Evolution of a Biological Battlefront

HHMI Investigator Nels Elde and his lab at the University of Utah work at the crossroads of evolutionary genetics and cell biology to study one of the biggest battlefronts in science: host-pathogen interactions. In an infection, the host – an organism such as a plant, animal, or human – confronts a pathogen – a virus, bacterium, fungus, or parasite. In many cases, the host can resist or tolerate the pathogen, but in others, as we know all too well, the pathogen can cause severe disease. In humans, infections not only impact our health, but ultimately cause changes to our immune system. As such, over time, infections give rise to creative immune strategies that ultimately protect us from pathogens. Across species, such evolutionary changes can sometimes only be discerned over a great deal of time – sometimes, millions and millions of years of divergence – as “records” of these pivotal changes found in DNA. Fortunately, scientists like Elde and his team are experts at decoding these records. “We’re really interested in the impact of infectious microbes on core aspects of [human] evolution,” Elde says. “How have viruses, bacteria, and fungi influenced the evolution of our immune systems and even the evolution of our cells? Are there echoes of interactions humans have had with microbes or with pathogens hiding in our genomes?” Typically, we tend to think about evolution in the same way we think about history: as distant events that happened in the past. But, Elde says his lab works to “flip the script,” noting that, even though evolution can be traced billions of years, it also still plays out today, sometimes in a matter of weeks or months. “The projects we set up in our lab try to reveal evolution in real time,” he says. “The question is: Can we use the experiments or observations we’re making today to look backwards, to understand the origins of life, the origins of our species, and the origins of the diversity of life all around us?” Today, evolutionary geneticists like Elde and his team have access to an incredible wealth of genomic information thanks to cutting-edge sequencing technologies. With so much data available, the trick, Elde says, is to look for patterns. As scientists working in Salt Lake City, Utah – where mountains, canyons, and streams offer stunning backdrops to the lab – there are plenty of places from which Elde’s group can collect new samples of countless organisms. “We’re busy in our lab sequencing the genomes of all kinds of critters that we collect from the world around us to decode their genomes and add them into this wealth of genetic information that we already have,” he says. Many researchers in Elde’s lab study the evolution of viruses. The viruses they work with are virtually harmless, but Elde and his team observe patterns of changes in these viruses that help shed light on how all kinds of viruses – including those capable of causing the next pandemic – might change and evolve. Looking at model systems HHMI Hanna Gray Fellow Katie Deets, a postdoc in Elde’s lab, has always been interested in how organisms protect themselves or respond to infections. Most recently, shifted her attention away from mammals to focus on the dynamic host-pathogen interactions found in aquatic ecosystems. Deets has long considered the field of immunology her home, but now is a particularly exciting time to work in the space, she says. That’s because, in recent years, scientists have taken a deeper dive into how all sorts of organisms respond to infections, and there has been increased awareness that studying these responses can impact our understanding of human and mammalian infections. For example, if you compare the antiviral responses of a species of bacteria to those of humans, you will see responses that look very different, she says. “But then, it’s kind of crazy, you will also see in those same bacteria some antiviral responses that are very similar to how our own immune systems work,” Deets says. “It raises really interesting questions about what is the same and what is different between the two, and what does that mean over a time scale and organismal scale.” Deets loves working in this space now, but she didn’t always picture herself in immunology. As a kid who grew up in Washington state, she told everyone that her dream was to be a meteorologist, or perhaps a storm chaser who covered tornadoes and hurricanes. But, as an undergraduate at Seattle University, Deets stumbled into an immunology class and things just clicked. The professor invited her to work in her lab and invested time in helping Deets tackle hard questions – not just about the research, but also, about her next steps: What kind of science interested Deets most, and what did she want to pursue in graduate school? Deets went on to earn her PhD at the University of California, Berkeley, where she studied host-microbe interactions in mouse models of the small intestine in HHMI Investigator Russell Vance’s lab. Afterwards, Elde’s lab caught her attention because of the group’s work on pathogen evolution. From mentee to mentor In the same way that mentorship changed Deets’s life, she’s already making an impact on others’ lives. Hands-on work in the lab could be intimidating to those newly setting out in academic science, but undergraduate Eleanor Wachtel fits right in with the Elde Lab. Coming into college, Wachtel first thought she wanted to pursue medical school, but she quickly felt it wouldn’t be the right fit. When she connected with the University of Utah’s Science Research Initiative program, Wachtel jumped at the opportunity to gain hands-on experience in Elde’s lab. Already, she credits this experience – and the mentorship both Elde and Deets provide – with opening her eyes to other opportunities in STEM. “Mentorship is the primary reason I’m still in this lab and still pursuing science,” Wachtel says. “Having hands-on research experience as an undergraduate is so valuable. I think, a lot of times, working towards a grade makes other aspects of life in science get lost, such as learning what the research process is like. Having a real purpose in a lab and studying the things that truly interest you alongside a mentor who is also working towards many of the same goals is so important to me and it has really helped me determine what I want to do in the future.” Where the energy is needed most Like Wachtel, PhD candidate Hannah Young first thought they wanted to be a medical doctor, too. Young earned their undergraduate degree at California State Polytechnic University, Pomona, a Hispanic-serving institution, where their mentors helped them realize that the pathway to a PhD might be a better fit. “Most of my mentors there were professors, and they were particularly impactful,” says Young. “Many had a similar background to me and so it helped me to kind of see myself in their position one day. Representation in science has become increasingly important to me as I move through my career. As you work up the ladder from PhD student to postdoc and onward, you often see fewer people who look like me or who come from a similar background. So, it becomes increasingly important to have those people in my corner.” Young says that the people in the Elde Lab were – and continue to be – a major driver for why they decided to work with the group. “I thought the science was awesome, but I was really looking for a lab where I could both become a more independent scientist and work with people who were very supportive and helpful in my growth as a scientist.” In the Elde Lab, Young’s early work focused on the evolution of double-stranded RNA (dsRNA) sensing in zebrafish. dsRNA sensing refers to a cellular mechanism whereby cells detect the presence of dsRNA, a major indicator of viral infection, and trigger an immune response to combat the virus. More broadly, in humans, Young is interested in studying how and why patients might experience incredibly different responses to drugs used to combat an infection. “We think if we can understand how the immune system plays a role in that variability, and how different cell types and tissues play an important role in infection, then we can get to the bottom of why patients respond so differently to treatments.” Moving forward, Young recognizes that mentorship will continue to play a key role in whatever they pursue beyond their PhD. “I think mentorship is one of the most important places where we, as scientists, can put our energy because we have the opportunity to influence and support the growth of future scientists,” Young says. “Science is a big place,” adds Elde. “Sometimes, we don’t realize that it’s happening everywhere. I think when we open our eyes and see all the talent around us, science can become much more inclusive. We need to be open-minded about the fact that there are great scientists with great ideas everywhere. The more open we are to that, the better things become.”