Category: Whitehead Institute

From snapshots to movie: capturing the complete process of embryonic development

New research from the Weissman Lab provides a comprehensive view of a process that has long been studied in pieces: how a single fertilized egg gives rise to hundreds of different kinds of cells, arranged in the right places and at the right times to build an animal.

Shafaq Zia | Whitehead Institute
October 9, 2026

For decades, scientists have been able to look at individual moments in the development of an embryo: a snapshot of a developing brain, a picture of how the heart takes shape, or a glimpse of cells beginning to form the nervous system.

But what if instead of taking snapshots, they could watch the entire process unfold?

A new study out of the lab of Whitehead Institute Member Jonathan Weissman, also a professor of biology at the Massachusetts Institute of Technology (MIT) and a Howard Hughes Medical Institute (HHMI) Investigator, offers one of the most detailed views yet of how a mammal is built, cell by cell.

By following the family history of over a million cells as a mouse embryo develops, the researchers have created a kind of developmental blueprint, or movie, showing how cells divide and ultimately become the tissues and organs in the body.

This work, published Oct. 8 in the journal Cell,  in collaboration with Zachary Smith’s group at Yale University and the Max Planck Institute for Molecular Genetics, provides a comprehensive view of a process that has long been studied in pieces: how a single fertilized egg gives rise to hundreds of different kinds of cells, arranged in the right places and at the right times to build an animal.

“This is really a view of how the information in the genome plays out over space and time to go from linear DNA to a three-dimensional animal,” Weissman says.

The map could have broad implications for understanding birth defects and cancer. Many birth defects arise when cells change course as tissues and organs are being assembled. A detailed map of typical development could help researchers pinpoint where and when those processes go awry. In cancer, the same approach could help scientists trace when cells acquire traits such as the ability to spread or resist treatment.

The map could also inform stem cell research by revealing the sequence of cell states that leads to mature, functional cell types.

In the 1980s, scientists ventured into similar territory by painstakingly following the development of Caenorhabditis elegans, a tiny worm whose transparent body contains only about 1,000 cells. Using microscopy, they could trace how individual cells divided and where their descendants ended up.

But achieving something similar in a mammal was a challenge on a vastly different scale. Mammalian embryos contain far more cells, develop inside the uterus — out of sight — and do not follow a completely predetermined script.

The new study tackles this challenge using a technology developed in the Weissman Lab called PEtracer. The system acts somewhat like a flight recorder inside a cell. PEtracer makes small, heritable changes to DNA that are passed down as cells divide. By reading those changes later, scientists can work backward to reconstruct which cells came from which ancestors, essentially building a family tree for the cells in the developing embryo.

In this work, the researchers combined these family trees with information about what genes were turned on in each cell and where these cells were located in the embryo. They analyzed over a million cells from mouse embryos collected at multiple points during development, allowing them to follow not just where cells ended up, but when they began heading toward particular fates.

A new study from Jay Shendure’s group at the University of Washington, published concurrently in the journal Science, uses a related approach called DNA Typewriter to track cell divisions in developing mouse embryos and build a record of their cellular history.

Both studies provide a much more comprehensive look at mammalian development than existed previously. The Weissman team, however, studied embryos at closely spaced stages of development, looking at multiple embryos at each stage. This gave them a more detailed picture of how development unfolds and allowed them to ask how consistently cells follow the same paths from one embryo to another.

With this detailed timeline, the researchers could also determine when cells commit to particular fates, how many early cells go on to form a tissue, and how they ultimately contribute to the developing organ.

While earlier studies might focus on one cell population, this approach puts those individual stories into the context of the entire developing animal — a  perspective that is particularly useful for understanding disease.

Cancer, for example, is not a single event but a process in which cells acquire new characteristics over time, including the ability to spread or resist treatment. A lineage map could allow researchers to trace when those characteristics emerge and how cells change as they acquire them.

“Development and cancer both depend on decisions cells make about what they will  become,” says Luke Koblan, a postdoc in the Weissman Lab and co-first author of the paper. “By tracing how cells develop in mouse embryos, we hope to better understand how cancer cells change in ways that help them spread or resist treatment.”

The work could also provide a new guide for stem cell research. Scientists have spent decades trying to coax stem cells into becoming mature, functional versions of particular cell types for research or potential therapies. But reproducing the precise conditions in an embryo is difficult.

“If we could have a step-by-step recipe for how to create every cell type in the body,” says graduate student and co-first author William Colgan, “that would be incredibly powerful for stem cell biology.”

Weissman compares the work to the Human Genome Project: knowing the sequence of the human genome gave scientists the ingredients — but not the instructions for how those ingredients are used — to build an organism.

“The genome is like the ingredient list for a four-course meal,” he says. “It tells you what the ingredients are, but it doesn’t tell you which ones you use when, how much you use, or where you put them. Without the recipe, it’s impossible to know how those ingredients can become the meal.”

This new map begins to fill in the details of that missing recipe. The result is a resource that researchers can use to explore mammalian development in a fundamentally new way. Rather than studying development as a collection of separate processes, scientists can now begin to see how those processes fit together into one unfolding story.

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

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.

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.

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.

How the Toxoplasma parasite adapts to crowded conditions in host cells

A new study by Whitehead Institute researchers identifies how the widespread parasite Toxoplasma gondii survives in crowded environments in infected cells, which helps it persist in long-lasting brain cysts.

Mackenzie White | Whitehead Institute
August 19, 2026

Toxoplasma gondii, or Toxoplasma, is a parasite that infects hundreds of millions of people around the world. Although cases are often mild, it can cause severe symptoms in in people with weakened immune systems, and in developing fetuses. It can also persist for years by forming long-lived cysts in tissues, allowing infection to become chronic.

During chronic infection, hundreds of Toxoplasma parasites can pack into a tissue cyst inside a brain or muscle cell. That crowded life carries a cost: Nutrients become harder to obtain, waste accumulates, and energy-producing reactions can become damaging.

How Toxoplasma reshapes its metabolism to keep growing under such strained conditions has been unclear. But a new study from the lab of MIT Associate Professor Sebastian Lourido, a member of the Whitehead Institute for Biomedical Research, identifies a parasite-specific protein that helps coordinate this response. The protein, named TgPRO, allows Toxoplasma to manage oxidative stress — the buildup of reactive oxygen molecules that can damage cells — by controlling genes involved in energy production and iron use.

The open-access findings, published on Aug. 11 in the journal Cell, reveal the first dedicated regulator of metabolic gene expression identified in apicomplexans, the group of parasites that includes Toxoplasma and the organisms that cause malaria. The study, led by co-first authors and Lourido lab affiliates Christopher Giuliano PhD ’26, a recent graduate student in biology, and Chinmay Kalluraya, a current graduate student in biology, reveals a previously unknown way that parasites regulate metabolism. The findings also point to a possible therapeutic strategy: Inhibiting pathways controlled by TgPRO could make Toxoplasma more vulnerable to antiparasitic drugs that induce oxidative stress, though this approach remains to be tested.

One gene at a time

To discover the genes that support Toxoplasma’s ability to live in crowded cells, the researchers used a genome-wide CRISPR screen to compare Toxoplasma growing at low and high densities. The screen tests the effects of turning off genes one by one at both population densities in order to determine which genes are essential specifically in crowded conditions. It highlighted pathways that make or recycle NAD and NADP, molecules important for energy production and defending against oxidative damage. It also pointed to TgPRO, a previously unstudied protein that was especially important when parasites became crowded.

“A genome-wide screen was a powerful way to ask how crowding affects parasite fitness,” Kalluraya says. “TgPRO emerged as very important at high density. Because almost nothing was known about it, we wanted to understand what it was doing.”

Parasites lacking functional TgPRO accumulated more reactive oxygen molecules and struggled to compete at high density. Experiments showed that the loss of TgPRO disrupted the mitochondrion — the structure that supplies much of a cell’s energy — and changed how parasites processed glucose and other nutrients. Providing additional iron or restoring an important chemical balance inside the mitochondrion improved parasite growth, connecting TgPRO’s effects to iron-dependent energy metabolism.

The team then traced the response to a molecular mechanism. TgPRO is an RNA-binding protein, meaning it attaches to the molecular messages (RNAs) that cells use to make proteins. The researchers found that it binds and stabilizes a select set of messages involved in nutrient use, mitochondrial activity, and the assembly of iron-sulfur clusters, small structures that many enzymes need to function. The experiments connected the original observation — that some parasites faltered only when crowded — to a precise interaction between a regulatory protein and its RNA targets.

“One of the really nice elements of the story is our ability to connect it all the way through — from the original observation and genome-wide screen to the metabolic consequences and the direct interaction between TgPRO and its target RNAs,” Lourido says.

The researchers found that lowering oxygen levels also reduced oxidative stress and partially restored the growth of parasites without TgPRO. Toxoplasma is commonly grown in laboratories at atmospheric oxygen levels, which are considerably higher than those found in most animal tissues. The result suggests that oxygen conditions can strongly shape parasite metabolism, and the researchers caution others studying Toxoplasma to take this into consideration.

Connecting TgPRO to chronic infection

After testing the role of TgPRO in artificially crowded settings, the team also tested whether TgPRO matters during chronic infection, when Toxoplasma forms cysts in the brain. Mice infected with parasites lacking functional TgPRO developed smaller brain cysts, suggesting TgPRO supports parasite growth in the naturally dense environment of a chronic-stage cyst.

“The chronic stage is still somewhat elusive,” Giuliano says. “Showing that TgPRO affects cyst growth suggests that these same metabolic changes are needed in the brain and gives us clues about how the parasites persist there for months or years.”

TgPRO bears little resemblance to the proteins that regulate similar metabolic programs in mammals, yeast, and bacteria, yet it controls many of the same kinds of genes that these organisms adjust when cells face oxidative stress or changing nutrient conditions. This is an example of convergent evolution: Distantly related organisms evolved different molecular machinery to solve a similar biological problem.

That convergence suggests that coordinating these metabolic pathways may be a fundamental requirement for cells adapting to stress.

Altogether, the study establishes a new paradigm for how apicomplexan parasites regulate their metabolism, and advances the foundation for investigating how Toxoplasma persists inside its hosts.

This work was supported by National Institutes of Health grants and by a Burroughs Wellcome Fund grant awarded to S.L. M.A.S is funded by an Early Career Award from the Wellcome Trust. C.R.H. is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society. J.K. is supported through funding by a generous donor advised by CARIGEST SA and acquired by D.S.-F.

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

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

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

Shafaq Zia | Whitehead Institute
April 30, 2026

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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