Research Area: Cancer Biology

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.”

3 Questions with new faculty member Matthew G. Jones: Building predictive models to characterize tumor progression

The assistant professor hopes to decode molecular processes on the genetic, epigenetic, and microenvironment levels to anticipate how and when tumors evolve to resist treatment.

Lillian Eden | Department of Biology
March 10, 2026

Just as Darwin’s finches evolved in response to natural selection in order to endure, the cells that make up a cancerous tumor similarly counter selective pressures in order to survive, evolve, and spread. Tumors are, in fact, complex sets of cells with their own unique structure and ability to change. 

Today, artificial Intelligence and machine learning tools offer an unparalleled opportunity to illuminate the generalizable rules governing tumor progression on the genetic, epigenetic, metabolic, and microenvironmental levels. 

Matthew G. Jones, an Assistant Professor in the Department of Biology at MIT, the Koch Institute for Integrative Cancer Research, and the Institute for Medical Engineering and Science, hopes to use computational approaches to build predictive models — to play a game of chess with cancer, making sense of a tumor’s ability to evolve and resist treatment with the ultimate goal of improving patient outcomes. 

Q: What aspect of tumor progression are you hoping to explore and characterize? 

A: A very common story with cancer is that patients will respond to a therapy at first, and then eventually that treatment will stop working. The reason this largely happens is that tumors have an incredible, and very challenging, ability to evolve: the ability to change their genetic makeup, protein signaling composition, and cellular dynamics. The tumor as a system also evolves at a structural level. Oftentimes, the reason why a patient succumbs to a tumor is because either the tumor has evolved to a state we can no longer control, or it evolves in an unpredictable manner. 

In many ways, cancers can be thought of as, on the one hand, incredibly dysregulated and disorganized, and on the other hand, as having their own internal logic, which is constantly changing. The central thesis of my lab is that tumors follow stereotypical patterns in space and time, and we’re hoping to use computation and experimental technology to decode the molecular processes underlying these transformations.  

We’re focused on one specific way tumors are evolving through a form of DNA amplification called extrachromosomal DNA. Excised from the chromosome, these ecDNAs are circularized and exist as their own separate pool of DNA particles in the nucleus. 

Initially discovered in the 1960s, ecDNA were thought to be a rare event in cancer. However, as researchers began applying next-generation sequencing to large patient cohorts in the 2010s, it seemed like not only were these ecDNA amplifications conferring the ability of tumors to adapt to stresses, and therapies, faster, but that they were far more prevalent than initially thought.

We now know these ecDNA amplifications are apparent in about 25% of cancers, in the most aggressive cancers: brain, lung, and ovarian cancers. We have found that, for a variety of reasons, ecDNA amplifications are able to change the rule book by which tumors evolve in ways that allow them to accelerate to a more aggressive disease in very surprising ways. 

Q: How are you planning to use machine learning and artificial intelligence to study ecDNA amplifications and tumor evolution? 

A: There’s a mandate to translate what I’m doing in the lab to improve patients’ lives. I want to start with patient data to discover how various evolutionary pressures are driving disease and the mutations we observe. 

One of the tools we use to study tumor evolution is single-cell lineage tracing technologies. Broadly, they allow us to study the lineages of individual cells. When we sample a particular cell, not only do we know what that cell looks like, but we can, ideally, pinpoint exactly when aggressive mutations appeared in the tumor’s history. That evolutionary history gives us a way of studying these dynamic processes that we otherwise wouldn’t be able to observe in real time and helps us make sense of how we might be able to intercept that evolution. 

I hope we’re going to get better at stratifying patients who will respond to certain drugs, to anticipate and overcome drug resistance, and to identify new therapeutic targets.

Q: What excites you about joining this community, and what sorts of trainees are you hoping to recruit to your lab? 

A: One of the things that I was really attracted to was the integration of excellence in both engineering and biological sciences. At the Koch Institute, every floor is structured to promote this interface between engineers and basic scientists, and beyond campus, we can connect with all the biomedical research enterprises in the Greater Boston Area. 

Another thing that drew me to MIT was the fact that it places such a strong emphasis on education, training, and investing in student success. I’m a personal believer that what distinguishes academic research from industry research is that academic research is fundamentally a service job, in that we are training the next generation of scientists. 

It was always a mission of mine to bring excellence to both computational and experimental technology disciplines. The types of trainees I’m hoping to recruit are those who are eager to collaborate and solve big problems that require both disciplines. The KI is uniquely set up for this type of hybrid lab: my dry lab is right next to my wet lab, and it’s a source of collaboration and connection, and that reflects the KI’s general vision. 

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.

Matthew G. Jones

Education

  • Graduate: University of California, San Francisco, 2022
  • Undergraduate: Computer Science; University of California, Berkeley, 2017

Research Summary

From the moment that a tumor is born, it is evolving across several levels, including at the genetic, epigenetic, metabolic, and microenvironmental levels. The central goal of the Jones Lab is to develop innovative computational and technological approaches to uncover the mechanisms of tumor evolution, with the ultimate aim of identifying new therapeutic targets and creating predictive models to monitor tumor initiation and progression.

Currently, the lab’s research focuses on three interrelated goals: (1) investigating the molecular mechanisms underlying the spatiotemporal dynamics of copy-number alterations (particularly extrachromosomal DNA) in cancer populations; (2) developing new computational methods to trace cellular lineages; and (3) elucidating the principles by which tumors are organized over time. To pursue these aims, the lab integrates advances in computation and AI with cutting-edge multi-omic approaches (including single-cell, spatial, and long-read technologies), lineage tracing, and high-resolution imaging. Broadly, they expect that their studies will reveal generalizable rules governing tumor progression and treatment resistance, enable the predictive modeling of tumors, and inspire new approaches to intercept tumor progression.

Awards

  • Keynote Speaker at Cancer Genetics and Epigenetics Gordon Research Seminar, 2025
  • Cancer Grand Challenges Future Leaders Conference Best Talk Awardee, 2024
  • NCI K99/R00 Early-Career Pathway to Independence Award, 2024
  • UCSF Discovery Fellow, 2019
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.

A more precise way to edit the genome

MIT researchers have dramatically lowered the error rate of prime editing, a technique that holds potential for treating many genetic disorders.

Anne Trafton | MIT News
September 17, 2025

A genome-editing technique known as prime editing holds potential for treating many diseases by transforming faulty genes into functional ones. However, the process carries a small chance of inserting errors that could be harmful.

MIT researchers have now found a way to dramatically lower the error rate of prime editing, using modified versions of the proteins involved in the process. This advance could make it easier to develop gene therapy treatments for a variety of diseases, the researchers say.

“This paper outlines a new approach to doing gene editing that doesn’t complicate the delivery system and doesn’t add additional steps, but results in a much more precise edit with fewer unwanted mutations,” says Phillip Sharp, an MIT Institute Professor Emeritus, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

With their new strategy, the MIT team was able to improve the error rate of prime editors from about one error in seven edits to one in 101 for the most-used editing mode, or from one error in 122 edits to one in 543 for a high-precision mode.

“For any drug, what you want is something that is effective, but with as few side effects as possible,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of the Koch Institute, and one of the senior authors of the new study. “For any disease where you might do genome editing, I would think this would ultimately be a safer, better way of doing it.”

Koch Institute research scientist Vikash Chauhan is the lead author of the paper, which appears today in Nature.

The potential for error

The earliest forms of gene therapy, first tested in the 1990s, involved delivering new genes carried by viruses. Subsequently, gene-editing techniques that use enzymes such as zinc finger nucleases to correct genes were developed. These nucleases are difficult to engineer, however, so adapting them to target different DNA sequences is a very laborious process.

Many years later, the CRISPR genome-editing system was discovered in bacteria, offering scientists a potentially much easier way to edit the genome. The CRISPR system consists of an enzyme called Cas9 that can cut double-stranded DNA at a particular spot, along with a guide RNA that tells Cas9 where to cut. Researchers have adapted this approach to cut out faulty gene sequences or to insert new ones, following an RNA template.

In 2019, researchers at the Broad Institute of MIT and Harvard reported the development of prime editing: a new system, based on CRISPR, that is more precise and has fewer off-target effects. A recent study reported that prime editors were successfully used to treat a patient with chronic granulomatous disease (CGD), a rare genetic disease that affects white blood cells.

“In principle, this technology could eventually be used to address many hundreds of genetic diseases by correcting small mutations directly in cells and tissues,” Chauhan says.

One of the advantages of prime editing is that it doesn’t require making a double-stranded cut in the target DNA. Instead, it uses a modified version of Cas9 that cuts just one of the complementary strands, opening up a flap where a new sequence can be inserted. A guide RNA delivered along with the prime editor serves as the template for the new sequence.

Once the new sequence has been copied, however, it must compete with the old DNA strand to be incorporated into the genome. If the old strand outcompetes the new one, the extra flap of new DNA hanging off may accidentally get incorporated somewhere else, giving rise to errors.

Many of these errors might be relatively harmless, but it’s possible that some could eventually lead to tumor development or other complications. With the most recent version of prime editors, this error rate ranges from one per seven edits to one per 121 edits for different editing modes.

“The technologies we have now are really a lot better than earlier gene therapy tools, but there’s always a chance for these unintended consequences,” Chauhan says.

Precise editing

To reduce those error rates, the MIT team decided to take advantage of a phenomenon they had observed in a 2023 study. In that paper, they found that while Cas9 usually cuts in the same DNA location every time, some mutated versions of the protein show a relaxation of those constraints. Instead of always cutting the same location, those Cas9 proteins would sometimes make their cut one or two bases further along the DNA sequence.

This relaxation, the researchers discovered, makes the old DNA strands less stable, so they get degraded, making it easier for the new strands to be incorporated without introducing any errors.

In the new study, the researchers were able to identify Cas9 mutations that dropped the error rate to 1/20th its original value. Then, by combining pairs of those mutations, they created a Cas9 editor that lowered the error rate even further, to 1/36th the original amount.

To make the editors even more accurate, the researchers incorporated their new Cas9 proteins into a prime editing system that has an RNA binding protein that stabilizes the ends of the RNA template more efficiently. This final editor, which the researchers call vPE, had an error rate just 1/60th of the original, ranging from one in 101 edits to one in 543 edits for different editing modes. These tests were performed in mouse and human cells.

The MIT team is now working on further improving the efficiency of prime editors, through further modifications of Cas9 and the RNA template. They are also working on ways to deliver the editors to specific tissues of the body, which is a longstanding challenge in gene therapy.

They also hope that other labs will begin using the new prime editing approach in their research studies. Prime editors are commonly used to explore many different questions, including how tissues develop, how populations of cancer cells evolve, and how cells respond to drug treatment.

“Genome editors are used extensively in research labs,” Chauhan says. “So the therapeutic aspect is exciting, but we are really excited to see how people start to integrate our editors into their research workflows.”

The research was funded by the Life Sciences Research Foundation, the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, 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.

Biologists identify targets for new pancreatic cancer treatments

Research from MIT and Dana-Farber Cancer Institute yielded hundreds of “cryptic” peptides that are found only on pancreatic tumor cells and could be targeted by vaccines or engineered T cells.

Anne Trafton | MIT News
May 7, 2025

Researchers from MIT and Dana-Farber Cancer Institute have discovered that a class of peptides expressed in pancreatic cancer cells could be a promising target for T-cell therapies and other approaches that attack pancreatic tumors.

Known as cryptic peptides, these molecules are produced from sequences in the genome that were not thought to encode proteins. Such peptides can also be found in some healthy cells, but in this study, the researchers identified about 500 that appear to be found only in pancreatic tumors.

The researchers also showed they could generate T cells targeting those peptides. Those T cells were able to attack pancreatic tumor organoids derived from patient cells, and they significantly slowed down tumor growth in a study of mice.

“Pancreas cancer is one of the most challenging cancers to treat. This study identifies an unexpected vulnerability in pancreas cancer cells that we may be able to exploit therapeutically,” says Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

Jacks and William Freed-Pastor, a physician-scientist in the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School, are the senior authors of the study, which appears today in Science. Zackery Ely PhD ’22 and Zachary Kulstad, a former research technician at Dana-Farber Cancer Institute and the Koch Institute, are the lead authors of the paper.

Cryptic peptides

Pancreatic cancer has one of the lowest survival rates of any cancer — about 10 percent of patients survive for five years after their diagnosis.

Most pancreatic cancer patients receive a combination of surgery, radiation treatment, and chemotherapy. Immunotherapy treatments such as checkpoint blockade inhibitors, which are designed to help stimulate the body’s own T cells to attack tumor cells, are usually not effective against pancreatic tumors. However, therapies that deploy T cells engineered to attack tumors have shown promise in clinical trials.

These therapies involve programming the T-cell receptor (TCR) of T cells to recognize a specific peptide, or antigen, found on tumor cells. There are many efforts underway to identify the most effective targets, and researchers have found some promising antigens that consist of mutated proteins that often show up when pancreatic cancer genomes are sequenced.

In the new study, the MIT and Dana-Farber team wanted to extend that search into tissue samples from patients with pancreatic cancer, using immunopeptidomics — a strategy that involves extracting the peptides presented on a cell surface and then identifying the peptides using mass spectrometry.

Using tumor samples from about a dozen patients, the researchers created organoids — three-dimensional growths that partially replicate the structure of the pancreas. The immunopeptidomics analysis, which was led by Jennifer Abelin and Steven Carr at the Broad Institute, found that the majority of novel antigens found in the tumor organoids were cryptic antigens. Cryptic peptides have been seen in other types of tumors, but this is the first time they have been found in pancreatic tumors.

Each tumor expressed an average of about 250 cryptic peptides, and in total, the researchers identified about 1,700 cryptic peptides.

“Once we started getting the data back, it just became clear that this was by far the most abundant novel class of antigens, and so that’s what we wound up focusing on,” Ely says.

The researchers then performed an analysis of healthy tissues to see if any of these cryptic peptides were found in normal cells. They found that about two-thirds of them were also found in at least one type of healthy tissue, leaving about 500 that appeared to be restricted to pancreatic cancer cells.

“Those are the ones that we think could be very good targets for future immunotherapies,” Freed-Pastor says.

Programmed T cells

To test whether these antigens might hold potential as targets for T-cell-based treatments, the researchers exposed about 30 of the cancer-specific antigens to immature T cells and found that 12 of them could generate large populations of T cells targeting those antigens.

The researchers then engineered a new population of T cells to express those T-cell receptors. These engineered T cells were able to destroy organoids grown from patient-derived pancreatic tumor cells. Additionally, when the researchers implanted the organoids into mice and then treated them with the engineered T cells, tumor growth was significantly slowed.

This is the first time that anyone has demonstrated the use of T cells targeting cryptic peptides to kill pancreatic tumor cells. Even though the tumors were not completely eradicated, the results are promising, and it is possible that the T-cells’ killing power could be strengthened in future work, the researchers say.

Freed-Pastor’s lab is also beginning to work on a vaccine targeting some of the cryptic antigens, which could help stimulate patients’ T cells to attack tumors expressing those antigens. Such a vaccine could include a collection of the antigens identified in this study, including those frequently found in multiple patients.

This study could also help researchers in designing other types of therapy, such as T cell engagers — antibodies that bind an antigen on one side and T cells on the other, which allows them to redirect any T cell to kill tumor cells.

Any potential vaccine or T cell therapy is likely a few years away from being tested in patients, the researchers say.

The research was funded in part by the Hale Family Center for Pancreatic Cancer Research, the Lustgarten Foundation, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Burroughs Wellcome Fund, a Conquer Cancer Young Investigator Award, the National Institutes of Health, and the National Cancer Institute.

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.