, about 60% were wearing masks and at the end of it, no one was wearing a mask as the mask was required only for persons in close contact with the patient. This communication helped a lot to clear the public fear.

In retrospect, how do you view this achievement of Nipah intervention and what do you think about it?

Looking back, I think there were some critical junctures where important decisions had to be taken. The district administration was very supportive and was with the health team all the time. There was very good participation and intervention by the state and central health services. Hon. Health minister of Kerala Smt. KK Shailaja Teacher, The Additional Chief Secretary of Health department Sri. Rajeev Sadanandan and the Director of Health Services Dr RL Sarita has provided exceptional leadership. The Nipah emergency operation room at Calicut worked flawlessly in coordinating the response. It was a very good model and I am afraid if it can be replicated in other places.

Recently, Manipal Institute of Virology was added as a centre of Excellence within Global Virus Network (GVN). Could you please tell me a little bit about GVN and how you view this addition?

Global Virus Network (GVN) was founded by Robert Gallo, who won the second Lasker Award for the discovery of HIV, in conjunction with William Hall of University College London and Reinhard Kurth of the Robert Koch Institute. It is a Non-Government network that brings virologists and institutes together in a collaborative effort to fight viral infections.

The idea of the network is to develop expertise through centres for excellence and to exchange it among them to act quickly during an outbreak. The aims of the network include collaboration among virus scholars, expansion of virologist training programs, and evidence-based policy advocacy. The network also collaborates with WHO and gives expert opinion helping in framing evidence-driven policies.

I think our addition to the GVN will help us in building our capacity, be instrumental in framing evidence-based policies and to work on one health – a concept that tells that the health of people is connected to the health of animals and the environment, which is nascent in India. This collaboration is going to help us in the study of these aspects.

What is your vision for MIV for the next 10 years?

As we are transitioning from a centre to an Institute we are redefining our vision and goals. In the next ten years, we envisage transforming MIV to the most preferred place for infectious diseases researchers especially in the area of emerging and re-emerging diseases.  We will enable and nurture basic, translational and public health virology research which is designed to contribute to achieving the sustainable developmental goals.

As a person who has been instrumental in building a centre of excellence in research, what is your advice for other academicians treading the path?

Three things are important to build a department or institution: (i) Your team: You need people who stay with you and understand your vision and philosophy (ii) An enabling leadership and environment (iii) Liaison with government systems and stakeholders.

It is also important that you grow in a niche area. For example, we specialized in disease surveillance, outbreak detection and pathogen detection, which requires quick mobilisation the team in the field.

However, it is important to periodically identify the strengths, weaknesses, opportunities and threats and strategize to reinvigorate the growth rate.

High resolution Cryo-EM structure from the recent national facility at Bangalore

Scientists at the Bengaluru-based Institute of Stem Cell Biology and Regenerative Medicine (InStem) and National Centre for Biological Sciences (NCBS) have unravelled the structure of a bacterial enzyme, PaaZ, using cryo-electron microscopy. The study was conducted in collaboration with the MRC Laboratory of Molecular Biology, Cambridge, UK and Carver College of Medicine, University of Iowa, USA. The structure was recently published in the journal Nature Communications.

This is the latest high resolution structure (less than 3A) to be published from the recently established state-of-the-art single electron Cryo-EM facility at Bangalore Life Science Cluster.

Here is an exclusive interview with Nitish Sathyanarayanan, one of the first authors of the paper, on this incredible journey.

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1. What got you interested in structural biology?

I began to get fascinated by structural biology during my Bachelor’s degree, where I spent a lot of time reading Lehninger “Principles of Biochemistry”. If you notice keenly, almost every section of this bible contains a structural explanation. It was this interest in biochemistry and enzymology that got me into the field of structural biology. Since I come from Biology training (not Physics or Chemistry), I have always used structural biology as a set of ‘tools/techniques’ to understand the functions of enzymes.

2. How did you come to study the structure of PaaZ?

We stumbled upon PaaZ due to our interest in multi-domain proteins which are involved in aromatic ring degradation. Phenyl Acetate (Paa) degradation pathway is also called “hybrid pathway” since its mechanism of ring degradation has features of both aerobic and anaerobic pathways. Our specific interest was to understand the functioning of this enzyme through its structure and biochemistry. It is also important since several environmental pollutants such as styrene converge to Paa through peripheral pathways.

3. What were the challenges you faced in the project?

We were essentially trying to understand how the enzyme functioned using its structure. We spent nearly 18-24 months crystallizing the protein, with no success in obtaining a diffraction quality crystal. We then attempted an integrated structure modelling approach (Light scattering, SAXS, MD and Modelling) to obtain a model with limited success. This was also the time when structural biology domain was undergoing “resolution revolution” (the term used to describe new advances in Cryo-EM). Since the protein was big and we had limited success with other methods, we decided to explore Cryo-EM to understand the structure.

4. What was your reaction when you first solved these structures?

I was amazed! Here was a protein that I purified for several years. I had only imagined it as a liquid or a blue band on an SDS-PAGE gel or as a gel filtration profile. I never knew how it looked. It was like a blind date. When you talk to someone only over the phone for several years, you build your own imagination. It was similar. But when I saw the structure as a Cryo-EM map, it was more beautiful than I ever imagined.

5. How do you plan on taking the findings of this project further as a scientist and entrepreneur?

For me, PhD was “one big project” since I was involved with multiple projects and simultaneously part of three labs (Bioinformatics, Structural biology and Cryo-EM). As my mentor Rams (Prof. S. Ramaswamy) always said, PhD is training – training an individual to ask tough questions, design an experiment to answer these questions, perform and reproduce an experiment, and find a conclusion. In between these four steps, a PhD student often goes through innumerable failed experiments. It is the ability to break a complex problem into simpler tasks, find answers to these smaller tasks (with several failures) and, in the end, put all pieces of the puzzle to build a complete picture. This is a life lesson I plan to leverage in my next journey as a tech entrepreneur.

6. Your message to academic peers struggling in their PhD?

If you are not struggling, then there is a problem. It’s called “re-search” for a reason. I feel that one should have read at least about a hundred papers in that area of research in the first 6 months. My humble suggestion is to spend a considerable amount of time reading and staying updated with literature. This can be a great source of new ideas. The other benefit is that you will become aware of the labs that work in a similar field. You could always request for plasmids, protocols, reagents, suggestions etc. from them. If you do not read enough, you cannot do any of this. And please remember, by the end of your PhD, you should have become an expert in that field.

Picture adapted from the published paper.

Link to the full-text of the article: https://www.nature.com/articles/s41467-019-11931-1