Research Area: Genetics

Neural activity helps circuit connections mature into optimal signal transmitters

By carefully tracking the formation and maturation of synaptic active zones in fruit flies, MIT scientists have discovered how neural activity helps circuit connections become tuned to the right size and degree of signal transmission capability over a period of days.

David Orenstein | The Picower Institute for Learning and Memory
October 14, 2025

Nervous system functions, from motion to perception to cognition, depend on the active zones of neural circuit connections, or “synapses,” sending out the right amount of their chemical signals at the right times. By tracking how synaptic active zones form and mature in fruit flies, researchers at The Picower Institute for Learning and Memory at MIT have revealed a fundamental model for how neural activity during development builds properly working connections.

Understanding how that happens is important, not only for advancing fundamental knowledge about how nervous systems develop, but also because many disorders such as epilepsy, autism, or intellectual disability can arise from aberrations of synaptic transmission, said senior author Troy Littleton, Menicon Professor in The Picower Institute and MIT’s Department of Biology. The new findings, funded in part by a 2021 grant from the National Institutes of Health, provide insights into how active zones develop the ability to send neurotransmitters across synapses to their circuit targets. It’s not instant or predestined, the study shows. It can take days to fully mature and that is regulated by neural activity.

If scientists can fully understand the process, Littleton said, then they can develop molecular strategies to intervene to tweak synaptic transmission when it’s happening too much or too little in disease.

“We’d like to have the levers to push to make synapses stronger or weaker, that’s for sure,” Littleton said. “And so knowing the full range of levers we can tug on to potentially change output would be exciting.”

Littleton Lab research scientist Yuliya Akbergenova led the study published Oct. 14 in the Journal of Neuroscience.

How newborn synapses grow up 

In the study, the researchers examined neurons that send the neurotransmitter glutamate across synapses to control muscles in the fly larvae. To study how the active zones in the animals matured, the scientists needed to keep track of their age. That hasn’t been possible before, but Akbergenova overcame the barrier by cleverly engineering the fluorescent protein mMaple, which changes its glow from green to red when zapped with 15 seconds of ultraviolet light, into a component of the glutamate receptors on the receiving side of the synapse. Then, whenever she wanted, she could shine light and all the synapses already formed before that time would glow red and any new once that formed subsequently would glow green.

With the ability to track each active zone’s birthday, the authors could then document how active zones developed their ability to increase output over the course of days after birth. The researchers actually watched as synapses were built over many hours by tagging each of eight kinds of proteins that make up an active zone. At first, the active zones couldn’t transmit anything. Then, as some essential early proteins accumulated, they could send out glutamate spontaneously, but not if evoked by electrical stimulation of their host neuron (simulating how that neuron might be signaled naturally in a circuit). Only after several more proteins arrived did active zones possess the mature structure for calcium ions to trigger the fusion of glutamate vesicles to the cell membrane for evoked release across the synapse.

Activity matters

Of course, construction does not go on forever. At some point, the fly larva stops building one synapse and then builds new ones further down the line as the neuronal axon expands to keep up with growing muscles. The researchers wondered whether neural activity had a role in driving that process of finishing up one active zone and moving on to build the next.

To find out, they employed two different interventions to block active zones from being able to release glutamate, thereby preventing synaptic activity. Notably, one of the methods they chose was blocking the action of a protein called Synaptotagmin 1. That’s important because mutations that disrupt the protein in humans are associated with severe intellectual disability and autism. Moreover, the researchers tailored the activity-blocking interventions to just one neuron in each larva because blocking activity in all their neurons would have proved lethal.

In neurons where the researchers blocked activity, they observed two consequences: the neurons stopped building new active zones and instead kept making existing active zones larger and larger. It was as if the neuron could tell the active zone wasn’t releasing glutamate and tried to make it work by giving it more protein material to work with. That effort came at the expense of starting construction on new active zones.

“I think that what it’s trying to do is compensate for the loss of activity,” Littleton said.

Testing indicated that the enlarged active zones the neurons built in hopes of restarting activity were functional (or would have been if the researchers weren’t artificially blocking them). This suggested that the way the neuron sensed that glutamate wasn’t being released was therefore likely to be a feedback signal from the muscle side of the synapse. To test that, the scientists knocked out a glutamate receptor component in the muscle and when they did, they found that the neurons no longer made their active zones larger.

Littleton said the lab is already looking into the new questions the discoveries raise. In particular, what are the molecular pathways that initiate synapse formation in the first place, and what are the signals that tell an active zone it has finished growing? Finding those answers will bring researchers closer to understanding how to intervene when synaptic active zones aren’t developing properly.

In addition to Littleton and Akbergenova, the paper’s other authors are Jessica Matthias and Sofya Makeyeva.

In addition to the National Institutes of Health, The Freedom Together Foundation provided funding for the study.

Little picture, large revelations

A summer intensive using microscopy to study a unique type of yeast was a dream come true for BSG-MSRP-Bio student Adryanne Gonzalez.

Lillian Eden | Department of Biology
September 11, 2025

For Adryanne Gonzalez, studying yeast using microscopy at MIT this summer has been a dream come true. 

“Whatever world we’re living in, there’s an even smaller one,” Gonzalez says. “Knowing and understanding the smaller one can help us learn about the bigger stuff, and I think that’s so fascinating.” 

Gonzalez was part of the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology, working in the Lew Lab this summer. The program offers talented undergraduates from institutions with limited research opportunities at their home institutions the chance to spend 10 weeks at MIT, where they gain experience, hone skills, and create the types of connections with potential collaborators and future colleagues that are critical for success in academia. 

Gonzalez was so excited about the opportunity that she didn’t apply for any other summer programs.  

“I really wanted to work on becoming more independent in the lab, and this program was research-intensive, and you get to lead your own project,” she says. “It was this or nothing.”

two people standing at a bench in front of a computer
Adryanne Gonzalez, right, with her mentor, Lew Lab graduate student Clara Fikry, left. Gonzalez spent the summer studying Aureobasidium pullulans, a type of yeast that produces large, root-like networks. Photo credit: Mandana Sassanfar/MIT Department of Biology

The fun of science & the rigors of mentoring

The Lew Lab works with two different specimens: a model baker’s yeast that multiplies by producing a round growth called a bud that eventually separates into a separate, daughter cell; and Aureobasidium pullulans, which is unusual because it can create multiple buds at the same time, and can also spread in large networks of branching, rootlike growths called hyphae. A. pullulans is an emerging model system, meaning that researchers are still defining what normal growth and behavior is for the fungus, like how it senses and responds to obstacles, and how resources and molecular machinery are allocated to its branching structures.  

“I’m really interested in all the diversity of biology that we don’t get to study if we’re only focused on the model species,” says Clara Fikry, a graduate student in the Lew Lab and Gonzalez’s mentor for the summer. 

On the mentoring side, Fikry learned how to balance providing a rigorous workload while not overwhelming her mentee with information. 

“Science should be fun,” Fikry says. “The goal of this isn’t to produce as much data as possible; it’s to learn what the process of science is like.”

Although her day-to-day work was with Fikry, Gonzalez also received guidance from Daniel Lew himself. For example, his advice was invaluable for honing a draft of her research statement for potential graduate school applications, which she’d previously written as part of a class assignment.

“It was an assignment where I needed to hit a page count, and he pointed out that I kind of wrote the same thing three times in the first paragraph,” she shares with a laugh. He helped her understand that “when you’re writing something professionally, you want your writing to be concise and understandable to a broad spectrum of readers.” 

Life in the cohort

The BSG-MSRP-Bio program gives undergraduate students a taste of what the day-to-day life of graduate school might feel like, from balancing one’s workload and reading research papers to learning new techniques and troubleshooting when experiments don’t go as planned. Gonzalez recalls that the application process felt very “adult” and “professional” because she was responsible for reaching out to the faculty member of the lab she was interested in on her own behalf, rather than going through a program intermediary. 

Gonzalez is one of just three students from Massachusetts participating in the program this year—the program draws students from across the globe to study at MIT. 

Every student also arrives with different levels of experience, from Gonzalez, who can only work in a lab during the school year about once a week, to Calo Lab student Adriana Camacho-Badillo, who is in her third consecutive summer in the program, and continuing work on a project she began last year.

“We’re all different levels of novice, and we’re coming together, and we’re all really excited about research,” Gonzalez says.

Gonzalez is a Gould Fellow, supported at MIT through the generous donations of Mike Gould and Sara Moss. The program funding was initiated in 2015 to honor the memory of Gould’s parents, Bernard S. and Sophie G. Gould. Gould and Moss take the time to come to campus and meet the students they’re supporting every year. 

“You don’t often get to meet the person that’s helping you,” Gonzalez said. “They were so warm and welcoming, and at the end, when they were giving everyone a nice, firm handshake, Mike Gould said, ‘Make sure you keep going. Don’t give up,’ which was so sweet.” 

Gonzalez is also supported by Cedar Tree, a Boston-based family foundation that primarily funds local environmental initiatives. In the interest of building a pipeline for future scientists with potential interest in the environmental sciences and beyond, Cedar Tree recently established a grant program for local high school and undergraduate students pursuing STEM research and training opportunities. 

Gonzalez discusses her summer research with attendees of the poster session that serves as the culmination of the 10-week summer research intensive for talented non-MIT undergraduate students from around the world. Photo credit: Lillian Eden/MIT Department of Biology.

Preparing for the future

The BSG-MSRP-Bio program culminates with a lively poster session where students present their summer projects to the MIT community—the first time some students are presenting their data to the public in that format.

Although the program is aimed at students who foresee a career in academia, the majority of students who participate are uncertain about the specific field, organism, or process they’ll eventually want to study during a PhD program. For Gonzalez, the program has helped her feel more prepared for the potential rigors of academic research.

“I think the hardest thing about this program is convincing yourself to apply,” she says. “Don’t let that hinder you from exploring opportunities that may seem out of reach.” 

Can a pill help you live longer? The science behind NAD and longevity

MIT professor, Dr. Leonard Guarente, conducts research into sirtuin genes and the power of a molecule called NAD.

WCVB
July 22, 2025

It might sound too good to be true: a pill that could help you live a longer, healthier life. But Leonard Guarente, a longtime MIT biologist, believes the idea holds promise.

Guarente, the Novartis Professor of Biology at MIT, has spent more than 40 years studying the science of aging. He started small, working with yeast cells.

“We decided to look for genes that could make yeast live longer,” he said. That’s when a gene called SIR2 caught his attention. Boosting SIR2 activity helped yeast cells live longer—and when the same effect was observed in roundworms, Guarente turned his attention to humans.

Humans, it turns out, have seven genes similar to SIR2. Collectively, these are called sirtuins, a group of proteins essential to cell health. According to Guarente, sirtuins help power cells, repair damage, and regulate which genes are turned on or off.

Guarente says sirtuins need NAD (nicotinamide adenine dinucleotide) to stay active, but NAD levels naturally decline as we get older.

“If we could restore NAD levels in an older person back to youthful levels, we thought that would do a lot of good,” he explained.

That idea became the foundation for Elysium Health, a company Guarente co-founded. Some critics question the ethics of a scientist selling supplements based on his own research, but Guarente stands by the rigor of his approach. “We ended up with eight Nobel Prize winners on the board,” he noted.

Of course, whether restoring NAD levels leads to longer life is still uncertain. “A person who is very healthy might not notice much initially because where is there to go?” Guarente explained. “But what about in 30 years? There’s no way to answer that question right now.”

A selfish gene unlike any other

Certain genes are “selfish," cheating the rules of inheritance to increase their chances of being transmitted. Researchers in the Yamashita Lab have uncovered a unique "self-limiting" mechanism keeping the selfish gene Stellate in check

Shafaq Zia | Whitehead Institute
May 7, 2025

When a species reproduces, typically, each parent passes on one of their two versions, or alleles, of a given gene to their offspring. But not all alleles play fair in their quest to be passed onto future generations.

Certain alleles, called meiotic drivers, are “selfish”—they cheat the rules of inheritance to increase their chances of being transmitted, often at the expense of the organism’s fitness.

The lab of Whitehead Institute Member Yukiko Yamashita investigates how genetic information is transmitted across generations through the germline—cells that give rise to egg and sperm. Now, Yamashita and first author Xuefeng Meng, a graduate student in the Yamashita Lab, have discovered a meiotic driver that operates differently from previously known drivers.

The researchers’ findings, published online in Science Advances on May 7, reveal that the Stellate (Ste) gene—which has multiple copies located close to one another—on the X chromosome in Drosophila melanogaster, a fruit fly species, is a meiotic driver that biases the transmission of the X chromosome. However, it also has a unique “self-limiting” mechanism that helps preserve the organism’s ability to have male offspring.

“This mechanism is an inherent remedy to the gene’s selfish drive,” says Yamashita, who is also a professor of biology at Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute. “Without it, the gene could severely skew the sex ratio in a population and drive the species to extinction—a paradox that has been recognized for a long time.”

Fatal success

Meiosis is a key process underlying sexual reproduction. This is when cells from the germline undergo two rounds of specialized cell division—meiosis I and meiosis II—to form gametes (egg and sperm cells). In males, this typically results in an equal number of X-bearing and Y-bearing sperm, which ensures an equal chance of having a male or female offspring.

Meiotic drivers located on sex chromosomes can skew this sex ratio by selectively destroying gametes that do not carry the driver allele. Among them is the meiotic driver Ste.

In male germline cells of fruit flies, Ste is kept in check by small RNA molecules, called piRNAs, produced by Suppressor of Stellate (Su(Ste)) located on the Y chromosome. These RNA molecules recruit special proteins to silence Ste RNA. This prevents the production of Ste protein that would otherwise disrupt the development of Y-bearing sperm, which helps maintain the organism’s ability to have male offspring.

“But the suppressing mechanism isn’t foolproof,” Meng explains. “When the meiotic driver and its suppressor are located on different chromosomes, they can get separated during reproduction, leaving the driver unchecked in the next generation.”

A skewed sex ratio toward females offers a short-term advantage: having more females than males could increase a population’s reproductive potential. But in the long run, the meiotic driver risks fatal success—driving the species toward extinction through depletion of males.

Interestingly, prior research suggests that un-silencing Ste only modestly skews a population’s sex ratio, even in the absence of the suppressor, unlike other meiotic drivers that almost exclusively produce females in the progeny. Could another mechanism be at play, keeping Ste’s selfish drive in check?

Practicing self-restraint

To explore this intriguing possibility, researchers in the Yamashita Lab began by examining the process of sperm development. Under moderate Ste expression, pre-meiotic germ cell development and meiosis proceeded normally but defects in sperm development began to emerge soon after. Specifically, a subset of spermatids—immature sperm cells produced after meiosis—failed to incorporate essential DNA-packaging proteins called protamines, which are required to preserve the integrity of genetic information in sperm.

To confirm if the spermatids impacted were predominantly those that carried the Y chromosome, the researchers used an imaging technique called immunofluorescence staining, which uses antibodies to attach fluorescent molecules to a protein of interest, making it glow. They combined this with a technique called FISH (fluorescence in-situ hybridization), which tags the X and Y chromosomes with fluorescent markers, allowing researchers to distinguish between cells that will become X-bearing or Y-bearing following meiosis.

Indeed, the team found that while Ste protein is present in all spermatocytes before meiosis I, it unevenly divides between the two daughter cells—a phenomenon called asymmetric segregation—during meiosis I and gets concentrated in Y-bearing spermatids, eventually inducing DNA-packaging defects in these spermatids.

These findings clarified Ste’s role as a meiotic driver but the researchers still wondered why expression of Ste only led to a moderate sex ratio distortion. The answer soon became clear when they observed Ste undergo another round of asymmetric segregation during meiosis II. This meant that even if a secondary spermatocyte inherited Ste protein after meiosis I, only half of the spermatids produced in this round of cell division ended up retaining the protein. Hence, only half of the Y-bearing spermatids were going to be killed off.

“This self-limiting mechanism is the ultimate solution to the driver-suppressor separation problem,” says Yamashita. “But the idea is so unconventional that had it been proposed as just a theory, without the evidence we have now, it would’ve been completely dismissed.”

These findings have solved some questions and raised others: Unlike female meiosis, which is known to be asymmetrical, male meiosis has traditionally been considered symmetrical. Does the unequal segregation of Ste suggest there’s an unknown asymmetry in male meiosis? Do meiotic drivers like Ste trigger this asymmetry, or do they simply exploit it to limit their selfish drive?

Answering them is the next big step for Yamashita and her colleagues. “This could fundamentally change our understanding of male meiosis,” she says. “The best moments in science are when textbook knowledge is challenged and it turns out to have been tunnel vision.”

Biologists identify targets for new pancreatic cancer treatments

Research from MIT and Dana-Farber Cancer Institute yielded hundreds of “cryptic” peptides that are found only on pancreatic tumor cells and could be targeted by vaccines or engineered T cells.

Anne Trafton | MIT News
May 7, 2025

Researchers from MIT and Dana-Farber Cancer Institute have discovered that a class of peptides expressed in pancreatic cancer cells could be a promising target for T-cell therapies and other approaches that attack pancreatic tumors.

Known as cryptic peptides, these molecules are produced from sequences in the genome that were not thought to encode proteins. Such peptides can also be found in some healthy cells, but in this study, the researchers identified about 500 that appear to be found only in pancreatic tumors.

The researchers also showed they could generate T cells targeting those peptides. Those T cells were able to attack pancreatic tumor organoids derived from patient cells, and they significantly slowed down tumor growth in a study of mice.

“Pancreas cancer is one of the most challenging cancers to treat. This study identifies an unexpected vulnerability in pancreas cancer cells that we may be able to exploit therapeutically,” says Tyler Jacks, the David H. Koch Professor of Biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

Jacks and William Freed-Pastor, a physician-scientist in the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School, are the senior authors of the study, which appears today in Science. Zackery Ely PhD ’22 and Zachary Kulstad, a former research technician at Dana-Farber Cancer Institute and the Koch Institute, are the lead authors of the paper.

Cryptic peptides

Pancreatic cancer has one of the lowest survival rates of any cancer — about 10 percent of patients survive for five years after their diagnosis.

Most pancreatic cancer patients receive a combination of surgery, radiation treatment, and chemotherapy. Immunotherapy treatments such as checkpoint blockade inhibitors, which are designed to help stimulate the body’s own T cells to attack tumor cells, are usually not effective against pancreatic tumors. However, therapies that deploy T cells engineered to attack tumors have shown promise in clinical trials.

These therapies involve programming the T-cell receptor (TCR) of T cells to recognize a specific peptide, or antigen, found on tumor cells. There are many efforts underway to identify the most effective targets, and researchers have found some promising antigens that consist of mutated proteins that often show up when pancreatic cancer genomes are sequenced.

In the new study, the MIT and Dana-Farber team wanted to extend that search into tissue samples from patients with pancreatic cancer, using immunopeptidomics — a strategy that involves extracting the peptides presented on a cell surface and then identifying the peptides using mass spectrometry.

Using tumor samples from about a dozen patients, the researchers created organoids — three-dimensional growths that partially replicate the structure of the pancreas. The immunopeptidomics analysis, which was led by Jennifer Abelin and Steven Carr at the Broad Institute, found that the majority of novel antigens found in the tumor organoids were cryptic antigens. Cryptic peptides have been seen in other types of tumors, but this is the first time they have been found in pancreatic tumors.

Each tumor expressed an average of about 250 cryptic peptides, and in total, the researchers identified about 1,700 cryptic peptides.

“Once we started getting the data back, it just became clear that this was by far the most abundant novel class of antigens, and so that’s what we wound up focusing on,” Ely says.

The researchers then performed an analysis of healthy tissues to see if any of these cryptic peptides were found in normal cells. They found that about two-thirds of them were also found in at least one type of healthy tissue, leaving about 500 that appeared to be restricted to pancreatic cancer cells.

“Those are the ones that we think could be very good targets for future immunotherapies,” Freed-Pastor says.

Programmed T cells

To test whether these antigens might hold potential as targets for T-cell-based treatments, the researchers exposed about 30 of the cancer-specific antigens to immature T cells and found that 12 of them could generate large populations of T cells targeting those antigens.

The researchers then engineered a new population of T cells to express those T-cell receptors. These engineered T cells were able to destroy organoids grown from patient-derived pancreatic tumor cells. Additionally, when the researchers implanted the organoids into mice and then treated them with the engineered T cells, tumor growth was significantly slowed.

This is the first time that anyone has demonstrated the use of T cells targeting cryptic peptides to kill pancreatic tumor cells. Even though the tumors were not completely eradicated, the results are promising, and it is possible that the T-cells’ killing power could be strengthened in future work, the researchers say.

Freed-Pastor’s lab is also beginning to work on a vaccine targeting some of the cryptic antigens, which could help stimulate patients’ T cells to attack tumors expressing those antigens. Such a vaccine could include a collection of the antigens identified in this study, including those frequently found in multiple patients.

This study could also help researchers in designing other types of therapy, such as T cell engagers — antibodies that bind an antigen on one side and T cells on the other, which allows them to redirect any T cell to kill tumor cells.

Any potential vaccine or T cell therapy is likely a few years away from being tested in patients, the researchers say.

The research was funded in part by the Hale Family Center for Pancreatic Cancer Research, the Lustgarten Foundation, Stand Up To Cancer, the Pancreatic Cancer Action Network, the Burroughs Wellcome Fund, a Conquer Cancer Young Investigator Award, the National Institutes of Health, and the National Cancer Institute.

Manipulating time with torpor

New research from the Hrvatin Lab recently published in Nature Aging indicates that inducing a hibernation-like state in mice slows down epigenetic changes that accompany aging.

Shafaq Zia | Whitehead Institute
March 7, 2025

Surviving extreme conditions in nature is no easy feat. Many species of mammals rely on special adaptations called daily torpor and hibernation to endure periods of scarcity. These states of dormancy are marked by a significant drop in body temperature, low metabolic activity, and reduced food intake—all of which help the animal conserve energy until conditions become favorable again.

The lab of Whitehead Institute Member Siniša Hrvatin studies daily torpor, which lasts several hours, and its longer counterpart, hibernation, in order to understand their effects on tissue damage, disease progression, and aging. In their latest study, published in Nature Aging on March 7, first author Lorna Jayne, Hrvatin, and colleagues show that inducing a prolonged torpor-like state in mice slows down epigenetic changes that accompany aging.

“Aging is a complex phenomenon that we’re just starting to unravel,” says Hrvatin, who is also an assistant professor of biology at Massachusetts Institute of Technology. “Although the full relationship between torpor and aging remains unclear, our findings point to decreased body temperature as the central driver of this anti-aging effect.”

Tampering with the biological clock

Aging is a universal process, but scientists have long struggled to find a reliable metric for measuring it. Traditional clocks fall short because biological age doesn’t always align with chronology—cells and tissues in different organisms age at varying rates.

To solve this dilemma, scientists have turned to studying molecular processes that are common to aging across many species. This, in the past decade, has led to the development of epigenetic clocks, new computational tools that can estimate an organism’s age by analyzing the accumulation of epigenetic marks in cells over time.

Think of epigenetic marks as tiny chemical tags that cling either to the DNA itself or to the proteins, called histones, around which the DNA is wrapped. Histones act like spools, allowing long strands of DNA to coil around them, much like thread around a bobbin. When epigenetic tags are added to histones, they can compact the DNA, preventing genetic information from being read, or loosen it, making the information more accessible. When epigenetic tags attach directly to DNA, they can alter how the proteins that “read” a gene bind to the DNA.

While it’s unclear if epigenetic marks are a cause or consequence of aging, this much is evident: these marks change over an organism’s lifespan, altering how genes are turned on or off, without modifying the underlying DNA sequence. These changes have enabled researchers to track the biological age of individual cells and tissues using dedicated epigenetic clocks.

In nature, states of stasis like hibernation and daily torpor help animals survive by conserving energy and avoiding predators. But now, emerging research in marmots and bats hints that hibernation may also slow down epigenetic aging, prompting researchers to explore whether there’s a deeper connection between prolonged bouts of torpor and longevity.

However, investigating this link has been challenging, as the mechanisms that trigger, regulate, and sustain torpor remain largely unknown. In 2020, Hrvatin and colleagues made a breakthrough by identifying neurons in a specific region of the mouse hypothalamus, known as the avMLPA, which act as core regulators of torpor.

“This is when we realized that we could leverage this system to induce torpor and explore mechanistically how the state of torpor might have beneficial effects on aging,” says Jayne. “You can imagine how difficult it is to study this in natural hibernators because of accessibility and the lack of tools to manipulate them in sophisticated ways.”

The age-old mystery

The researchers began by injecting adeno-associated virus in mice, a gene delivery vehicle that enables scientists to introduce new genetic material into target cells. They employed this technology to instruct neurons in the mice’s avMLPA region to produce a special receptor called Gq-DREADD, which does not respond to the brain’s natural signals but can be chemically activated by a drug. When the researchers administered this drug to the mice, it bound to the Gq-DREADD receptors, activating the torpor-regulating neurons and triggering a drop in the animals’ body temperature.

However, to investigate the effects of torpor on longevity, the researchers needed to maintain these mice in a torpor-like state for days to weeks. To achieve this, the mice were continuously administered the drug through drinking water.

The mice were kept in a torpor-like state with periodic bouts of arousal for a total of nine months. The researchers measured the blood epigenetic age of these mice at the 3-, 6-, and 9-month marks using the mammalian blood epigenetic clock. By the 9-month mark, the torpor-like state had reduced blood epigenetic aging in these mice by approximately 37%, making them biologically three months younger than their control counterparts.

To further assess the effects of torpor on aging,  the group evaluated these mice using the mouse clinical frailty index, which includes measurements like tail stiffening, gait, and spinal deformity that are commonly associated with aging. As expected, mice in the torpor-like state had a lower frailty index compared to the controls.

With the anti-aging effects of the torpor-like state established, the researchers sought to understand how each of the key factors underlying torpor—decreased body temperature, low metabolic activity, and reduced food intake—contributed to longevity.

To isolate the effects of reduced metabolic rate, the researchers induced a torpor-like state in mice, while maintaining the animal’s normal body temperature. After three months, the blood epigenetic age of these mice was similar to that of the control group, suggesting that low metabolic rate alone does not slow down epigenetic aging.

Next, Hrvatin and colleagues isolated the impact of low caloric intake on blood epigenetic aging by restricting the food intake of mice in the torpor-like state, while maintaining their normal body temperature. After three months, these mice were a similar blood epigenetic age as the control group.

When both low metabolic rate and reduced food intake were combined, the mice still exhibited higher blood epigenetic aging after three months compared to mice in the torpor state with low body temperature. These findings, combined, led the researchers to conclude that neither low metabolic rate nor reduced caloric intake alone are sufficient to slow down blood epigenetic aging. Instead, a drop in body temperature is necessary for the anti-aging effects of torpor.

Although the exact mechanisms linking low body temperature and epigenetic aging are unclear, the team hypothesizes that it may involve the cell cycle, which regulates how cells grow and divide: lower body temperatures can potentially slow down cellular processes, including DNA replication and mitosis. This, over time, may impact cell turnover and aging. With further research, the Hrvatin Lab aims to explore this link in greater depth and shed light on the lingering mystery.

Taking the pulse of sex differences in the heart

Work led by Talukdar and Page Lab postdoc Lukáš Chmátal shows that there are differences in how healthy male and female heart cells—specifically, cardiomyocytes, the muscle cells responsible for making the heart beat—generate energy.

Greta Friar | Whitehead Institute
February 18, 2025

Heart disease is the number one killer of men and women, but it often presents differently depending on sex. There are sex differences in the incidence, outcomes, and age of onset of different types of heart problems. Some of these differences can be explained by social factors—for example, women experience less-well recognized symptoms when having heart attacks, and so may take longer to be diagnosed and treated—but others are likely influenced by underlying differences in biology. Whitehead Institute Member David Page and colleagues have now identified some of these underlying biological differences in healthy male and female hearts, which may contribute to the observed differences in disease.

“My sense is that clinicians tend to think that sex differences in heart disease are due to differences in behavior,” says Harvard-MIT MD-PhD student Maya Talukdar, a graduate student in Page’s lab. “Behavioral factors do contribute, but even when you control for them, you still see sex differences. This implies that there are more basic physiological differences driving them.”

Page, who is also an HHMI Investigator and a professor of biology at the Massachusetts Institute of Technology, and members of his lab study the underlying biology of sex differences in health and disease, and recently they have turned their attention to the heart. In a paper published on February 17 in the women’s health edition of the journal Circulation, work led by Talukdar and Page lab postdoc Lukáš Chmátal shows that there are differences in how healthy male and female heart cells—specifically, cardiomyocytes, the muscle cells responsible for making the heart beat—generate energy.

“The heart is a hard-working pump, and heart failure often involves an energy crisis in which the heart can’t summon enough energy to pump blood fast enough to meet the body’s needs,” says Page. “What is intriguing about our current findings and their relationship to heart disease is that we’ve discovered sex differences in the generation of energy in cardiomyocytes, and this likely sets up males and females differently for an encounter with heart failure.”

Page and colleagues began their work by looking for sex differences in healthy hearts because they hypothesize that these impact sex differences in heart disease. Differences in baseline biology in the healthy state often affect outcomes when challenged by disease; for example, people with one copy of the sickle cell trait are more resistant to malaria, certain versions of the HLA gene are linked to slower progression of HIV, and variants of certain genes may protect against developing dementia.

Identifying baseline traits in the heart and figuring out how they interact with heart disease could not only reveal more about heart disease, but could also lead to new therapeutic strategies. If one group has a trait that naturally protects them against heart disease, then researchers can potentially develop medical therapies that induce or recreate that protective feature in others. In such a manner, Page and colleagues hope that their work to identify baseline sex differences could ultimately contribute to advances in prevention and treatment of heart disease.

The new work takes the first step by identifying relevant baseline sex differences. The researchers combined their expertise in sex differences with heart expertise provided by co-authors Christine Seidman, a Harvard Medical School professor and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital; Harvard Medical School Professor Jonathan Seidman; and Zoltan Arany, a professor and director of the Cardiovascular Metabolism Program at the University of Pennsylvania.

Along with providing heart expertise, the Seidmans and Arany provided data collected from healthy hearts. Gaining access to healthy heart tissue is difficult, and so the researchers felt fortunate to be able to perform new analyses on existing datasets that had not previously been looked at in the context of sex differences. The researchers also used data from the publicly available Genotype-Tissue Expression Project. Collectively, the datasets provided information on bulk and single cell gene expression, as well as metabolomics, of heart tissue—and in particular, of cardiomyocytes.

The researchers searched these datasets for differences between male and female hearts, and found evidence that female cardiomyocytes have higher activity of the primary pathway for energy generation than male cardiomyocytes. Fatty acid oxidation (FAO) is the pathway that produces most of the energy that powers the heart, in the form of the energy molecule ATP. The researchers found that many genes involved in FAO have higher expression levels in female cardiomyocytes. Metabolomic data reinforced these findings by showing that female hearts had greater flux of free fatty acids, the molecules used in FAO, and that female hearts used more free fatty acids than did males in the generation of ATP.

Altogether, these findings show that there are fundamental differences in how female and male hearts generate energy to pump blood. Further experiments are needed to explore whether these differences contribute to the sex differences seen in heart disease. The researchers suspect that an association is likely, because energy production is essential to heart function and failure.

In the meantime, Page and his lab members continue to investigate the biology underlying sex differences in tissues and organs throughout the body.

“We have a lot to learn about the molecular origins of sex differences in health and disease,” Chmátal says. “What’s exciting to me is that the knowledge that comes from these basic science discoveries could lead to treatments that benefit men and women, as well as to policy changes that take sex differences into account when determining how doctors are trained and patients are diagnosed and treated.”

A planarian’s guide to growing a new head

Researchers at the Whitehead Institute have described a pathyway by which planarians, freshwater flatworms with spectacular regenerative capabilities, can restore large portions of their nervous system, even regenerating a new head with a fully functional brain.

Shafaq Zia | Whitehead Institute
February 6, 2025

Cut off any part of this worm’s body and it will regrow. This is the spectacular yet mysterious regenerative ability of freshwater flatworms known as planarians. The lab of Whitehead Institute Member Peter Reddien investigates the principles underlying this remarkable feat. In their latest study, published in PLOS Genetics on February 6, first author staff scientist M. Lucila Scimone, Reddien, and colleagues describe how planarians restore large portions of their nervous system—even regenerating a new head with a fully functional brain—by manipulating a signaling pathway.

This pathway, called the Delta-Notch signaling pathway, enables neurons to guide the differentiation of a class of progenitors—immature cells that will differentiate into specialized types—into glia, the non-neuronal cells that support and protect neurons. The mechanism ensures that the spatial pattern and relative numbers of neurons and glia at a given location are precisely restored following injury.

“This process allows planarians to regenerate neural circuits more efficiently because glial cells form only where needed, rather than being produced broadly within the body and later eliminated,” said Reddien, who is also a professor of biology at Massachusetts Institute of Technology and an Investigator with the Howard Hughes Medical Institute.

Coordinating regeneration

Multiple cell types work together to form a functional human brain. These include neurons and a more abundant group of cells called glial cells—astrocytes, microglia, and oligodendrocytes. Although glial cells are not the fundamental units of the nervous system, they perform critical functions in maintaining the connections between neurons, called synapses, clearing away dead cells and other debris, and regulating neurotransmitter levels, effectively holding the nervous system together like glue. A few years ago, Reddien and colleagues discovered cells in planarians that looked like glial cells and performed similar neuro-supportive functions. This led to the first characterization of glial cells in planarians in 2016.

Unlike in mammals where the same set of neural progenitors give rise to both neurons and glia, glial cells in planarians originate from a separate, specialized group of progenitors. These progenitors, called phagocytic progenitors, can not only give rise to glial cells but also pigment cells that determine the worm’s coloration, as well as other, lesser understood cell types.

Why neurons and glia in planarians originate from distinct progenitors—and what factors ultimately determine the differentiation of phagocytic progenitors into glia—are questions that still puzzled Reddien and team members. Then, a study showing that planarian neurons regenerate before glia formation led the researchers to wonder whether a signaling mechanism between neurons and phagocytic progenitors guides the specification of glia in planarians.

The first step to unravel this mystery was to look at the Notch signaling pathway, which is known to play a crucial role in the development of neurons and glia in other organisms, and determine its role in planarian glia regeneration. To do this, the researchers used RNA interference (RNAi)—a technique that decreases or completely silences the expression of genes—to turn off key genes involved in the Notch pathway and amputated the planarian’s head. It turned out Notch signaling is essential for glia regeneration and maintenance in planarians—no glial cells were found in the animal following RNAi, while the differentiation of other types of phagocytic cells was unaffected.

Of the different Notch signaling pathway components the researchers tested, turning of the genes notch-1, delta-2, and suppressor of hairless produced this phenotype. Interestingly, the signaling molecules Delta-2 was found on the surface of neurons, whereas Notch-1 was expressed in phagocytic progenitors.

With these findings in hand, the researchers hypothesized that interaction between Delta-2 on neurons and Notch-1 on phagocytic progenitors could be governing the final fate determination of glial cells in planarians.

To test the hypothesis, the researchers transplanted eyes either from planarians lacking the notch-1 gene or from planarians lacking the delta-2 gene into wild-type animals and assessed the formation of glial cells around the transplant site. They observed that glial cells still formed around the notch-1 deficient eyes, as notch-1 was still active in the glial progenitors of the host wild-type animal. However, no glial cells formed around the delta-2 deficient eyes, even with the Notch signaling pathway intact in phagocytic progenitors, confirming that delta-2 in the photoreceptor neurons is required for the differentiation of phagocytic progenitors into glia near the eye.

“This experiment really showed us that you have two faces of the same coin—one is the phagocytic progenitors expressing Notch-1, and one is the neurons expressing Delta-2—working together to guide the specification of glia in the organism,”said Scimone.

The researchers have named this phenomenon coordinated regeneration, as it allows neurons to influence the pattern and number of glia at specific locations without the need for a separate mechanism to adjust the relative numbers of neurons and glia.

The group is now interested in investigating whether the same phenomenon might also be involved in the regeneration of other tissue types.

A cell protector collaborates with a killer

New research from the Horvitz Lab reveals what it takes for a protein that is best known for protecting cells against death to take on the opposite role.

Jennifer Michalowski | McGovern Institute
November 1, 2024

From early development to old age, cell death is a part of life. Without enough of a critical type of cell death known as apoptosis, animals wind up with too many cells, which can set the stage for cancer or autoimmune disease. But careful control is essential, because when apoptosis eliminates the wrong cells, the effects can be just as dire, helping to drive many kinds of neurodegenerative disease.

By studying the microscopic roundworm Caenorhabditis elegans—which was honored with its fourth Nobel Prize last month—scientists at MIT’s McGovern Institute have begun to unravel a longstanding mystery about the factors that control apoptosis: how a protein capable of preventing programmed cell death can also promote it. Their study, led by McGovern Investigator Robert Horvitz and reported October 9, 2024, in the journal Science Advances, sheds light on the process of cell death in both health and disease.

“These findings, by graduate student Nolan Tucker and former graduate student, now MIT faculty colleague, Peter Reddien, have revealed that a protein interaction long thought to block apoptosis in C. elegans, likely instead has the opposite effect,” says Horvitz, who shared the 2002 Nobel Prize for discovering and characterizing the genes controlling cell death in C. elegans.

Mechanisms of cell death

Horvitz, Tucker, Reddien and colleagues have provided foundational insights in the field of apoptosis by using C. elegans to analyze the mechanisms that drive apoptosis as well as the mechanisms that determine how cells ensure apoptosis happens when and where it should. Unlike humans and other mammals, which depend on dozens of proteins to control apoptosis, these worms use just a few. And when things go awry, it’s easy to tell: When there’s not enough apoptosis, researchers can see that there are too many cells inside the worms’ translucent bodies. And when there’s too much, the worms lack certain biological functions or, in more extreme cases, can’t reproduce or die during embryonic development.

Work in the Horvitz lab defined the roles of many of the genes and proteins that control apoptosis in worms. These regulators proved to have counterparts in human cells, and for that reason studies of worms have helped reveal how human cells govern cell death and pointed toward potential targets for treating disease.

A protein’s dual role

Three of C. elegans’ primary regulators of apoptosis actively promote cell death, whereas just one, CED-9, reins in the apoptosis-promoting proteins to keep cells alive. As early as the 1990s, however, Horvitz and colleagues recognized that CED-9 was not exclusively a protector of cells. Their experiments indicated that the protector protein also plays a role in promoting cell death. But while researchers thought they knew how CED-9 protected against apoptosis, its pro-apoptotic role was more puzzling.

CED-9’s dual role means that mutations in the gene that encode it can impact apoptosis in multiple ways. Most ced-9 mutations interfere with the protein’s ability to protect against cell death and result in excess cell death. Conversely, mutations that abnormally activate ced-9 cause too little cell death, just like mutations that inactivate any of the three killer genes.

An atypical ced-9 mutation, identified by Reddien when he was a PhD student in Horvitz’s lab, hinted at how CED-9 promotes cell death. That mutation altered the part of the CED-9 protein that interacts with the protein CED-4, which is proapoptotic. Since the mutation specifically leads to a reduction in apoptosis, this suggested that CED-9 might need to interact with CED-4 to promote cell death.

The idea was particularly intriguing because researchers had long thought that CED-9’s interaction with CED-4 had exactly the opposite effect: In the canonical model, CED-9 anchors CED-4 to cells’ mitochondria, sequestering the CED-4 killer protein and preventing it from associating with and activating another key killer, the CED-3 protein —thereby preventing apoptosis.

To test the hypothesis that CED-9’s interactions with the killer CED-4 protein enhance apoptosis, the team needed more evidence. So graduate student Nolan Tucker used CRISPR gene editing tools to create more worms with mutations in CED-9, each one targeting a different spot in the CED-4-binding region. Then he examined the worms. “What I saw with this particular class of mutations was extra cells and viability,” he says—clear signs that the altered CED-9 was still protecting against cell death, but could no longer promote it. “Those observations strongly supported the hypothesis that the ability to bind CED-4 is needed for the pro-apoptotic function of CED-9,” Tucker explains. Their observations also suggested that, contrary to earlier thinking, CED-9 doesn’t need to bind with CED-4 to protect against apoptosis.

When he looked inside the cells of the mutant worms, Tucker found additional evidence that these mutations prevented CED-9’s ability to interact with CED-4. When both CED-9 and CED-4 are intact, CED-4 appears associated with cells’ mitochondria. But in the presence of these mutations, CED-4 was instead at the edge of the cell nucleus. CED-9’s ability to bind CED-4 to mitochondria appeared to be necessary to promote apoptosis, not to protect against it.

Looking ahead

While the team’s findings begin to explain a long-unanswered question about one of the primary regulators of apoptosis, they raise new ones, as well. “I think that this main pathway of apoptosis has been seen by a lot of people as more or less settled science. Our findings should change that view,” Tucker says.

The researchers see important parallels between their findings from this study of worms and what’s known about cell death pathways in mammals. The mammalian counterpart to CED-9 is a protein called BCL-2, mutations in which can lead to cancer.  BCL-2, like CED-9, can both promote and protect against apoptosis. As with CED-9, the pro-apoptotic function of BCL-2 has been mysterious. In mammals, too, mitochondria play a key role in activating apoptosis. The Horvitz lab’s discovery opens opportunities to better understand how apoptosis is regulated not only in worms but also in humans, and how dysregulation of apoptosis in humans can lead to such disorders as cancer, autoimmune disease and neurodegeneration.

An elegant switch regulates production of protein variants during cell division

Cells make variants of thousands of proteins. These variants are not produced indiscriminately, but rather through precise regulatory mechanisms that can meet rapidly changing needs of the cell according to new research from the Cheeseman Lab.

Greta Friar | Whitehead Institute
October 18, 2024

Our cells contain thousands of proteins that have gone largely undetected and unstudied until recent years: these are variants of known proteins, which cells can make when their protein-building machinery interacts differently with the same stretch of genetic code. These protein variants have typically been overlooked as occasional accidents of gene expression, but researchers including Whitehead Institute Member Iain Cheeseman are discovering that they are actually abundant and can play important roles in cell functions. Researchers in Cheeseman’s lab are studying individual protein variants to learn more about them and their roles in health and disease, but they also wanted to understand broader patterns of protein variant production: how do cells control when to make one variant of a protein versus another, and what are the consequences of such switches?

Cheeseman, who is also a professor of biology at the Massachusetts Institute of Technology, and graduate student in his lab Jimmy Ly have now identified how cells switch to a different pattern of protein variant production during mitosis, or cell division. In research published in the journal Nature on October 23, they show that this broad regulatory switch helps cells survive paused cell divisions that can sometimes occur in healthy humans or be triggered by certain chemotherapy treatments. The work confirms that cells make variants of thousands of proteins, and also demonstrates that cells do not do so indiscriminately. Rather, cells use precise regulatory mechanisms to switch between different patterns of protein variant production, in order to rapidly tailor the proteins available to fit the changing needs of the cell.

A plethora of hidden proteins

Hw can our cells contain unknown proteins? In high school biology classes, students learn the rule that each gene codes for exactly one protein, such that if you know an organism’s genetic code, you should know every protein it can make. In fact, there are instead many genes that code for multiple proteins. For a protein to be made, first the genetic code for it is copied from DNA into a messenger RNA (mRNA). Then, a ribosome, the cellular machine that follows the instructions in genetic code to build a protein, locates the coding sequence within the mRNA by scanning for the start codon, a sequence of the three bases A, U, and G – bases are the chemical building blocks of RNA, abbreviated as A, U, C, and G. The ribosome recognizes the AUG start codon as the place to begin following instructions, and builds a protein based on the genetic sequence from there through to another trio of bases called a stop codon. However, one way that different versions of a protein can be produced is that a ribosome may begin reading the instructions from multiple different starting points.

Sometimes, a ribosome may miss the first AUG start codon and skip ahead to another AUG somewhere in the middle of the gene’s code, creating a truncated version of the protein. Sometimes, a ribosome may treat a similar trio of bases, such as CUG or GUG, as a start codon. This can cause it to begin earlier, creating a protein based on an extended genetic sequence. These possibilities mean that cells contain thousands more different proteins, or variants of proteins, than are represented by the dogma of one gene, one protein.

In order to understand protein variant production, the researchers—in collaboration with researchers from Whitehead Institute Member David Bartel’s lab–used a method that let them carefully track ribosomes to compare which start sites ribosomes tended to use. They looked at start site selection during mitosis versus during the rest of the cell cycle and found that a dramatic shift in use occurred for thousands of start sites. Specifically, the researchers found that during mitosis, ribosome scanning becomes more stringent. The ribosome will only begin making proteins at AUG sequences, and even then, only at AUGs that have preferable sequences of bases surrounding them—known as a strong Kozak context. This increased selectivity does not always lead to the familiar version of the protein being made during mitosis; sometimes the first AUG start codon has a weak Kozak context, so a truncated protein gets made from an AUG start codon with a stronger Kozak context that lies within the gene.

“Coming into this project, we knew very little about protein production during mitosis—for a long time, people didn’t think much protein production happened in mitosis at all,” Ly says. “It was satisfying to show not only that it is occurring, but that there’s a shift in which proteins are being made—and that this shift is important for cellular viability.”

How cells switch between protein variant programs

The researchers next identified how the switch to increased stringency is initiated during mitosis. They discovered that the key player is a protein called eIF1, which is one of many partners that can pair with ribosomes to help them select their start site. In particular, increased eIF1 pairing with ribosomes causes the ribosomes to be more stringent in their start codon selection, inhibiting the usage of non-AUG initiation sites or sites with weak Kozak contexts.

During mitosis, ribosome pairing with eIF1 increases sharply, leading to the shift in stringency. This change in pairing rate during mitosis puzzled the researchers: ribosomes and their partners, including eIF1, all typically reside together in the main body of the cell—where ribosomes make proteins—so they should be able to pair freely at any time. The researchers looked for other molecules in the same location that could be altering how ribosomes and eIF1 interact during different parts of the cell cycle, but they couldn’t find anything. Eventually, the researchers realized that the answer to the puzzle lay in a separate location: the nucleus.

They found that cells maintain a large pool of eIF1 inside of the nucleus, locked away from the ribosomes. Then, during cell division, the wall of the nucleus dissolves, mixing its contents with the rest of the cell. This is necessary for the dividing cell to divvy up its DNA, but it also releases the pool of eIF1 to pair with ribosomes, increasing stringency. At the end of mitosis, the nucleus reforms and eIF1 is re-incorporated into the nucleus of each of the two daughter cells, and the cells return to a less stringent program.

“The explanation for increased interaction between eIF1 and ribosomes during mitosis had really stumped us, and so when I saw eIF1 localizing to the nucleus, that was a really exciting ‘aha’ moment,” Ly says. “Discovering this mechanism of nuclear release during mitosis was unexpected, and it’s interesting to think about how else cells might be using it.”

Consequences of increased stringency for the cell

Once the researchers understood the how, they then wanted to understand the why? What they discovered is that when cells have no nuclear pool of eIF1, and so no change in stringency during mitosis, they are more likely to die during mitosis. In particular, these cells fare poorly during mitotic arrest, a state in which cells get stuck in mitosis for hours or even days–much longer than typical mitosis. Arrest occurs when cells detect a possible cell division error and so halt their division until the error is corrected or the cell dies.

One effect of increased stringency during mitosis is related to mitochondria, which are required for energy production in many cell types and are therefore required for maintaining viability. Cells stuck in mitotic arrest need energy to keep them going through this unexpected delay. The researchers found that increased stringency during mitosis led to an increase in the production of important mitochondrial proteins, boosting the cells’ energy supply to get them through arrest.

Increased stringency also gives cells the tools they need to escape arrest, even if they haven’t fixed the error that caused them to pause division. In a Nature paper in 2023, Cheeseman and then-postdoc in his lab Mary-Jane Tsang showed that when cells build up enough of the truncated version of a protein called CDC20, they can escape arrest. Ly’s work adds to this story by showing that the nuclear release of eIF1 increases stringency, leading to more production of truncated CDC20 during mitosis, which explains how cells build up enough of this protein variant during mitosis to trigger their escape. These findings may have important potential implications for some cancer chemotherapy strategies.

Some chemotherapies work by trapping cancer cells in mitotic arrest until they die. Cheeseman, Tsang, and Ly’s work collectively shows that when cancer cells lack sufficient truncated CDC20—as can occur in the absence of nuclear eIF1—the cells cannot escape arrest and so are killed off by these chemotherapies at higher rates. These results could be used to improve the efficacy of antimitotic chemotherapy drugs.

The switch in protein variant production that the researchers found affects thousands of proteins. These newly identified protein variants serve as a foundation for many future projects in the lab.

As the researchers continue to examine the consequences of this switch to stringency during mitosis, they are also searching for other cases in which cells regulate protein variant production outside of mitosis. For example, the researchers are interested in how this switch in stringency affects fertility; immature egg cells spend a long time in a form of arrested cell division without an intact nucleus, and Ly observed eIF1 in the nucleus of the immature female eggs.

“Cells have axes of control that they use to quickly make broad changes in gene expression,” Cheeseman says. “Several of these are central to controlling cell division—for example, the role of phosphorylation as a regulatory switch in mitosis has been well studied. Our work identifies another axis of control, and we’re excited to discover more about when and how cells make use of it.”