PSU graduate student Pat Clouser stands next to rows of labeled tanks containing killifish
At ten o'clock in the morning, Pat Clouser feeds the fish in the Podrabsky Laboratory at Portland State University (PSU).
They are a species of small killifish, Austrofundulus limnaeus, that he's spending almost all his time thinking about while working on his doctorate. He is attempting to analyze their genome and isolate the drivers of one specific trait.
"This particular species only lives in these ponds in Venezuela, and for part of the year, the ponds completely dry out. All of the matured members of the species die. Anything that's been hatched, that's swimming around, dies. The only survivors are the tiny embryos that the adults lay in the soil before they die that keep the species going. When the pond fully dries out, the embryos enter a state of dormancy called diapause. They can stay in this state until the pond is again refilled with water, which can sometimes mean many, many months of living in diapause," Clouser explains.
During diapause, the embryos are extremely tolerant to stress – including variation in temperature, light, moisture, and even oxygen. Embryos at certain stages of development are able to survive a complete lack of oxygen – a state known as anoxia – for hundreds of days.
How they do it is a question of great interest to researchers.
FROM PROVIDENCE TO PSU
Before coming to PSU, Clouser was working as a laboratory technician at the Molecular Genomics Laboratory at Providence, which provides genomic sequencing for cancer care and clinical research at the Earle A. Chiles Research Institute, the research arm of the Providence Cancer Institute. With a Bachelor's degree in Clinical Laboratory Science from Oregon Health and Science University, his daily work as a bench tech consisted of things like pipetting liquids into other liquids, loading the solutions into a machine, and helping to analyze the results. But he always had questions.
His technical director at Providence, Brian Piening, noticed that they were good questions.
"Pat was definitely an outlier. He would ask things like, how are these mutations driving this person's cancer? Why does this treatment work for people with these genomic-based biomarkers? It was clear he was destined for graduate study."
Piening was acquainted with PSU biology professor Jason Podrabsky; their paths had crossed because they were both studying aspects of space exploration. Piening was part of the formative NASA twin study, and Podrabsky was interested in the potential of his killifish to survive space transport, given their unique tolerances. At some point during their conversations, Clouser's name came up, and Piening and Podrabsky agreed that it might be fruitful to pilot a collaboration where they could co-advise him as a graduate student.
Pat remembers the day he got the call from Piening.
"I was off one afternoon and he called me, and he goes, hey, are you still interested in getting a doctorate? I said, give me a little time to think about it, and it didn't take me long to think about it. I thought, I'm probably never going to get a call, ever again, from somebody offering me an opportunity to go get a doctorate," he said.
So Clouser applied to the PSU biology program and was accepted. Now, Podrabsky is his academic advisor at PSU during the school term, and Providence supports his work during the summers. As he works with killifish, he is learning how to interpret massive datasets and how to design various genetic experiments; valuable skills that will help with his ultimate goal of returning to cancer research.
"The data sets that he works with are huge and complex. I've had these kinds of data sets for a while, and I needed somebody that had the stomach and the skills to analyze them properly," Podrabsky said.
FROM KILLIFISH TO CANCER: ANALYZING THE GENOME
Piening and Podrabsky didn't just share an interest in space exploration; their two fields of study overlap in other ways. In Podrabsky's lab, he studies a specific organism (the killifish) that thrives under exceptionally harsh conditions considered lethal to humans. At Providence, Piening studies cancer, which is similar in that it can survive an environment - the human body - that it's not really supposed to arise in. Like Austrofundulus limnaeus, tumors can survive without access to resources that most living organisms need.
"How can biological life grow and thrive and proliferate in such extreme settings? If we can figure out the mechanisms by which organisms do that in general, we could maybe figure out additional ways of shutting down a tumor," Piening said.
The killifish also have the ability to arrest cell proliferation.
"Killifish can actively stop cells from dividing. Cancer is uncontrolled cell division. So there are potential lessons that we could learn from the killifish that might help us to better understand how to treat heart attack, stroke, and cancer in humans," Podrabsky said.
Last summer, under Piening's guidance, Clouser worked on a project testing patents' genomes for "homologous recombination deficiency,"or HRD, which can make cells more susceptible to DNA-damaging agents and potentially contribute to cancer development.
"To be positive for HRD can essentially rule you out of certain treatments, which is important, because if we didn't test for this, your oncologist, or whoever is leading your treatment, might sign you up for specific types of treatments that wouldn't work. Knowing if you are positive or negative for this can direct you to a treatment that has better outcomes for your specific type of cancer," Clouser said.
A SYMBIOTIC PARTNERSHIP
The Molecular Genomics Laboratory and the Earle A. Chiles Research Institute (EACRI) are part of the larger Providence Health system. If a Providence patient needs their genome to be sequenced for the purposes of personalized medicine, it will likely pass through here. The EACRI employs a large team of scientists, yet since it is not a university, the scientists don't have many chances to directly mentor graduate and undergraduate students. This is a gap that leaders at Providence have been looking for ways to address for some time; Podrabsky recalls several past meetings between PSU and Providence exploring the possibility of a collaboration.
Podrabsky and Piening's co-advising of Pat Clouser serves as a template for a new student pathway between PSU and Providence. At this point however, no program has been formally established. Annie Lindgren, the Associate Vice President of Research at PSU, hopes to strengthen the partnership and give PSU graduate students more routes to finding research funding and success.
"Providence has an amazing array of researchers who really want to train and mentor students, but they don't have access to students. PSU has fabulous students who are looking for more direct research experience. So the question is, how can we establish a formal relationship so that PSU graduate students can be mentored by biomedical researchers at Providence?" Lindgren said.
Involving PSU students in the work being done at Providence would not only introduce students to the realities of working in molecular genomics, it could also strengthen the research and enrich the skills of the researchers.
"We always say, how you learn something deeply is to teach it to someone else. And students coming in have all sorts of new perspectives, and they can help you think about a project in a way you haven't thought about before," Piening said.
"I didn't learn bench skills or how to do all the things required for genomic testing from reading a book. You have to do it. But that means you have to have the facilities and the opportunities. This is how we train new scientists. And if we can't train new scientists, we can't keep learning anything new," Clouser said.
If a more robust partnership between PSU and Providence is successfully created, the environment between the two institutions could lead to more innovative health outcomes and a better understanding of the human genome. It could also become a spawning ground for future scientists.