Author: mantulin

Why lung cancer doesn’t respond well to immunotherapy

A new study reveals that lymph nodes near the lungs create an environment that weakens T-cell responses to tumors.

Anne Trafton | MIT News Office
February 2, 2023

Immunotherapy — drug treatment that stimulates the immune system to attack tumors — works well against some types of cancer, but it has shown mixed success against lung cancer.

A new study from MIT helps to shed light on why the immune system mounts such a lackluster response to lung cancer, even after treatment with immunotherapy drugs. In a study of mice, the researchers found that bacteria naturally found in the lungs help to create an environment that suppresses T-cell activation in the lymph nodes near the lungs.

The researchers did not find that kind of immune-suppressive environment in lymph nodes near tumors growing near the skin of mice. They hope that their findings could help lead to the development of new ways to rev up the immune response to lung tumors.

“There is a functional difference between the T-cell responses that are mounted in the different lymph nodes. We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells,” says Stefani Spranger, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the new study.

MIT graduate student Maria Zagorulya is the lead author of the paper, which appears today in the journal Immunity.

Failure to attack

For many years, scientists have known that cancer cells can send out immunosuppressive signals, which leads to a phenomenon known as T-cell exhaustion. The goal of cancer immunotherapy is to rejuvenate those T cells so they can begin attacking tumors again.

One type of drug commonly used for immunotherapy involves checkpoint inhibitors, which remove the brakes on exhausted T cells and help reactivate them. This approach has worked well with cancers such as melanoma, but not as well with lung cancer.

Spranger’s recent work has offered one possible explanation for this: She found that some T cells stop working even before they reach a tumor, because of a failure to become activated early in their development. In a 2021 paper, she identified populations of dysfunctional T cells that can be distinguished from normal T cells by a pattern of gene expression that prevents them from attacking cancer cells when they enter a tumor.

“Despite the fact that these T cells are proliferating, and they’re infiltrating the tumor, they were never licensed to kill,” Spranger says.

In the new study, her team delved further into this activation failure, which occurs in the lymph nodes, which filter fluids that drain from nearby tissues. The lymph nodes are where “killer T cells” encounter dendritic cells, which present antigens (tumor proteins) and help to activate the T cells.

To explore why some killer T cells fail to be properly activated, Spranger’s team studied mice that had tumors implanted either in the lungs or in the flank. All of the tumors were genetically identical.

The researchers found that T cells in lymph nodes that drain from the lung tumors did encounter dendritic cells and recognize the tumor antigens displayed by those cells. However, these T cells failed to become fully activated, as a result of inhibition by another population of T cells called regulatory T cells.

These regulatory T cells became strongly activated in lymph nodes that drain from the lungs, but not in lymph nodes near tumors located in the flank, the researchers found. Regulatory T cells are normally responsible for making sure that the immune system doesn’t attack the body’s own cells. However, the researchers found that these T cells also interfere with dendritic cells’ ability to activate killer T cells that target lung tumors.

The researchers also discovered how these regulatory T cells suppress dendritic cells: by removing stimulatory proteins from the surface of dendritic cells, which prevents them from being able to turn on killer-T-cell activity.

Microbial influence

Further studies revealed that the activation of regulatory T cells is driven by high levels of interferon gamma in the lymph nodes that drain from the lungs. This signaling molecule is produced in response to the presence of commensal bacterial — bacteria that normally live in the lungs without causing infection.

The researchers have not yet identified the types of bacteria that induce this response or the cells that produce the interferon gamma, but they showed that when they treated mice with an antibody that blocks interferon gamma, they could restore killer T cells’ activity.

Interferon gamma has a variety of effects on immune signaling, and blocking it can dampen the overall immune response against a tumor, so using it to stimulate killer T cells would not be a good strategy to use in patients, Spranger says. Her lab is now exploring other ways to help stimulate the killer T cell response, such as inhibiting the regulatory T cells that suppress the killer-T-cell response or blocking the signals from the commensal bacteria, once the researchers identify them.

The research was funded by a Pew-Stewart Scholarship, the Koch Institute Frontier Research program, the Ludwig Center at the Koch Institute, and an MIT School of Science Fellowship in Cancer Research.

Paying it forward

When she’s not analyzing data about her favorite biomolecule, senior Sherry Nyeo focuses on improving the undergraduate experience at MIT.

Phie Jacobs | School of Science
January 31, 2023

Since arriving at MIT in fall 2019, senior Sherry Nyeo has conducted groundbreaking work in multiple labs on campus, acted as a mentor to countless other students, and made a lasting mark on the Institute community. But despite her well-earned bragging rights, Nyeo isn’t one to boast. Instead, she takes every opportunity to express just how grateful she is to the professors, alumni, and fellow students who have helped and inspired her during her time at MIT. “I like helping people if I can,” says Nyeo, who is majoring in computer science and molecular biology, “because I got helped so much.”

Nyeo’s passion for science began when she applied for the Selective Science Program at Tainan First Senior High School, widely considered one of the most prestigious high schools in Taiwan. “Preparing for that process made me realize that biology was pretty cool,” she recalls.

When Nyeo was 16, her family moved from Taiwan to Colorado, where she continued to cultivate her interest in STEM. Although she excelled at biology, she initially struggled to master computer science. “[Programming] was really hard for me,” she says. “It was a completely different way of thinking.” When she arrived at MIT, she decided to pursue a degree in computer science precisely because she knew she would find it challenging and because she appreciates how vital data analysis is to the field of biology. After all, she says, when you’re working at the scale of cells and molecules, “you need a lot of data to describe what’s going on.”

In the winter of her first year at MIT, Nyeo began doing hands-on research in laboratories on campus through the Undergraduate Research Opportunities Program (UROP). Her work in the lab of Whitehead Fellow Silvi Rouskin sparked an enduring interest in RNA, which she has come to regard as her “favorite biomolecule.”

Nyeo’s work in the Rouskin lab focused on alternative RNA structures and the roles they play in human and viral biology. While DNA mostly exists as a double helix, RNA can fold itself into a huge variety of structures in order to fulfill different functions. During her time as a student researcher, Nyeo has demonstrated a similar ability to adapt to different circumstances. When MIT campus members evacuated due to the Covid-19 pandemic in March 2020, and her UROP became entirely remote, she treated her time away from the lab as an opportunity to explore the computational side of research. Her work was subsequently included in a Nature Communications paper on the SARS-CoV-2 genome, on which she is listed as a co-author.

Since returning to campus, Nyeo has often worked in multiple labs simultaneously, conducting innovative research while also juggling classes, internships, and several demanding extracurriculars. Through it all, she has continued to pursue her fascination with RNA, a tiny, somewhat unassuming molecule that nonetheless has a massive impact on practically every aspect of our biology. Nyeo, who has shown herself to be equally multifaceted, seems especially well-suited to the study of this remarkable biomolecule.

Although Nyeo’s work in the life sciences keeps her busy, she finds time to nurture a diverse set of other passions. She took a class on experimental ethics, is working on an original screenplay, and has even picked up a minor in German. Since her sophomore year, she has also been a part of the New Engineering Education Transformation (NEET) program, which provides students with multidisciplinary interests the opportunity to collaborate across departments. Through NEET, currently directed by professor of biological engineering Mark Bathe, Nyeo has been able to pursue her interest in bioengineering research and connect to a vast community of students and professors. Most recently, she has been working within the Bathe BioNano Lab to use DNA to engineer new materials at the nanometer scale.

Nyeo hopes to put her skills to use by pursuing a career in biotechnology. She is currently minoring in management and dreams of one day starting her own company. But she doesn’t want to leave academia behind just yet and has begun working on applications for PhD programs in biology. “I originally came in thinking that I would just go straight into the biotech industry,” Nyeo explains. “And then I realized that I don’t dislike research and that I actually enjoy it.”

As part of her current work in the lab of professor of biology David Bartel, Nyeo investigates how viral infection affects RNA metabolism, and she often finds herself using her computational skills to help postdocs with their data analysis. In fact, one of the things Nyeo has most enjoyed about working as a student researcher is the opportunity to join a network of people who provide one another with support and guidance.

Nyeo’s willingness to help others is perhaps the aspect of her personality that best suits her to the study of RNA. Over the past few decades, researchers have discovered an increasingly large number of therapeutic uses for RNA, including cancer immunotherapy and vaccine development. In the summer of 2022, Nyeo worked as an intern at Eli Lilly and Company, where she helped identify potential targets for RNA therapeutics. She may continue to explore this area of research when she eventually enters the biotech industry. In the meantime, however, she’s finding ways to help people closer to home.

Since her first year, Nyeo has been a part of the MIT Biotech Group. When she first joined, the group had a fairly small undergraduate presence, and most events were geared toward graduate students and postdocs. Nyeo immediately dedicated herself to making the group more welcoming for undergraduates. As the director of the Undergraduate Initiative and later the undergraduate student president, she was a leading architect of a new seminar series in which MIT alumni came to campus to teach undergraduates about biotechnology. “There are a lot of technical terms associated with [biotech],” Nyeo explains. “If you just come in as an undergrad, not knowing what’s happening, that can be a bit daunting.”

Between her research in the Bartel lab and her work with NEET and the MIT Biotech Group, Nyeo doesn’t have a lot of free time, but she dedicates most of it to making MIT a friendlier environment for new students. She promotes research opportunities as a UROP panelist and has worked as an associate advisor since her junior year. She helps first-year students choose and register for classes, works with faculty advisors, and provides moral support to students who are feeling overwhelmed with options. “When I came [to MIT], I also didn’t know what I wanted to do,” Nyeo explains. “Upperclassmen helped me a lot with that process, and I want to pay it forward.”

Compassion in the details

The late MIT Professor Angelika Amon was recognized as Committed to Caring for her generous and encompassing mentorship.

Daniel Korsun | Office of Graduate Education
January 17, 2023

The late MIT Professor Angelika Amon, renowned for her groundbreaking contributions to our understanding of how chromosomes are regulated and partitioned during cell division, was also beloved among the MIT community for her kind and supportive mentorship of students.

An engaged and valued member of the MIT community, Amon passed away in late 2020 after a difficult battle with ovarian cancer. She was the Kathleen and Curtis Marble Professor in Cancer Research within the Department of Biology at MIT, the associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT, a member of the Ludwig Center for Molecular Oncology at MIT, and a member of the Koch Institute for Integrative Cancer Research. Amon’s research focused on understanding the biological impacts of cell aneuploidy, or the presence of too many chromosomes, in both healthy and cancerous cells. Her research also touched upon the relationships between cell size, cell growth, and age.

Care and consideration

Amon’s nominators describe in detail how she placed a large emphasis on her students’ lives outside the classroom. She recognized that in order to be a productive scientist, it is important to prioritize self-care; one student wrote that Amon emphasized how important it was “to take care of [your] own mental health first, because as she put it, ‘the best data was produced by happy scientists.’”

However, Amon’s concern for her students’ well-being went far beyond her desire for them to be productive members of academia. Her nomination letters are filled with anecdotes demonstrating how much she truly cared about her students as colleagues and friends.

One nominator summed Amon up thusly: “At her core, Angelika was a tremendously generous human being, and she never displayed it more than in caring for her students.” She “opened her home” to celebrate the achievements of her mentees, welcomed students into her home for the holidays, and offered to take care of pets when some of her group members had to leave the country temporarily due to visa issues.

These touching acts demonstrate, without a doubt, that Amon’s care and consideration for her students knew no bounds. No matter the circumstances, “as her student, you knew that you were valued and cared for, and that she would be your safety net even when you were struggling.”

A dynamic mentorship style

In addition to making sure her students were cared for and healthy, Amon also recognized that her relationship with each student was not static, but instead needed to evolve and adjust depending on the current circumstances.

As one nominator wrote, “one of Angelika’s most impressive qualities was her ability to adjust her mentoring to what I needed at the time.” When meeting with her students one-on-one, Amon had a keen eye for identifying what they needed most; she could instinctively tell when it was appropriate to push them to complete an experiment, encourage them to change direction, or even to take a step back and take time for themselves.

This intuition was possible because of the unique, personal relationship she developed with each of her students. Amon was meticulous about understanding and keeping track of each student’s interests and goals, and made sure to provide each student with useful opportunities tailored to those goals. One nominator described how Amon “used all of her personal and professional connections (and made many new ones!) to ensure that her students ended up where they wanted to be.”

Even after she was diagnosed with ovarian cancer, Amon made it a priority to ensure the success and happiness of her students. She wrote out extensive plans for each of her students to use in the event of her passing, and she made sure to routinely check in with her students about their research and personal lives.

A brilliant scientist and a caring mentor, Amon never missed an opportunity to check in with her students and ensure their happiness, well-being, and success. MIT Professor Li-Huei Tsai, a collaborator of Amon’s, describes Amon as being “a champion for her female colleagues, fellow researchers, and students. She was very supportive in so many ways, but what struck me in particular was that she kept an eye out for those who might not be doing so well and would work to provide the help they needed.”

Amon’s students and the entire MIT community will miss her unrelenting enthusiasm and her kind, caring ways.

Enzyme “atlas” helps researchers decipher cellular pathways

Biologists have mapped out more than 300 protein kinases and their targets, which they hope could yield new leads for cancer drugs.

Anne Trafton | MIT News Office
January 11, 2023

One of the most important classes of human enzymes are protein kinases — signaling molecules that regulate nearly all cellular activities, including growth, cell division, and metabolism. Dysfunction in these cellular pathways can lead to a variety of diseases, particularly cancer.

Identifying the protein kinases involved in cellular dysfunction and cancer development could yield many new drug targets, but for the vast majority of these kinases, scientists don’t have a clear picture of which cellular pathways they are involved in, or what their substrates are.

“We have a lot of sequencing data for cancer genomes, but what we’re missing is the large-scale study of signaling pathway and protein kinase activation states in cancer. If we had that information, we would have a much better idea of how to drug particular tumors,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

Yaffe and other researchers have now created a comprehensive atlas of more than 300 of the protein kinases found in human cells, and identified which proteins they likely target and control. This information could help scientists decipher many cellular signaling pathways, and help them to discover what happens to those pathways when cells become cancerous or are treated with specific drugs.

Lewis Cantley, a professor of cell biology at Harvard Medical School and Dana Farber Cancer Institute, and Benjamin Turk, an associate professor of pharmacology at Yale School of Medicine, are also senior authors of the paper, which appears today in Nature. The paper’s lead authors are Jared Johnson, an instructor in pharmacology at Weill Cornell Medical College, and Tomer Yaron, a graduate student at Weill Cornell Medical College.

“A Rosetta stone”

The human genome includes more than 500 protein kinases, which activate or deactivate other proteins by tagging them with a chemical modification known as a phosphate group. For most of these kinases, the proteins they target are unknown, although research into kinases such as MEK and RAF, which are both involved in cellular pathways that control growth, has led to new cancer drugs that inhibit those kinases.

To identify additional pathways that are dysregulated in cancer cells, researchers rely on phosphoproteomics using mass spectrometry — a technique that separates molecules based on their mass and charge — to discover proteins that are more highly phosphorylated in cancer cells or healthy cells. However, until now, there has been no easy way to interrogate the mass spectrometry data to determine which protein kinases are responsible for phosphorylating those proteins. Because of that, it has remained unknown how those proteins are regulated or misregulated in disease.

“For most of the phosphopeptides that are measured, we don’t know where they fit in a signaling pathway. We don’t have a Rosetta stone that you could use to look at these peptides and say, this is the pathway that the data is telling us about,” Yaffe says. “The reason for this is that for most protein kinases, we don’t know what their substrates are.”

Twenty-five years ago, while a postdoc in Cantley’s lab, Yaffe began studying the role of protein kinases in signaling pathways. Turk joined the lab shortly after, and the three have since spent decades studying these enzymes in their own research groups.

“This is a collaboration that began when Ben and I were in Lew’s lab 25 years ago, and now it’s all finally really coming together, driven in large part by what the lead authors, Jared and Tomer, did,” Yaffe says.

In this study, the researchers analyzed two classes of kinases — serine kinases and threonine kinases, which make up about 85 percent of the protein kinases in the human body — based on what type of structural motif they put phosphate groups onto.

Working with a library of peptides that Cantley and Turk had previously created to search for motifs that kinases interact with, the researchers measured how the peptides interacted with all 303 of the known serine and threonine kinases. Using a computational model to analyze the interactions they observed, the researchers were able to identify the kinases capable of phosphorylating every one of the 90,000 known phosphorylation sites that have been reported in human cells, for those two classes of kinases.

To their surprise, the researchers found that many kinases with very different amino acid sequences have evolved to bind and phosphorylate the same motifs on their substrates. They also showed that about half of the kinases they studied target one of three major classes of motifs, while the remaining half are specific to one of about a dozen smaller classes.

Decoding networks

This new kinase atlas can help researchers identify signaling pathways that differ between normal and cancerous cells, or between treated and untreated cancer cells, Yaffe says.

“This atlas of kinase motifs now lets us decode signaling networks,” he says. “We can look at all those phosphorylated peptides, and we can map them back onto a specific kinase.”

To demonstrate this approach, the researchers analyzed cells treated with an anticancer drug that inhibits a kinase called Plk1, which regulates cell division. When they analyzed the expression of phosphorylated proteins, they found that many of those affected were controlled by Plk1, as they expected. To their surprise, they also discovered that this treatment increased the activity of two kinases that are involved in the cellular response to DNA damage.

Yaffe’s lab is now interested in using this atlas to try to find other dysfunctional signaling pathways that drive cancer development, particularly in certain types of cancer for which no genetic drivers have been found.

“We can now use phosphoproteomics to say, maybe in this patient’s tumor, these pathways are upregulated or these pathways are downregulated,” he says. “It’s likely to identify signaling pathways that drive cancer in conditions where it isn’t obvious what the genetics that drives the cancer are.”

The research was funded by the Leukemia and Lymphoma Society, the National Institutes of Health, Cancer Research UK, the Brain Tumour Charity, the Charles and Marjorie Holloway foundation, the MIT Center for Precision Cancer Medicine, and the Koch Institute Support (core) grant from the National Cancer Institute.

Portraiture at the intersection of art, science, and society

Exhibit at MIT's Koch Institute attempts to make visible the luminary personalities behind major scientific and engineering advances.

Koch Institute
January 5, 2023

“For me, this project is about making science visible in society,” says Herlinde Koelbl, a renowned German photo artist whose portrait series, “Fascination of Science,” is now on display at MIT.

Koelbl set herself the goal to photograph scientists and to show their motivation, influences, and ways of thinking — through the eyes of an artist. The portraits juxtapose the subjects’ faces with scientific concepts, advice, or reflections playfully inscribed on their palms. Individually, each picture or phrase speaks to the researcher’s personal quest for knowledge — everything from nucleotide base pairings and “learn from failures!” to “make malaria history!” and a sailing vessel beset by sea creatures — but collectively, the broad sweep of disciplines and backgrounds represented in the portraits reveals the interconnectedness of the scientific endeavor across institutions, geography, and subject matter.

The MIT venue for Koelbl’s work is the Public Galleries of the Koch Institute for Integrative Cancer Research, a research center that combines MIT’s rich traditions of interdisciplinary inquiry and technological innovation with discovery-based biological research to develop new insights, tools, and technologies to fight cancer.

Through Koelbl’s lens, MIT’s “mind and hand” motto is made visible, along with the diversity of ideas that fuel society’s collective fascination with science. The exhibit includes portraits of MIT scientists Sangeeta Bhatia, Ed Boyden, Sallie “Penny” Chisholm, Wolfgang Ketterle, Robert Langer, and Robert Weinberg, along with other internationally acclaimed scientists such as George Church, Jennifer Doudna, Emmanuelle Charpentier, and 2022 Nobel laureate Carolyn Bertozzi.

Visitors are welcome to view Koelbl’s work at the Koch Institute’s Public Galleries (open to the public on weekdays 8 a.m. – 6 p.m.) through Jan. 27.

Scientists discover a new way of sharing genetic information in a common ocean microbe

Prochlorococcus, the world’s most abundant photosynthetic organism, reveals a gene-transfer mechanism that may be key to its abundance and diversity.

David L. Chandler | MIT News Office
January 5, 2023

From the tropics to the poles, from the sea surface to hundreds of feet below, the world’s oceans are teeming with one of the tiniest of organisms: a type of bacteria called Prochlorococcus, which despite their minute size are collectively responsible for a sizable portion of the oceans’ oxygen production. But the remarkable ability of these diminutive organisms to diversify and adapt to such profoundly different environments has remained something of a mystery.

Now, new research reveals that these tiny bacteria exchange genetic information with one another, even when widely separated, by a previously undocumented mechanism. This enables them to transmit whole blocks of genes, such as those conferring the ability to metabolize a particular kind of nutrient or to defend themselves from viruses, even in regions where their population in the water is relatively sparse.

The findings describe a new class of genetic agents involved in horizontal gene transfer, in which genetic information is passed directly between organisms — whether of the same or different species — through means other than lineal descent. The researchers have dubbed the agents that carry out this transfer “tycheposons,” which are sequences of DNA that can include several entire genes as well as surrounding sequences, and can spontaneously separate out from the surrounding DNA. Then, they can be transported to other organisms by one or another possible carrier system including tiny bubbles known as vesicles that cells can produce from their own membranes.

The research, which included studying hundreds of Prochlorococcus genomes from different ecosystems around the world, as well as lab-grown samples of different variants, and even evolutionary processes carried out and observed in the lab, is reported today in the journal Cell, in a paper by former MIT postdocs Thomas Hackl and Raphaël Laurenceau, visiting postdoc Markus Ankenbrand, Institute Professor Sallie “Penny” Chisholm, and 16 others at MIT and other institutions.

Chisholm, who played a role in the discovery of these ubiquitous organisms in 1988, says of the new findings, “We’re very excited about it because it’s a new horizontal gene-transfer agent for bacteria, and it explains a lot of the patterns that we see in Prochlorococcus in the wild, the incredible diversity.” Now thought to be the world’s most abundant photosynthetic organism, the tiny variants of what are known as cyanobacteria are also the smallest of all photosynthesizers.

Hackl, who is now at the University of Groningen in the Netherlands, says the work began by studying the 623 reported genome sequences of different species of Prochlorococcus from different regions, trying to figure out how they were able to so readily lose or gain particular functions despite their apparent lack of any of the known systems that promote/boost horizontal gene transfer, such as plasmids or viruses known as prophages.

What Hackl, Laurenceau, and Ankenbrand investigated were “islands” of genetic material that seemed to be hotspots of variability and often contained genes that were associated with known key survival processes such as the ability to    assimilate essential, and often limiting, nutrients such as iron, or nitrogen, or phosphates. These islands contained genes that varied enormously between different species, but they always occurred in the same parts of the genome and sometimes were nearly identical even in widely different species — a strong indicator of horizontal transfer.

But the genomes showed none of the usual features associated with what are known as mobile genetic elements, so initially this remained a puzzle. It gradually became apparent that this system of gene transfer and diversification was different from any of the several other mechanisms that have been observed in other organisms, including in humans.

Hackl describes what they found as being something like a genetic LEGO set, with chunks of DNA bundled together in ways that could almost instantly confer the ability to adapt to a particular environment. For example, a species limited by the availability of particular nutrients could acquire genes necessary to enhance the uptake of that nutrient.

The microbes appear to use a variety of mechanisms to transport these tycheposons (a name derived from the name of the Greek goddess Tyche, daughter of Oceanus). One is the use of membrane vesicles, little bubbles pouched off from the surface of a bacterial cell and released with tycheposons inside it. Another is by “hijacking” virus or phage infections and allowing them to carry the tycheposons along with their own infectious particles, called capsids. These are efficient solutions, Hackl says, “because in the open ocean, these cells rarely have cell-to-cell contacts, so it’s difficult for them to exchange genetic information without a vehicle.”

And sure enough, when capsids or vesicles collected from the open ocean were studied, “they’re actually quite enriched” in these genetic elements, Hackl says. The packets of useful genetic coding are “actually swimming around in these extracellular particles and potentially being able to be taken up by other cells.”

Chisholm says that “in the world of genomics, there’s a lot of different types of these elements” — sequences of DNA that are capable of being transferred from one genome to another. However, “this is a new type,” she says. Hackl adds that “it’s a distinct family of mobile genetic elements. It has similarities to others, but no really tight connections to any of them.”

While this study was specific to Prochlorococcus, Hackl says the team believes the phenomenon may be more generalized. They have already found similar genetic elements in other, unrelated marine bacteria, but have not yet analyzed these samples in detail. “Analogous elements have been described in other bacteria, and we now think that they may function similarly,” he says.

“It’s kind of a plug-and-play mechanism, where you can have pieces that you can play around with and make all these different combinations,” he says. “And with the enormous population size of Prochlorococcus, it can play around a lot, and try a lot of different combinations.”

Nathan Ahlgren, an assistant professor of biology at Clark University who was not associated with this research, says “The discovery of tycheposons is important and exciting because it provides a new mechanistic understanding of how Prochlorococcus are able to swap in and out new genes, and thus ecologically important traits. Tycheposons provide a new mechanistic explanation for how it’s done.” He says “they took a creative way to fish out and characterize these new genetic elements ‘hiding’ in the genomes of Prochlorococcus.”

He adds that genomic islands, the portions of the genome where these tycheposons were found, “are found in many bacteria, not just marine bacteria, so future work on tycheposons has wider implications for our understanding of the evolution of bacterial genomes.”

The team included researchers at MIT’s Department of Civil and Environmental Engineering, the University of Wuerzburg in Germany, the University of Hawaii at Manoa, Ohio State University, Oxford Nanopore Technologies in California, Bigelow Laboratory for Ocean Sciences in Maine, and Wellesley College. The work was supported by the Simons Foundation, the Gordon and Betty Moore Foundation, the U.S. Department of Energy, and the U.S. National Science Foundation.

Uncovering how cells control their protein output

Gene-Wei Li investigates the rules that cells use to maintain the correct ratio of the proteins they need to survive.

Anne Trafton | MIT News Office
January 4, 2023

A typical bacterial genome contains more than 4,000 genes, which encode all of the proteins that the cells need to survive. How do cells know just how much of each protein they need for their everyday functions?

Gene-Wei Li, an MIT associate professor of biology, is trying to answer that question. A physicist by training, he uses genome-wide measurements and biophysical modeling to quantify cells’ protein production and discover how cells achieve such precise control of those quantities.

Using those techniques, Li has found that cells appear to strictly control the ratios of proteins that they produce, and that these ratios are consistent across cell types and across species.

“Coming from a physics background, it’s surprising to me that these cells have evolved to be really precise in making the right amount of their proteins,” Li says. “That observation was enabled by the fact that we are able to design measurements with a precision that matches what is actually happening in biology.”

From physics to biology

Li’s parents — his father, a marine biologist who teaches at a university in Taiwan, and his mother, a plant biologist who now runs a science camp for high school students — passed their affinity for science on to Li, who was born in San Diego while his parents were graduate students there.

The family returned to Taiwan when Li was 2 years old, and Li soon became interested in math and physics. In Taiwan, students choose their college major while still in high school, so he decided to study physics at National Tsinghua University.

While in college, Li was drawn to optical physics and spectroscopy. He went to Harvard University for graduate school, where after his first year, he started working in a lab that works on single-molecule imaging of biological systems.

“I realized there are a lot of really exciting fields at the boundary between disciplines. It’s something that we didn’t have in Taiwan, where the departments are very strict that physics is physics, and biology is biology,” Li says. “Biology is a lot messier than physics, and I had some hesitancy, but I was happy to see that biology does have rules that you can observe.”

For his PhD research, Li used single-molecule imaging to study proteins called transcription factors — specifically, how quickly they can bind to DNA and initiate the copying of DNA into RNA. Though he had never taken a class in biology, he began to learn more about it and decided to do a postdoc at the University of California at San Francisco, where he worked in the lab of Jonathan Weissman, a professor of cellular and molecular pharmacology.

Weissman, who is now a professor of biology at MIT, also trained as a physicist before turning to biology. In Weissman’s lab, Li developed techniques for studying gene expression in bacterial cells, using high-throughput DNA sequencing. In 2015, Li joined the faculty at MIT, where his lab began to work on tools that could be used to measure gene expression in cells.

When genes are expressed in cells, the DNA is first copied into RNA, which carries the genetic instructions to ribosomes, where proteins are assembled. Li’s lab has developed ways to measure protein synthesis rates in cells, along with the amount of RNA that is transcribed from different genes. Together, these tools can yield precise measurements of how much a particular gene is expressed in a given cell.

“We had the qualitative tools before, but now we can really have quantitative information and learn how much protein is made and how important those protein levels are to the cell,” Li says.

Precise control

Using these tools, Li and his students have discovered that different species of bacteria can have different strategies for making proteins. In E. coli, transcription of DNA and translation of RNA into proteins had long been known to be a coupled process, meaning that after RNA is produced, ribosomes immediately translate it into protein.

Many researchers assumed that this would be true for all bacteria, but in a 2020 study, Li found that Bacillus subtilis and hundreds of other bacterial species use a different strategy.

“A lot of other species have what we call runaway transcription, where the transcription happens really fast and the proteins don’t get made at the same time. And because of this uncoupling, these species have very different mechanisms of regulating their gene expression,” Li says.

Li’s lab has also found that across species, cells make the same proportions of certain proteins that work together. Many cellular processes, such as breaking down sugar and storing its energy as ATP, are coordinated by enzymes that perform a series of reactions in a specified sequence.

“Evolution, it turns out, gives us the same proportion of those enzymes, whether in E. coli or other bacteria or in eukaryotic cells,” Li says. “There are apparently rules and principles for designing these pathways that we didn’t know of before.”

Mutations that cause too much or too little of a protein to be produced can cause a variety of human diseases. Li now plans to investigate how the genome encodes the rules governing the correct quantities of each protein, by measuring how changes to genetic and regulatory sequences affect gene expression at each step of the process — from initiation of transcription to protein assembly.

“The next level that we’re trying to focus on is: How is that information stored in the genome?” he says. “You can easily read off protein sequences from a genome, but it’s still impossible to tell how much protein is going to be made. That’s the next chapter.”

MIT’s departments, labs, and centers celebrate the holidays

Across the Institute, MIT’s communities took part in light-hearted traditions new and old.

Zach Winn | MIT News Office
December 23, 2022

Amid final exams and year-end research crunches, this is also the time of year when many in the MIT community take time to have some fun and express gratitude for the people that make their work possible. Each year across the Institute, community members gather for holiday parties and socializing in a more relaxed environment than the lab or classroom.

Across MIT’s five schools and the Schwarzman College of Computing, most departments, labs, and centers have festivities of some sort, from gatherings of Sloanies to holiday parties in the School of Humanities, Arts, and Social Science. Below we’ve highlighted just a few of the more unique traditions that some groups have to mark the end of a busy semester.

Department of Architecture

Ahead of the semester’s final review, the Department of Architecture surprised its first-year graduate students with a hands-on challenge to reconsider the design of a gingerbread house, providing everyone with sweet-smelling houses and the tools to deconstruct them.

“We’re giving them some opportunities to destress,” Associate Professor William O’Brien Jr. said, noting the department did something similar with a pumpkin carving contest in October. “Being somewhere new during the semester, things can get stressful.”

The challenge made for a chaotic scene in room 7-432 as teaching assistants, fellows, instructors, and students got their hands dirty — and sticky — in the quest to create a more inclusive gingerbread structure.

“It’s awesome to have a non-hierarchical social setting, whereas ordinarily students are presenting and we’re giving feedback,” O’Brien Jr. said.

The students agreed.

“It’s spectacularly fun,” said graduate student Mateo Fernandez, who is new to the United States and had never seen a gingerbread house before. “It’s a nice relief from everything we’re usually doing. It also helps us get to know each other outside of the serious academic environment, and helps us learn to work together.”

Department of Chemical Engineering

For as long as anyone can remember, the chemical engineering department’s holiday party has begun with elaborate skits by students, faculty, and sometimes staff, that humorously depict faculty members, courses, and current events.

Institute Professor and department head Paula Hammond describes them as “drama ensembles of sorts, sometimes with multiple acts — and many inside jokes.”

“We use the skits as a chance to lampoon ourselves,” says Hammond, who participated as a student in the department in the 1980s. “Faculty gets lampooned more than anyone, but that’s the spirit of the whole thing.”

Over the years the skits have moved more to video format, but the one constant is a depiction of faculty, often by students with fitting outfits and spot-on impressions. Hammond says the student skits are always better than the faculty skits.

“Students who spend an entire semester watching a faculty member know exactly how they write erratically on the chalkboard, or ramble off into stories from the old days, or get overexcited about an integral,” Hammond says.

Hammond says faculty members consider it an honor to be roasted by students, and remembers one faculty member upset after not getting riffed on enough in the annual tradition. She also says it’s a great way for students to tell their stories and build empathy.

“It’s fun to laugh and wink at faculty members and share the student perspective,” Hammond says. “What makes you laugh is the everyday, unusual little things about all of us that make us human. It acknowledges that the faculty aren’t superpowers. They’re regular people with their own little flaws. That’s comforting.”

Department of Earth, Atmospheric, and Planetary Sciences

In another longstanding tradition, each year the Department of Earth, Atmospheric, and Planetary Science has a party in early December where faculty, staff, and students get together and create their own ornaments to hang on a department tree. This year’s event doubled as an ice cream social.

Members of the department admire the tree for a week, and everybody votes on their favorite ornament at the ensuing holiday party. The three top winners get a prize.

“It brings everyone together,” says administrative assistant Madelyn Musick, who bought paint, glitter, and other festive decorations for this year’s event. “It gives everyone a break from their research to do something fun that’s relaxing but that also encourages creativity.”

Surendranath Lab

Researchers in the lab of associate professor of chemistry Yogesh Surendranath are used to mixing ingredients and catalyzing reactions. But around the holidays, they direct their talents to a more tasty kind of chemical processing.

Each year, graduate students and postdocs gather to make cookies and other baked goods for the staff members that make their work possible.

The holidays also happen to be the time when first-year graduate students join the lab, so it doubles as a fun way to get to know their fellow researchers outside of the lab setting.

“We spend a lot of time here. It’s not just a normal 9-5 job, and so it’s always nice to have a good relationship outside of work,” graduate student Bryan Yuk-Wah Tang says. “It’s something I really appreciate about our lab.”

This year, the event took place at a student’s house and culminated in a holiday party where the students distributed the goods along with cards expressing thanks.

“It’s a good opportunity to thank everybody who works hard and goes out of their way to support us,” Tang says. “A lot of staff members at MIT go above and beyond. It’s great to have this community, and we love to show our appreciation for that.”

Professor Laurie Boyer’s Lab

Laurie Boyer, a professor of biology and biological engineering, took her lab group — graduate students, research staff, and undergraduates — to a new minigolf venue in the Seaport District to mark the end of the semester. The group also got dinner together and explored an outdoor market nearby. Highlights included several improbable hole-in-ones (no one in the group considered themselves minigolf experts before the outing) and some much-needed hot chocolate at the outdoor market.

“I think it builds community,” says Catherine Della Santina, a PhD student in Boyer’s lab. “We see each other every day, but we mostly talk about science. Instead, we talked about stuff like the summer camps we went to growing up, which you might not mention when you’re inoculating cells or doing protocol prep. You get to know people better.”

Della Santina also said the outing provided a year-end refresher.

“It gets people excited to come back after the break,” she says.

Koch Institute celebrates inaugural winners of the Angelika Amon Young Scientist Award

Graduate students Alejandro Aguilera Castrejón and Melanie de Almeida honored for their passion for fundamental biology and discovery science.

Bendta Schroeder | Koch Institute
December 13, 2022

On Nov. 17, the Koch Institute for Integrative Cancer Research hosted the inaugural winners of the Angelika Amon Young Scientist Award, Alejandro Aguilera Castrejón and Melanie de Almeida.

The award was established at the Koch Institute by family and friends of MIT faculty member Angelika Amon, a professor of biology and a member of the Koch Institute who died in 2020 following a two-and-a-half-year battle with ovarian cancer. The award is given annually to two graduate students in the life sciences or biomedical research from institutions outside the United States who embody Amon’s infectious enthusiasm for discovery science.

Winners are invited to the Koch Institute for an award ceremony and presentations to the MIT community, friends and family of the winners, and Amon Lab alumni. Attendees joined online from countries around the world, including Argentina, Austria, Denmark, France, Israel, Italy, Mexico, and the United Kingdom.

Amon was born in Vienna, Austria, and studied genetics at the University of Vienna as an undergraduate student and at the Research Institute of Molecular Pathology (IMP). Amon arrived in the United States in 1994 as a postdoc at the Whitehead Institute for Biomedical Research, and joined the MIT faculty in 1999. Widely recognized for her profound contributions to our understanding of the fundamental biology of cell division and proliferation, as well as the causes of chromosome mis-segregation and its consequences for human diseases such as cancer, Amon was equally well-known for her mentorship and advocacy for her students, postdocs, and colleagues.

“Angelika was a dedicated mentor, guide, advocate, and friend to many scientists,” said MIT Koch Institute Director Matthew Vander Heiden at the award ceremony. “She trained countless undergraduate and graduate students, postdoctoral researchers, and technicians, sharing with them her lifelong passion for fundamental biology and discovery science. The ripple effect of Angelika’s inspiration and counsel is profound.”

De Almeida, who recently completed her PhD in the lab of Johannes Zuber at IMP, presented on the development of a time-controlled CRISPR-based system for screening for the effects of gene knockouts. While using the system to knock out genes essential to regulating MYC, a protein often dysregulated in cancer, de Almeida and a fellow grad student stumbled across a poorly understood gene, AKIRIN2, which they discovered to control the import of enzymes that break down unnecessary or damaged proteins into the nucleus of mammalian cells.

When de Almeida started studying AKIRN2, she felt that doing science was “like solving a riddle, where you really need to ask the right questions to get closer to the solution. The best part about science is when you come to the end of a long experiment to find out whether your hypothesis is actually true.”

Aguilera Castrejón, currently a doctoral student in the lab of Jacob Hanna at the Weizmann Institute of Science in Rehovot, Israel, delivered a talk on his work developing in vitro systems for the culture of mammalian embryos outside the maternal uterus and then using these systems to gain insights into mammalian embryogenesis. Aguilera Castrejón’s platform allows post-implantation mouse embryos to develop outside the uterus for up to 6 days, and can also be used to culture stem cell-derived embryo models.

A first-generation graduate student from a working-class family in Mexico City, Aguilera Castrejón hopes that the Amon Award will help him “promote developmental biology in Mexico and other underdeveloped countries, and importantly, will show others that leading-edge science is not only for those born in wealthy or educated families, or in rich countries, but that science is for everyone who is passionate about discovery.”

After their presentations, Aguilera Castrejón and De Almeida were given their awards by Amon’s family, husband Johannes Weis and daughters Theresa and Clara.

“Today I could see some of the same love and passion for science that I saw in Angelika, and that just what we wanted to capture,” said Weis. “In future years, we will try to keep that spirit alive with this award.”

Three MIT seniors win 2024 Schwarzman Scholarships

Sara V. Fernandez, Amanda Hu, and Brigette Wang will spend the 2023-24 academic year at Tsinghua University in China studying global affairs.

Julia Mongo | Office of Distinguished Fellowships
December 7, 2022

Three MIT seniors — Sara V. Fernandez, Amanda Hu, and Brigette Wang — have been named 2024 Schwarzman Scholars and will join the program’s eighth cohort, consisting of 151 scholars from 36 countries. The students were selected from a pool of over 3,000 applicants.

Schwarzman Scholars pursue a master’s degree in global affairs at Tsinghua University in Beijing. The fellowship program aims to develop leadership skills and deepen understanding of China’s changing role in the world. Candidates are chosen through a rigorous application process designed to identify leadership potential, intellect, and strength of character. In the finalist stage, select candidates are invited to interview with panels composed of CEOs, government officials, nonprofit executives, and others.

MIT’s Schwarzman Scholar applicants receive guidance and mentorship from the distinguished fellowships team in Career Advising and Professional Development and the Presidential Committee on Distinguished Fellowships. “Sara, Brigette, and Amanda have demonstrated strong leadership abilities at MIT in their research and extracurricular activities,” says Kim Benard, associate dean of distinguished fellowships. “We are proud that they will represent MIT in China as Schwarzman Scholars, as this will provide them further opportunities to hone their leadership so that they may tackle the world’s problems.”

Sara V. Fernandez

Sara V. Fernandez will graduate MIT in June 2023 with a BS in materials science and engineering and minors in entrepreneurship and innovation and in Chinese. As a Latinx researcher in the MIT Conformable Decoders lab, Fernandez developed innovative medical devices, yielding high-impact publications. Throughout her time at MIT, she has been committed to international student outreach; diversity, equity, and inclusion initiatives; and peer mentorship, both academically and as a varsity tennis team captain. Fernandez looks forward to enriching her study of Chinese language and culture through the Schwarzman Scholars program, and gaining understanding on how to leverage China’s economies of scale for increasing health care accessibility in Latin America.

Amanda Hu

Amanda Hu is a senior majoring in biology and business management. She is passionate about health care entrepreneurship and financing strategies to drive innovation in medical fields. Hu is a founding member of Encreto Therapeutics, a startup discovering treatments for obesity, and is engaged in women’s health research at Massachusetts General Hospital. She also provides strategic support to AI health care portfolio companies at Aegis Ventures. As a Schwarzman Scholar, Hu hopes to work at the intersection of policy, technology, and business to bridge health care innovations between the United States and China.

Brigette Wang

Brigette Wang is a senior majoring in computation and cognition, with a humanities concentration in political science. Her undergraduate research includes studying the effects of the antidepressant ketamine on dendritic spines and evaluating operative outcomes of superior semicircular canal dehiscence, a rare hearing disorder. Wang is a student-athlete on the varsity women’s soccer team and the president of her sorority, where she has advocated for increased accessibility and inclusion in Greek life. She is passionate about health equity and, through Schwarzman Scholars, hopes to gain the global insight necessary to push health policy reform worldwide.