Research Area: Stem Cell and Developmental Biology

High-fat diets make liver cells more likely to become cancerous

New research from the Yilmaz Lab suggests liver cells exposed to too much fat revert to an immature state that is more susceptible to cancer-causing mutations.

Anne Trafton | MIT News
December 22, 2025

One of the biggest risk factors for developing liver cancer is a high-fat diet. A new study from MIT reveals how a fatty diet rewires liver cells and makes them more prone to becoming cancerous.

The researchers found that in response to a high-fat diet, mature hepatocytes in the liver revert to an immature, stem-cell-like state. This helps them to survive the stressful conditions created by the high-fat diet, but in the long term, it makes them more likely to become cancerous.

“If cells are forced to deal with a stressor, such as a high-fat diet, over and over again, they will do things that will help them survive, but at the risk of increased susceptibility to tumorigenesis,” says Alex K. Shalek, director of the Institute for Medical Engineering and Sciences (IMES), the J. W. Kieckhefer Professor in IMES and the Department of Chemistry, and a member of the Koch Institute for Integrative Cancer Research at MIT, the Ragon Institute of MGH, MIT, and Harvard, and the Broad Institute of MIT and Harvard.

The researchers also identified several transcription factors that appear to control this reversion, which they believe could make good targets for drugs to help prevent tumor development in high-risk patients.

Shalek; Ömer Yilmaz, an MIT associate professor of biology and a member of the Koch Institute; and Wolfram Goessling, co-director of the Harvard-MIT Program in Health Sciences and Technology, are the senior authors of the study, which appears today in Cell. MIT graduate student Constantine Tzouanas, former MIT postdoc Jessica Shay, and Massachusetts General Brigham postdoc Marc Sherman are the co-first authors of the paper.

Cell reversion

A high-fat diet can lead to inflammation and buildup of fat in the liver, a condition known as steatotic liver disease. This disease, which can also be caused by a wide variety of long-term metabolic stresses such as high alcohol consumption, may lead to liver cirrhosis, liver failure, and eventually cancer.

In the new study, the researchers wanted to figure out just what happens in cells of the liver when exposed to a high-fat diet — in particular, which genes get turned on or off as the liver responds to this long-term stress.

To do that, the researchers fed mice a high-fat diet and performed single-cell RNA-sequencing of their liver cells at key timepoints as liver disease progressed. This allowed them to monitor gene expression changes that occurred as the mice advanced through liver inflammation, to tissue scarring and eventually cancer.

In the early stages of this progression, the researchers found that the high-fat diet prompted hepatocytes, the most abundant cell type in the liver, to turn on genes that help them survive the stressful environment. These include genes that make them more resistant to apoptosis and more likely to proliferate.

At the same time, those cells began to turn off some of the genes that are critical for normal hepatocyte function, including metabolic enzymes and secreted proteins.

“This really looks like a trade-off, prioritizing what’s good for the individual cell to stay alive in a stressful environment, at the expense of what the collective tissue should be doing,” Tzouanas says.

Some of these changes happened right away, while others, including a decline in metabolic enzyme production, shifted more gradually over a longer period. Nearly all of the mice on a high-fat diet ended up developing liver cancer by the end of the study.

When cells are in a more immature state, it appears that they are more likely to become cancerous if a mutation occurs later on, the researchers say.

“These cells have already turned on the same genes that they’re going to need to become cancerous. They’ve already shifted away from the mature identity that would otherwise drag down their ability to proliferate,” Tzouanas says. “Once a cell picks up the wrong mutation, then it’s really off to the races and they’ve already gotten a head start on some of those hallmarks of cancer.”

The researchers also identified several genes that appear to orchestrate the changes that revert hepatocytes to an immature state. While this study was going on, a drug targeting one of these genes (thyroid hormone receptor) was approved to treat a severe form of steatotic liver disease called MASH fibrosis. And, a drug activating an enzyme that they identified (HMGCS2) is now in clinical trials to treat steatotic liver disease.

Another possible target that the new study revealed is a transcription factor called SOX4, which is normally only active during fetal development and in a small number of adult tissues (but not the liver).

Cancer progression

After the researchers identified these changes in mice, they sought to discover if something similar might be happening in human patients with liver disease. To do that, they analyzed data from liver tissue samples removed from patients at different stages of the disease. They also looked at tissue from people who had liver disease but had not yet developed cancer.

Those studies revealed a similar pattern to what the researchers had seen in mice: The expression of genes needed for normal liver function decreased over time, while genes associated with immature states went up. Additionally, the researchers found that they could accurately predict patients’ survival outcomes based on an analysis of their gene expression patterns.

“Patients who had higher expression of these pro-cell-survival genes that are turned on with high-fat diet survived for less time after tumors developed,” Tzouanas says. “And if a patient has lower expression of genes that support the functions that the liver normally performs, they also survive for less time.”

While the mice in this study developed cancer within a year or so, the researchers estimate that in humans, the process likely extends over a longer span, possibly around 20 years. That will vary between individuals depending on their diet and other risk factors such as alcohol consumption or viral infections, which can also promote liver cells’ reversion to an immature state.

The researchers now plan to investigate whether any of the changes that occur in response to a high-fat diet can be reversed by going back to a normal diet, or by taking weight-loss drugs such as GLP-1 agonists. They also hope to study whether any of the transcription factors they identified could make good targets for drugs that could help prevent diseased liver tissue from becoming cancerous.

“We now have all these new molecular targets and a better understanding of what is underlying the biology, which could give us new angles to improve outcomes for patients,” Shalek says.

The research was funded, in part, by a Fannie and John Hertz Foundation Fellowship, a National Science Foundation Graduate Research Fellowship, the National Institutes of Health, and the MIT Stem Cell Initiative through Foundation MIT.

Celebrating worm science

Time and again, an unassuming roundworm has illuminated aspects of biology with major consequences for human health.

Jennifer Michalowski | McGovern Institute
December 12, 2025

For decades, scientists with big questions about biology have found answers in a tiny worm. That worm–a millimeter-long creature called Caenorhabditis elegans–has helped researchers uncover fundamental features of how cells and organisms work. The impact of that work is enormous: Discoveries made using C. elegans have been recognized with four Nobel prizes and have led to the development of new treatments for human disease.

In a perspective piece published in the November 2025 issue of the journal PNAS, eleven biologists including Robert Horvitz, the David H. Koch (1962) Professor of Biology at MIT, celebrate Nobel Prize-winning advances made through research in C. elegans. The authors discuss how that work has led to advances for human health and highlight how a uniquely collaborative community among worm researchers has fueled the field.

MIT scientists are well represented in that community: The prominent worm biologists who coauthored the PNAS paper include former MIT graduate students Andy Fire and Paul Sternberg, now at Stanford University and the California Institute of Technology, and two past postdoctoral researchers in Horvitz’s lab, University of Massachusetts Medical School professor Victor Ambros and Massachusetts General Hospital investigator Gary Ruvkun. Ann Rougvie at the University of Minnesota is the paper’s corresponding author.

Early worm discoveries

“This tiny worm is beautiful—elegant both in its appearance and in its many contributions to our understanding of the biological universe in which we live,” says Horvitz, who in 2002 was awarded the Nobel Prize in Medicine along with colleagues Sydney Brenner and John Sulston for discoveries that helped explain how genes regulate programmed cell death and organ development. Horvitz is also a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research as well as an investigator at the Howard Hughes Medical Institute.

Those discoveries were among the early successes in C. elegans research, made by pioneering scientists who recognized the power of the microscopic roundworm. C. elegans offers many advantages for researchers: The worms are easy to grow and maintain in labs; their transparent bodies make cells and internal processes readily visible under a microscope; they are cellularly very simple (e.g., they have only 302 nerve cells, compared with about 100 billion in a human) and their genomes can be readily manipulated to study gene function.

Most importantly, many of the molecules and processes that operate in C. elegans have been retained throughout evolution, meaning discoveries made using the worm can have direct relevance to other organisms, including humans. “Many aspects of biology are ancient and evolutionarily conserved,” Horvitz explains. “Such shared mechanisms can be most readily revealed by analyzing organisms that are highly tractable in the laboratory.”

In the 1960s, Brenner, a molecular biologist who was curious about how animals’ nervous systems develop and function, recognized that C. elegans offered unique opportunities to study these processes. Once he began developing the worm into a model for laboratory studies, it did not take long for other biologists to join him to take advantage of the new system.

In the 1970s, the unique features of the worm allowed Sulston to track the transformation of a fertilized egg into an adult animal, tracing the origins of each of the adult worm’s 959 cells. His studies revealed that in every developing worm, cells divide and mature in predictable ways. He also learned that some of the cells created during development do not survive into adulthood and are instead eliminated by a process termed programmed cell death.

By seeking mutations that perturbed the process of programmed cell death, Horvitz and his colleagues identified key regulators of that process, which is sometimes referred to as apoptosis. These regulators, which both promote and oppose apoptosis, turned out to be vital for programmed cell death across the animal kingdom.

In humans, apoptosis shapes developing organs, refines brain circuits, and optimizes other tissue structures. It also modulates our immune systems and eliminates cells that are in danger of becoming cancerous. The human version of CED-9, the anti-apoptotic regulator that Horvitz’s team discovered in worms, is BCL-2. Researchers have shown that activating apoptotic cell death by blocking BCL-2 is an effective treatment for certain blood cancers. Today, researchers are also exploring new ways of treating immune disorders and neurodegenerative disease by manipulating apoptosis pathways.

Collaborative worm community

Horvitz and his colleagues’ discoveries about apoptosis helped demonstrate that understanding C. elegans biology has direct relevance to human biology and disease. Since then, a vibrant and closely connected community of worm biologists—including many who trained in Horvitz’s lab—has continued to carry out impactful work. In their PNAS article, Horvitz and his coauthors highlight that early work, as well as the Nobel Prize-winning work of:

  • Andrew Fire and Craig Mello, whose discovery of an RNA-based system of gene silencing led to powerful new tools to manipulate gene activity. The innate process they discovered in worms, known as RNA interference, is now used as the basis of six FDA-approved therapeutics for genetic disorders, silencing faulty genes to stop their harmful effects.
  • Martin Chalfie, who used a fluorescent protein made by jellyfish to visualize and track specific cells in C. elegans, helping launch the development of a set of tools that transformed biologists’ ability to observe molecules and processes that are important for both health and disease.
  • Victor Ambros and Gary Ruvkun, who discovered a class of molecules called microRNAs that regulate gene activity not just in worms, but in all multicellular organisms. This prize-winning work was started when Ambros and Ruvkun were postdoctoral researchers in Horvitz’s lab. Humans rely on more than 1,000 microRNAs to ensure our genes are used at the right times and places. Disruptions to microRNAs have been linked to neurological disorders, cancer, cardiovascular disease, and autoimmune disease, and researchers are now exploring how these small molecules might be used for diagnosis or treatment.

Horvitz and his coauthors stress that while the worm itself made these discoveries possible, so too did a host of resources that facilitate collaboration within the worm community and enable its scientists to build upon the work of others. Scientists who study C. elegans have embraced this open, collaborative spirit since the field’s earliest days, Horvitz says, citing the Worm Breeder’s Gazette, an early newsletter where scientists shared their observations, methods, and ideas.

Today, scientists who study C. elegans—whether the organism is the centerpiece of their lab or they are looking to supplement studies of other systems—contribute to and rely on online resources like WormAtlas and WormBase, as well as the Caenorhabditis Genetics Center, to share data and genetic tools. Horvitz says these resources have been crucial to his own lab’s work; his team uses them every day.

Just as molecules and processes discovered in C. elegans have pointed researchers toward important pathways in human cells, the worm has also been a vital proving ground for developing methods and approaches later deployed to study more complex organisms. For example, C. elegans, with its 302 neurons, was the first animal for which neuroscientists successfully mapped all of the connections of the nervous system. The resulting wiring diagram, or connectome, has guided countless experiments exploring how neurons work together to process information and control behavior. Informed by both the power and limitations of the C. elegans’ connectome, scientists are now mapping more complex circuitry, such as the 139,000-neuron brain of the fruit fly, whose connectome was completed in 2024.

C. elegans remains a mainstay of biological research, including in neuroscience. Scientists worldwide are using the worm to explore new questions about neural circuits, neurodegeneration, development, and disease. Horvitz’s lab continues to turn to C. elegans to investigate the genes that control animal development and behavior. His team is now using the worm to explore how animals develop a sense of time and transmit that information to their offspring.

Also at MIT, Steven Flavell’s team in the Department of Brain and Cognitive Sciences and the Picower Institute for Learning and Memory is using the worm to investigate how neural connectivity, activity, and modulation integrate internal states, such as hunger, with sensory information, such as the smell of food, to produce sometimes long-lasting behaviors. Flavell is Horvitz’s academic grandson, as Flavell trained with one of Horvitz’s postdoctoral trainees. As new technologies accelerate the pace of scientific discovery, Horvitz and his colleagues are confident that the humble worm will bring more unexpected insights.

Paper: “From nematode to Nobel: How community-shared resources fueled the rise of Caenorhabditis elegans as a research organism”

Research Threads: One lab’s detective work reveals secrets of immortal cells

Most cells in our body live and die. But the germline, the cells that produce eggs and sperm, must carry on forever. How the germline successfully produces the next generation is a long-studied question. Through a string of discoveries made over years, the Yamashita lab is teasing apart how the germline remains immortal.

Madeleine Turner | Whitehead Institute
October 7, 2025

Most cells in our body live and die. But the germline, the cells that produce eggs and sperm, must carry on forever. How the germline successfully produces the next generation is a long-studied question. Research Threads examines how answering one question uncovers more questions to be solved. In our first installment of Research Threads, we follow the research of Whitehead Institute Member Yukiko Yamashita. Through a string of discoveries made over years, the Yamashita lab is teasing apart how the germline remains immortal.

“The germline is the only cell type responsible for transmitting the genome from generation to generation,” Whitehead Institute Member Yukiko Yamashita says. “We’ve done that for 1.5 billion years.”

The germline is the population of cells in an organism that give rise to gametes, either egg or sperm cells. These gametes contain genetic information, encoded in DNA, needed to produce the next generation. The act of transmitting this information — the instructions that a new individual needs to develop and function — is like a relay race that never ends. While a skin or gut cell may be prone to genetic errors and is generally replaceable, germline stem cells (GSCs) must maintain their genomes with precision. Otherwise, any mistakes or imbalances would be inherited by offspring and accumulated over generations, potentially driving a species to extinction. In other words, to keep passing the baton in this relay, the germline must be faithfully preserved.

Although germline preservation is paramount to the existence and survival of a species, some fundamental parts of its biology have remained a mystery. Yamashita, who is also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute Investigator, has focused her research on unraveling the secrets of the germline. To study these cells’ immortality, her lab utilizes the model organism Drosophila melanogaster, or the fruit fly. Along the way, research in the Yamashita lab has highlighted how the process of scientific discovery can be circuitous, often pulling scientists in surprising directions, revealing new questions and avenues to explore.

For decades, scientists had observed an aspect of germline behavior that was hard to explain. Most cells in the body divide to produce two identical copies, or daughter cells. GSCs in male fruit flies, however, divide “asymmetrically,” meaning they yield two daughter cells that are not identical. Instead, one daughter cell becomes a new GSC, while the other goes on to become a gamete, in this case a sperm cell. It might be easy to assume that asymmetric cell division is about producing gametes while maintaining a pool of stem cells. But an additional detail complicates this theory: when a daughter cell is on the path to becoming sperm, it can loop back around to become another stem cell, instead of continuing differentiation to become a sperm cell.

“If it can do that, why divide asymmetrically in the first place?” Yamashita says.

To shed light on why GSCs divide asymmetrically, researchers wanted to know how genetic information was actually divvied up between daughter cells. “After I started my own lab, there was this question hanging in the field,” Yamashita says. It made sense to find some difference in inheritance, DNA-based or otherwise: something to distinguish between the daughter fated to become a gamete, and the other that would remain in the GSC pool.

Preparing for division, a cell duplicates its DNA. Chromosomes happen to be shaped like the letter “X” as a result of this duplication: the left and right sides of the “X” are called matching sister chromatids, each a copy of the other. Later in cell division, these two sister chromatids part ways, winding up in separate daughter cells.

In 2013, Yamashita and her former graduate student, Swathi Yadlapalli, made a strange but important discovery. In fruit flies, for the X and Y chromosomes (the sex chromosomes), sister chromatids were not being sorted randomly. Instead, one was more likely to go to the daughter cell that would become a gamete; the other to the daughter on the GSC track. There had to be a reason for this preference, but no one had an explanation.

Initial experiments did not reveal obvious differences between these sister chromatid pairs. “Everyone would say, ‘oh, there’s probably some sort of epigenetic information in there,” Yamashita says, referring to heritable changes not carried in DNA. With few promising leads, the lab decided to take a systematic approach. George Watase, then a postdoc in the lab, began the painstaking work of removing different a parts of flies’ X chromosomes, seeing if the absence of any particular element would disrupt the pattern of preferential segregation.

“We thought it was going to be satellite DNA,” Yamashita says, referring to large swathes of DNA in the genome that are highly repetitive but don’t code for any genes. (While this initial guess was wrong, it kickstarted a separate project in the lab — one which led to discovering the unexpected role that satellite DNA plays when one species forks into two.)

Eventually the team narrowed in on the true culprit: ribosomal DNA (rDNA). The primary role of rDNA is to produce the components that make up ribosomes. Ribosomes, in turn, perform the crucial task of synthesizing proteins.

“We didn’t like this finding in the beginning. I always say that ribosomal DNA is ‘too important to be interesting.’ You don’t get excited about something you really need, like toilet paper,” Yamashita says. “In the case of ribosomal DNA, bacteria needs it, humans need it, everybody needs it.”

But what did rDNA have to do with asymmetric cell division in the germline?

“Around that time, we started reading lots of papers,” Yamashita says. “Then we discovered a phenomenon called rDNA magnification. These were studies from the 1960s and ’80s — most of the people in my lab were not even born yet.”

These studies from decades ago described mutant flies that lacked a sufficient amount of rDNA and, as a result, had a “bobbed” phenotype, or appearance. Since these flies possessed fewer ribosomes to produce proteins, the bristles on their back were shorter; the protective cuticle covering their bodies weakened. But when they reproduced, many of their offspring possessed a normal amount of rDNA. These observations pointed towards a mechanism that allowed flies to replenish their supply of rDNA.

At the time rDNA magnification was first observed, the phenomenon was regarded as an oddity, something that only happened in mutant flies and did not have physiological relevance. But Yamashita realized there was a connection between rDNA magnification and asymmetric division in the germline.

To make enough protein, a cell must produce ample ribosomes. To do that, the fruit fly genome contains hundreds of copies of rDNA in a row. But the DNA replication process can struggle to handle so many rDNA copies strung together, and can sometimes experience a hiccup, resulting in the loss of rDNA copies with each new division. It’s an outcome that might be okay on occasion, but would wreak havoc over many generations.

“All of a sudden, [rDNA magnification] was not about a mutant chromosome,” Yamashita says. “We were like, holy moly. This is about germline immortality.”

Soon many different pieces became part of a cohesive story: asymmetric cell division is not about producing a balance of gametes and stem cells; it’s about maintaining rDNA in the germline. Sister chromatids are almost identical — but one contains more copies of rDNA than the other, and that copy is fated to stay in the GSC pool. Through this asymmetry, the germline is replenished of rDNA; it can pass the baton to the next generation.

“For quite some time, for so many observations that everyone knew in the field, we felt we had an explanation. But from that ‘aha!’ moment, we took multiple years to test everything,” Yamashita says.

In subsequent years, the Yamashita lab pinned down additional details about how rDNA is diverted back to the germline. First, in 2022, the team identified a specific protein, which they named Indra, which binds to rDNA. The presence of Indra helps assign the sister chromatid containing more rDNA copies to the GSC daughter cell.

Their next discovery was another plot twist. If one sister chromatid contained more rDNA than the other, and those rDNA copies weren’t appearing out of thin air, it meant that one chromatid needed to be stealing rDNA from its sister. The lab discovered a genetic element that facilitated this transfer: a retrotransposon.

Retrotransposons are usually considered “genetic parasites,” copying and pasting themselves into the genome. In an attempt to reinsert itself, this particular retrotransposon, called R2, slices open sections containing rDNA on both chromatids. As the cell repairs these breaks, it may inadvertently stitch copies of rDNA from one chromosome to the other, creating an unequal number of copies between the two.

“Not many people thought retrotransposons could be beneficial to the host. They’re seen as parasites,” Yamashita says. “But it turns out that they are essential for germline immortality.”

Sometimes, one research project is a spin off of a spin off. That was true for Xuefeng Meng, a graduate student in the lab who was working on satellite DNA, the genetic element that turned out to be unrelated to asymmetric cell division, but was interesting in its own right.

While studying satellite DNA, Meng noticed that a particular stock of flies had a problem producing normal sperm, that their cells’ nuclei were abnormally packaged. The problem had to do with a gene called Stellate on the flies’ X chromosome. While most flies have few copies of Stellate, these flies had a higher number of copies.

Stellate was already known in the field as a meiotic driver, or “selfish-gene”: a genetic element that has evolved ways to preferentially transmit itself to the next generation. Some meiotic drivers, including Stellate, are on the sex chromosomes and, when not suppressed, cause an excess of either male or female progeny. In this case, Stellate produces a protein, Ste, which is found to concentrate in Y-carrying cells during meiosis, the specialized type of cell division that produces gametes (meiosis follows the earlier round of asymmetric cell division described above). High concentrations of Ste impede the proper packaging of nuclei in cells, leading to their eventual death. When Stellate is widely expressed, fewer male flies emerge in the next generation.

But here lies an inherent tension: if a selfish gene is too good at propagating itself, and produces only males or females, its host species would go extinct — and so would the gene. Meng and Yamashita were interested in this paradox. Through this work, they identified a novel mechanism that keeps Stellate in check. To balance selfish propagation with the host species’ survival, Stellate has a built-in system for pumping the brakes. After Ste concentrates in Y-carrying cells during the first meiotic division, the protein is unevenly distributed a second time. This second step spares a portion of Y-carrying cells that go on to create males.

How the germline is able to counter disruptive forces, thereby renewing itself, continues to be a ripe research area. Researchers still don’t know all the secrets to how a line of cells can achieve perpetuity — but the Yamashita lab continues to investigate the question.

“What I really like about people in my lab is that they don’t jump to the easiest conclusion,” Yamashita says. “If you start embracing surprise, then good things happen. Because you are surprised, you start testing your finding in multiple ways. Then you can build confidence about the result.”

Notes

Xuefeng Meng and Yukiko Yamashita (2025). “Intrinsically weak sex chromosome drive through sequential asymmetric meiosis.” Science Advances. https://doi.org/10.1126/sciadv.adv7089

Jonathan O. Nelson, Tomohiro Kumon, Yukiko M. Yamashita. (2023) “rDNA magnification is a unique feature of germline stem cells.” PNAS. https://doi.org/10.1073/pnas.2314440120

Jonathan O. Nelson, Alyssa Slicko, Yukiko M. Yamashita. (2023) “The retrotransposon R2 maintains Drosophila ribosomal DNA repeats.” PNAS. https://doi.org/10.1073/pnas.2221613120

George J. Watase, Jonathan O. Nelson, Yukiko M. Yamashita. (2022) “Nonrandom sister chromatid segregation mediates rDNA copy number maintenance in Drosophila.” Science Advances. https://www.science.org/doi/10.1126/sciadv.abo4443

Madhav Jagannathan and Yukiko Yamashita. (2021) “Defective satellite DNA clustering into chromocenters underlies hybrid incompatibility in Drosophila.” Molecular Biology and Evolution. https://doi.org/10.1093/molbev/msab221

Swathi Yadlapalli and Yukiko Yamashita (2013) “Chromosome-specific nonrandom sister chromatid segregation during stem-cell division.” Nature. 10.1038/nature12106

A cysteine-rich diet may promote regeneration of the intestinal lining, study suggests

The findings from the Yilmaz Lab recently published in Nature, may offer a new way to help heal tissue damage from radiation or chemotherapy treatment.

Anne Trafton | MIT News
October 1, 2025

A diet rich in the amino acid cysteine may have rejuvenating effects in the small intestine, according to a new study from MIT. This amino acid, the researchers discovered, can turn on an immune signaling pathway that helps stem cells to regrow new intestinal tissue.

This enhanced regeneration may help to heal injuries from radiation, which often occur in patients undergoing radiation therapy for cancer. The research was conducted in mice, but if future research shows similar results in humans, then delivering elevated quantities of cysteine, through diet or supplements, could offer a new strategy to help damaged tissue heal faster, the researchers say.

“The study suggests that if we give these patients a cysteine-rich diet or cysteine supplementation, perhaps we can dampen some of the chemotherapy or radiation-induced injury,” says Omer Yilmaz, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research. “The beauty here is we’re not using a synthetic molecule; we’re exploiting a natural dietary compound.”

While previous research has shown that certain types of diets, including low-calorie diets, can enhance intestinal stem cell activity, the new study is the first to identify a single nutrient that can help intestinal cells to regenerate.

Yilmaz is the senior author of the study, which appears today in Nature. Koch Institute postdoc Fangtao Chi is the paper’s lead author.

Boosting regeneration

It is well-established that diet can affect overall health: High-fat diets can lead to obesity, diabetes, and other health problems, while low-calorie diets have been shown to extend lifespans in many species. In recent years, Yilmaz’s lab has investigated how different types of diets influence stem cell regeneration, and found that high-fat diets, as well as short periods of fasting, can enhance stem cell activity in different ways.

“We know that macro diets such as high-sugar diets, high-fat diets, and low-calorie diets have a clear impact on health. But at the granular level, we know much less about how individual nutrients impact stem cell fate decisions, as well as tissue function and overall tissue health,” Yilmaz says.

In their new study, the researchers began by feeding mice a diet high in one of 20 different amino acids, the building blocks of proteins. For each group, they measured how the diet affected intestinal stem cell regeneration. Among these amino acids, cysteine had the most dramatic effects on stem cells and progenitor cells (immature cells that differentiate into adult intestinal cells).

Further studies revealed that cysteine initiates a chain of events leading to the activation of a population of immune cells called CD8 T cells. When cells in the lining of the intestine absorb cysteine from digested food, they convert it into CoA, a cofactor that is released into the mucosal lining of the intestine. There, CD8 T cells absorb CoA, which stimulates them to begin proliferating and producing a cytokine called IL-22.

IL-22 is an important player in the regulation of intestinal stem cell regeneration, but until now, it wasn’t known that CD8 T cells can produce it to boost intestinal stem cells. Once activated, those IL-22-releasing T cells are primed to help combat any kind of injury that could occur within the intestinal lining.

“What’s really exciting here is that feeding mice a cysteine-rich diet leads to the expansion of an immune cell population that we typically don’t associate with IL-22 production and the regulation of intestinal stemness,” Yilmaz says. “What happens in a cysteine-rich diet is that the pool of cells that make IL-22 increases, particularly the CD8 T-cell fraction.”

These T cells tend to congregate within the lining of the intestine, so they are already in position when needed. The researchers found that the stimulation of CD8 T cells occurred primarily in the small intestine, not in any other part of the digestive tract, which they believe is because most of the protein that we consume is absorbed by the small intestine.

Healing the intestine

In this study, the researchers showed that regeneration stimulated by a cysteine-rich diet could help to repair radiation damage to the intestinal lining. Also, in work that has not been published yet, they showed that a high-cysteine diet had a regenerative effect following treatment with a chemotherapy drug called 5-fluorouracil. This drug, which is used to treat colon and pancreatic cancers, can also damage the intestinal lining.

Cysteine is found in many high-protein foods, including meat, dairy products, legumes, and nuts. The body can also synthesize its own cysteine, by converting the amino acid methionine to cysteine — a process that takes place in the liver. However, cysteine produced in the liver is distributed through the entire body and doesn’t lead to a buildup in the small intestine the way that consuming cysteine in the diet does.

“With our high-cysteine diet, the gut is the first place that sees a high amount of cysteine,” Chi says.

Cysteine has been previously shown to have antioxidant effects, which are also beneficial, but this study is the first to demonstrate its effect on intestinal stem cell regeneration. The researchers now hope to study whether it may also help other types of stem cells regenerate new tissues. In one ongoing study, they are investigating whether cysteine might stimulate hair follicle regeneration.

They also plan to further investigate some of the other amino acids that appear to influence stem cell regeneration.

“I think we’re going to uncover multiple new mechanisms for how these amino acids regulate cell fate decisions and gut health in the small intestine and colon,” Yilmaz says.

The research was funded, in part, by the National Institutes of Health, the V Foundation, the Koch Institute Frontier Research Program via the Kathy and Curt Marble Cancer Research Fund, the Bridge Project — a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center, the American Federation for Aging Research, the MIT Stem Cell Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Inflammation jolts “sleeping” cancer cells awake, enabling them to multiply again

A paper from the Weinberg Lab indicates that inflammation may be a factor in how metastatic cancer cells, those that have broken away from the original tumor, can erupt into a frenzy of growth and division months, years, or decades after initial treatment, seeding new, life-threatening tumors.

Shafaq Zia | Whitehead Institute
September 3, 2025

This migration of cancer cells, called metastasis, is especially common in breast cancer. For many patients, the disease can return months—or even decades—after initial treatment, this time in an entirely different organ.

Whitehead Institute Founding Member Robert Weinberg, also the Daniel K. Ludwig Professor for Cancer Research at Massachusetts Institute of Technology (MIT), has spent decades unraveling the complex biology of metastasis and pursuing research that could improve survival rates among patients with metastatic breast cancer—or prevent metastasis altogether.

In their latest study, Weinberg, postdoctoral fellow Jingwei Zhang, and colleagues ask a critical question: what causes these dormant cancer cells to erupt into a frenzy of growth and division? The group’s findings, published Sept. 1 in The Proceedings of the National Academy of Sciences (PNAS), point to a unique culprit.

This awakening of dormant cancer cells, they’ve discovered, isn’t a spontaneous process. Instead, the wake-up call comes from the inflamed tissue surrounding the cells. One trigger for this inflammation is bleomycin, a common chemotherapy drug that can scar and thicken lung tissue.

“The inflammation jolts the dormant cancer cells awake,” Weinberg says. “Once awakened, they start multiplying again, seeding new life-threatening tumors in the body.”

Decoding metastasis

There’s a lot that scientists still don’t know about metastasis, but this much is clear: cancer cells must undergo a long and arduous journey to achieve it. The first step is to break away from their neighbors within the original tumor.

Normally, cells stick to one another using surface proteins that act as molecular “velcro” but some cancer cells can acquire genetic changes that disrupt the production of these proteins and make them more mobile and invasive, allowing them to detach from the parent tumor.

Once detached, they can penetrate blood vessels and lymphatic channels, which act as highways to distant organs.

While most cancer cells die at some point during this journey, a few persist. These cells exit the bloodstream and invade different tissues—lungs, liver, bone, and even the brain—to give birth to new, often more aggressive tumors.

“Almost 90% of cancer-related deaths occur not from the original tumor but when cancer cells spread to other parts of the body,” says Weinberg. “This is why it’s so important to understand how these ‘sleeping’ cancer cells can wake up and start growing again.”

Setting up shop in new tissue comes with changes in surroundings—the “tumor microenvironment”—to which the cancer cells may not be well-suited. These cells face constant threats, including detection and attack by the immune system.

To survive, they often enter a protective state of dormancy that puts a pause on growth and division. This dormant state also makes them resistant to conventional cancer treatments, which often target rapidly dividing cells.

To investigate what makes this dormancy reversible months or years down the line, researchers in the Weinberg Lab injected human breast cancer cells into mice. These cancer cells were modified to produce a fluorescent protein, allowing the scientists to track their behavior in the body.

The group then focused on cancer cells that had lodged themselves in the lung tissue. By examining them for specific proteins—Ki67, ITGB4 and p63—that act as markers of cell activity and state, the researchers were able to confirm that these cells were in a non-dividing, dormant state.

Previous work from the Weinberg Lab had shown that inflammation in organ tissue can provoke dormant breast cancer cells to start growing again. In this study, the team tested bleomycin—a chemotherapy drug known to cause lung inflammation—that can be given to patients after surgery to lower the risk of cancer recurrence.

The researchers found that lung inflammation from bleomycin was sufficient to trigger the growth of large lung cancer colonies in treated mice—and to shift the character of these once dormant cells to those that are more invasive and mobile.

Zeroing in on the tumor microenvironment, the team identified a type of immune cells, called M2 macrophages, as drivers of this process. These macrophages release molecules called epidermal growth factor receptor (EGFR) ligands, which bind to receptors on the surface of dormant cancer cells. This activates a cascade of signals that provoke dormant cancer cells to start multiplying rapidly.

But EGFR signaling is only the initial spark that ignites the fire. “We found that once dormant cancer cells are awakened, they retain what we call an ‘awakening memory,’” Zhang says. “They no longer require ongoing inflammatory signals from the microenvironment to stay active [growing and multiplying]—they remember the awakened state.”

While signals related to inflammation are necessary to awaken dormant cancer cells, exactly how much signaling is needed remains unclear. “This aspect of cancer biology is particularly challenging because multiple signals contribute to the state change in these dormant cells,” Zhang says.

The team has already identified one key player in the awakening process but understanding the full set of signals and how each contributes is far more complex—a question they are continuing to investigate in their new work.

Studying these pivotal changes in the lives of cancer cells—such as their transition from dormancy to active growth—will deepen our scientific understanding of metastasis and, as researchers in the Weinberg Lab hope, lead to more effective treatments for patients with metastatic cancers.

Can a pill help you live longer? The science behind NAD and longevity

MIT professor, Dr. Leonard Guarente, conducts research into sirtuin genes and the power of a molecule called NAD.

WCVB
July 22, 2025

It might sound too good to be true: a pill that could help you live a longer, healthier life. But Leonard Guarente, a longtime MIT biologist, believes the idea holds promise.

Guarente, the Novartis Professor of Biology at MIT, has spent more than 40 years studying the science of aging. He started small, working with yeast cells.

“We decided to look for genes that could make yeast live longer,” he said. That’s when a gene called SIR2 caught his attention. Boosting SIR2 activity helped yeast cells live longer—and when the same effect was observed in roundworms, Guarente turned his attention to humans.

Humans, it turns out, have seven genes similar to SIR2. Collectively, these are called sirtuins, a group of proteins essential to cell health. According to Guarente, sirtuins help power cells, repair damage, and regulate which genes are turned on or off.

Guarente says sirtuins need NAD (nicotinamide adenine dinucleotide) to stay active, but NAD levels naturally decline as we get older.

“If we could restore NAD levels in an older person back to youthful levels, we thought that would do a lot of good,” he explained.

That idea became the foundation for Elysium Health, a company Guarente co-founded. Some critics question the ethics of a scientist selling supplements based on his own research, but Guarente stands by the rigor of his approach. “We ended up with eight Nobel Prize winners on the board,” he noted.

Of course, whether restoring NAD levels leads to longer life is still uncertain. “A person who is very healthy might not notice much initially because where is there to go?” Guarente explained. “But what about in 30 years? There’s no way to answer that question right now.”

A selfish gene unlike any other

Certain genes are “selfish," cheating the rules of inheritance to increase their chances of being transmitted. Researchers in the Yamashita Lab have uncovered a unique "self-limiting" mechanism keeping the selfish gene Stellate in check

Shafaq Zia | Whitehead Institute
May 7, 2025

When a species reproduces, typically, each parent passes on one of their two versions, or alleles, of a given gene to their offspring. But not all alleles play fair in their quest to be passed onto future generations.

Certain alleles, called meiotic drivers, are “selfish”—they cheat the rules of inheritance to increase their chances of being transmitted, often at the expense of the organism’s fitness.

The lab of Whitehead Institute Member Yukiko Yamashita investigates how genetic information is transmitted across generations through the germline—cells that give rise to egg and sperm. Now, Yamashita and first author Xuefeng Meng, a graduate student in the Yamashita Lab, have discovered a meiotic driver that operates differently from previously known drivers.

The researchers’ findings, published online in Science Advances on May 7, reveal that the Stellate (Ste) gene—which has multiple copies located close to one another—on the X chromosome in Drosophila melanogaster, a fruit fly species, is a meiotic driver that biases the transmission of the X chromosome. However, it also has a unique “self-limiting” mechanism that helps preserve the organism’s ability to have male offspring.

“This mechanism is an inherent remedy to the gene’s selfish drive,” says Yamashita, who is also a professor of biology at Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute. “Without it, the gene could severely skew the sex ratio in a population and drive the species to extinction—a paradox that has been recognized for a long time.”

Fatal success

Meiosis is a key process underlying sexual reproduction. This is when cells from the germline undergo two rounds of specialized cell division—meiosis I and meiosis II—to form gametes (egg and sperm cells). In males, this typically results in an equal number of X-bearing and Y-bearing sperm, which ensures an equal chance of having a male or female offspring.

Meiotic drivers located on sex chromosomes can skew this sex ratio by selectively destroying gametes that do not carry the driver allele. Among them is the meiotic driver Ste.

In male germline cells of fruit flies, Ste is kept in check by small RNA molecules, called piRNAs, produced by Suppressor of Stellate (Su(Ste)) located on the Y chromosome. These RNA molecules recruit special proteins to silence Ste RNA. This prevents the production of Ste protein that would otherwise disrupt the development of Y-bearing sperm, which helps maintain the organism’s ability to have male offspring.

“But the suppressing mechanism isn’t foolproof,” Meng explains. “When the meiotic driver and its suppressor are located on different chromosomes, they can get separated during reproduction, leaving the driver unchecked in the next generation.”

A skewed sex ratio toward females offers a short-term advantage: having more females than males could increase a population’s reproductive potential. But in the long run, the meiotic driver risks fatal success—driving the species toward extinction through depletion of males.

Interestingly, prior research suggests that un-silencing Ste only modestly skews a population’s sex ratio, even in the absence of the suppressor, unlike other meiotic drivers that almost exclusively produce females in the progeny. Could another mechanism be at play, keeping Ste’s selfish drive in check?

Practicing self-restraint

To explore this intriguing possibility, researchers in the Yamashita Lab began by examining the process of sperm development. Under moderate Ste expression, pre-meiotic germ cell development and meiosis proceeded normally but defects in sperm development began to emerge soon after. Specifically, a subset of spermatids—immature sperm cells produced after meiosis—failed to incorporate essential DNA-packaging proteins called protamines, which are required to preserve the integrity of genetic information in sperm.

To confirm if the spermatids impacted were predominantly those that carried the Y chromosome, the researchers used an imaging technique called immunofluorescence staining, which uses antibodies to attach fluorescent molecules to a protein of interest, making it glow. They combined this with a technique called FISH (fluorescence in-situ hybridization), which tags the X and Y chromosomes with fluorescent markers, allowing researchers to distinguish between cells that will become X-bearing or Y-bearing following meiosis.

Indeed, the team found that while Ste protein is present in all spermatocytes before meiosis I, it unevenly divides between the two daughter cells—a phenomenon called asymmetric segregation—during meiosis I and gets concentrated in Y-bearing spermatids, eventually inducing DNA-packaging defects in these spermatids.

These findings clarified Ste’s role as a meiotic driver but the researchers still wondered why expression of Ste only led to a moderate sex ratio distortion. The answer soon became clear when they observed Ste undergo another round of asymmetric segregation during meiosis II. This meant that even if a secondary spermatocyte inherited Ste protein after meiosis I, only half of the spermatids produced in this round of cell division ended up retaining the protein. Hence, only half of the Y-bearing spermatids were going to be killed off.

“This self-limiting mechanism is the ultimate solution to the driver-suppressor separation problem,” says Yamashita. “But the idea is so unconventional that had it been proposed as just a theory, without the evidence we have now, it would’ve been completely dismissed.”

These findings have solved some questions and raised others: Unlike female meiosis, which is known to be asymmetrical, male meiosis has traditionally been considered symmetrical. Does the unequal segregation of Ste suggest there’s an unknown asymmetry in male meiosis? Do meiotic drivers like Ste trigger this asymmetry, or do they simply exploit it to limit their selfish drive?

Answering them is the next big step for Yamashita and her colleagues. “This could fundamentally change our understanding of male meiosis,” she says. “The best moments in science are when textbook knowledge is challenged and it turns out to have been tunnel vision.”

MIT Down syndrome researchers work on ways to ensure a healthy lifespan

An Alana Down Syndrome Center webinar, co-sponsored by the Massachusetts Down Syndrome Congress, presented numerous MIT studies that all share the goal of improving health throughout life for people with trisomy 21.

David Orenstein | The Picower Institute for Learning and Memory
April 24, 2025

In recent decades the life expectancy of people with Down syndrome has surged past 60 years, so the focus of research at the Alana Down Syndrome Center at MIT has been to make sure people can enjoy the best health during that increasing timeframe.

“A person with Down syndrome can live a long and happy life,” said Rosalind Mott Firenze, scientific director of the center founded at MIT in 2019 with a gift from the Alana Foundation. “So the question is now how do we improve health and maximize ability through the years? It’s no longer about lifespan, but about healthspan.”

Firenze and three of the center’s Alana Fellows scientists spoke during a webinar, hosted on April 17th, where they described the center’s work toward that goal. An audience of 99 people signed up to hear the webinar titled “Building a Better Tomorrow for Down Syndrome Through Research and Technology,” with many viewers hailing from the Massachusetts Down Syndrome Congress, which co-sponsored the event.

The research they presented covered ways to potentially improve health from stages before birth to adulthood in areas such as brain function, heart development, and sleep quality.

Boosting brain waves

One of the center’s most important areas of research involves testing whether boosting the power of a particular frequency of brain activity—“gamma” brain waves of 40Hz—can improve brain development and function. The lab of the center’s Director Li-Huei Tsai, Picower Professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences, uses light that flickers and sound that clicks 40 times a second to increase that rhythm in the brain. In early studies of people with Alzheimer’s disease, which is a major health risk for people with Down syndrome, the non-invasive approach has proved safe, and appears to improve memory while preventing brain cells from dying. The reason it works appears to be because it promotes a healthy response among many types of brain cells.

Working with mice that genetically model Down syndrome, Alana Fellow Dong Shin Park has been using the sensory stimulation technology to study whether the healthy cellular response can affect brain development in a fetus while a mother is pregnant. In ongoing research, he said, he’s finding that exposing pregnant mice to the light and sound appears to improve fetal brain development and brain function in the pups after they are born.

In his research, Postdoctoral Associate Md. Rezaul Islam worked with 40Hz sensory stimulation and Down syndrome model mice at a much later stage in life—when they are adult aged. Together with former Tsai Lab member Brennan Jackson, he found that when the mice were exposed to the light and sound, their memory improved. The underlying reason seemed to be an increase not only in new connections among their brain cells, but also an increase in the generation of new ones. The research, currently online as a preprint, is set to publish in a peer-reviewed journal very soon.

Firenze said the Tsai lab has also begun to test the sensory stimulation in human adults with Down syndrome. In that testing, which is led by Dr. Diane Chan, it is proving safe and well tolerated, so the lab is hoping to do a year-long study with volunteers to see if the stimulation can delay or prevent the onset of Alzheimer’s disease.

Studying cells

Many Alana Center researchers are studying other aspects of the biology of cells in Down syndrome to improve healthspan. Leah Borden, an Alana Fellow in the lab of Biology Professor Laurie Boyer, is studying differences in heart development. Using advanced cultures of human heart tissues grown from trisomy 21 donors, she is finding that tissue tends to be stiffer than in cultures made from people without the third chromosome copy. The stiffness, she hypothesizes, might affect cellular function and migration during development, contributing to some of the heart defects that are common in the Down syndrome population.

Firenze pointed to several other advanced cell biology studies going on in the center. Researchers in the lab of Computer Science Professor Manolis Kellis, for instance, have used machine learning and single cell RNA sequencing to map the gene expression of more than 130,000 cells in the brains of people with or without Down syndrome to understand differences in their biology.

Researchers the lab of Y. Eva Tan Professor Edward Boyden, meanwhile, are using advanced tissue imaging techniques to look into the anatomy of cells in mice, Firenze said. They are finding differences in the structures of key organelles called mitochondria that provide cells with energy.

And in 2022, Firenze recalled, Tsai’s lab published a study showing that brain cells in Down syndrome mice exhibited a genome-wide disruption in how genes are expressed, leading them to take on a more senescent, or aged-like, state.

Striving for better sleep

One other theme of the Alana Center’s research that Firenze highlighted focuses on ways to understand and improve sleep for people with Down syndrome. In mouse studies in Tsai’s lab, they’ve begun to measure sleep differences between model and neurotypical mice to understand more about the nature of sleep disruptions.

“Sleep is different and we need to address this because it’s a key factor in your health,” Firenze said.

Firenze also highlighted how the Alana Center has collaborated with MIT’s Desphande Center for Technological Innovation to help advance a new device for treating sleep apnea in people with Down syndrome. Led by Mechanical Engineering Associate Professor Ellen Roche, the ZzAlign device improves on current technology by creating a custom-fit oral prosthesis accompanied by just a small tube to provide the needed air pressure to stabilize mouth muscles and prevent obstruction of the airway.

Through many examples of research projects aimed at improving brain and heart health and enhancing sleep, the webinar presented how MIT’s Alana Down Syndrome Center is working to advance the healthspan of people with Down syndrome.

 

New study reveals how cleft lip and cleft palate can arise

MIT biologists have found that defects in some transfer RNA molecules can lead to the formation of these common conditions.

Anne Trafton | MIT News
April 17, 2025

Cleft lip and cleft palate are among the most common birth defects, occurring in about one in 1,050 births in the United States. These defects, which appear when the tissues that form the lip or the roof of the mouth do not join completely, are believed to be caused by a mix of genetic and environmental factors.

In a new study, MIT biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate.

Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth.

“Until now, no one had made the connection that we made. This particular gene was known to be part of the complex involved in the splicing of transfer RNA, but it wasn’t clear that it played such a crucial role for this process and for facial development. Without the gene, known as DDX1, certain transfer RNA can no longer bring amino acids to the ribosome to make new proteins. If the cells can’t process these tRNAs properly, then the ribosomes can’t make protein anymore,” says Michaela Bartusel, an MIT research scientist and the lead author of the study.

Eliezer Calo, an associate professor of biology at MIT, is the senior author of the paper, which appears today in the American Journal of Human Genetics.

Genetic variants

Cleft lip and cleft palate, also known as orofacial clefts, can be caused by genetic mutations, but in many cases, there is no known genetic cause.

“The mechanism for the development of these orofacial clefts is unclear, mostly because they are known to be impacted by both genetic and environmental factors,” Calo says. “Trying to pinpoint what might be affected has been very challenging in this context.”

To discover genetic factors that influence a particular disease, scientists often perform genome-wide association studies (GWAS), which can reveal variants that are found more often in people who have a particular disease than in people who don’t.

For orofacial clefts, some of the genetic variants that have regularly turned up in GWAS appeared to be in a region of DNA that doesn’t code for proteins. In this study, the MIT team set out to figure out how variants in this region might influence the development of facial malformations.

Their studies revealed that these variants are located in an enhancer region called e2p24.2. Enhancers are segments of DNA that interact with protein-coding genes, helping to activate them by binding to transcription factors that turn on gene expression.

The researchers found that this region is in close proximity to three genes, suggesting that it may control the expression of those genes. One of those genes had already been ruled out as contributing to facial malformations, and another had already been shown to have a connection. In this study, the researchers focused on the third gene, which is known as DDX1.

DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. Each transfer RNA molecule transports a specific amino acid to the ribosome — a cell structure that strings amino acids together to form proteins, based on the instructions carried by messenger RNA.

While there are about 400 different tRNAs found in the human genome, only a fraction of those tRNAs require splicing, and those are the tRNAs most affected by the loss of DDX1. These tRNAs transport four different amino acids, and the researchers hypothesize that these four amino acids may be particularly abundant in proteins that embryonic cells that form the face need to develop properly.

When the ribosomes need one of those four amino acids, but none of them are available, the ribosome can stall, and the protein doesn’t get made.

The researchers are now exploring which proteins might be most affected by the loss of those amino acids. They also plan to investigate what happens inside cells when the ribosomes stall, in hopes of identifying a stress signal that could potentially be blocked and help cells survive.

Malfunctioning tRNA

While this is the first study to link tRNA to craniofacial malformations, previous studies have shown that mutations that impair ribosome formation can also lead to similar defects. Studies have also shown that disruptions of tRNA synthesis — caused by mutations in the enzymes that attach amino acids to tRNA, or in proteins involved in an earlier step in tRNA splicing — can lead to neurodevelopmental disorders.

“Defects in other components of the tRNA pathway have been shown to be associated with neurodevelopmental disease,” Calo says. “One interesting parallel between these two is that the cells that form the face are coming from the same place as the cells that form the neurons, so it seems that these particular cells are very susceptible to tRNA defects.”

The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function. Some of their preliminary work has found that oxidative stress — a buildup of harmful free radicals — can lead to fragmentation of tRNA molecules. Oxidative stress can occur in embryonic cells upon exposure to ethanol, as in fetal alcohol syndrome, or if the mother develops gestational diabetes.

“I think it is worth looking for mutations that might be causing this on the genetic side of things, but then also in the future, we would expand this into which environmental factors have the same effects on tRNA function, and then see which precautions might be able to prevent any effects on tRNAs,” Bartusel says.

The research was funded by the National Science Foundation Graduate Research Program, the National Cancer Institute, the National Institute of General Medical Sciences, and the Pew Charitable Trusts.

Restoring healthy gene expression with programmable therapeutics

CAMP4 Therapeutics is targeting regulatory RNA, whose role in gene expression was first described by co-founder and MIT Professor Richard Young.

Zach Winn | MIT News
April 16, 2025

Many diseases are caused by dysfunctional gene expression that leads to too much or too little of a given protein. Efforts to cure those diseases include everything from editing genes to inserting new genetic snippets into cells to injecting the missing proteins directly into patients.

CAMP4 is taking a different approach. The company is targeting a lesser-known player in the regulation of gene expression known as regulatory RNA. CAMP4 co-founder and MIT Professor Richard Young has shown that by interacting with molecules called transcription factors, regulatory RNA plays an important role in controlling how genes are expressed. CAMP4’s therapeutics target regulatory RNA to increase the production of proteins and put patients’ levels back into healthy ranges.

The company’s approach holds promise for treating diseases caused by defects in gene expression, such as metabolic diseases, heart conditions, and neurological disorders. Targeting regulatory RNAs as opposed to genes could also offer more precise treatments than existing approaches.

“If I just want to fix a single gene’s defective protein output, I don’t want to introduce something that makes that protein at high, uncontrolled amounts,” says Young, who is also a core member of the Whitehead Institute. “That’s a huge advantage of our approach: It’s more like a correction than sledgehammer.”

CAMP4’s lead drug candidate targets urea cycle disorders (UCDs), a class of chronic conditions caused by a genetic defect that limits the body’s ability to metabolize and excrete ammonia. A phase 1 clinical trial has shown CAMP4’s treatment is safe and tolerable for humans, and in preclinical studies the company has shown its approach can be used to target specific regulatory RNA in the cells of humans with UCDs to restore gene expression to healthy levels.

“This has the potential to treat very severe symptoms associated with UCDs,” says Young, who co-founded CAMP4 with cancer genetics expert Leonard Zon, a professor at Harvard Medical School. “These diseases can be very damaging to tissues and causes a lot of pain and distress. Even a small effect in gene expression could have a huge benefit to patients, who are generally young.”

Mapping out new therapeutics

Young, who has been a professor at MIT since 1984, has spent decades studying how genes are regulated. It’s long been known that molecules called transcription factors, which orchestrate gene expression, bind to DNA and proteins. Research published in Young’s lab uncovered a previously unknown way in which transcription factors can also bind to RNA. The finding indicated RNA plays an underappreciated role in controlling gene expression.

CAMP4 was founded in 2016 with the initial idea of mapping out the signaling pathways that govern the expression of genes linked to various diseases. But as Young’s lab discovered and then began to characterize the role of regulatory RNA in gene expression around 2020, the company pivoted to focus on targeting regulatory RNA using therapeutic molecules known as antisense oligonucleotides (ASOs), which have been used for years to target specific messenger RNA sequences.

CAMP4 began mapping the active regulatory RNAs associated with the expression of every protein-coding gene and built a database, which it calls its RAP Platform, that helps it quickly identify regulatory RNAs to target  specific diseases and select ASOs that will most effectively bind to those RNAs.

Today, CAMP4 is using its platform to develop therapeutic candidates it believes can restore healthy protein levels to patients.

“The company has always been focused on modulating gene expression,” says CAMP4 Chief Financial Officer Kelly Gold MBA ’09. “At the simplest level, the foundation of many diseases is too much or too little of something being produced by the body. That is what our approach aims to correct.”

Accelerating impact

CAMP4 is starting by going after diseases of the liver and the central nervous system, where the safety and efficacy of ASOs has already been proven. Young believes correcting genetic expression without modulating the genes themselves will be a powerful approach to treating a range of complex diseases.

“Genetics is a powerful indicator of where a deficiency lies and how you might reverse that problem,” Young says. “There are many syndromes where we don’t have a complete understanding of the underlying mechanism of disease. But when a mutation clearly affects the output of a gene, you can now make a drug that can treat the disease without that complete understanding.”

As the company continues mapping the regulatory RNAs associated with every gene, Gold hopes CAMP4 can eventually minimize its reliance on wet-lab work and lean more heavily on machine learning to leverage its growing database and quickly identify regRNA targets for every disease it wants to treat.

In addition to its trials in urea cycle disorders, the company plans to launch key preclinical safety studies for a candidate targeting seizure disorders with a genetic basis, this year. And as the company continues exploring drug development efforts around the thousands of genetic diseases where increasing protein levels are can have a meaningful impact, it’s also considering collaborating with others to accelerate its impact.

“I can conceive of companies using a platform like this to go after many targets, where partners fund the clinical trials and use CAMP4 as an engine to target any disease where there’s a suspicion that gene upregulation or downregulation is the way to go,” Young says.