Research Area: Cell Biology

How an embryo draws the line between body and germline

The molecules that form cell membranes help establish a boundary between cell types early in development which is essential for an animal's ability to produce offspring.

Mackenzie White | Whitehead Institute
September 7, 2026

Every embryo of an organism that reproduces sexually faces an early and consequential decision: which of its cell lineages will make up the mortal body, and which will become the germline, the lineage that eventually makes eggs or sperm and carries genetic information to the next generation. Get this wrong, and an organism can live but cannot reproduce and, evolutionarily, ceases to exist.

Like most embryos, fruit fly embryos begin as one mega-cell, the fertilized egg cell, full of the ingredients for future development. What’s different in fly embryos is that not all cells form at the same time. Before most of the embryo has been subdivided into individual cells, a small group of cells that will eventually produce eggs or sperm has already begun to form. These primordial germ cells emerge at the back end of the embryo, where small buds rise from its surface and pinch free from the shared interior.

A new study from the lab of Whitehead Institute Director Ruth Lehmann reveals that this process depends on preparations made before the buds appear. The researchers found that a protein, aptly named Germ Cell-less (GCL), produced at the posterior, organizes a distinct region of the embryo’s membrane so that the molecular machinery needed to separate the future germ cells can assemble.

The findings, published on July 22 in the Journal of Cell Biology, show how the local organization of lipids, the molecules that form cell membranes, helps to establish a boundary between the germline and the soma or body cells. This separation is essential for the animal’s ability to produce offspring.

How that separation begins depends on location. As the embryo’s nuclei travel outward to its surface, only those that reach the posterior go on to become germ cells, each sealing into a membrane and pinching away from the rest of the embryo as one of its first true cells. The germplasm, a specialized material the mother deposits at the posterior end, carries the factors that set these cells apart.

Previous work from the Lehmann lab showed that GCL is essential for this pinching-off. GCL directs the cell’s protein-disposal machinery to recognize and destroy Torso, a receptor that transmits signals from the embryo’s surface. Torso is best known for its role in the soma, where it triggers a signaling cascade switching on genes needed for head and tail development. Without GCL, Torso remains active at the posterior end, and germ cells usually fail to form. What Torso was doing to interfere with the process, however, remained unclear, since none of the hallmarks of its gene-activating pathways seemed involved.

To trace the signal downstream of Torso, the team, including lead author Mariyah Saiduddin, a graduate student in the Lehmann lab, used genetic experiments, live imaging, and optogenetics (a method that uses light to switch protein activity on or off with precise timing and spatial control). The results revealed a previously unknown and surprising role for Torso in early development: activating an enzyme called PI3K. That enzyme produces PIP3, a signaling lipid embedded in the embryo’s membrane.

Collaborating with Whitehead’s W.M. Keck Microscopy Innovation Center, the researchers developed image-analysis approaches to measure subtle changes in PIP3 signals in living embryos in real time.

In a normal embryo, PIP3 was abundant near the posterior end but excluded from the region where germ cells form. Without GCL, PIP3 spread into that region. Experimentally boosting PI3K activity sharply reduced germ cell formation, while dialing it down allowed extra cells to form. The lipid acted like a chemical switch: with PIP3 levels reduced by GCL’s action, Myosin II, a motor protein that generates contractile force, assembled into a ring-like structure to pinch each bud coming off of the embryo membrane at its base, separating each developing germ cell from the rest of the embryo. With too much PIP3 on the membrane, the Myosin structure was unable to assemble, the buds flattened, and germ cells failed to form.

“What was surprising was that the membrane was already being prepared before the nuclei reached it,” says Saiduddin. “We had thought of germ cell formation as beginning when the nuclei arrived at the surface, but GCL is acting earlier, preventing PIP3 from building up in advance.”

This study shows that the boundary between soma and germline isn’t drawn by turning genes on or off in the early embryo, but depends in part on locally shaping the chemistry of the cell membranes. In Drosophila, the antagonistic relationship between Torso and its destroyer, GCL, determines where in the membrane signaling molecules are positioned before the embryo even starts developing. This in turn provides constraints on where to exert mechanical force to round up and bud into a new cell, thereby helping to specify germ cell fate.

Because the signaling pathways involved here are conserved or present across the animal kingdom, the work offers broader clues about how local signaling cascades can organize membrane lipids and shape cell behavior and fate, beyond fruit flies.

The work also raises new questions about why the embryo uses more than one mechanism to protect germ cells from signals that would otherwise push them toward a somatic fate.

“This is a beautiful illustration of discovery science,” Lehmann says. “We solve one puzzle only to realize that there is so much more we do not understand.”

Paper: Mariyah Saiduddin, Juhee Pae, Asier M. Vidal, Martin L. Alani, Ruth Lehmann; GCL pruning of PIP3 establishes the soma-germline boundary. J Cell Biol 7 September 2026; 225 (9): e202604036. doi: https://doi.org/10.1083/jcb.202604036

Biologists identify a cellular pathway that allows colorectal cancer to metastasize

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

Anne Trafton | MIT News
September 24, 2026

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

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

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

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

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

A hijacked pathway

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

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

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

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

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

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

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

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

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

Preventing metastasis

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

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

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

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

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

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

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

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

Alice McCarthy | Whitehead Institute
September 14, 2026

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Notes:

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

Funding:

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

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

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

Shafaq Zia | Whitehead Institute
August 14, 2026

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Enzymes that assemble into droplets can speed up cellular reactions

MIT biologists find highly concentrated droplets can help cells keep enzymes organized and control growth signals.

Anne Trafton | MIT News
June 1, 2026

Within the past decade, biologists have discovered that one strategy cells use to keep their contents organized is a phenomenon known as phase separation.

Similar to the way oil forms droplets that float in a vinegar solution, proteins inside cells can phase separate to form highly concentrated droplets that keep them organized within the cell. In a new study, MIT researchers have now shown that this droplet formation is critical for controlling the function of a class of enzymes called kinases.

The researchers found that condensing into droplets optimizes the biochemical conditions needed for kinases to catalyze reactions, allowing them to more rapidly activate cell signaling pathways. In some cases, droplet formation can even change which reactions the kinases perform.

“Many biological molecules have this propensity to spontaneously separate. We were really interested in asking, if we have these kinases forming droplets, what is the consequence of that in the context of signaling?” says Lindsay Case, an assistant professor of biology at MIT and the senior author of the study.

Learning more about how these droplets form could help researchers design drugs that target kinases, some of which can be overactive in cancer cells.

“Understanding the chemistry of these compartments, and what molecules go into them and what molecules don’t go into them, could help us design drugs that better localize to their target of interest,” Case says.

Nicholas Lea, an MIT graduate student, is the lead author of the paper, which appears today in Cell Reports.

Forming droplets

Since her days as a graduate student, Case has been studying how the physical organization of molecules inside cells affects their function. As a postdoc, she began studying how phase separation might affect a signaling pathway that allows cells to sense when they’re attached to their environment, so they can respond appropriately.

Some of the proteins in this pathway are kinases, which activate other proteins by adding phosphate groups to them. Kinases can also activate themselves through a process called autophosphorylation.

“Inside of the cell, you have these kinase molecules that are responsible for carrying a signal through the cell, and we know that the organization of these molecules changes. When the information is present, they’re organized in a different way than when the information is not present,” Case says. “We think that having the right molecules in the right place is incredibly important for the right biochemistry to occur.”

Phase separation is one of the methods that cells appear to use for this organization. The most familiar example of phase separation can be seen in a salad dressing, where oil forms droplets to minimize contact with water-based vinegar. Proteins can phase separate when they are highly concentrated, leading them to self-assemble into dense droplets floating in the cell’s cytoplasm.

Case hypothesized that this phase separation, which brings kinases together at a high density, might help cells to boost the enzymes’ activity because they are more likely to bump into and phosphorylate each other.

In this study, Case and Lea set out to test that hypothesis, focusing on an enzyme called focal adhesion kinase (FAK). This kinase, which becomes activated when cells attach to their surrounding environment, activates pro-growth and pro-survival signals. In cancer cells, this signaling pathway can go awry, allowing cells to proliferate even when they detach from their original locations.

Scientists already knew that when cells are properly attached to their environment, that adhesion signal causes FAK to accumulate at the cell membrane. In the new study, the MIT team mimicked that effect by overexpressing FAK in cells. These cells were floating freely in a solution, not attached to any surface. Even so, the high concentration of FAK caused the kinase to phase separate into droplets, which turned on the pro-growth signal.

“It was surprising that just by condensing this protein into a droplet, you can actually turn on a signaling pathway that should be turned off,” Case says. “If FAK concentration is too high, you’re always getting these droplets and you’re always signaling, regardless of what the receptors that are supposed to be controlling this are doing.”

The findings suggest that in cancer cells, overexpression of FAK may lead to phase separation, which then helps to drive cancer progression and metastasis.

“It may be that for some kinases, you’re not supposed to form these droplets in the cytoplasm because it leads to this always-on signal, and then the cells no longer listen to the information coming from the environment,” Case says.

Interfering with FAK’s ability to form droplets could offer a new strategy for cancer drug development, she says.

Controlling reactions

The researchers also studied two other kinases, Mst2 and Abl. They found that these enzymes could also phase separate at high concentrations, and that this increased their activity. While phase separation of FAK in the cytoplasm may occur only in cancerous cells, for Mst2, it appears to be a strategy that healthy cells use to control a signaling pathway called Hippo, which promotes cell growth and survival.

Additionally, for both Mst2 and Abl, the researchers discovered that phase separation can lead the enzymes to phosphorylate additional targets, which may lead them to activate different signaling pathways.

“It’s not just that you’re getting faster phosphorylation, but in those cases, the patterns of what is actually getting phosphorylated were very different inside of the droplet compared to what might be happening in a non-droplet context,” Case says. “The kinase is able to phosphorylate amino acid residues beyond the set of canonical sites that have been described before.”

The researchers also found that when these droplets form, they attract high concentrations of ATP, the molecule that kinases use as a source of phosphate. This occurs because kinases tend to contain floppy sections containing many positively charged amino acids, which attract negatively charged ATP.

Using a machine-learning model, the researchers predicted that about 45 percent of the 500 kinases found in human cells would have the ability to form droplets like those seen in this study. Those kinases were also more likely to be highly positively charged, which could help them to recruit ATP into the droplets.

In future work, Case hopes to explore the possibility of designing drugs that could mimic ATP’s ability to be attracted into droplets within a cell, which could help reduce negative side effects of the drugs.

“By localizing drugs to the compartment where your target localizes, that could reduce off-target effects by concentrating the drug with the target of interest and reducing interactions with other molecules,” Case says.

The research was funded by a Searle Scholars Program Award, the U.S. Air Force Office of Scientific Research, the National Institutes of Health, the Royal G. and Mae H. Westaway Family Memorial Fund, and a David H. Koch Graduate Fellowship.

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).

CryoPRISM: A new tool for observing cellular machinery in a more natural environment

The method allows researchers to observe biomolecular complexes in a quick, accurate, and budget-friendly way, providing new insights into bacterial protein synthesis.

Ekaterina Khalizeva | Department of Biology
March 20, 2026

The blobfish, once considered the ugliest animal in the world, has since had quite the redemption arc. Years after it was first discovered, scientists realized that the deep-sea creature appeared so unnervingly blobby only because it went through an extreme change in pressure when it was brought up to the surface. In its natural environment, 4,000 feet underwater, the fish looks perfectly handsome.

Structural biologists, whose goal is to deduce a molecule’s structure and function within a cell, face the risk of making a similar mistake. If biomolecular complexes are extracted from the cell, better-quality images can be obtained, but the molecules may not look natural. On the other hand, studying molecules without disrupting their environment at all is technically challenging, like filming deep underwater.

A new method, called purification-free ribosome imaging from subcellular mixtures (cryoPRISM), offers an appealing compromise. Developed by graduate students Mira May and Gabriela López-Pérez in the Davis lab in the MIT Department of Biology and recently published in PNAS, the technique allows biologists to visualize molecular complexes without taking them too far out of their natural context.

CryoPRISM captures molecular structures in cells that have just been broken open. This comes as close to preserving the natural interactions between molecules as possible, short of the extremely resource-intensive in-cell structural imaging, according to associate professor of biology Joey Davis, the faculty lead of the study.

“We think that the cryoPRISM method is a sweet spot where we preserve much of the native cellular contacts, but still have the resolution that lets us actually see molecular details,” Davis says. “Even in the extremely well-trodden system of translation in E. coli, which people have worked on for over 50 years, we are still finding new states that had just escaped people’s attention.”

A negative control that was not so negative

The development of cryoPRISM, as many discoveries in science, resulted from an unexpected observation that Mira May, the co-first author of the study, made while working on a different project.

Like all living organisms, bacteria rely on a process called translation to manufacture the proteins that carry out essential functions within the cell, from copying DNA to digesting nutrients. A key machine involved in translation is the ribosome — a biomolecular complex that assembles proteins based on instructions encoded by another molecule called mRNA. To regulate its activity, cells employ additional proteins that can change the shape of the ribosome, thus guiding its function.

May sought to identify new players in ribosomal regulation using cryoEM, by rapidly freezing lots of purified molecules and collecting thousands of 2D images to reconstruct their 3D structures. May was trying to pull ribosomes out of cells to visualize them together with their regulators. For her experiments, she designed a negative control containing unpurified bacterial lysate — a mixture of everything spilled from burst cells.

May expected to get noisy, low-quality images from this sample. To her surprise, instead, she saw intact ribosomes together with their natural interacting partners.

In just a few days, this technique experimentally validated data that would have taken months to acquire using other approaches.

“As I found more and more ribosomal states, this project became a method, not just a one-off finding,” May recalls.

Discovering new biology in a saturated field

Once May and her colleagues were confident that cryoPRISM could detect known ribosomal states, they began searching for ones that had previously escaped detection.

“It’s not just that we can recapitulate things that have been previously observed, but we can actually also discover novel ribosomal biology,” May says.

One of the novel states May identified has important implications for our understanding of the evolution of translation regulation.

During active translation, bacterial ribosomes are accompanied by a group of helper proteins called elongation factors. These factors bring in the materials for protein synthesis, like tRNAs and amino acids.

When cells encounter unfavorable conditions, such as colder temperatures, they reduce translation, which means that many ribosomes are out of work. These idle, hibernating ribosomes stop decoding mRNA, and the interface where they usually interact with helper molecules gets blocked by a hibernation factor called RaiA. This protein helps idle ribosomes avoid reactivation, like a sleeping mask that prevents a person from being woken up by light.

May observed the idle ribosomal state in her data, which on its own did not surprise her – this state had been described before. What surprised her was that some inactive ribosomes were interacting not only with RaiA, but also with an elongation factor called EF-G, which in bacteria was previously believed to only interact with active ribosomes.

A similar phenomenon has been seen before in more complex organisms, but observing it in a microbe suggests that its evolutionary origin may be older than previously thought.

“It fits an emerging model in the field, that elongation factors might bind to hibernating ribosomes to protect both the ribosome and themselves from degradation during periods of stress,” May explains. “Think of it like short-term storage.”

An unstressed cell might quickly eliminate unneeded inactive ribosomes, but because any stressor that puts ribosomes to sleep could be temporary, the cell may prefer to hold off on destroying them. That way, the ribosomes can be quickly reactivated if conditions improve.

The future of cryoPRISM

May has already teamed up with other MIT researchers to use cryoPRISM to visualize ribosomes in cells that are notoriously difficult to work with, including pathogenic organisms, which can be challenging to culture at the scale required for particle purification, and red blood cells isolated from patients, which cannot be cultured at all.

Besides its immediate application for translation research, cryoPRISM is a stepping stone toward the broader goal of structural biology: studying biomolecules in their natural environment.

To truly learn about deep-sea fish, scientists need to look at them in the deep sea; and to learn about cellular machines, scientists need to look at them in cells. According to Davis, cryoPRISM perfectly fits into the “theme of structural biology moving closer and closer to cellular context.”

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

 

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