Research Area: Genetics

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.”

Laub Lab News Brief: anti-viral defense system in bacteria modifies mRNA

Killing the messenger

Lillian Eden | Department of Biology
October 23, 2024

Newly characterized anti-viral defense system in bacteria aborts infection through novel mechanism by chemically modifying mRNA.

Like humans and other complex multicellular organisms, single-celled bacteria can fall ill and fight off viral infections. A bacterial virus is known as a bacteriophage, or, more simply, a phage, which is one of the most ubiquitous life forms on Earth. Phages and bacteria are engaged in a constant battle, the virus attempting to circumvent the bacteria’s defenses, and the bacteria racing to find new ways to protect itself.

These anti-phage defense systems are carefully controlled and prudently managed — dormant but always poised to strike. 

New research recently published in Nature from the Laub Lab in the Department of Biology at MIT has characterized an anti-phage defense system in bacteria known as CmdTAC. CmdTAC prevents viral infection by altering mRNA, the single-stranded genetic code used to produce proteins, of both the host and the virus.  

This defense system detects phage infection at a stage when the viral phage has already commandeered the host’s machinery for its own purposes. In the face of annihilation, the ill-fated bacterium activates a defense system that will halt translation, preventing the creation of new proteins and aborting the infection — but dooming itself in the process. 

“When bacteria are in a group, they’re kind of like a multicellular organism that is not connected to one another. It’s an evolutionarily beneficial strategy for one cell to kill itself to save another identical cell,” says Christopher Vassallo, a postdoc and co-author of the study. “You could say it’s like self-sacrifice: one cell dies to protect the other cells.” 

The enzyme responsible for altering the mRNA is called an ADP-ribosyltransferase.  Researchers have characterized hundreds of these enzymes — although only a few are known to target DNA or other types of RNA, all but a handful target proteins. This is the first time these enzymes have been characterized targeting mRNA within cells.

Expanding understanding of anti-phage defense

Co-first author and graduate student Chris Doering noted that it is only within the last decade or so that researchers have begun to appreciate the breadth of diversity and complexity of anti-phage defense systems. For example, CRISPR gene editing, a technique used in everything from medicine to agriculture, is rooted in research on the bacterial CRISPR-Cas9 anti-phage defense system. 

CmdTAC is a subset of a widespread anti-phage defense mechanism called a toxin-antitoxin system. A TA system is just that: a toxin capable of killing or altering the cell’s processes rendered inert by an associated antitoxin. 

Although these TA systems can be identified — if the toxin is expressed by itself, it kills or inhibits the growth of the cell; if the toxin and antitoxin are expressed together, the toxin is neutralized — characterizing the cascade of circumstances that activates these systems requires extensive effort. In recent years, however, many TA systems have been shown to serve as anti-phage defenses. 

Two general questions need to be answered to understand a viral defense system: how do bacteria detect an infection, and how do they respond?

Detecting infection

CmdTAC is a TA system with an additional element, and the three components generally exist in a stable complex: the toxin CmdT, the antitoxin CmdA, and an additional component that mediates the system, the chaperone CmdC. 

If the phage’s protective capsid protein is present, CmdC disassociates from CmdT and CmdA and interacts with the phage capsid protein instead. In the model outlined in the paper, the chaperone CmdC is, therefore, the sensor of the system, responsible for recognizing when an infection is occurring. Structural proteins, such as the capsid that protects the phage genome, are a common trigger because they’re abundant and essential to the phage.

The uncoupling of CmdC leads to the degradation of the neutralizing antitoxin CmdA, which releases the toxin CmdT to do its lethal work.

Toxicity on the loose

Guided by computational tools, the researchers knew that CmdT was likely an ADP-ribosyltransferase due to its similarities to other such enzymes. As the name suggests, the enzyme transfers an ADP ribose onto its target.

To determine how CmdT was altering mRNA, the researchers tested a mix of short sequences of single-stranded RNA to see if the enzyme was drawn to any sequences or positions in particular. RNA has four bases: A, U, G, and C, and the evidence points to the enzyme recognizing GA sequences. 

The CmdT modification of GA sequences in mRNA blocks its translation. The cessation of creating new proteins aborts the infection, preventing the phage from spreading beyond the host to infect other bacteria. 

“Not only is it a new type of bacterial immune system, but the enzyme involved does something that’s never been seen before: the ADP-ribsolyation of mRNA,” Vassallo says. 

Although the paper outlines the broad strokes of the anti-phage defense system, there’s more to learn: it’s unclear how CmdC interacts with the capsid protein, and how the chemical modification of GA sequences prevents translation. 

Beyond Bacteria

While exploring anti-phage defense aligns with the Laub Lab’s overall goal of understanding how bacteria function and evolve, these results may have broader implications beyond bacteria.

Senior author Michael Laub, Salvador E. Luria Professor and HHMI Investigator, says the ADP-ribosyltransferase has homologs in eukaryotes, including human cells. They are not well studied, and not currently among the Laub Lab’s research topics, but they are known to be up-regulated in response to viral infection. 

“There are so many different — and cool — mechanisms by which organisms defend themselves against viral infection,” Laub says. “The notion that there may be some commonality between how bacteria defend themselves and how humans defend themselves is a tantalizing possibility.” 

Establishing boundaries of the genetic kind

The pseudoautosomal region (PAR) is a critical area on the Y chromosome that swaps genetic information with the X chromosome. Recent research from the Page Lab reaffirms the location of PAR and offers a refined understanding of where crossover events occur.

Shafaq Zia | Whitehead Institute
October 14, 2024

At first, the X and the Y sex chromosomes seemed like an unlikely pair. But then, researchers, including Whitehead Institute Member David Page, began finding clues that suggested otherwise: identical DNA sequences on the X and Y chromosomes.

Soon, it became clear that the tips of the X and Y chromosomes join together in a tight embrace, swapping genetic material during the process of sperm production from immature male germ cells. This limited area of genetic exchange between the two sex chromosomes is called the pseudoautosomal region (PAR).

But science is an iterative process—a continuous cycle of questioning, testing, and revising knowledge. Last fall, what had long been considered well established in genetics was called into question when new research suggested that the boundary of the PAR might be half a million base pairs away from the accepted location. Given that a typical human gene is about tens of thousands of base pairs, this length would potentially span multiple genes on the X and Y chromosomes, raising serious concerns about the accuracy and validity of decades of scientific literature.

Fortunately, new work from Page, research scientist Daniel Winston Bellott, and colleagues—published Oct. 14 in the American Journal of Human Genetics—offers clarity. In this study, the group re-examines the size of the PAR using sequencing data presented by outside researchers in their 2023 work, alongside decades of genomic resources, and single-cell sequencing of human sperm. Their findings confirm that the location of the boundary to the PAR, as identified by scientists in 1989, still holds true.

“If one is interested in understanding sex differences in health and disease, the boundary of the pseudoautosomal region is arguably the most fundamental landmark in the genome,” says Page, who is also a professor of biology at the Massachusetts Institute of Technology and an Investigator with Howard Hughes Medical Institute. “Had this boundary been multiple genes off, the field would have been shaken to its foundations.”

Dance of the chromosomes

The X and Y chromosomes evolved from an ancestral pair of chromosomes with identical structures. Over time, the Y chromosome degenerated drastically, losing hundreds of functional genes. Despite their differences, the X and Y chromosomes come together during a special type of cell division called male meiosis, which produces sperm cells.

This process begins with the tips of the sex chromosomes aligning side by side like two strands of rope. As the X and Y chromosomes embrace each other, enzymes create breaks in the DNA. These breaks are repaired using the opposite chromosome as a template, linking the X and Y together. About half of the time, an entire segment of DNA, which often contains multiple genes, will cross over onto the opposite chromosome.

The genetic exchange, called recombination, concludes with the X and Y chromosomes being pulled apart to opposite ends of the dividing cell, ensuring that each chromosome ends up in a different daughter cell. “This intricate dance of the X and Y chromosomes is essential to a sperm getting either an X or a Y—not both, and not neither,” says Page.

This way when the sperm—carrying either an X or a Y—fuses with the egg—carrying an X—during fertilization, the resulting zygote has the right number of chromosomes and a mix of genetic material from both parents.

But that’s not all. The swapping of DNA during recombination also allows for the chromosomes to have the same genes but with slight variations. These unique combinations of genetic material across sex chromosomes are key to genetic diversity within a species, enabling it to survive, adapt, and reproduce successfully.

Beyond the region of recombination, the Y chromosome contains genes that are important for sex determination, for sperm production, and for general cellular functioning. The primary sex-defining gene, SRY, which triggers the development of an embryo into a male, is located only 10,000 bases from the boundary of the PAR.

Advancing together

To determine whether the location of this critical boundary on the human sex chromosomes—where they stop crossing over during meiosis and become X-specific or Y-specific—had been misidentified for over three decades, researchers began by comparing publicly-available DNA sequences from the X and the Y chromosomes of seven primate species: humans, chimpanzees, gorillas, orangutans, siamangs, rhesus macaques, and colobus monkeys.

Based on the patterns of crossover between the X and the Y chromosomes of these species, the researchers constructed an evolutionary tree. Upon analyzing how DNA sequences close to and distant from the PAR boundary group together across species, the researchers found a substitution mutation—where a letter in a long string of letters is swapped for a different one—in the DNA of the human X and Y chromosomes. This change was also present in the chimpanzee Y chromosome, suggesting that the mutation originally occurred in the last common ancestor of humans and chimpanzees and was then transferred to the human X chromosome.

“These alignments between various primates allowed us to observe where the X and the Y chromosomes have preserved identity over millions of years and where they have diverged,” says Bellott. “That [pseudoautosomal] boundary has remained unchanged for 25 million years.”

Next, the group studied crossover events in living humans using a vast dataset of single-cell sequencing of sperm samples. They found 795 sperm with clear swapping of genetic material somewhere between the originally proposed boundary of the PAR and the newly-proposed 2023 boundary.

Once these analyses confirmed that the original location of the PAR boundary remains valid, Page and his team turned their attention to data from the 2023 study that contested this 1989 finding. The researchers focused on 10 male genomes assembled by the outside group, which contained contiguous sequences from the PAR.

Since substitutions on the Y chromosome typically occur at a steady rate, but in the PAR, changes on the X chromosome can transfer to the Y through recombination, the researchers compared the DNA sequences from the ten genomes to determine whether they followed the expected steady rate of change or if they varied.

The team found that close to the originally proposed PAR boundary, the DNA sequences changed at a steady rate. But further away from the boundary, the rate of change varied, suggesting that crossover events likely occurred in this region. Furthermore, the group identified several shared genetic differences between the X and the Y chromosomes of these genomes, which demonstrates that recombination has occurred even closer to the PAR boundary than scientists observed in 1989.

“Ironically, instead of contradicting the original boundary, the 2023 work has helped us refine the location of crossover to an even narrower area near the boundary,” says Page.

Thanks to the efforts of Page’s group at Whitehead Institute, our understanding of the PAR is clearer than ever, and business can go on as usual for researchers investigating sex differences in health and disease.

Growing to greatness: Professor Mary Gehring on plant epigenetics and becoming an HHMI Investigator

From the intricacies of plant reproduction to genome-wide analyses, Gehring’s lab delves deep into the epigenetic mechanisms shaping plant biology.

Jayashabari Shankar and Alex Tang | The Tech
September 5, 2024

Dr. Mary Gehring is a professor of biology at MIT and a core member of the Whitehead Institute for Biomedical Research. Her research focuses on how epigenetic mechanisms like DNA methylation influence gene regulation during plant reproduction and seed development in the model organism Arabidopsis thaliana. In the classroom, she teaches genetics (7.03), a required course for biology and biological engineering majors.

With her recent appointment as an Howard Hughes Medical Institute (HHMI) investigator, Gehring joins an elite legion of HHMI investigators at the Institute. New cohorts of investigators are only announced once every three years, and they receive $11 million in funding over a seven year term (which can be renewed). Three other MIT faculty received HHMI appointments this year: Gene-Wei Li, associate professor of biology, and brain and cognitive sciences professors Mehrdad Jazayeri and Steven Flavell.

Here, she shares her lab’s research, journey into plant biology, and what she values in undergraduate researchers.

TT: What does your lab conduct research in, and how has being named an HHMI investigator changed your plans, if at all?

My lab focuses on plant biology, particularly on how epigenetic mechanisms like DNA methylation affect gene regulation in plants, especially during reproduction and seed development. We mostly work with Arabidopsis thaliana, a model plant, but we’re also exploring other plant systems.

A typical day in the lab can vary, but it often starts with checking on our plants in the greenhouse. Depending on the day, we might pollinate plants for genetic crosses or genotyping them by isolating DNA and performing PCR. We’re particularly focused on understanding gene expression within seeds: we isolate different seed tissues, sort nuclei based on their properties, and then perform RNA sequencing. We also do a lot of chromatin profiling, histone modifications and DNA methylation analyses across the genome. Since much of our work is genome-wide, bioinformatics plays a big role in our research, with a significant amount of time spent on analyzing data.

It’s still sinking in, but being named an HHMI investigator certainly provides a new level of freedom. It allows us to pursue ideas without the constraints of specific grant funding, which is incredibly liberating. We’re considering expanding our research into new areas beyond epigenetics, like genome structure and chromosome dosage changes, while sticking with plant biology. This recognition has encouraged us to think bigger and explore new directions in our work.

TT: How far back do these interests extend for you?

My interest in plant biology started during my undergraduate years. I majored in biology and was eager to get involved in research. My real fascination with plants began when a new professor, with a background in plant biology, came to my school. I took her course on plant growth and development, which I found incredibly exciting. I was drawn to how plants communicate within their tissues and with each other. This led me to work on a research project for two years, culminating in a senior thesis on root development. After college, I took a year off to work in environmental consulting before heading to graduate school in Plant Biology at UC Berkeley.

TT: What perspectives and characteristics do you appreciate in undergraduate researchers?

Whether it’s undergraduates or postdocs, I value curiosity and dedication. For undergraduates, especially those in UROPs, it’s crucial that they are genuinely interested in the research and willing to ask questions when they don’t understand something. Balancing research with coursework and extracurriculars at MIT is challenging, so I also look for students who can manage their time well. It’s about being curious, dedicated, and communicative.

I hope there are students at MIT who are excited about plant research. It’s a vital area of biology, especially with the growing focus on climate change. While there isn’t a large presence of plant biology at MIT yet, I’m hopeful that it will expand in the coming years, and I’d love to see more students getting involved in this important field.