Placement: Promote to Homepage

Yunha Hwang

Education 

  • PhD, 2024, Evolutionary and Organismic Biology, Harvard University
  • MS, 2018, Earth Systems, Stanford University
  • B.Sc, 2018, Computer Science, Stanford University

Research Summary

Microbial genomes encode the largest molecular, biochemical, and functional diversity on Earth. We focus on developing machine learning models and experimental approaches to discover and design novel biological functions. We integrate computation with expertise in evolution, ecology, and biochemistry to characterize and harness the functional potential of microbes.

A shining light in the lab

Sriram “Sri” Srikant was known for insightful questions and irrepressible love of the pursuit of knowledge.

Lillian Eden | Department of Biology
July 24, 2025

Sriram “Sri” Srikant, a postdoctoral Scholar in the Laub Lab in the Department of Biology at MIT, succumbed to cancer in March. He was 35.

Srikant received a degree in Chemical Engineering with a minor in chemistry from the Indian Institute of Technology Madras in 2011, and a PhD in Molecular and Cellular Biology from Harvard University in 2019. Among many accomplishments, Srikant was awarded an HHMI International Student Research Fellowship and a Peralta Prize for an outstanding dissertation proposal, both in 2013.

Srikant is described by mentors and colleagues alike as brilliant — a remarkable researcher who was both knowledgeable and approachable and whose enthusiasm was a bright beacon to all who had the chance to know him.

“There’s a blues line that I love, ‘Let the Midnight Special shine the ever lovin’ light on me,’” says Harvard College Professor Andrew Murray, one of Srikant’s thesis advisors. “For me, Sri was that Midnight Special, and we were lucky to have his ever lovin’ light shine on us.”

Academics are often equally motivated by a mix of a love of the work and a desire to succeed, whether it be by publications, grants, or high-impact findings. According to colleagues, however, Srikant’s passion came entirely from his need to know more.

“He told me once that ‘A life without science wouldn’t be worth living,’” said Dia Ghose, PhD ’24, a graduate student in the Laub Lab. “He wanted to move his career forward so he could keep doing science, but he didn’t care about impressing people. He just loved science and wanted to keep doing it.”

In the face of a terminal diagnosis, Srikant kept coming into the lab until his illness made it impossible. His marks on Building 68, however, remain — people are and will continue using the strains he built, the technique he developed, and the expertise he was so generous in sharing.

“There’s so many reminders of him, which is how it should be, because he contributed so much,” Ghose says. “He’s living on in the lab, and we’re still using everything that he gave us every day.”

The generosity of Sri Standard Time

As a graduate student at Harvard, Srikant pursued his thesis work in a joint PhD in the labs of both Murray and Professor of Molecular and Cellular Biology Rachelle Gaudet.

“The experiments in Rachelle’s lab failed utterly, and those in mine failed miserably, but gave enough glimmers of possibility for him to make a series of technical innovations to turn something that looked hopeless into a very nice paper,” recalls Murray. “There was no part of science he wasn’t curious about, there was nothing he wouldn’t discuss, and there was no technical challenge he wouldn’t take on.”

In the Laub Lab, Srikant developed an experimental evolution approach to studying phage, the viruses that infect bacteria. Srikant set up an experimental pipeline to explore how phages can evolve to overcome anti-phage defense systems in bacteria. He was also investigating the broader mechanisms of how phage genomes evolve, and the types of mutations they acquire. In the case of recombination between co-infecting phages, he was developing a new methodology to study exactly how recombination between different phages occurs.

The experimental evolution approach swept through not just the lab at MIT but across the world, and Srikant assisted other labs in implementing his process.

“He was this incredibly selfless, generous guy who was always willing to help out other people,” says Michael Laub, Salvador E. Luria Professor and HHMI Investigator. “He also had this incredible encyclopedic knowledge and memory about all aspects of phages, and he was constantly drawing on that to help people with their projects.”

Srikant was so generous with his time and expertise that he was usually on “SST” or “Sri standard time”—which was, often, running late. He would declare he was heading out or needed to start experiments, and then engage in hours-long conversations with lab mates on topics ranging from physics to visa issues.

Srikant’s hobbies included reading papers from other fields — he was, simply put, interested in the pursuit of knowledge. If he wasn’t an expert on some topic, he could spend hours studying it, just in case he could be helpful. After ChatGPT was released, lab mates joked that ChatGP-Sri was more knowledgeable, had more reliable answers, and was usually available 24/7, says Tong Zhang, PhD ’24, another graduate student in the Laub Lab.

Srikant’s sole area of ignorance was seemingly was pop culture. He didn’t know who Taylor Swift was, and only knew of Lady Gaga from the one time she wore a meat dress more than a decade ago—which, Ghose noted, was a rather niche reference.

Always curious, never quiet

Murray recalls an incident when he was flying from Boston to San Francisco with Srikant, discussing science every minute of the flight. Srikant was so passionate about the subject that his neighbor felt the need to shush him repeatedly, which Srikant took in stride, saying, with a smile, “People have been telling me to be quieter my entire life, and they’re probably right!”

From his first year at Harvard to his final days in the Laub Lab, Srikant was known for his boundless curiosity. Murray says that it’s a rare thing, after a department seminar, for students to ask questions, but Srikant would always put his hand up. That habit continued through graduate school and at science and lab meetings during his too-brief time at MIT.

“It was remarkable,” Laub says. “After any talk, he always had the most probing, incisive, and really helpful questions, across very broad fields.”

Every time he asked a question, whether it was in class during his time at Harvard or at the Building 68 research retreat on the cape, Srikant would begin with, “One of the things I’m curious about.” Ghose says the phrase became something akin to a meme in the lab, and Srikant even commemorated the colloquialism with a bracelet that read ‘I’m curious.’

“For a person that brilliant and knowledgeable, Sri was so special. His impact on me and others will last forever,” Zhang says. “I have always been, and I will continue, looking up to him, honoring his passion for science, his brilliance as a scientist, and his kindness and generosity as a great friend.”

Putting liver cells in context: new method combines imaging and sequencing to study gene function in living tissue

Researchers in the Weissman Lab have developed a powerful approach that simultaneously measures how genetic changes such as turning off individual genes affect both gene expression and cell structure in intact liver tissue, with the goal of discovering how genes control organ function and disease.

Whitehead Institute
June 12, 2025

 

However, capturing both the “visuals and sound” of biological data, such as gene expression and cell structure data, from the same cells requires researchers to develop new approaches. They also have to make sure that the data they capture accurately reflects what happens in living organisms, including how cells interact with each other and their environments.

Whitehead Institute and Harvard University researchers have taken on these challenges and developed Perturb-Multimodal (Perturb-Multi), a powerful new approach that simultaneously measures how genetic changes such as turning off individual genes affect both gene expression and cell structure in intact liver tissue. The method, described in Cell on June 12, aims to accelerate discovery of how genes control organ function and disease.

The research team, led by Whitehead Institute Member Jonathan Weissman and then-graduate student in his lab Reuben Saunders, along with Xiaowei Zhuang, the David B. Arnold Professor of Science at Harvard University, and then-postdoc in her lab Will Allen, created a system that can test hundreds of different genetic modifications within a single mouse liver while capturing multiple types of data from the same cells.

“Understanding how our organs work requires looking at many different aspects of cell biology at once,” Saunders says. “With Perturb-Multi, we can see how turning off specific genes changes not just what other genes are active, but also how proteins are distributed within cells, how cellular structures are organized, and where cells are located in the tissue. It’s like having multiple specialized microscopes all focused on the same experiment.”

“This approach accelerates discovery by both allowing us to test the functions of many different genes at once, and then for each gene, allowing us to measure many different functional outputs or cell properties at once—and we do that in intact tissue from animals,” says Zhuang, who is also an HHMI Investigator.

A more efficient approach to genetic studies

Traditional genetic studies in mice often turn off one gene in an animal, and then observe what changes in that gene’s absence to learn about what the gene does. The researchers designed their approach to turn off hundreds of different genes across a single liver, while still only turning off one gene per cell—using what is known as a mosaic approach. This allowed them to study the roles of hundreds of individual genes at once in a single animal. The researchers then collected diverse types of data from cells across the same liver to get a full picture of the consequences of turning off the genes.

“Each cell serves as its own experiment, and because all the cells are in the same animal, we eliminate the variability that comes from comparing different mice,” Saunders says. “Every cell experiences the same physiological conditions, diet, and environment, making our comparisons much more precise.”

“The challenge we faced was that tissues, to perform their functions, rely on thousands of genes, expressed in many different cells, working together. Each gene, in turn, can control many aspects of a cell’s function. Testing these hundreds of genes in mice using current methods would be extremely slow and expensive—near impossible in practice,” Allen says.

Revealing new biology through combined measurements

The team applied Perturb-Multi to study genetic controls of liver physiology and function. Their study led to discoveries in three important aspects of liver biology: fat accumulation in liver cells—a precursor to liver disease; stress responses; and hepatocyte zonation (how liver cells specialize, assuming different traits and functions, based on their location within the liver).

“Overcoming the inherent complexity of biology in living animals required developing new tools that bridge multiple disciplines – including, in this case, genomics, imaging, and AI,” Allen says.

One striking finding emerged from studying genes that, when disrupted, cause fat accumulation in liver cells. The imaging data revealed that four different genes all led to similar fat droplet accumulation, but the sequencing data showed they did so through three completely different mechanisms.

“Without combining imaging and sequencing, we would have missed this complexity entirely,” Saunders says. “The imaging told us which genes affect fat accumulation, while the sequencing revealed whether this was due to increased fat production, cellular stress, or other pathways. This kind of mechanistic insight could be crucial for developing targeted therapies for fatty liver disease.”

The researchers also discovered new regulators of liver cell zonation. Unexpectedly, the newly discovered regulators include genes involved in modifying the extracellular matrix—the scaffolding between cells. “We found that cells can change their specialized functions without physically moving to a different zone,” Saunders says. “This suggests that liver cell identity is more flexible than previously thought.”

Technical innovation enables new science

Developing Perturb-Multi required solving several technical challenges. The team created new methods for preserving the content of interest in cells—RNA and proteins—during tissue processing, for collecting many types of imaging data and single-cell gene expression data from tissue samples that have been fixed with a preservative, and for integrating multiple types of data from the same cells.

“Overcoming the inherent complexity of biology in living animals required developing new tools that bridge multiple disciplines – including, in this case, genomics, imaging, and AI,” Allen says.

The two components of Perturb-Multi—the imaging and sequencing assays—together, applied to the same tissue, provide insights that are unattainable through either assay alone.

“Each component had to work perfectly while not interfering with the others,” says Weissman, who is also a professor of biology at the Massachusetts Institute of Technology and an HHMI Investigator. “The technical development took considerable effort, but the payoff is a system that can reveal biology we simply couldn’t see before.”

Expanding to new organs and other contexts

The researchers plan to expand Perturb-Multi to other organs, including the brain, and to study how genetic changes affect organ function under different conditions like disease states or dietary changes.

“Without combining imaging and sequencing, we would have missed this complexity entirely,” Saunders says.

“We’re also excited about using the data we generate to train machine learning models,” adds Saunders. “With enough examples of how genetic changes affect cells, we could eventually predict the effects of mutations without having to test them experimentally—a ‘virtual cell’ that could accelerate both research and drug development.”

“Perturbation data are critical for training such AI models and the paucity of existing perturbation data represents a major hindrance in such ‘virtual cell’ efforts,” Zhuang says. “We hope Perturb-Multi will fill this gap by accelerating the collection of perturbation data.”

The approach is designed to be scalable, with the potential for genome-wide studies that test thousands of genes simultaneously. As sequencing and imaging technologies continue to improve, the researchers anticipate that Perturb-Multi will become even more powerful and accessible to the broader research community.

“Our goal is to keep scaling up. We plan to do genome-wide perturbations, study different physiological conditions, and look at different organs,” says Weissman. “That we can now collect so many types of data from so many cells, at speed, is going to be critical for building AI models like virtual cells, and I think it’s going to help us answer previously unsolvable questions about health and disease.”

Notes

Reuben A. Saunders, William E. Allen, Xingjie Pan, Jaspreet Sandhu, Jiaqi Lu, Thomas K. Lau, Karina Smolyar, Zuri A. Sullivan, Catherine Dulac, Jonathan S. Weissman, Xiaowei Zhuang. “Perturb-Multimodal: a Platform for Pooled Genetic Screens with Sequencing and Imaging in Intact Mammalian Tissue.” Cell, June 12, 2025. DOI: 10.1016/j.cell.2025.05.022.

Student Spotlight: Alexa Mallar ’27

Computer science and molecular biology major Alexa Mallar ’27 has a passion for the visual, pursuing her love of art while also working as an undergraduate researcher in the Cheeseman Lab.

Mark Sullivan | Spectrum
June 4, 2025

“Visual art has been a passion and a core part of my identity since before attending MIT,” says Alexa Mallar ’27, a computer science and molecular biology major from Miami who is a recipient of the Norman L. Greenman (1944) Memorial Scholarship.

As an undergraduate researcher in the lab of Iain Cheeseman, MIT professor of biology and member of the Whitehead Institute, she helps develop computational tools for biological data analysis. Outside the lab, Mallar pursues her love of art, creating detailed graphite pieces in a hyperrealistic-surrealist style and experimenting with various media, including color pencil, charcoal, and multimedia sculpture, sharing her work on Instagram. Expanding her creative interests, she has explored 3-D printing through MIT MakerLodge, has taken 21T.101 Intro to Acting, and is taking 21W.756 Reading and Writing poetry in spring 2025. “Through visual and performing arts and creative writing, I continue to find new ways to express my creativity and grow as an artist,” she says.

What inspires you about creating art?

It’s a multitude of things. It’s a technical fascination with capturing details on a piece of paper and trying really hard to make it look like a photograph. There’s the enjoyment of the technical aspects of the task. There’s also an intellectual satisfaction that comes with creating art.  I like incorporating surrealism into my work often because it lends itself to creating more visual meaning than a purely realistic piece would; there are several artists I follow and try to incorporate aspects of their work into mine, trying different things. There’s the experimental value of trying different media and artistic styles. I love exploring. I love expressing new ideas. Art is really a great way to do it.

Is there a connection between what you do as a scientist and as an artist?

The nature of my art is very visual, and I think about what I do in computer science or in research now in a very visual way. I map a diagram in my head of input and output. Anything I do is inherently visualized.

Sometimes the connection goes the other way—my interest in math and science bleeds into my art. Designing counterweights to balance sculptures or geometrically mapping out perspective and proportions are a few examples. I also love sneaking in little “easter eggs.” A few years ago, I created a piece featuring a woman with a third eye and a tree-branch crown, where the branching levels followed the Fibonacci sequence.

What is the story behind the mermaid drawings on your Instagram page?

“There’s an event every May called MerMay. Artists on Instagram will do successive drawings of different mermaids based on prompts. I wanted to join in, so I designed my own mermaid. I just started by imagining her face, and it evolved into her holding an orb I called the Eye of the Sea. It was really fun.”

After college, will you be pursuing both science and art?

“That’s a good question. I kind of have a 30-degree angle I’m heading in, not a specific path. I know that I will keep drawing in my free time, and the creative thinking and visualization skills will bleed into any other part of my work that I do, whether that be in computer science or research. Maybe designing a front end is where my creative spirit will contribute to the computer science work that I do.

“I plan to work for Amazon [in summer 2025], having received a return offer after working there last summer. I’m getting a sense of the different environments I could go to. If I can find a way to combine [art and career] I will. I’ll find a way to do as many things as I can that interest me.”

How has your MIT experience helped you on your path?

“It has been an amazing resource. MIT offers so many different classes and interdisciplinary opportunities. I was able to explore entrepreneurship through the Martin Trust Center at MIT, enrolling in the Undergraduate Engineering Entrepreneurship Certificate program. That’s one avenue I wouldn’t have been able to explore otherwise without MIT. Acting is not something I would have even tried before having the opportunity to do it at MIT. I’m rediscovering my love for creative writing through classes at MIT, and I’m really enjoying it. If I hadn’t been able to fit a poetry workshop into my class schedule, I probably wouldn’t be writing nearly as much this semester. I’m really glad I have that opportunity.

“MIT is in an amazing spot for someone in my specific major, with the huge presence of biotech in Cambridge. This is an optimal place for both computer science and biological research. We have the Whitehead Institute, Pfizer, Moderna, all within walking distance of campus. There’s a lot to explore, an intersection of interests, and I really appreciate that is available to me at MIT.”

A selfish gene unlike any other

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

Shafaq Zia | Whitehead Institute
May 7, 2025

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

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

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

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

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

Fatal success

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

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

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

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

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

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

Practicing self-restraint

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

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

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

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

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

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

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

Student spotlight: Aria Eppinger ’24

The multitalented member of the varsity swim team graduated with her undergraduate degree in computer science and molecular biology in 2024 and will complete her MEng this month.

Jane Halpern | Department of Electrical Engineering and Computer Science
May 9, 2025

This interview is part of a series of short interviews from the MIT Department of Electrical Engineering and Computer Science, called Student Spotlights. Each spotlight features a student answering their choice of questions about themselves and life at MIT. Today’s interviewee, Aria Eppinger ’24, graduated with her undergraduate degree in Course 6-7 (Computer Science and Molecular Biology) last spring. This spring, she will complete her MEng in 6-7. Her thesis, supervised by Ford Professor of Engineering Doug Lauffenburger in the Department of Biological Engineering, investigates the biological underpinnings of adverse pregnancy outcomes, including preterm birth and preeclampsia, by applying polytope-fitting algorithms.

Q: Tell us about one teacher from your past who had an influence on the person you’ve become.

A: There are many teachers who had a large impact on my trajectory. I would first like to thank my elementary and middle school teachers for imbuing in me a love of learning. I would also like to thank my high school teachers for not only teaching me the foundations of writing strong arguments, programming, and designing experiments, but also instilling in me the importance of being a balanced person. It can be tempting to be ruled by studies or work, especially when learning and working are so fun. My high school teachers encouraged me to pursue my hobbies, make memories with friends, and spend time with family. As life continues to be hectic, I’m so grateful for this lesson (even if I’m still working on mastering it).

Q: Describe one conversation that changed the trajectory of your life.

A: A number of years ago, I had the opportunity to chat with Warren Buffett. I was nervous at first, but soon put to ease by his descriptions of his favorite foods — hamburgers, French fries, and ice cream — and his hitchhiking stories. His kindness impressed and inspired me, which is something I carry with me and aim to emulate all these years later.

Q: Do you have any pets?

A: I have one dog who lives at home with my parents. Dodger, named after “Artful Dodger” in Oliver Twist, is as mischievous as beagles tend to be. We adopted him from a rescue shelter when I was in elementary school.

Q: Are you a re-reader or a re-watcher — and if so, what are your comfort books, shows, or movies?

A: I don’t re-read many books or re-watch many movies, but I never tire of Jane Austen’s “Pride and Prejudice.” I bought myself an ornately bound copy when I was interning in New York City last summer. Austen’s other novels, especially “Sense and Sensibility,” “Persuasion,” and “Emma,” are also favorites, and I’ve seen a fair number of their movie and miniseries adaptations. My favorite adaptation is the 1995 BBC production of “Pride and Prejudice” because of the cohesion with the original book and the casting of the leads, as well as the touches and plot derivations added by the producer and director to bring the work to modern audiences. The adaptation is quite long, but I have fond memories of re-watching it with some fellow Austinites at MIT.

Q: If you had to teach a really in-depth class about one niche topic, what would you pick?

A: There are two types of people in the world: those who eat to live, and those who live to eat. As one of the latter, I would have to teach some sort of in-depth class on food. Perhaps I would teach the science behind baking chocolate cake, or churning the perfect ice cream. Or maybe I would teach the biochemistry of digesting. In any case, I would have to have lots of hands-on demos and reserve plenty for taste-testing!

Q: What was the last thing you changed your mind about?

A: Brisket! I never was a big fan of brisket until I went to a Texas BBQ restaurant near campus, The Smoke Shop BBQ. Growing up, I had never had true BBQ, so I was quite skeptical. However, I enjoyed not only the brisket but also the other dishes. The Brussels sprouts with caramelized onions is probably my favorite dish, but it feels like a crime to say that about a BBQ place!

Q: What are you looking forward to about life after graduation? What do you think you’ll miss about MIT?

A: I’m looking forward to new adventures after graduation, including working in New York City and traveling to new places. I cross-registered to take Intensive Italian at Harvard this semester and am planning a trip to Italy to practice my Italian, see the historic sites, visit the Vatican, and taste the food. Non vedo l’ora di viaggiare all’Italia! [I can’t wait to travel to Italy!]

While I’m excited for what lies ahead, I will miss MIT. What a joy it is to spend most of the day learning information from a fire hose, taking a class on a foreign topic because the course catalog description looked fun, talking to people whose viewpoint is very similar or very different from my own, and making friends that will last a lifetime.

Biologists identify targets for new pancreatic cancer treatments

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

Anne Trafton | MIT News
May 7, 2025

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

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

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

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

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

Cryptic peptides

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

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

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

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

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

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

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

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

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

Programmed T cells

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

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

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

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

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

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

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

Dopamine signals when a fear can be forgotten

Study shows how a dopamine circuit between two brain regions enables mice to extinguish fear after a peril has passed.

David Orenstein | The Picower Institute for Learning and Memory
May 7, 2025

Dangers come but dangers also go, and when they do, the brain has an “all-clear” signal that teaches it to extinguish its fear. A new study in mice by MIT neuroscientists shows that the signal is the release of dopamine along a specific interregional brain circuit. The research therefore pinpoints a potentially critical mechanism of mental health, restoring calm when it works, but prolonging anxiety or even post-traumatic stress disorder when it doesn’t.

“Dopamine is essential to initiate fear extinction,” says Michele Pignatelli di Spinazzola, co-author of the new study from the lab of senior author Susumu Tonegawa, Picower Professor of biology and neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics within The Picower Institute for Learning and Memory at MIT, and a Howard Hughes Medical Institute (HHMI) investigator.

In 2020, Tonegawa’s lab showed that learning to be afraid, and then learning when that’s no longer necessary, result from a competition between populations of cells in the brain’s amygdala region. When a mouse learns that a place is “dangerous” (because it gets a little foot shock there), the fear memory is encoded by neurons in the anterior of the basolateral amygdala (aBLA) that express the gene Rspo2. When the mouse then learns that a place is no longer associated with danger (because they wait there and the zap doesn’t recur), neurons in the posterior basolateral amygdala (pBLA) that express the gene Ppp1r1b encode a new fear extinction memory that overcomes the original dread. Notably, those same neurons encode feelings of reward, helping to explain why it feels so good when we realize that an expected danger has dwindled.

In the new study, the lab, led by former members Xiangyu Zhang and Katelyn Flick, sought to determine what prompts these amygdala neurons to encode these memories. The rigorous set of experiments the team reports in the Proceedings of the National Academy of Sciences show that it’s dopamine sent to the different amygdala populations from distinct groups of neurons in the ventral tegmental area (VTA).

“Our study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,” says Zhang, who also led the 2020 study and is now a senior associate at Orbimed, a health care investment firm. “We found that dopamine activates specific amygdala neurons tied to reward, which in turn drive fear extinction. We now see that unlearning fear isn’t just about suppressing it — it’s a positive learning process powered by the brain’s reward machinery. This opens up new avenues for understanding and potentially treating fear-related disorders, like PTSD.”

Forgetting fear

The VTA was the lab’s prime suspect to be the source of the signal because the region is well known for encoding surprising experiences and instructing the brain, with dopamine, to learn from them. The first set of experiments in the paper used multiple methods for tracing neural circuits to see whether and how cells in the VTA and the amygdala connect. They found a clear pattern: Rspo2 neurons were targeted by dopaminergic neurons in the anterior and left and right sides of the VTA. Ppp1r1b neurons received dopaminergic input from neurons in the center and posterior sections of the VTA. The density of connections was greater on the Ppp1r1b neurons than for the Rspo2 ones.

The circuit tracing showed that dopamine is available to amygdala neurons that encode fear and its extinction, but do those neurons care about dopamine? The team showed that indeed they express “D1” receptors for the neuromodulator. Commensurate with the degree of dopamine connectivity, Ppp1r1b cells had more receptors than Rspo2 neurons.

Dopamine does a lot of things, so the next question was whether its activity in the amygdala actually correlated with fear encoding and extinction. Using a method to track and visualize it in the brain, the team watched dopamine in the amygdala as mice underwent a three-day experiment. On Day One, they went to an enclosure where they experienced three mild shocks on the feet. On Day Two, they went back to the enclosure for 45 minutes, where they didn’t experience any new shocks — at first, the mice froze in anticipation of a shock, but then relaxed after about 15 minutes. On Day Three they returned again to test whether they had indeed extinguished the fear they showed at the beginning of Day Two.

The dopamine activity tracking revealed that during the shocks on Day One, Rspo2 neurons had the larger response to dopamine, but in the early moments of Day Two, when the anticipated shocks didn’t come and the mice eased up on freezing, the Ppp1r1b neurons showed the stronger dopamine activity. More strikingly, the mice that learned to extinguish their fear most strongly also showed the greatest dopamine signal at those neurons.

Causal connections

The final sets of experiments sought to show that dopamine is not just available and associated with fear encoding and extinction, but also actually causes them. In one set, they turned to optogenetics, a technology that enables scientists to activate or quiet neurons with different colors of light. Sure enough, when they quieted VTA dopaminergic inputs in the pBLA, doing so impaired fear extinction. When they activated those inputs, it accelerated fear extinction. The researchers were surprised that when they activated VTA dopaminergic inputs into the aBLA they could reinstate fear even without any new foot shocks, impairing fear extinction.

The other way they confirmed a causal role for dopamine in fear encoding and extinction was to manipulate the amygdala neurons’ dopamine receptors. In Ppp1r1b neurons, over-expressing dopamine receptors impaired fear recall and promoted extinction, whereas knocking the receptors down impaired fear extinction. Meanwhile in the Rspo2 cells, knocking down receptors reduced the freezing behavior.

“We showed that fear extinction requires VTA dopaminergic activity in the pBLA Ppp1r1b neurons by using optogenetic inhibition of VTA terminals and cell-type-specific knockdown of D1 receptors in these neurons,” the authors wrote.

The scientists are careful in the study to note that while they’ve identified the “teaching signal” for fear extinction learning, the broader phenomenon of fear extinction occurs brainwide, rather than in just this single circuit.

But the circuit seems to be a key node to consider as drug developers and psychiatrists work to combat anxiety and PTSD, Pignatelli di Spinazzola says.

“Fear learning and fear extinction provide a strong framework to study generalized anxiety and PTSD,” he says. “Our study investigates the underlying mechanisms suggesting multiple targets for a translational approach, such as pBLA and use of dopaminergic modulation.”

Marianna Rizzo is also a co-author of the study. Support for the research came from the RIKEN Center for Brain Science, the HHMI, the Freedom Together Foundation, and The Picower Institute.

Staff Spotlight: Lighting up biology’s basement lab

Senior Technical Instructor Vanessa Cheung ’02 brings the energy, experience, and excitement needed to educate students in the biology teaching lab.

Samantha Edelen | Department of Biology
April 29, 2025

For more than 30 years, Course 7 (Biology) students have descended to the expansive, windowless basement of Building 68 to learn practical skills that are the centerpiece of undergraduate biology education at the Institute. The lines of benches and cabinets of supplies that make up the underground MIT Biology Teaching Lab could easily feel dark and isolated.

In the corner of this room, however, sits Senior Technical Instructor Vanessa Cheung ’02, who manages to make the space seem sunny and communal.

“We joke that we could rig up a system of mirrors to get just enough daylight to bounce down from the stairwell,” Cheung says with a laugh. “It is a basement, but I am very lucky to have this teaching lab space. It is huge and has everything we need.”

This optimism and gratitude fostered by Cheung is critical, as MIT undergrad students enrolled in classes 7.002 (Fundamentals of Experimental Molecular Biology) and 7.003 (Applied Molecular Biology Laboratory) spend four-hour blocks in the lab each week, learning the foundations of laboratory technique and theory for biological research from Cheung and her colleagues.

Running toward science education

Cheung’s love for biology can be traced back to her high school cross country and track coach, who also served as her second-year biology teacher. The sport and the fundamental biological processes she was learning about in the classroom were, in fact, closely intertwined.

“He told us about how things like ATP [adenosine triphosphate] and the energy cycle would affect our running,” she says. “Being able to see that connection really helped my interest in the subject.”

That inspiration carried her through a move from her hometown of Pittsburgh, Pennsylvania, to Cambridge, Massachusetts, to pursue an undergraduate degree at MIT, and through her thesis work to earn a PhD in genetics at Harvard Medical School. She didn’t leave running behind either: To this day, she can often be found on the Charles River Esplanade, training for her next marathon.

She discovered her love of teaching during her PhD program. She enjoyed guiding students so much that she spent an extra semester as a teaching assistant, outside of the one required for her program.

“I love research, but I also really love telling people about research,” Cheung says.

Cheung herself describes lab instruction as the “best of both worlds,” enabling her to pursue her love of teaching while spending every day at the bench, doing experiments. She emphasizes for students the importance of being able not just to do the hands-on technical lab work, but also to understand the theory behind it.

“The students can tend to get hung up on the physical doing of things — they are really concerned when their experiments don’t work,” she says. “We focus on teaching students how to think about being in a lab — how to design an experiment and how to analyze the data.”

Although her talent for teaching and passion for science led her to the role, Cheung doesn’t hesitate to identify the students as her favorite part of the job.

“It sounds cheesy, but they really do keep the job very exciting,” she says.

Using mind and hand in the lab

Cheung is the type of person who lights up when describing how much she “loves working with yeast.”

“I always tell the students that maybe no one cares about yeast except me and like three other people in the world, but it is a model organism that we can use to apply what we learn to humans,” Cheung explains.

Though mastering basic lab skills can make hands-on laboratory courses feel “a bit cookbook,” Cheung is able to get the students excited with her enthusiasm and clever curriculum design.

“The students like things where they can get their own unique results, and things where they have a little bit of freedom to design their own experiments,” she says. So, the lab curriculum incorporates opportunities for students to do things like identify their own unique yeast mutants and design their own questions to test in a chemical engineering module.

Part of what makes theory as critical as technique is that new tools and discoveries are made frequently in biology, especially at MIT. For example, there has been a shift from a focus on RNAi to CRISPR as a popular lab technique in recent years, and Cheung muses that CRISPR itself may be overshadowed within only a few more years — keeping students learning at the cutting edge of biology is always on Cheung’s mind.

“Vanessa is the heart, soul, and mind of the biology lab courses here at MIT, embodying ‘mens et manus’ [‘mind and hand’],” says technical lab instructor and Biology Teaching Lab Manager Anthony Fuccione.

Support for all students

Cheung’s ability to mentor and guide students earned her a School of Science Dean’s Education and Advising Award in 2012, but her focus isn’t solely on MIT undergraduate students.

In fact, according to Cheung, the earlier students can be exposed to science, the better. In addition to her regular duties, Cheung also designs curriculum and teaches in the LEAH Knox Scholars Program. The two-year program provides lab experience and mentorship for low-income Boston- and Cambridge-area high school students.

Paloma Sanchez-Jauregui, outreach programs coordinator who works with Cheung on the program, says Cheung has a standout “growth mindset” that students really appreciate.

“Vanessa teaches students that challenges — like unexpected PCR results — are part of the learning process,” Sanchez-Jauregui says. “Students feel comfortable approaching her for help troubleshooting experiments or exploring new topics.”

Cheung’s colleagues report that they admire not only her talents, but also her focus on supporting those around her. Technical Instructor and colleague Eric Chu says Cheung “offers a lot of help to me and others, including those outside of the department, but does not expect reciprocity.”

Professor of biology and co-director of the Department of Biology undergraduate program Adam Martin says he “rarely has to worry about what is going on in the teaching lab.” According to Martin, Cheung is ”flexible, hard-working, dedicated, and resilient, all while being kind and supportive to our students. She is a joy to work with.”

Staff Spotlight: Always looking to home

Mingmar Sherpa, a researcher in the Martin Lab in the Department of Biology, has remained connected to his home in Nepal at every step of his career.

Ekaterina Khalizeva | Department of Biology
April 29, 2025

For Mingmar Sherpa, a senior research support associate in the Martin Lab in the Department of Biology, community is more than just his colleagues in the lab, where he studies how mechanical forces affect cell division timing during embryogenesis. On his long and winding path to MIT, he never left behind the people he grew up among in Nepal. Sherpa has been dedicated, every step of his career — from rural Solukhumbu to Kathmandu to Alabama to Cambridge — to advancing education and health care among his people in any way he can.

Despite working more than 7,000 miles away from home, Mingmar Sherpa makes every effort to keep himself connected to his community in Nepal. Every month, for example, he sends home money to support a computer lab that he established in his hometown in rural Solukhumbu, the district of Nepal that houses Mount Everest — just $250 a month covers the costs of a teacher’s salary, electricity, internet, and a space to teach. In this lab, almost 250 students thus far have learned computer skills essential to working in today’s digitally driven world. In college, Sherpa also started The Bright Vision Foundation (The Bright Future), an organization to support health and education in Nepal, and during the pandemic raised funds to provide personal protective equipment (PPE) and health care services across his home country.

While Sherpa’s ambition to help his home can be traced back to his childhood, he didn’t have it all figured out from the start, and found inspiration at each step of his career.

“This mindset of giving back to the community, helping policymakers or establishing an organization to help people do science, helping the scientific community to find cures for diseases — all these ideas came to me along the way,” Sherpa says. “It is the journey that matters.”

A journey driven by hope and optimism

“Sherpa” is a reference to the ethnic group native to the mountainous regions of Nepal and Tibet, whose members are well-known for their mountaineering skills, which they use to guide and assist tourists who want to climb Mount Everest. Growing up in rural Solukhumbu, Sherpa was surrounded by people working in the tourism industry; few other occupations appeared feasible. There was just one hospital for the whole district, requiring locals to walk for days to get medical assistance.

The youngest of seven siblings, Sherpa went to an English-language middle school, which he had to walk for over an hour to get to. He excelled there, soon becoming the top student in his class and passing the national exam with distinction — success that allowed him to both dream of and accomplish a move to Kathmandu, the capital city of Nepal, to study in the best school in the country.

It was an overwhelming transition, surrounded as he was for the first time by people from a very different social class, privileged with far more technological resources. The gaps between this well-equipped community and the one he left back home became increasingly obvious and left a strong impression on Sherpa.

There, he started thinking about how to use his newly acquired access to education and technology to uplift his community at home. He was especially fascinated by questions surrounding biology and human health, and next set his sights on attending college in the United States.

“If I came to the U.S., I could learn skills which I could not learn in Nepal,” he says. “I could prepare myself to solve the problems that I want to solve.”

At the University of Alabama in Birmingham, Sherpa continued to deepen his passion for biological science and joined a research lab. Through that work, he discovered the joys of basic research and the diverse set of skills it fosters.

“I joined the lab to learn science, but to do science, you need other skills, like research communication,” he says. “I was learning unintentionally from being in a research position.”

When Covid-19 spread around the globe, Sherpa wanted to apply the expertise and resources he had gained to help his people address the crisis. It was then that he started The Bright Vision Foundation, an organization aiming to raise the standards of health care and education in underserved communities in Nepal. Through the foundation, he raised funds to distribute PPE, provide health care services, and set up the computer lab in his childhood home.

“Today’s world is all about technology and innovation, but here are good people in my community who don’t even know about computers,” he says.

With the help of his brother, who serves as the lab instructor, and his parents, who provide the space and support the lab, and Sherpa’s own fundraising, he aims to help youths from backgrounds similar to his own be better prepared for the technologically advanced, globalized world of today.

The MIT chapter

Now, at MIT, Sherpa speaks with deep appreciation of the opportunities that the university has opened up for him — the people he has been meeting here, and the skills he has been learning.

Professor of biology Adam C. Martin, Sherpa’s principal investigator, views making sure that international trainees like Mingmar are aware of the wide range of opportunities MIT offers — whether it be workshops, collaborations, networking and funding possibilities, or help with the pathway toward graduate school — as a key part of creating a supportive environment.

Understanding the additional burdens on international trainees gives Martin extra appreciation for Sherpa’s perseverance, motivation, and desire to share his culture with the lab, sharing Nepalese food and providing context for Nepalese customs.

Being at such a research-intensive institution as MIT has helped Sherpa further clarify his goals and his view of the paths he can take to achieve them. Since college, his three passions have been intertwined: leadership, research, and human health.

Sherpa will pursue a PhD in biomedical and biological sciences with a focus in cancer biology at Cornell University in the fall. In the longer term, he plans to focus on developing policy to improve public health.

Although Sherpa recognizes that Nepal is not the only place that might need his help, he has a sharp focus and an acute sense of what he is best positioned to do now. Sherpa is gearing up to organize a health camp in the spring to bring doctors to rural areas in Nepal, not only to provide care, but also to gather data on nutrition and health in different regions of the country.

“I cannot, in a day, or even a year, bring the living conditions of people in vulnerable communities up to a higher level, but I can slowly increase the living standard of people in less-developed communities, especially in Nepal,” he says. “There might be other parts of the world which are even more vulnerable than Nepal, but I haven’t explored them yet. But I know my community in Nepal, so I want to help improve people’s lives there.”