Lab Meeting: Pardis Sabeti
“Always do the thing that keeps you up at night, wakes you up in the morning, and then just keeps you fascinated.”
Indie-rock frontwoman, rollerblader, tennis player, mentor, math educator, biotech co-founder and creator of extremely elaborate lab holiday cards, Dr. Pardis Sabeti wears many hats, and wears them well.
Yet to the global science community, she is best known for being one of our generation’s most creative geneticists. Dr. Sabeti began her research career as an undergraduate at MIT, working with David Bartel and Eric Lander. She completed her PhD in evolutionary genetics as a Rhodes Scholar in 2002 before enrolling in Harvard Medical School. As a 26 year-old med student, she developed a novel computational approach to pinpoint regions of the genome under recent selective pressure; this framework has been leveraged to search the genome for alleles associated with resistance to malaria and other diseases: “I set things in motion, ran the algorithm, and something amazing happened. I saw evidence of evolution at a gene linked to malaria resistance. I saw a path to study the entire human genome” (Q #4).
Sabeti graduated summa cum laude from Harvard Medical School (an impossible feat strictly off-limits for mortals like this author) and was a Soros fellow. She has received accolades almost too numerous to count—World Economic Forum (WEF) Young Global Leader, National Geographic Emerging Explorer, Smithsonian American Ingenuity Award for Natural Science, TIME’s “Person of the Year” (as one of the Ebola fighters), TIME’s “100 Most Influential,” the Vilcek Prize for Creative Promise, the NIH Innovator Award, the Packard Fellowship, and an Ellis Island Medal of Honor. She is a member of the National Academy of Medicine and has served on the MIT Board of Trustees. She is currently an institute member of the Broad Institute of MIT and Harvard and a professor in the Department of Organismic and Evolutionary Biology at Harvard University, a professor in the Department of Immunology and Infectious Disease at Harvard School of Public Health, and a Howard Hughes Medical Institute investigator. Her lab develops cutting-edge computational and experimental approaches to study how genomes evolve, and has aided response efforts to outbreaks of Ebola virus, Zika virus, Lassa virus, and Sars-CoV-2.
Sabeti describes her approach to science as unconventional: “I've gravitated towards the things that were off the beaten path, not of interest to others” (Q #8). Just as she rises to the top of a field, she changes tack, searching for new ways to pursue creative science: “I went where I thought there was something important, and it allowed me to do my best work in that space.” As Sabeti has already been compared to hockey legend Wayne Gretzky, I have no reservations invoking another “great one,” Bob Dylan. As Dylan became the preeminent folk artist in 1965, he famously went electric—to the shock (and initially dismay) of fans and mentors. In doing so, he created a new genre of “folk-rock” music, which was the first in a series of reinventions that have characterized his career. Sabeti has already pioneered several new “genres” of genomics; I am excited to see where this scientific “rolling stone” goes next.
Below is an interview with Dr. Pardis Sabeti from August 2022:
1. Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings. What were the killer experiments?
It’s actually interesting; I think with the way that science is done today and the way that Nobel Prizes work, so many scientists are overlooked. We know such few names of the scientists driving us forward, and even for the projects that we are aware of, there are many individuals on them who are driving this work. I recently co-wrote a textbook on outbreak science with my students, and as part of the project, we started each chapter with a story about a scientific discovery. In every instance where we were telling the story of one major person credited for a discovery, there were many different people who came before who were overlooked. Take Edward Jenner for example, who is classically credited for leading the invention of the vaccine because of the studies that he had done on variolation to inoculate individuals from smallpox. This was in fact a practice that was thousands of years old, first documented in China and practiced in Africa, long before coming to America. We told a story about Oneismus, an African slave of Cotton Mather’s who convinced him to use inoculation in smallpox and finally convinced Dr. Zabdiel Boylston to run experiments during a smallpox outbreak. The results demonstrated definitively that inoculation could greatly reduce fatality from smallpox. It was a killer/savior experiment, but little is known about it. Boylston is a major street in Boston, but Oneismus is largely unknown. To think of science and the history of science only through the names we know, is to not understand how science works at all or how history is written.
2. What are you reading in your free time?
I have very little free time, so if I do any reading, it's only Audible that I am able to listen to for 10 minutes at a time. The latest one I'm going through right now is Creativity Inc [by Amy Wallace and Edwin Catmull] on the formation of Pixar. It's a terrific read/listen.
3. What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor?
I had a taste of and passion for science since an early age in high school, but I really didn't understand what it meant to practice science. My science fair projects would not in any way indicate that I would ever do science and were very silly projects. When I came to MIT as a freshman, a friend of the family told me that I would do right by reaching out to Dave Bartel and working in his lab. At that time, Dave was just a little-known fellow at the Whitehead Institute, and little did I know that he would go on to become one of the most prominent scientists in the world, revolutionizing the field of RNA, catalytic RNA, and non-coding RNA. When my family friend suggested I meet with him, she said, “He’s the most rigorous scientist I know, and there's no better place to learn how to do science than by him.” While it was a grueling experience and I was a pretty terrible trainee, it certainly set things in motion for my career, and I will always thank Dave for that.
4. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?
Science is truly amazing. If you stay in it long enough, there are a lot of losses, but also so many exhilarating wins; this is a tough question. It's like being in a band, where every song is my favorite song, and it's really hard for me to choose between them. I think every discovery is unique and holds a special place in my heart. For one example, I will always remember my first major hit. I had a number of really young, early moments in my early papers. My first big paper was based on an algorithm I had been twiddling my way on in obscurity for a long time and had an idea that there's a way we could detect natural selection in the genome. I'll always remember it – I was in medical school, it was 3am, Napster became a thing, and I was listening to music all night, every night. I set things in motion, ran the algorithm, and something amazing happened. I saw evidence of evolution at a gene linked to malaria resistance. [From this result] I saw a path to study the entire human genome.
5. What set of research questions or projects has you most excited about coming into lab today?
With the amount of data that we've been generating and awareness from around the world during COVID, there's finally an opportunity to really see if we can stay ahead of infectious diseases. I've been really excited about work we've been doing to try to use genomic data to track pathogen spread in real time and to connect that with lots of multimodal data from wastewater, WiFi, personal symptom reporting, location mapping, and beyond. I'm eager to see how we can get the upper hand of pathogens. Also, with the sheer amount of data that we're generating for the first time across species, being able to really understand the logic of mammalian and viral genomes; to understand not just the proteins, but all of the different elements in the genome, what they're doing, and how they're evolving. We have a series of projects that have been interrogating human and microbial genomes to understand how they adapt and evolve, what mutations are important, and what the function of these elements are. It's work we've been doing for a decade, but are finally closer than ever to answering them definitively.
6. Which areas of science, outside of your direct field, are you most excited about seeing develop in the next 5-10 years?
I also have a personal passion for cognitive science, and I have been following some work trying to understand natural variation in cognition. To be honest, many of the ideas come from outside of classic Western thought and are closer to Eastern thought, which really [are focused on] understanding the origins of different archetypes. I still think that there might be a biological basis, but we will really begin to understand how each of us see the world quite differently. In essence, from Eastern and unconventional ways of thought, really understanding the extraordinary amount of diverse ingenuity in the human population. At some point, I may move my own work toward bridging the divide between Eastern and Western medicine, and there are a number of areas at this intersection that I'm excited to try to cross.
7. Who are a couple up-and-coming scientists in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?
I'm a big fan of Kizzmekia Corbett, and full disclosure, I'm one of her faculty mentors. In all honesty, I think I'm learning from her. She's just an outstanding bright light, who already has made her name by being the force of nature behind the Moderna vaccine. Seeing the work that she's presenting on understanding how viruses are presenting to our immune systems, and how that can be leveraged for vaccines is extraordinary. Along that same line, Shira Weingarten-Gabbay, who is a postdoc in my group and will be a faculty one day soon, works to dissect and understand what is being produced and translated by viruses, as well as what they are presenting to the immune system. Together, their [KC and SWG] combined work is really going to transform the way that we think about vaccines, viruses and their interactions with the world around them.
8. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
Always do the thing that keeps you up at night, wakes you up in the morning, and then just keeps you fascinated. You will need that fascination when projects inevitably fall into the valley of despair at some point in their life. In my own career, I've gravitated towards the things that were off the beaten path, not of interest to others: working on esoteric methods of studying evolution in the human genome when the there was no genome to sequence, or jumping ship from human genetics to viruses when the human genetics field was exploding and no one could publish their papers on viruses. I went where I thought there was something important, and it allowed me to do my best work in that space. Ultimately, it's not that you can work on absolutely anything you want to, but rather looking for things that you're 100% excited to work on and at things where there's potential for continued work. If you can find what you are passionate about and it is something you believe in, you will make your best discoveries.
9. Who was your biggest scientific mentor? Why were they such a great mentor?
There is really no question in my mind that I wouldn't fundamentally be the scientist I am today if it weren't for Eric Lander. He believed in me as a freshman in college and supported me through every major decision I made in undergraduate, graduate school, medical school and faculty. I want to honor and show gratitude toward what he did for my career and the belief he had in me and many other women around me. I also respect that this was not the experience others had with him. In everything that I've known of Eric, he wants to be a source of good in the world, and I hope there is a path for reflection and redemption for him, like all of us.
Check out Pardis’ band Thousand Days on Instagram