Questioning Metabolic Dogma
Lucas Sullivan, Cancer Metabolism Researcher
Dr. Lucas Sullivan’s first interest was chemistry: He wanted to understand how matter and energy are used to make up our chemical world. How do molecules transition and transform to make this possible?
Cancer cell metabolism — what fast-growing cancer cells eat and how they use their food to make more cells — was a natural extension of this curiosity.
“Metabolism is the study of the chemical reactions of small molecules in biology, how we use those transitions to extract energy and make the building blocks for other molecules. It’s this bridge between naturally arising chemistry and the biological systems in which [that chemistry] operates,” Sullivan said.
The cellular chemistry that most interests him occurs in mitochondria, which are best known as the place where our cells extract energy from oxygen and food. Textbooks outline a complex and seemingly rigid set of reactions — many mapped out decades ago — that govern the process. How did a set of steps so long agreed upon become his obsession?
Sullivan doesn’t accept the biochemical rules written in textbooks as gospel. He questions every assumption he can.
“I like to be pedantically naïve about what we actually know,” Sullivan said of his scientific philosophy. “My lab probably gets annoyed at times, because I constantly say, ‘Do we actually know that?’”
He even questioned the dogma that cells need mitochondria for energy. Cancer cells use a different metabolic pathway to extract energy from food — but still rely on mitochondria. What gives?
Sullivan showed that mitochondria are not just powerhouses. They can also be factories, the sources of the molecular building blocks that cancer cells need to make more cells and drive tumor growth.
He didn’t start out expecting to make a career of charting new scientific terrain.
Science as creative pursuit
Sullivan went to college expecting to choose a solid major that would lead to a solid job. He didn’t have scientists in his family and didn’t plan to become a researcher. He chose his major based on difficulty, not passion.
“I knew I wanted to be challenged,” he said. “Chemistry sounded hard, and biochemistry sounded like it must be even harder.”
It wasn’t love at first biochem lab. Instead, an unexpected approach in sophomore biology opened Sullivan’s eyes to science’s possibilities. Rather than demanding rote memorization, the professor explained how basic processes, from mitochondrial respiration to photosynthesis, actually worked, and what makes them so interesting.
“I went from being someone who was planning to simply graduate and get a job, to being fascinated with the concept of science and more importantly, the process of it,” Sullivan recalled. “I was fascinated with … the reality that there are boundaries to our knowledge. … Even the processes we describe as being very definitive — there are huge, unknown aspects.”
Sullivan’s approach (and life path) was upended.
Science had become “creative pursuit, where you get to ask questions that bump up against the edge of human knowledge, and maybe identify something that no one has ever known before,” he said.
His route from epiphany to research faculty wasn’t a straight shot. It followed more of a “just-in-time process,” Sullivan said. His first role models were his professors, who blended teaching with research. After discovering that he needed a Ph.D. to emulate them, Sullivan entered a graduate program at research-focused Northwestern University, where he studied how mitochondrial mutations alter cell signaling and metabolism.
After learning that a postdoctoral fellowship is the steppingstone from Ph.D. to faculty position, Sullivan did a postdoc studying metabolism and mitochondria in cancer cells. There, he learned that some people do nothing but research — which took him in another new direction.
“[My postdoc] gave me the opportunity to get a job like this one, where I am fortunate enough to get to think about deep questions of biology and chemistry all day long and mentor the next generation of scientists,” he said.
His graduate work also gave Sullivan his first opportunity to trip over the cracks in established metabolic knowledge. He found, unexpectedly, that cancer-causing metabolic alterations can generate a previously unknown metabolites. He also contributed to work which showed that, depending on cell state, mitochondria can reverse the direction of some textbook metabolic reactions.
“Both findings made me realize how oversimplified our “didactic metabolism” is and that there is a lot left to be discovered,” Sullivan said.
“I like to be pedantically naïve about what we actually know. … I constantly say, ‘Do we actually know that?’”
Different cells, different metabolic needs
The inflexible, linear way metabolism is often taught in school couldn’t be further from the truth, Sullivan said. The foundation for our understanding of mitochondria was laid in studies of pigeon breast muscles. But cancer cells don’t power flight and muscle cells typically don’t divide. Lessons learned in one cell type shouldn’t be applied too generously to others, Sullivan said.
While muscle cells need energy above all else, cancer cells need to grow. They need to make more cells — many, many more cells. And to make those cells, they need cellular building blocks.
Decades ago, researchers noted that cancer cells bypass normal cellular processes for generating energy. When these insights didn’t quickly lend themselves to new therapies, interest in cancer metabolism waned and it became an interesting side note instead of a field of fruitful study. But over the last decade, researchers like Sullivan have revisited this phenomenon and begun reimagining the field.
They’ve discovered many connections between metabolism and cancer. Mutations in metabolic enzymes can drive cancer. Loss of genes that suppress tumor formation, or mutations that release the brakes on cancer-promoting genes, can cause drastic changes to cellular metabolism. Buildup of certain unusual metabolic byproducts can also promote cancer.
“Any way you look at it, there’s interesting biology to be uncovered,” Sullivan said.
His work demonstrating how cancer cells use mitochondria sprang from his desire to understand exactly why rapidly dividing cells such as cancer cells need them to begin with. On its face, it was a naïve question — of course cells need mitochondria! Where else would their energy come from?
But cancer cells can use a process called glycolysis, which occurs outside mitochondria, to make energy. Sullivan’s willingness to question a long-established fact allowed him to reveal a previously unknown role for mitochondria in cell growth.
“Mitochondria have multifaceted roles that tie in nicely with the idea that cells in different states generally have access to the same metabolic reactions. But how they use them is going to be very different,” Sullivan said.
He is continuing to plumb the mysteries of mitochondria, metabolism and cancer. For example, even though cancer cells need mitochondria, sometimes mutations that cause mitochondrial dysfunction also drive cancer, but only in certain tissues. Why? And how do those metabolic defects change cells’ dietary demands? he asks. Meanwhile, he is also working to fill out the metabolic map, identifying new metabolites in more types of cancer cells.
But Sullivan’s interests extend beyond helping make textbooks more complete. The metabolic changes and adaptations in cancer cells could form the basis of anti-cancer therapeutics. As a postdoc, Sullivan showed that proliferating cells rely on mitochondria to maintain levels of a precursor for the building blocks of both proteins and DNA, called aspartate. He showed that the diabetes drug metformin causes aspartate levels to fall, potentially explaining the link between metformin use and lower levels of cancer. He’s continuing to explore why, exactly, cells slow their growth when aspartate levels fall.
“In a field like metabolism, which was discovered so long ago, … it takes a very specific kind of effort to step back from that and question things directly,” he said.
— By Sabrina Richards, Nov. 19, 2021
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