Author: mantulin

Postdoc Andrew Savinov among 2024 Infinite Expansion Award recipients

Nine postdocs and research scientists honored for contributions to the Institute.

School of Science
March 3, 2024

The MIT School of Science has announced nine postdocs and research scientists as recipients of the 2024 Infinite Expansion Award, which highlights extraordinary members of the MIT community.

The following are the 2024 School of Science Infinite Expansion winners:

  • Sarthak Chandra, a research scientist in the Department of Brain and Cognitive Sciences, was nominated by Professor Ila Fiete, who wrote, “He has expanded the research abilities of my group by being a versatile and brilliant scientist, by drawing connections with a different area that he was an expert in from his PhD training, and by being a highly involved and caring mentor.”
  • Michal Fux, a research scientist in the Department of Brain and Cognitive Sciences, was nominated by Professor Pawan Sinha, who wrote, “She is one of those figurative beams of light that not only brilliantly illuminate scientific questions, but also enliven a research team.”
  • Andrew Savinov, a postdoc in the Department of Biology, was nominated by Associate Professor Gene-Wei Li, who wrote, “Andrew is an extraordinarily creative and accomplished biophysicist, as well as an outstanding contributor to the broader MIT community.”
  • Ho Fung Cheng, a postdoc in the Department of Chemistry, was nominated by Professor Jeremiah Johnson, who wrote, “His impact on research and our departmental community during his time at MIT has been outstanding, and I believe that he will be a worldclass teacher and research group leader in his independent career next year.”
  • Gabi Wenzel, a postdoc in the Department of Chemistry, was nominated by Assistant Professor Brett McGuire, who wrote, “In the one year since Gabi joined our team, she has become an indispensable leader, demonstrating exceptional skill, innovation, and dedication in our challenging research environment.”
  • Yu-An Zhang, a postdoc in the Department of Chemistry, was nominated by Professor Alison Wendlandt, who wrote, “He is a creative, deep-thinking scientist and a superb organic chemist. But above all, he is an off-scale mentor and a cherished coworker.”
  • Wouter Van de Pontseele, a senior postdoc in the Laboratory for Nuclear Science, was nominated by Professor Joseph Formaggio, who wrote, “He is a talented scientist with an intense creativity, scholarship, and student mentorship record. In the time he has been with my group, he has led multiple facets of my experimental program and has been a wonderful citizen of the MIT community.”
  • Alexander Shvonski, a lecturer in the Department of Physics, was nominated by Assistant Professor Andrew Vanderburg, who wrote, “… I have been blown away by Alex’s knowledge of education research and best practices, his skills as a teacher and course content designer, and I have been extremely grateful for his assistance.”
  • David Stoppel, a research scientist in The Picower Institute for Learning and Memory, was nominated by Professor Mark Bear and his research group, who wrote, “As impressive as his research achievements might be, David’s most genuine qualification for this award is his incredible commitment to mentorship and the dissemination of knowledge.”

Winners are honored with a monetary award and will be celebrated with family, friends, and nominators at a later date, along with recipients of the Infinite Mile Award.

How early-stage cancer cells hide from the immune system

A new study finds precancerous colon cells turn on a gene called SOX17, which helps them evade detection and develop into more advanced tumors.

Anne Trafton | MIT News
February 28, 2024

One of the immune system’s primary roles is to detect and kill cells that have acquired cancerous mutations. However, some early-stage cancer cells manage to evade this surveillance and develop into more advanced tumors.

A new study from MIT and Dana-Farber Cancer Institute has identified one strategy that helps these precancerous cells avoid immune detection. The researchers found that early in colon cancer development, cells that turn on a gene called SOX17 can become essentially invisible to the immune system.

If scientists could find a way to block SOX17 function or the pathway that it activates, this may offer a new way to treat early-stage cancers before they grow into larger tumors, the researchers say.

“Activation of the SOX17 program in the earliest innings of colorectal cancer formation is a critical step that shields precancerous cells from the immune system. If we can inhibit the SOX17 program, we might be better able to prevent colon cancer, particularly in patients that are prone to developing colon polyps,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

Judith Agudo, a principal investigator at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School, is also a senior author of the study, which appears today in Nature. The paper’s lead author is MIT Research Scientist Norihiro Goto. Other collaborators include Tyler Jacks, a professor of biology and a member of MIT’s Koch Institute; Peter Westcott, a former Jacks lab postdoc who is now an assistant professor at Cold Spring Harbor Laboratory; and Saori Goto, an MIT postdoc in the Yilmaz lab.

Immune evasion

Colon cancer usually arises in long-lived cells called intestinal stem cells, whose job is to continually regenerate the lining of the intestines. Over their long lifetime, these cells can accumulate cancerous mutations that lead to the formation of polyps, a type of premalignant growth that can eventually become metastatic colon cancer.

To learn more about how these precancerous growths evade the immune system, the researchers used a technique they had previously developed for growing mini colon tumors in a lab dish and then implanting them into mice. In this case, the researchers engineered the tumors to express mutated versions of cancer-linked genes Kras, p53, and APC, which are often found in human colon cancers.

Once these tumors were implanted in mice, the researchers observed a dramatic increase in the tumors’ expression of SOX17. This gene encodes a transcription factor that is normally active only during embryonic development, when it helps to control development of the intestines and the formation of blood vessels.

The researchers’ experiments revealed that when SOX17 is turned on in cancer cells, it helps the cells to create an immunosuppressive environment. Among its effects, SOX17 prevents cells from synthesizing the receptor that normally detects interferon gamma, a molecule that is one of the immune system’s primary weapons against cancer cells.

Without those interferon gamma receptors, cancerous and precancerous cells can simply ignore messages from the immune system, which would normally direct them to undergo programmed cell death.

“One of SOX17’s main roles is to turn off the interferon gamma signaling pathway in colorectal cancer cells and in precancerous adenoma cells. By turning off interferon gamma receptor signaling in the tumor cells, the tumor cells become hidden from T cells and can grow in the presence of an immune system,” Yilmaz says.

Without interferon gamma signaling, cancer cells also minimize their production of molecules called MHC proteins, which are responsible for displaying cancerous antigens to the immune system. The cells’ insensitivity to interferon gamma also prevents them from producing immune molecules called chemokines, which normally recruit T cells that would help destroy the cancerous cells.

Targeting SOX17

When the researchers generated colon tumor organoids with SOX17 knocked out, and implanted those into mice, the immune system was able to attack those tumors much more effectively. This suggests that preventing cancer cells from turning off SOX17 could offer a way to treat colon cancer in its earliest stages.

“Just by turning off SOX17 in fairly complex tumors, we were able to essentially obliterate the ability of these tumor cells to persist,” Goto says.

As part of their study, the researchers also analyzed gene expression data from patients with colon cancer and found that SOX17 tended to be highly expressed in early-stage colon cancers but dropped off as the tumors became more invasive and metastatic.

“We think this makes a lot of sense because as colorectal cancers become more invasive and metastatic, there are other mechanisms that create an immunosuppressive environment,” Yilmaz says. “As the colon cancer becomes more aggressive and activates these other mechanisms, then there’s less importance for SOX17.”

Transcription factors such as SOX17 are considered difficult to target using drugs, in part because of their disorganized structure, so the researchers now plan to identify other proteins that SOX17 interacts with, in hopes that it might be easier to block some of those interactions.

The researchers also plan to investigate what triggers SOX17 to turn on in precancerous cells.

The research was funded by the MIT Stem Cell Initiative via Fondation MIT, the National Institutes of Health/National Cancer Institute, and a Koch Institute-Dana Farber Harvard Cancer Center Bridge Project grant.

What can super-healing species teach us about regeneration?

Albert Almada PhD ’13 studies the mechanics of how stem cells rebuild tissues. “Digging deep into the science is what MIT taught me,” he says.

Lillian Eden | Department of Biology
February 21, 2024

When Albert E. Almada PhD ’13 embarks on a new project, he always considers two criteria instilled in him during his time as a graduate student in the Department of Biology at MIT.

“If you want to make a big discovery, you have to approach it from a unique perspective — a unique angle,” Almada says. “You also have to be willing to dive into the unknown and go to the leading edge of your field.”

This is not without its challenges — but with an innovative spirit, Almada says, one can find ways to apply technologies and approaches to a new area of research where a roadmap doesn’t yet exist.

Now an assistant professor of orthopedic surgery and stem cell biology and regenerative medicine at the Keck School of Medicine of the University of Southern California (USC), Almada studies the mechanics of how stem cells rebuild tissues after trauma and how stem cell principles are dysregulated and drive conditions like degenerative disease and aging, exploring these topics through an evolutionary lens.

He’s also trying to solve a mystery that has intrigued scientists for centuries: Why can some vertebrate species like fish, salamanders, and lizards regenerate entire body parts, but mammals cannot? Almada’s laboratory at USC tackles these critical questions in the musculoskeletal system.

Almada’s fascination with muscle development and regeneration can be traced back to growing up in southern California. Almada’s brother had a degenerative muscle disease called Duchenne muscular dystrophy — and, while Almada grew stronger and stronger, his brother grew weaker and weaker. Last summer, Almada’s brother, unfortunately, lost his battle with his disorder at the age of 41.

“Watching his disease progress in those early years is what inspired me to become a scientist,” Almada recalls. “Sometimes science can be personal.”

Almada went to the University of California at Irvine for his undergraduate degree, majoring in biological sciences. During his summers, he participated in the Undergraduate Research Program (URP) at the Cold Spring Harbor Laboratory and the MIT Summer Research Program-Bio (now the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology, BSG-MSRP-Bio), where he saw the passion, rigor, and drive that solidified his desire to pursue a PhD.

Despite his interest in clinical applications, skeletal muscle, and regenerative biology, Almada was drawn to the Department of Biology at MIT, which is focused on basic fundamental research.

“I was willing to bet that it all came down to understanding basic cellular processes and things going wrong with the cell and how it interacts with its environment,” he says. “The MIT biology program really helped me define an identity for myself and gave me a template for how to tackle clinical problems from a molecular perspective.”

Almada’s PhD thesis work was based on a curious finding that Phillip Sharp, Institute Professor emeritus, professor emeritus of biology, and intramural faculty at the Koch Institute for Integrative Cancer Research, had made in 2007 — that transcription, the process of copying DNA into a messenger molecule called RNA, can occur in both directions at gene promoters. In one direction, it was long understood that fully formed mRNA is transcribed and can be used as a blueprint to make a protein. The transcription Sharp observed, in the opposite direction, results in a very short RNA that is not used as a gene product blueprint.

Almada’s project dug into what those short RNA molecules are — their structure and sequence, and why they’re not produced the same way that coding messenger RNA is. In two papers published in PNAS and Nature, Almada and colleagues discovered that a balance between splicing and transcription termination signals controls the length of an RNA. This finding has wider implications because toxic RNAs are produced and can build up in several degenerative diseases; being able to splice out or shorten RNAs to remove the harmful segments could be a potential therapeutic treatment.

“That experience convinced me that if I want to make big discoveries, I have to focus on basic science,” he says. “It also gave me the confidence that if I can succeed at MIT, I can succeed just about anywhere and in any field of biology.”

At the time Almada was in graduate school, there was a lot of excitement about transcription factor reprogramming. Transcription factors are the proteins responsible for turning on essential genes that tell a cell what to be and how to behave; a subset of them can even theoretically turn one cell type into another.

Almada began to wonder whether a specialized set of transcription factors instructs stem cells to rebuild tissues after trauma. After MIT, Almada moved on to a postdoctoral position in the lab of Amy Wagers, a leader in muscle stem cell biology at Harvard University, to immerse himself in this problem.

In many tissues in our bodies, a population of stem cells typically exists in an inactive, non-dividing state called quiescence. Once activated, these stem cells interact with their environment, sense damage signals, and turn on programs of proliferation and differentiation, as well as self-renewal, which is critical to maintaining a pool of stem cells in the tissue.

One of the biggest mysteries in the field of regenerative biology is how stem cells transition from dormancy into that activated, highly regenerative state. The body’s ability to turn on stem cells, including those in the skeletal muscle system, declines as we age and is often dysregulated in degenerative diseases — diseases like the one Almada’s brother suffered from.

In a study Almada published in Cell Reports several years ago, he identified a family of transcription factors that work together to turn on a critical regenerative gene program within hours of muscle trauma. This program drives muscle stem cells out of quiescence and speeds up healing.

“Now my lab is studying this regenerative program and its potential dysregulation in aging and degenerative muscle diseases using mouse and human models,” Almada says. “We’re also drawing parallels with super-healing species like salamanders and lizards.”

Recently, Almada has been working on characterizing the molecular and functional properties of stem cells in lizards, attempting to understand how the genes and pathways differ from mammalian stem cells. Lizards can regenerate massive amounts of skeletal muscle from scratch — imagine if human muscle tissue could be regrown as seamlessly as a lizard’s tail can. He is also exploring whether the tail is unique, or if stem cells in other tissues in lizards can regenerate faster and better than the tail, by comparing analogous injuries in a mouse model.

“This is a good example of approaching a problem from a new perspective: We believe we’re going to discover new biology in lizards that we can use to enhance skeletal muscle growth in vulnerable human populations, including those that suffer from deadly muscle disorders,” Almada says.

In just three years of starting his faculty position at USC, his work and approach have already received recognition in academia, with junior faculty awards from the Baxter Foundation and the Glenn Foundation/American Federation of Aging Research. He also received his first RO1 award from the National Institutes of Health with nearly $3 million in funding. Almada and his first graduate student, Alma Zuniga Munoz, were also awarded the HHMI Gilliam Fellowship last summer. Zuniga Munoz is the first to be recognized with this award at USC; fellowship recipients, student and advisor pairs, are selected with the goal of preparing students from underrepresented groups for leadership roles in science.

Almada himself is a second-generation Mexican American and has been involved in mentoring and training throughout his academic career. He was a graduate resident tutor for Spanish House at MIT and currently serves as the chair of the Diversity, Equity, and Inclusion Committee in the Department of Stem Cell Biology and Regenerative Medicine at USC; more than half of his lab members identify as members of the Hispanic community.

“The focus has to be on developing good scientists,” Almada says. “I learned from my past research mentors the importance of putting the needs of your students first and providing a supportive environment for everyone to excel, no matter where they start.”

As a mentor and researcher, Almada knows that no question and no challenge is off limits — foundations he built in Cambridge, where his graduate studies focused on teaching him to think, not just do.

“Digging deep into the science is what MIT taught me,” he says. “I’m now taking all of my knowledge in molecular biology and applying it to translationally oriented questions that I hope will benefit human health and longevity.”

Nancy Hopkins awarded the National Academy of Sciences Public Welfare Medal

The MIT professor emerita and influential molecular biologist is being honored for her advocacy for women in science.

Bendta Schroeder | Koch Institute
January 30, 2024

The National Academy of Sciences has awarded MIT biologist Nancy Hopkins, the Amgen Professor of Biology Emerita, with the 2024 Public Welfare Medal in recognition of “her courageous leadership over three decades to create and ensure equal opportunity for women in science.”

The award recognizes Hopkins’s role in catalyzing and leading MIT’s “A Study on the Status of Women Faculty in Science,” made public in 1999. The landmark report, the result of the efforts of numerous members of the MIT faculty and administration, revealed inequities in the treatment and resources available to women versus men on the faculty at the Institute, helped drive significant changes to MIT policies and practices, and sparked a national conversation about the unequal treatment of women in science, engineering, and beyond.

Since the medal was established in 1914 to honor extraordinary use of science for the public good, it has been awarded to several MIT-affiliated scientists, including Karl Compton, James R. Killian Jr., and Jerome B. Wiesner, as well as Vannevar Bush, Isidor I. Rabi, and Victor Weiskopf.

“The Public Welfare Medal has been awarded to MIT faculty who have helped define our Institute and scientists who have shaped modern science on the national stage,” says Susan Hockfield, MIT president emerita. “It is more than fitting for Nancy to join their ranks, and — importantly — celebrates her critical role in increasing the participation of women in science and engineering as a significant national achievement.”

When Hopkins joined the faculty of the MIT Center for Cancer Research (CCR) in 1973, she did not set out to become an advocate for equality for women in science. For the first 15 years, she distinguished herself in pioneering studies linking genes of RNA tumor viruses to their roles in causing some forms of cancer. But in 1989, Hopkins changed course: She began developing molecular technologies for the study of zebrafish that would help establish it as an important model for vertebrate development and cancer biology.

To make the pivot, Hopkins needed more space to accommodate fish tanks and new equipment. Although Hopkins strongly suspected that she had been assigned less lab space than her male peers in the building, her hypothesis carried little weight and her request was denied. Ever the scientist, Hopkins believed the path to more lab space was to collect data. One night in 1993, with a measuring tape in hand, she visited each lab to quantify the distribution of space in her building. Her hypothesis appeared correct.

Hopkins shared her initial findings — and her growing sense that there was bias against women scientists — with one female colleague, and then others, many of whom reported similar experiences. The senior women faculty in MIT’s School of Science began meeting to discuss their concerns, ultimately documenting them in a letter to Dean of Science Robert Birgeneau. The letter was signed by professors Susan Carey, Sylvia Ceyer, Sallie “Penny” Chisholm, Suzanne Corkin, Mildred Dresselhaus, Ann Graybiel, Ruth Lehmann, Marcia McNutt, Terry Orr-Weaver, Mary-Lou Pardue, Molly Potter, Paula Malanotte-Rizzoli, Leigh Royden, Lisa Steiner, and Joanne Stubbe. Also important were Hopkins’s discussions with Lorna Gibson, a professor in the Department of Materials Science and Engineering, since Gibson had made similar observations with her female colleagues in the School of Engineering. Despite the biases against these women, they were highly accomplished scientists. Four of them were eventually awarded the U.S. National Medal of Science, and 11 were, or became, members of the National Academy of Sciences.

In response to the women in the School of Science, Birgeneau established the Committee on the Status of Women Faculty in 1995, which included both female faculty and three male faculty who had been department chairs: Jerome Friedman, Dan Kleitman, and Robert Silbey. In addition to interviewing essentially all the female faculty members in the school, they collected data on salaries, space, and other resources. The committee found that of 209 tenured professors in the School of Science only 15 were women, and they often had smaller wages and labs, and were raising more of their salaries from grants than equivalent male faculty.

At the urging of Lotte Bailyn, a professor at the MIT Sloan School of Management and chair of the faculty, Hopkins and the committee summarized their findings to be presented to MIT’s faculty. Struck by the pervasive and well-documented pattern of bias against women across the School of Science, both Birgeneau and MIT President Charles Vest added prefaces to the report before it was published in the faculty newsletter. Vest commented, “I have always believed that contemporary gender discrimination within universities is part reality and part perception. True, but I now understand that reality is by far the greater part of the balance.”

Vest took an “engineers’ approach” to addressing the report’s findings, remarking “anything I can measure, I can fix.” He tasked Provost Robert Brown with establishing committees to produce reports on the status of women faculty for all five of MIT’s schools. The reports were published in 2002 and drew attention to the small number of women faculty in some schools, as well as discrepancies similar to those first documented in the School of Science.

In response, MIT implemented changes in hiring practices, updated pay equity reviews, and worked to improve the working environment for women faculty. On-campus day care facilities were built and leave policies were expanded for the benefit of all faculty members with families. To address underrepresentation of individuals of color, as well as the unique biases against women of color, Brown established the Council on Faculty Diversity with Hopkins and Philip Clay, then MIT’s chancellor and a professor in the Department of Urban Studies and Planning. Meanwhile, Vest spearheaded a collaboration with presidents of other leading universities to increase representation of women faculty.

MIT increased the numbers of women faculty by altering hiring procedures  — particularly in the School of Engineering under Dean Thomas Magnanti and in the School of Science under Birgeneau, and later Associate Dean Hazel Sive. MIT did not need to alter its standards for hiring to increase the number of women on its faculty: Women hired with revised policies at the Institute have been equally successful and have gone on to important leadership roles at MIT and other institutions.

In the wake of the 1999 report the press thrust MIT — and Hopkins — into the national spotlight. The careful documentation in the report and first Birgeneau’s and then Vest’s endorsement of and proactive response to its findings were persuasive to many reporters and their readers. The reports and media coverage resonated with women across academia, resulting in a flood of mail to Hopkins’s inbox, as well as many requests for speaking engagements. Hopkins would eventually undertake hundreds of talks across the United States and many other countries about advocating for the equitable treatment of women in science.

Her advocacy work continued after her retirement. In 2019, Hopkins, along with Hockfield and Sangeeta Bhatia, the John J. and Dorothy Wilson Professor of Health Sciences and Technology and of the Department of Electrical Engineering and Computer Science, founded the Boston Biotech Working Group — which later evolved into the Faculty Founder Initiative — to increase women’s representation as founders and board members of biotech companies in Massachusetts.

Hopkins, however, believes she became “this very visible person by chance.”

“An almost uncountable number of people made this happen,” she continues. “Moreover, I know how much work went on before I even set foot on campus, such as by Emily Wick, Shirley Ann Jackson, Sheila Widnall, and Mildred Dresselhaus. I stood on the shoulders of a great institution and the long, hard work of many people that belong to it.”

The National Academy of Sciences will present the 2024 Public Welfare Medal to Hopkins in April at its 161st annual meeting. Hopkins is the recipient of many other awards and honors, both for her scientific achievements and her advocacy for women in science. She is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the AACR Academy. Other awards include the Centennial Medal from Harvard University, the MIT Gordon Y. Billard Award for “special service” to MIT, the MIT Laya Wiesner Community Award, the Maria Mitchell Women in Science Award, and the STAT Biomedical Innovation Award. In addition, she has received eight honorary doctorates, most recently from Rockefeller University, the Hong Kong University of Science and Technology, and the Weizmann Institute.

Capsid of HIV-1 behaves like cell’s cargo receptor to enter the nucleus

Biologists demonstrate that HIV-1 capsid acts like a Trojan horse to pass viral cargo across the nuclear pore.

Lillian Eden | Department of Biology
January 24, 2024

Retroviruses cannot replicate on their own — they must insert their genetic code into the DNA of a host and exploit the host cell’s resources to make more copies of themselves, furthering infection. Some retroviruses only infect cells as they divide, when the nuclear envelope that protects the host’s genetic material breaks down, making it easily accessible. HIV-1 is a type of retrovirus, called a lentivirus, that can infect non-dividing cells.

HIV-1 delivers its genome into the nucleus by packaging it into a large, cone-shaped structure called a capsid — but the exact mechanism has remained elusive for decades. Travel through the nuclear envelope occurs through, and is regulated by, nuclear pores, doughnut-shaped protein assemblies. Human cells have about 2,000 nuclear pores perforating the nuclear envelope. Some earlier evidence suggested that the capsid remains intact during its delivery into the nucleus — but this created a dimensional conundrum. The cone-shaped HIV-1 capsid is about 120 nanometers long and 60 nm wide — too large, researchers thought, to fit through the opening of the nuclear pore, measured at only 43 nm wide.

Members of the Schwartz Lab at MIT, in the Department of Biology, became interested in this question when a postdoc in the lab used cryo-electron tomography, slicing up sections of frozen cells to examine structures, to show that nuclear pores in the nuclear envelope are larger than 43nm. They deflate and shrink, it turns out, when removed from their native conditions. In native conditions, the nuclear pore complex is about 60nm wide — wide enough to accommodate the HIV-1 capsid.

Knowing that it could fit, a question remained: How can the capsid navigate the dense mesh of spaghetti-like proteins that act like a sieve in the nuclear pore channel? That spaghetti-like mesh allows small cargo to diffuse through, but prevents large cargo from entering unless it is escorted by proteins called nuclear transport receptors.

In an open-access paper published today in Nature, researchers present evidence that the HIV-1 capsid mimics the cell’s transport receptors to traverse the nuclear pore.

To support that conclusion, the researchers showed three things in vitro: that an HIV-1 capsid can deliver cargo through a nuclear pore analog; that the capsid can interact with the sieve of proteins in the nuclear pore channel; and that the capsid targets the nuclear pore in the absence of native transport proteins.

Nuclear transport receptors escort large cargo through the nuclear pore by “batting away” the spaghetti-like mesh of proteins inside the channel — like someone holding your hand and guiding you across a crowded dance floor. The HIV-1 capsid interacts with the spaghetti-like proteins, but its purpose is more like a Trojan horse — the capsid encapsulates the viral cargo, protecting it from detection in the cytoplasm and as it enters the nuclear pore complex.

“What’s really amazing about cells is that they are incredibly complex. What’s really difficult about studying cells is that they are incredibly complex,” jokes co-first author Erika Weiskopf, a graduate student in the Schwartz lab. “Biochemists are constantly trying to find ways to study their system in a simplified context, but still give it a flavor of cell biology.”

To do that, the Schwartz lab collaborated with Dirk Görlich, the director of cellular logistics at the Max Planck Institute for Multidisciplinary Sciences. Görlich is a co-senior author on the paper with MIT’s Boris Magasanik Professor of Biology Thomas Schwartz. Görlich’s lab has produced concentrated droplets of the spaghetti-like proteins found inside the nuclear pore, and those droplets allow and exclude cargo the same way a nuclear pore will. In experiments, fluorescently-labeled cargo did not enter the droplets, but fluorescently-labeled cargo packaged in an HIV-1 capsid was delivered. This indicated that the capsid could deliver cargo through a nuclear pore.

Using a biophysical binding assay, the researchers also showed that the HIV-1 capsid interacts with the proteins inside the channel. Different spaghetti-like proteins are found in different channel sections, such as at the cytoplasmic side’s entrance or only inside the channel; there are 10 such proteins in human cells. The capsid is a promiscuous binder — it can interact with all the spaghetti-like proteins found in the channel.

The capsid can target the nuclear pore complex even without the cell’s transport receptors, indicating that it is not commandeering native transport receptors to find and enter the nuclear pore. The team used a classic assay in the nucleocytoplasmic transport field to collect this evidence: When cells are treated with digitonin, their membranes become porous. Everything in the cytoplasm will leak out of the cells, but the nuclear envelope will remain intact. Despite the absence of native proteins, the capsid was attracted to the nuclear pore complex, a behavior indicative of a nuclear transport receptor.

Although the capsid behaves like a nuclear transport receptor to penetrate the nuclear pore, it is fundamentally different. A transport receptor doesn’t need to conceal material for delivery the way the capsid does to avoid detection.

These findings open new lines of inquiry for what the nuclear pore complex is capable of accommodating.

“The HIV-1 capsid is one of the largest things that we now know can go through the nuclear pore complex intact,” Weiskopf says. “It raises all kinds of questions — what other things could be going through the pore that we thought was impossible?”

Schwartz said another question is whether all of the 2,000 nuclear pores in human cells are identical or whether there is something that makes certain pores more amenable to allowing the capsid through.

The capsid is also known to be unusually elastic, a property that may be key for passage through the pore. Another interesting question for the field is whether the cone-shaped capsid gains entry into the pore by squeezing through.

Although the team has shown that the capsid can enter the pore, what happens at the other end of the channel is still unknown — whether the capsid fully or partially enters the nucleus or breaks down inside the channel. Weiskopf is working on perturbing parts of the capsid or the spaghetti-like proteins to learn more about which interactions are most important for successful capsid entry.

Although these results have expanded our understanding of the nuclear pore, much remains unknown, both for HIV-1 infection and for the transport process through the nuclear pore complex.

“The nuclear pore is such an important element of cell biology, we thought it would be interesting to understand it better — and that’s how we figured out that the pore is much bigger than we anticipated,” Schwartz says. “We will certainly try to see whether we can understand the mechanism of HIV-1 infection, how the capsid is released on the other side of the channel, and what factors are important there — and to what extent you can manipulate it or influence it for therapeutic applications.”

Pulin Li among recipients of 2023 School of Science teaching prizes

Roger Levy, Pulin Li, and David McGee were nominated by peers and students for their exceptional instruction.

School of Science
January 10, 2024

The MIT School of Science has announced the winners of its 2023 Teaching Prizes for Graduate and Undergraduate Education. The prizes are awarded to School of Science faculty members who demonstrate excellence in teaching. Winners are chosen from nominations by their students or colleagues.

Roger Levy, a professor in the Department of Brain and Cognitive Sciences, was awarded a prize for developing and teaching class 9.19 (Computational Psycholinguistics). Levy’s nominators highlighted his success in adapting courses to synchronous and asynchronous instruction during the first year of the Covid-19 pandemic and in leading an engaging and challenging course for students across disciplines.

Pulin Li, the Eugene Bell Career Development Professor of Tissue Engineering in the Department of Biology and a member of the Whitehead Institute for Biomedical Research, was awarded the prize for teaching classes 7.06 (Cell Biology) and 7.46/7.86: (Building with Cells). Nominators praised Li’s talent for teaching complex topics effectively and her exceptional accomplishments as a teaching partner.

David McGee, associate professor and associate department head for diversity, equity, and inclusion in the Department of Earth, Atmospheric and Planetary Sciences, was awarded the prize for achieving an outstanding level of community learning in class 12.000 (Solving Complex Problems), also known as “Terrascope.” Nominators noted McGee’s extraordinary investment in both the class material and his students’ learning experiences.

The School of Science welcomes nominations for the teaching prize at the end of each semester. Nominations can be submitted at the school’s website.

Food for thought

Biology graduate student Juana De La O is building connections through her thesis work in mouse development and her passion for cooking and baking.

Lillian Eden | Department of Biology
January 10, 2024

MIT graduate student Juana De La O describes herself as a food-motivated organism, so it’s no surprise that she reaches for food and baking analogies when she’s discussing her thesis work in the lab of undergraduate officer and professor of biology Adam Martin.

Consider the formative stages of a croissant, she offers, occasionally providing homemade croissants to accompany the presentation: When one is forming the puff pastry, the dough is folded over the butter again and again. Tissues in a developing mouse embryo must similarly fold and bend, creating layers and structures that become the spine, head, and organs — but these tissues have no hands to induce those formative movements.

De La O is studying neural tube closure, the formation of the structure that becomes the spinal cord and the brain. Disorders like anencephaly and craniorachischisis occur when the head region fails to close in a developing fetus. It’s a heartbreaking defect, De La O says, because it’s 100 percent lethal — but the fetus fully develops otherwise.

“Your entire central nervous system hinges on this one event happening successfully,” she says. “On the fundamental level, we have a very limited understanding of the mechanisms required for neural closure to happen at all, much less an understanding of what goes wrong that leads to those defects.”

Hypothetically speaking

De La O hails from Chicago, where she received an undergraduate degree from the University of Chicago and worked in the lab of Ilaria Rebay. De La O’s sister was the first person in her family to go to and graduate from college — De La O, in turn, is the first person in her family to pursue a PhD.

From her first time visiting campus, De La O could see MIT would provide a thrilling environment in which to study.

“MIT was one of the few places where the students weren’t constantly complaining about how hard their life was,” she says. “At lunch with prospective students, they’d be talking to each other and then just organically slip into conversations about science.”

The department emails acceptance letters and sends a physical copy via snail mail. De La O’s letter included a handwritten note from department head Amy Keating, then a graduate officer, who had interviewed De La O during her campus visit.

“That’s what really sold it for me,” she recalls. “I went to my PI [principal investigator]’s office and said, ‘I have new data’” and I showed her the letter, and there was lots of unintelligible crying.”

To prepare her for graduate school, her parents, both immigrants from Mexico, spent the summer teaching De La O to make all her favorite dishes because “comfort food feels like home.”

When she reached MIT, however, the Covid-19 pandemic ground the world to a halt and severely limited what students could experience during rotations. Far from home and living alone, De La O taught herself to bake, creating the confections she craved but couldn’t leave her apartment to purchase. De La O didn’t get to work as extensively as she would have liked during her rotation in the Martin lab.

Martin had recently returned from a sabbatical that was spent learning a new research model; historically a fly lab, Martin was planning to delve into mouse research.

“My final presentation was, ‘Here’s a hypothetical project I would hypothetically do if I were hypothetically going to work with mice in a fly lab,’” De La O says.

Martin recalls being impressed. De La O is skilled at talking about science in an earnest and engaging way, and she dug deep into the literature and identified points Martin hadn’t considered.

“This is a level of independence that I look for in a student because it is important to the science to have someone who is contributing their ideas and independent reading and research to a project,” Martin says.

After agreeing to join the lab — news she shared with Martin via a meme — she got to work.

Charting mouse development

The neural tube forms from a flat sheet whose sides rise and meet to create a hollow cylinder. De La O has observed patterns of actin and myosin changing in space and time as the embryo develops. Actin and myosin are fibrous proteins that provide structure in eukaryotic cells. They are responsible for some cell movement, like muscle contraction or cell division. Fibers of actin and myosin can also connect across cells, forming vast networks that coordinate the movements of whole tissues. By looking at the structure of these networks, researchers can make predictions about how force is affecting those tissues.

De La O has found indications of a difference in the tension across the tissue during the critical stages of neural tube closure, which contributes to the tissue’s ability to fold and form a tube. They are not the first research group to propose this, she notes, but they’re suggesting that the patterns of tension are not uniform during a single stage of development.

“My project, on a really fundamental level, is an atlas for a really early stage of mouse development for actin and myosin,” De La O says. “This dataset doesn’t exist in the field yet.”

However, De La O has been performing analyses exclusively in fixed samples, so she may be quantifying phenomena that are not actually how tissues behave. To determine whether that’s the case, De La O plans to analyze live samples.

The idea is that if one could carefully cut tissue and observe how quickly it recoils, like slicing through a taught rubber band, those measurements could be used to approximate force across the tissue. However, the techniques required are still being developed, and the greater Boston area currently lacks the equipment and expertise needed to attempt those experiments.

A big part of her work in the lab has been figuring out how to collect and analyze relevant data. This research has already taken her far and wide, both literally and virtually.

“We’ve found that people have been very generous with their time and expertise,” De La O says. “One of the benefits we, as fly people, brought into this field is we don’t know anything — so we’re going to question everything.”

De La O traveled to the University of Virginia to learn live imaging techniques from associate professor of cell biology Ann Sutherland, and she’s also been in contact with Gabriel Galea at University College London, where Martin and De La O are considering a visit for further training.

“There are a lot of reasons why these experiments could go wrong, and one of them is that I’m not trained yet,” she says. “Once you know how to do things on an optimal setup, you can figure out how to make it work on a less-optimal setup.”

Collaboration and community

De La O has now expanded her cooking repertoire far beyond her family’s recipes and shares her new creations when she visits home. At MIT, she hosts dinner parties, including one where everything from the savory appetizers to the sweet desserts contained honey, thanks to an Independent Activities Period course about the producers of the sticky substance, and she made and tried apple pie for the first time with her fellow graduate students after an afternoon of apple picking.

De La O says she’s still learning how to say no to taking on additional work outside of her regular obligations as a PhD student; she’s found there’s a lot of pressure for underrepresented students to be at the forefront of diversity efforts, and although she finds that work extremely fulfilling, she can, and has, stretched herself too thin in the past.

“Every time I see an application that asks ‘How will you work to increase diversity,’ my strongest instinct is just to write ‘I’m brown and around — you’re welcome,’” she jokes. “The greatest amount of diversity work I will do is to get where I’m going. Me achieving my goals increases diversity inherently, but I also want to do well because I know if I do, I will make everything better for people coming after me.”

De La O is confident her path will be in academia, and troubleshooting, building up protocols, and setting up standards for her work in the Martin Lab has been “an excellent part of my training program.”

De La O and Martin embarked on a new project in a new model for the lab for De La O’s thesis, so much of her graduate studies will be spent laying the groundwork for future research.

“I hope her travels open Juana’s eyes to science being a larger community and to teach her about how to lead a collaboration,” Martin says. “Overall, I think this project is excellent for a student with aspirations to be a PI. I benefited from extremely open-ended projects as a student and see, in retrospect, how they prepared me for my work today.”

High school students gain skills by working on digital learning materials

As a summer intern, high school student Thomas Esayas worked remotely with MIT Digital Learning Lab scientists to create and improve online learning content as part of a pilot of a new internship program from the MIT Digital Learning Lab and Empowr.

Stefanie Koperniak | Katherine Ouellette | MIT Open Learning
November 30, 2023

For Thomas Esayas, now a high school senior in Texas, the shift to virtual learning in the earlier days of the Covid-19 pandemic provided an opportunity to dive further into his interests in computer science. He started learning the fundamentals of Python and developing projects, such as trying to make a bot that could scour Amazon for computer parts in stock with the goal of ultimately building a computer.

“Once you know the syntax of language, computer science is really just problem-solving,” Esayas says. “I enjoy challenging problems, especially things that require much more consideration than something that takes a lot less time. I like the feeling of doing a challenging thing and overcoming it.”

Esayas’ aspirations to gain iOS development experience led him to Empowr, a program offering computer science training to Black high school students with the goal of providing support throughout students’ entire high school career. After already participating in Empowr for a year, he joined a pilot internship program this past summer, in which two Empowr students worked remotely with MIT Digital Learning Lab (DLL) scientists to create and improve online learning content.

The DLL, a joint program between MIT Open Learning and MIT’s academic departments, is composed of academic staff and postdocs who collaborate on digital learning innovations on campus and beyond. The idea for the internship grew out of a conversation between Empowr Executive Director Adrian Devezin and Mary Ellen Wiltrout PhD ’09, director of blended and online initiatives in MIT’s Department of Biology. They discussed how Empowr might support students by connecting students with high-quality internship opportunities, specially at MIT.

“There were lots of motivations to start this internship program,” says Wiltrout. “The DLL needed extra help, and Empowr had some motivated students wanting coding experience and ready to solve some complicated problems.”

The two interns in this pilot program worked with MIT digital learning scientists across disciplines, including Wiltrout and Darcy Gordon in biology; Alex Shvonski, Michelle Tomasik PhD ’15, and Aidan MacDonagh in physics; and Jessica Sandland ’99, PhD ’04 in materials science and engineering. By working with so many individuals in DLL, the interns were exposed to a wide range of professional projects and learning opportunities. Interns had regular communication with the DLL mentors, with at least one DLL scientist checking in with them every day — with other meetings as needed — in addition to a lot of asynchronous work and checking in via Slack.

“The interns are a lot like MIT students,” says Wiltrout. “Both showed a lot of promise, quickly tackled assignments, and found ways to figure things out on their own when they faced a barrier.”

Specific projects included translating assessment content from Google Docs to the Open edX platform, creating custom XML code for problem or grading functionality in the course running in Open edX, and developing interactive graphs with multiple programming languages. The interns made these contributions within the 7.03.3x (Genetics: Population and Human Traits) course. They gained valuable, hands-on experience in important principles of online content development, including universal design.

“The course I was working on had to feature elements that made it more accessible,” says Esayas. “It opened my eyes to realize you should expand the scope to be more accessible to more people.”

Shvonski worked with the interns on the physics course 8.03x (Vibrations and Waves). Shvonski had developed interactive physics visualizations in Jupyter notebooks but wanted to embed them in web pages more easily, which required that they be rewritten in JavaScript.

“It was an important step to revise the course,” says Shvonski. “Learning how to rewrite these course elements in JavaScript myself would have been time consuming, so the interns made a significant contribution.”

Shvonski implemented the products the interns developed for the fall 2023 semester of Vibrations and Waves, including Esayas’ interactive plot project and other visualizations. “MIT students taking 8.03 have benefited from using these interactive elements this semester,” he says.

Esayas says the internship helped him to understand how computer science skills can be applied across disciplines.

“I like computer science a lot,” he says. “The internship helped me to look at it differently. I see it’s very interdisciplinary. I worked in physics and biology — you can use computer science almost anywhere, like a tool that can be implemented in different places.”

In addition to growing their technical skills, the interns also gained professional experience, learning what it is like to work, report hours, participate in professional conversations and scheduled meetings, and more. The Digital Learning Lab also helped Empowr brainstorm ways to support the other high school juniors in the program, such as trainings on resume writing or what to expect when beginning a job.

MIT Open Learning would like to continue exploring areas for future collaborative efforts with Empowr, says Christopher Capozzola, senior associate dean.

“The interns learned more about themselves and all that they were capable of,” says Shvonski, “and we all learned from each other.”

Gene-Wei Li and Michael Birnbaum named Pew Innovation Fund investigators

MIT researchers will partner on interdisciplinary research in human biology and disease.

School of Science
November 14, 2023

MIT professors Gene-Wei Li and Michael Birnbaum are among the 12 researchers named 2023 Innovation Fund investigators by The Pew Charitable Trusts.

Six pairs of scientists — alumni or advisors of Pew’s biomedical programs in the United States and Latin America — will partner on interdisciplinary research in human biology and disease.

A biophysicist, Gene-Wei Li, an associate professor in MIT’s Department of Biology, studies how bacteria optimize the levels of proteins they produce at both mechanistic and systems levels. His lab focuses on design principles of transcription, translation, and RNA maturation. Li and his collaborator Katsuhiko Murakami, a professor of biochemistry and molecular biology at the Pennsylvania State University, will explore the complex genetics of cyanobacteria.

The pair will look at transcription termination, a key step in cyanobacteria gene regulation that tells the cell when to stop converting genetic information from DNA to RNA. While the mechanisms behind transcription termination are well known in other organisms, the inner workings of this process in cyanobacteria are still largely unknown. Drawing on Murakami’s expertise in structural biology and Li’s knowledge of transcription regulation, the two investigators will establish a model for microbial transcriptional termination in cyanobacteria. This work could unveil new scientific approaches used to study cyanobacteria, photosynthesis-promoting plant cells, and other bacterial groups.

Birnbaum, Class of 1956 Career Development Professor, associate professor of biological engineering, and faculty member at the Koch Institute for Integrative Cancer Research at MIT, works on understanding and manipulating immune recognition in cancer and infections. By using a variety of techniques to study the antigen recognition of T cells, he and his team aim to develop the next generation of immunotherapies.

In the case of people with inflammatory bowel disease (IBD), a bacterium alerts the body’s disease-fighting T cells and triggers an inflammatory response characterized by abdominal pain and persistent diarrhea. IBD affects millions of people in the United States, and cases are on the rise in older adults, yet the cause of this autoimmune disorder is largely unknown.

Dan Littman, a professor of molecular immunology at New York University, and Birnbaum are looking for IBD’s root cause. The pair will merge Littman’s work exploring how and why specific bacteria affect T cell development with Birnbaum’s expertise in T cell receptor-antigen binding in an effort to characterize the specific microbes and antigens that drive these harmful responses in the gut. Together, their work could offer new treatment avenues for IBD, such as novel therapies targeting pathogenic microbes or T cells.

In 2018, Birnbaum was also named a Pew-Steward Scholar for Cancer Research.

“An interdisciplinary approach to research is critical to uncovering scientific breakthroughs and making lasting change,” says Donna Frisby-Greenwood, senior vice president for Philadelphia and scientific advancement at The Pew Charitable Trusts. “Pew is thrilled to support this exceptional group of investigators, whose collective efforts will help move the needle in important areas of health and medicine.”

The Pew Charitable Trusts has supported more than 1,000 early-career scientists spearheading high-risk, high-reward research across a variety of disciplines. In 2017, Pew launched the Innovation Fund to spark scientific collaboration among alumni of its biomedical programs in the United States and Latin America.

3 Questions: Daniel Lew on what we can learn about cells from yeast

New professor of biology uses budding yeast to address fundamental questions in cell biology.

Lillian Eden | Department of Biology
September 28, 2023

Sipping a beer on an early autumn evening, one might not consider that humans and yeast have been inextricably linked for thousands of years; winemaking, baking, and brewing all depend on budding yeast. Outside of baking and fermentation, researchers also use Saccharomyces cerevisiae, classified as a fungus, to study fundamental questions of cell biology.

Budding yeast gets its name from the way it multiplies. A daughter cell forms first as a swelling, protruding growth on the mother cell. The daughter cell projects further and further from the mother cell until it detaches as an independent yeast cell.

How do cells decide on a front and back? How do cells decode concentration gradients of chemical signals to orient in useful directions, or sense and navigate around physical obstacles? New Department of Biology faculty member Daniel “Danny” Lew uses the model yeast S. cerevisiae, and a non-model yeast with an unusual pattern of cell division, to explore these questions. 

Q: Why is it useful to study yeast, and how do you approach the questions you hope to answer?

A: Humans and yeast are descended from a common ancestor, and some molecular mechanisms developed by that ancestor have been around for so long that yeast and mammals often use the same mechanisms. Many cells develop a front and migrate or grow in a particular direction, like the axons in our nervous system, using similar molecular mechanisms to those of yeast cells orienting growth towards the bud.

When I started my lab, I was working on cell cycle control, but I’ve always been interested in morphogenesis and the cell biology of how cells change shape and decide to do different things with different parts of themselves. Those mechanisms turn out to be conserved between yeast and humans.

But some things are very different about fungal and animal cells. One of the differences is the cell wall and what fungal cells have to do to deal with the fact that they have a cell wall.

Fungi are inflated by turgor pressure, which pushes their membranes against the rigid cell wall. This means they’ll die if there is any hole in the cell wall, which would be expected to happen often as cells remodel the wall in order to grow. We’re interested in understanding how fungi sense when any weak spots appear in the wall and repair them before those weak spots become dangerous.

Yeast cells, like most fungi, also mate by fusing with a partner. To succeed, they must do the most dangerous thing in the fungal life cycle: get rid of the cell wall at the point of contact to allow fusion. That means they must be precise about where and when they remove the wall. We’re fascinated to understand how they know it is safe to remove the wall there, and nowhere else.

We take an interdisciplinary approach. We’ve used genetics, biochemistry, cell biology, and computational biology to try and solve problems in the past. There’s a natural progression: observation and genetic approaches tend to be the first line of attack when you know nothing about how something works. As you learn more, you need biochemical approaches and, eventually, computational approaches to understand exactly what mechanism you’re looking at.

I’m also passionate about mentoring, and I love working with trainees and getting them fascinated by the same problems that fascinate me. I’m looking to work with curious trainees who love addressing fundamental problems.

Q: How does yeast decide to orient a certain way — toward a mating partner, for example?

A: We are still working on questions of how cells analyze the surrounding environment to pick a direction. Yeast cells have receptors that sense pheromones that a mating partner releases. What is amazing about that is that these cells are incredibly small, and pheromones are released by several potential partners in the neighborhood. That means yeast cells must interpret a very confusing landscape of pheromone concentrations. It’s not apparent how they manage to orient accurately toward a single partner.

That got me interested in related questions. Suppose the cell is oriented toward something that isn’t a mating partner. The cell seems to recognize that there’s an obstacle in the way, and it can change direction to go around that obstacle. This is how fungi get so good at growing into things that look very solid, like wood, and some fungi can even penetrate Kevlar vests.

If they recognize an obstacle, they have to change directions and go around it. If they recognize a mating partner, they have to stick with that direction and allow the cell wall to get degraded. How do they know they’ve hit an obstacle? How do they know a mating partner is different from an obstacle? These are the questions we’d like to understand.

Q: For the last couple of years, you’ve also been studying a budding yeast that forms multiple buds when it reproduces instead of just one. How did you come across it, and what questions are you hoping to explore?

A: I spent several years trying to figure out why most yeasts make one bud and only one bud, which I think is related to the question of why migrating cells make one and only one front. We had what we thought was a persuasive answer to that, so seeing a yeast completely disobey that and make as many buds as it felt like was a shock, which got me intrigued.

We started working on it because my colleague, Amy Gladfelter, had sampled the waters around Woods Hole, Massachusetts. When she saw this specimen under a microscope, she immediately called me and said, “You have to look at this.”

A question we’re very intrigued by is if the cell makes five, seven, or 12 buds simultaneously, how do they divide the mother cell’s material and growth capacity five, seven, or 12 ways? It looks like all of the buds grow at the same rate and reach about the same size. One of our short-term goals is to check whether all the buds really get to exactly the same size or whether they are born unequal.

And we’re interested in more than just growth rate. What about organelles? Do you give each bud the same number of mitochondria, nuclei, peroxisomes, and vacuoles? That question will inevitably lead to follow-up questions. If each bud has the same number of mitochondria, how does the cell measure mitochondrial inheritance to do that? If they don’t have the same amount, then buds are each born with a different complement and ratio of organelles. What happens to buds if they have very different numbers of organelles?

As far as we can tell, every bud gets at least one nucleus. How the cell ensures that each bud gets a nucleus is a question we’d also very much like to understand.

We have molecular candidates because we know a lot about how model yeasts deliver nuclei, organelles, and growth materials from the mother to the single bud. We can mutate candidate genes and see if similar molecular pathways are involved in the multi-budding yeast and, if so, how they are working.

It turns out that this unconventional yeast has yet to be studied from the point of view of basic cell biology. The other thing that intrigues me is that it’s a poly-extremophile. This yeast can survive under many rather harsh conditions: it’s been isolated in Antarctica, from jet engines, from all kinds of plants, and of course from the ocean as well. An advantage of working with something so ubiquitous is we already know it’s not toxic to us under almost any circumstances. We come into contact with it all the time. If we learn enough about its cell biology to begin to manipulate it, then there are many potential applications, from human health to agriculture.