Category: Faculty Locations

Whitehead Institute Member Jonathan Weissman joins global Cancer Grand Challenges team

Whitehead Institute Member Jonathan Weissman has been named to a newly funded Cancer Grand Challenges team that will tackle one of the most elusive frontiers in cancer biology: the “dark proteome.”

Mackenzie White | Whitehead Institute
March 4, 2026

Whitehead Institute Member Jonathan Weissman has been named to a newly funded Cancer Grand Challenges team that will tackle one of the most elusive frontiers in cancer biology: the “dark proteome.”

The interdisciplinary team, ILLUMINE, will receive up to $25 million over approximately five years through Cancer Grand Challenges to investigate proteins expressed by cancer cells that don’t correspond exactly to known genes. These include proteins produced from previously unrecognized regions of the genome, proteins created from offset start sites of known genes, and proteins with altered amino acid sequences that cannot be explained by known DNA mutations. The origins and functions of this dark proteome remain largely unknown.

Cancer Grand Challenges is a global research initiative co-founded in 2020 by Cancer Research UK and the National Cancer Institute (part of the National Institutes of Health) in the United States. The initiative supports a global community of diverse, world-class research teams to come together, think differently, and take on some of cancer’s toughest challenges.

The ILLUMINE team is led by Reuven Agami of the Netherlands Cancer Institute and brings together clinicians, advocates, and scientists across eight institutions in four countries. The team is funded by Cancer Research UK, the National Cancer Institute, the Cancer Research Institute, and KiKa (Children Cancer Free Foundation) through Cancer Grand Challenges. It is one of five new teams announced this year, representing a total investment of $125 million.

Weissman, also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute, studies how proteins are produced and folded inside cells, and how disruptions in these processes contribute to disease. His laboratory developed ribosome profiling, a technique that reveals which parts of the genome are actively being translated into proteins inside cells.

This method is directly relevant to the dark proteome challenge. If cancer cells generate proteins from unexpected regions of the genome, understanding when and how those proteins are made is critical. Weissman’s lab continues to refine tools that measure protein production at scale, helping to illuminate these hidden products and their potential role in cancer.

By comprehensively identifying and characterizing the dark proteome, the ILLUMINE team aims to uncover novel, potentially universal tumor antigens — cancer cell molecules that are recognizable by the immune system — and develop innovative immunotherapies for hard-to-treat cancers.

Collectively, the newly funded teams unite researchers from nine countries and 34 institutions, bringing together more than 40 investigators to address long-standing barriers in cancer research.

Dr. David Scott, Director of Cancer Grand Challenges, said of the initiative: “Together, we’re creating opportunities for bold team science that could redefine what’s possible for people affected by cancer.”

How changes on the Y chromosome may make species reproductively incompatible

Closely related species often produce infertile offspring, especially in males. New research from the Yamashita Lab identifies a cellular defect that contributes to this phenomenon in fruit flies, which may help explain how diverging species become reproductively incompatible.

Mackenzie White | Whitehead Institute
March 6, 2026

In a new study published in Molecular Biology and Evolution on February 16, Whitehead Institute Member Yukiko Yamashita, graduate student in her lab Adrienne Fontan, and senior scientist in her lab Romain Lannes identify a cellular defect that contributes to this phenomenon in fruit flies. This finding may help explain how diverging species become reproductively incompatible.

The team found that in hybrid males, several genes required for sperm production fail during an early step in gene expression. Because these genes cannot be processed correctly, cells are unable to produce the proteins needed for sperm formation.

The researchers studied hybrids produced from two closely related fruit fly species that diverged from a common ancestor roughly 250,000 years ago. Although these species can still mate in the laboratory, their hybrid males cannot produce functional sperm.

To investigate why, the researchers focused on genes located on the Y chromosome that are essential for sperm development.

“These genes on the Y chromosome are required to produce sperm,” says co-first author and Yamashita lab senior scientist Romain Lannes. “They are very large and difficult for the cell to process, and in the hybrid, it’s a total failure—the hybrid cannot make them.”

Like all genes, these Y-linked genes work by first producing an RNA copy of their DNA instructions. Before the RNA can be used to make proteins, cells must remove segments that do not contain coding information and join the remaining pieces together.

In hybrid flies, this process frequently fails.

Instead of assembling the RNA pieces in the correct order, the cell sometimes flips the order of pieces. The resulting molecule cannot produce a functional protein. Because the affected genes are required for sperm development, the defect prevents hybrid males from making sperm.

The researchers traced the problem to a distinctive feature of these genes: their unusual size.

Much of their length consists of repetitive DNA embedded within the gene. These repetitive sequences, known as satellite DNA, consist of short DNA patterns repeated many times in a row.

“Satellite DNA is made of short repeated sequences that can extend for very long regions,” says Yamashita who is also a professor of biology at MIT and an HHMI Investigator. “Because they don’t encode proteins and are difficult to analyze with standard genetic tools, people historically didn’t study them much.”

One notable property of satellite DNA is that it changes quickly over evolutionary time. Even closely related species can carry very different versions of these sequences.

The researchers suspect that these differences contribute to the defect they observed. Each species may evolve cellular systems adapted to handle its own repetitive DNA. When DNA from two species is combined in a hybrid, those systems may no longer function properly.

Large genes already pose challenges for the cell’s gene-processing machinery, Yamashita explained. In hybrids, those challenges appear to become harder to overcome.

“Even in a pure species, these big genes are challenging to process,” says Yamashita. “But that species has evolved ways to deal with that challenge. When you combine two species in a hybrid, that system can break.”

The findings also offer insight into a widely observed pattern in evolutionary biology: when hybrids between species are sterile, the sex with two different sex chromosomes is often the one affected. In fruit flies and humans, males carry an X and a Y chromosome, while females carry two X chromosomes.

Because the Y chromosome evolves rapidly and contains many repetitive sequences, it may be particularly sensitive to incompatibilities that arise when species interbreed.

The researchers say fruit flies provide a useful model for investigating these questions because they reproduce quickly and are easy to study in the laboratory. The two species used in the study diverged relatively recently, allowing scientists to examine the early stages of reproductive isolation between species.

Although the work focused on flies, the researchers think similar processes could occur in other organisms. Rapid changes in the Y chromosome are observed across many species, including mammals.

“I’m really interested in understanding why species split and become incompatible,” says Yamashita.

The team is now exploring whether the computational approaches developed in this study could help investigate human diseases involving extremely large genes. Some human genes span millions of DNA bases and can be difficult for cells to process correctly, including genes implicated in muscular and neurological disorders.

By identifying a specific failure in gene processing, the study provides a clearer picture of how genetic differences between species can disrupt reproduction.

Adrienne Fontan, Romain Lannes, Jaclyn M Fingerhut, Jullien M Flynn, Yukiko M Yamashita, ­­­”Defective splicing of Y-chromosome-linked gigantic genes contributes to hybrid male sterility in Drosophila,” Molecular Biology and Evolution, 2026; https://doi.org/10.1093/molbev/msag045

 

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 Zuri Sullivan: Exploring the mechanisms underlying changes during infection

Zuri Sullivan, a new assistant professor of biology and Whitehead Institute member, studies why we get sick, and whether aspects of illness, such as disrupted appetite, contribute to host defense.

Lillian Eden | Department of Biology
February 20, 2026

With respiratory illness season in full swing, a bad night’s sleep, sore throat, and desire to cancel dinner plans could all be considered hallmark symptoms of the flu, Covid-19 or other illnesses. Although everyone has, at some point, experienced illness and these stereotypical symptoms, the mechanisms that generate them are not well understood.

Zuri Sullivan, a new assistant professor in the MIT Department of Biology and core member of the Whitehead Institute for Biomedical Research, works at the interface of neuroscience, microbiology, physiology, and immunology to study the biological workings underlying illness. In this interview, she describes her work on immunity thus far as well as research avenues — and professional collaborations — she’s excited to explore at MIT.

Q: What is immunity, and why do we get sick in the first place?

A: We can think of immunity in two ways: the antimicrobial programs that defend against a pathogen directly, and sickness, the altered organismal state that happens when we get an infection.

Sickness itself arises from brain-immune system interaction. The immune system is talking to the brain, and then the brain has a system-wide impact on host defense via its ability to have top-down control of physiologic systems and behavior. People might assume that sickness is an unintended consequence of infection, that it happens because your immune system is active, but we hypothesize that it’s likely an adaptive process that contributes to host defense.

If we consider sickness as immunity at the organismal scale, I think of my work as bridging the dynamic immunological processes that occur at the cellular scale, the tissue scale, and the organismal scale. I’m interested in the molecular and cellular mechanisms by which the immune system communicates with the brain to generate changes in behavior and physiology, such as fever, loss of appetite, and changes in social interaction.

Q: What sickness behaviors fascinate you?

A: During my thesis work at Yale University, I studied how the gut processes different nutrients and the role of the immune system in regulating gut homeostasis in response to different kinds of food. I’m especially interested in the interaction between food, the immune system, and the brain. One of the things I’m most excited about is the reduction in appetite, or changes in food choice, because we have what I would consider pretty strong evidence that these may be adaptive.

Sleep is another area we’re interested in exploring. From their own subjective experience, everyone knows that sleep is often altered during infection.

I also don’t just want to examine snapshots in time. I want to characterize changes over the course of an infection. There’s probably going to be individual variability, which I think may be in part because pathogens are also changing over the course of an illness — we’re studying two different biological systems interacting with each other.

Q: What sorts of expertise are you hoping to recruit to your lab, and what collaborations are you excited about pursuing?

A: I really want to bring together different areas of biology to think about organism-wide questions. The thing that’s most important to me is people who are creative — I’d rather trainees come in with an interesting idea than a perfectly formed question within the bounds of what we already believe to be true. I’m also interested in people who would complement my expertise; I’m fascinated by microbiology, but I don’t have any formal training.

The Whitehead Institute is really invested in interdisciplinary work, and there’s a natural synergy between my work and the other labs in this small community at the Whitehead Institute.

I’ve been collaborating with Sebastian Lourido’s lab for a few years, looking at how Toxoplasma gondii influences social behavior, and I’m excited to invest more time in that project. I’m also interested in molecular neuroscience, which is a focus of Siniša Hrvatin’s lab. That lab is interested in the hypothalamus, and trying to understand the mechanisms that generate torpor. My work also focuses on the hypothalamus because it regulates homeostatic behaviors that change during sickness, such as appetite, sleep, social behavior, and body temperature.

By studying different sickness states generated by different kinds of pathogens — parasites, viruses, bacteria — we can ask really interesting questions about how and why we get sick.

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. 

New insights into a hidden process that protects cells from harmful mutations

To make up for the loss of an important gene's function, cells are known to ramp up activity of other genes with similar functions. New research from the Weissman Lab reveals insights into how cells coordinate this response.

Shafaq Zia | Whitehead Institute
February 12, 2026

Some genetic mutations that are expected to completely stop a gene from working surprisingly cause only mild or even no symptoms. Researchers in previous studies have discovered one reason why: cells can ramp up the activity of other genes that perform similar functions to make up for the loss of an important gene’s function. A new study, published Feb. 12 in the journal Science, from the lab of Whitehead Institute Member Jonathan Weissman now reveals insights into how cells can coordinate this compensation response.

Cells are constantly reading instructions stored in DNA. These instructions, called genes, tell them how to make the many proteins that carry out complex processes needed to sustain life. But first, they need to make a temporary copy of these genetic instructions called messenger RNA, or mRNA.

As part of normal maintenance, cells routinely break down these temporary messages. This process helps control gene activity — or how much protein is made from a given gene — and ensures that old or unnecessary messages don’t accumulate. Cells also destroy faulty mRNAs that contain errors. These messages, if used, could produce damaged proteins that clump together and interfere with normal cellular processes.

In 2019, external studies suggested that this cleanup could be serving as more than just a quality-control check. The researchers showed that when faulty mRNAs are broken down, this breakdown can signal cells to activate the compensation response. These works also suggested that cells decide which backup genes to turn up based on how closely these genes resemble the mRNA that’s being degraded.

But mRNA decay is a process that happens in the cytoplasm, outside the nucleus where DNA, and thereby genes, are stored. So, Mohamed El-Brolosy, a postdoc in the Weissman Lab and lead author of the study, and colleagues wondered how those two processes in different compartments of the cell could be connected. Understanding this mechanism with greater depth could enable development of therapeutics that trigger it in a targeted fashion.

The researchers started by investigating a specific gene that scientists know triggers a compensation response when its mRNA is destroyed by causing a closely related gene to become more active. To find out which molecules within the cell aid this process, the researchers systematically switched other genes off, one at a time.

That’s when they found a protein called ILF3. When the gene encoding this protein was turned off, cells could no longer ramp up the activity of the backup gene following mRNA decay.

Upon further investigation, the researchers identified small RNA fragments — left behind when faulty mRNAs are destroyed — underlying this response. These fragments contain a special sequence that acts like an “address”. The team proposed that this address guides ILF3 to related backup genes that share the same sequence as the faulty mRNA.

In fact, when they introduced mutations in this sequence, the cells’ compensation response dropped, suggesting that the system relies on precise sequence matching to target the correct backup genes.

“That was very exciting for us,” says Weissman, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI). “It showed us that this isn’t a generic stress response. It’s a regulated system.”

The researchers’ findings point toward new therapeutic possibilities, where boosting the activity of a related gene could mitigate symptoms of certain genetic diseases. More broadly, their work characterizes a mysterious layer of gene regulation.

El-Brolosy, M. A., et al. (2026). Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation. Science, 391, eaea1272. https://doi.org/10.1126/science.aea1272

How a unique class of neurons may set the table for brain development

A new MIT study from the Nedivi Lab finds that somatostatin-expressing neurons follow a unique trajectory when forming connections in the brain’s visual cortex that may help establish the conditions needed for sensory experience to refine circuits.

David Orenstein | The Picower Institute for Learning and Memory
January 14, 2026

The way the brain develops can shape us throughout our lives, so neuroscientists are intensely curious about how it happens. A new study by researchers in The Picower Institute for Learning and Memory at MIT that focused on visual cortex development in mice, reveals that an important class of neurons follows a set of rules that while surprising, might just create the right conditions for circuit optimization.

During early brain development, multiple types of neurons emerge in the visual cortex (where the brain processes vision). Many are “excitatory,” driving the activity of brain circuits, and others are “inhibitory,” meaning they control that activity. Just like a car needs not only an engine and a gas pedal, but also a steering wheel and brakes, a healthy balance between excitation and inhibition is required for proper brain function. During a “critical period” of development in the visual cortex, soon after the eyes first open, excitatory and inhibitory neurons forge and edit millions of connections, or synapses, to adapt nascent circuits to the incoming flood of visual experience. Over many days, in other words, the brain optimizes its attunement to the world.

In the new study in The Journal of Neuroscience, a team led by MIT research scientist Josiah Boivin and Professor Elly Nedivi visually tracked somatostatin (SST)-expressing inhibitory neurons forging synapses with excitatory cells along their sprawling dendrite branches, illustrating the action before, during and after the critical period with unprecedented resolution. Several of the rules the SST cells appeared to follow were unexpected—for instance, unlike other cell types, their activity did not depend on visual input—but now that the scientists know these neurons’ unique trajectory, they have a new idea about how it may enable sensory activity to influence development: SST cells might help usher in the critical period by establishing the baseline level of inhibition needed to ensure that only certain types of sensory input will trigger circuit refinement.

“Why would you need part of the circuit that’s not really sensitive to experience? It could be that it’s setting things up for the experience-dependent components to do their thing,” said Nedivi, William R. and Linda R. Young Professor in The Picower Institute and MIT’s Departments of Biology and Brain and Cognitive Sciences.

Boivin added: “We don’t yet know whether SST neurons play a causal role in the opening of the critical period, but they are certainly in the right place at the right time to sculpt cortical circuitry at a crucial developmental stage.”

A unique trajectory

To visualize SST-to-excitatory synapse development, Nedivi and Boivin’s team used a genetic technique that pairs expression of synaptic proteins with fluorescent molecules to resolve the appearance of the “boutons” SST cells use to reach out to excitatory neurons. They then performed a technique called eMAP, developed by Kwanghun Chung’s lab in the Picower Institute, that expands and clears brain tissue to increase magnification, allowing super-resolution visualization of the actual synapses those boutons ultimately formed with excitatory cells along their dendrites. Co-author and postdoc Bettina Schmerl helped lead the eMAP work.

These new techniques revealed that SST bouton appearance and then synapse formation surged dramatically when the eyes opened and then as the critical period got underway. But while excitatory neurons during this timeframe are still maturing, first in the deepest layers of the cortex and later in its more superficial layers, the SST boutons blanketed all layers simultaneously, meaning that, perhaps counter intuitively, they sought to establish their inhibitory influence regardless of the maturation stage of their intended partners.

Many studies have shown that eye opening and the onset of visual experience sets in motion the development and elaboration of excitatory cells and another major inhibitory neuron type (parvalbumin-expressing cells). Raising mice in the dark for different lengths of time, for instance, can distinctly alter what happens with these cells. Not so for the SST neurons. The new study showed that varying lengths of darkness had no effect on the trajectory of SST bouton and synapse appearance; it remained invariant, suggesting it is pre-ordained by a genetic program or an age-related molecular signal, rather than experience.

Moreover, after the initial frenzy of synapse formation during development, many synapses are then edited, or pruned away, so that only the ones needed for appropriate sensory responses endure. Again, the SST boutons and synapses proved to be exempt from these redactions. Though the pace of new SST synapse formation slowed at the peak of the critical period, the net number of synapses never declined and even continued increasing into adulthood.

“While a lot of people think that the only difference between inhibition and excitation is their valence, this demonstrates that inhibition works by a totally different set of rules,” Nedivi said.

In all, while other cell types were tailoring their synaptic populations to incoming experience, the SST neurons appeared to provide an early but steady inhibitory influence across all layers of the cortex. After excitatory synapses have been pruned back by the time of adulthood, the continued upward trickle of SST inhibition may contribute to the increase in the inhibition to excitation ratio that still allows the adult brain to learn, but not as dramatically or as flexibly as during early childhood.

A platform for future studies

In addition to shedding light on typical brain development, Nedivi said, the study’s techniques can enable side-by-side comparisons in mouse models of neurodevelopmental disorders such as autism or epilepsy where aberrations of excitation and inhibition balance are implicated.

Future studies using the techniques can also look at how different cell types connect with each other in brain regions other than the visual cortex, she added.

Boivin, who will soon open his own lab as a faculty member at Amherst College, said he is eager to apply the work in new ways.

“I’m excited to continue investigating inhibitory synapse formation on genetically defined cell types in my future lab,” Boivin said. “I plan to focus on the development of limbic brain regions that regulate behaviors relevant to adolescent mental health.”

In addition to Nedivi, Boivin and Schmerl, the paper’s other authors are Kendyll Martin, and Chia-Fang Lee.

Funding for the study came from the National Institutes of Health, the Office of Naval Research and the Freedom Together Foundation.

New chemical method makes it easier to select desirable traits in crops

Whitehead Institute Member Mary Gehring and colleagues offer a new method for generating large-scale genetic changes without irradiation.

Mackenzie White | Whitehead Institute
January 8, 2026

Crops increasingly need to thrive in a broader range of conditions, including drought, salinity, and heat. Traditional plant breeding can select for desirable traits, but is limited by the genetic variation that already exists in plants. In many crops, domestication and long-term selection have narrowed genetic diversity, constraining efforts to develop new varieties.

To work around these limits, researchers have developed ways to introduce helpful traits, such as drought or salt tolerance, into plants through mutation breeding. This deliberately introduces random genetic changes into plants. Then researchers screen the genetically altered plants to see which have acquired useful traits. One widely used approach relies on radiation to generate structural variants—large-scale DNA changes that can affect multiple genes at once. However, irradiation introduces logistical and regulatory hurdles that restrict who can use it and which crops can be studied.

In a paper published in PLOS Genetics on December 18, Whitehead Institute Member Mary Gehring and colleagues offer a new method for generating large-scale genetic changes without irradiation.

Lead author Lindsey Bechen, the Gehring lab manager; Gehring; former postdoc P.R.V. Satyaki (now a faculty member at the University of Toronto); and their colleagues developed the approach by exposing germinating seeds to etoposide, a chemotherapy drug, during early growth.

The drug interferes with an enzyme that helps manage DNA structure during cell division. When cells attempt to repair the resulting breaks in their DNA, errors in the repair process can produce large-scale rearrangements in the genome. Seeds collected from treated plants carry these changes in a heritable form.

The process relies on standard laboratory tools: seeds are germinated on growth medium containing the drug, then transferred to soil to complete their life cycle.

“I was surprised at how efficient it was,” says Gehring, who is also a professor of biology at MIT and an HHMI Investigator. “The diversity of new traits that you could see just by looking at the plants in the first generation was extensive.”

The researchers demonstrated the method in Arabidopsis thaliana, a model plant widely used in genetic studies. Roughly two-thirds of treated plant lines showed visible differences, including changes in leaf shape, plant size, pigmentation, and fertility. Genetic analyses linked these traits to deletions, duplications, and rearrangements of DNA segments.

In several cases, the team linked specific plant traits to individual genetic changes. A dwarf plant with thick stems and unusual leaves carried a large change that disrupted a gene involved in leaf development. Another plant, marked by green-and-white mottled leaves, carried a deletion in the gene IMMUTANS—the same gene identified in radiation-induced mutants described more than 60 years ago.

Beyond Arabidopsis, Gehring’s lab is applying the technique to pigeon pea, a drought-tolerant legume and an important source of dietary protein in parts of Asia and Africa. Pigeon pea is an underutilized crop with the potential to become a staple crop—if its lack of genetic diversity, caused by a historical cultivation bottleneck, can be overcome. Often referred to as orphan crops, species like pigeon pea receive limited research attention and often lack the genetic variation needed for breeding improved varieties.

“All of the traits that we might want to see in pigeon pea are not present in the existing population,” says Gehring. “The idea is to do a large-scale mutation experiment to increase genetic diversity.”

The team, which includes Gehring lab postdoc Sonia Boor, is now screening treated pigeon pea lines for salt tolerance, a trait that shapes where crops can be grown and how they perform in saline soils. Although pigeon pea takes longer to grow than Arabidopsis, the researchers have reached the second generation and identified several lines that show promising responses under saline conditions.

The researchers’ chemical approach may also be beneficial for crops that are difficult to modify using gene-editing tools such as CRISPR. Although CRISPR enables precise genetic changes, it often relies on genetic transformation, a technically challenging step for many plant species.

“A lot of species that one works with, either in agriculture or horticulture, are not amenable to genetic transformation,” says Gehring.

The new method complements existing genetic tools rather than replacing them. By providing a more accessible alternative to irradiation, chemical mutation could expand the availability of large-scale genetic changes and novel plant varieties.

Looking ahead, Gehring’s lab plans to develop comprehensive collections of Arabidopsis mutants carrying well-characterized structural variants. Such resources could help researchers better understand how large-scale changes in genome structure influence plant development and performance, informing future efforts to study and enhance crops.

Bechen, L. L., Ahsan, N., Bahrainwala, A., Gehring, M., & Satyaki, P. R. (2025). A simple method to efficiently generate structural variation in plants. PLOS Genetics, 21(12). https://doi.org/10.1371/journal.pgen.1011977
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.

3 Questions with new faculty member Yunha Hwang: Using computation to study the world’s best single-celled chemists

The assistant professor utilizes microbial genomes to examine the language of biology. Her appointment reflects MIT’s commitment to exploring the intersection of genetics research and AI.

Lillian Eden | Department of Biology
December 15, 2025

Today, out of an estimated 1 trillion species on Earth, 99.999 percent are considered microbial — bacteria, archaea, viruses, and single-celled eukaryotes. For much of our planet’s history, microbes ruled the Earth, able to live and thrive in the most extreme of environments. Researchers have only just begun in the last few decades to contend with the diversity of microbes — it’s estimated that less than 1 percent of known genes have laboratory-validated functions. Computational approaches offer researchers the opportunity to strategically parse this truly astounding amount of information.

An environmental microbiologist and computer scientist by training, new MIT faculty member Yunha Hwang is interested in the novel biology revealed by the most diverse and prolific life form on Earth. In a shared faculty position as the Samuel A. Goldblith Career Development Professor in the Department of Biology, as well as an assistant professor at the Department of Electrical Engineering and Computer Science and the MIT Schwarzman College of Computing, Hwang is exploring the intersection of computation and biology.  

Q: What drew you to research microbes in extreme environments, and what are the challenges in studying them?

A: Extreme environments are great places to look for interesting biology. I wanted to be an astronaut growing up, and the closest thing to astrobiology is examining extreme environments on Earth. And the only thing that lives in those extreme environments are microbes. During a sampling expedition that I took part in off the coast of Mexico, we discovered a colorful microbial mat about 2 kilometers underwater that flourished because the bacteria breathed sulfur instead of oxygen — but none of the microbes I was hoping to study would grow in the lab.

The biggest challenge in studying microbes is that a majority of them cannot be cultivated, which means that the only way to study their biology is through a method called metagenomics. My latest work is genomic language modeling. We’re hoping to develop a computational system so we can probe the organism as much as possible “in silico,” just using sequence data. A genomic language model is technically a large language model, except the language is DNA as opposed to human language. It’s trained in a similar way, just in biological language as opposed to English or French. If our objective is to learn the language of biology, we should leverage the diversity of microbial genomes. Even though we have a lot of data, and even as more samples become available, we’ve just scratched the surface of microbial diversity.

Q: Given how diverse microbes are and how little we understand about them, how can studying microbes in silico, using genomic language modeling, advance our understanding of the microbial genome?

A: A genome is many millions of letters. A human cannot possibly look at that and make sense of it. We can program a machine, though, to segment data into pieces that are useful. That’s sort of how bioinformatics works with a single genome. But if you’re looking at a gram of soil, which can contain thousands of unique genomes, that’s just too much data to work with — a human and a computer together are necessary in order to grapple with that data.

During my PhD and master’s degree, we were only just discovering new genomes and new lineages that were so different from anything that had been characterized or grown in the lab. These were things that we just called “microbial dark matter.” When there are a lot of uncharacterized things, that’s where machine learning can be really useful, because we’re just looking for patterns — but that’s not the end goal. What we hope to do is to map these patterns to evolutionary relationships between each genome, each microbe, and each instance of life.

Previously, we’ve been thinking about proteins as a standalone entity — that gets us to a decent degree of information because proteins are related by homology, and therefore things that are evolutionarily related might have a similar function.

What is known about microbiology is that proteins are encoded into genomes, and the context in which that protein is bounded — what regions come before and after — is evolutionarily conserved, especially if there is a functional coupling. This makes total sense because when you have three proteins that need to be expressed together because they form a unit, then you might want them located right next to each other.

What I want to do is incorporate more of that genomic context in the way that we search for and annotate proteins and understand protein function, so that we can go beyond sequence or structural similarity to add contextual information to how we understand proteins and hypothesize about their functions.

Q: How can your research be applied to harnessing the functional potential of microbes?

A: Microbes are possibly the world’s best chemists. Leveraging microbial metabolism and biochemistry will lead to more sustainable and more efficient methods for producing new materials, new therapeutics, and new types of polymers.

But it’s not just about efficiency — microbes are doing chemistry we don’t even know how to think about. Understanding how microbes work, and being able to understand their genomic makeup and their functional capacity, will also be really important as we think about how our world and climate are changing. A majority of carbon sequestration and nutrient cycling is undertaken by microbes; if we don’t understand how a given microbe is able to fix nitrogen or carbon, then we will face difficulties in modeling the nutrient fluxes of the Earth.

On the more therapeutic side, infectious diseases are a real and growing threat. Understanding how microbes behave in diverse environments relative to the rest of our microbiome is really important as we think about the future and combating microbial pathogens.