Sarah Gaffen: I thrive on turning my vision for the lab into reality

I grew up in northern Virginia in the Washington DC area. No one in my family was a scientist, but we often watched educational TV programs on public television. I became fascinated by genetics and inheritance at an early age, and I was particularly struck by a documentary in the 1970s depicting a kid (boy) who was born with no immune system (known as X-linked SCID), dubbed the “Bubble Boy.”

In high school, I did a rather crude class science project on Drosophila genetics. I kept trying to induce mutations in my flies with ultraviolet light but never found any, a good early lesson in scientific failure. In retrospect, I was using the wrong wavelength of light and far too few flies (I didn’t learn about statistical power analyses until graduate school). When I was a senior, a teacher pointed out an opportunity for summer jobs in military research labs. I was accepted into a virology lab at the Uniformed Services University of the Health Sciences (USUHS), across the street from the National Institutes of Health. There, I learned about general virology, how to do DNA minipreps and maxipreps (before kits!), how to sequence DNA by hand with lots of ³²P (200 base pairs at a time), and generally what the day-to-day life of a scientist actually entails.

I did my undergraduate degree at Carnegie Mellon (discovering what a great city Pittsburgh is). I worked in a Drosophila lab doing fly transgenesis, a fairly new technique at the time. I received a strong grounding in molecular biology and went to Berkeley for my PhD, originally thinking I would study something in the area of gene regulation or RNA biology. I still had an interest in immunology, though, so I did my thesis under Marian Koshland (National Academy of Sciences, second woman president of the American Association of Immunologists), who studied B cell development and particularly the immunoglobulin J chain gene. My project focused on how cytokines, especially IL-2, regulated the J chain gene, and I began to appreciate how much of a black box the downstream signaling pathways of cytokines were. Interestingly, my childhood inspiration from the Bubble Boy documentary came full circle during my PhD when X-SCID was found to be caused by mutations in the IL-12Rγ chain.

I became increasingly interested in cytokine receptors and their downstream signal transduction mechanisms, so for postdoc I joined the Gladstone Institute for Virology and Immunology at the University of California, San Francisco, an AIDS research institute, to work on IL-2 signaling in T cells. The JAK-STAT pathway was just starting to be deciphered, so I joined the race to identify the “IL-2 STAT” (STAT5) (Gaffen et al., 1995). Over time, I broadened my interests to other cytokines that used STAT5 as well, and became interested in cytokines and cytokine families more broadly.

I always felt I should be in academia, as I love the thrill that comes from mentoring, and I also like to be in charge. My first faculty job was at the University at Buffalo in the State University of New York, in the basic research arm of the dental school. This environment opened my eyes to opportunities in oral immunology, which was (and still is) a neglected mucosal tissue. In another full circle situation, the chair of the microbiology department was none other than my boss from USUHS. Buffalo was also where I started to work seriously on IL-17. In 2008, I moved to Pitt, where the immunology community was larger and more relevant to my work, but oral biology remains a substantial part of my lab’s program.

Do you want the funny answer or the real one? During grad school and postdoc, I worked on IL-2 receptors and how they mediate signaling. Of course, immunologists know that IL-2 and IL-15 use the same core signaling receptor subunits (IL-2Rβ and γc). So, IL-2 + IL-15 = … IL-17.

During postdoc, I was starting to view myself as a “cytokine biologist,” thinking of these molecules holistically, beyond just a single family of cytokines. I became intrigued by cytokine homologues encoded by viruses, such as viral-IL-10 in EBV. Not many people realize that IL-17 was originally discovered as an open reading frame in Herpesvirus saimiri, though it’s still unclear what the benefit is to the virus (Gaffen, 2011; Yao et al., 1995). When the IL-17 receptor was cloned in 1995, it was surprisingly distinct from other cytokine receptor families in sequence and structure, so I thought it would be a fruitful area to work on. I began my independent lab in 1999 and had the luxury of a wide-open field for a few years, because no one much cared about this obscure cytokine. We made some progress in understanding the principles by which IL-17 acts; for example, although IL-17 is produced by T cells (and recently innate lymphoid cells), IL-17’s targets are not immune cells, but rather fibroblasts and epithelial cells, meaning that this cytokine acts as a bridge between the immune system and the infected or damaged tissue. Our early microarray studies defined the core IL-17 target gene signature, and a lot of those genes pointed directly to how this cytokine activates signals, such as transcription factors (C/EBPs, IκBζ, etc.), as well as post-transcriptional regulators of mRNA (Regnase-1, Arid5a, IMP2, etc.) (Li et al., 2019). Th17 cells were described in 2005, and overnight I found myself in the midst of the hottest thing in the field.

In the early days of my lab, we dabbled in various animal models to get a handle on the biological relevance of IL-17 in vivo. Being in a dental school, we looked at oral infections, including periodontal disease and oropharyngeal candidiasis (OPC, thrush). From my postdoc work at the Gladstone Institute, I was aware oral thrush was an AIDS-defining infection, so obviously T cells matter in the oral mucosa. Even so, there was not a lot known about how T cells mediated antifungal signals, or even which subset was required. In our first paper on OPC, a courageous and incredibly gifted student in my lab, Heather Conti (now a PI [principal investigator] at the University of Toledo) showed that IL-17 signaling, IL-23, and type 17 cells were absolutely vital for antifungal immunity in mice (Conti et al., 2009). This discovery established an entirely new direction in my lab that we are still pursuing. Gratifyingly, shortly thereafter, the importance of IL-17 in immunity to Candida albicans was validated in humans, where rare congenital mutations in the IL-17 receptor or its downstream signaling intermediates similarly predispose to OPC.

Now that I am at Pitt in a rheumatology department, half my lab also studies autoimmunity, again using various models of disease. The throughline for both “sides” of the lab is how IL-17 mediates signaling, and how those signals apply to the physiological events driven by this no-longer-obscure cytokine.

That’s like asking to choose your favorite child! The central theme of my lab is how IL-17 and related cytokines mediate intracellular signaling, and the resulting implications for host defense and autoimmunity. Therefore, about half the lab works on various autoimmune projects, and the other half works on host defense against various manifestations of candidiasis (oral, systemic, vaginal). However, the lines between these groups are blurred, since everything we do comes back to what IL-17 does and how it does it. IL-17 activates a very intricate post-transcriptional signaling network through various RNA-binding proteins. Our recent JEM paper, for example, describes a noncanonical RNA binding protein called Arid5a that is induced by IL-17. Arid5a is required for pathology in experimental autoimmune encephalomyelitis and in autoantibody-induced kidney disease. In humans, the ARID5A gene has hallmarks as a biomarker of chronic kidney disease (Amatya et al., 2018; Li et al., 2024). Surprisingly, though, Arid5a is not required for IL-17–mediated host defense against murine candidiasis (Taylor et al., 2022), and so the pathways that activated autoimmune pathology may sometimes be separable from those that drive antifungal defense. This could be very relevant for developing drugs to inhibit IL-17 signaling, suggesting it might be possible to target molecules that activate pathological inflammation yet spare the signals that prevent opportunistic infections.

I like this question. One frontier I am keeping an eye on is neuroimmunology and the gut–brain axis. A couple of groups have shown that IL-17 signaling on nerves impacts behavior in mice, in part triggered by consortia of intestinal fungi that include C. albicans. However, not a lot is known about how immune cytokines signal within neurons, and I predict it will be different from what happens in epithelial or mesenchymal cells. Another area I find utterly fascinating, though it’s not remotely close to my field, is human paleontology and paleogenetics. Who’d have thought even just a few years ago that we would know so much about the extinct human species that lived contemporaneously with Homo sapiens? I love that we can piece together human history on the basis of genetics. How cool is it that modern humans carry Neanderthal and Denisovan DNA in our genomes? I love the idea that there was a branch of hobbit-sized humans living on an isolated island. Being a Shakespeare fan and Anglophile, I was riveted by the discovery of Richard III in a car park in Leicester and the sequencing studies that proved his maternal lineage (but intriguingly, not his paternal ancestry) (King et al., 2014).

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  From not-so-good experiences in training, I became acutely aware that I should avoid the trap of comparing myself to peers. This is easier said than done—most scientists are ambitious and desperately want to be the “best,” but what defines that? It turns out that getting a first-author paper published in Science or Cell is a poor predictor of long-term success. Everyone’s path and pace are different, so it’s best to focus on your own, not anyone else’s.

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  It’s critical to speak up and be noticed, particularly for women. It’s a bit paradoxical, but asking questions aloud in seminars, lab meetings, or research-in-progress sessions makes you look smarter than those who keep quiet for fear of looking foolish. My lab members will verify that I say this all the time. I jokingly threaten not to reimburse them for meeting expenses unless they ask at least one question at the microphone to a speaker. …They know I am kidding (I think), but it works.

• (3)

  I learned from my mentors’ examples to be fearless (though selective) about delving into new scientific areas—when my group first started our work on oral candidiasis, I barely knew anything about the mouth or about fungi. Now, half my lab works on fungal immunology.

I added a “We Believe” section on my lab web site in response to the George Floyd murder and the rising tide of racism and hate that came in the wake of the Trump administration. This also hit close to home in Pittsburgh with the Tree of Life Synagogue shooting. My lab has always been diverse in every possible way, and I think this makes us better people and better scientists. “In the end, we will not remember the words of our enemies, but the silence of our friends.” (Martin Luther King Jr.) Therefore, I felt it was imperative to take a vocal and public stand to communicate the priority I place on tolerance, diversity, and equal rights (not to mention, coffee, chocolate, ice cream, and anything related to the number seventeen). I encourage others to make their priorities clear—it shows your lab members what you value and can even be a good recruiting tool.

Oh gosh, how much time do you have? There is so much posturing and subtle bullying that goes on in science, often in the name of “rigor.” It is really important for minoritized groups to understand the dynamics of this, yet not to be so discouraged they quit.

Something not always recognized in well-meaning discussions of parity is the burden of unrewarded service placed disproportionately on women (also minorities). Rarely is such service helpful to one’s career, yet women are asked to do more and tend to say yes more often than men. This concept is beautifully outlined in The No Club, a book written by professors in economics and business at Carnegie Mellon and Pitt (Babcock et al., 2022). The gist of The No Club is the toll taken on women’s careers and the collateral damage to their organizations when their most talented employees are wasting time with “non-promotable tasks” (NPTs). NPTs are defined as tasks that are important to an organization but do not advance the career of the person doing them. This is rampant in academia—all committees are told to create parity with women and minority members, but without acknowledging that such participation drains from time doing work that actually matters, both to their careers but also to the university. Being on a committee does not lead to a published paper or a grant. Advising your own student or reading a paper does. Saying no is hard, because often we want to be a team player, to be on a diversity committee, to help junior faculty, to advise someone else’s student on a problem they are having, to review papers for a journal (sorry, JEM!)… Yet none of that moves the needle on one’s personal career trajectory. I have a “no partner” whom I run all requests by—she nearly always tells me, “Heck no!” (using stronger language). The No Club also made me realize that I was perpetuating the problem myself, as I more frequently recommended other women for tasks I chose to decline. So, my advice to everyone is to (1) read The No Club, (2) find a “no partner,” and (3) think carefully about asking a female colleague to take on a task—you may not be doing her a favor. Is there a male colleague who might be just as good?

Ask me after November 5th.

I love seeing graduate students mature into being independent thinkers. There is nothing like the moment when a student argues with you and wins. I love setting the vision of our lab and seeing it come to fruition. I even enjoy writing grants, since that is putting our vision on paper (I just hate not getting them). I like traveling and having really smart colleagues who are also friends.

I do some political volunteering, and I have been ballroom dancing for many years. I am a fan of theater, especially musicals. I read a lot, particularly fiction (Andy Weir’s Project Hail Mary is one of my favorite books, and I will happily re-read Jane Austen any time).