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Exploring the links between diet and cancer

Omer Yilmaz’s work on how diet influences intestinal stem cells could lead to new ways to treat or prevent gastrointestinal cancers.

Anne Trafton | MIT News Office
May 25, 2023

Every three to five days, all of the cells lining the human intestine are replaced. That constant replenishment of cells helps the intestinal lining withstand the damage caused by food passing through the digestive tract.

This rapid turnover of cells relies on intestinal stem cells, which give rise to all of the other types of cells found in the intestine. Recent research has shown that those stem cells are heavily influenced by diet, which can help keep them healthy or stimulate them to become cancerous.

“Low-calorie diets such as fasting and caloric restriction can have antiaging effects and antitumor effects, and we want to understand why that is. On the other hand, diets that lead to obesity can promote diseases of aging, such as cancer,” says Omer Yilmaz, the Eisen and Chang Career Development Associate Professor of Biology at MIT.

For the past decade, Yilmaz has been studying how different diets and environmental conditions affect intestinal stem cells, and how those factors can increase the risk of cancer and other diseases. This work could help researchers develop new ways to improve gastrointestinal health, either through dietary interventions or drugs that mimic the beneficial effects of certain diets, he says.

“Our findings have raised the possibility that fasting interventions, or small molecules that mimic the effects of fasting, might have a role in improving intestinal regeneration,” says Yilmaz, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

A clinical approach

Yilmaz’s interest in disease and medicine arose at an early age. His father practiced internal medicine, and Yilmaz spent a great deal of time at his father’s office after school, or tagging along at the hospital where his father saw patients.

“I was very interested in medicines and how medicines were used to treat diseases,” Yilmaz recalls. “He’d ask me questions, and many times I wouldn’t know the answer, but he would encourage me to figure out the answers to his questions. That really stimulated my interest in biology and in wanting to become a doctor.”

Knowing that he wanted to go into medicine, Yilmaz applied and was accepted to an eight-year, combined bachelor’s and MD program at the University of Michigan. As an undergraduate, this gave him the freedom to explore areas of interest without worrying about applying to medical school. While majoring in biochemistry and physics, he did undergraduate research in the field of protein folding.

During his first year of medical school, Yilmaz realized that he missed doing research, so he decided to apply to the MD/PhD program at the University of Michigan. For his PhD research, he studied blood-forming stem cells and identified new markers that allowed such cells to be more easily isolated from the bone marrow.

“This was important because there’s a lot of interest in understanding what makes a stem cell a stem cell, and how much of it is an internal program versus signals from the microenvironment,” Yilmaz says.

After finishing his PhD and MD, he thought about going straight into research and skipping a medical residency, but ended up doing a residency in pathology at Massachusetts General Hospital. During that time, he decided to switch his research focus from blood-forming stem cells to stem cells found in the gastrointestinal tract.

“The GI tract seemed very interesting because in contrast to the bone marrow, we knew very little about the identity of GI stem cells,” Yilmaz says. “I knew that once GI stem cells were identified, there’d be a lot of interesting questions about how they respond to diet and how they respond to other environmental stimuli.”

Dietary questions

To delve into those questions, Yilmaz did postdoctoral research at the Whitehead Institute, where he began investigating the connections between stem cells, metabolism, diet, and cancer.

Because intestinal stem cells are so long-lived, they are more likely to accumulate genetic mutations that make them susceptible to becoming cancerous. At the Whitehead Institute, Yilmaz began studying how different diets might influence this vulnerability to cancer, a topic that he carried into his lab at MIT when he joined the faculty in 2014.

One question his lab has been exploring is why low-calorie diets often have protective effects, including a boost in longevity — a phenomenon that has been seen in many studies in animals and humans.

In a 2018 study, his lab found that a 24-hour fast dramatically improves stem cells’ ability to regenerate. This effect was seen in both young and aged mice, suggesting that even in old age, fasting or drugs that mimic the effects of fasting could have a beneficial effect.

On the flip side, Yilmaz is also interested in why a high-fat diet appears to promote the development of cancer, especially colorectal cancer. In a 2016 study, he found that when mice consume a high-fat diet, it triggers a significant increase in the number of intestinal stem cells. Also, some non-stem-cell populations begin to resemble stem cells in their behavior. “The upshot of these changes is that both stem cells and non-stem-cells can give rise to tumors in a high-fat diet state,” Yilmaz says.

To help with these studies, Yilmaz’s lab has developed a way to use mouse or human intestinal stem cells to generate miniature intestines or colons in cell culture. These “organoids” can then be exposed to different nutrients in a very controlled setting, allowing researchers to analyze how different diets affect the system.

Recently, his lab adapted the system to allow them to expand their studies to include the role of immune cells, fibroblasts, and other supportive cells found in the microenvironment of stem cells. “It would be remiss of us to focus on just one cell type,” Yilmaz says. “We’re looking at how these different dietary interventions impact the entire stem cell neighborhood.”

While Yilmaz spends most of his time running his lab at MIT, he also devotes six to eight weeks per year to his work at MGH, where he is an associate pathologist focusing on gastrointestinal pathology.

“I enjoy my clinical work, and it always reminds me about the importance of the research we do,” he says. “Seeing colon cancer and other GI cancers under the microscope, and seeing their complexity, reminds me of the importance of our mission to figure out how we can prevent these cancers from forming.”

MIT community members who work to eradicate sexual violence recognized at 2023 Change-Maker Awards

Violence Prevention and Response and the Institute Discrimination and Harassment Response Office celebrate students and employees for their efforts in combating sexual misconduct.

Vera Grbic | Office of the Chancellor
May 24, 2023

On April 24, MIT celebrated outstanding students and employees at the annual Change-Maker Awards for their diligent work to eradicate sexual misconduct and support survivors. These architects of positive change exemplify one of MIT’s core values: striving to make our community a more humane and welcoming place where all can thrive.

Hosted by MIT Violence Prevention and Response (VPR) and the Institute Discrimination and Harassment Response Office (IDHR), the awards are held each April to coincide with Sexual Assault Awareness Month. The awardees were recognized at a ceremony among invited senior leaders and the faculty, staff, and students involved in the Institute’s sexual misconduct prevention and response work. The awards were held in person for the first time since 2019, making this year’s celebration with fellow community members a very special event.

Chancellor Melissa Nobles opened the event by noting that, “Tonight’s honorees — individual students and staff members, a student group, and an entire office — are all amazing leaders and advocates. Day-in and day-out, they are making enduring contributions so that MIT is a more safe, supportive, respectful, and welcoming community for all.”

Nominated by peers and colleagues from across MIT, this year’s Change-Makers were selected for their multifaceted contributions, creative approaches, and breadth and depth of impact. Honors went to an undergraduate student; a graduate student; a student group; an employee group; and a PLEASURE Peer Educator of the Year. For the first time in Change-Maker Awards history, Provost Cynthia Barnhart recognized a longtime MIT employee and Change-Maker with a special recognition award.

The following students and employees are MIT’s 2023 Change-Makers:

  • Outstanding Undergraduate Student: Ana Velarde, a third-year undergraduate student in biology and women’s and gender studies, is an MIT Change-Maker who goes out of her way to volunteer her time, lifts up fellow community members doing this important work, and regularly facilitates workshops that challenge harmful cultural norms around sexual violence and harassment. Velarde serves on PLEASURE’s Executive Committee and has led over 30 hours of peer-to-peer trainings. She co-chaired PLEASURE’s biggest event of the year — PLEASURE Week, a week-long series of educational events that reach hundreds of students — to support the student group’s mission of ending sexual violence and promoting healthy relationships. Velarde’s collaboration with MIT faculty also led to a Queer Faculty and Staff Panel.
  • Outstanding Graduate Student: Jules Drean, a fifth-year PhD student in electrical engineering and computer science and Computer Science and Artificial Intelligence Laboratory affiliate, is this year’s graduate student Change-Maker. Drean advocates for survivors of sexual violence by educating peers about reporting options and supportive measures. He is also a member of the MIT student group Student Advocates for Survivors (SAS). Through his work with the Department of Electrical Engineering and Computer Science’s Thrive — a student group that supports all forms of diversity — he curated various initiatives, from a discussion group about a TV show that portrays violence to a self-care class. In all these endeavors, Drean’s thoughtful presence and unhurried compassion bring other graduate students along with him in this critical work.
  • Outstanding Employee Group: The Office of Graduate Education (OGE) Graduate Support Staff were honored for helping graduate students navigate the aftermath of harassment or assault. They represent graduate students’ concerns on numerous committees and are helping create an online training module about navigating power dynamics. They have also taken on the day-to-day work of managing the Guaranteed Transitional Support Program, advancing funding for graduate students seeking a new lab or principal investigator. The team gladly stepped up to take on this new responsibility because they recognize the positive impact the program has on graduate students.
  • Outstanding Student Group: The MIT Monologues (MITMo) is an annual show run by students who create and produce an adaptation of the Vagina Monologues tailored to the MIT community. These students embody what it means to be a Change-Maker as they use theater, one of our most powerful modes of societal change, to challenge and reflect on the harmful attitudes that support sexual violence. The show is a series of performances highlighting subjects ranging from sex, gender equity, and sexual assault. The performances also actively work to highlight the experiences of those from marginalized communities. MITMo donates all profits from the show to the Boston Area Rape Crisis Center, a local nonprofit agency dedicated to helping victims of sexual assault.
  • Outstanding PLEASURE Peer Educator: Em McDermott, a graduating senior in biology, is this year’s PLEASURE Peer Educator Change-Maker. PLEASURE is a student-led peer education program that promotes healthy relationships and strives to eliminate sexual violence at MIT. As a Change-Maker, McDermott’s impact at MIT has been profound. This past year, they continued to serve on PLEASURE’s executive board as the communications chair. In the spring, they co-led a seminar on body positivity, body neutrality, and self-love, exploring body shaming systems and offering insight into how to reconnect with the self. Ultimately, McDermott leads with compassion and intentionally empowers others to make their voices heard, serving as a role model for peer educators for years to come.
  • Special Recognition Award: Maryanne Kirkbride was recognized for her many years of creating change at MIT. As MIT’s deputy Institute community and equity officer and co-founder and former executive director of MindHandHeart, Kirkbride has been serving the MIT community for over 20 years. She is lauded for her creative and committed leadership at MindHandHeart, where she created and led a coalition of students, faculty, and staff who strengthened the fabric of the MIT community. At MindHandHeart she added the Department Support Program to enhance the welcoming and inclusive climate of each academic department. While Kirkbride was a nurse at MIT Medical, focused on public health, she helped secure a federal grant to fund the formation of Violence Prevention and Response, an office that provides support and advocacy for students who have experienced sexual violence. As Kirkbride will be retiring, the Change-Makers Committee felt it was important to celebrate the many ways she has worked to create a more welcoming and supportive MIT.
3 Questions: A new model of nervous system form, function, and evolution

Developing a new neuroscience model is no small feat. New faculty member Brady Weissbourd has risen to the challenge in order to study nervous system evolution, development, regeneration, and function.

Lillian Eden | Department of Biology
May 22, 2023

How does animal behavior emerge from networks of connected neurons? How are these incredible nervous systems and behaviors actually generated by evolution? Are there principles shared by all nervous systems or is evolution constantly innovating? What did the first nervous system look like that gave rise to the incredible diversity of life that we see around us?

Combining the study of animal behavior with studies of nervous system form, function, and evolution, Brandon “Brady” Weissbourd, a new faculty member in the Department of Biology and investigator in The Picower Institute for Learning and Memory, uses the tiny, transparent jellyfish Clytia hemisphaerica, a new neuroscience model.

Q: In 2021, you developed a new model organism for neuroscience research, the transparent jellyfish Clytia hemisphaerica. How do these jellyfish answer questions about neuroscience, the nervous system, and evolution in ways that other models cannot?

A: First, I believe in the importance of more broadly understanding the natural world and diversifying the organisms that we deeply study. One reason is to find experimentally tractable organisms to identify generalizable biological principles — for example, we understand the basis of how neurons “fire” from studies of the squid giant axon. Another reason is that transformative breakthroughs have come from identifying evolutionary innovations that already exist in nature — for example, green fluorescent protein (GFP, from jellyfish) or CRISPR (from bacteria). In both ways, this jellyfish is a valuable complement to existing models.

I have always been interested in the intersection of two types of problems: how nervous systems generate our behaviors; and how these incredible systems were actually created by evolution.

On the systems neuroscience side, ever since working on the serotonin system during my PhD I have been fascinated by the problem of how animals control all of their behaviors simultaneously in a flexible and context-dependent manner, and how behavioral choices depend not just on incoming stimuli but on how those stimuli interact with constantly changing states of the nervous system and body. These are extremely complex and difficult problems, with the particular challenge of interactions across scales, from chemical signaling and dynamic cell biology to neural networks and behavior.

To address these questions, I wanted to move into a model organism with exceptional experimental tractability.

There have been exciting breakthroughs in imaging techniques for neuroscience, including these incredible ways in which we can actually watch and manipulate neuronal activity in a living animal. So, the first thing I wanted was a small and transparent organism that would allow for this kind of optical approach. These jellyfish are a few millimeters in diameter and perfectly transparent, with interesting behaviors but relatively compact nervous systems. They have thousands of neurons where we have billions, which also puts them at a nice intermediate complexity compared to other transparent models that are widely used — for example, C. elegans have 302 neurons and larval zebrafish have something like 100,000 in the brain alone. These features will allow us to look at the activity of the whole nervous system in behaving animals to try to understand how that activity gives rise to behaviors and how that activity itself arises from networks of neurons.

On the evolution side of our work, we are interested in the origins of nervous systems, what the first nervous systems looked like, and broadly what the options are for how nervous systems are organized and functioning: to what extent there are principles versus interesting and potentially useful innovations, and if there are principles, whether those are optimal or somehow constrained by evolution. Our last common ancestor with jellyfish and their relatives (the cnidarians) was something similar to the first nervous system, so by comparing what we find in cnidarians with work in other models we can make inferences about the origins and early evolution of nervous systems. As we further explore these highly divergent animals, we are also finding exciting evolutionary innovations: specifically, they have incredible capabilities for regenerating their nervous systems. In the future, it will be exciting to better understand how these neural networks are organized to allow for such robustness.

Q: What work is required to develop a new organism as a model, and why did you choose this particular species of jellyfish?

A: If you’re choosing a new animal model, it’s not just about whether it has the right features for the questions you want to ask, but also whether it technically lets you do the right experiments. The model we’re using was first developed by a research group in France, who spent many years doing the really hard work of figuring out how to culture the whole life cycle in the lab, injecting eggs, and developing other key resources. For me, the big question was whether we’d be able to use the genetic tools that I was describing earlier for looking at neural activity. Working closely with collaborators in France, our first step was figuring out how to insert things into the jellyfish genome. If we couldn’t figure that out, I was going to switch back to working with mice. It took us about two years of troubleshooting, but now we can routinely generate genetically modified jellyfish in the lab.

Switching to a new animal model is tough — I have a mouse neuroscience background and joined a postdoc lab that used mice and flies; I was the only person working with jellyfish, but had no experience. One of my goals is now to optimize and simplify this whole process so that when other labs want to start working with jellyfish we have a simple aquaculture platform to get them started, even if they have no experience.

In addition to the fact that these things are tiny and transparent, the main reason that we chose this particular species is because it has an amazing life cycle that makes it an exciting laboratory animal.

They have separate sexes that spawn daily with the fertilized eggs developing into larvae that then metamorphose into polyps. We grow these polyps on microscope slides, where they form colonies that are thought to be immortal. These colonies are then constantly releasing jellyfish, which are all genetically identical “clones” that can be used for experiments. That means that once you create a genetically modified strain, like a transgenic line or a knockout, you can keep it forever as a polyp colony — and since the animals are so small, we can culture them in large numbers in the lab.

There’s still a huge amount of foundational work to do, like characterizing their behavioral repertoire and nervous system organization. It’s shocking how little we know about the basics of jellyfish biology — particularly considering that they kill more people per year than sharks and stingrays combined — and the more we look into it, the more questions there are.

Q: What drew you to a faculty position at MIT?

A: I wanted to be in a department that does fundamental research, is enthusiastic about basic science, is open-minded, and is very diverse in what people work on and think about. My goal is also to be able to ultimately link mechanisms at the molecular and cellular level to organismal behavior, which is something that [the] MIT [Department of] Biology is particularly strong at doing. It’s been an exciting first few months! MIT Biology is such an amazing place to do science and it’s been wonderful how enthusiastic and supportive everyone in the department has been.

I was additionally drawn to MIT by the broader community and have already found it so easy to start collaborations with people in neuroscience, engineering, and math. I’m also thrilled to have recently become a member of The Picower Institute for Learning and Memory, which further enables these collaborations in a way that I believe will be transformational for the work in my lab.

It’s a new lab. It’s a new organism. There isn’t a huge, well-established field that is taking these approaches. There’s so much we don’t know, and so much that we have to establish from scratch. My goal is for my lab to have a sense of adventure and fun, and I’m really excited to be doing that here in MIT Biology.

3 Questions: Sara Prescott on the brain-body connection

New MIT faculty member investigates how sensory input from within the body controls mammalian physiology and behavior.

Lillian Eden | Department of Biology | Picower Institute for Learning and Memory
May 17, 2023

Many of our body’s most important functions occur without our conscious knowledge, such as digestion, heartbeat, and breathing. These vital functions depend on the signals generated by the “interoceptive nervous system,” which enables the brain to monitor our internal organs and trigger responses that sometimes save our lives. One second you are breathing normally as you eat your salad and the next, when a vinegar-soaked crouton enters your throat, you are coughing or swallowing to protect and clear your airway. We know our bodies are sensitive to cues like irritants, but we still have a lot to learn about how the interoceptive system works to meet our physiological needs, keep organs safe and healthy, and affect our behavior. We can also learn how chronic insults may lead to organ dysfunction and use what we learn to create therapeutic interventions.

Focusing on the airway, Sara Prescott, a new faculty member in the Department of Biology and investigator in The Picower Institute for Learning and Memory, seeks to understand the ways our nervous systems detect and respond to stimuli in health and disease. Here, she describes her work.

Q: Why is understanding the peripheral nervous system important, and what parts of your background are you drawing on for your current research?

A: The lab focuses on really trying to explore the body-brain connection.

People often think that our mind exists in a vacuum, but in reality, our nervous system is heavily integrated with the rest of the body, and those neural interfaces are important, both for taking information from our body or environment and turning it into an internal representation of the world, and, in reverse, being able to process that information and being able to enact changes throughout the body. That includes things like autonomic reflexes, basic functions of the body like breathing, blood-gas regulation, digestion, and heart rate.

I’ve integrated both my graduate training and postdoctoral training into thinking about biology across multiple scales.

Graduate school for me was quite focused on deep molecular mechanism questions, particularly gene regulation, so I feel like that has been very useful for me in my general approach to neuroscience because I take a very molecular angle to all of this.

It also showed me the power of in vitro models as reductionist tools to explore fundamental aspects of cell biology. During my postdoc, I focused on larger, emergent phenotypes. We were able to manipulate specific circuits and see very impressive behavioral responses in animals. You could stimulate about 100 neurons in a mouse and see that their breathing would just stop until you remove the stimulation, and then the breathing would return to normal.

Both of those experiences inform how we approach a problem in my research. We need to understand how these circuits work, not just their connectivity at the anatomical level but what is driving their changes in sensitivity over time, the receptor expression programs that affect how they sense and signal, how these circuits emerge during development, and their gene expression.

There are still s­o many foundational questions that haven’t been answered that there’s enough to do in the mouse for quite some time.

Q: How are you specifically looking into interoceptive biology at MIT?

A: Our flagship system is the mammalian airway. We use a mouse model and modern molecular neuroscience tools to manipulate various neural pathways and observe what the effects are on respiratory function and animal health.

Neuroscience and mouse work have a reputation for being a little challenging and intense, but I think this is also where we can ask really important questions that are useful for our everyday lives — and the only place where we can fully recapitulate the complexity of nervous system signaling all the way down to our organs, back to our brain, and back to our organs.

It’s a very fun place to do science with lots of open questions.

One of the core discoveries from my postdoctoral work was focusing on the vagus nerve as a major body-to-brain conduit, as it innervates our lungs, heart, and gastrointestinal tract. We found that there were about 40 different subtypes of sensory neurons within this small nerve, which is really a remarkable amount of diversity and reflects the massive sensory space within the body. About a dozen of those vagal neurons project to the airways.

We identified a rare neuron type specifically responsible for triggering protective responses, like coughing when water or acid entered the airway. We also discovered a separate population of neurons that make us feel and act sick when we get a flu infection. The field now knows what four to five vagal populations of neurons are actually sensing in the airways, but the remaining populations are still a mystery to us; we don’t know what those populations of sensory neurons are detecting, what their anatomy is, and what reflex effects those neurons are evoking.

Looking ahead, there are many exciting directions for the interoceptive biology field. For example, there’s been a lot of focus on characterizing the circuits underlying acute motor reflexes, like rapid responses to visceral stimuli on the timescale of minutes to hours. But we don’t have a lot of information about what happens when these circuits are activated over long periods of time. For example, respiratory tract infections often last for weeks or longer. We know that the airways undergo changes in composition when they’re exposed to different types of infection or stress to better accommodate future threats. One of the hypotheses we’re testing is that chronically activating neural circuits may drive changes in organ composition. We have this idea, which we’re calling reflexive remodeling: neurons may be communicating with stem cells and progenitor cells in the periphery to drive adaptive remodeling responses.

We have the genetic, molecular, and circuit scale tools to explore this pheno­­­menon in mice. In parallel, we’re also setting up some in vitro models of the mouse airway mucosa to expedite receptor screening and to explore basic mechanisms of neuron-epithelium cross-talk. We hope this will inform our understanding of how the airway surface senses and responds to different types of irritants or damage.

Q: This all sounds fascinating. Where does it lead?

A: Human health has been my north star for a long time and I’ve taken a long, wandering path to find particular areas where I can scratch whatever intellectual itch that I have.

I originally thought I would be a doctor and then realized that I felt like I could have a more lasting impact by discovering fundamental truths about how our bodies work. I think there are a number of chronic diseases in which autonomic imbalance is actually a huge clinical component of the disorder.

We have a lot of interest in some of these very common airway remodeling diseases, like chronic obstructive pulmonary disorder — COPD — asthma, and potentially lung cancer. We want to ask questions like how autonomic circuits are altered in disease contexts, and when neurons actually drive features of disease.

Perhaps this research will help us come up with better molecular, cellular, or tissue engineering approaches to improve the outcomes for a variety of autonomic diseases.

It’s very easy for me to imagine how one day, not too far from now, we can turn these findings into something actionable for human health.

Siniša Hrvatin Named a Searle Scholar

Biology Professor and Whitehead Institute Member Siniša Hrvatin has been named as one of the 15 researchers to be selected as 2023 Searle Scholars. The Searle Scholars Program supports the research of exceptional young faculty in the biomedical sciences and chemistry.

Merrill Meadow | Whitehead Institute
May 12, 2023

Whitehead Institute Member Siniša Hrvatin has been named as one of the 15 researchers to be selected as 2023 Searle Scholars. The Searle Scholars Program supports the research of exceptional young faculty in the biomedical sciences and chemistry.

Chosen by an advisory board of eminent scientists, Searle Scholars are considered among the most creative researchers pursuing careers in academic research. Their investigations address challenging research questions and can lead to new insights that fundamentally change their fields—and to opportunities for translating discoveries into new therapeutics and diagnostics.

“I am truly grateful for the support of the Searle Scholar Program as we embark on this ambitious project,” says Hrvatin, who joined the Institute in 2021 and is also an assistant professor of biology at Massachusetts Institute of Technology. The three-year grant accompanying the award will support his work developing a new animal model for the study of hibernation.

“The ability to maintain nearly constant body temperature is a defining feature of mammalian and avian evolution; but, when challenged by harsh environments, many species decrease body temperature and metabolic rate and initiate energy-conserving states of torpor and hibernation,” Hrvatin notes. “Science has not yet answered the fundamental questions of how mammals initiate, regulate, and survive these extraordinary hypometabolic and hypothermic states.

“However, those answers could have profound medical applications,” he explains. “For example, harnessing the mechanisms behind hibernation might provide new approaches to protect neurons from ischemic injury and to preserve tissues and organs for transplantation.”

In the Searle-supported study, Hrvatin aims to discover a control center in the brain that regulates distinct stages of hibernation in the Syrian hamster. His lab will start by identifying the brain regions active during the deep torpor stage of hibernation and, using molecular profiling techniques, will then identify the specific neuronal populations and molecular pathways involved. Finally, the team will develop new tools to determine specific activities in those neural populations that are necessary for natural hibernation—and that may be sufficient to induce a synthetic state of hibernation.

“Taken together,” Hrvatin says, “I believe that our discoveries and the tools we build will help establish the first controllable animal model of hibernation.”

Since 1981, 677 scientists have been named Searle Scholars and the Program has awarded more than $152 million in support for Scholars’ research. To date, 85 Searle Scholars have been inducted into the National Academy of Sciences, 20 have been recognized with a MacArthur Fellowship, and two have been awarded the Nobel Prize for Chemistry.

Thirteen from MIT win 2023 Fulbright fellowships

The Fulbright US Student Program funds opportunities for research, graduate study, and teaching abroad.

Julia Mongo | Office of Distinguished Fellowships
May 15, 2023

Thirteen MIT undergraduates, graduate students, and alumni have been awarded Fulbright fellowships and will embark on projects overseas in the 2023-24 grant year. Four other MIT affiliates were offered awards but declined them to pursue other opportunities.

Sponsored by the U.S. Department of State, the Fulbright U.S. Student Program offers American citizen students and recent alumni year-long grants for independent research, graduate study, and English teaching in over 140 countries.

For the past four years, MIT has been a Fulbright Top-Producing Institution. MIT students and alumni interested in applying should contact Julia Mongo in Distinguished Fellowships in Career Advising and Professional Development.

Lainie Beauchemin ’22 earned a BS in biological engineering at MIT, where she researched the molecular underpinnings of schizophrenia and other neurological diseases at the Broad Institute of MIT and Harvard. Her Fulbright project will focus on broadening neurological diagnostic care in rural India, in conjunction with IIT Delhi and Project Prakash. During her time at MIT, Beauchemin was co-president of a math mentorship program for underserved middle school girls in the Cambridge/Boston area and worked in various roles for The Educational Justice Institute, including teaching Python to incarcerated women. She was chair of the MIT Shakespeare ensemble as well as an actress, producer, and designer for multiple productions. She looks forward to working with the children of Project Prakash to put on a performance to celebrate Diwali.

Shelly Ben-David is a senior studying electrical engineering and computer science with a minor in mechanical engineering. Her Fulbright research fellowship will take her to Lausanne, Switzerland, where she will work on germanium nanowire networks for spin-qubit applications. Beyond her research, Ben-David is excited to improve her French skills and explore the nature and culture that Switzerland has to offer. At MIT, Ben-David mentored over 300 middle school girls and non-binary students in Scratch through CodeIt; served her community in Maseeh Hall’s Executive Council; and spent much of her time in MIT.nano conducting research, leading building tours, and writing stories about science to inspire young students to pursue STEM. After Fulbright, she plans to return to MIT to pursue a PhD in electrical engineering.

Victor Damptey will graduate in June with a major in biological engineering and a minor in Spanish. At the Chemical Institute of Sarrià in Barcelona, Spain, Damptey will test alternative conduits for cardiovascular grafting surgery. He gained a passion for conducting impactful research at the Hammond Lab, where he helped develop a drug delivery system for osteoarthritis. Damptey has cultivated his interest in applying his Spanish fluency to alleviate real-world problems by serving as an English-as-a-second-language tutor and leading a medical interpreting initiative within ActLingual. He plans to continue utilizing his Spanish skills to effectively engage with local communities in Spain and reinforce his cultural awareness. After his Fulbright year, Damptey will continue his studies in medical school while combining research and public service.

Maggie Freeman is a PhD candidate in the History, Theory and Criticism of Architecture and Art Program and the Aga Khan Program for Islamic Architecture. During her Fulbright year in Amman, Jordan, she will conduct research for her doctoral dissertation, “Principles for Desert Control: Architecture, Imperialism, and Nomadic Peoples during the British Mandate (1920-1948).” Freeman’s research investigates British imperial uses of architecture as a mechanism of control over nomadic Bedouin and Kurdish populations in Palestine, Jordan, and Iraq. In Jordan, she will study transformations of the built environment under British colonial rule and the resulting, ongoing effects on Jordan’s Bedouin community.

Jola Idowu will graduate this spring from the Master of Architecture and Master of City Planning programs at MIT. Her thesis is on the historical preservation of tabby concrete, a global material whose presence in the United States was made possible by the labor of enslaved Blacks and Indigenous peoples along the Eastern Gulf of the United States. For her Fulbright grant, Idowu will research implementation methods of coastal resilience across complicated networks of stakeholders Senegal, focusing on Gorée and the greater Dakar area. She hopes that this work will contribute to centering Black Atlantic narratives within discourses on climate change. As a Nigerian-American, she is excited to explore other parts of West Africa. She will be hosted by the Department of Urban Planning at Cheikh Anta Diop University in Dakar. After Fulbright, Idowu hopes to pursue her licensure in architecture.

Nathan Liang ’21 graduated with a double major in biological engineering and comparative media studies. He is currently teaching high school biology with Teach For America Miami-Dade. As a Fulbright English teaching assistant in Taiwan, he hopes to hone his skills as a teacher leader and share his love of American media with his students. At MIT, his passion for education developed through his work with dynaMIT, Concourse, and InterphaseEDGE, where he filled the roles of co-director, associate advisor, and communications and writing teaching assistant, respectively. He also enjoyed leading the MIT Lion Dance Team and performing as part of Odaiko New England. After Fulbright, Nathan plans to pursue a PhD in education with focuses on social work and uplifting LGBTQ+ communities.

Liam Ludington ’22 graduated from MIT with a mathematics degree and will receive a master’s in mathematics from the University of Oxford this spring. As a Fulbright Germany research grantee at the University of Heidelberg, he is eager to investigate biologically plausible learning algorithms and implement them in brain-inspired computing systems, with the dual aims of bringing the efficiency of the brain to AI systems and better understanding how the brain performs inference. At MIT, Ludington’s research ranged from building flexible solar panel deployment systems to the advantages of a generalized first-price ad auction. He was also a member of the men’s heavyweight crew and the Number Six Club fraternity. After Fulbright, Ludington hopes to pursue a PhD in computational neuroscience.

Rachana Madhukara is a senior double majoring in mathematics and electrical engineering and computer science. She is the recipient of the Fulbright Budapest Semesters in Mathematics-Rényi Institute award. In Hungary, Madhukara will take classes and conduct research on combinatorics. She also looks forward to immersing herself in Hungary’s rich culture and engaging in mathematics teaching outreach to Romani students in the community. At MIT, Madhukara is president of the MIT Undergraduate Society for Women in Mathematics and a mentor for PRIMES Circle and the Research Science Institute. She has been active with the MIT Educational Studies Program, the Ring Committee, and the Borderline murals art project. She has published five papers in mathematical journals and has conducted research at MIT with Professor Henry Cohn as well as through NSF Research Experiences for Undergraduates programs at the University of Minnesota Duluth and the University of Virginia.

Mercy Oladipo will graduate this spring with a BS in computer science and molecular biology. Having always had a passion for health equity and technology, she will continue this work through her Fulbright research in São Paulo, Brazil, with support from the University of São Paulo. In Brazil, Oladipo will use the lens of reproductive justice to investigate disparities in obstetric care experiences and outcomes for Black Brazilian women and create impactful resources to improve care. Oladipo has taught STEM topics to students in Aguascalientes, Mexico, through the MIT International Science and Technology Initiatives (MISTI); conducted research at the Computer Science and Artificial Intelligence Laboratory and Tufts’s MOTHER Lab; and is co-founder of Birth By Us, a health equity-focused digital platform that has been supported by MIT’s Experimental Study Group, the PKG Center, MIT Sandbox, and more

Erica P. Santana ’18 graduated MIT with a bachelor’s degree in electrical engineering and computer science. After MIT, Santana returned to her home island of Puerto Rico, aspiring to leverage data science and artificial intelligence to drive positive change and enhance the local tech ecosystem. Santana’s passion for international education stems from her transformative MISTI undergraduate experiences in Brazil, Chile, and Mexico. As a recipient of a Fulbright graduate studies grant, Santana will pursue an International MBA at IE University in Madrid, Spain, with the goal of advancing her business skills to foster innovation. Combining her technology background and business acumen, Santana hopes to create a lasting global impact in the education and technology sectors.

Sophia Sonnert will graduate this spring with a major in mechanical engineering, concentrating in micro/nanoengineering, and a minor in German. At the Lucerne University of Applied Sciences and Arts in Switzerland, she will create new equipment to observe salt segregation to advance our understanding of salt hydrates as a phase change material for thermal energy storage. She is also excited to explore the Alpine scenery and practice her German. Her previous research experiences at MIT have ranged from microfluidics and studying algae adhesion to a life-cycle assessment of the benefits of sustainability classes as well as e-scooters. During her undergraduate studies, she enjoyed participating in international opportunities in Germany and Mexico. Before starting her Fulbright fellowship, she will conduct droplet sorting research at the Norwegian University of Science and Technology in Trondheim.

Michael Sutton is a senior majoring in computer science and minoring in Chinese. He will be an English teaching assistant in Taiwan. With a deep interest in the intersection of technology and education, Sutton has conducted research on utilizing machine learning techniques to improve classroom assessments and interned for a company focused on using virtual reality for language immersion. Especially committed to language acquisition, he was awarded the MIT Global Languages Excellence prize for his studies in Spanish, Portuguese, and Chinese. Alongside his own language learning, Sutton tutors English through the ESOL (English for Speakers of Other Languages) office and ITEC (Individualized Tutoring for English and Citizenship), helping others achieve their language goals. He is excited to develop his Mandarin skills while immersing himself in Taiwan’s natural beauty and vibrant culture. Sutton is passionate about education and the impact it can have on individuals and communities, and he is eager to contribute to Taiwan’s educational system while learning from the local community.

Veronica Will is a senior majoring in biological engineering. She is a recipient of the Fulbright Taiwan Award in Mind, Brain, and Consciousness. For her Fulbright grant in Taiwan, she will pursue a two-year master’s degree in neuroscience at Taipei Medical University. At MIT, Will was an undergraduate researcher in Professor Polina Anikeeva’s lab, where she worked on developing a soft neural interface device that combined electrical recording, optical stimulation, and microfluidic delivery for use in studying brain tumors. Outside of her research, Will volunteers as an emergency medical technician with MIT Emergency Medical Services and is excited to learn more about the differences in health-care delivery between the United States and Taiwan. After her Fulbright grant, Will hopes to pursue an MD-PhD to combine her passions for research and patient care.

Five MIT faculty elected to the National Academy of Sciences for 2023

Joshua Angrist, Gang Chen, Catherine Drennan, Dina Katabi, and Gregory Stephanopoulos are recognized by their peers for their outstanding contributions to research.

Mary Beth Gallagher | School of Engineering
May 11, 2023

The National Academy of Sciences has elected 120 members and 23 international members, including five faculty members from MIT. Joshua Angrist, Gang Chen, Catherine Drennan, Dina Katabi, and Gregory Stephanopoulos were elected in recognition of their “distinguished and continuing achievements in original research.” Membership to the National Academy of Sciences is one of the highest honors a scientist can receive in their career.

Established in 1863 by a Congressional charter that was signed by Abraham Lincoln, the National Academy of Sciences is a private, nonprofit society of distinguished scholars. Each year, new members are elected by their peers in recognition of their outstanding contributions to their field of research. Together with the National Academy of Engineering and National Academy of Medicine, the National Academy of Sciences aims to “encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine.”

As of this year, the National Academy of Sciences has 2,565 active members and 526 international members. Among the new members added this year are eight MIT alumni, including Thomas Banks PhD ’73; Joan W. Bresnan PhD ’72; Jennifer Elisseeff PhD ’99; current faculty member Dina Katabi SM ’99, PhD ’03; Maria C. Lemos SM ’90, PhD ’95; William B. McKinnon ’76; Emmanuel Saez PhD ’99; and Gunther Uhlmann PhD ’76.

Joshua Angrist

Joshua Angrist is the Ford Professor of Economics at MIT, a co-founder and director of MIT’s Blueprint Labs, and a research associate at the National Bureau of Economic Research. Angrist and his collaborators have pioneered the use of natural experiments to answer important economic questions and developed new econometric tools that help social scientists and policymakers discover the causal effects of individual choices and government policy changes. Angrist’s research explores the economics of education and school reform, the impact of social programs on the labor market, and the labor market effects of immigration, regulation, and economic institutions.

Angrist received his bachelor’s degree in economics from Oberlin College in 1982 and completed his PhD in economics at Princeton University in 1989. He taught at Harvard University and the Hebrew University of Jerusalem before coming to MIT in 1996.

Angrist received the Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel in 2021 with co-laureates Guido Imbens of the Stanford Graduate School of Business and David Card of the University of California at Berkeley. Angrist is a fellow of the American Academy of Arts and Sciences and the Econometric Society, a Margaret MacVicar Faculty Fellow, and has served as co-editor of the Journal of Labor Economics.

Gang Chen

Gang Chen is the Carl Richard Soderberg Professor of Power Engineering in the Department of Mechanical Engineering. Chen is a pioneer in nanoscale heat transfer and energy conversion. He has significantly contributed to the understanding of heat transfer and energy conversion mechanisms; developed high-performance thermoelectric materials, superior semiconductors, highly heat-conductive polymers, and water desalination materials; and advanced solar-thermal and solar photovoltaic technologies. Physics World chose Chen’s work on cubic boron arsenide being a superior semiconductor as a Top 10 Breakthrough in 2022. Scientific American highlighted his directional solvent extraction and thermally charged batteries technologies as one of its annual top 10 World Changing Ideas in 2012 and 2014. His work on high-performance thermoelectric materials won an R&D 100 award.

Chen earned both his bachelor’s and master’s degrees from Huazhong University of Science and Technology in China and his PhD from UC Berkeley. He worked at Duke University and UCLA before joining the MIT faculty in 2001. Chen served as department head of MIT’s Department of Mechanical Engineering from 2013 to 2018 and director of the Solid-State Solar-Thermal Energy Conversion Center for the U.S. Department of Energy EFRC from 2009 to 2018.

Chen is a dedicated mentor and advocate for diversity and inclusion in STEM fields. He has supervised 86 master’s and PhD theses and 60 postdocs. Chen received an NSF Young Investigator Award, an ASME Heat Transfer Memorial Award, an ASME Frank Kreith Award in Energy, a Nukiyama Memorial Award from Japan Heat Transfer Society, a World Technology Network Award in Energy, an SES Eringen Medal, and the Capers and Marion McDonald Award for Excellence in Mentoring and Advising from MIT. He is an academician of Academy Sinica, a fellow of the American Academy of Arts and Sciences, and a National Academy of Engineering member.

Catherine Drennan

Catherine Drennan, professor of biology and chemistry, combines X-ray crystallography, cryo-electron microscopy and other biophysical methods, with the goal of “visualizing” molecular processes by obtaining snapshots of enzymes in action.

Drennan earned her bachelor’s degree from Vassar College, and her PhD from the University of Michigan. Following a postdoctoral fellowship at Caltech, she joined the MIT faculty in 1999, and was named a Howard Hughes Medical Institute Professor in recognition of her teaching in 2006 and a Howard Hughes Medical Institute Investigator in recognition of her research in 2008. Drennan has led by example, dedicating herself to both research and teaching. Her educational initiatives include creating free resources for educators that help students recognize the underlying chemical principles in biology and medicine, and training graduate student teaching assistants and mentors to be effective teacher–scholars.

Recently, the American Society for Biochemistry and Molecular Biology chose Drennan as the recipient of the 2023 William C. Rose Award for her outstanding contributions to biochemical research and commitment to training younger scientists. Among her additional honors are the Everett Moore Baker Memorial Award for Excellence in Undergraduate Teaching, the Harold E. Edgerton Faculty Achievement Award, the Dean’s Educational and Student Advising Award, a Committed to Caring Award, and a Presidential Early Career Award for Scientists and Engineers (PECASE). She has also been named an MIT MacVicar Fellow, a AAAS fellow, an ASBMB fellow, an Alfred P Sloan Fellow, and a Searle Scholar, and she is a member of the American Academy of Arts and Sciences.

Dina Katabi

Dina Katabi is the Thuan and Nicole Pham Professor of Electrical Engineering and Computer Science (EECS), director of the MIT Center for Wireless Networks and Mobile Computing, and a principal investigator at both the Computer Science and Artificial Intelligence Laboratory (CSAIL) and the Abdul Latif Jameel Clinic for Machine Learning in Health (Jameel Clinic), and a co-founder of Emerald Innovations. At CSAIL, she conducts mobile computing, machine learning, and computer vision research while leading the NETMIT group. Katabi is known for her contributions to wireless data transmission, developing wireless devices that assist with digital health using AI and radio signals. These works include an in-home wireless device that continuously monitors the gait speed of patients with Parkinson’s to better track the progression of the disease, an AI model that detects Parkinson’s from individuals’ breathing patterns, and BodyCompass, a radio-frequency-based wireless device that captures sleep data without using cameras or body sensors.

Katabi received a bachelor’s of science from the University of Damascus and continued her studies at MIT, where she earned a master’s of science and a PhD in computer science. She joined EECS faculty in 2003.

She is a member of the American Academy of Arts and Sciences, the National Academy of Engineering, and the National Academy of Sciences, having received the 2013 MacArthur “genius grant” Fellowship as well as the Association for Computing Machinery Prize in Computing in 2018. Additionally, Katabi has earned the ACM Grace Murray Hopper Award, two Test of Time Awards from the ACM’s Special Interest Group on Data Communications, and a Sloan Research Fellowship.

Gregory Stephanopoulos

Gregory Stephanopoulos is the W. H. Dow Professor of Chemical Engineering and Biotechnology. His work focuses on biotechnology, specifically metabolic and biochemical engineering. His research group conducts research on various projects aiming at the development of biological production routes to chemical products and biofuels. The group is also investigating cancer as metabolic disease. He is renowned for his work in reprogramming the gene transcription network of particular bacteria in order to improve their efficiency in converting renewable raw material into valuable chemical products.

Stephanopoulos graduated from the National Technical University of Athens in 1973 with the a bachelor’s degree in chemical engineering. In 1975, he obtained his master’s degree from the University of Florida and, three years later, his PhD from the University of Minnesota. His professional career started in 1978 as assistant professor at Caltech, where he was promoted in 1984 to the rank of associate professor with tenure. In 1985, Stephanopoulos moved to MIT as a professor of chemical engineering. He was Bayer Professor between 2000 and 2006, when he was appointed to the W. H. Dow Professorship of Chemical Engineering and Biotechnology. From 1990 to 1997 he served as associate director of the Biotechnology Process Engineering Center (BPEC) at MIT. In 2016, he served as president of the American Institute of Chemical Engineers (AIChE).

Stephanopoulos has received many honors, including the 2019 Gaden Award for Biotechnology and Bioengineering, the 2017 Novozymes Award for Excellence in Biochemical and Chemical Engineering, and the 2016 Eric and Sheila Samson Prime Minister’s Prize for Innovation in Alternative Fuels. In 2010, he received the George Washington Carver Award for Innovation in Industrial Biotechnology and the ACS E. V. Murphree Award. From AIChE, he has received the R.H. Wilhelm Award (2001), the Founders Award (2007) and the William Walker Award (2014). In 2011, he received the Eni Prize in Renewable and Non-Conventional Energy, and in 2013 the John Fritz Medal from the American Association of Engineering Societies. Stephanopoulos is a member of the National Academy of Engineering and a corresponding member of the Academy of Athens.

Gene-editing technique could speed up study of cancer mutations

With the new method, scientists can explore many cancer mutations whose roles are unknown, helping them develop new drugs that target those mutations.

Anne Trafton | MIT News Office
May 11, 2023

Genomic studies of cancer patients have revealed thousands of mutations linked to tumor development. However, for the vast majority of those mutations, researchers are unsure of how they contribute to cancer because there’s no easy way to study them in animal models.

In an advance that could help scientists make a dent in that long list of unexplored mutations, MIT researchers have developed a way to easily engineer specific cancer-linked mutations into mouse models.

Using this technique, which is based on CRISPR genome-editing technology, the researchers have created models of several different mutations of the cancer-causing gene Kras, in different organs. They believe this technique could also be used for nearly any other type of cancer mutation that has been identified.

Such models could help researchers identify and test new drugs that target these mutations.

“This is a remarkably powerful tool for examining the effects of essentially any mutation of interest in an intact animal, and in a fraction of the time required for earlier methods,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research at MIT, and one of the senior authors of the new study.

Francisco Sánchez-Rivera, an assistant professor of biology at MIT and member of the Koch Institute, and David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, are also senior authors of the study, which appears today in Nature Biotechnology.

Zack Ely PhD ’22, a former MIT graduate student who is now a visiting scientist at MIT, and MIT graduate student Nicolas Mathey-Andrews are the lead authors of the paper.

Faster editing

Testing cancer drugs in mouse models is an important step in determining whether they are safe and effective enough to go into human clinical trials. Over the past 20 years, researchers have used genetic engineering to create mouse models by deleting tumor suppressor genes or activating cancer-promoting genes. However, this approach is labor-intensive and requires several months or even years to produce and analyze mice with a single cancer-linked mutation.

“A graduate student can build a whole PhD around building a model for one mutation,” Ely says. “With traditional models, it would take the field decades to catch up to all of the mutations we’ve discovered with the Cancer Genome Atlas.”

In the mid-2010s, researchers began exploring the possibility of using the CRISPR genome-editing system to make cancerous mutations more easily. Some of this work occurred in Jacks’ lab, where Sánchez-Rivera (then an MIT graduate student) and his colleagues showed that they could use CRISPR to quickly and easily knock out genes that are often lost in tumors. However, while this approach makes it easy to knock out genes, it doesn’t lend itself to inserting new mutations into a gene because it relies on the cell’s DNA repair mechanisms, which tend to introduce errors.

Inspired by research from Liu’s lab at the Broad Institute, the MIT team wanted to come up with a way to perform more precise gene-editing that would allow them to make very targeted mutations to either oncogenes (genes that drive cancer) or tumor suppressors.

In 2019, Liu and colleagues reported a new version of CRISPR genome-editing called prime editing. Unlike the original version of CRISPR, which uses an enzyme called Cas9 to create double-stranded breaks in DNA, prime editing uses a modified enzyme called Cas9 nickase, which is fused to another enzyme called reverse transcriptase. This fusion enzyme cuts only one strand of the DNA helix, which avoids introducing double-stranded DNA breaks that can lead to errors when the cell repairs the DNA.

The MIT researchers designed their new mouse models by engineering the gene for the prime editor enzyme into the germline cells of the mice, which means that it will be present in every cell of the organism. The encoded prime editor enzyme allows cells to copy an RNA sequence into DNA that is incorporated into the genome. However, the prime editor gene remains silent until activated by the delivery of a specific protein called Cre recombinase.

Since the prime editing system is installed in the mouse genome, researchers can initiate tumor growth by injecting Cre recombinase into the tissue where they want a cancer mutation to be expressed, along with a guide RNA that directs Cas9 nickase to make a specific edit in the cells’ genome. The RNA guide can be designed to induce single DNA base substitutions, deletions, or additions in a specified gene, allowing the researchers to create any cancer mutation they wish.

Modeling mutations

To demonstrate the potential of this technique, the researchers engineered several different mutations into the Kras gene, which drives about 30 percent of all human cancers, including nearly all pancreatic adenocarcinomas. However, not all Kras mutations are identical. Many Kras mutations occur at a location known as G12, where the amino acid glycine is found, and depending on the mutation, this glycine can be converted into one of several different amino acids.

The researchers developed models of four different types of Kras mutations found in lung cancer: G12C, G12D, G12R, and G12A. To their surprise, they found that the tumors generated in each of these models had very different traits. For example, G12R mutations produced large, aggressive lung tumors, while G12A tumors were smaller and progressed more slowly.

Learning more about how these mutations affect tumor development differently could help researchers develop drugs that target each of the different mutations. Currently, there are only two FDA-approved drugs that target Kras mutations, and they are both specific to the G12C mutation, which accounts for about 30 percent of the Kras mutations seen in lung cancer.

The researchers also used their technique to create pancreatic organoids with several different types of mutations in the tumor suppressor gene p53, and they are now developing mouse models of these mutations. They are also working on generating models of additional Kras mutations, along with other mutations that help to confer resistance to Kras inhibitors.

“One thing that we’re excited about is looking at combinations of mutations including Kras mutations that drives tumorigenesis, along with resistance associated mutations,” Mathey-Andrews says. “We hope that will give us a handle on not just whether the mutation causes resistance, but what does a resistant tumor look like?”

The researchers have made mice with the prime editing system engineered into their genome available through a repository at the Jackson Laboratory, and they hope that other labs will begin to use this technique for their own studies of cancer mutations.

The research was funded by the Ludwig Center at MIT, the National Cancer Institute, a Howard Hughes Medical Institute Hanna Grey Fellowship, the V Foundation for Cancer Research, a Koch Institute Frontier Award, the MIT Research Support Committee, a Helen Hay Whitney Postdoctoral Fellowship, the David H. Koch Graduate Fellowship Fund, the National Institutes of Health, and the Lustgarten Foundation for Pancreatic Cancer Research.

Other authors of the paper include Santiago Naranjo, Samuel Gould, Kim Mercer, Gregory Newby, Christina Cabana, William Rideout, Grissel Cervantes Jaramillo, Jennifer Khirallah, Katie Holland, Peyton Randolph, William Freed-Pastor, Jessie Davis, Zachary Kulstad, Peter Westcott, Lin Lin, Andrew Anzalone, Brendan Horton, Nimisha Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, and Qiaobing Xu.

Inaugural J-WAFS Grand Challenge aims to develop enhanced crop variants and move them from lab to land

Matt Shoulders will lead an interdisciplinary team to improve RuBisCO — the photosynthesis enzyme thought to be the holy grail for improving agricultural yield.

Carolyn Blais | Abdul Latif Jameel Water and Food Systems Lab
May 10, 2023

According to MIT’s charter, established in 1861, part of the Institute’s mission is to advance the “development and practical application of science in connection with arts, agriculture, manufactures, and commerce.” Today, the Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) is one of the driving forces behind water and food-related research on campus, much of which relates to agriculture. In 2022, J-WAFS established the Water and Food Grand Challenge Grant to inspire MIT researchers to work toward a water-secure and food-secure future for our changing planet. Not unlike MIT’s Climate Grand Challenges, the J-WAFS Grand Challenge seeks to leverage multiple areas of expertise, programs, and Institute resources. The initial call for statements of interests returned 23 letters from MIT researchers spanning 18 departments, labs, and centers. J-WAFS hosted workshops for the proposers to present and discuss their initial ideas. These were winnowed down to a smaller set of invited concept papers, followed by the final proposal stage.

Today, J-WAFS is delighted to report that the inaugural J-WAFS Grand Challenge Grant has been awarded to a team of researchers led by Professor Matt Shoulders and research scientist Robert Wilson of the Department of Chemistry. A panel of expert, external reviewers highly endorsed their proposal, which tackles a longstanding problem in crop biology — how to make photosynthesis more efficient. The team will receive $1.5 million over three years to facilitate a multistage research project that combines cutting-edge innovations in synthetic and computational biology. If successful, this project could create major benefits for agriculture and food systems worldwide.

“Food systems are a major source of global greenhouse gas emissions, and they are also increasingly vulnerable to the impacts of climate change. That’s why when we talk about climate change, we have to talk about food systems, and vice versa,” says Maria T. Zuber, MIT’s vice president for research. “J-WAFS is central to MIT’s efforts to address the interlocking challenges of climate, water, and food. This new grant program aims to catalyze innovative projects that will have real and meaningful impacts on water and food. I congratulate Professor Shoulders and the rest of the research team on being the inaugural recipients of this grant.”

Shoulders will work with Bryan Bryson, associate professor of biological engineering, as well as Bin Zhang, associate professor of chemistry, and Mary Gehring, a professor in the Department of Biology and the Whitehead Institute for Biomedical Research. Robert Wilson from the Shoulders lab will be coordinating the research effort. The team at MIT will work with outside collaborators Spencer Whitney, a professor from the Australian National University, and Ahmed Badran, an assistant professor at the Scripps Research Institute. A milestone-based collaboration will also take place with Stephen Long, a professor from the University of Illinois at Urbana-Champaign. The group consists of experts in continuous directed evolution, machine learning, molecular dynamics simulations, translational plant biochemistry, and field trials.

“This project seeks to fundamentally improve the RuBisCO enzyme that plants use to convert carbon dioxide into the energy-rich molecules that constitute our food,” says J-WAFS Director John H. Lienhard V. “This difficult problem is a true grand challenge, calling for extensive resources. With J-WAFS’ support, this long-sought goal may finally be achieved through MIT’s leading-edge research,” he adds.

RuBisCO: No, it’s not a new breakfast cereal; it just might be the key to an agricultural revolution

A growing global population, the effects of climate change, and social and political conflicts like the war in Ukraine are all threatening food supplies, particularly grain crops. Current projections estimate that crop production must increase by at least 50 percent over the next 30 years to meet food demands. One key barrier to increased crop yields is a photosynthetic enzyme called Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase (RuBisCO). During photosynthesis, crops use energy gathered from light to draw carbon dioxide (CO2) from the atmosphere and transform it into sugars and cellulose for growth, a process known as carbon fixation. RuBisCO is essential for capturing the CO2 from the air to initiate conversion of CO2 into energy-rich molecules like glucose. This reaction occurs during the second stage of photosynthesis, also known as the Calvin cycle. Without RuBisCO, the chemical reactions that account for virtually all carbon acquisition in life could not occur.

Unfortunately, RuBisCO has biochemical shortcomings. Notably, the enzyme acts slowly. Many other enzymes can process a thousand molecules per second, but RuBisCO in chloroplasts fixes less than six carbon dioxide molecules per second, often limiting the rate of plant photosynthesis. Another problem is that oxygen (O2) molecules and carbon dioxide molecules are relatively similar in shape and chemical properties, and RuBisCO is unable to fully discriminate between the two. The inadvertent fixation of oxygen by RuBisCO leads to energy and carbon loss. What’s more, at higher temperatures RuBisCO reacts even more frequently with oxygen, which will contribute to decreased photosynthetic efficiency in many staple crops as our climate warms.

The scientific consensus is that genetic engineering and synthetic biology approaches could revolutionize photosynthesis and offer protection against crop losses. To date, crop RuBisCO engineering has been impaired by technological obstacles that have limited any success in significantly enhancing crop production. Excitingly, genetic engineering and synthetic biology tools are now at a point where they can be applied and tested with the aim of creating crops with new or improved biological pathways for producing more food for the growing population.

An epic plan for fighting food insecurity

The 2023 J-WAFS Grand Challenge project will use state-of-the-art, transformative protein engineering techniques drawn from biomedicine to improve the biochemistry of photosynthesis, specifically focusing on RuBisCO. Shoulders and his team are planning to build what they call the Enhanced Photosynthesis in Crops (EPiC) platform. The project will evolve and design better crop RuBisCO in the laboratory, followed by validation of the improved enzymes in plants, ultimately resulting in the deployment of enhanced RuBisCO in field trials to evaluate the impact on crop yield.

Several recent developments make high-throughput engineering of crop RuBisCO possible. RuBisCO requires a complex chaperone network for proper assembly and function in plants. Chaperones are like helpers that guide proteins during their maturation process, shielding them from aggregation while coordinating their correct assembly. Wilson and his collaborators previously unlocked the ability to recombinantly produce plant RuBisCO outside of plant chloroplasts by reconstructing this chaperone network in Escherichia coli (E. coli). Whitney has now established that the RuBisCO enzymes from a range of agriculturally relevant crops, including potato, carrot, strawberry, and tobacco, can also be expressed using this technology. Whitney and Wilson have further developed a range of RuBisCO-dependent E. coli screens that can identify improved RuBisCO from complex gene libraries. Moreover, Shoulders and his lab have developed sophisticated in vivo mutagenesis technologies that enable efficient continuous directed evolution campaigns. Continuous directed evolution refers to a protein engineering process that can accelerate the steps of natural evolution simultaneously in an uninterrupted cycle in the lab, allowing for rapid testing of protein sequences. While Shoulders and Badran both have prior experience with cutting-edge directed evolution platforms, this will be the first time directed evolution is applied to RuBisCO from plants.

Artificial intelligence is changing the way enzyme engineering is undertaken by researchers. Principal investigators Zhang and Bryson will leverage modern computational methods to simulate the dynamics of RuBisCO structure and explore its evolutionary landscape. Specifically, Zhang will use molecular dynamics simulations to simulate and monitor the conformational dynamics of the atoms in a protein and its programmed environment over time. This approach will help the team evaluate the effect of mutations and new chemical functionalities on the properties of RuBisCO. Bryson will employ artificial intelligence and machine learning to search the RuBisCO activity landscape for optimal sequences. The computational and biological arms of the EPiC platform will work together to both validate and inform each other’s approaches to accelerate the overall engineering effort.

Shoulders and the group will deploy their designed enzymes in tobacco plants to evaluate their effects on growth and yield relative to natural RuBisCO. Gehring, a plant biologist, will assist with screening improved RuBisCO variants using the tobacco variety Nicotiana benthamianaI, where transient expression can be deployed. Transient expression is a speedy approach to test whether novel engineered RuBisCO variants can be correctly synthesized in leaf chloroplasts. Variants that pass this quality-control checkpoint at MIT will be passed to the Whitney Lab at the Australian National University for stable transformation into Nicotiana tabacum (tobacco), enabling robust measurements of photosynthetic improvement. In a final step, Professor Long at the University of Illinois at Urbana-Champaign will perform field trials of the most promising variants.

Even small improvements could have a big impact

A common criticism of efforts to improve RuBisCO is that natural evolution has not already identified a better enzyme, possibly implying that none will be found. Traditional views have speculated a catalytic trade-off between RuBisCO’s specificity factor for CO2 / O2 versus its CO2 fixation efficiency, leading to the belief that specificity factor improvements might be offset by even slower carbon fixation or vice versa. This trade-off has been suggested to explain why natural evolution has been slow to achieve a better RuBisCO. But Shoulders and the team are convinced that the EPiC platform can unlock significant overall improvements to plant RuBisCO. This view is supported by the fact that Wilson and Whitney have previously used directed evolution to improve CO2 fixation efficiency by 50 percent in RuBisCO from cyanobacteria (the ancient progenitors of plant chloroplasts) while simultaneously increasing the specificity factor.

The EPiC researchers anticipate that their initial variants could yield 20 percent increases in RuBisCO’s specificity factor without impairing other aspects of catalysis. More sophisticated variants could lift RuBisCO out of its evolutionary trap and display attributes not currently observed in nature. “If we achieve anywhere close to such an improvement and it translates to crops, the results could help transform agriculture,” Shoulders says. “If our accomplishments are more modest, it will still recruit massive new investments to this essential field.”

Successful engineering of RuBisCO would be a scientific feat of its own and ignite renewed enthusiasm for improving plant CO2 fixation. Combined with other advances in photosynthetic engineering, such as improved light usage, a new green revolution in agriculture could be achieved. Long-term impacts of the technology’s success will be measured in improvements to crop yield and grain availability, as well as resilience against yield losses under higher field temperatures. Moreover, improved land productivity together with policy initiatives would assist in reducing the environmental footprint of agriculture. With more “crop per drop,” reductions in water consumption from agriculture would be a major boost to sustainable farming practices.

“Our collaborative team of biochemists and synthetic biologists, computational biologists, and chemists is deeply integrated with plant biologists and field trial experts, yielding a robust feedback loop for enzyme engineering,” Shoulders adds. “Together, this team will be able to make a concerted effort using the most modern, state-of-the-art techniques to engineer crop RuBisCO with an eye to helping make meaningful gains in securing a stable crop supply, hopefully with accompanying improvements in both food and water security.”

Seychelle Vos and Hernandez Moura Silva named HHMI Freeman Hrabowski Scholars

The program supports early-career faculty who have strong potential to become leaders in their fields and to advance diversity, equity, and inclusion.

Lillian Eden | Department of Biology
May 9, 2023

Two faculty members from the MIT Department of Biology have been selected by the Howard Hughes Medical Institute (HHMI) for the inaugural cohort of HHMI Freeman Hrabowski Scholars.

Seychelle Vos, the Robert A. Swanson Career Development Professor of Life Sciences, and Hernandez Moura Silva, an assistant professor of biology and core member of the Ragon Institute of MGH, MIT and Harvard, are among 31 early-career faculty selected for their potential to become leaders in their research fields and to create diverse and inclusive lab environments in which everyone can thrive, according to a press release.

Freeman Hrabowski Scholars are appointed to a five-year term, renewable for a second five-year term after a successful progress evaluation. Each scholar will receive up to $8.6 million over 10 years, including full salary, benefits, a research budget, and scientific equipment. In addition, they will participate in professional development to advance their leadership and mentorship skills.

The Freeman Hrabowski Scholars Program represents a key component of HHMI’s diversity, equity, and inclusion goals. Over the next 20 years, HHMI expects to hire and support up to 150 Freeman Hrabowski Scholars — appointing roughly 30 scholars every other year for the next 10 years. The institute has committed up to $1.5 billion for the Freeman Hrabowski Scholars to be selected over the next decade. The program was named for Freeman A. Hrabowski III, president emeritus of the University of Maryland at Baltimore County, who played a major role in increasing the number of scientists, engineers, and physicians from backgrounds underrepresented in science in the United States.

Seychelle Vos

Seychelle Vos studies how DNA organization impacts gene expression at the atomic level, using cryogenic electron microscopy (cryo-EM), X-ray crystallography, biochemistry, and genetics. Human cells contain about 2 meters of DNA, which is packed so tightly that its entirety is contained within the nucleus, which is only a few microns across. Although DNA needs to be compacted, it also needs to be accessible to, and readable by, the cell’s molecular machinery.

Vos received a BS in genetics from the University of Georgia in 2008 and a PhD from University of California at Berkeley in 2013. During her postdoctoral research at the Max Planck Institute for Biophysical Chemistry in Germany, she determined how the molecular machine responsible for gene expression is regulated near gene promoters.

Vos joined MIT as an assistant professor of biology in fall 2019.

“I am very humbled and honored to have been named a HHMI Freeman Hrabowski Scholar,” Vos says. “It would not have been possible without the hard work of my lab and the help of my colleagues. It provides us with the support to achieve our ambitious research goals.”

Hernandez Moura Silva

Hernandez Moura Silva studies the role of immune cells in the maintenance and normal function of our bodies and tissues, beyond their role in battling infection. Specifically, he looks at a specific type of immune cell called a macrophage and its role in the proper function of white adipose tissue — our fat. White adipose tissue in a healthy state is highly populated by macrophages, including very abundant ones known as “vasculature-associated adipose tissue macrophages,” which are located around the blood vessels. When the activity of these adipose macrophages is disrupted, there are changes in the proper function of the white adipose tissue, which may ultimately link to disease. By understanding macrophage function in healthy tissues, Hernandez hopes to learn how to restore tissue homeostasis in disease.

Hernandez Moura Silva received a BS in biology in 2005 and an MSc in molecular biology in 2008 from the University of Brazil. He received his PhD in 2011 from the University of São Paulo Heart Institute. Silva pursued his postdoctoral work as the Bernard Levine Postdoctoral Fellow in immunology and immuno-metabolism at the New York University School of Medicine Skirball Institute of Biomolecular Medicine.

He joined MIT as an assistant professor of biology in 2022. He is also a core member of the Ragon Institute.

“For an immigrant coming from an underrepresented group, it’s a huge privilege to be granted this opportunity from HHMI that will empower me and my lab to shape the next generation of scientists and provide an environment where people can feel welcome and encouraged to do the science that they love and be successful,” Silva says. “It also aligns with MIT’s commitment to increase diversity and opportunity across the Institute and to become a place where all people can thrive.”