Category: Whitehead Institute

Scientists map which genes are active in a developing seed to build hardier crops

Many of the basic biological processes that allow seeds of global food staples like wheat, rice, and corn, to grow, transport nutrients, and develop useful traits like withstanding heat and drought are not yet fully understood. A new gene expression map of seed development offers a framework to better understand, and even guide, seed development to improve crop productivity.

Shafaq Zia | Whitehead Institute
May 19, 2026

Seeds like wheat, rice, and corn are at the center of the global food supply and provide most of the daily calories consumed worldwide. But despite their importance, scientists still do not fully understand many of the basic biological processes that allow these seeds to grow, transport nutrients, and develop traits that determine crop resiliency.

With fluctuating environmental conditions and other stressors threatening agriculture, there is a need to develop hardier crops better able to withstand heat, drought, and changing soil conditions. Scientists are increasingly looking to understand the hidden biology of seed development that could one day help them achieve this.

Now, researchers in the lab of Mary Gehring have created a detailed gene expression “map” of seed development in Arabidopsis thaliana, a small flowering plant in the mustard family that is widely used to study plant biology and is closely related to major crops like canola.

This map, also known as a transcriptional atlas, shows which genes are turned on or off in different cell types as the seed develops. Active genes make messenger RNA (mRNA) that guides the production of proteins necessary for cellular processes. By tracking which genes are active where, researchers can better understand the role each cell type plays across different stages of seed development.

The work, published May 21 in Nature Plants, offers scientists new clues about how plants coordinate key biological processes tied to agriculturally significant traits, including seed size and nutrient storage.

“Seeds are fundamental to sustaining human life,” says Caroline (Carly) Martin, lead author of the paper and a graduate student in the Gehring Lab. “By building this atlas, we now have a framework researchers can use to start asking much more precise questions about how seeds develop and if those processes might eventually be improved in different crops.”

Unlike previous atlases of Arabidopsis, which do not distinguish many cell types due to technological limitations, the new atlas provides a more complete and higher resolution view of the developing seed. The researchers have captured seed development at three precisely timed stages after pollination when the plant embryo, the nutrient-rich tissue that feeds it (called the endosperm), and the surrounding tissues from the mother plant rapidly grow and reorganize. Using this dataset, they have identified where genes that regulate how seeds grow and store nutrients are active.

The researchers have found a small group of cells near the plant embryo that activate genes involved in producing brassinosteroids, plant hormones that regulate growth. Previous studies had shown that disrupting the production of this hormone can reduce seed size, but it was not known where within the developing seed the hormone is made.

The new data shows that these hormone-producing cells sit directly next to cells in the endosperm that might respond to the hormone. This close arrangement suggests the two cell types may work together to help fine-tune seed size.

The atlas has also revealed that the endosperm, which nourishes the embryo during development and later becomes the edible portion of many staple crops, contains far more specialized cell types than previously understood by researchers.

The team has identified a small “founder” population of cells that may help establish a key region of the endosperm located at the boundary where nutrients enter the seed from the mother plant.

Because the amount and timing of resources supplied by the mother plant determine how much energy the seed can store, this region of the endosperm helps shape the seed’s nutritional profile. These reserves — oils, starches, and proteins — are essential for both seed development and human nutrition.

These findings, taken together, could allow researchers to better understand — and even guide — seed development to improve crop productivity.

“We’re already seeing that seed filling in many crops is vulnerable to heat stress,” says Gehring, who is also a professor of biology at MIT and an investigator at the Howard Hughes Medical Institute (HHMI). “If we are to solve the humanitarian crises of food insecurity and malnutrition, we need to understand, at a fundamental level, how seeds of different crops form, store nutrients, and survive environmental stress.”

Caroline A. Martin, Kylee R. Cogdill, Alesandra L. Pusey, and Mary Gehring. “A transcriptional atlas of early Arabidopsis seed development suggests mechanisms for inter-tissue coordination.” Nature Plants, May 21, 2026. https://doi.org/10.1038/s41477-026-02295-8

How tissues tune immune responses to match the threat

Organs which interface with the outside world, like the lungs, skin, and intestines, must balance responding quickly to threats while also avoiding triggering unnecessary inflammation. A new study has found that immune sensitivity in the communities of epithelial cells that line the lungs is not evenly distributed, with cells deeper in the tissue more likely to sound the alarm in response to a threat such as viruses, microbes, allergens, and other particles.

Mackenzie White | Whitehead Institute
May 14, 2026

Barrier organs that form boundaries between the body and the outside environment, such as the lungs, skin, and intestines, face a difficult balancing act. They must respond quickly to threats such as infection, but they also need to avoid triggering unnecessary inflammation that can damage the tissue. A new study led by Whitehead Institute member Pulin Li and graduate student in her lab Diep Nguyen reveals one way the lung manages that tradeoff.

Published on May 15 in Cell Systems, the research found that immune sensitivity is not evenly distributed across the lung. Instead, it arranges in tiers: cells at the outer surface respond cautiously, while cells deeper in the tissue are more likely to sound the alarm when a threat breaks through.

“The central question was how tissues balance the benefits and harmful effects of immune activation when they face different degrees of danger or stress,” says Li, who is also a professor of biology at MIT. “Too little immune activation leaves the tissue unprotected, but too much can create inflammation and damage.”

The team focused on the lung, where epithelial cells line the airways and air sacs and form a physical barrier between the body and the outside world. These cells sit at the point of first contact with inhaled viruses, microbes, allergens, and other particles. For that reason, they are often thought of as front-line defenders.

But the new study suggests that the lung’s outermost defenders are deliberately cautious.

Using mouse models of influenza infection and imaging methods that allowed them to measure infection and immune responses in individual cells, the researchers found that epithelial cells were the least likely to respond to infection by producing interferons, signaling proteins that help alert the immune system. Cells deeper in the tissue, especially endothelial cells that line blood vessels, were much more likely to respond.

This arrangement suggests that the lung uses location as a clue to the seriousness of a threat. A stimulus that remains at the surface may not require a large immune response. But when infection breaches the epithelial barrier and reaches deeper tissue, the lung treats that as a more dangerous threat and activates a stronger defense.

“A less severe threat only requires a lower level of immune response,” says Nguyen. “As a threat goes deeper into the tissue, the inner cell types can encode that information and indicate that the threat has invaded further.”

The researchers traced these differences in sensitivity, in part, to immune-sensing proteins called pattern recognition receptors. These receptors detect molecular signs of infection or damage. One receptor, RIG-I, helps cells recognize viral RNA. Epithelial cells had relatively low levels of RIG-I and related sensors, while deeper stromal cells had higher levels.

That lower sensitivity appears to protect the lung from unnecessary damage. When the researchers increased RIG-I levels in lung epithelial cells in mice, the animals mounted a stronger immune response to a non-infectious inflammatory trigger. But the heightened response caused more tissue damage and interfered with repair.

The finding helps explain why the lung’s surface cells may be tuned not to overreact. The lung constantly encounters harmless or low-level irritants. If epithelial cells responded too readily, they could turn minor disturbances into damaging false alarms.

The researchers also found evidence that similar patterns may exist in other barrier organs, including the intestine and trachea. That raises the possibility that spatially tiered immune sensing is a broader strategy for protecting organs that face the outside world.

“One impact of this work is that it helps us look at an old question in a new way: how do tissues balance protection with tissue damage?” says Nguyen. “We can start to understand that when we look at the building blocks of the tissue and how they work together.”

Li says the work also reflects the value of studying tissues as communities of cells rather than collections of identical responders.

“To understand physiology, you have to take a multicellular approach,” she says. “Thinking about tissues as communities of cells can reveal new insights into how they function.”

Diep H. Nguyen, Jiakun Tian, Sean-Luc Shanahan, Connie Kangni Wang, Tyler Jacks, Xiao Wang, and Pulin Li. “A tissue-scale strategy for sensing threats in barrier organs.” Cell Systems, May 14, 2026. https://doi.org/10.1016/j.cels.2026.101611

Q&A: Why feeling sick may be important for surviving infection

Zuri Sullivan studies sickness behavior to understand how the immune system communicates with the brain to produce changes during illness, hoping to learn more about how the brain interprets immune signals, how these responses may help organisms fight infection, and what they could reveal about disease and immunity.

Shafaq Zia | Whitehead Institute
April 30, 2026

Now, in a new perspective published in Trends in Immunology on April 30, Whitehead Institute Member Zuri Sullivan and colleagues propose a different way of thinking: what if these behaviors are part of an integrated immune strategy that operates across scales — from individual cells to tissues and organs, to the whole organism — and helps promote survival?

Sullivan studies “sickness behavior” to understand how the immune system communicates with the brain to produce these changes during illness — and what they can reveal about how the body coordinates its defense. This work points to a broader biological question: how living systems, from single cells to whole organisms, detect and respond to threats.

We sat down with Sullivan to learn more about how the brain interprets immune signals, how these responses may help organisms fight infection, and what they could reveal about disease and immunity. This interview has been edited for length and clarity.

Whitehead Institute: What led you to start thinking about sickness behavior as a form of whole-organism immunity?

Zuri Sullivan: In graduate school, I found that immune cells in the intestine do more than defend against pathogens — they also help regulate how the body responds to food by changing how intestinal tissue functions depending on the diet.

That work shifted how I thought about immunity, from a local defense system to something broader: a whole-body program that helps shape how we interact with the environment in ways that support survival, including avoiding foods that are harmful or allergenic.

That idea stayed with me in my postdoctoral work in neuroscience, where I studied sickness behavior — things like reduced appetite and social withdrawal during infection. I was interested in how inflammation affects behavior, especially through the hypothalamus, a brain region that controls many of the body’s responses during illness.

Putting those two lines of work together — immunology and neuroscience — led me to an integrated view in which immunity operates across scales, shaping both bodily function and behavior as part of a coordinated system.

WI: We often think of the brain and immune system as separate systems. How are they connected, and why does this connection matter?

ZS: For a long time, the brain was thought to be mostly separate from the immune system, protected by what’s called the blood–brain barrier, which tightly controls what can enter the brain from the bloodstream. That barrier is still very important, but we now know the brain isn’t isolated. The brain and immune system communicate with each other, and that communication can influence both brain activity and behavior. This connection is called the brain–immune axis.

The brain–immune axis is one of the ways the body senses and responds to what’s happening in the outside world. The nervous system does this through our senses, while the immune system uses molecular sensors to detect pathogens and other signs of danger.

The two-way communication between these systems helps coordinate how the body responds to threats. We see this most clearly during infection, in what’s called sickness behavior — things like loss of appetite, fatigue, or social withdrawal. But this connection also matters beyond infection, including in conditions like long COVID and the effects of chronic inflammation on the brain.

In our work, we try to construct  a bigger picture of how the body protects itself. Individual cells can defend themselves, tissues like the gut can mount local immune responses, and the brain–immune axis represents the highest level of this system, where the immune system and the brain coordinate to affect both physiology and behavior across the whole body as part of a unified defense response.

WI: Is the brain–immune axis disrupted in chronic diseases like long COVID or other neuropsychiatric disorders?

ZS: In some conditions, the immune response that is normally helpful can become dysregulated. This can happen after infections or due to genetic and environmental factors. When that happens, it can lead to chronic inflammation that starts to damage tissues—for example, scarring in the lungs after infection, or conditions in the gut like inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS).

There are still two main possibilities being studied for long COVID. One is that a small amount of virus remains in the body and keeps the immune system activated. The other is that the virus is gone, but the brain–immune axis becomes dysregulated and keeps the immune system in an activated state. Researchers are still working to distinguish between these two.

What’s also striking is that there are strong associations between inflammation and both neurodevelopmental and neuropsychiatric disorders. For example, people with autism have higher rates of inflammatory gut conditions like IBD and IBS, and many also experience gastrointestinal symptoms. People with IBD and IBS are associated with being at a higher risk of developing anxiety and depression, especially during a flare-up.

What this suggests is that brain–immune communication can influence both brain function and body function in both directions. The challenge now is figuring out causality — whether inflammation drives changes in the brain, the brain drives inflammation, or if it’s a feedback loop between the two.

WI: How can your proposed framework inform how we think about treating infections in the clinic?

ZS: I think it can inform treatment in a few ways. Right now, when people get sick, we often focus on treating symptoms: reducing fever with medications like Tylenol, overriding behaviors like reduced appetite by providing nutrition through feeding tubes in critically-ill patients. But if sickness behavior is part of an organized response, then it becomes important to understand what these behaviors are actually doing before deciding when to suppress them and when to support them.

A useful example comes from a 2016 mouse study. Researchers found that force-feeding sick mice using feeding tubes had a different outcome based on the type of infection they had. Mice with a bacterial infection became more likely to die, but mice with a viral infection had improved survival. What this tells us is that behavioral changes like reduced appetite may actually be tuned to the type of immune challenge the body is facing. So, if we could understand how these behavioral changes affect the course of infection, it could help clarify which interventions are helpful and which might interfere with recovery.

There are also implications beyond acute infection, especially for conditions like long COVID and other neuropsychiatric or post-inflammatory disorders. One key possibility is that the immune system is playing a causal role in either triggering or maintaining some of these conditions. If that’s the case, it becomes especially relevant that the immune system is highly “druggable”— there are already many therapies that target immune pathways. So, understanding how immune signals influence the brain could open up new ways to intervene in conditions where current treatments aren’t working for patients.

What we need is a better map of how different infections affect the brain over time—what we might call “neural signatures” of infection. In animal studies, where we can track both immune responses and brain activity over time, we can start to build that kind of map: how you go from a healthy state and through infection to changes in brain function and behavior.

The hope is that this kind of framework would eventually help us interpret complex symptoms during and post-infection in humans and have more targeted ways to treat them.

How stem cell descendants preserve flexibility while maintaining distinct identities

In many tissues, some early descendants of stem cells, the body's ultimate shape-shifters, can revert back to a stem cell state through a process known as dedifferentiation. Researchers in the Yamashita Lab have identified two complementary mechanisms that allow cells to preserve stem cell potential while adopting distinct identities.

Mackenzie White | Whitehead Institute
April 6, 2026

Stem cells are the body’s ultimate shape-shifters, sustaining tissues by balancing two competing demands: maintaining their own population and generating specialized descendants. In many tissues, some early descendants can revert to a stem cell state through a process known as dedifferentiation. This ability can help replenish the stem cell pool when stem cells are lost.

In a new study published on April 6 in PNAS, researchers at Whitehead Institute identify two complementary mechanisms that allow cells to preserve stem cell potential while adopting distinct identities.

Led by Whitehead Institute Member Yukiko Yamashita and Yamashita Lab postdoc Amelie Raz, the study focuses on the male fruit fly germline stem cells, which give rise to sperm. These cells sit at the foundation of a lineage that continues across generations.

To understand what distinguishes these stem cells, the researchers analyzed RNA, the intermediary molecules that link genes in DNA to the proteins they encode. RNA quantities typically reflect which genes a cell is using—which in turn reflects a cell’s identity. The researchers expected to find a set of RNAs unique to stem cells. Instead, they discovered that stem cells and their immediate descendants share seemingly identical RNA profiles.

“We didn’t have anything that was specific to stem cells,” Raz says. “It turned out that that was actually the key to understanding how you make them.”

The difference between these cell types lies not only in which RNAs are present, but in whether the cells are still making them. Stem cells continue producing these RNAs, while their descendants inherit many of the same molecules but stop making new copies of RNA.

This means RNA alone does not fully define a cell’s state. In these descendant cells, the shared RNAs reflect an earlier state, not the same productive gene program seen in stem cells.

“On the level of RNA, they’re the same,” Raz says. “But they’re different in what’s actually happening in the nucleus—whether that RNA is being actively produced.”

The study also clarifies how signals from the surrounding environment help determine what path a cell follows. Stem cells reside in a specialized microenvironment known as a niche, which sends molecular cues that influence cell behavior. Two well-studied signaling pathways—Bmp and Jak-Stat—have long been known to regulate germline stem cells.

Previous models assumed these pathways worked together or redundantly. However, the new findings show that they instead act independently, each controlling a different subset of genes.

“What we found was that they’re acting on completely separate parts of this gene activity program,” Raz says.

Because the pathways operate independently, their combined activity defines distinct cellular states. When both signals are active, cells maintain stem cell identity. When neither is active, cells continue along a differentiation pathway. When only one pathway is active, cells can revert toward a stem cell state through dedifferentiation. This modular arrangement allows cells with the same underlying potential to follow different paths depending on the signals they receive.

The findings help explain why many stem cell populations rely on multiple signaling pathways. Rather than serving as backups for one another, these pathways can regulate different parts of cell behavior and work together to shape a cell’s trajectory.

“In many stem cell populations, multiple signals have been thought to be redundant,” says Yamashita, who is also a professor of biology at MIT and an HHMI Investigator. “Here, we show that they can have distinct roles to determine whether a cell self-renews, differentiates, or reverts in combination.”

More broadly, the work shows that knowing which molecules are present in a cell does not always reveal how that cell is functioning. Two cells can appear identical by standard molecular measures even when they are operating in different regulatory states.

The study also lays the groundwork for future research. Raz and colleagues have identified a set of genes linked to this early germline state in fruit flies and are now investigating what those genes do and how they help govern stem cell behavior.

“Now that we know what’s there, the next step is understanding what those RNA molecules are doing,” Raz says.

Additionally, the work suggests that long-standing models of stem cell regulation may be incomplete, even in systems that have been studied for decades.

“What we are showing is that these pathways aren’t necessarily working in the way people had assumed,” Raz says. “There’s almost certainly more to it.”

A. Raz, H. Hassan, & Y.M. Yamashita, Niche-dependent modular regulation of the stem cell transcriptome separates cell identity and potential, Proc. Natl. Acad. Sci. U.S.A. 123 (15) e2533973123, https://doi.org/10.1073/pnas.2533973123 (2026).

Study reveals “two-factor authentication” system that controls microRNA destruction

A new study led by researchers in the Bartel Lab and Germany’s Max Planck Institute of Biochemistry reveals how cells selectively eliminate certain microRNAs, which tune which genes are active and when, through an unexpectedly intricate molecular recognition system.

Mackenzie White | Whitehead Institute
March 17, 2026

Cells rely on tiny molecules called microRNAs to tune which genes are active and when. Cells must carefully control the lifespan of microRNAs to prevent widespread disruption to gene regulation.

A new study led by researchers at Whitehead Institute and Germany’s Max Planck Institute of Biochemistry reveals how cells selectively eliminate certain microRNAs through an unexpectedly intricate molecular recognition system. The work, published on March 18 in Nature, shows that the process requires two separate RNA signals, similar to how many digital systems require two forms of identity verification before granting access.

The findings explain how cells use this “two-factor authentication” system to ensure that only intended microRNAs are destroyed, leaving the rest of the gene regulation machinery in operation.

MicroRNAs are short strands of RNA that help control gene expression. Working together with a protein called Argonaute, they bind to specific messenger RNAs—the molecules that carry genetic instructions from DNA to the cell’s protein-making machinery—and trigger their destruction. In this way, microRNAs can reduce the production of specific proteins.

While scientists recognized that microRNAs could be destroyed through a pathway known as target-directed microRNA degradation, or TDMD, the details of how cells recognized which microRNAs to eliminate remained unclear.

“We knew there was a pathway that could target microRNAs for degradation, but the biochemical mechanism behind it wasn’t understood,” says David Bartel, Whitehead Institute Member and co-senior author of the study.

Earlier work from Bartel’s lab and others had identified a key player in this pathway: the ZSWIM8 E3 ubiquitin ligase. E3 ubiquitin ligases are involved in the cell’s recycling system and attach a small molecular tag called ubiquitin to other proteins, marking them for destruction.

The researchers first showed that the ZSWIM8 E3 ligase specifically binds and tags Argonaute, the protein that holds microRNAs and helps regulate genes. The researchers’ next challenge was to understand how this machinery recognized only Argonaute complexes carrying specific microRNAs that should be degraded.

The answer turned out to be surprisingly sophisticated.

Using a combination of biochemistry and cryo-electron microscopy—an imaging technique that reveals molecular structures at near-atomic resolution—the researchers discovered that the degradation system relies on a dual-RNA recognition process. First, Argonaute must carry a specific microRNA. Second, another RNA molecule called a “trigger RNA” must bind to that microRNA in a particular way.

The degradation machinery activates only when both signals are present.

This dual requirement ensures exquisite specificity. Each cell contains over a hundred thousand Argonaute–microRNA complexes regulating many genes, and destroying them indiscriminately would disrupt essential biological processes.

“The vast majority of Argonaute molecules in the cell are doing useful work regulating gene expression,” says Bartel, who is also a professor of biology at MIT and an HHMI Investigator. “You only want to degrade the ones carrying a particular microRNA and bound to the right trigger RNA. Without that specificity, the cell would lose its microRNAs and the essential regulation that they provide.”

The structural images revealed complex molecular interactions. The ZSWIM8 ligase detects multiple structural changes that occur when the two RNAs bind together within the Argonaute protein.

“When we saw the structure, everything clicked,” says Elena Slobodyanyuk, a graduate student in Bartel’s lab and co-first author of the study. “You could see how the pairing of the trigger RNA with the microRNA reshapes the Argonaute complex in a way that the ligase can recognize.”

Beyond explaining how TDMD works, the findings may impact how scientists think about the regulation of RNA molecules more broadly.

“A lot of E3 ligases recognize their targets through simpler signals,” says Jakob Farnung, co-first author and researcher in the Department of Molecular Machines and Signaling at the Max Planck Institute of Biochemistry. “It was like opening a treasure chest where every detail revealed something new and mesmerizing.”

MicroRNAs typically persist in cells for much longer time periods than most messenger RNAs, but some degrade far more quickly, and the TDMD pathway appears to account for many of these unusually short-lived microRNAs.

The researchers are now investigating whether other RNAs can trigger similar degradation pathways and whether additional microRNAs are regulated through variations of the mechanism shown in this study.

“This opens up a whole new way of thinking about how RNA molecules can control protein degradation,” says Brenda Schulman, study co-senior author and Director of the Department of Molecular Machines and Signaling at the Max Planck Institute of Biochemistry. “Here, the recognition was far more elaborate than expected. There’s likely much more left to discover.”

Uncovering the details of this intricate regulatory system required interdisciplinary collaboration, combining expertise in RNA biochemistry, structural biology, and ubiquitin enzymology to solve this long-standing molecular puzzle.

“This was a project that required the strengths of two labs working at the forefront of their fields,” says Schulman, who is also an alum of Whitehead Institute. “It was an incredible team effort.”

Paper: Jakob Farnung, Elena Slobodyanyuk, Peter Y. Wang, Lianne W. Blodgett, Daniel H. Lin, Susanne von Gronau, Brenda A. Schulman & David P. Bartel. “The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.” Nature (2026). https://doi.org/10.1038/s41586-026-10232-0

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

 

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.

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

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