Pilot Awards Lead to Career Success

We spoke with Sebastian Alejandro Riquelme Colet, PhD, about his experience working with the Irving Institute for Clinical and Translational Research.  

Can you tell us about your work here at Columbia?

I am originally from Chile. I studied biochemistry at university for five years plus a two-year thesis in immunology. I then started my PhD in Santiago, and when I had the opportunity to travel to France, I finished my PhD studies there. I developed an interest in metabolism and decided to come to the U.S. to do my postdoctoral studies. And that's how I landed here in the Department of Pediatrics at Columbia. I started working with Alice Prince [MD] and did my postdoctoral training in immunometabolism and infectious diseases in the lung.

As part of that research, I got some fascinating results about a specific protein that regulates metabolism in cancer cells. We observed that this protein was also relevant in infectious diseases. The protein is called PTEN, and it helps regulate metabolism. We saw that if you remove this protein from cells and then infect them, you have excessive inflammation. We realized this was mimicking what was going on in the airways of patients with cystic fibrosis [CF], where patients have this same immunodysregulation.

So we wondered if maybe PTEN has a big role in this disease. We started analyzing samples from patients with CF and observed that this protein was down-regulated, basically almost not there. So we tried to establish a link between the function of PTEN and how it was being altered in CF. Based on that information, we decided to write a grant with the Irving Institute through the Collaborative and Multidisciplinary Pilot Research – Integrating Special Populations (CaMPR-ISP) Pilot Award program.

What was your experience with the Irving Institute?

It was wonderful; everyone was friendly and encouraging. After we got the funding in 2017, we had the opportunity to perform a lot of experiments, so we were super thankful. And those experiments helped me a lot, personally. Because with that data, I was able to apply for other grants and fellowships. I ended up getting a fellowship of my own from the Cystic Fibrosis Foundation to pay for my postdoctoral training. So it was super cool that because of the Irving Institute, I had this opportunity to generate even more quality data.

The data allowed us to publish a lot of important papers for the field. I was first author on those papers, so I got a lot of visibility. And because of that visibility, I was able to get some grants on my own, and the department felt confident enough with my work to promote me to assistant professor.

The CTSA also invited me to present at their yearly meeting [with NCATS Director Mike Kurilla, during his site visit of the CTSA]. It was hosted here at Columbia and allowed everyone participating in the program to present and show people from the NIH what we were doing. It was super interesting. The CTSA also invited me to make a poster presentation at another important meeting for the American Thoracic Society Congress in Washington, D.C. The CTSA gave me the opportunity to do experiments with the funding, but at the same time they went out of their way to show my work to the rest of the community. So it's been a great experience in many ways.

What’s next for your research?

I'm exploring the link between metabolism and inflammation, specifically how different metabolic pathways regulate the intensity of the inflammatory response during infection.

It’s a fascinating analysis. For example, there is a metabolic program called ketogenesis in the host that is activated when cells undergo an energetic crisis. As you know, nowadays a lot of people are eating ketogenic diets. We're addressing this from the point of view of infection. We know that during an airway infection with some pathogens, the host itself activates this ketogenic pathway. But the question is, Why? So what we did was we fed animals a ketogenic diet, and we observed that if you establish this metabolic program in the host through the diet, the animals are more protected against infection. So it's not only that metabolism regulates infection, but at the same time nutrition itself can regulate how your metabolism copes with that infection.

Another area I'm focusing on will be studying other metabolites called nucleotides; they are the building blocks of DNA and RNA. We have information showing that these nucleotides are also important for regulating inflammation. So we are trying to understand these metabolic pathways and how nucleotides regulate inflammation during pneumonia with bacteria. The NIH just gave me my first grant as a PI for this topic.

Everything started with comparing and contrasting what we were getting in the lab with cystic fibrosis. We are learning that what's going on in CF has a lot to do with metabolic alterations. People with CF have mutations in a protein called CFTR, and these mutations promote excessive inflammation in the airways. And if a CF patient gets an infection, it gets even worse. Much of this inflammation happens because CFTR is a regulator of the metabolism of the cells. So when you have a mutation in CFTR, the metabolism of the cell—the way a cell produces energy—is altered. And that has an impact on how immune cells react to infection; they become overactivated and instead of being protective, they start damaging the infected tissue.

The connection between inflammation and metabolism can feel super obscure for people working in certain diseases like CF. At the beginning, when we were going to conferences and I was talking about the connection, people weren't getting it. I've been trying to push and push and help people see the connection. I think people are starting to appreciate how important the link is now, and more people are working in metabolism now. I'm really happy about that.

What advice would you give researchers here at CUIMC about the Irving Institute?

I think the most important thing is perseverance. With so much in science, 90% of the things you do in the lab, they just don't work. So there's a lot of frustration. You have to stay focused, keep going, and be data driven.

But the deeper you go, you run the risk of growing disconnected from reality, as a scientist. You have to try to keep taking the bigger picture into consideration. Always ask the question of relevance: Even if this data has biological significance in my animal model or to my cells in vitro, is this relevant for people, for patients?

To make this easier, I think feedback is one of the most important things to have. Things like weekly lab meetings and going to conferences to discuss your data with your colleagues, with your peers. For example, I have a PhD degree so I don't have direct contact with patients. Learning what physicians see or don’t see in patients is so necessary. And it's important to discuss your work with your colleagues from different fields; it can tell you how significant your research is. If you don't get that background, you can get lost.

The Irving Institute makes it so much easier to make these connections and get your work seen by others. And of course, help with funding to get the opportunity to focus on experiments is super important.

I think it's good to have this CTSA connection at all stages. In my case, the Irving Institute helped me in my early stage as a postdoctoral researcher, when I wrote this grant with my PI. And now that I am in this position as an assistant professor, I will probably get a new postdoc now. I know there are other opportunities for grants and support, and I think that I will be coming back in the future.

About the Irving Institute

The Irving Institute for Clinical and Translational Research is home to Columbia University’s Clinical and Translational Science Award (CTSA) Program Hub. As part of our commitment to training and supporting the next generation of clinical and translational researchers here at Columbia University Irving Medical Center, we offer over 70 services and programs covering six broad categories: research support services, core facilities, funding opportunities, community engagement, seminars and workshops, and education, training, and mentoring. We encourage researchers and collaborators at every level to explore our offerings and learn how we can help you develop your skills and advance your research.

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