Understanding disease mechanisms and analysing the role of different proteins in regulating cancer progression has huge potential in development of new drugs for the Indian population.

Keerthi Harikrishnan, our next pathbreaker, Experimental Scientist at at IISER, Pune, works on identifying the role of extracellular matrix proteins in lung cancer progression, to identify new genes that can be used to develop new drug targets. 

Keerthi talks to  Shyam Krishnamurthy from The Interview Portal about her fascination for the human heart that led her to a PhD on identifying the underlying causes of congenital valve defects, after completing an undergraduate program that had a special emphasis on cardiovascular diseases with clinical exposure.

For students, the battle against cancer can be successful only when we have young bright minds who can take up experimental research to build a robust scientific pipeline that can lead to drug discovery

Keerthi, tell us about Your background?

I grew up in small towns (Ambur and Ranipet) which are famous for their leather industries. Both my parents come from rural agricultural families and my dad works in the leather industry. Growing up in a large family with 10 siblings, my dad is a self-made man who truly believed in the power of education. My mom is a homemaker and coming from a rural conservative family, she was not allowed to go to college. My parents were hence very particular that we (me and my younger brother) get a good education, so we moved from our hometown Ambur to Ranipet when I was 7 years old since Ranipet was known to have the best schools in the Vellore district. I went to Little Flower Convent which shaped my early days and has made me what I’m today.

When I’m not experimenting in the lab, I experiment with food in my kitchen and love creating recipes. I explore new places around Pune and spend my free time with family and friends.

What did you do for graduation/post-graduation?

I took up a work-integrated 4-year B.S Physician Assistant undergraduate program jointly offered by BITS Pilani and Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai. This was a completely offbeat program. I chose this because I could get hands-on clinical experience in addition to strong fundamentals. My undergraduate experience was very unique because it involved being in the clinic in the mornings (In-service training) and attending regular lectures in the afternoons. So, you could see the clinical/practical aspects of everything you learnt in your classes. The curriculum had everything including things like visual basic, principles of management, scientific writing in addition to the regular coursework that covered human anatomy, physiology, pharmacology, biochemistry and cell biology, etc. Coursework advanced as we progressed in our years. The days were long and required doing well in both the in-service training sessions as well as the theoretical exams. I spent my summer months doing projects at SMH Vellore, BM hospital Mysore and Vijaya hospital Chennai to get exposure across other fields in medicine. I chose to work in paediatric and adult cardiac intensive care for my final year. My work was in the clinic with real patient responsibilities (attending rounds, writing up discharge summaries and other clinical procedures). I also did two projects focusing on paediatric congenital heart defects. I developed a strong interest in cardiovascular research which led me towards a PhD program. 

My applications to PhD programs in the US were not successful the first time since they thought I lacked research experience. I wanted to show my strong commitment to research. So, with my father’s help, I did an internship at CLRI Chennai and applied for PhD again in 2007 and got admission into the best cardiovascular research programs at the Medical University of South Carolina, Charleston, USA.

What made you choose such an offbeat, unconventional and unique career?

During my school days, I had wonderful science teachers like Ms Helen, Ms Sudha and Sr. Sunitha who designed amazing experiments which fueled my scientific curiosity. The Kreb’s Cycle taught by Ms Sudha and human heart physiology by Sr. Sunitha (using real pig’s heart) in my 12th standard is something I remember even to this day. I think this set a stage for my future. 

I continued to benefit from great teachers in college as well. In particular, we had a biochemistry professor (Dr Gino Kurian) who conducted open book exams which were unheard of. These were the hardest to crack and they were all applied questions which made it quite interesting. His teaching style was impeccable and he introduced us to reading research articles and conducted journal clubs periodically. Gino sir did not have any favourites in the class and always assigned tasks to students by calling roll numbers. This was something rare and I have never met anyone who was so unbiased and took interest in every student of the class. This had a profound influence on me and it was a quality I hoped to inculcate in myself. So when I was admitted into a PhD program, I found a mentor (Dr Scott Argraves) who was a great scientist and also an incredible human being. My years spent as a graduate student working in Scott’s lab has been the best years of my life which has shaped me personally and professionally. I was completely uninhibited and not afraid to pursue avenues that were curious to me. It made me move back to India to give back to the scientific community in whatever way possible.

How did you plan the steps to get into the career you wanted? Or how did you make a transition to a new career? Tell us about your career path

During my school days, my grandfather would often hand me the inserts from his medications and ask me to explain how the drugs worked. In particular, I was drawn to the mechanisms by which the blood pressure medication (ACE inhibitors) not only controlled the blood pressure but also provided additional benefits by inhibiting fibrosis in the heart and preserving cardiac function. So I applied for an undergraduate program that had a special emphasis on cardiovascular diseases. During the 4 year tenure, I had a really good clinical exposure and gained a good insight into the fundamental research as well. I had a strong interest in basic research, so I started applying for a PhD program at the beginning of my fourth year in the undergraduate program. Through my father’s contact with a professor, I applied to the PhD program at MUSC. My application was not successful and the admission’s committee felt I needed some practical experience of working in a research lab. I applied for the summer research program at CCMB and didn’t get through. With my father’s help, I finally managed to get an internship at Central Leather Research Institute (CLRI), Chennai in a lab that worked on developing biomaterials for cardiovascular research. During this time, I isolated heart cells from mice and made collagen sheets to grow them. 

Collagens are a group of sticky proteins that are widely in clinical settings. They are used for a range of things like wound dressing for burns, making artificial tissues, as fillers in cosmetic surgeries, for strengthening up teeth and bone. So it was a cool project to work on.

I was sending out applications for PhD programs while I was doing my internship. It was a really difficult time for me because all of my classmates had a job and I was still financially dependent on my parents. My dad earned a modest salary and I felt guilty for not being able to contribute towards my applications. So as soon as I sent out my applications, I took up a short term job as Physician Assistant at MMM Chennai. I worked for a few months until I got a PhD admission offer from MUSC. The PhD program came with tuition support and fellowship which meant I didn’t have to worry about money and spent my time doing research happily. 

Since I was always fascinated by the human heart, my PhD work was focused on identifying the underlying for congenital valve defects. This is a very relevant field of research because bicuspid aortic valve (a congenital valve defect) is the second most common cause for surgery. I specifically discovered a role for Fibulin-1 protein in regulating pulmonary and aortic valves and how lack of Fibulin-1 causes congenital valve defects in mice. 

As I was progressing in my PhD, I made a serendipitous discovery of the receptor for Fibulin-1. Matrix proteins are important for keeping cells together and function by interacting with other proteins on the cell surface. Fibulin-1 was discovered by my PhD mentor in the 1980s, but I was the first one to discover that it binds EGFR. This was very exciting because EGFR is a protein whose levels are high in cancer. EGFR plays a major role in tumour progression. This was exciting for me and I wanted to pursue this for my postdoctoral work, especially in the context of lung cancer in India.

After my graduation, I moved back to India and being a complete outsider, I took a leap of faith and wrote to Dr Nagaraj Balasubramanian at IISER Pune. I gave an informal talk followed by a formal interview for my postdoctoral position. As I progressed in my tenure, I applied for an independent scientist grant funded by DST- WOSA division and kick-started my career in the field of matrix biology with an emphasis on lung cancer.

How did you get your first break?

When I was finishing up my PhD, I knew I wanted to come back to India and contribute to Indian science. So, I moved to India soon after my PhD and looked for positions where my research would complement the ongoing work in a lab. I did not know anyone in Indian academia and wrote a cold email to Dr Nagaraj Balasubramanian at IISER Pune about wanting to work with him. I was pleasantly surprised by his swift response and invited me to present my work. When I met him and his lab, I felt it was a good match and he encouraged me to apply for the institutional postdoctoral fellowship which I applied for and secured funding for two years. I started my research career in India with a focus on lung cancer. As I was almost nearing completion of my postdoctoral fellowship, Dr Nagaraj motivated me to write for independent grants. I wrote to and got the DST- Women Scientist grant. Despite the COVID19 setback, I have published my first research article in June 2020 and work is underway on publishing other research works as well. I have been happy so far with the progress I made.

What were the challenges you faced in your career? How did you address them?

Challenge 1: 

Initial days during my college were tough because I was seen as a small-town girl who had no exposure to city life. As time went by, I had some wonderful friends who supported me, but there were still some people in my class who never really treated me well. I developed a lot of resilience which helped me deal with people later on in life.

Challenge 2: 

When I was finishing my PhD, my mentor was diagnosed with brain cancer and it was the most challenging time for me. I wouldn’t have been able to finish my PhD without the support of my lab members and I feel so blessed to have worked with such a great team.

Where do you work now? Tell us about your research

Currently, I’m a Scientist at IISER, Pune and I work on identifying the role of extracellular matrix proteins in lung cancer. 

The human body is made up of millions of cells. A framework of proteins called extracellular matrix proteins holds these cells together, thus providing physical support. Matrix proteins can control how the cell functions by transmitting the signals from the outside of the cell to the inside of the cell through specialized proteins that can selectively bind molecules (receptors) on the cell surface. In diseases like cancer, changes in matrix composition, and function can affect how the disease progresses. One such matrix protein whose levels are decreased in lung cancer is Fibulin-1. My research is focused on identifying the role of Fibulin-1 (a matrix protein) in regulating lung cancer progression. 

My graduate training was intense which helped me develop critical thinking and problem-solving skills that I use in day-to-day activities at work. A typical day involves planning and performing experiments, meeting with lab members, reading scientific articles and thinking about the impact of my current research in the greater picture.

In a country where the average income of a person is less than 10,000 INR per month, I consider myself lucky to not only do the job I love but also get paid a salary for doing it. I love the fact I wake up every day and get a chance to ask questions that could lead to making a change in someone’s life.

How does your work benefits society?

I work on cancer, to identify new genes that can be used to develop new drug targets. Take lung cancer for example, while a mutation in a gene affects only 10% of the western population, the same gene mutation affects 50% of our Indian population and we don’t have drugs specifically available to treat our patients. All the drug discoveries primarily come from the western world where the research is focused on their population. We continue to use those drugs in our Indian population since we are yet to build a robust pipeline to drug discovery. We have made some significant advances towards building infrastructure, but it can only be successful when we have young bright minds who will join us in this battle against cancer.

Tell us an example of a specific memorable work you did that is very close to you!

During my PhD, I contributed to a project that was making artificial blood vessels using 3D printing. It took us a long time to get this project running. Finally, on one fine day, we got this cylindrical tube that looked absolutely perfect and withstood all the testing. It was a very special moment for all of us to see our dream come true.

Your advice to students based on your experience?

● Be curious.

● Be driven.

● Chase after your dreams no matter how crazy they are.

● Stand up to (for yourself and also for others) bullying and harassment.

● Don’t let people in power tell you what you can or cannot do.

Future Plans?

I want to move from bench to bedside and act as a bridge between fundamental research and clinic. My ambitions would be to shape key opinions in cancer research and to make an impact in people’s lives. I will continue my contribution to cancer research in whatever way I can.