Even scientists leave room for a little serendipity. That certainly was the case for Andrea L. Graham, Professor of Ecology and Evolutionary Biology, whose aspirations took an unexpected turn while she interned at a koala veterinary hospital in Queensland, Australia. Interestingly, her experience with these charming marsupials led to an obsession with parasites (especially worms), which remain a cornerstone of her pioneering research on host-parasite interactions.
In this Spotlight, Professor Graham, Co-Director of the Global Health Program (GHP) at the Center for Health and Wellbeing (CHW), shares her passion for disease ecology and evolutionary immunology. She discusses her notable contributions to the field, highlighting her particular interests in the mammalian immune system and the evolutionary and ecological dynamics that drive heterogeneity in hosts, parasites, and infectious disease.
A. I knew that I liked mathematics and chemistry, but it wasn’t until college that I discovered my love for biology. That’s where I learned that biology is not a set of given facts; it’s a whole area of inquiry where you’re always at the edge of the unknown. It is an opportunity to follow your curiosity, and I was very excited about that. So instead of studying mathematics, I decided to major in biology.
I minored in sculpture to satisfy my interest in art, particularly welding. Biology and sculpture were both engaging, while offering me different outlets and ways of thinking. For my sculpture thesis, I welded a throne out of scrap metal, which is still on display in my living room.
Q. In a recent documentary, you highlight a college internship that opened your eyes to another branch of ecology. Could you tell us about this unique opportunity, and how an unforeseen set of circumstances shaped the course of your career?
A. I have always loved natural history and the outdoors, so I jumped at the opportunity to spend time working on a koala conservation project in Australia. The internship was perfect, giving me the chance to study these charismatic animals in their natural habitat. I thought I was going to “save the koalas” by protecting the eucalyptus trees, until I got there and found the koala population battling a huge outbreak of a sexually transmitted disease that was dramatically reducing female fertility. As it turned out, that was a defining moment for me. I realized that this opportunistic bacterium could wipe out an entire species, which blew my mind. I thought, “Wow, this is really cool. I need to study host-parasite interactions.” And I’ve been doing it ever since.
Q. What led you to a career in academia – and Princeton University? When did you affiliate with CHW and assume the role of Co-Director of the Global Health Program?
A. I was not planning to become a professor. I was thinking about some kind of government science role or working for an NGO – non-academic ways of studying diseases of fish or wildlife. But I got hooked on research, and it’s pretty hard to beat the freedom of pursuing ideas in academia.
After earning my Ph.D. at Cornell and spending a decade at University of Edinburgh in Scotland – first as a postdoctoral researcher and then as an independent research fellow – I accepted a position at Princeton. About two years in, I joined CHW and have been co-directing the Global Health Program ever since I received tenure, about five years ago. GHP is a natural fit for me, given my interest in infectious and inflammatory diseases and my appreciation for interdisciplinary research, especially within the realm of global health. Global health relevance inescapably requires multiple perspectives. We can’t just understand the molecular, cellular and physiological basis of diseases to protect human health; we also need to understand how disease processes unfold through the various cultures, geographical settings, economies, and societies in which people live.
Q. Let’s get into your research. You characterize yourself as an evolutionary ecologist specializing in immunity and disease ecology. Can you explain the nature of this concentration?
A. My research sits at the crossroads of disease ecology and evolutionary immunology. At heart, I’m a disease ecologist who thinks about transmission dynamics as other disease ecologists do, but I do so primarily in the context of immune systems and parasitology. For instance, I want to understand the evolution of parasitic worms, which have crazy life cycles. Their migrations in host bodies are just astounding... they swim around in the blood stream, yet the immune system can’t get a handle on them. They can dodge the immune system for years and obtain transmission opportunities galore. This helps to explain why parasitic worms continue to infect over a billion people in 2020.
I’m also an evolutionary biologist, because my research is all about explaining variation – in host defenses, parasite attacks, and the severity of diseases. Let’s take COVID-19, for example. One of the most striking things about this virus is the variation in how sick people get. Some people can be infected and never know it. Some people lose their sense of smell and have no other symptoms. And some people experience exceptionally severe disease and even death. This is a vivid illustration of how a newly emergent virus causes divergent outcomes on the host side. Ultimately, I think that evolutionary biology will help explain why human hosts vary so much in the immune pathways that are required to fight this virus, and in the pathophysiology of COVID-19. Understanding such heterogeneity is a challenge and a top priority in medicine.
Q. Has your research yielded any explanations for this kind of variation – why infections affect people so differently?
A. Well, one hypothesis is resource allocation, which is something I explore in my research. Hosts have a limited amount of resources available to them, a budget to allocate among life’s priorities. Investing in an immune response is really important if that infection might kill you. However, when those resources – such as calories, amino acids, and proteins – are invested in an immune response, they can’t be invested in other things, like making babies.
This point is clearly demonstrated in a study my collaborators and I conducted on wild sheep in Scotland several years ago. Some sheep mounted a very strong immune response to parasites but had lower reproductive rates. Other sheep had weak immune responses but made babies like crazy. We concluded, since exposure to parasites varies across years, that long-lived slow breeders and short-lived fast breeders may continue to coexist, and that heterogenous immune strategies can therefore be maintained in the population.
Q. Earlier this year, Princeton University awarded a grant to you and some of your colleagues to investigate asymptomatic spread of COVID-19. Can you share a bit about that project and any other coronavirus research you’re working on?
A. Sure. I’m currently involved in two big collaborations related to COVID-19. The grant-funded project, which is led by Jessica Metcalf, Julien Ayroles, and Bryan Grenfell, is focused on studying SARS-CoV-2 transmission and antibody responses in the Princeton area. We are trying to assess the variation and durability of human antibodies and how rapidly the virus spreads by examining our small corner of the world. This project is in its infancy, but we’re hoping our findings will contribute to the understanding of genetic susceptibility to COVID-19 and how varied population immunity will modulate transmission dynamics. There is still a lot to be done.
I’m also participating in a COVID-related research collaboration based at Mt. Sinai Hospital in New York, which was the epicenter of the epicenter when the virus emerged last Spring. This data-driven project explores causes of the big inflammatory responses induced in the most severe COVID cases. We’re analyzing data from Mt. Sinai’s Emergency Room and Intensive Care Units to investigate what determines the difference between somebody who gets really, really sick and has a huge, insurmountable inflammatory response – even after the virus is long gone – and somebody who turns the corner and ultimately survives. Underlying genetics may play a role, but we’re hypothesizing that causes of the different trajectories may be detectable as an ecological problem, too. If you study the human body as an ecological system, you can track the exponential increase of inflammation, for example, and identify points at which the inflammation begins to spiral out of control in that system. It’s a complicated process and one that continues to challenge the medical and scientific communities. Ideally, ecological analysis can help to reveal the optimal timing and type of clinical interventions.
Q. What else is happening in the lab? Perhaps you could touch on a couple of other major projects probing infectious disease and public health.
A. I’m working on a bunch of other things… lots of exciting, ongoing projects. I just learned, in fact, that a paper on another zoonotic virus was accepted for publication. This work explores interactions between worms and hantaviruses, especially one called Sin Nombre virus (ironically). Sin Nombre virus infects wild rodents but can be transmitted to humans and is risky to human health. Our research shows that Appalachian deer mice that test positive for this hantavirus and also have worms in their bellies live longer than deer mice that only have the virus. Somehow having the worm is associated with longevity, which has real transmission implications. It means that a mouse that is infected with both a virus that might hurt us and a worm that allows it to live longer poses greater zoonotic risk potential.
I also work at the EEB [Department of Ecology and Evolutionary Biology] field station near Hopewell, releasing lab mice into semi-natural environments for various immunological experiments. We cannot study COVID, in part because our mice don’t have the receptors that make them susceptible to SARS-CoV-2, but we can study the effects of natural environmental microbes on the maturation of the mammalian immune response.
Q. You were recently named a 2020 Fellow of the America Association for the Advancement of Science (AAAS) for distinguished contributions to the field of ecological and evolutionary immunology. Congratulations! Could you share your thoughts about receiving this award? Does it recognize a specific project or your collective body of work?
A. Thanks! I am deeply honored that the Association felt my research on mammalian immune function merited this recognition. It’s a bit of cheery news in this remarkably difficult year!
I’d say that this election acknowledges the body of my research at the unusual interface between biomedical immunology and evolutionary ecology. In particular, when nominating me, the AAAS cited my discoveries pertaining to ecological and evolutionary causes of heterogeneity among hosts in susceptibility to infectious and inflammatory diseases, including life history trade-offs affecting the strength of immune response, signaling feedbacks affecting the type of immune response, and co-infections affecting the efficacy of defense and severity of disease.
Q. In addition to your research and academic responsibilities, you are active in the broader campus community. Are there any programs or initiatives about which you are particularly passionate?
A. Advocating for diversity, equity, and inclusion is a really important part of my workload at Princeton. It’s something I care about deeply. As part of that commitment, I serve as Chair of the EEB Climate Committee, which is dedicated to making Princeton a better, more welcoming place for women, people of color, and other underrepresented populations. A lot of great projects have come through this committee, including the now annual EEB Scholars Program. Designed and led by our graduate students in collaboration with Vanessa Gonzalez-Perez [Assistant Dean for Diversity Initiatives in the Natural Sciences], the program aims to break down barriers and demystify the path to graduate school. Plans for 2021 will be crystalized and announced this spring.
Q. Do you have any advice for students interested in pursuing a career in disease ecology?
A. Be fearless about crossing interdisciplinary boundaries… and allow for serendipity. Many of my undergraduate students feel like they need to have it all figured out at the age of 18. They stress about not finding the “perfect” internship and not knowing exactly what each step needs to be along their career path. So I try to emphasize that careers are not always linear, and insights can emerge from surprising places. As long as you continue to pursue interesting things and follow your curiosity, you’re on the right path.
Q. In closing, would you be willing to share a fun fact about yourself - something that might surprise your students and colleagues?
A. I guess what leaps to mind is that I really love folk music, and I am an amateur folk singer. In the Celtic world, singing together is a very important part of social life. There is a tradition where you sit in a circle with your friends and take turns leading a song. I just love that. I miss many things about living in Scotland, but I miss the folk singing most of all. I don’t think that anyone in Princeton knows that about me, except my husband! We sing together a lot.