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.

W.M. Keck Foundation to support research on healthy aging at MIT

Assistant Professor of Biology Alison Ringel will investigate the intersection of immunology and aging biology, aiming to define the mechanisms that underlie aging-related decline, thanks to grant from prestigious foundation.

Lillian Eden | Department of Biology
October 9, 2025

A prestigious grant from the W.M. Keck Foundation to Assistant Professor of Biology Alison Ringel will support groundbreaking healthy aging research at MIT.

Ringel, also a Core Member of the Ragon Institute, will draw on her background in cancer immunology to create a more comprehensive biomedical understanding of the cause and possible treatments for aging-related decline.

“It is such an honor to receive this grant,” Ringel says. “This support will enable us to draw new connections between immunology and aging biology. As the U.S. population grows older, advancing this research is increasingly important, and this line of inquiry is only possible because of the W.M. Keck Foundation.”

Understanding how to extend healthy years of life is a fundamental question of biomedical research with wide-ranging societal implications. Although modern science and medicine have greatly expanded global life expectancy, it remains unclear why everyone ages differently; some maintain physical and cognitive fitness well into old age, while others become debilitatingly frail later in life.

Our immune systems are adaptable, but they do naturally decline as we get older. One critical component of our immune system is CD8+ T cells, which are known to target and destroy cancerous or damaged cells. As we age, our tissues accumulate cells that can no longer divide. These senescent cells are present throughout our lives, but reach seemingly harmful levels as a normal part of aging, causing tissue damage and diminished resilience under stress.

There is now compelling evidence that the immune system plays a more active role in aging than previously thought.

“Decades of research have revealed that T cells can eliminate cancer cells, and studies of how they do so have led directly to the development of cancer immunotherapy,” Ringel says. “Building on these discoveries, we can now ask what roles T cells play in normal aging, where the accumulation of senescent cells, which are remarkably similar to cancer cells in some respects, may cause health problems later in life.”

In animal models, reconstituting elements of a young immune system has been shown to improve age-related decline, potentially due to CD8+ T cells selectively eliminating senescent cells. CD8+ T cells progressively losing the ability to cull senescent cells could explain some age-related pathology.

Ringel aims to build models for the express purpose of tracking and manipulating T cells in the context of aging and to evaluate how T cell behavior changes over a lifespan.

“By defining the protective processes that slow aging when we are young and healthy, and defining how these go awry in older adults, our goal is to generate knowledge that can be applied to extend healthy years of life,” Ringel says. “I’m really excited about where this research can take us.”

The W. M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation’s largest philanthropic organizations, the W. M. Keck Foundation supports outstanding science, engineering and medical research. The Foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health and community service projects.

Alnylam Pharmaceuticals establishes named fund in honor of co-founder

The Phil Sharp-Alnylam Fund for Emerging Scientists will support graduate students and faculty in MIT Biology.

Lillian Eden | Department of Biology
October 8, 2025

It’s no question that graduate school in fundamental research was never for the faint of heart, but academia’s nationwide funding disruptions threaten not just research happening now, but the critical pipeline for the next generation of scientists.

“What’s keeping me up at night is the uncertainty,” says Nobel Laureate Phillip A. Sharp, Institute Professor and Professor of Biology Emeritus, and Intramural Faculty at the Koch Institute.

In the short term, Sharp foresees challenges in sustaining students so they can complete their degrees, postdoctoral scholars to finish their professional preparation, and faculty to set up and sustain their labs. In the long term, the impact becomes potentially existential — fewer people pursuing academia now means fewer advancements in the decades to come.

So, when Sharp was looped into discussions about a gift in his honor, he knew exactly where it should be directed. Established this year thanks to a generous donation from Alnylam Pharmaceuticals, the Phil Sharp-Alnylam Fund for Emerging Scientists will support graduate students and faculty within life sciences.

“This generosity by Alnylam provides an opportunity to bridge the uncertainty and ideally create the environment where students and others will feel that it’s possible to do science and have a career,” Sharp says. 

The fund is set up to be flexible, so the expendable gift can be used to address the evolving needs of the Department of Biology, including financial support, research grants, and seed funding. 

“This fund will help us fortify the department’s capacity to train new generations of life science innovators and leaders,” says Amy E. Keating, Department Head and Jay A. Stein (1968) Professor of Biology and Professor of Biological Engineering. “It is a great privilege for the department to be part of this recognition of Phil’s key role at Alnylam.”

Alnylam Pharmaceuticals, a company Sharp cofounded in 2002, is, in fact, a case study for the type of long-term investment in fundamental discovery that leads to paradigm-shifting strides in biomedical science, such as: what if the genetic drivers of diseases could be silenced by harnessing a naturally occurring gene regulation process? 

Good things take time

In 1998, Andrew Fire, PhD ’83, who was trained as a graduate student in the Sharp Lab at MIT, and Craig Mello published a paper showing that double-stranded RNA suppresses the expression of the protein from the gene that encodes its sequence. The process, known as RNA interference, was such a groundbreaking revelation that Fire and Mello shared a Nobel Prize in Medicine and Physiology less than a decade later. 

Four of the five cofounders of Alnylam Pharmaceuticals: (from left to right) Tom Tuschl, Phil Sharp, David Bartel, and Phil Zamore. Not pictured: Paul Schimmel. Photo credit: Christoph Westphal

RNAi is an innate cellular gene regulation process that can, for example, assist cells in defending against viruses by degrading viral RNA, thereby interfering with the production of viral proteins. Taking advantage of this natural process to fine-tune the expression of genes that encode specific proteins was a promising option for disease treatment, as many diseases are caused by the creation or buildup of mutated or faulty proteins. This approach would address the root cause of the disease, rather than its downstream symptoms.

The details of the biochemistry of RNAi were characterized and patented, and in 2002, Alnylam was founded by Sharp, David Bartel, Paul Schimmel, Thomas Tuschl, and Phillip Zamore. 

“16 years later, we got our first approval for a totally novel therapeutic agent to treat disease,” Sharp says. “Something in a research laboratory, translated in about as short a time as you can do, gave rise to this whole new way of treating critical diseases.” 

This timeline isn’t atypical. Particularly in healthcare, Sharp notes, investments often occur five or ten years before they come to fruition. 

“Phil Sharp’s visionary idea of harnessing RNAi to treat disease brought brilliant people together to pioneer this new class of medicines. RNAi therapeutics would not exist without the bridge Phil built between academia and industry. Now there are six approved Alnylam-discovered RNAi therapeutics, and we are exploring potential treatments for a range of rare and prevalent diseases to improve the lives of many more patients in need,” says Kevin Fitzgerald, Chief Scientific Officer of Alnylam Pharmaceuticals

Today, the company has grown to over 2,500 employees, markets its six approved treatments worldwide, and has a long list of research programs that are likely to yield new therapeutic agents in the years to come. 

Change is always on the horizon

Sharp foresees potential benefits for companies investing in academia, in the way Alnylam Pharmaceuticals has through the Phil Sharp-Alnylam Fund for Emerging Scientists

“We are proud to support the MIT Department of Biology because investments in both early-stage and high-risk research have the potential to unlock the next wave of medical breakthroughs to help so many patients waiting for hope throughout the world,” says Yvonne Greenstreet, Chief Executive Officer of Alnylam Pharmaceuticals

It is prudent for industry to keep its finger on the pulse — for becoming aware of new talent and for anticipating landscape-shifting advancements, such as Artificial Intelligence. Sharp notes that academia, in its pursuit of fundamental knowledge, “creates new ideas, new opportunities, and new ways of doing things.” 

“All of society, including biotech, is anticipating that AI is going to be a great accelerator,” Sharp says. “Being associated with institutions that have great biology, chemistry, neuroscience, engineering, and computational innovation is how you sort through this anticipation of what the future is going to be.” 

But, Sharp says, it’s a two-way street: academia should also be asking how it can best support the future workplaces for their students who will go on to have careers in industry. To that end, the Department of Biology recently launched a career connections initiative for current trainees to draw on the guidance and experience of alums, and to learn how to hone their knowledge so that they are a value-add to industry’s needs.  

“The symbiotic nature of these relationships is healthy for the country, and for society, all the way from basic research through innovative companies of all sizes, healthcare delivery, hospitals, and right down to primary care physicians meeting one-on-one with patients,” Sharp says. “We’re all part of that, and unless all parts of it remain healthy and appreciated, it will bode poorly for the future of the country’s economy and well-being.”

Pathology and the Allure of Analytical Thinking

Susan Fuhrman ’75 pursued pathology because she liked providing clear answers to diagnostic questions, and has spent her retirement making complex beaded jewelry, a hobby she started more than 30 years ago as a foil for the stresses of work.

Kathryn M. O'Neill | Slice of MIT
October 7, 2025

Susan Fuhrman ’75 became a pathologist because she likes providing clear answers to diagnostic questions. “As opposed to guessing what people have, you’ve got the lab results, you have reviewed the pathology slides,” she says. “It’s pretty analytical. Your answer is the answer.”

That clarity of focus was never more valuable than in 2020, when Fuhrman was charged with answering the question everyone was asking: Is it Covid?

As the system director for pathology and laboratory services at OhioHealth, a major hospital system based in Columbus, Ohio, Fuhrman led efforts to address the epidemic—through hospital protocols and, of course, testing—all while fielding seemingly endless requests for her expertise in identifying disease.

“Everybody—from hospital vice presidents to the chief medical officer for the system— was calling me late at night and multiple times on weekends. It was incredible,” she says.

Within a year, the system’s labs had performed over half a million Covid tests and Fuhrman had been featured several times in CAP Today, a publication of the College of American Pathologists. She discussed general testing challenges as well as whom to test when and on which testing platform.

As it happened, however, Fuhrman was already famous thanks to work dating back to the 1980s.

Understanding Renal Cancer

The daughter of two chemists, Fuhrman majored in biology at MIT and earned her medical degree from the University of Michigan in 1978. She then went to the University of Minnesota Medical Center for her residency in pathology and laboratory medicine and found herself in need of a research topic. “I remember asking the head of our surgical pathology department, Dr. Juan Rosai, ‘What is a question in pathology that hasn’t been answered?’” she says. “He said, ‘Well, we don’t have a good way of determining which renal cell cancers have a bad prognosis. Currently we go by size, but there must be more than that. No one’s cracked the code. Why don’t you try that?’”

So, Fuhrman teamed up with another doctor at the Minneapolis veterans hospital, Dr. Catherine Limas, and together they developed and proposed a set of parameters to grade kidney cancers that might predict cancer outcomes. Then, Fuhrman did the painstaking work of reviewing and analyzing thousands of tumor slides, as well as cancer registry clinical data and medical charts. Her husband, Larry Lasky ’72—whom she had met at MIT and who also became a pathologist—programmed the analysis and helped her run the data she found through an early computer. “I input everything with computer cards and a teletype, super primitive stuff,” she says.

The data produced clear patterns in the predictive value of the appearance of cell nuclei, and the three published a paper proposing a grading system classifying which renal tumors are most aggressive and likely to spread based on their findings. The system, which is still the standard, is known as the Fuhrman Nuclear Grade for Clear Cell Renal Carcinoma.

American Board of Pathology President

After her residency, Fuhrman taught laboratory medicine to senior medical students as an assistant professor at the University of Minnesota for 12 years before moving to Ohio in 1994. In addition to working at OhioHealth, Fuhrman served for several years as president and CEO of CORPath, a private pathology practice. In 2022, she served a term as president of the American Board of Pathology, which later named her a life trustee in honor of her many years of service.

Fuhrman retired at the end of 2020 and has since spent much of her time making beaded jewelry—a hobby she started 35 years ago as a foil to work. “The job was stressful, and beading uses a totally different part of your brain. The left side can rest,” she says. “I can sit and sort beads by size and color for hours. That’s really weird and mindless, but I love it. I also love bead weaving; it’s like physics and architecture, building beautiful, structurally sound pieces from tiny beads.”

She creates elaborate bracelets and necklaces, often giving them away to friends or donating them to charity. “Jewelry making doesn’t pay very well, but I’m very lucky I don’t need to support myself on my hobby,” she says. “I do this for me.”

Gene-Wei Li joins MIT Department of Biology leadership team as Associate Department Head

During a time of academic uncertainty, Li aims to help guide the department in continuing to be a worldwide leader in education, biological sciences, and fundamental research.

Lillian Eden | Department of Biology
October 6, 2025

Associate Professor of Biology Gene-Wei Li has accepted the position of Associate Department Head starting in the 2025-2026 academic year. 

Li, who has been a member of the department since 2015, brings a history of departmental leadership, service, and research and teaching excellence to his new role. He has received many awards, including a Sloan Research Fellowship (2016), an NSF Career Award (2019), Pew and Searle scholarships, and MIT’s Committed to Caring Award (2020), In 2024, he was appointed as an HHMI Investigator

“I am grateful to Gene-Wei for joining the leadership team,” says Department Head and Jay A. Stein (1968) Professor of Biology and Professor of Biological Engineering Amy E. Keating. “Gene will be a key leader in our educational initiatives, both digital and residential, and will be a critical part of keeping our department strong and forward-looking.” 

A great environment to do science

Li says he was inspired to take on the role in part because of the way MIT Biology facilitates career development during every stage—from undergraduate and graduate students to postdocs and junior faculty members, as he was when he started in the department as an assistant professor just ten years ago. 

“I think we all benefit a lot from our environment, and I think this is a great environment to do science and educate people, and to create a new generation of scientists,” he says. “I want us to keep doing well, and I’m glad to have the opportunity to contribute to this effort.” 

As part of his portfolio as Associate Department Head, Li will continue in the role of Scientific Director of the Koch Biology Building, Building 68. In the last year, the previous Scientific Director, Stephen Bell, Uncas and Helen Whitaker Professor of Biology and HHMI Investigator, has continued to provide support and ensured a steady ramp-up, transitioning Li into his new duties. The building, which opened its doors in 1994, is in need of a slate of updates and repairs. 

Although Li will be managing more administrative duties, he has provided a stable foundation for his lab to continue its interdisciplinary work on the quantitative biology of gene expression, parsing the mechanisms by which cells control the levels of their proteins and how this enables cells to perform their functions. His recent work includes developing a method that leverages the AI tool AlphaFold to predict whether protein fragments can recapitulate the native interactions of their full-length counterparts.  

“I’m still very heavily involved, and we have a lab environment where everyone helps each other. It’s a team, and so that helps elevate everyone,” he says. “It’s the same with the whole building: nobody is working by themselves, so the science and administrative parts come together really nicely.” 

Teaching for the future

Li is considering how the department can continue to be a global leader in biological sciences while navigating the uncertainty surrounding academia and funding, as well as the likelihood of reduced staff support and tightening budgets.

“The question is, how do you maintain excellence?” Li says. “That involves recruiting great people and giving them the resources that they need, and that’s going to be a priority within the limitations that we have to work with.” 

Li will also be serving as faculty advisor for the MIT Biology Teaching and Learning Group, headed by Mary Ellen Wiltrout, and will serve on the Department of Biology Digital Learning Committee and the new Open Learning Biology Advisory Committee. Li will serve in the latter role in order to represent the department and work with new faculty member and HHMI Investigator Ron Vale on institute-level online learning initiatives. Li will also chair the Biology Academic Planning Committee, which will help develop a longer-term outlook on faculty teaching assignments and course offerings. 

Li is looking forward to hearing from faculty and students about the way the institute teaches, and how it could be improved, both for the students on campus and for the online learners from across the world. 

“There are a lot of things that are changing—what are the core fundamentals that the students need to know, what should we teach them, and how should we teach them?” 

Although the commitment to teaching remains unchanged, there may be big transitions on the horizon. With two young children in school, Li is all too aware that the way that students learn today is very different from what he grew up with, and also very different from how students were learning just five or ten years ago—writing essays on a computer, researching online, using AI tools, and absorbing information from media like short-form YouTube videos. 

“There’s a lot of appeal to a shorter format, but it’s very different from the lecture-based teaching style that has worked for a long time,” Li says. “I think a challenge we should and will face is figuring out the best way to communicate the core fundamentals, and adapting our teaching styles to the next generation of students.” 

Ultimately, Li is excited about balancing his research goals along with joining the department’s leadership team and knows he can look to his fellow researchers in Building 68 and beyond for support.

“I’m privileged to be working with a great group of colleagues who are all invested in these efforts,” Li says. “Different people may have different ways of doing things, but we all share the same mission.” 

A cysteine-rich diet may promote regeneration of the intestinal lining, study suggests

The findings from the Yilmaz Lab recently published in Nature, may offer a new way to help heal tissue damage from radiation or chemotherapy treatment.

Anne Trafton | MIT News
October 1, 2025

A diet rich in the amino acid cysteine may have rejuvenating effects in the small intestine, according to a new study from MIT. This amino acid, the researchers discovered, can turn on an immune signaling pathway that helps stem cells to regrow new intestinal tissue.

This enhanced regeneration may help to heal injuries from radiation, which often occur in patients undergoing radiation therapy for cancer. The research was conducted in mice, but if future research shows similar results in humans, then delivering elevated quantities of cysteine, through diet or supplements, could offer a new strategy to help damaged tissue heal faster, the researchers say.

“The study suggests that if we give these patients a cysteine-rich diet or cysteine supplementation, perhaps we can dampen some of the chemotherapy or radiation-induced injury,” says Omer Yilmaz, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research. “The beauty here is we’re not using a synthetic molecule; we’re exploiting a natural dietary compound.”

While previous research has shown that certain types of diets, including low-calorie diets, can enhance intestinal stem cell activity, the new study is the first to identify a single nutrient that can help intestinal cells to regenerate.

Yilmaz is the senior author of the study, which appears today in Nature. Koch Institute postdoc Fangtao Chi is the paper’s lead author.

Boosting regeneration

It is well-established that diet can affect overall health: High-fat diets can lead to obesity, diabetes, and other health problems, while low-calorie diets have been shown to extend lifespans in many species. In recent years, Yilmaz’s lab has investigated how different types of diets influence stem cell regeneration, and found that high-fat diets, as well as short periods of fasting, can enhance stem cell activity in different ways.

“We know that macro diets such as high-sugar diets, high-fat diets, and low-calorie diets have a clear impact on health. But at the granular level, we know much less about how individual nutrients impact stem cell fate decisions, as well as tissue function and overall tissue health,” Yilmaz says.

In their new study, the researchers began by feeding mice a diet high in one of 20 different amino acids, the building blocks of proteins. For each group, they measured how the diet affected intestinal stem cell regeneration. Among these amino acids, cysteine had the most dramatic effects on stem cells and progenitor cells (immature cells that differentiate into adult intestinal cells).

Further studies revealed that cysteine initiates a chain of events leading to the activation of a population of immune cells called CD8 T cells. When cells in the lining of the intestine absorb cysteine from digested food, they convert it into CoA, a cofactor that is released into the mucosal lining of the intestine. There, CD8 T cells absorb CoA, which stimulates them to begin proliferating and producing a cytokine called IL-22.

IL-22 is an important player in the regulation of intestinal stem cell regeneration, but until now, it wasn’t known that CD8 T cells can produce it to boost intestinal stem cells. Once activated, those IL-22-releasing T cells are primed to help combat any kind of injury that could occur within the intestinal lining.

“What’s really exciting here is that feeding mice a cysteine-rich diet leads to the expansion of an immune cell population that we typically don’t associate with IL-22 production and the regulation of intestinal stemness,” Yilmaz says. “What happens in a cysteine-rich diet is that the pool of cells that make IL-22 increases, particularly the CD8 T-cell fraction.”

These T cells tend to congregate within the lining of the intestine, so they are already in position when needed. The researchers found that the stimulation of CD8 T cells occurred primarily in the small intestine, not in any other part of the digestive tract, which they believe is because most of the protein that we consume is absorbed by the small intestine.

Healing the intestine

In this study, the researchers showed that regeneration stimulated by a cysteine-rich diet could help to repair radiation damage to the intestinal lining. Also, in work that has not been published yet, they showed that a high-cysteine diet had a regenerative effect following treatment with a chemotherapy drug called 5-fluorouracil. This drug, which is used to treat colon and pancreatic cancers, can also damage the intestinal lining.

Cysteine is found in many high-protein foods, including meat, dairy products, legumes, and nuts. The body can also synthesize its own cysteine, by converting the amino acid methionine to cysteine — a process that takes place in the liver. However, cysteine produced in the liver is distributed through the entire body and doesn’t lead to a buildup in the small intestine the way that consuming cysteine in the diet does.

“With our high-cysteine diet, the gut is the first place that sees a high amount of cysteine,” Chi says.

Cysteine has been previously shown to have antioxidant effects, which are also beneficial, but this study is the first to demonstrate its effect on intestinal stem cell regeneration. The researchers now hope to study whether it may also help other types of stem cells regenerate new tissues. In one ongoing study, they are investigating whether cysteine might stimulate hair follicle regeneration.

They also plan to further investigate some of the other amino acids that appear to influence stem cell regeneration.

“I think we’re going to uncover multiple new mechanisms for how these amino acids regulate cell fate decisions and gut health in the small intestine and colon,” Yilmaz says.

The research was funded, in part, by the National Institutes of Health, the V Foundation, the Koch Institute Frontier Research Program via the Kathy and Curt Marble Cancer Research Fund, the Bridge Project — a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center, the American Federation for Aging Research, the MIT Stem Cell Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute.

A more precise way to edit the genome

MIT researchers have dramatically lowered the error rate of prime editing, a technique that holds potential for treating many genetic disorders.

Anne Trafton | MIT News
September 17, 2025

A genome-editing technique known as prime editing holds potential for treating many diseases by transforming faulty genes into functional ones. However, the process carries a small chance of inserting errors that could be harmful.

MIT researchers have now found a way to dramatically lower the error rate of prime editing, using modified versions of the proteins involved in the process. This advance could make it easier to develop gene therapy treatments for a variety of diseases, the researchers say.

“This paper outlines a new approach to doing gene editing that doesn’t complicate the delivery system and doesn’t add additional steps, but results in a much more precise edit with fewer unwanted mutations,” says Phillip Sharp, an MIT Institute Professor Emeritus, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

With their new strategy, the MIT team was able to improve the error rate of prime editors from about one error in seven edits to one in 101 for the most-used editing mode, or from one error in 122 edits to one in 543 for a high-precision mode.

“For any drug, what you want is something that is effective, but with as few side effects as possible,” says Robert Langer, the David H. Koch Institute Professor at MIT, a member of the Koch Institute, and one of the senior authors of the new study. “For any disease where you might do genome editing, I would think this would ultimately be a safer, better way of doing it.”

Koch Institute research scientist Vikash Chauhan is the lead author of the paper, which appears today in Nature.

The potential for error

The earliest forms of gene therapy, first tested in the 1990s, involved delivering new genes carried by viruses. Subsequently, gene-editing techniques that use enzymes such as zinc finger nucleases to correct genes were developed. These nucleases are difficult to engineer, however, so adapting them to target different DNA sequences is a very laborious process.

Many years later, the CRISPR genome-editing system was discovered in bacteria, offering scientists a potentially much easier way to edit the genome. The CRISPR system consists of an enzyme called Cas9 that can cut double-stranded DNA at a particular spot, along with a guide RNA that tells Cas9 where to cut. Researchers have adapted this approach to cut out faulty gene sequences or to insert new ones, following an RNA template.

In 2019, researchers at the Broad Institute of MIT and Harvard reported the development of prime editing: a new system, based on CRISPR, that is more precise and has fewer off-target effects. A recent study reported that prime editors were successfully used to treat a patient with chronic granulomatous disease (CGD), a rare genetic disease that affects white blood cells.

“In principle, this technology could eventually be used to address many hundreds of genetic diseases by correcting small mutations directly in cells and tissues,” Chauhan says.

One of the advantages of prime editing is that it doesn’t require making a double-stranded cut in the target DNA. Instead, it uses a modified version of Cas9 that cuts just one of the complementary strands, opening up a flap where a new sequence can be inserted. A guide RNA delivered along with the prime editor serves as the template for the new sequence.

Once the new sequence has been copied, however, it must compete with the old DNA strand to be incorporated into the genome. If the old strand outcompetes the new one, the extra flap of new DNA hanging off may accidentally get incorporated somewhere else, giving rise to errors.

Many of these errors might be relatively harmless, but it’s possible that some could eventually lead to tumor development or other complications. With the most recent version of prime editors, this error rate ranges from one per seven edits to one per 121 edits for different editing modes.

“The technologies we have now are really a lot better than earlier gene therapy tools, but there’s always a chance for these unintended consequences,” Chauhan says.

Precise editing

To reduce those error rates, the MIT team decided to take advantage of a phenomenon they had observed in a 2023 study. In that paper, they found that while Cas9 usually cuts in the same DNA location every time, some mutated versions of the protein show a relaxation of those constraints. Instead of always cutting the same location, those Cas9 proteins would sometimes make their cut one or two bases further along the DNA sequence.

This relaxation, the researchers discovered, makes the old DNA strands less stable, so they get degraded, making it easier for the new strands to be incorporated without introducing any errors.

In the new study, the researchers were able to identify Cas9 mutations that dropped the error rate to 1/20th its original value. Then, by combining pairs of those mutations, they created a Cas9 editor that lowered the error rate even further, to 1/36th the original amount.

To make the editors even more accurate, the researchers incorporated their new Cas9 proteins into a prime editing system that has an RNA binding protein that stabilizes the ends of the RNA template more efficiently. This final editor, which the researchers call vPE, had an error rate just 1/60th of the original, ranging from one in 101 edits to one in 543 edits for different editing modes. These tests were performed in mouse and human cells.

The MIT team is now working on further improving the efficiency of prime editors, through further modifications of Cas9 and the RNA template. They are also working on ways to deliver the editors to specific tissues of the body, which is a longstanding challenge in gene therapy.

They also hope that other labs will begin using the new prime editing approach in their research studies. Prime editors are commonly used to explore many different questions, including how tissues develop, how populations of cancer cells evolve, and how cells respond to drug treatment.

“Genome editors are used extensively in research labs,” Chauhan says. “So the therapeutic aspect is exciting, but we are really excited to see how people start to integrate our editors into their research workflows.”

The research was funded by the Life Sciences Research Foundation, the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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.” 

Inflammation jolts “sleeping” cancer cells awake, enabling them to multiply again

A paper from the Weinberg Lab indicates that inflammation may be a factor in how metastatic cancer cells, those that have broken away from the original tumor, can erupt into a frenzy of growth and division months, years, or decades after initial treatment, seeding new, life-threatening tumors.

Shafaq Zia | Whitehead Institute
September 3, 2025

This migration of cancer cells, called metastasis, is especially common in breast cancer. For many patients, the disease can return months—or even decades—after initial treatment, this time in an entirely different organ.

Whitehead Institute Founding Member Robert Weinberg, also the Daniel K. Ludwig Professor for Cancer Research at Massachusetts Institute of Technology (MIT), has spent decades unraveling the complex biology of metastasis and pursuing research that could improve survival rates among patients with metastatic breast cancer—or prevent metastasis altogether.

In their latest study, Weinberg, postdoctoral fellow Jingwei Zhang, and colleagues ask a critical question: what causes these dormant cancer cells to erupt into a frenzy of growth and division? The group’s findings, published Sept. 1 in The Proceedings of the National Academy of Sciences (PNAS), point to a unique culprit.

This awakening of dormant cancer cells, they’ve discovered, isn’t a spontaneous process. Instead, the wake-up call comes from the inflamed tissue surrounding the cells. One trigger for this inflammation is bleomycin, a common chemotherapy drug that can scar and thicken lung tissue.

“The inflammation jolts the dormant cancer cells awake,” Weinberg says. “Once awakened, they start multiplying again, seeding new life-threatening tumors in the body.”

Decoding metastasis

There’s a lot that scientists still don’t know about metastasis, but this much is clear: cancer cells must undergo a long and arduous journey to achieve it. The first step is to break away from their neighbors within the original tumor.

Normally, cells stick to one another using surface proteins that act as molecular “velcro” but some cancer cells can acquire genetic changes that disrupt the production of these proteins and make them more mobile and invasive, allowing them to detach from the parent tumor.

Once detached, they can penetrate blood vessels and lymphatic channels, which act as highways to distant organs.

While most cancer cells die at some point during this journey, a few persist. These cells exit the bloodstream and invade different tissues—lungs, liver, bone, and even the brain—to give birth to new, often more aggressive tumors.

“Almost 90% of cancer-related deaths occur not from the original tumor but when cancer cells spread to other parts of the body,” says Weinberg. “This is why it’s so important to understand how these ‘sleeping’ cancer cells can wake up and start growing again.”

Setting up shop in new tissue comes with changes in surroundings—the “tumor microenvironment”—to which the cancer cells may not be well-suited. These cells face constant threats, including detection and attack by the immune system.

To survive, they often enter a protective state of dormancy that puts a pause on growth and division. This dormant state also makes them resistant to conventional cancer treatments, which often target rapidly dividing cells.

To investigate what makes this dormancy reversible months or years down the line, researchers in the Weinberg Lab injected human breast cancer cells into mice. These cancer cells were modified to produce a fluorescent protein, allowing the scientists to track their behavior in the body.

The group then focused on cancer cells that had lodged themselves in the lung tissue. By examining them for specific proteins—Ki67, ITGB4 and p63—that act as markers of cell activity and state, the researchers were able to confirm that these cells were in a non-dividing, dormant state.

Previous work from the Weinberg Lab had shown that inflammation in organ tissue can provoke dormant breast cancer cells to start growing again. In this study, the team tested bleomycin—a chemotherapy drug known to cause lung inflammation—that can be given to patients after surgery to lower the risk of cancer recurrence.

The researchers found that lung inflammation from bleomycin was sufficient to trigger the growth of large lung cancer colonies in treated mice—and to shift the character of these once dormant cells to those that are more invasive and mobile.

Zeroing in on the tumor microenvironment, the team identified a type of immune cells, called M2 macrophages, as drivers of this process. These macrophages release molecules called epidermal growth factor receptor (EGFR) ligands, which bind to receptors on the surface of dormant cancer cells. This activates a cascade of signals that provoke dormant cancer cells to start multiplying rapidly.

But EGFR signaling is only the initial spark that ignites the fire. “We found that once dormant cancer cells are awakened, they retain what we call an ‘awakening memory,’” Zhang says. “They no longer require ongoing inflammatory signals from the microenvironment to stay active [growing and multiplying]—they remember the awakened state.”

While signals related to inflammation are necessary to awaken dormant cancer cells, exactly how much signaling is needed remains unclear. “This aspect of cancer biology is particularly challenging because multiple signals contribute to the state change in these dormant cells,” Zhang says.

The team has already identified one key player in the awakening process but understanding the full set of signals and how each contributes is far more complex—a question they are continuing to investigate in their new work.

Studying these pivotal changes in the lives of cancer cells—such as their transition from dormancy to active growth—will deepen our scientific understanding of metastasis and, as researchers in the Weinberg Lab hope, lead to more effective treatments for patients with metastatic cancers.

Rudolf Jaenisch awarded Ogawa-Yamanaka Stem Cell Prize

Rudolf Jaenisch is recognized for his trailblazing contributions to epigenetics and stem cell biology, which have shaped modern regenerative medicine.

Sarah Stanley | Gladstone Institutes
August 28, 2025

Rudolf Jaenisch, MD, was announced today as the recipient of the 2025 Ogawa-Yamanaka Stem Cell Prize by Gladstone Institutes. He was selected for his trailblazing contributions to epigenetics and stem cell biology. His pivotal discoveries have profoundly advanced our understanding of gene regulation, cellular reprogramming, and the potential of regenerative medicine.

A founding member of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, Jaenisch is also a professor of biology at the Massachusetts Institute of Technology. He is widely recognized for his role in establishing the use in science of induced pluripotent stem (iPS) cells—adult cells that have been reprogrammed into an embryonic stem cell–like state with the potential to become any cell type in the body.

Among his many achievements, Jaenisch was the first to show the potential therapeutic applications of iPS cells after they were discovered by Gladstone Senior Investigator Shinya Yamanaka, MD, PhD. In fact, Jaenisch effectively cured mice of sickle cell anemia by using iPS cells that had been derived from the animals’ own skin cells and in which the disease-causing genetic defect had been corrected.

“Until then, iPS cells were just an exciting lab tool—but Dr. Jaenisch provided the first real proof that they could be used to treat human disease,” says Deepak Srivastava, MD, chair of the selection committee, president of Gladstone Institutes, and director of the Rodenberry Stem Cell Center at Gladstone. “We’re very happy to recognize his outstanding career with this year’s award. His many contributions to stem cell research and disease modeling have helped shape modern regenerative medicine as we know it.”

Jaenisch has been at the forefront of exploring, expanding, and refining the processes by which iPS cells are created and applied in labs around the world. His work has opened the door to the development of therapies for a wide range of genetic and degenerative diseases.

Since its establishment in 2015, the Ogawa-Yamanaka Stem Cell Prize has honored scientists and doctors leading groundbreaking work in translational regenerative medicine using reprogrammed cells. Each year, it is made possible by a generous gift from the Hiro and Betty Ogawa family.

The prize, supported by Gladstone and Cell Press, also pays tribute to Yamanaka, whose discovery of iPS cells earned him a Nobel Prize in 2012 and is tightly intertwined with Jaenisch’s work.

“Shinya’s discovery completely transformed the world of stem cell science and opened up so many promising new paths for understanding and addressing disease,” Jaenisch says. “What an honor it is to be recognized for my contributions in this field.”

One of Jaenisch’s earliest marks on science came in 1974, when he co-created the first transgenic animal—an organism whose genetic material has been intentionally altered by adding foreign genes—with pioneering embryologist Beatrice Mintz, PhD. This work became the foundation for genetically engineered animal models, which are used in nearly every area of biomedical research today.

“This single study was a major leap in molecular biology,” says Srivastava. “It gave birth to the very concept of modeling human diseases in animals, allowing scientists to deliberately change an animal’s genetic code in order to study the mechanisms of disease and test therapies.”

In his more than 40 years at the Whitehead Institute, Jaenisch has led research exploring how stem cells and reprogramming technologies could be harnessed to better understand and treat disease. In the process, he has continued to develop innovative tools, including adapting CRISPR technology for gene editing and epigenome editing in stem cell systems.

An independent committee of international stem cell experts selected Jaenisch for the 2025 Ogawa-Yamanaka Stem Cell Prize from a highly competitive pool of nominees. As this year’s winner, he will receive an unrestricted prize of $150,000. Gladstone will host a ceremony on December 1, 2025, in San Francisco, California, where Jaenisch will deliver a scientific lecture and be presented with the award.

About Gladstone Institutes

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.

About Rudolf Jaenisch

Rudolf Jaenisch, MD, is a founding member of the Whitehead Institute for Biomedical Research and a professor of biology at the Massachusetts Institute of Technology. He is a pioneer of transgenic science, in which an animal’s genetic makeup is altered.

Jaenisch received his MD from the University of Munich in 1967 and carried out postdoctoral research at Princeton University, Fox Chase Institute for Cancer Research, and the Salk Institute. Before joining Whitehead in 1982, he was head of the Department of Tumor Virology at the Heinrich Pette Institute at the University of Hamburg.

His current research focuses on the epigenetic regulation of gene expression, which has led to major advances in creating embryonic stem cells and iPS cells, as well as their therapeutic applications. His lab also focuses on the epigenetic mechanisms involved in cancer and brain development, as well as coronavirus biology.

Jaenisch has co-authored more than 500 research papers and received various awards during his career, including the Max Delbrück Medal, the Vilcek Prize, the National Medal of Science, the Wolf Prize in Medicine, and the Otto Warburg Medal. He is a fellow of the American Academy of Arts and Sciences and an elected member of the U.S. National Academy of Sciences. He also was president of the International Society for Stem Cell Research in 2014–15.

About the Ogawa-Yamanaka Stem Cell Prize

The Ogawa-Yamanaka Stem Cell Prize recognizes individuals whose original translational research has advanced cellular reprogramming technology for regenerative medicine. Supported by Gladstone Institutes, in partnership with Cell Press, the prize was established in 2015 through a generous gift from Betty and Hiro Ogawa. It has been maintained through their sons, Andrew and Marcus Ogawa, to honor the Ogawas’ memory by continuing the philanthropic legacy they shared during their 46-year marriage. It also recognizes the importance of induced pluripotent stem cells (iPS cells), discovered by Gladstone Senior Investigator and Nobel laureate Shinya Yamanaka, MD, PhD.

Past recipients include Masayo Takahashi, MD, PhD, in 2015; Douglas Melton, PhD, in 2016; Lorenz Studer, MD, in 2017; Marius Wernig, MD, PhD, in 2018; Gordon Keller, PhD, in 2019; Juan Carlos Izpisua Belmonte, PhD, in 2022; Magdalena Zernicka-Goetz, PhD, in 2023; and Rusty Gage, PhD, in 2025.

The 2025 selection committee was composed of George Daley, MD, PhD, dean of Harvard Medical School; Hideyuki Okano, MD, PhD, dean of the School of Medicine at Keio University; Deepak Srivastava, MD, president of Gladstone Institutes and director of the Roddenberry Stem Cell Center at Gladstone; Lorenz Studer, MD, director of the Center for Stem Cell Biology at Memorial Sloan Kettering Cancer Center; Fiona Watt, FRS, FMedSci, director of the Centre for Stem Cells and Regenerative Medicine at King’s College, London; and Shinya Yamanaka, MD, PhD, senior investigator at Gladstone and director emeritus of the Center for iPS Cell Research and Application at Kyoto University.