Many concepts that we are anecdotally familiar with, like immunity, disease and metabolism, fundamentally occur at the molecular or structural level !
Sriram Aiyer, our next pathbreaker, PostDoctoral Fellow at the Salk Institute of Biological Studies, San Diego, uses electron microscopes to study a group of proteins within the cell, that are frequently mutated in cancer.
Sriram talks to Shyam Krishnamurthy from The Interview Portal about being strongly influenced by the role of Fundamental Biology and Genetic Engineering in solving the puzzle of life, that led him to a career in Life Sciences.
For students, if you don’t want to give up on either engineering or medical, you should opt for life sciences, which is all about exploring life based on engineering principles !
Sriram, can you take us through your background?
I was born in Chennai, grew up in Nagpur and Mumbai. Presently my parents are still in Mumbai, so Mumbai is home for me. My mother is a homemaker and my father is an HR consultant. Looking back to however far I can remember, our lifestyle has always been rather simple. My parents always wanted me to focus on studies whenever needed, maximize enjoying free time when I got some, and have an overall positive outlook as much as possible. My initial interest was shaped by my cousins and grandparents and that was to try and get into an engineering or medical stream. So my ideal career path would have been some sort of an intersection between the two.
What did you do for graduation/post graduation?
I have a Bachelor’s in Microbiology and Master’s in Biotechnology. I did my PhD in Biochemistry from Rutgers, The State University of New Jersey-New Brunswick
Tell us, what drove you to take up such an offbeat, unconventional and unusual career?
As I mentioned before, an intersection of medicine and engineering seemed ideal career for me and that drove me towards exploring Life Sciences / Biotechnology as a career path. The earliest influence that I can remember was the career advice column in the Education Times (newspaper supplement in Mumbai) where there was an article on genetics and genetic engineering. It completely caught my attention as the draft Human Genome project had received a lot of attention and at that point it still seemed like a pipe dream to get your entire genome sequenced within a few weeks. But now, not only is that possible, but we are also on the cusp of multiple gene editing therapies, and life science in general is in a very exciting space.
My mother’s cousin is the only other person in my family and extended family who made a career out of life sciences. Her route to becoming a professor was a good roadmap for me and I loosely used that template to target becoming a faculty member at a reputed research institute or university.
Funnily, immediately after high school, my father asked me to seriously reconsider a career in science and instead focus on trying to become a sports journalist because of my avid interest in a variety of sports! But somehow wanting to make a mark in the life sciences field still held its sway. Fortunately, my parents have always been very supportive and have always encouraged me and my brother to make our own decisions. Over the years this has certainly helped, since making a career in the life sciences requires a lot of time and patience.
Though my Bachelor’s in Microbiology gave a solid foundation, the lecturers I met during my Master’s program were absolutely instrumental in giving me a push towards doctoral and postdoctoral studies. Despite having a rather rough time trying to graduate from my Master’s program, the continuous encouragement I received from those lecturers helped me boost my confidence a lot.
Scientifically, the key turning point for me was listening to a talk from a scientist studying aging. It blew my mind to learn that much of the initial work in studying this phenomenon was done in Baker’s yeast! The fact that you can use such diverse and unpredictable approaches to solve some of the most fundamental concepts of life convinced me that the life sciences would have endless opportunities to explore these fascinating subjects.
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 high school when I was planning for career options, it appeared to me that there weren’t a lot of options in India. Right after 12th grade, I tried to apply for programs in the US with a view of studying life sciences during undergraduate education. Unlike graduate programs, very few institutions provided scholarships for international students, so despite giving the SATs and applying for undergraduate programs, the cost of studying in the US would have been prohibitive. As a result, I pursued a 3-year degree in microbiology, with additional subjects such as botany, biochemistry and chemistry. Since most US universities required a 4-year undergraduate degree, I applied to Master’s programs within India itself. My aunt, who was a professor in the Madras University campus, suggested I join a college in Chennai that she had scouted. That location had excellent learning resources and in hindsight, also had lecturers who nudged me in the right direction. During this time, I had the opportunity of interacting with someone who had graduated from our department and was doing doctoral studies in Scotland. I realized that a lot of what I was studying was knowledge-based, and not important for the day-to-day aspects of what a scientist does. In order to get better practical knowledge, I sought out internships at Bhabha Atomic Research Center in Mumbai and Indian Institute of Science in Bangalore. Many doctoral programs in the US look for individuals with some evidence of having published in major research journals. In my circumstance, landing a publication was far-fetched, so I decided to work on gaining at least basic research experience. My hope was that this would help showcase a good college application since my GRE scores were competitive. My combined application package, when compared with that of my peers, was still reasonably well-rounded. These days biotech and life sciences in general appear to be better developed in India. Though it still doesn’t compare to the US, China or some European countries in terms of output and infrastructure, the general trend appears to be heading in the right direction.
Biology or life sciences in general, is a highly interdisciplinary field. This is even more apparent these days due to the intersection of computer science and biology. My doctoral degree was in biochemistry, which is the study of chemical reactions at the molecular level. But my thesis study involved the use of a wide variety of subjects, including biochemistry. These included virology (studying techniques for propogating and assessing functions of viruses), nuclear magnetic resonance spectroscopy (use of powerful magnets to study position of atoms), genome sequencing (studying patterns of DNA sequences) and molecular biology (studying molecules that are invisible using tools that extrapolate function and can be visualized using the naked eye). More specifically, my thesis was based on studying a virus that has been used in the past as a gene-delivery vehicle. Despite successful gene-delivery, a common side effect was induction of cancer in patients. I studied mechanisms by which the gene-delivery protocol was causing cancer and whether strategies can be developed to avoid cancer without compromising the gene-delivery function. Such a thesis topic has use in developing safer gene-therapy solutions. Though my doctoral degree started fine academically, the research component needed some getting used to. After about 2 years, I was beginning to get the hang of what was expected and what was required to succeed. Despite taking 7 years to graduate, my doctoral degree was highly productive in terms of scientific publications.
After graduating, I was briefly looking for scientist positions in industry as a career path. But the general feeling I got was that even for scientist level positions, they were looking for applicants with a few years of postdoctoral experience. All the opportunities I was getting at that point seemed to be a better fit for those with a Master’s degree. So, I started looking at postdoc positions and my current lab seemed like a natural fit. Incidentally, my current boss had come to my doctoral degree granting institution for a seminar. I had an informal interview at that time and a more formal interview later. I was offered the job immediately and I have been at this position for the past 4.5 years.
How did you get your first break?
I had an internship at Bhabha Atomic Research Center in Mumbai followed by one at the Indian Institute of Science in Bangalore. Both these opportunities were through word-of-mouth through relatives and family friends. These experiences helped me understand the expectations and inner workings of what it takes to perform experiments and what entails the day-to-day routine of a scientist. To my surprise, in the combined total of 9 months of internships, the only successful period of time was 2 weeks. The remaining 8 and a half weeks were failed experiments or time spent optimizing experiments in order to get 2 weeks of useful data. Had it not been for these internships, I would not have realized that most part of your career in research is failed experiments. But every failed experiment is a step in the right direction as it really helps you think a lot about devising the perfect experimental set-up. Both these stints have had no bearing on how my doctoral and postdoctoral work have panned out though. But they gave me a bird’s eye view of understanding the kind of work ethic and routine that is needed to succeed in research. I credit both these stints with clarifying expectations and providing a framework for gauging whether I can perform well in such an environment.
If people are looking for their first break in research, I believe it is helpful to understand the workflow that most scientific experiments have in common-
1. You have some pre-existing knowledge and there are knowledge gaps. What claims or observations do you hypothesize will fill those knowledge gap(s)?
2. What experiments can prove or disprove your hypothesis?
3. Can you reproducibly repeat the experiments that support the claims of your hypothesis?
4. What can you deduce from the performed experiments? Have they or have they not plugged the knowledge gaps? If not, what can the next steps be?
If I were to look for internships all over again, I will keep an eye out to see if I can get trained or at least get a taste of the different aspects of workflow listed above. If that experience is fun and intellectually stimulating, then a career in science would be really enjoyable.
What were some of the challenges you faced? How did you address them?
Not applicable. As most of my first few stints in research were internships, it was a structured experience.
Where do you work now? What problems do you solve?
I am currently a PostDoctoral fellow at the Salk Institute in San Diego, USA. Our lab uses electron microscopes to study the shapes of protein, DNA, viruses, cells etc. My project involves studying a group of proteins within the cell that are frequently mutated in cancer. In order to study these proteins, we first grow a large volume of cells using bioreactors. Next, we break open cells using a variety of different techniques to isolate and purify our protein of interest. Once purified and validated, we rapidly freeze the proteins in an extremely thin layer (nanometer scale) of ice by plunging them in liquid ethane. This is an important step for imaging using electron microscopes. Usually this process of breaking open cells to freezing proteins, can take anywhere from a few days to a week. Assuming we are successful thus far, we will have a good sample for high resolution data collection. During high resolution data collection, we collect thousands of images of proteins embedded in ice. Using computational algorithms we then pick individual protein particles and reconstruct a 3-D image of the protein. This entire process provides a very high resolution snapshot of the protein, where a good quality imaging session can show details of individual atoms and how they are organized. Such detailed views are important for identifying targets for developing therapeutic drugs and in the times we are living in now, the technique can be used to identify the molecular differences of the different coronavirus variants.
What are the skills needed in your role as a scientist?
Since we are working with very small entities and very small volumes, accuracy and reproducibility is of paramount importance. Thus, good technique, good note keeping and strong discipline is needed to be consistently successful. Also, not all proteins behave the same way, so each experiment has to be tailor-made to suit the biochemical properties of these entities. Although the general process of purifying proteins is similar, there is usually a lot of trial-and-error to identify the best technique for obtaining a high yield of pure protein. Most experiments almost always don’t work the first time. Troubleshooting to overcome these challenges makes this very intellectually stimulating and I would say, the best part of the job.
How does your work benefit society?
Many concepts that we are at least anecdotally familiar with, like immunity, disease, diet etc fundamentally occur at the molecular level of cells, even though the effects are at a much more macroscopic level. Since we use electron microscopes, which are powerful tools for magnifying tiny molecules like DNA, viruses, proteins etc., studying the shape of these entities provides a lot of clues about how they function in the context of things like immunity, disease, diet etc. My specific project deals with using electron microscopy to study proteins that reside in the nucleus of the cell and to learn more about how they engage with genes. There is growing evidence that misregulation of these proteins has an important role in a wide variety of cancers. With high resolution snapshots of these proteins, we are hoping to understand in great detail how this misregulation occurs. Eventually these studies will inform and provide a platform for curing these diseases.
Tell us an example of a specific memorable work you did that is very close to you!
One of my favorite projects was at the very beginning of my postdoc. We solved the structure of a virus capsid, which is a shell that protects viral DNA, to the highest resolution (atomic clarity) known at the time for a protein, using single particle cryo-electron microscopy. It was an incredible experience to work on that project and a great example of how great collaborative work can really improve the quality of different projects.
Your advice to students based on your experience?
In my view there are three things that are absolutely important for a well-rounded and satisfactory career.
A- You need to understand what type of personality you are and what kind of work you are likely to succeed in. It is not a prerequisite for success, but it definitely helps you to manage your career and handle expectations better. This is important, since it may be natural or easy to focus on your strengths, though a good part of being successful is also about trying to successfully know and navigate through your weaknesses. Having a clear idea of both, will definitely give you a better chance at sustained success. This also allows you to strategize better in terms of time and effort.
B- If you are not happy doing whatever job you are doing, work life will be mentally taxing. Always look for a career path where executing your job and problem solving are not only naturally enjoyable but also align with your aptitude. Nothing should drastically affect your mental health or constrain your talents, as these tend to have far reaching effects even if they aren’t always apparent. Another aspect that affects mental health is competition. Competition should always be viewed as a way of testing yourself to know how much you can push your limits. It should never be used to measure yourself to others. Some amount of comparison becomes inevitable as it is human nature, but it shouldn’t be the driving force of your life. The higher you reach in your career, the more probable it is that you will work with people who are as talented as you are. So if you lose out at a particular phase, it may just be bad luck. But if you still love doing the job you do, it is a lot easier to get over it and carry on doing what you enjoy the most.
C- A good part of success these days is all about thinking ahead in addition to performing in the present. Spend a few hours a week reading or learning something that you normally don’t come across in your daily routine. This could be reading newspaper articles, magazines, or even watching informative YouTube videos.
Like I mentioned before, I am gearing up to lead a lab at a major research institution or university and would prefer to stay in academic research. But research in the biotech industry these days is starting to look quite attractive as well. My hope is to continue working within the life science sector in some form or another.