Research Area: Genetics

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

Lung cancers can use two different mechanisms to evade KRAS-inhibiting drugs

Some tumor cells develop resistance by amplifying the KRAS gene, while others change their tumor type, MIT researchers have found.

Anne Trafton | MIT News
September 30, 2026

About 25 percent of lung adenocarcinomas have mutations of the gene KRAS, which drives uncontrolled cell growth. In recent years, the FDA has approved two KRAS inhibitors to treat patients with KRAS mutations. While these drugs can work well initially, tumors almost always develop resistance to them.

Usually, resistance emerges because cells reactivate KRAS activity, through mutations that prevent drug binding or by increasing KRAS expression that overpowers the effects of the inhibitor. However, in a new study, MIT researchers have modeled an alternative mechanism that cancer cells can use to become resistant to KRAS inhibition.

The researchers found that in some cases, lung tumors undergo transformation from adenocarcinoma to squamous cell carcinoma. Both of these tumor types are commonly found in the lungs, but they are thought to  arise from different cells and have different genetic profiles.

When this transition occurs, tumor cells no longer require KRAS, and appear to turn on alternative signaling pathways that help them continue to grow. Ongoing work to identify those pathways may reveal targets for new drugs that could help prevent resistance to KRAS inhibitors.

“The main takeaway is that there seem to be different routes of resistance to KRAS inhibitors, and so we need to be thinking about how we can address this,” says Carrie Rodriguez, an MIT graduate student and one of the lead authors of the paper.

Nicolas Mathey-Andrews PhD ’25 is also a lead author of the study, which appears today in the journal Nature Genetics. The paper’s senior author is Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT’s Koch Institute for Integrative Cancer Research.

Tissue transformation

The two FDA-approved KRAS inhibitors both target a mutation called KRAS-G12C. These drugs are approved only for use in patients whose tumors have failed to respond to other drugs, and these patients usually have cancer that has spread beyond the lungs.

KRAS inhibitors are effective in about 35 percent of the patients who receive them. However, in those cases, the tumors almost always end up becoming resistant by generating additional copies of the KRAS gene or finding other ways to turn on the MAP kinase signaling pathway, which is usually triggered by KRAS and stimulates cell growth.

“Resistance to targeted therapies is a very serious problem,” Rodriguez says. “Sometimes these KRAS inhibitors can hold cancers at bay, but most cases do end up relapsing.”

A 2021 study from researchers at Dana-Farber Cancer Institute, which analyzed tumors from 17 non-small cell lung cancer patients treated with KRAS-G12C inhibition, identified secondary resistance mutations in a majority of patients. In two of these patients, however, the researchers found that tumors transformed from adenocarcinomas to squamous cell carcinomas, but they did not harbor obvious resistance mutations.

Both adenocarcinomas and squamous cell carcinomas are classified as non-small cell lung cancers (NSCLCs), which are the most common type of primary lung cancer. Adenocarcinomas, the most common type of NSCLCs, often originate from the surfactant-producing cells that line the lungs, while squamous cell carcinomas originate in the cells that line the central airways of the lungs.

Mutations of KRAS are found much more frequently in adenocarcinomas than in squamous cell carcinomas

In this study, the researchers set out to model the factors that might drive the transition from adenocarcinomas to squamous cell carcinomas. To do that, they engineered a mouse lung cancer model to express the mutation that is targeted by the FDA-approved KRAS inhibitors.

Following treatment with a KRAS-G12C inhibitor, tumors with genetic loss of Nkx2-1, which normally helps maintain alveolar epithelial identity, were able to undergo adeno-to-squamous transition. Turning on a transcription factor called DeltaNp63, which is overactive in many squamous cell carcinomas, also made this transition more likely. Another transcription factor known as SOX2 also helped stimulate the transition, but this gene could not initiate the transition on its own.

Paths to resistance

Tumors that underwent these tissue transformations did not acquire the mutations that typically boost KRAS expression in adenocarcinomas. Instead, KRAS signaling was shut off. The researchers hypothesize that these cells may turn on another signaling pathway that helps them to continue growing.

“There seem to be several different routes where you can get to squamous transformation, either through loss of lung-lineage-defining transcription factors, or overexpression of these squamous master regulators, SOX2 or DeltaNp63. Those resistant squamous tumors no longer respond to KRAS inhibition because they shut off the signaling or at least dampen it significantly,” Rodriguez says.

The researchers are now further exploring what happens to tumor cells as they transition to a squamous state, in hopes of identifying vulnerabilities that could be targeted with new drugs.

“Fundamentally this is a transition that’s poorly understood, and we were happy to see that we were able to model it,” Mathey-Andrews says. “Future directions that have an eye toward translation will utilize those models to understand the process and conditions by which histologic transformation occurs, and then also nominate potential targets downstream.”

The research was funded, in part, by the Koch Institute Support (core) Grant from the National Cancer Institute, a Ruth Kirschstein National Service Research Award, the National Institute of General Medical Sciences, and the Ludwig Center at MIT.

AI model decodes the language cells use to communicate

New research from the Li Lab at the Whitehead Institute characterizes the signaling pathways whose patterns of gene activity shape cell's structure and function, enabling cells in an organism to take on specific, specialized roles.

Whitehead Institute
September 4, 2026

As an embryo develops from a small cluster of stem cells, those once “blank slate” cells begin to take on more specialized roles like brain, liver, or muscle cells, and organize themselves into three-dimensional structures such as tissues and organs.

The fate of each cell — what type of specialized cell it will become — depends on which genes are turned on or off in the cell. These patterns of gene activity shape the cell’s structure and function, enabling it to take on a specific role in the body.

But this decision isn’t up to individual cells. They constantly send and receive chemical signals to and from neighboring cells, which help them understand where they are, what stage of development they are in, and what they should become. These messages spread through multi-step sequences called signaling pathways, which translate external signals into specific changes in gene activity in the cell.

For researchers, being able to retrace the sequence of instructions a cell has received would offer a powerful way to understand how tissues develop and how these processes go awry in disease.

But this has been difficult to achieve because scientists have long assumed that the effects of signaling pathways vary widely across cell types, meaning they would need to map each pathway separately in each cell type — an arduous and painstaking process.

Now, in a new study led by Whitehead Institute Member Pulin Li and graduate student Nicholas Hutchins, researchers have discovered that each signaling pathway leaves behind a unique “fingerprint” — a distinctive pattern of gene activity that reflects the particular signals the cell has encountered.

Importantly, these fingerprints are consistent across different cell types for the same signaling pathway, which means that instead of mapping each cell type separately, scientists can reconstruct signaling histories across many cell types using these pathway-specific fingerprints.

This discovery was made possible through a machine learning model called IRIS. This model can detect fingerprints of different signaling pathways and pinpoint which signals a cell received at different stages of development inside an embryo, even for cell types it hasn’t encountered before.

This AI-driven approach marks a major advance over traditional methods, which require researchers to experimentally test every pathway in every possible cell type, and opens up the possibility to comprehensively map the signaling histories of every cell inside a mouse or human embryo at an unprecedented scale.

“Think of voice recognition systems like Siri, which are trained mainly in English, but then use that training to help them recognize other languages,” says Li, who is also an assistant professor of biology at the Massachusetts Institute of Technology (MIT). “This is called transfer learning, and this is why IRIS can work across many different cell types.”

The researchers’ detailed findings, published in the journal Nature Methods on Sept. 8, could accelerate stem cell engineering for regenerative medicine and improve the creation of organoids — miniature, 3-D models that mimic real organs — for studying disease mechanisms and testing new drugs. This is because once researchers learn the pattern of signals that drives a stem cell to become a specific cell type, they can recreate those signals to control the fate of stem cells in a lab or medical setting.

IRIS is a neural network-based model, which, in essence, is an AI-driven system designed to recognize patterns in complex data, similar to how our brains spot patterns. It examines a cell’s overall gene activity and estimates which signaling pathways were likely “on” at specific times during development.

Li and Hutchins trained IRIS on a large experimental dataset that measured how thousands of human embryonic stem cells responded to dozens of combinations of six major signaling pathways at multiple stages of development. This created a comprehensive map, or atlas, of how signaling combinations influence cell behavior.

The team then tested IRIS using single cells from mouse embryos during gastrulation, a stage when cells are rapidly branching into different fates. IRIS could accurately predict when and where specific signaling pathways would activate in cells destined to become part of heart, gut, muscle, and spinal cord tissue. This variation in signaling molecules is what guides cells to form the right structures in the right places.

With this approach, scientists can not only begin to understand the fundamentals of cell-to-cell communication, but also gain a practical roadmap for guiding stem cells into specific, functional cell types in the lab.

When the researchers employed IRIS to identify signals needed to create a cell type critical for lung development, the model predicted that activating a specific signaling pathway would encourage lung-specific development. Experiments in mouse embryos confirmed the model’s prediction. By identifying the precise combinations of signals that drive lung cell development, they can more reliably generate accurate, lab-grown models of lung tissue.

“In these ways, IRIS is helping us decode the language cells use to talk to each other at a much faster rate than we could realistically achieve through experiments,” Hutchins says.

These improved models would allow researchers to study diseases like asthma, lung cancer, and pulmonary fibrosis, in which lung tissue becomes scarred, often without a known cause. They can then use these models to test potential therapies, and ultimately design regenerative treatments that can repair the damaged tissue.

Notes:

Hutchins, N. T., Meziane, M., Lu, C., Mitalipova, M., Fischer, D. S., & Li, P. (2026). Reconstructing signaling histories of single cells via perturbation screens and transfer learning. Nature Methods. https://doi.org/10.1038/s41592-026-03213-8

Research reported in this press release was supported by the National Institutes of Health grant number DP2HD108777 awarded to P.L., which funded 30% of the project’s costs. Additional support was provided by the National Science Foundation Graduate Research Fellowship, MathWorks Graduate Fellowship, Allen Family Philanthropies, and Centurion Foundation. This work was made possible by the Whitehead Institute’s Human Stem Cell Core, in collaboration with Maya Mitalipova.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

DNA shaper steers nervous system development

A team in the Horvitz Lab have discovered that cohesin, a protein complex that helps shape the structure of the genome, is also critical for establishing the identity of some neurons. This could help scientists find a way to treat rare developmental disorders caused by mutations to the cohesin complex.

Jennifer Michalowski | McGovern Institute
August 3, 2026

A functional nervous system depends on the cooperation of many kinds of cells. So as developing organisms build their nervous systems, their neurons must take on different forms and functions to fulfill their designated roles. That carefully orchestrated process gives rise to thousands of different cell types in the human brain.

In the tiny worm known as C. elegans, the nervous system is far simpler, comprising a mere 118 classes of neurons.

At MIT, scientists in H. Robert Horvitz’s lab are studying the worms to learn about how nervous systems develop. Horvitz is the David H. Koch Professor of Biology at MIT, an Investigator at the McGovern Institute for Brain Research at MIT, and an Investigator at the Howard Hughes Medical Institute. His team has just discovered that a protein complex called cohesin, which helps shape the three-dimensional structure of the genome in both worms and humans, is critical for establishing some neurons’ identities as development unfolds.

The findings, reported July 31, 2026, in the journal Science Advances, could help scientists find a way to treat a rare developmental disorder called Cornelia de Lange syndrome, which is caused by mutations that interrupt the cohesin complex.

Model organism

Postdoctoral researcher Dongyeop Lee explains that C. elegans is a powerful model for studying neurodevelopment not just because its nervous system has been comprehensively mapped, but also because of the ease and speed with which scientists can study the function of its genes.

Because many of the worm’s genes have been retained through evolution, findings from studies of C. elegans often reveal important aspects of human biology. The current study began with worms that, because of a genetic mutation, make too many neurons of a certain type.

Adrenergic neurons, named for the kind of neurotransmitter they use to communicate with other neurons, are vital for enabling worms to respond to both their environment and their own internal state. Normally, C. elegans has just two pairs of adrenergic neurons: two RIM neurons and two RIC neurons. But the worms Lee studied had extras of both.

Takashi Hirose, a former member of the Horvitz lab, first observed this change in 2007.

Lee later continued the study and discovered that worms carrying a mutation in a gene called coh-1 have extra adrenergic neurons. The coh-1 gene encodes one part of the cohesin complex.

When Lee tested other mutations that disrupt cohesin, he found the same effect: Worms without fully functional cohesin had too many RIM neurons and too many RIC neurons.

Molecular switch

With a series of experiments designed to tease apart how cohesin impacts neurons’ identities, Lee discovered that cohesin cooperates with a gene-regulating protein called EOR-1 (known in humans as PLZF) to direct some neurons to develop into neurons that communicate with the inhibitory neurotransmitter GABA.

By reorganizing the structure of the genome, cohesin can change the way gene regulators like EOR-1 interact with DNA. Lee’s experiments showed that when either cohesin or EOR-1 couldn’t do its job, cells that should have become GABA-producing neurons become adrenergic neurons instead.

“What we found is that there are two alternative possible fates of certain neurons, and cohesin acts as a molecular switch that decides one of the possible neuronal fates,” Lee explains. “This means the structure of genomic DNA in the nucleus is important for neuronal fate determination.”

Disease connection

Lee adds that extra adrenergic neurons were not the only abnormality he observed in worms with cohesin mutations. Cohesin is important for shaping cells and tissues throughout the body. “The mutants have severe developmental defects,” Lee says. “They grow slowly. They don’t move well, and they also have defects in reproduction.”

Notably, the problems Lee saw in the worms echo aspects of Cornelia de Lange syndrome, a rare genetic disorder that impacts physical, cognitive, and behavioral development. Cornelia de Lange syndrome can be caused by mutations in cohesin genes, and Lee says that the discovery of how cohesin mutations affect worm development and behavior opens new opportunities to study the disease and search for potential therapeutic targets in C. elegans.

The Horvitz lab already has some promising leads. Taking advantage of the quick genetic screens that are possible in worms, Lee has found additional mutations that can counteract impaired cohesin, improving the health of worms with cohesin mutations. The team is now working to identify the genes where these suppressor mutations occur, so they can investigate whether they might make good therapeutic targets in humans.

Meanwhile, the team is also exploring a potential role for cohesin in shaping the fates of other neuron types, as well as searching broadly for additional molecules that work with cohesin to guide development. “We expect we have opened up a new biology,” Lee says. “This paper is just the beginning.”

Paper.

Advancing stem cell research and building the next generation of biologists

Biology PhD student Giselle Valdes (Reddien Lab) studies stem cell regeneration while encouraging aspiring students and researchers.

Stefanie Koperniak | Division of Graduate and Undergraduate Education
June 11, 2026

As an undergraduate at Florida International University, Giselle Valdes tackled rigorous studies in the school’s Honors College while simultaneously caring for family members with medical needs.

“I think that the choice to pursue any field in the space of biology and medical research was entirely shaped by having to be there for my family,” says Valdes.

As a McNair Scholar and biomedical engineering major who also did extensive research in biochemistry, she leaned more toward undergraduate courses in mechanical and electrical engineering that were geared primarily toward equipping students to build medical devices. She began to shift her research interests more firmly into biology, however, the summer before her senior year in 2018. She spent 10 weeks on the MIT campus as a participant in the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio), working in the lab of Associate Professor Eliezer Calo PhD ’11, also a former BSG-MSRP-Bio participant. The Calo Lab focuses on ribosomes, small cellular particles that translate RNA into proteins, and looks at how mutations in ribosome development can lead to disorders.

After working in Calo’s lab, she could see herself as a biology graduate student at MIT. In January 2019, she attended the MIT biology department’s Quantitative Methods Workshop, a weeklong, intensive workshop designed to introduce non-MIT undergraduates to tools and programming languages used to analyze experimental data in biology and neuroscience. While there, she was elated to receive an email from the department inviting her to interview for the PhD program. She was accepted and began her doctoral studies in the fall of that year.

“When I think about my experiences at MIT, both as an undergraduate in MIT programs and as a PhD candidate in biology, I think about all the great mentors who have helped me along the way,” says Valdes. “I’ve also really valued the richly collaborative community, and being able to take a lot of risks in how I address the questions I have the opportunity to pursue.”

Researching stem cell regeneration

Since she came from a biomedical engineering background, Valdes spent the first year of the biology doctoral program taking foundational biology courses and working in different labs to decide which type of research she wanted to do. She gravitated toward cell and developmental biology and joined the lab of Professor Peter Reddien, associate director of the Whitehead Institute for Biomedical Research. Valdes was awarded an MIT Fund for the Future of Science Fellowship to support her research.

“Giselle is doing terrific work on a fundamental problem related to adult stem cells and regeneration — how do progenitor cells choose what cell types to make? Fate choice in progenitors is typically studied in embryogenesis, and how it occurs in the context of adult regeneration is poorly understood and very important to address,” says Reddien.

Valdes has worked extensively with stem cells in highly regenerative flatworms, called planaria. analyzing the process of “cell fate choice,” or how cells determine which specific cell types and functions to develop. To date, Valdes, Reddien, and other researchers have studied “neighborhoods” of neoblasts (adult stem cells) and their fate choices, finding that different neighboring stem cells often chose different fate options — suggesting that cell fate choices are largely made by processes autonomous to individual cells.

Her current research aims to better understand the driving mechanism for cell fate choice, both within planaria and an additional model system: the evolutionarily distant acoel Hofstenia miamia.

“A lot of the things I’m doing in my current project have involved developing techniques that didn’t previously exist in our model organism,” says Valdes.

Working on model systems with limitations in the toolkit traditionally available to more well-established systems, such as transgenics, has allowed her to be creative in the techniques she applies to determine how stem cells choose what to become. It has also opened doors to collaborations, such as one with Ye Zhang of the Manalis Lab in the biological engineering department (now an assistant professor of biomedical engineering at Virginia Tech), that have allowed Valdes and team to sort neoblasts in novel ways based on their morphology, and better relate that to their dynamic state.

In summer 2024, Valdes mentored a BSG-MSRP-Bio student who now works with her on a current research project.

“She’s been with me as a technical assistant in the lab now for over a year, and we’ve been able to work on one of my projects together,” says Valdes. “It’s been exciting to come full circle in this way.”

Teaching and mentoring, near and far

In addition to her research, Valdes devotes a lot of her time to teaching and mentoring, both for MIT biology students and younger students discovering an interest in STEM.

“It’s been so rewarding to have a lot of opportunities to do for others what has been done for me,” she says.

Valdes has worked with secondary students both locally and abroad. She participates in the biology department’s developmental biology lab for high-school students and teaches in an annual biology lecture series for high schoolers. She has worked with the Enroot program from Cambridge Community Services, acting as a direct mentor to local high-school and community college students. At the Whitehead Institute’s Expedition: Bio program, for middle- and high-school students, she runs a planarian workshop. And she gives lab tours through the Whitehead Discovery Lab initiative, engaging in discussion with local high-school students.

Valdes has also assisted with a hackathon for Sprouting, a social impact venture providing STEM education opportunities to under-resourced communities in Puerto Rico. Sprouting was launched by Taylor Baum, a doctoral student in MIT’s Department of Electrical Engineering and Computer Science. Valdes taught coding essentials to Spanish-speaking middle- and high-school students in Puerto Rico.

“That was really emotional,” says Valdes. “The parents were so grateful, and there were kids who were clearly brilliant and gifted. They were able to really take off with the tools that we gave them.”

In her department, Valdes has been a teaching assistant for classes 7.003 (Applied Molecular Biology Laboratory) and 7.03 (Genetics). She is also a teaching assistant for the Quantitative Methods Workshop and teaches a Python module to students in the program.

“Giselle may be quite small in physical stature, yet she dominates the room when she speaks, and commands the full attention of an audience of 80 students when giving a lecture,” says Mandana Sassanfar, a biology senior lecturer and director of outreach who runs the Quantitative Methods Workshop. “She is highly respected both for her knowledge and the way she interacts with people. She is extremely approachable, very generous with her time, and always very supportive and encouraging. She is a wonderful mentor, teacher, and scientist.”

Valdes says she is always happy to help mentor undergrads and graduate students. She is co-founder and coordinator of the MIT Biology Application Assistance Program (BAAP), which aims to demystify the graduate school application process and offer interested applicants the tools and direct mentorship necessary for putting together a successful application. She also helped to coordinate, and has been an active participant in, the MIT BioPals Program, a student-organized peer mentorship initiative within the department that connects incoming first-year graduate students with senior graduate students. During the Covid-19 pandemic, this program provided critical support and social connection for new students navigating remote learning and social distancing.

After she completes her doctoral program, she envisions pursuing a postdoc and, ultimately, a faculty role, citing her passion for both academic research and teaching.

“My goal is to stay in academia in some way,” says Valdes. “I love mentorship and curiosity-driven science.”

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

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).

Slice and dice

SNIPE, a newly characterized defense system, directly protects bacteria by chopping up invading viral DNA.

Lillian Eden | Department of Biology
April 9, 2026

What if the Trojan horse had been pulled to pieces, revealing the ruse and fending off the invasion, just as it entered the gates of Troy?

That’s an apt description of a newly characterized bacterial defense system that chops up foreign DNA.

Bacteria and the viruses that infect them, bacteriophages — phages for short — are ceaselessly at odds, with bacteria developing methods to protect themselves against phages that are constantly striving to overcome those safeguards.

New research from the Department of Biology at MIT, recently published in Nature, describes a defense system that is integrated into the protective membrane that encapsulates bacteria. SNIPE, which stands for surface-associated nuclease inhibiting phage entry, contains a nuclease domain that cleaves genetic material, chopping the invading phage genome into harmless fragments before it can appropriate the host’s molecular machinery to make more phages.

Daniel Saxton, a postdoc in the Laub Lab and the paper’s first author, was initially drawn to studying this bacterial defense system in E. coli, in part because it is highly unusual to have a nuclease that localizes to the membrane, as most nucleases are free-floating in the cytoplasm, the gelatinous fluid that fills the space inside cells.

“The other thing that caught my attention is that this is something we call a direct defense system, meaning that when a phage infects a cell, that cell will actually survive the attack,” Saxton says. “It’s hard to fend off a phage directly in a cell and survive — but this defense system can do it.”

Light it up

For Saxton, the project came into focus during a fluorescence-based experiment in which viral genetic material would light up if it successfully penetrated the bacteria.

“SNIPE was obliterating the phage DNA so fast that we couldn’t even see a fluorescent spot,” Saxton recalls. “I don’t think I’ve ever seen such an effective defense system before — you can barrage the bacteria with hundreds of phage per cell, but SNIPE is like god-tier protection.”

When the nuclease domain of SNIPE was mutated so it couldn’t chop up DNA, fluorescent spots appeared as usual, and the bacteria succumbed to the phage infection.

Bacteria maintain tight control over all their defense systems, lest they be turned against their host. Some systems remain dormant until they flare up, for example, to halt all translation of all proteins in the cell, while others can distinguish between bacterial DNA and foreign, invading phage DNA. There were only two previously characterized mechanisms in the latter category before researchers uncovered SNIPE.

“Right now, the phage field is at a really interesting spot where people are discovering phage defense systems at a breakneck pace,” Saxton says.

Problems at the periphery

Saxton says they had to approach the work in a somewhat roundabout way because there are currently no published structures depicting all the steps of phage genome injection. Studying processes at the membrane is challenging: Membranes are dense and chaotic, and phage genome injection is a highly transient process, lasting only a few minutes.

SNIPE seems to discern viral DNA by interacting with proteins the phage uses to tunnel through the bacteria’s protective membrane. This “subcellular localization,” according to Saxton, may also prevent SNIPE from inadvertently chopping up the bacteria’s own genetic material.

The model outlined in the paper is that one region of SNIPE binds to a bacterial membrane protein called ManYZ, while another region likely binds to the tape measure protein from the phage.

The tape measure protein got its name because it determines the length of the phage tail — the part of the phage between the small, leglike protrusions and the bulbous head, which contains the phage’s genetic material. The researchers revealed that the phage’s tape measure protein enters the cytoplasm during injection, a phenomenon that had not been physically demonstrated before.

There may also be other proteins or interactions involved.

“If you shunt the phage genome injection through an alternate pathway that isn’t ManYZ, suddenly SNIPE doesn’t defend against the phage nearly as well,” Saxton says. “It’s unclear exactly how these proteins interact, but we do know that these two proteins are involved in this genome injection process.”

Future directions

Saxton hopes that future work will expand our understanding of what occurs during phage genome injection and uncover the structures of the proteins involved, especially the tunnel complex in the membrane through which phages insert their genome.

Members of the Laub Lab are already collaborating with another lab to determine the structure of SNIPE. In the meantime, Saxton has been working on a new defense system in which molecular mimicry — bacterial proteins imitating phage proteins — may play a role.

Michael T. Laub, the Salvador E. Luria Professor of Biology and a Howard Hughes Medical Institute investigator, notes that one of the breakthrough experiments for demonstrating how SNIPE works came from a brainstorming session at a lab retreat.

“Daniel and I were kind of stuck with how to directly measure the effect of SNIPE during infection, but another postdoc in the lab, Ian Roney, who is a co-author on the paper, came up with a very clever idea that ultimately worked perfectly,” Laub recalls. “It’s a great example of how powerful internal collaborations can be in pushing our science forward.”

A new lens on autism’s sex bias

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

Shafaq Zia | Whitehead Institute
March 30, 2026

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

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

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

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

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

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

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

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

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

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

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

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

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

The female protective effect beyond autism

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

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

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

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

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

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