Q&A with Rayna Magesh and Arshia Kaur

Rayna Magesh is a Research Associate and Arshia Kaur is a graduate student in Emma Watson’s lab.

Tell us a little bit about yourselves. Where are you from? Tell us about your journey to your current position.

Rayna Magesh: I was born in Kansas City, Kansas and grew up in Dallas, Texas. I moved to Colorado, where I finished high school and went to the University of Colorado at Boulder. I got my bachelor’s degree in Integrative Physiology and was on the premed track. I graduated pretty early, so I decided to get a master’s before applying to medical school. I attended Boston University, where I earned my MS in Medical Sciences. After finishing the first year of my master’s program, we were told to spend the second year working on a thesis project. We were given the choice to either write a literature thesis or a laboratory thesis. I knew that I wanted to get some hands-on lab experience, but all of the opportunities through the school were unpaid. So, I decided to write a literature thesis while also working as a Research Assistant. I applied to jobs across CT, MA, and NY, but it was tough to find someone willing to hire someone with zero lab experience! Luckily, Emma came across my resume and decided to interview me. I felt like we clicked pretty immediately, and I felt like her lab would be a safe place for me to learn how to become a scientist. And I am so glad I did- it really has been one of the best decisions I ever made!

Arshia Kaur: I grew up in Natick, MA and went to UMass Amherst for undergrad where I was a microbiology major. I met my undergraduate PI, Dr. Margaret Riley, in my second semester of freshman year in one of my introductory biology courses. I was lucky enough to be invited to join her lab studying the potential of bacteriocins as alternatives to antibiotics in a variety of contexts. I ended up working in the Riley lab for the rest of my tenure at UMass, and really enjoyed the process of doing wet lab research. Additionally, I interned at an immunotherapeutics start-up and got to spend time working with patient samples. I ended up applying to graduate school my senior year at UMass, and matriculated to UMass Chan in August of 2022. Coming directly from undergrad, I felt I really didn’t have a great idea of what research I might want to do long term, so I chose 3 fairly disparate labs to rotate in, which were the Thompson, Watson, and Shank labs. While I had great experiences in all 3, I was super excited to join Emma as she started up her lab.

What motivated you to become a scientist?

Rayna: I have always had an inclination towards physiology. I really enjoy learning about the human body and how it works, so I tailored my education around these topics. Once I was in college, I knew that my passions truly lay in medicine, and I started working toward that goal. Through college, I really didn’t have any opportunities to explore my abilities as a scientist (thanks to COVID) so it wasn’t something I had seriously considered. It wasn’t until I joined Emma’s lab that I realized how much I enjoy basic science. It is so exciting to take a problem, design experiments, and collect data to try and better understand that problem. This journey has been incredibly rewarding and enriching- far more than I ever expected! I am so grateful to have had this opportunity to explore my love for science, and it is something I will carry with me throughout my career.

Arshia: I initially majored in microbiology at UMass because it was one of the only subjects I was interested in, and I had planned to go to dental school after graduation. Once I joined the Riley lab I was spending hours in the lab daily, and grew to really appreciate the scientific process.

Getting to spend your time investigating questions no one else has ever answered was incredibly exciting to me. There is something so rewarding about seeing an experiment you put hours into designing and troubleshooting work and seeing a research project progress. I also really enjoyed working in the lab as we had a great environment and so I got to do work I was interested in while spending time with people I liked. While interning, I got to experience working on therapeutics development and found myself very motivated that I was able to apply the concepts I was working on in school to the lives of real patients. This was the final push for me to decide in my senior year at UMass to apply to PhD programs instead of dental school. I’m really glad that I made that switch, but am also bummed I took the DAT before I did!

What drew you to the Watson lab? Why did you start working on this project? What excites you about the project(s)?

Rayna: My first few months in the lab were focused on learning a ton of new skills to try and become a competent bench scientist. Eventually, Emma started to ask us to carry out some experiments that she had designed and brought over from her postdoc. After successfully carrying out a few of the earlier experiments, I got a better sense of what the project was really about and became really excited to help design and carry out new experiments to dig deeper at the question we were asking. As I grew more comfortable with this project- and science in general- I started presenting this work at seminars and retreats. This project has been incredibly special to me because it has taken me from someone who couldn’t even work a multi-channel pipette to a competent scientist!

Arshia: I met Emma initially at the research retreat during my first year. I received some (really useful!) advice to choose a PI for your thesis research that you get along with well as you have to work with them for years. I had been intrigued by her talk at the retreat, and when I went to chat with her I felt super comfortable with her. I met her again at UMass to talk more about a rotation, and she had a slide or two in her powerpoint on rare cancers and the fusion oncogene ORF library she was working on. The scope and potential impact of the project was super exciting to me, and I ended up asking her to rotate on it. I spent my second rotation trying to get a cloning pipeline for individual fusions going with mild success, but by that point I felt a strong sense of ownership over the project and I ended up joining the Watson lab. Looking back, the Watson lab would have not been where I expected to end up at the beginning of my first year- I was not interested in doing any dry lab work and was hesitant about joining a newer lab. But Emma is a great scientist and mentor so I’ve never thought twice about coming here. She is really smart and innovative so discussing science and brainstorming with her is fun and inspiring. I also appreciate how easy she is to talk to and how supportive she is. This particular project is particularly cool because it was my first foray into metabolism, which I’ve really enjoyed learning more about!

In 3-4 sentences can you tell us what you think are the key main findings presented in your current paper.

Rayna and Arisha: The paper focuses on how we can specifically target aneuploidy-associated vulnerabilities in the context of breast cancer, specifically with cells with copy number gains. We found that aneuploid cells have a higher demand for nucleotide production to accommodate their increased chromosomal load and were therefore more dependent on the de novo pyrimidine biosynthesis pathway. Aneuploid cells exhibit S-phase arrest and p53 activation when forced to rely on nucleotide salvage alone, representing a potential vulnerability to exploit and selectively target cancer cells. Thus, we suggest a novel adjacent therapy that compounds pyrimidine inhibitors with clinically used chemotherapeutics, and patient stratification based on tumor ploidy.

Can you remember the first experiment you did for the paper?

Rayna: The first experiment that I did for this paper was the RNAseq experiment! It was the first time I successfully created an RNA library and it was so rewarding to see the data from that. It was really after seeing that first heat map that I really understood the bigger picture and the direction that the project was starting to take.

Arshia: The first experiment I was part of that actually made it into the paper was when I inserted myself into helping with the first metabolomics experiment because I wanted to learn a new skill. I think I kind of kept doing this for a lot of aspects of the paper. This is funny for me to look back on, especially because this became a first author publication for me. I’m super glad I did, this project has been super interesting and I think I’ve grown a lot as a scientist getting to work on it!

What was the most difficult experiment to carry out successfully?

Rayna: Probably the dose curve! In theory, it sounded pretty straightforward, but the execution was tricky and super time-consuming. It involved multiple drugs at different doses and had to be done in several cell lines, so setting up the experiment usually took at least 5 hours in the hood. The experiment could also be a bit finicky, and just the sheer size of the experiment made it pretty susceptible to failing- so it took a few tries!

Arshia: This isn’t something technically challenging but it was super frustrating! I was doing color competition CRISPR validation assays which were supposed to be very simple in theory. Briefly, guides that dropped out in the screen should be outcompeted in a 1:1 coculture assay with control cells, which we would be able to decipher using fluorescent markers in the 2 cell types. When trying to do this with a guide for DHODH, we kept running into an issue where the DHODH KO cells were not dropping out, and retaining a 1:1 ratio with the control cells. I ended up spending a couple of months (maybe longer!) troubleshooting every technical aspect of the experiment I could think of to try and figure out what I was doing wrong. Turns out, the cells were sharing different metabolites between each other, which was rescuing the S phase arrest of the DHODH KO cells we were looking for. Eventually this spurred a completely separate project that Rayna and I are working on now about metabolite sharing between different cells.

We ended up having to find a new way to do the validations without using another population of cells and those worked beautifully.