A molecular dive into how cells sense nutrients
Krystle Kalafut, PhD ’24, studies the liver’s response to insulin, revealing potential mechanisms involved in obesity and diabetes
May 9, 2024 – Krystle Kalafut has always been passionate about fitness. She takes indoor cycling classes, does strength training and yoga, and takes her dog on long walks in the park.
But her interest in health goes beyond exercising. She has also focused much of her career on nutrition. She has tackled the topic both from a public health approach—as an AmeriCorps volunteer providing nutrition education to communities—and from a molecular biology approach, as a graduate student conducting lab research on how cells sense and respond to nutrients.
Kalafut is completing a PhD in the Harvard Griffin Graduate School of Arts and Sciences (GSAS), studying in the Biological Sciences in Public Health program at Harvard T.H. Chan School of Public Health.
“I always saw my role being on the more analytical side of things and thought that my strengths were well-suited for lab research. However, a broad career goal of mine is to bridge the gap between basic science and public health,” Kalafut said.
She said she loves her molecular science research because it requires a lot of imagination.
“I learn by visualizing concepts in my mind, and this is essentially what it takes to generate hypotheses at the molecular or cellular level,” Kalafut said. “Through laboratory techniques used to detect the interactions and functions of cellular proteins, my research elucidates the complex molecular networks that facilitate communication between cells and tissues throughout the body. I love that I get to glimpse into the intricate details underpinning biological life in both health and disease.”
Basic science through a public health lens
After earning an undergraduate degree in molecular biology at the University of Pittsburgh, Kalafut wanted to apply her basic science knowledge to improve health outcomes, so she joined AmeriCorps for a year of service. She worked in a rural area of southern Ohio, providing nutrition education and outreach to children and adults.
“That was my first immersive experience in public health,” she said. “It was really great to have that perspective of how to build trust within a community and apply evidence-based practices.”
Her work focused on promoting access to fresh, healthy foods and exercise, which got her thinking more about how socioeconomic factors, such as food insecurity and income, impact the risk of chronic diseases related to nutrition, including obesity and type 2 diabetes.
“My AmeriCorps experience furthered my interest in the development and progression of these diseases, and I wanted to look more deeply,” Kalafut said.
To do that, Kalafut returned to basic science. She took a position as a post-baccalaureate fellow in a lab at the National Institute of Aging, researching how diet influences the aging process. As she considered the next step in her research career, she searched for a graduate program that focused on basic science as well as public health—and landed at Harvard Chan School.
Looking at liver processes
Kalafut conducts her research in the lab of Brendan Manning, professor of molecular metabolism and acting chair of the Department of Molecular Metabolism. The lab focuses on a protein complex called mTORC1, which regulates cell growth and metabolism in response to signals relaying nutrient availability both in and outside of the cell. Impaired regulation of mTORC1 signaling can lead to a wide range of diseases, including obesity, diabetes, and cancer.
Specifically, Kalafut is interested in how mTORC1 is regulated in the liver. The organ helps keep levels of glucose—the body’s main source of energy—steady and constant. The hormone insulin plays a role in this function, providing a signal to the liver as to whether glucose needs to be stored or released. Using a mouse model, Kalafut was able to isolate the signaling interactions between mTORC1 and insulin.
“Much of what we know regarding mTORC1 regulation and function has been defined using cell culture models,” she said. “But it’s not clear what is relevant in physiological settings, including the predominant signals regulating mTORC1 and its functions in different tissues. And so using our mouse model is one way that we can start to understand.”
Kalafut’s research confirmed that the way insulin activates mTORC1 that was previously identified in cell culture models does indeed occur in mice. But she also discovered something unexpected.
“I found that, in the liver, mTORC1 activation can be triggered from food intake alone, and that the mode of insulin regulation we previously observed is not necessary for this process to occur. Preliminary data suggests that dietary protein, or amino acids, can bypass insulin signaling to activate mTORC1,” she said. “So far, this seems to be unique to the liver. In other tissues, such as the muscle, both insulin and nutrient signals are required for full activation of mTORC1 signaling.”
Kalafut also identified a new player in the mTORC1 signaling pathway—a protein that may be involved in insulin resistance, a health issue that can lead to diabetes. She said that if the details of the mTORC1 signaling pathway she discovered in the mouse liver also occur in the human liver, the information could potentially be used to develop future treatments.
“Krystle came to my lab with a deep interest in how dietary intake alters systemic metabolism and metabolic health,” said Manning. “She is one of the first people in my lab to tackle the critical challenge of understanding the regulation and function of mTORC1 in mammalian organs, with a focus on the liver as being central to our metabolic response to food intake. I have been immensely impressed by her growth as a scientist during her time in my lab and her fearless nature in studying this complex signaling network in animals to define the physiological impact of diet on metabolic transitions between fasting and fed states. It is a remarkable and novel body of work.”
Developing new therapies, ensuring accessibility
After graduation, Kalafut hopes to further expand her scientific expertise by working in the academic, biotechnology, or pharmaceutical sectors. “The mTORC1 signaling pathway is implicated in so many different diseases, like cancer and metabolic disease and aging.” she said. “I’m really excited to be able to apply my knowledge to the development of new therapies.”
She also wants her research to have an impact beyond the lab. During her time at Harvard, Kalafut has explored her interest in science policy. She attended career discussions held by the Harvard GSAS Science Policy Group, where she met science policy professionals working at organizations such as the Union of Concerned Scientists. She also co-authored an article published in the MIT Science Policy Review about the public health challenges of the world’s expanding aging population, highlighting policies that could promote the development of therapies for age-related diseases.
“Scientists are motivated by finding and developing these new therapies, and they’re the ones who actually put in the work to do it. But then, when it comes to the actual price and accessibility of the medications when they come on the market, it’s a completely separate business,” she said. “I’d like to be involved in some way to ensure that our work on the research side really does translate into improved health outcomes.”
– Jay Lau
Photo: Tom Kelleher
