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Biophysicist in Profile

César A. Ramírez-Sarmiento

César A. Ramírez-Sarmiento

March 2021 // 2784

César A. Ramírez-Sarmiento grew up with an eye for visual and performing arts, which provided an outlet for his creativity through his high school years. One day in his advanced biology class, the teacher introduced him to protein evolution, and he was in awe. “I could not help to wonder if pro­tein evolution could also be a space for creativity and innovation, which led me to step away from my artistic preferences and pursue a bachelor’s degree in biology,” he shares.

Toward the end of his undergraduate studies at Universidad de Chile, César A. Ramírez-Sarmiento had the opportunity to present a poster at a scientific conference in Chile. It was there that he first found himself drawn to biophysics. “My classmate and friend Felipe Merino, now a senior scientist at the Max Planck Institute for Developmental Biology in Germa­ny, presented his work on the changes in substrate specificity and thermal stability of an enzyme family using phylogenetic analysis, molecular modeling, and simulations. At that time these computational studies were rare in our country and it blew my mind,” he explains. “Right after the conference was over, I contacted his master’s supervisor at Universidad de Chile, Victoria Guixé, who then became my PhD supervisor.”

There were no PhD programs in biophysics in Chile at that time, so he pursued his PhD in molecular and cellular biology and neurosciences at Universidad de Chile. As a graduate stu­dent, he was able to attend several workshops on molecular dynamics organized by Fernando D. Gonzalez-Nilo from Uni­versidad Andrés Bello in Chile. He also received a scholarship to go to the University of California, San Diego, as a visiting graduate student under the supervision of Elizabeth Komives. “With Victoria as my PhD supervisor, I learned everything I could about enzyme catalysis and the evolution of substrate specificity in enzyme families, whereas Betsy taught me ev­erything about how to experimentally explore protein folding and oligomerization using many techniques with different degrees of detail,” he shares. “Also, both Victoria and Betsy encouraged me to learn as much as I could about computa­tional biology at the same time that I was doing all of these experiments in their laboratories.” During his time at the University of California, he also learned about protein folding simulations from Jeffrey Noel, who was then a PhD student in Jose Onuchic’s lab and is now a scientist at Max Delbrück Center in Germany.

Ramírez-Sarmiento continued at the Universidad de Chile for a postdoctoral position with Jorge Babul. “The work we devel­oped was focused on the evolution of domain swapping in the P subfamily of FOX proteins, key transcription factors involved in the regulation of gene expression during crucial cellular processes and that are remarkable due to their ability to bind condensed chromatin,” he explains. “We still work together on FOXP proteins, alongside one of our former co-supervised PhD students, Exequiel Medina, using both computational and experimental approaches.”

Medina, now a postdoctoral fellow at the Universidad de Chile, shares, “We determined different structural aspects FOXP proteins that allowed us to publish three articles. Currently we are interested in defining the energetics behind FOXP heterodimerization and DNA binding, considering more complex scenarios such as interdomain communication and intrinsic disorder. His expertise in protein biophysics and molecular dynamics simulations are extremely useful as a complementary vision to the experimental approaches that I use. […] As a scientist, I appreciate that Cesar tries to get the best out of you and push you to improve by going out of your comfort zone. As a person, I really appreciate his constant interest in all people, especially those who are close to him. He deserves all the great things that he has had so far in life, and those that are to come.”

Ramírez-Sarmiento is now an assistant professor at the Institute for Biological and Medical Engineering at Pontificia Universidad Catolica de Chile and an adjunct researcher at the Millennium Institute for Integrative Biology. “Our research projects are focused on the biophysical and evolutionary characterization of metamorphic proteins involved in crucial cellular processes as exemplar cases of the evolution of novel folds in nature, the discovery and engineering of enzymes that can efficiently degrade the PET plastic at different tem­peratures, and the development of molecular kits based on public domain enzymes and reagents for the detection of viral infections, including SARS-CoV-2,” he explains.

The biggest challenge of his career has been his transition from student to supervisor. “I constantly feared my skill set and experience was insufficient to be a good leader for my research group, to live up to the experience I had during my PhD with Victoria Guixé in Chile and Elizabeth Komives in the United States as supervisors. I questioned not only my ability to train new students, but also to provide them with the confidence and encouragement that they needed in such crucial times of our paths as scientists. I also wondered if the research path I wanted to follow was interesting for the stu­dents and the research community,” he shares. “After being very secretive about my fears and concerns, I decided to be straightforward and make my students aware of the pros and cons of being a researcher, from the challenges we confront­ed when establishing a new experimental and computational laboratory from scratch to the struggles of submitting and resubmitting grant applications. It turned out to be an exer­cise of mutual support and trust in ourselves and our research that strengthened our group. In turn, our research has flour­ished, and we collectively have been recipients of recognition and awards.”

One such award was the 2020 Biophysical Journal Paper of the Year Award, which Ramírez-Sarmiento won for his paper “Dif­ferential Local Stability Governs the Metamorphic Fold-switch of Bacterial Virulence Factor RfaH” written in collaboration with Pablo Galaz-Davison, José Alejandro Molina, Steve Silletti, Elizabeth A. Komives, Stefan H. Knauer, and Irina Artsimovitch.

Komives, who has worked with Ramírez-Sarmiento since his graduate school days, shares, “César embodies what I like to refer to as the ‘no-fear’ approach to science. If a question can only be answered with a particular approach, he finds someone who can help him do the experiment and he learns how to do it, and how to interpret the data. The resources for science in Chile are sparse, so Chilean scientists need to travel to be able to do cutting-edge science. César is driven to understand how proteins work, and he stops at nothing to get the answers to his questions. He has built a research program that fully integrates theory, computation, and experiment and this has been a real bootstrap effort. I am most impressed with what he has been able to accomplish with limited resources. I am also impressed with his ability to recognize talent and the impact he is making through his educational efforts, both in the classroom and in the lab, to train the next generation of top Chilean scientists.”

As for his plans for the future, he shares, “Since our incorpo­ration into the Millennium Institute of Integrative Biology in Chile, we are determining how we can contribute through our work on protein biophysics to other research areas, such as synthetic biology, systems biology, and functional genomics. We are also rethinking the way we do research in our labo­ratory to be able to continue our experimental and computa­tional work uninterrupted in the aftermath of the COVID-19 pandemic. We also hope to contribute to combatting the COVID-19 pandemic in underdeveloped regions through the development of low-cost and open-source methods for de­tecting viral infections.”

Ramírez-Sarmiento tells students and trainees to keep an open mind: “Do not be afraid of exploring biophysics through different perspectives. If you are working on experimental biophysics, give computational biophysics a try. If your experi­ence is only in computational work, do not be afraid to consid­er joining a lab performing experimental work. The feeling of being able to freely converse with researchers from diverse backgrounds and to understand their vision is always satis­fying, especially in such an interdisciplinary world. Also, never forget that life is more than science and that science is meant to be enjoyed, so have fun!”

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