Hello, Umanshi!
When did you first get excited and interested in science and how has it been since then?
I became interested in science when I was in my 9th or 10th grade. I was not an extremely bright student, but I had an excellent teacher. His tutoring is what sparked my fascination with Science and Mathematics. In my school, along with PCM, we also had Biotechnology as a subject. I chose this in my 11th grade. This was when I started learning about cancer, and the different therapeutics that were coming up. We read about how insulin was being developed recombinantly. What was really fascinating to me was that we could do all of this in the lab and combine biology with technology. This got me going. I did my BTech in Biotechnology from Govind Ballabh Pant University of Agriculture and Technology in Uttarakhand. There I was introduced to basic botany and zoology courses as well as Molecular Biology, Recombinant DNA technology. This gave me a strong foundation for higher studies. I then did my masters from IIT Kanpur, where I worked on flies. I was working as a joint student under the guidance of Dr. Bushra Ateeq and Dr. Pradeep Sinha in IIT-K. We were looking at how overexpression of human prostate cancer-linked genes causes abnormalities in flies, and how we can use it to study and dissect the pathways. Very interestingly, we found that it did not cause cancer because the fly landscape of genes and tumorigenesis is very different. But we got abnormal phenotypes like flies with an extra antenna in place of an eye, missing antennas, etc. So, we dissected why the developmental decision changed. Our results led us to the identification of interaction between PCa-linked genes and known cancer-related relevant pathways.
How did you make your decision to join a PhD program?
I was not thinking seriously about a PhD then. I thought it would be a good opportunity to get into industry, so I joined the Research and Development Department at Intas Pharmaceuticals in Ahmedabad. They were trying to develop Adeno-associated virus (AAV) based vaccines for hemophilia and different genetic disorders. That was a very fascinating time. I had a good team of scientists as mentors. But somewhere I felt like I needed to grow as a scientist and develop my thinking. This is when I decided to do a PhD. So, after completing one year at Intas, I started preparing for competitive exams like DBT JRF, CSIR, etc. After clearing GATE and DBT JRF, I ultimately joined the National Institute of Immunology, Delhi for my PhD.
And what are your research questions now? What are you looking at?
My research focuses on reproductive aging and germline development. We use C. elegans as a model system. Initially, I didn’t know much about C. elegans as I have not worked previously with worms. But my experience with flies helped me in some ways. Working with a model organism offers a unique perspective on how different tissues communicate to regulate various processes, and this fascinated me.
At first, I tried a few projects that didn’t work out. By the end of my first year, I got involved in a project with one of my seniors. His work focused on the interaction between CDK-12, a kinase involved in DNA damage response, and insulin-IGF1 signaling (IIS) to regulate germline development. The study was published in Development last year. My project built on this work, and we began screening cyclins that may interact with the insulin signaling pathway, which is a nutrient-signaling pathway. We wanted to see how different cyclins influence reproductive decisions. My work emerged from this screening.
Previous studies have shown that insulin signaling, which is crucial for oocyte maturation, results in reproductive aging if overactivated. In mice, for instance, overactivation of IIS leads to premature activation of oocytes, which are then unable to complete maturation and eventually die. Lowering insulin signaling has been shown to improve oocyte quality and delay reproductive aging in C. elegans.
In our study, we show that in wild-type worms, knocking down cyd-1 (worm cyclin D ortholog) compromises reproductive fidelity. In contrast, in daf-2 mutant worms (which have a mutation in the insulin receptor, leading to reduced insulin signaling), cyd-1 knock-down resulted in sterility. These were two contrasting phenotypes that we observed at the start of this project. We found that CYD-1 in the uterus is crucial for maintaining oocyte quality in wild-type worms. This was very interesting as CYD-1/cyclin D, typically known for its role in the cell cycle, is also involved in regulating the quality of oocytes and reproductive fidelity cells non-autonomously. In daf-2 mutant worms, cyd-1 knock-down causes abnormalities in the uterus, vulva, and sheath cells (sheath cells surround the developing germline). This suggested that CYD-1 might, possibly play a role in somatic gonad development. Here too, lowering CYD-1 in the uterus of daf-2 mutants was sufficient to cause sterility. We found that this sterility in the daf-2 mutant was dependent on the activation of the downstream FOXO transcription factor, DAF-16 (which is activated when insulin signaling is reduced). Surprisingly, if DAF-16 is removed in these cyd-1 depleted daf-2 mutant worms, somatic gonad defects are alleviated and fertility is restored but poor quality oocytes are produced, similar to wild-type worms with cyd-1 knock-down. Therefore, we speculate that activated DAF-16 may sense the perturbations in the uterus (such as lowering of CYD-1 levels) and exacerbate defects in the somatic gonad, as a means of halting the production of poor-quality oocytes. Such mechanisms could be a strategy to ensure progeny fitness in a species.
This work is now accepted for publication by PLOS Genetics and I’ll be defending my thesis soon!
Since you are nearing the end of your PhD, what has been your PhD journey like?
PhD is a journey with both ups and downs. There was a time when I doubted my data and worried that things weren’t working. I was worried whether my controls were working, if I was setting things up right, or if we were thinking in the right direction. We had initially tried to link CYD-1 to DNA damage repair, but most of the DNA damage assays did not support this hypothesis. That was a low point for me because I wasn’t sure what direction to take. I was almost in the middle of my PhD and had no other backups. I didn’t know what the next course of action was. After more reading and discussions with my guide Dr. Arnab and my senior Gautam, I conducted some additional experiments that hinted at a new direction. This shift gave me confidence, especially when the results started making sense. I am thankful for the mentoring I received from Dr. Arnab and Gautam, which has helped me immensely during my journey.
Once things began to fall into place, and I started getting results, I became more confident. Dr. Arnab really pushed me to start looking at the whole story. That sense of finally understanding what was happening was a huge relief and a proud moment for me. I was confident about my work.
When things got hard, how did you find a support system?
I initially gave my 100% in my PhD and felt I hardly had time for anything else. So, it was difficult to cope initially. I was feeling exhausted too, and was not able to manage my time properly. I am an introverted person. So initially, it was really difficult for me to share and ask for support, and I used to keep a lot of things to myself. All of this has caused some misunderstandings with people I am close with. Now, I have realized that it is important to express your feelings and be open to discussing things because, when things go wrong, which is bound to happen at some point, you need people who understand and support you. Now, if something is bothering me, I try to solve it as soon as I can, or I talk to a friend who can help me with it. None of this would be possible without the constant love and support of my family.
Before we wrap this up, how do you balance work?
I do not have a lot of hobbies at the moment. But I think it is very important to stay grounded. I like to do simple things like listening to songs and going to my friends and having tea with them, just relaxing and spending time with them helps. Spending quality time with my mother and my partner is a blessing.
