Nutrition advice is everywhere. Eat more protein. Cut back on sugar. Get more fiber. But beneath all that advice is a surprisingly basic gap in our understanding: Scientists still have a limited view of what happens when specific nutrients reach individual cells inside the body.
Cell metabolism is dynamic. As nutrient availability changes — through diet, disease, exercise or other shifts in the body — cells can change which nutrients they use and how they use them. Those metabolic changes, in turn, can influence how those cells behave and function.
With support from an NIH Director’s New Innovator Award, UCLA scientist Tara TeSlaa is developing a new way to record nutrient use in specific cell types in their natural environment. Her team will use those measurements to build maps of cellular metabolism across tissues and conditions.
That kind of mechanistic understanding is often missing from nutrition research. Studies may find associations between a nutrient and a health outcome without explaining what’s happening inside individual cells — which can make seemingly conflicting results difficult to interpret.
“This is how we end up with one study saying dietary fat is good and another study saying it’s bad for you,” said TeSlaa, an assistant professor of molecular and medical pharmacology and member of the UCLA Broad Stem Cell Research Center. “What’s good for one cell type may not necessarily be good for another.”
The award, which supports early-career scientists pursuing highly innovative and broadly impactful research, provides up to $2.375 million in direct research costs over five years.
That support will help TeSlaa tackle a problem that has long frustrated metabolism researchers: Metabolites — the small molecules cells use or produce as they process nutrients — can change faster than researchers can isolate the cells they want to study.
Many metabolites last only seconds or minutes. Isolating a particular cell type requires researchers to break apart a tissue and parse out its different cell populations, a process that is not only time-consuming but removes cells from their natural environment, potentially changing the metabolic processes they set out to measure.
Growing cells in a dish avoids some of those challenges, but cells can use nutrients differently in culture than they do inside the body. Cancer cells grown in culture, for example, have been found to use more glutamine and less glucose than the same cells inside tumors — a difference that may help explain why some metabolism-targeting cancer drugs that look promising in the lab fail in preclinical models.
That limitation is especially important for understanding human metabolism: Researchers cannot routinely make these cell-specific measurements inside living people, so they must rely on models that may not fully reproduce what happens in the body.
TeSlaa’s approach is designed to get around that problem by creating a durable record of nutrient use while cells are still in their natural environment — a record researchers can read after the cells have been isolated.
Creating a molecular record
Her lab calls the approach STOMP, short for Stable isotope Tracing of Orthogonal Metabolites into bioPolymers. Researchers introduce nutrients marked with stable isotopes — nonradioactive labels that allow them to follow where those nutrients go. As cells break down and transform the labeled nutrients, the labels can pass into metabolites and ultimately into longer-lasting molecules such as proteins and DNA.
Because proteins and DNA are built over time, they can preserve a longer-term record of nutrient use rather than the fleeting snapshot provided by short-lived metabolites. After isolating a particular cell type, researchers can use mass spectrometry — an analytical technique sensitive enough to detect the isotope labels — to read that record.
TeSlaa’s team has already shown that the approach can work, and the award will allow the lab to scale up its efforts.
From individual cells to a metabolic map
TeSlaa’s team will start with the liver and pancreas, two organs with central roles in metabolic diseases such as fatty liver disease and diabetes.
The liver helps regulate metabolism throughout the body, and the pancreas contains beta cells that sense blood glucose and release insulin. Because beta cells make up only a small portion of the pancreas and take time to isolate, however, studying their metabolism inside the body has been particularly challenging.
With STOMP, TeSlaa hopes to build a resource showing which nutrients different cell types use, how those patterns change across tissues and conditions and, ultimately, whether those metabolic differences are more or less advantageous for how a cell functions.
That cell-type-level view could also help researchers study less abundant cells whose metabolic activity can be obscured in measurements of whole tissues — even when those cells play a critical role in disease.
In the liver, for example, hepatocytes perform many of the organ’s major metabolic functions. But during injury, less abundant cells can become especially important.
“A lot of times the minority cell types in the tissue, like the immune cells or hepatic stellate cells, drive inflammation and fibrosis when there’s tissue damage,” TeSlaa said. “We also want to understand their metabolism to understand how they’re reacting to changes in the diet or even disease.”
She envisions eventually extending the STOMP approach across major tissues including the brain, heart, skeletal muscle, spleen, kidney, intestine, skin and fat.
Finding more faithful models of metabolism
Another potential impact of the project is helping scientists understand how faithfully laboratory models reproduce metabolic processes that occur inside the body.
Because directly studying human metabolism inside the body is often impractical, researchers rely on systems such as tissue slices and stem cell-derived organoids. TeSlaa plans to compare those systems with measurements made in mouse models to assess which best preserve cells’ natural metabolic behavior.
That question is especially important for tissue stem cells, which often exist in very small numbers and can change their behavior when removed from their surroundings. TeSlaa’s lab is particularly interested in muscle stem cells, which normally remain relatively quiet but become activated when muscle needs to repair itself.
“No one’s really been able to measure the metabolism of a muscle stem cell in the tissue,” TeSlaa said. “They usually have to take it out and then feed it nutrients. And we know that environment is totally different.”
Being able to preserve a record of that metabolism before the cells are removed could help researchers understand how nutrient use changes as stem cells activate and regenerate tissue — and how those patterns shift with aging or exercise.
Ultimately, TeSlaa sees the metabolic map not as an endpoint, but as a starting point for understanding metabolic dynamics — one cell type at a time.
From trainee to New Innovator
An alumna of the Broad Stem Cell Research Center Training Program, TeSlaa’s scientific training helped her think more broadly about how the tools she develops as a metabolism researcher could be applied to stem cell biology.
In 2016, while working with her mentor, UCLA Health Jonsson Comprehensive Cancer Center director Dr. Michael Teitell, she led a study published in Cell Metabolism that examined how metabolism influences stem cell differentiation — the first paper she says was driven primarily by her own work.
More recently, a BSCRC Transformative Technology Development Award supported her lab’s efforts to apply the same STOMP tracing strategy specifically to stem cells. TeSlaa said that early support proved critical, funding the experiments she needed to make her application for the NIH grant competitive.
