Q&A with Nick Harper

 

Nick Harper is a Graduate Student in Mike Lee’s Lab

 

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

I was born in Houston, Texas and moved to Massachusetts when I was eight. As many kids are, I was fascinated by the wonders of the natural world: the diversity of bugs I could find outside, books about dinosaurs, television shows about planets outside our solar system. I was very fortunate to grow up in a family that valued and embraced science and curiosity. As such, I grew up with the understanding that science was something that you could do for a living—simply having this notion in the back of my mind would turn out to be very important.

After high school, I attended the University of Vermont for my undergraduate studies. The first semester, I tried to major in biology, thinking that was what I was most interested in. It quickly became clear to me, though, that it wasn’t meant to be. I was mostly disinterested in the coursework and found many of the topics difficult to absorb. Luckily that semester I also took a wonderfully taught linear algebra course, which motivated me to change my direction. I then switched to studying mathematics, not because I was especially good at it (I wasn’t), nor because I dreamed of being a mathematician (I didn’t), but because the coursework was far and away the most intellectually stimulating. Following graduation, I wanted to transition into biological research. I knew that modern biology demands quantitative skills, and that my undergraduate degree may in some way be useful, but I had little idea of where to start. Mostly by luck and happenstance, I came across a job posting for a research technician position in a cancer bio lab and applied—completely ignorant of what cancer research really entailed or what exactly my role would be. I got an offer from the Polyak Lab at Dana-Farber, where I applied bioinformatic approaches to study breast cancer. There, through fantastic mentorship, I developed new skills and a passion for research. The experience was both extremely humbling and exciting, and led me to graduate school where I am now.

What motivated you to become a scientist?

I’d like to say I had a spark of inspiration—a eureka moment—that sent me down a singularly focused path towards being a scientist. I did not. Instead, the development was slow, and more than once I questioned if I was making the right decision in pursuing science. I think the best decision I made early on was to put myself in positions where I could become a scientist, even though I didn’t totally know if that was what I wanted. Then, I gave myself time to grow into the role. Now, I cannot envision something I would rather do more. That being said, I do feel like there are several other career paths I could have also found passion in had my trajectory gone a different way.

Why did you start working on this project? What first drew you to the question?

Several different anticancer therapeutics are thought to owe their efficacy—at least in part—to modulating the transcriptional state of a cancer cell. The idea that cancer cells become “addicted” to their transcriptional state, and that this vulnerability is targetable, has led to lots of development in this space. However, we lack a clear way to predict which cancer types will be sensitive to which transcriptional modulators. Our original goal was to predict outcome based on transcriptional state. Classic transcriptional inhibitors—those that turn off transcription genome wide through the degradation of Pol II, such as a-amanitin—served as controls, though we quickly realized that even these drugs behaved in unexpected ways. This led us down the unexpected path of unraveling precisely why these “controls” behaved the way they did.

In 3-4 sentences can you tell us what you think are the key main findings from your work.

The transcriptional activity of RNA Polymerase II (Pol II) is considered a life-essential function. This study demonstrates that Pol II inhibition activates cell death due to loss of the Pol II protein, rather than loss of Pol II transcriptional activity. We characterize a signaling mechanism that activates cell death when cells lose Pol II. Furthermore, we find drugs with diverse annotated mechanisms owe their lethality to loss of Pol II protein.

What was the most exciting moment for you, or was there a particular result that surprised you?

One finding that surprised me the most was that several clinically used anticancer therapeutics—even those assigned to drug classes unrelated to Pol II degrading drugs like triptolide—owe their lethality to loss of Pol II protein. This highlights just how much opportunity remains to uncover, at the cellular level, the mechanism of action of even our most commonly used drugs.

What was the most difficult experiment to carry out successfully?

A major challenge in this project was functionally demonstrating that loss of Pol II protein, not loss of Pol II enzymatic activity (ie. mRNA production), was causal for cell death. This required us moving beyond correlative arguments and necessitated functional experiments where we dissociate the existence of Pol II protein from the existence of mRNA. This is of course challenging because Pol II protein is required for producing mRNA, and mRNA is required for producing Pol II protein—a chicken and egg problem of sorts. We came up with three complementary strategies, none of which were perfect on their own, but which together well supported our hypothesis. No one experiment was in and of itself challenging to perform, but rather the task was conceptually challenging and took us a while to put together. 

Looking back, what advice would you have given yourself at the start of the project?

As a young student, I think it is easy to fall into the trap of focusing on the experiments you know how to do—quickly generating data can feel productive. Yet, often, the most pertinent and important experiment is the hardest one to do, the one that requires you to learn a new technique or develop a new reagent for. Indeed, directly answering the most pressing questions during this project required me spending extra time learning new things, even at the expense of feeling productive. In hindsight, my advice would have been to dive headfirst into these challenges with confidence. The time spent on the hard and important questions turned out to be the most productive in the end. Furthermore, once I dove into a new problem or technique, I found it was never as difficult as I had initially imagined.

In your opinion, what are the most pressing questions for the field currently?

In the world of cancer pharmacology, there is a significant focus on identifying new drug targets and discovering how cancer cells become resistant to existing drugs. These studies are essential for improving cancer outcomes. However, a question that is too often neglected is, when a drug does work, why? This question must move past an initial understanding of drug binding, and towards a mechanistically resolved systems-level understanding of cellular response. I would go as far as to say that we lack a complete understanding of how almost all chemotherapies work. Our paper highlights one example. By better understanding the functional mechanisms of drug response, we can uncover both new biological principles and new therapeutic potential.

Do you have any advice for other young scientists at any career stage from undergraduate through postdoc?

At the undergraduate level, for those who are broadly interested in the life sciences, it is important to know that the science done today is incredibly cross-disciplinary. As such, expertise in fields outside of biology—such as chemistry, physics, mathematics, computer science, etc.—are also highly desired and are applicable to research. So, my advice to undergraduates would be to study what excites you, interests you and challenges you, and know that you will still be able to transition into life science research in the future.

For graduate students, I would recommend training to become a versatile scientist. This requires stepping out of your comfort zone to learn new skills, often in areas that you are novice in. Being competent in multiple areas—from different experimental assays to computational methods—will allow you to ask and answer questions that others cannot and will help prepare you for a future after graduate school.

And finally, what’s next for you?

Hopefully, I will find a postdoc position in an exciting new lab and have the opportunity to do innovative science surrounded by many inspiring people.