Research Area: Human Disease

Biologists identify a cellular pathway that allows colorectal cancer to metastasize

They also found that obesity may put patients at higher risk for activation of the pathway. Drugs that block the pathway may help prevent metastasis.

Anne Trafton | MIT News
September 24, 2026

Most colon cancer deaths are caused by the spread of tumor cells beyond the colon, usually to the liver. In a new study, MIT biologists identified a cellular pathway necessary for colorectal cancer metastasis.

The pathway they identified, controlled by a protein known as YAP1, is normally involved in tissue repair. When activated in cancer cells, it promotes cell proliferation and migration. The researchers also found that a high-fat diet is more likely to turn on this pathway, through the production of fatty molecules called ceramides.

Drugs that block ceramide production could offer a new way to help prevent metastasis in patients diagnosed with colon cancer, the researchers say.

“We’ve found a pathway that we think is druggable. If we shut down the enzymes that make ceramides, tumor cells can’t switch on this regenerative program, and they largely fail to seed metastases in the liver,” says Omer Yilmaz, director of the MIT Stem Cell Initiative, a professor of biology at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research. He is also a gastrointestinal pathologist and director of translational research in pathology at Beth Israel Deaconess Medical Center.

Yilmaz, Nilay Sethi, an associate professor of medicine at Harvard Medical School and Dana Farber Cancer Institute, and Alpaslan Tasdogan, head of the Institute for Tumor Metabolism and a professor in the Department of Dermatology at University Hospital Essen and the German Cancer Consortium (DKTK), are the senior authors of the study, which appears today in Science. MIT postdocs Swagata Goswami, Qiming Zhang, and Abdullah Burak Yildiz are the paper’s lead authors.

A hijacked pathway

In the United States, colon cancer is usually diagnosed at stage 2 or 3 — before the cancer has spread. However, even after successful surgery, up to a third of these patients will relapse with metastatic disease.

While scientists have identified many genetic mutations that drive the development of colon cancer, it’s unknown exactly what prompts them to spread beyond the colon.

“Many studies have looked for a genetic driver of metastasis and come up empty,” Yilmaz says. “There isn’t a defining mutational signature that separates metastatic cells from the primary tumor, which points to metastasis being driven largely by changes in which genes are switched on and off, rather than by new mutations.”

In this study, the researchers sought to identify epigenetic programs that enable colon cancer cells to metastasize. Using tumor organoids from mouse models of several types of colon cancer and from patients with colorectal cancer, they found that metastatic cells shared one key feature: activation of the YAP1 program.

YAP1 is a protein that works with partner factors to switch on genes related to development, stem cell maintenance, and regeneration. In normal tissue, it is active during fetal development, and after injury, to promote healing.

In the gut, that repair response runs through a rare, fetal-like cell type, which normally appears only briefly to rebuild the intestinal lining after damage. YAP1 has been linked to cancer for years, but the new work shows that diet-derived lipids push tumor cells into this specific regenerative state — and that the state itself is what licenses metastasis.

“The regenerative program that we described is generally observed in the gut when there is severe injury or infection and the gut needs to regenerate. We see the tumor cells hijack this program to drive metastatic progression,” Goswami says.

Activation of this set of genes helps cancer cells to break free from the original tumor site and spread to other locations in the body. For colon cancer, the most common site of metastasis is the liver, followed by the lungs.

In mouse studies, the researchers also found that cancer cells in animals fed a high-fat diet turned on YAP1 to a greater extent than mice fed a healthy diet. A high-fat diet, the researchers found, triggers activation of enzymes that produce ceramides, a type of lipid. Ceramides then release the molecular brake that normally keeps YAP1 inactive, allowing it to move into the nucleus and switch on its target genes.

Preventing metastasis

The researchers showed that genetically targeting YAP1, or the genes involved in ceramide production, markedly reduced the spread of colon cancer to the liver in mice.

To determine if YAP1 is also involved in metastasis in humans, the researchers analyzed RNA sequencing data from patients with colorectal cancer. They found that YAP1 was more active in metastatic cancer cells, and that patients with higher body mass index (BMI) showed higher expression of the genes activated by YAP1 than normal-weight patients. Patients with higher levels of those genes also had lower survival rates.

“We don’t think that the YAP1 program is specific to obesity. It’s just that it becomes accentuated in obesity, and that may account for why obesity is known to drive the progression of colorectal cancer,” Yilmaz says.

They now plan to develop drugs that inhibit two of the enzymes involved in ceramide production, DEGS1 and DEGS2, in hopes that such drugs could help prevent colon cancer metastasis.

The researchers caution that the findings do not yet translate into dietary advice for patients who have already been diagnosed, and that any drug targeting ceramide synthesis will have to clear a high bar for selectivity, since these lipids are also essential in healthy tissues.

The research was funded by the National Institutes of Health/National Cancer Institute, the MIT Stem Cell Initiative, a Koch Institute Frontier grant, and the NRW Junior Research Program.

Avoiding a sticky situation: how cells stop messenger RNAs from clumping together

Although cells contain many thousands of mRNA molecules crowded into a tiny space, these molecules typically don't form the clumping aggregates often seen when they're removed from their native context for study. New research from the Jain Lab suggests that evolution has shaped mRNA sequences to reduce unwanted interactions.

Alice McCarthy | Whitehead Institute
September 14, 2026

Messenger RNA, or mRNA, is best known for carrying genetic instructions from DNA to the cellular machinery that makes proteins. But all RNA molecules have another, less appreciated property: they are naturally sticky.

When RNA is removed from cells and studied in the laboratory, the molecules readily interact with one another and can clump together, or aggregate. This creates a biological puzzle. Cells contain many thousands of mRNA molecules crowded into a tiny space, yet their mRNAs do not routinely form the large aggregates that their physical properties would seem to favor. This puzzling behavior is important for cell function: unwanted RNA interactions can prevent mRNAs from being accessible to make proteins, and large RNA aggregates can be toxic to cells.

Now, researchers at Whitehead Institute have uncovered one way cells may have evolved to avoid these sticky situations. Their findings suggest that evolution has shaped mRNA sequences to reduce unwanted interactions with other mRNAs. The work could potentially inform the development of RNA therapeutics, allowing drug designers to learn from evolution when selecting RNA sequences.

The study, led by Whitehead Institute Member Ankur Jain, also an associate professor of biology at MIT, and Marco Todisco, a postdoctoral researcher in his lab, reveals a previously unrecognized constraint on the evolution of genetic sequences: DNA must not only encode functional proteins, but also produce mRNAs with physical properties that help keep them soluble inside the cell.

The researchers’ findings were published in the Proceedings of the National Academy of Sciences on September 14.

Scientists studying purified RNA have known for decades that the molecules can readily aggregate. But if the chemistry of RNA makes these interactions so favorable outside cells, Todisco wondered, why shouldn’t the same thing happen inside them?

To investigate, Todisco and colleagues focused on Escherichia coli, or E. coli, a bacterium whose biology has been extensively studied. Researchers have detailed information about which mRNAs are present in an E. coli cell, how many copies of each are present, and what those molecules look like — making it possible to model the behavior of an entire collection of cellular mRNAs, known as the transcriptome.

Todisco developed computer simulations that tracked individual mRNA molecules and predicted how they would behave at concentrations similar to those found inside a cell. Based on the physical chemistry of RNA alone, the simulations indicated that the molecules should aggregate. Longer mRNAs were particularly prone to joining these clusters.

The team then tested that prediction experimentally. With help from Christalyn Ausler, a research technician in the Jain lab, they purified mRNA from E. coli cells. The authors found that without proteins and other components normally surrounding it in the cell, the purified mRNA readily aggregated. Using RNA sequencing, the researchers identified which mRNAs were enriched in the aggregates and found that their properties closely matched the simulations.

Those findings strengthened the original puzzle: If mRNA has such a strong physical tendency to associate with other RNA molecules, how have cells managed that problem?

The researchers found part of the answer written into the genetic sequences themselves.

DNA carries the instructions for building proteins using three-letter sequences called codons, each of which specifies an amino acid, one of the building blocks of proteins. But the genetic code contains redundancy: most amino acids can be encoded by more than one codon. That means an enormous number of different DNA and mRNA sequences can produce exactly the same protein. Evolution therefore has some freedom in which sequence it uses.

The researchers took advantage of that flexibility to computationally create alternative versions of E. coli mRNAs. They changed the RNA sequences while preserving the proteins they encoded — in effect creating alternative evolutionary paths in which an organism could make the same proteins from different mRNAs.

When the researchers compared these randomized sequences with naturally occurring E. coli mRNAs, they found that the natural sequences were less prone to interacting with one another. Native mRNAs tended to fold onto themselves and to avoid exposing sticky stretches, reducing opportunities to form stable and unwanted interactions with other mRNA molecules.

In other words, stickiness is unavoidable, but evolution appears to have favored not just DNA sequences that make the right proteins, but sequences that produce less sticky mRNAs along the way.

The researchers found evidence that the phenomenon extends beyond bacteria. When they performed sequence analyses on a set of abundant human mRNAs, they found similar signatures: naturally occurring human RNA sequences also showed a reduced potential for aggregation compared with alternative sequences.

The discovery adds another dimension to the familiar “central dogma” of molecular biology, in which information flows from DNA to RNA to protein. Scientists have traditionally thought about genetic sequences largely in terms of their ultimate product: the protein. The new findings suggest that evolution also has to contend with the physical behavior of the mRNA intermediate.

That may not be the whole solution. Although naturally occurring mRNA sequences are less prone to aggregation, purified mRNA still readily clumps together. The fact that widespread aggregation is not normally seen inside healthy cells suggests that proteins or other cellular components may provide an additional layer of protection by buffering inappropriate RNA-RNA interactions. These findings help build a broader picture of how cells may use multiple mechanisms to manage RNA interactions and prevent inappropriate aggregation.

The findings could also have implications for the growing field of mRNA therapeutics. When researchers design synthetic mRNAs for vaccines and other treatments, they can choose among different codons that ultimately produce the same protein. The new work suggests that how the resulting RNA folds and interacts with other RNAs may be another important consideration when selecting those sequences.

“What this gives us is a new lens for thinking about how genomes evolve,” Jain says. “Sequences aren’t evolving just to encode functional proteins; there is an additional constraint to produce mRNAs that are less likely to stick to one another. These findings could also provide guiding principles for designing the sequences used in mRNA vaccines and other RNA therapeutics.”

Notes:

Todisco, M., Ausler, C., and Jain, A. “Maintaining transcriptome solubility constrains mRNA sequence composition.” Proceedings of the National Academy of Sciences (2026). https://doi.org/10.1073/pnas.2622980123.

Funding:

This work is supported by grants from the NIH (R35GM151111), Chan Zuckerberg Initiative (DAF2022-250422), Richard and Susan Smith Family Foundation, and the David and Lucile Packard Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Cells use a little-known molecule to protect themselves from iron overload

Research from the Jain and Henry Labs in the Whitehead Institute and Koch Institute respectively have discovered that cells are protected from destructive levels of iron buildup by small molecules called polyamines, which act like storage lockers, safely holding the metal in a non-reactive state until cells need it.

Shafaq Zia | Whitehead Institute
August 14, 2026

Iron is essential. Our cells need it to produce energy, carry oxygen throughout the body, and power countless chemical reactions that sustain life. But this metal has a dark side. When too much of it is left free inside cells, it can trigger destructive reactions that break down DNA, proteins, and even cell membranes.

Now, Whitehead Institute Member Ankur Jain and Whitney Henry, an investigator in MIT’s Department of Biology and the Koch Institute for Integrative Cancer Research, together with graduate student Pushkal Sharma have discovered that cells rely on an unexpected protector against this threat: small molecules called polyamines.

The researchers’ detailed findings, published Aug. 14 in the journal Cell, reveal that polyamines act like storage lockers for iron, safely holding the metal in a non-reactive state until cells need it.

These findings solve a decades-old mystery about why cells maintain such extraordinarily high levels of polyamines and uncover a previously unknown defense mechanism that protects cells from toxic iron overload.

This work could also help scientists develop better cancer treatments, by allowing iron overload to trigger cancer cell death. It could also offer new clues about diseases like early-onset Parkinson’s disease, in which mutations affect polyamine levels within neurons.

The Jain Lab studies RNA, the intermediary between DNA and the tiny molecular machines called proteins that perform most of the essential tasks inside cells. The lab is particularly interested in how RNA folds, misfolds, and sometimes clumps inside cells.

Jain and Sharma first began studying polyamines because these molecules bind to RNA and help shape its structure. However, they suspected that polyamines must be playing other roles inside cells: they’re among the most abundant small molecules within cells, present at levels comparable to ATP, the molecule cells use as their energy currency.

“We’ve known that without polyamines, cells stop growing and dividing,” says Jain, who is also an associate professor of biology at the Massachusetts Institute of Technology (MIT). “But their best-known function only requires a small fraction of the polyamine levels cells actually have.”

To uncover polyamines’ hidden function inside cells, the researchers used a large-scale genetic approach that allows them to screen the entire genome at once, rather than testing genes one-by-one, in order to find out which cellular processes are impacted when polyamine levels are changed within cells.

The screen revealed that when cells have reduced levels of polyamines, a protein called GPX4 becomes essential for survival. GPX4 is known to prevent harmful chemical reactions that damage the fatty molecules that make up cell membranes.

The team also found that cells with lower polyamine levels have higher amounts of another protein that acts as an iron sponge and keeps the metal in a mineralized form. Together, these findings led the researchers to hypothesize that polyamines might be helping keep iron in a safe, non-reactive state within cells.

To test this idea, they developed a new fluorescent sensor that would allow them to measure chemically reactive iron inside living cells. The new sensor causes living cells to glow based on the amount of chemically reactive iron they contain, allowing researchers to track any changes under a microscope in real time.

The team paired the new iron sensor with another sensor they had previously developed that measures polyamine levels within cells. By employing them simultaneously, they observed a striking pattern: as polyamine levels dropped within cells, the amount of chemically reactive iron went up, offering new evidence that polyamines play a key role in preventing toxic iron build up inside cells.

Beyond answering a fundamental biological question, these findings could have implications for cancer treatment. Cancer cells often rely on high polyamine levels to support their rapid growth and division. However, cancer drugs designed to lower polyamine levels to stop cell division have had limited success.

“We saw that when polyamine levels fall, cells rely on GPX4 to protect themselves from iron toxicity,” says Sharma, who is also the first author of the study. “This could mean that combining drugs that lower polyamine levels with those that block GPX4 might be more effective for killing cancer cells than targeting either pathway alone.”

The discovery may also have implications beyond cancer. Mutations in genes that help move polyamines around cells are linked to a rare form of early-onset Parkinson’s disease, and scientists have long observed unusually high levels of iron in the brains of Parkinson’s patients.

While it is still unclear whether excess iron directly contributes to neuron death in Parkinson’s, the discovery that polyamines help buffer reactive iron inside cells offers a possible explanation for this link and opens new directions for future investigation.

In addition, the researchers expect the new iron sensor to be a valuable tool for other scientists. By allowing them to track chemically reactive iron inside living cells, it could power new discoveries in aging, cancer, and neurodegeneration.

“There are a lot of promising future directions for this work,” Jain says. “It’s exciting to think about how these tools and findings could help answer further questions about disease pathways and potentially help design better therapies.”

Sharma, P., Keys, H. R., Mansell, R. P., Stark, J., Girard, L., Ausler, C., Anderson, R., Müller, S., Imada, S., Pires, I. S., Kunchok, T., Waite, M., Yuan, B., Deik, A., Ferro, L., Hammond, P. T., Rodriguez, R., Pandelia, M., Henry, W. S., & Jain, A. (2026). Polyamines buffer labile iron to suppress ferroptosis. Cell. https://doi.org/10.1016/j.cell.2026.07.040

Research reported in this press release was supported by the National Institutes of Health under grant number R35GM151111 awarded to A.J., which funded 25% of the project’s costs. Additional support was provided by the Bumpus Foundation and the Pew Charitable Trusts. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

A new lens on autism’s sex bias

A perspective from the lab of Whitehead Institute Member David Page, published in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism’s strong sex bias.

Shafaq Zia | Whitehead Institute
March 30, 2026

Autism has a significant and enduring sex bias, with roughly four boys diagnosed for every girl. For many years, experts have believed this disparity arises primarily from diagnostic inequities because much of autism research — and the screening tools that grew out of it — has historically focused on boys, effectively setting a male standard for what autism “looks like.” As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.

This disparity has also shaped the science around autism. When fewer females with the condition are identified, fewer are included in research studies, creating a feedback loop where scientific understanding of autism in females remains limited. Because of this underrepresentation of females, it has been difficult for scientists to disentangle how much of the sex bias in autism reflects social inequities versus underlying biological differences between the sexes.

While the search for biological explanations has largely lagged behind, one leading theory, known as the “female protective effect,” proposes that females may be biologically buffered against developing autism in a way males aren’t.

The idea can be traced back to studies showing that females diagnosed with autism tend to carry a higher number of genetic mutations or “hits” than males with the condition, meaning that they require a higher load of the same genetic mutations for autism to manifest. But, until now, there’s been little clarity on the exact biological mechanism behind this apparent resilience.

Now, a perspective from the lab of Whitehead Institute Member David Page, published March 30 in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism’s strong sex bias.

The work is one of many projects from the Page lab uncovering the biological underpinnings of sex bias in everything from heart health and autoimmune disease to certain cancers.

“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI).

The researchers propose that this protective effect extends beyond autism, and could help explain why 17 other congenital and developmental disorders predominantly affect males. By characterizing the biological factors that make one sex more or less likely to develop certain health conditions, scientists see an opportunity to improve how these conditions are diagnosed and how people receive care.

Page and Harvard-MIT MD-PhD student Maya Talukdar trace the female protective effect to the X chromosome. Talukdar is a graduate student in Page’s lab and the lead author of the perspective.

Most females have two X chromosomes (XX) while most males have one X and one Y chromosome (XY). Sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body.

Historically, scientists believed that the second X chromosome in females is largely inactive. But, in recent years, research out of the Page lab has shown that the so-called “inactive X,” also called Xi, plays a crucial role in regulating gene expression on the active X chromosome, and the rest of the chromosomes.

In this perspective, the researchers point to a subset of genes that are expressed from both the active and inactive X chromosome — often known as genes that “escape” X chromosome inactivation. Many of these genes are dosage-sensitive regulators of key cellular processes. These processes influence thousands of other genes across the genome, including many linked to autism.

Because females have an extra copy of these regulatory genes expressed from Xi, Page and Talukdar propose that they may be better able to buffer the effects of autism-associated mutations than males.

The female protective effect beyond autism

This mechanism, the researchers say, extends beyond autism to a range of congenital and developmental diseases with a male bias.

“Many of the other congenital or developmental conditions we’re pointing to aren’t subject to diagnostic inequities in the way autism is,” says Talukdar. “This strengthens the idea that the female protective effect is emerging from genetic differences in males and females.”

One example is pyloric stenosis, which like autism, affects four boys for every girl. Infants with the condition experience severe vomiting due to thickening of the pyloric sphincter, the passage between the stomach and small intestine. As with autism, girls with pyloric stenosis appear to require more genetic “hits” in order to develop the condition.

The researchers’ new framework of looking at Xi to understand sex differences in disease could impact treatment and care not just for conditions that predominately affect males, but also for those that are more common in women, such as autoimmune diseases.

“Our biology isn’t one-size-fits-all,” Talukdar says “Sex differences clearly play a huge role in health, and it’s so important that we understand them.”

Maya Talukdar, David C. Page, “The inactive X chromosome as a female protector in autism and beyond,” Nature Genetics, 2026; https://doi.org/10.1038/s41588-026-02534-w 

Studying the genetic basis of disease to explore fundamental biological questions

Eliezer Calo’s studies of craniofacial malformations have yielded insight into protein synthesis and embryonic development.

Anne Trafton | MIT News
March 6, 2026

When Associate Professor Eliezer Calo PhD ’11 was applying for faculty positions, he was drawn to MIT not only because it’s his alma mater, but also because the Department of Biology places high value on exploring fundamental questions in biology.

In his own lab, Calo studies how craniofacial malformations arise. One motivation is to seek new treatments for those conditions, but another is to learn more about fundamental biological processes such as protein synthesis and embryonic development.

“We use genes that are mutated in disease to uncover fundamental biology,” Calo says. “Mutations that happen in disease are an experiment of nature, telling us that those are the important genes, and then we follow them up not only to understand the disease, but to fundamentally understand what the genes are doing.”

Calo’s work has led to new insights into how ribosomes form and how they control protein synthesis, as well as how the nucleolus, the birthplace of ribosomes in eukaryotic cells, has evolved over hundreds of millions of years.

In addition to earning his PhD at MIT, Calo is also an alumnus of MIT’s Summer Research Program (MSRP), which helps to prepare undergraduate students to pursue graduate education. Since starting his lab at MIT, Calo has made a point to serve as a research mentor for the program every summer.

“I feel that it’s important to pay back to the program that helped me realize what I wanted to do,” he says.

A nontraditional path

Growing up in a mountainous region of Puerto Rico, Calo was the first person from his family to finish high school. While attending the University of Puerto Rico at Rio Piedras, the largest university in Puerto Rico, he explored a few different majors before settling on chemistry.

One of Calo’s chemistry professors invited him to work in her lab, where he did a research project studying the pharmacokinetics of cell receptors found on the surface of astrocytes, a type of brain cell.

“It was a good mix of biology and chemistry,” he says. “I think that that was the catalyst to my pursuit of a career in the sciences.”

He learned about MSRP from Mandana Sassanfar, a senior lecturer in biology at MIT and director of outreach for several MIT departments, at an event hosted by the University of Puerto Rico for students interested in careers in science. He was accepted into the program, and during the summer after his junior year, he worked in the lab of Stephen Bell, an MIT professor of biology. That experience, he says, was transformative.

“Without that experience, I would have probably chosen another career,” Calo says. In Puerto Rico, “science was fun, but it was a struggle. We had to make everything from scratch, and then you spend more time making reagents than doing the experiments. When I came to MIT, I was always doing experiments.”

During that time, he realized he liked working in biology labs more than chemistry labs, so when he applied to graduate school, he decided to move into biology. He applied to five schools, including MIT. “Once MIT sent me the acceptance, I just had to say yes. There was no saying no.”

At MIT, Calo thought he might study biochemistry, but he ended up focusing on cancer biology instead, working with Jacqueline Lees, an MIT biology professor, to study the role of the tumor suppressor protein Rb.

After finishing his PhD, Calo felt burnt out and wasn’t sure if he wanted to continue along the academic track. His thesis committee advisors encouraged him to do a postdoc just to try it out, and he ended up going to Stanford University, where he fell in love with California and switched to a new research focus. Working with Joanna Wysocka, a professor of developmental biology at Stanford, he began investigating how development is affected by the regulation of proteins that make up cellular ribosomes — a topic his lab still studies today.

Returning to MIT

When searching for faculty jobs, Calo focused mainly on schools in California, but also sent an application to MIT. As he was deciding between offers from MIT and the University of California at Berkeley, a phone call from Angelika Amon, the late MIT professor of biology, convinced him to take the cross-country leap back to MIT.

“She had me on the phone for more than one hour telling me why I should come to MIT,” he recalls. “And that was so heartwarming that I could not say no.”

Since starting his lab in 2017, Calo has been studying how defects in the production of ribosomes give rise to diseases, in particular craniofacial malformations such as cleft palate.

Ribosomes, the organelles where protein synthesis occurs, consist of two subunits made of about 80 proteins. A longstanding question in biology has been why mutations that affect ribosome formation appear to primarily affect the development of the face, but not the rest of the body.

In a 2018 study, Calo discovered that this is because the mutations that affect ribosomes can have secondary effects that influence craniofacial development. In embryonic cells that form the face, a mutation in a gene called TCOF1 activates p53 at a higher level than in other embryonic cells. High levels of p53 cause some of those cells to undergo programmed cell death, leading to Treacher-Collins Syndrome, a disorder that produces underdeveloped bones in the jaw and cheek.

His lab has shown that p53 overactivation is also responsible for craniofacial disorders caused by mutations in RNA splicing factors.

Calo’s work on ribosome formation also led him to explore another cell organelle known as the nucleolus, whose role is to help build ribosomes. In 2023, he found that a gene called TCOF1, which can lead to craniofacial malformations when mutated, is critical for forming the three compartments that make up the nucleolus.

That finding, he says, could help to explain a major evolutionary shift that occurred around 300 million years ago, when the nucleolus transitioned from two to three compartments. This “tripartite” nucleolus is found in all reptiles, birds, and mammals.

“That was quite surprising,” Calo says. “Studying disease-related genes allowed us to understand a very fundamental biological process of how the nucleolus evolved, which has been a question in the field that nobody could figure out the answer for.”

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.

Q&A: Picower researchers including MIT Biology faculty Sara Prescott join effort to investigate the ‘Biology of Adversity’

Assistant Professor Sara Prescott and Research Affiliate Ravikiran Raju are key collaborators in a new Broad Institute research project to better understand physiological and medical effects of acute and chronic life stressors.

David Orenstein | The Picower Institute for Learning and Memory
November 3, 2025

Adverse experiences such as abuse and violence or poverty and deprivation have always been understood to be harmful, but the tools to understand how they may cause specific medical conditions and outcomes have only emerged recently. Technologies such as RNA or chromatin sequencing, for instance, can help scientists observe how stressors change gene expression, which can help establish mechanistic biological explanations for why people who’ve suffered adversity also experience higher risks of conditions such as stroke or Alzheimer’s disease.

Advancing scientific understanding of the physiological connections between adversity and disease can help pharmaceutical developers, physicians and public officials to develop meaningful interventions. Led by researcher Jason Buenrostro, the Broad Institute has launched a new research program, the “Biology of Adversity” project.. As leading collaborators in the effort, Picower Institute investigator Sara Prescott, assistant professor of biology, and Tsai Lab research affiliate Ravikiran Raju, a pediatrician at Boston Children’s Hospital, plan research projects in their Picower Institute labs to better elucidate how life stress leads to medical distress.

How can biology and neuroscience studies help people who’ve experienced adversity?

Prescott: Adversity comes in many flavors. But across different types of adversity, there is a common theme that it leads to psychological and emotional distress. If you were to ask a random person on the street, they’d probably tell you that distress is simply a feeling that exists only in the mind, rather than a biological process. But this is not true. We now appreciate that stress has predictable effects on the body, and there are severe long-term health consequences of experiencing chronic stress. Unfortunately, it’s been difficult to argue based on epidemiological data that stress itself (rather than other lifestyle factors like diet, smoking or access to health care services) is causally linked to poor health outcomes. This is confounded by the fact that we haven’t had good ways to empirically measure people’s levels of adversity and stress. This is part of what we want to address at the Biology of Adversity Project.

From a scientific perspective, there is still much to be understood about stress and the biological processes that lead to stress-associated diseases. And so that’s hopefully where efforts like the Biology of Adversity Project are going to come in. We can use scientific practices to come up with better guidelines for ways to track levels of stress, develop diagnostics, and then, hopefully, one day this will turn into actionable interventions. It’s not a random process of things going awry. There are going to be biological programs that are engaged in predictable ways. And we’re trying to understand, what exactly are these neural or biological programs? How many different types of programs are there? And how do each of those programs actually work down to the cellular and molecular level?

Raju: Efforts to combat adversity and stress have largely remained in the social space to date. But what we know from a growing body of epidemiological literature is that social stressors can have profound biological impact. They cause increases in mental health disorders, physical disorders like cancer, stroke, and heart disease. Individuals who experience chronic and high levels of stress are dying sooner. I think there is an imperative to understand what these forces are doing to our biology and how they’re dysregulating our physiology. Armed with that information, we can start to be more mechanistic and evidence-based in our promotion of resilience. What are the pathways that are made vulnerable when individuals are stressed? How do we rescue those deficiencies, whether it be through existing practices or novel interventions? A lot of the research we’re doing here at Picower is focusing on pathways that could be targeted and leveraged using specific micronutrients or specific small molecules that help promote resilience and prevent the onset of premature illness in individuals who are stress exposed.

What is the Biology of Adversity Project and how are each of you involved?

Prescott: My lab studies the autonomic nervous system, and we’re involved in the project’s animal studies. We think of stress as an adaptive response to prepare the body for an impending threat. When people experience stress, what happens? You engage a fight or flight response—you sweat, start to breathe harder, your heart rate goes up, your pupils dilate. This is protective in acute settings, but can become very maladaptive when these systems are activated for too long or in inappropriate settings, like when someone is having a panic attack. We predict that a lot of the long-term health consequences associated with adversity could relate to dysregulated autonomic stress responses.

And so that’s where our lab’s tools come in. We have good ways in animals to measure their heart rate and breathing in response to stress. We also have a wide range of genetic tools to specifically target different neural pathways in the periphery, possibly blocking stress pathways at the source. With these tools, we can explore what role those circuits have in long-term changes in these animals with greater precision than what was possible in the past.

Raju: My involvement came through my work on the Environmental and Social Determinants of Child Mental Health Conference in 2023, which I co-hosted with Li-Huei Tsai. I think this conference made the scientific community in Boston more aware that this was something of deep interest to researchers at Picower and MIT. In the creation of the Biology of Adversity Project, the center director, Jason Buenrostro, was doing a survey of the landscape of folks who were studying stress and adversity, and who were passionate about it and connected with us because of that symposium. Since then, I’ve been engaged in really exciting conversations with him and a exciting group of collaborators, including Sara Prescott. And so I’m really excited that a few of our projects are being showcased as flagship projects. We are currently using animal models of early life stress to try and build preclinical models to deepen our understanding of how stress dysregulates physiology. We’re developing pipelines for trying to think about promoting resilience through targeted interventions, using those preclinical models.

What research questions do you each plan to tackle?

Prescott: Broadly, we’re interested in the body-brain connection and how this relates to stress. How do different cues from within the body—like diet, or taking a deep breath–promote or regulate stress levels? These are interesting questions about how sensory inputs from the body feed into stress circuits in the brain. We’re also interested in the other direction—understanding how stress causes changes to peripheral organs, for example, by engaging the sympathetic nervous system. It’s well understood that sympathetic neurons are responsible for making you sweat and your heart race, but do they do other things as well? For example, the field is starting to appreciate that these same neurons regulate the immune system, and can signal to stem cells to promote or suppress tissue repair. These are important pathways to understand, as they could explain some of the links between chronic stress (where sympathetic neurons are over-activated) and increased rates of diseases like cancer. It also may have therapeutic applications down the road. I’m incredibly excited for the opportunity to work with people like Ravi, and others in the project, to apply our expertise in physiology and autonomic signaling towards this immensely important problem. I’m hoping that through this work we can move to an era where we can, from a societal perspective, understand how much our stress levels are damaging our body, be able to track that, and then find better ways to prevent the damage that’s happening.

Raju:  We are leveraging three key mouse models of environmental perturbations in this work: environmental enrichment, social isolation and resource deprivation. In studying enrichment, we are trying to better study the factors that promote resilience to stress. In our previous work on resilience, for example, we identified a transcription factor that’s specifically recruited to help ensure that neurons are resilient to the onset of Alzheimer’s pathology. So we’ve leveraged these enrichment models to study that mechanism and are able to then think of how that pathway might be leveraged in stress-exposed individuals. We are also using models of stress, specifically social isolation and resource deprivation. The idea here is that because mice are social mammals and rely on resources and social interactions and social networks in order to thrive, we can modulate these in a species-relevant way, and then study the pathways that are dysregulated. This will allow us to define vulnerable pathways in these preclinical models, and then assess if those same pathways are dysregulated in humans that are experiencing analagous environmental conditions. Armed with the right model, we can then determine how to reverse the physiological derangements induced by environmental stressors.

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.

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.”

Dopamine signals when a fear can be forgotten

Study shows how a dopamine circuit between two brain regions enables mice to extinguish fear after a peril has passed.

David Orenstein | The Picower Institute for Learning and Memory
May 7, 2025

Dangers come but dangers also go, and when they do, the brain has an “all-clear” signal that teaches it to extinguish its fear. A new study in mice by MIT neuroscientists shows that the signal is the release of dopamine along a specific interregional brain circuit. The research therefore pinpoints a potentially critical mechanism of mental health, restoring calm when it works, but prolonging anxiety or even post-traumatic stress disorder when it doesn’t.

“Dopamine is essential to initiate fear extinction,” says Michele Pignatelli di Spinazzola, co-author of the new study from the lab of senior author Susumu Tonegawa, Picower Professor of biology and neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics within The Picower Institute for Learning and Memory at MIT, and a Howard Hughes Medical Institute (HHMI) investigator.

In 2020, Tonegawa’s lab showed that learning to be afraid, and then learning when that’s no longer necessary, result from a competition between populations of cells in the brain’s amygdala region. When a mouse learns that a place is “dangerous” (because it gets a little foot shock there), the fear memory is encoded by neurons in the anterior of the basolateral amygdala (aBLA) that express the gene Rspo2. When the mouse then learns that a place is no longer associated with danger (because they wait there and the zap doesn’t recur), neurons in the posterior basolateral amygdala (pBLA) that express the gene Ppp1r1b encode a new fear extinction memory that overcomes the original dread. Notably, those same neurons encode feelings of reward, helping to explain why it feels so good when we realize that an expected danger has dwindled.

In the new study, the lab, led by former members Xiangyu Zhang and Katelyn Flick, sought to determine what prompts these amygdala neurons to encode these memories. The rigorous set of experiments the team reports in the Proceedings of the National Academy of Sciences show that it’s dopamine sent to the different amygdala populations from distinct groups of neurons in the ventral tegmental area (VTA).

“Our study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,” says Zhang, who also led the 2020 study and is now a senior associate at Orbimed, a health care investment firm. “We found that dopamine activates specific amygdala neurons tied to reward, which in turn drive fear extinction. We now see that unlearning fear isn’t just about suppressing it — it’s a positive learning process powered by the brain’s reward machinery. This opens up new avenues for understanding and potentially treating fear-related disorders, like PTSD.”

Forgetting fear

The VTA was the lab’s prime suspect to be the source of the signal because the region is well known for encoding surprising experiences and instructing the brain, with dopamine, to learn from them. The first set of experiments in the paper used multiple methods for tracing neural circuits to see whether and how cells in the VTA and the amygdala connect. They found a clear pattern: Rspo2 neurons were targeted by dopaminergic neurons in the anterior and left and right sides of the VTA. Ppp1r1b neurons received dopaminergic input from neurons in the center and posterior sections of the VTA. The density of connections was greater on the Ppp1r1b neurons than for the Rspo2 ones.

The circuit tracing showed that dopamine is available to amygdala neurons that encode fear and its extinction, but do those neurons care about dopamine? The team showed that indeed they express “D1” receptors for the neuromodulator. Commensurate with the degree of dopamine connectivity, Ppp1r1b cells had more receptors than Rspo2 neurons.

Dopamine does a lot of things, so the next question was whether its activity in the amygdala actually correlated with fear encoding and extinction. Using a method to track and visualize it in the brain, the team watched dopamine in the amygdala as mice underwent a three-day experiment. On Day One, they went to an enclosure where they experienced three mild shocks on the feet. On Day Two, they went back to the enclosure for 45 minutes, where they didn’t experience any new shocks — at first, the mice froze in anticipation of a shock, but then relaxed after about 15 minutes. On Day Three they returned again to test whether they had indeed extinguished the fear they showed at the beginning of Day Two.

The dopamine activity tracking revealed that during the shocks on Day One, Rspo2 neurons had the larger response to dopamine, but in the early moments of Day Two, when the anticipated shocks didn’t come and the mice eased up on freezing, the Ppp1r1b neurons showed the stronger dopamine activity. More strikingly, the mice that learned to extinguish their fear most strongly also showed the greatest dopamine signal at those neurons.

Causal connections

The final sets of experiments sought to show that dopamine is not just available and associated with fear encoding and extinction, but also actually causes them. In one set, they turned to optogenetics, a technology that enables scientists to activate or quiet neurons with different colors of light. Sure enough, when they quieted VTA dopaminergic inputs in the pBLA, doing so impaired fear extinction. When they activated those inputs, it accelerated fear extinction. The researchers were surprised that when they activated VTA dopaminergic inputs into the aBLA they could reinstate fear even without any new foot shocks, impairing fear extinction.

The other way they confirmed a causal role for dopamine in fear encoding and extinction was to manipulate the amygdala neurons’ dopamine receptors. In Ppp1r1b neurons, over-expressing dopamine receptors impaired fear recall and promoted extinction, whereas knocking the receptors down impaired fear extinction. Meanwhile in the Rspo2 cells, knocking down receptors reduced the freezing behavior.

“We showed that fear extinction requires VTA dopaminergic activity in the pBLA Ppp1r1b neurons by using optogenetic inhibition of VTA terminals and cell-type-specific knockdown of D1 receptors in these neurons,” the authors wrote.

The scientists are careful in the study to note that while they’ve identified the “teaching signal” for fear extinction learning, the broader phenomenon of fear extinction occurs brainwide, rather than in just this single circuit.

But the circuit seems to be a key node to consider as drug developers and psychiatrists work to combat anxiety and PTSD, Pignatelli di Spinazzola says.

“Fear learning and fear extinction provide a strong framework to study generalized anxiety and PTSD,” he says. “Our study investigates the underlying mechanisms suggesting multiple targets for a translational approach, such as pBLA and use of dopaminergic modulation.”

Marianna Rizzo is also a co-author of the study. Support for the research came from the RIKEN Center for Brain Science, the HHMI, the Freedom Together Foundation, and The Picower Institute.