Cell biology provides the basis for understanding the mechanics of cell development, and the role of its aberrant development in diseases.

Srinidhi Rao, our next pathbreaker, Staff Scientist at Lieber Institute of Brain Development, works on development of stem cell-based assays to study the pathophysiology of neurodevelopmental and neurodegenerative disorders.

Srinidhi talks to Shyam Krishnamurthy from The Interview Portal about taking up stem cell biology based on the potential breakthroughs in the field of regenerative medicine through Gene Therapy and Stem Cells .

For students, aim to be a part of scientific discoveries that contribute towards translational real-world applications in healthcare.

Srinidhi, Your background?

I’m Srinidhi, and I was born and brought up in Chennai. I grew up in a joint family until I was 12, and most of my childhood memories revolve around my cousins, uncles, aunts, and grandparents. My parents are both pharma graduates, which was a huge influence on me, that resulted in a fascination and interest for human biology to begin with. I did my entire schooling at Padma Seshadri Bala Bhavan Senior Secondary School, Chennai, taking up the science stream with Physics, Chemistry, Mathematics and Biotechnology, rather than the more traditional Biology or Computer Science electives.

My parents have always been very supportive of my dreams and passions. They instilled in me and my brother, a love for learning and growing. I’m the older of two siblings. My brother is currently pursuing his graduate degree in robotics.

My hobbies – arts and crafts! I love painting (all sorts of painting – oil, watercolors, everything!). I also love travelling and hiking, which has been more of a newfound love for me!

What did you do for graduation/post-graduation?

I think very early on I knew I wanted to study Biology, specifically human biology. I opted to study Genetic Engineering at SRM University, Chennai for my undergraduate education. Not only was this program newly offered but there was significant focus on genetics and therapeutics which was not offered in more mainstream biology programs. My program offered a variety of courses, ranging from fundamentals of Biology and Biochemistry to more focused courses such as Stem Cell Biology, and Immunology. I also enjoyed working in the laboratory, designing, and conducting experiments, especially hands-on work relating to cell culture and molecular biology. SRM University offers a semester abroad program providing international opportunities and global exposure for its students. As a part of this program, I spent a semester of my senior year at Umeå University, Sweden. Following that, I did my Master of Science degree in Stem Cell Biology, at the University of Minnesota, Twin-Cities with human induced-pluripotent stem cells technology and its therapeutic applications as my focus.

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

I don’t think there was one event that led me to pursue a career as a scientist. I think my initial love for biology came from my artsy side, as I loved drawing the different structures of cells, mitochondria, etc. That, coupled with my fascination towards human biology, and my inquisitive nature led me to where I am today. I’ve had a great support system all my life, from my parents, brother, grandparents to my husband, giving me the confidence and courage to travel down a lane I love.

Prior to starting my undergraduate degree, Biotechnology or Genetics was considered too unconventional. It was a learning curve to understand the merits and demerits of a career as a stem cell biologist. But this is changing at a steady pace with better understanding and acceptance of the potential and applications that Gene Therapy and Stem Cells offer. I’m seeing way more people choosing this branch of science of study, and it’s exciting to see that!

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

I always knew I wanted to be in the science/medicine field, because I loved wet lab work and research, more than the idea of being a physician. This was a big influence on my decision to pursue Genetic Engineering for my undergraduate degree at SRM University. Here, I was awarded the Founders Scholarship, which funded my undergraduate expenses completely (all college and transportation fees).

Besides the course curriculum, I wanted to explore research opportunities in other institutions and the industry. I interned at Indo-American Hybrid Seeds in Bangalore on advanced molecular techniques during my sophomore year. I also was a Research Assistant at Sri Ramachandra Institute of Higher Education and Research exploring clinical symptoms and performing case studies. In my junior year, I was awarded the Indian Academy of Sciences (IAS)Fellowship, which is an annual fellowship offered in different streams of core sciences giving undergraduate students an opportunity to conduct a mini project in their fields of study. This experience was huge for me, as it gave me a real experience of working in a research laboratory. Here, I studied cryptochrome expression patterns in differential light sensitivity of early and late emerging populations of Drosophila melanogaster (fruit fly), identifying inter-individual chronobiological variation using a comparative analysis. 

After that, I spent my last semester in Umeå University, Sweden, where I led the project studying phosphorylation and upregulation of Op18 in human malignancies, specifically the role of the protein Sm16, described as Op18-like, in immuno-modulation of Toll-Like receptors (TLRs) upon activation of innate immunity. It was here that I recognized that learning various techniques (PCR or immunocytochemistry) is just the first step, but learning how to apply these techniques to answer specific questions in your project is the crux of research.

I moved to the US soon after and which is where I currently reside. I attended the University of Minnesota, for my Masters degree in Stem Cell Biology. It was one of the few Master of Science programs that specifically offered specialization in stem cell biology. In addition to coursework, the program required us to choose a thesis lab and project, and I chose to study adenoviral based reprogramming of endodermal cells as a potential therapy for Type I Diabetes Mellitus with my mentor Dr. James Dutton. Diabetes is an incurable lifelong condition occurring due to high blood glucose levels in the body as the body is unable to produce insulin. The aim of my thesis was to find a way using gene therapy to make the cells of body produce insulin. We identified 3 genes that are crucial to produce beta-cells (cells in the pancreas that produce insulin). Using an adenovirus, we delivered these genes to cells in the liver and other endodermal cells to make them more like beta-cells and produce insulin. This process is called directed reprogramming and revolves around the fundamentals of how stem cells can be ‘reprogrammed’ to become any cell in your body.

After graduation, I was offered the ‘Research Associate’ position at the Lieber Institute for Brain Development, a Johns Hopkins School of Medicine affiliated institute to work on a ‘pipeline’ project – an institute-wide project to study the pathogenesis of Schizophrenia using patient-derived induced pluripotent stem cells. My day-to-day work mainly was to reprogram, grow, and differentiate these stem cells to neurons. I think this was the most impactful experience in shaping my career and interests. I got to design my own projects and grow as an independent scientist, thanks to all the opportunities and advice from my peers and mentor (Dr. Brady Maher) on avenues to improve. This has been a great motivator and provided excitement to learn and grow within and beyond my position. I then got promoted to ‘Staff Scientist’ – with new projects, and more exciting challenges such as growing 3D organoids, which have been grown for over 300 days.

Looking back, the best approach is taking the time to find avenues that excite you! It’s also very important to be self-critical, evaluate yourself and know your limitations. Find mentors throughout your career who will provide you with opportunities to grow and understand your aspirations and goals moving forward as well.

How did you get your first break? 

My first break was my opportunity to spend a semester in Sweden as a research student. The head of my department, Dr. Parani, was the first to recognize my research interests and helped me find a lab that I should apply to, for my undergraduate thesis project. Finding Dr. Martin Gullberg’s lab was a turning point, as I was given the opportunity to lead my own project. He also funded my expenses for my time as a research student in Sweden. 

What were some of the challenges you faced? How did you address them?

Challenge 1: First time traveling abroad to Sweden as an exchange student

It was my first time ever travelling outside of India (my comfort zone, should I say?), and not only just to any country, a Scandinavian country. It was my first-time experiencing extreme snowy winters, my first-time visiting a country where English was not the primary language, and my first-time away from all my friends and family. Overcoming my nervousness was a challenge, though I can now say that it was one of the best experiences, both academically and culturally that I’ve had. It helped ease my anxiety when I decided to move to the US following my graduation.

Challenge 2: Finding a support system

As an immigrant in a foreign country, it’s crucial that you find a good support system of friends, family, and mentors, to keep you motivated, driven and eager to grow! I had a good number of friends during my schooling and undergrad who also moved to the US around the same time that I did. I also made a new bunch of friends during my graduate school who are still very much a part of my life.

Challenge 3: Competition and opportunities; and networking

The US is always regarded as the ‘Land of Opportunities’. Yes, there are many opportunities, but with that also comes fierce competition. Being aware of the caliber of your peers and aspects of your own self to improve your skills is a very important trait to have. In addition, networking is also an impactful skill that should be inculcated.

Where do you work now? What problems do you solve as a scientist?

I work as a ‘Staff Scientist’ at the Lieber Institute for Brain Development. I develop stem cell-based assays to study the pathophysiology of neurodevelopmental and neurodegenerative disorders. I currently work on growing/differentiating neuronal cultures from human patient-derived stem cells of individuals with neuropsychiatric disorders and neurotypical controls in both 2D and 3D model systems. My work also involves a lot of downstream molecular assays such as immunocytochemistry, protein biology and RNA-sequencing to understand the developmental trajectory of these neuronal cells in culture. A big part of my job currently is also related to project management, focusing on prioritizing, documenting, and organizing various stem cell projects in the lab.

What skills are needed for your role? How did you acquire the skills?

Basic skills for my job are expertise in stem cell culture, aseptic techniques, and molecular biology techniques (immunocytochemistry, imaging, protein handling, RNA handling and qualitative PCR reactions) which are all skills that can be developed while working in a laboratory and honed with experience.

What’s a typical day like?

A typical day involves– (1) hands-on wet lab work, that includes working on cell culture, and molecular assays and (2) Data analysis, and interpretation of the data collected from performing the assays. 

What is it you love about this job? 

It’s never a dull day, there’s always more to learn and more avenues to explore and skills to gain. There’s so much to learn, and I love that with every small discovery we get a bit closer to understanding more about the complexity of the human brain.

How does your work benefit society? 

My research is focused on understanding the basis of brain disorders. Psychiatric disorders are increasing in prevalence all over the world, and yet we have a very rudimentary understanding of our brain in such cases. Understanding this will help us identify candidate genes that can be used for better diagnosis and therapeutics. As a cell biologist, you can better understand the mechanics of cell development, and its aberrant development in diseases. Besides studying psychiatric disorders, specifically stem cell technology has been a great tool that has been developed and increasingly used to study disorders ‘in a dish’. Stem cells have been isolated from the umbilical cord blood and placenta after childbirth and stored as they are used (if necessary) as therapies (for certain cancer treatments, anemia, etc.) and regenerative medicine applications. 

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

I’ve enjoyed every project I’ve worked on till now. But the most memorable project I’ve worked on is the first project I worked on at the Lieber Institute. I was one of the primary stem cell biologists in my team, designing in collaboration with 3 other labs, a mammoth project of studying a cohort of 32 schizophrenia and neurotypical controls patient-derived neuronal cultures. This project taught me a lot about my capabilities and has helped me mature as a well-rounded and seasoned scientist.

Your advice to students based on your experience?

  • Pursue a career path you love. Evaluate your goals and it’s okay if they change as you progress, but make sure to make every experience count. There’s always a takeaway from every experience, and you should learn and grow from them.
  • Get out of your comfort zone. Spending time away from friends and family, I learnt a lot about myself and how well/not well I handle situations. It might be hard at first but gives you a different level of confidence and strength to face adversities in life.
  • Experience life outside of your academics and professional life. I’ve learnt that ‘Work-Life’ balance is very important – I love travel and food experiences, which I’ve made a priority to take time and enjoy!

Future Plans?

I’m as excited now as when I started a career in research. I know I want to continue this journey and focus on developing cell-based platforms targeted towards therapeutics. I want to be a part of the scientific discoveries that cumulatively over time contribute towards translational real-world applications!