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Studying learner engagement during the Covid-19 pandemic

Researchers analyze and compare pre- and post-pandemic data for introductory biology MOOC 7.00x.

Stefanie Koperniak | MIT Open Learning
November 17, 2021

While massive open online classes (MOOCs) have been a significant trend in higher education for many years now, they have gained a new level of attention during the Covid-19 pandemic. Open online courses became a critical resource for a wide audience of new learners during the first stages of the pandemic — including students whose academic programs had shifted online, teachers seeking online resources, and individuals suddenly facing lockdown or unemployment and looking to build new skills.

Mary Ellen Wiltrout, director of online and blended learning initiatives and lecturer in digital learning in the Department of Biology, and Virginia “Katie” Blackwell, currently an MIT PhD student in biology, published a paper this summer in the European MOOC Stakeholder Summit (EMOOCs 2021) conference proceedings evaluating data for the online course 7.00x (Introduction to Biology). Their research objective was to better understand whether the shift to online learning that occurred during the pandemic led to increased learner engagement in the course.

Blackwell participated in this research as part of the Bernard S. and Sophie G. Gould MIT Summer Research Program (MSRP) in Biology, during the uniquely remote MSRPx-Biology 2020 student cohort. She collaborated on the project while working toward her bachelor’s degree in biochemistry and molecular biology from the University of Texas at Dallas, and collaborated on the research while in Texas. She has since applied and been accepted into MIT’s PhD program in biology.

“MSRP Biology was a transformative experience for me. I learned a lot about the nature of research and the MIT community in a very short period of time and loved every second of the program. Without MSRP, I would never have even considered applying to MIT for my PhD. After MSRP and working with Mary Ellen, MIT biology became my first-choice program and I felt like I had a shot at getting in,” says Blackwell.

Many MOOC platforms experienced increased website traffic in 2020, with 30 new MOOC-based degrees and more than 60 million new learners.

“We find that the tremendous, lifelong learning opportunities that MOOCs provide are even more important and sought-after when traditional education is disrupted. During the pandemic, people had to be at home more often, and some faced unemployment requiring a career transition,” says Wiltrout.

Wiltrout and Blackwell wanted to build a deeper understanding of learner profiles rather than looking exclusively at enrollments. They looked at all available data, including: enrollment demographics (i.e., country and “.edu” participants); proportion of learners engaged with videos, problems, and forums; number of individual engagement events with videos, problems, and forums; verification and performance; and the course “track” level — including auditing (for free) and verified (paying and receiving access to additional course content, including access to a comprehensive competency exam). They analyzed data in these areas from five runs of 7.00x in this study, including three pre-pandemic runs of April, July, and November 2019 and two pandemic runs of March and July 2020.

The March 2020 run had the same count of verified-track participants as all three pre-pandemic runs combined. The July 2020 run enrolled nearly as many verified-track participants as the March 2020 run. Wiltrout says that introductory biology content may have attracted great attention during the early days and months of the Covid-19 pandemic, as people may have had a new (or renewed) interest in learning about (or reviewing) viruses, RNA, the inner workings of cells, and more.

Wiltrout and Blackwell found that the enrollment count for the March 2020 run of the course increased at almost triple the rate of the three pre-pandemic runs. During the early days of March 2020, the enrollment metrics appeared similar to enrollment metrics for the April 2019 run — both in rate and count — but the enrollment rate increased sharply around March 15, 2020. The July 2020 run began with more than twice as many learners already enrolled by the first day of the course, but continued with half the enrollment rate of the March 2020 course. In terms of learner demographics, during the pandemic, there was a higher proportion of learners with .edu addresses, indicating that MOOCs were often used by students enrolled in other schools.

Viewings of course videos increased at the beginning of the pandemic. During the March 2020 run, both verified-track and certified participants viewed far more unique videos during March 2020 than in the pre-pandemic runs of the course; even auditor-track learners — not aiming for certification — still viewed all videos offered. During the July 2020 run, however, both verified-track and certified participants viewed far fewer unique videos than during all prior runs. The proportion of participants who viewed at least one video decreased in the July 2020 run to 53 percent, from a mean of 64 percent in prior runs. Blackwell and Wiltrout say that this decrease — as well as the overall dip in participation in July 2020 — might be attributed to shifting circumstances for learners that allowed for less time to watch videos and participate in the course, as well as some fatigue from the extra screen time.

The study found that 4.4 percent of March 2020 participants and 4.5 percent of July 2020 participants engaged through forum posting — which was 1.4 to 3.3 times higher than pre-pandemic proportions of forum posting. The increase in forum engagement may point to a desire for community engagement during a time when many were isolated and sheltering in place.

“Through the day-to-day work of my research team and also through the engagement of the learners in 7.00x, we can see that there is great potential for meaningful connections in remote experiences,” says Wiltrout. “An increase in participation for an online course may not always remain at the same high level, in the long term, but overall, we’re continuing to see an increase in the number of MOOCs and other online programs offered by all universities and institutions, as well as an increase in online learners.”

Stem Cell Research Zeroes in on Cancer

Collaborators investigate colon health with novel tools

Deborah Halber | Spectrum
November 9, 2021

In a building at the edge of the Massachusetts General Hospital (MGH) complex, Ömer Yilmaz, MD, and a group of pathology residents gather around a microscope. A resident reads from a chart: a growth was found in the intestine of a patient who had complained of abdominal pain.

Yilmaz, an MIT cancer researcher and a gastrointestinal pathologist, hoped a closer look at the tumor would reveal a noncancerous collection of fat cells or lymphoid cells.

It had taken a couple of days to prepare the biopsy. Somewhere in the hospital, the patient and her family were anxiously awaiting a diagnosis. Yilmaz leaned forward and adjusted the focus on the microscope.

On the tracks of cancer

If the long, twisting tube of the human digestive tract were stretched out straight, it would extend 30 feet, and its absorptive surface area is roughly comparable to the size of a tennis court. A significant chunk of that tube is the large intestine, an intricate place rife with microscopic structures called niches and crypts, evoking an underground cavern or the ocean floor. Besides the skin, the intestines are the body’s primary barrier against external invaders.

Yilmaz, an associate professor of biology at the Koch Institute for Integrative Cancer Research, believes certain cancers and diseases such as inflammatory bowel disease originate with a breakdown of the intestine’s protective barrier. Diet appears to affect intestinal stem cells; these cells can morph into a variety of cell types, and changes in stem cells can lead to cancer, but no one understands exactly how this occurs.

That’s where Yilmaz’s partnership with MIT biomedical engineer and chemist Alex Shalek comes in. Yilmaz and Shalek are both members of the MIT Stem Cell Initiative, which focuses on fundamental biological questions about benign and cancerous adult stem cells.

Shalek, a core member of the Institute for Medical Engineering and Science (IMES), a member of the Koch Institute, and an associate professor of chemistry, develops experimental and computational tools that provide researchers with detailed snapshots of what’s going on inside living cells at a moment in time. Some of these tools, Yilmaz hoped, would enable him to see how intestinal cells react when they encounter an influx of fat or are deprived of food for hours or days.

“In the past, people would have taken a piece of gut that had many different cell types and said, ‘What changes, on average, under different dietary conditions?’” Shalek says. His tools give him and Yilmaz more precise information, providing a window into the discrete molecular responses of individual cells within the colon.

The role of stem cells

Growing up in Battle Creek, Michigan, Yilmaz spent all his free time trailing after his father, a physician who had immigrated from Turkey. He’d make hospital rounds with his dad, visiting the pathology and radiology labs. As Yilmaz grew older, the two would talk about the mechanisms underlying disease.

After completing his MD/PhD at the University of Michigan, Yilmaz did his residency in pathology, the study of disease, at MGH. He began working at the Whitehead Institute with MIT biology professor David M. Sabatini, a pioneer in elucidating the mechanisms under-lying the regulation of growth and metabolism in mammals. Yilmaz had long been fascinated with stem cells’ seemingly miraculous ability to become any kind of cell the body needed. In adults, stem cells are relatively rare, best studied in bone marrow.

When scientists first found stem cells in the intestine in 2007, Yilmaz shifted his research focus. “As soon as intestinal stem cells were identified, I became interested in understanding how they are regulated by diet and aging,” he says.

“We know obesity elevates cancer risk in a wide range of tissues, including the colon, but we don’t know exactly how. And fasting regimens have been known to improve organ and tissue health, but this, too, is not well understood.”

To better study the transition from healthy to diseased cells in the colon, Yilmaz’s team generated colon tumors in mice that closely resemble human tumors. These colon tumors from mice or humans can be grown in culture, creating miniature three-dimensional tumors called organoids.

Subjecting the organoids to different conditions, Yilmaz and Sabatini found that in mice, age-related loss of stem cell function can be reversed by a 24-hour fast. Other studies looked at the type of high-fat diet leading to obesity. Yilmaz determined that a high-fat diet boosted the population of intestinal stem cells and generated even more cells that behaved like stem cells. These stem cells and stem-like cells are more likely to give rise to intestinal tumors.

What’s happening inside

In the microenvironment of the digestive system, the single layer of epithelial cells that line the colon die after only a few days of ferrying nutrients into the bloodstream and lymphatic system.

Stem cells sheltered in protected spaces with fanciful names like the crypts of Lieberkühn generate a hundred grams of new intestinal tissue every day. The source of all the epithelial cells as well as the cells of the villi, a velvety layer of fingerlike projections that line the intestine, stem cells repair and replace tissue continually assaulted by stomach acid, pancreatic enzymes, bile, fats, and bacteria.

Nearby cells guard the stem cells by secreting agents that fight off harmful bacteria, fungi, and viruses and help regulate the composition of the microbiome.

Most of the body’s stem cells, like those deep within bone marrow, are not nearly as prolific as intestinal stem cells, likely because there’s a risk associated with the stem cells’ ability to rapidly replace themselves: mutations.

At the heart of a cell’s behavior is its messenger RNA, or mRNA, the technology used in the Moderna and Pfizer Covid-19 vaccines. These mRNA vaccines teach cells how to make a protein that triggers an immune response to the virus. Each mRNA transcript, a single strand of RNA carrying a specific genetic instruction from the DNA in the nucleus to the cell’s protein-making machinery, determines which protein gets made to help support the cell’s activity.

“From a snapshot of all of the cell’s mRNA, its transcriptome, we can see how it is trying to respond to change,” Shalek says.

Shalek’s tools help him and Yilmaz measure the properties of multiple types of intestinal cells—immune cells, stem cells, and epithelial cells, to name a few—at once to see precisely how these otherwise invisible, minute features collectively orchestrate tissue-wide responses to external signals.

Sequencing a cell’s mRNA makeup requires smashing the cell open and collecting all of its transcripts. Shalek jokingly likened the process to an alien invader beaming human specimens up to a spaceship and investigating what’s happening inside them.

One of the methods Shalek helped develop tags each mRNA within a cell so that it can be traced back to its cell of origin even after it’s been ripped apart. The inexpensive, portable system, called Seq-Well, looks like an ice cube tray. Around the size of a stick of gum, it contains roughly a hundred thousand miniature wells, each approximately 50-by-50-by-50 microns.

Each cell is deposited into its own well, which contains a bead coated with uniquely barcoded DNA molecules; those DNA molecules are designed to latch onto mRNA and ignore the rest of the cell’s components. The wells are sealed and the cells broken apart. The beads are then extracted, processed, and analyzed, providing a record of each cell’s intentions in its last living moments.

The fact that the system can look simultaneously at thousands of individual cells of any type allows Shalek and Yilmaz to check the effect of nutrients on epithelial cells, immune cells, and stem cells all at once.

The Shalek lab is also developing screening tools that are particularly useful for exposing the Yilmaz lab’s organoids to hundreds of nutrients or drugs at one time, potentially reducing the effort needed to identify substances that boost or hinder stem cell function.

Already, Yilmaz and Shalek have used Seq-Well to identify an enzyme that could be a potential future target for a drug that would counter the negative effects of a high-fat diet on intestinal stem cells. More broadly, Yilmaz says, their collaboration is helping develop a very nuanced understanding of a very complex organ.

“Understanding that complexity is what has really driven our collaboration,” Yilmaz says. “Alex has developed the tools that enable us to dissect out individual cell populations and start to understand how environmental factors impact gene expression.”

“Scientists have spent the past 40 years delineating the genetic drivers of colon cancer, and we still have more to learn. But we’ve now entered the era in which we want to understand the impact of environmental and host factors,” Yilmaz says.

Yilmaz hopes to identify nutrients and metabolites that can enhance stem cell function to repair damage after injury, or to identify mechanisms that dampen tumor formation. In addition, biomarkers such as levels of certain substances in the blood could be a key to early intervention, he says.

“Can we identify which obese patients are more prone to developing colon cancer? If so, can we identify therapies that go after weaknesses in their tumors?”

Battling colon cancer

During the time Yilmaz spends at MGH, he looks at slide after slide of biopsied cells. Normal epithelial cells line up in a single, orderly row. After 15 years in medicine, the twisted appearance of diseased cells still shocks him. “You know, in most cases, the number one predictor of how bad a tumor is going to behave isn’t its genetic signature,” he says. “It’s how deep they invade into their organ of origin, whether they have spread to distant organs, and how bad they look under the microscope.” The cells of this patient’s tumor are misshapen, haphazardly stacked on top of each other.

The patient is in her forties. Yilmaz recalled that when he was a resident, colon cancer in a 40-year-old or 30-year-old was a rarity. He now sees such cases almost weekly. Colorectal cancer is among the top three leading causes of cancer-related deaths in the United States, according to the American Cancer Society. It’s expected to cause around 53,000 deaths during 2021. Yilmaz writes up his diagnosis: invasive cancer of the sigmoid colon. The patient’s oncologist will consult with Yilmaz, radiologists, and the surgical team to come up with a treatment plan.

Ultimately, Yilmaz wants to develop strategies to prevent and reduce the growth of tumors in the intestinal tract. The fact that increasingly younger patients are being diagnosed highlights, for him, the importance of diet. “It’s very worrisome,” he says. “We’re at the beginning of a trend where we’re going to see more and more young people afflicted with what can be a fatal disease if not caught early.” Diet could be an important place to start.

He says, “If you can prevent cancer, that’s the best treatment.”

How sea stars get their symmetry
Greta Friar | Whitehead Institute
November 4, 2021

In a paper published Nov. 4 in the journal Current Biology, Zak Swartz, a postdoctoral researcher at Whitehead Institute, along with researchers in the lab of Whitehead Institute Member Iain Cheeseman and collaborators at the Massachusetts Institute of Technology (MIT), the University of Miami, and the Marine Biological Laboratory Embryology Course delve into the origins of the initial polarity in an animal’s first cell, which establishes an axis of symmetry for the developing organism and underlies the first steps of development. Their research reveals how a specific protein, called Dishevelled, localizes in a cell to help create this polarity.

All multicellular organisms begin as a single cell — the oocyte, precursor cell to the egg — which carries within it a “plan” for the fully developed, complex creature it will become. “How that multifunctional body plan is created is one of the deepest questions in developmental biology,” said Swartz.

“Sea stars, and a huge diversity of other animals, have an incredibly complex body plan, none of which is possible without the polarity of the initial cell,” said Cheeseman. “This work shows how the polarity originates as early as the meiotic divisions in the developing oocyte through an unexpected strategy to break its symmetry and achieve the asymmetric distribution of developmental factors.”

To study the intricate process of body patterning, Cheeseman Lab researchers used a type of sea star called the bat star, or Patiria miniata. These colorful animals are radially symmetric as adults — they usually have five arms, sometimes more — but as larvae they are bilaterally symmetric like humans.

The sea star larvae’s mirror-image symmetry is established when they are egg cells, called oocytes. A key step in the development of this organization involves a protein called Dishevelled, which localizes to the vegetal, or “bottom” end of the oocyte (which will define the posterior end of the embryo) as the cell gets ready to divide into two daughter cells.

Dishevelled — so named because a mutation in the homologous protein in fruit flies lends their tiny hairs a messy, tousled look  — is a component of a common signaling pathway called the Wnt pathway, which is found in many creatures throughout the animal kingdom. The pathway serves various purposes in the cells, from body patterning to cell proliferation. “The Wnt pathway is evolutionarily ancient,” Swartz said. “Jellyfish use it, sea stars use it, people use it, and I think that’s really quite profound.”

In the sea stars, the pathway provides a link between the initial asymmetry of the oocyte and the polarity of the resulting embryo. Dishevelled serves as a messenger on the inside of the sea star’s cells, relaying external signals that are then transmitted through a molecular pathway to the cells’ nuclei.

The researchers used time-lapse imaging to visualize how Dishevelled moved around the oocyte as the cell went through different phases of its development. When the sea star oocyte was in a non-dividing phase, Dishevelled could be found distributed uniformly in small aggregations throughout the cytoplasm.

As the oocyte got ready to divide, however, Dishevelled aggregations dissolved and then reformed at the bottom of the cell at the furthest point from the nucleus.  This provided a clear difference between the two ends of the oocyte.

Swartz was curious about how exactly the protein was localizing to the bottom of the oocyte. There were a number of protein transport options to investigate, so he began systematically ruling them out; the protein was not transported by the cell’s cytoskeleton (“You can think of these like little railroad tracks,” Swartz said), nor was it buoyed along on cytoplasmic currents, nor repelled by some factor at the “top” of the oocyte.

At this interval, Swartz reached out to two collaborators in MIT’s physics department, who helped design experiments to further probe the behavior of Dishevelled in the oocytes. “That’s when we started to consider the idea of dissolution and reassembly, which is kind of the punchline of the paper,” Swartz said. “You can think of it like salt crystals dissolving in water — rather than taking a pre-assembled thing and physically transporting it down [to the bottom of the oocyte], the idea is that these Dishevelled assemblies start out everywhere, get dissolved into their individual components, and then selectively reform in the vegetal region.”

The exact mechanism of this dissolution and reformation is not yet clear. Swartz was able to show that the reformation could not take place in the absence of another Wnt pathway protein called Frizzled, but because Frizzled is not exclusive to the bottom of the oocyte, it is not the only thing driving the reassembly.

In the future, Swartz plans to investigate whether the Dishevelled aggregates are formed in precise structures, or whether they group together as phase-separated droplets such as the RNA molecules studied in Whitehead Institute Member Ankur Jain’s lab or the protein molecules involved in transcription from Whitehead Institute Member Richard Young’s lab. “I’m interested in the broader composition of these structures,” he added. “Do they only contain Dishevelled, or are there other ingredients?”

Regardless of how the assemblies form, the new information on how Dishevelled localizes shines a light on a previously mysterious step in how the Wnt pathway plays a role in early body patterning in sea stars.

“It’s quite striking that Dishevelled localization seems to be an important feature in the Wnt pathway in sea stars, but also in distantly related vertebrates,” Swartz said. “My feeling is that the ability to activate this pathway in selective parts of the early embryo by interpreting polarity built into the oocyte may be a really critical feature of the evolution of the animal body plan.”

School of Science appoints 11 faculty members to named professorships

Those selected for these positions receive additional support to pursue their research and develop their careers.

School of Science
November 2, 2021

The School of Science has announced that 11 faculty members have been appointed to named professorships. These positions offer additional support to professors to advance their research and develop their careers.

Andrew Babbin was named a Cecil and Ida Green Career Development Professor. A marine biogeochemist, Babbin studies the processes that return fixed nitrogen in the ocean back to nitrogen gas, exploring marine nitrogen’s control on life in the ocean and its effects on climate. His research sheds light on the ocean’s potential to sustain life and store carbon. Babbin earned a BS degree from Columbia University in 2008 and a PhD from Princeton University in 2014. He came to MIT in 2014 as a postdoc in the Department of Civil and Environmental Engineering before joining the Department of Earth, Atmospheric and Planetary Sciences in January 2017.

Gloria Choi was selected as the Mark Hyman Jr. Career Development Professor. Choi, an associate professor in the Department of Brain and Cognitive Sciences and an investigator with the Picower Institute, examines the interaction of the immune system with the brain and the effects of that interaction on neurodevelopment, behavior, and mood. She also studies how social behaviors are regulated according to sensory stimuli, context, internal state, and physiological status, and how these factors modulate neural circuit function via a combinatorial code of classic neuromodulators and immune-derived cytokines. She received her bachelor’s degree from the University of California at Berkeley, and her PhD from Caltech, where she studied with David Anderson. She was a postdoc in the laboratory of Richard Axel at Columbia University. Choi joined the MIT faculty as an assistant professor in 2013.

Arlene Fiore joined MIT as the inaugural Peter H. Stone and Paola Malanotte Stone Professor in Earth, Atmospheric and Planetary Sciences in July 2021. Her research encompasses air pollution, chemistry-climate connections, trends and variability in atmospheric constituents, and biosphere-atmosphere interactions. Fiore’s group investigates regional meteorology and climate feedbacks due to aerosols versus greenhouse gases, future air pollution responses to climate change, as well as the factors controlling the oxidizing capacity of the atmosphere. After earning a bachelor’s degree and PhD from Harvard University, Fiore held a research scientist position at the Geophysical Fluid Dynamics Laboratory and was appointed as an associate professor with tenure at Columbia University in 2011.

Peter H. Fisher is now the Thomas A. Frank (1977) Professor of Physics. His interests include the detection of dark matter, development of new particle detectors, compact energy supplies, and wireless energy transmission. Currently serving as the head of the Department of Physics, Fisher also holds appointments in the Institute for Soldier Nanotechnologies, the Laboratory for Nuclear Science, and the Kavli Institute. He is involved in CERN’s Alpha Magnetic Spectrometer experiment to make high-precision measurements of cosmic rays and the development of new ideas for dark matter. After receiving a BS in engineering physics from the University of California at Berkeley in 1983 and a PhD in nuclear physics from Caltech in 1988, Fisher was at the Johns Hopkins University from 1989 to 1994 and joined MIT in 1994.

Danna Freedman has been named the Frederick George Keyes Professor of Chemistry. Freedman leverages inorganic chemistry to solve problems in physics. Her research focuses on creating spin-based quantum bits and synthesizing new emergent materials. Freedman received her bachelor’s degree from Harvard University and her PhD from the University of California at Berkeley, then conducted postdoctoral research at MIT before joining the faculty at Northwestern University as an assistant professor in 2012, where she was promoted to associate professor in 2018 and full professor in 2020. Freedman returned to MIT’s Department of Chemistry in 2021.

Michel Goemans has been named the RSA Professor of Mathematics. Goemans has been head of the Department of Mathematics since July 1, 2018, following a year as interim head. He received his undergraduate degree in applied mathematics from Université Catholique de Louvain in 1987 and completed his PhD at MIT in 1990. He has been on the faculty since 1992, receiving tenure in 1999, and held the Leighton Family Professorship from 2007 to 2017. The RSA cryptosystem is the brainchild of Ron Rivest, Adi Shamir, and Len Adleman, whose fruitful collaboration spanned the Laboratory for Computer Science — today the Computer Science and Artificial Intelligence Laboratory (CSAIL) — and the Department of Mathematics. Goemans is also a member of the Theory of Computation Group of CSAIL, and recently joined the Computing Council of the MIT Schwarzman College of Computing. Goemans’ research interests include combinatorics, optimization and algorithms. In particular, his pioneering use of semidefinite optimization and other techniques for designing approximation algorithms for hard combinatorial optimization problems has been rewarded with several awards, such as the Fulkerson, Farkas and Dantzig prizes.

Or Hen was named the Class of 1956 Career Development Associate Professor of Physics. He investigates quantum chromodynamic effects in the nuclear medium and the interplay between partonic and nucleonic degrees of freedom in nuclei. Specifically, Hen utilizes high-energy scattering of electron, neutrino, photon, proton, and ion off atomic nuclei to study short-range correlations: temporal fluctuations of high-density, high-momentum, nucleon clusters in nuclei with important implications for nuclear, particle, atomic, and astrophysics. He received his undergraduate degree in physics and computer engineering from the Hebrew University and earned his PhD in experimental physics at Tel-Aviv University. Hen was an MIT Pappalardo Fellow in Physics from 2015 to 2017 before joining the physics faculty in July 2017.

Brett McGuire is now the Class of 1943 Career Development Assistant Professor of Chemistry. He uses the tools of physical chemistry, molecular spectroscopy, and observational astrophysics to understand how the chemical ingredients for life evolve with and help shape the formation of stars and planets. His group aims to detect more new molecules in space and to better understand their significance, advancing the field of astrochemistry. McGuire obtained a bachelor’s degree from the University of Illinois at Urbana-Champaign in 2009, a master’s degree from Emory University in 2011, and a PhD from Caltech in 2015. McGuire joined the Department of Chemistry in 2020.

Iain W. Stewart has been selected for the Otto (1939) and Jane Morningstar Professorship in Science. Stewart is a professor of physics and the director of the Center for Theoretical Physics. His research interests involve theoretical nuclear and particle physics. In particular, he focuses upon the development and application of effective field theories to answer fundamental questions about interactions between elementary particles. Stewart earned a bachelor’s degree in physics and mathematics and a master’s degree in physics from the University of Manitoba in Canada. He then received his PhD from Caltech in 1999. Stewart joined the physics faculty at MIT in 2003, was promoted to associate professor with tenure in 2009, and became a full professor in 2013.

Ankur Moitra, a theoretical computer scientist, is now the Norbert Wiener Professor of Mathematics. The aim of his work is to bridge the gap between theoretical computer science and machine learning by developing algorithms with provable guarantees and foundations for reasoning about their behavior. Moitra received his bachelor’s degree in electrical and computer engineering from Cornell University in 2007 and his master’s degree and PhD from MIT in computer science in 2009 and 2011, respectively, then spent two years as a fellow at the Institute for Advanced Study and Princeton University. Moitra returned to MIT in 2013 as a professor in applied mathematics and a principal investigator in CSAIL.

Seychelle M. Vos has been named a Robert A. Swanson (1969) Career Development Professor of Life Sciences. Vos examines the interplay of genome organization and gene expression to gain insight into how the organization of a cell affects what it becomes. Vos’ lab examines these pieces at a molecular scale using varied approaches from single-particle cryo-electron microscopy to X-ray crystallography, biochemistry to genetics. This work can help to build a biological understanding of diseases such as developmental disorders or cancers. She received her BS in genetics in 2008 from the University of Georgia and her PhD in molecular and cell biology in 2013 from the University of California at Berkeley. Vos joined the Department of Biology in 2019.

Differences in T cells’ functional state determine resistance to cancer therapy

Researchers decipher when and why immune cells fail to respond to immunotherapy, suggesting that T cells need a different kind of prodding to re-engage the immune response.

Grace van Deelen
October 29, 2021

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in humans. Some patients with NSCLC receive a therapy called immune checkpoint blockade (ICB) that helps kill cancer cells by reinvigorating a subset of immune cells called T cells, which are “exhausted” and have stopped working. However, only about 35% of NSCLC patients respond to ICB therapy. Stefani Spranger’s lab at the MIT Department of Biology explores the mechanisms behind this resistance, with the goal of inspiring new therapies to better treat NSCLC patients. In a new study published on Oct. 29 in Science Immunology, a team led by Spranger lab postdoc Brendan Horton revealed what causes T cells to be non-responsive to ICB — and suggested a possible solution.

Scientists have long thought that the conditions within a tumor were responsible for determining when T cells stop working and become exhausted after being overstimulated or working for too long to fight a tumor. That’s why physicians prescribe ICB to treat cancer — ICB can invigorate the exhausted T cells within a tumor. However, Horton’s new experiments show that some ICB-resistant T cells stop working before they even enter the tumor. These T cells are not actually exhausted, but rather they become dysfunctional due to changes in gene expression that arise early during the activation of a T cell, which occurs in lymph nodes. Once activated, T cells differentiate into certain functional states, which are distinguishable by their unique gene expression patterns.

In order to determine why some tumors are resistant to ICB, Horton and the research team studied T cells in murine models of NSCLC. The researchers sequenced messenger RNA from the responsive and non-responsive T cells in order to identify any differences between the T cells. Supported in part by the Koch Institute Frontier Research Program, they used a technique called Seq-Well, developed in the lab of fellow Koch Institute member J. Christopher Love, the Raymond A. (1921) and Helen E. St. Laurent Professor of Chemical Engineering and a co-author of the study. The technique allows for the rapid gene expression profiling of single cells, which permitted Spranger and Horton to get a very granular look at the gene expression patterns of the T cells they were studying.

Seq-Well revealed distinct patterns of gene expression between the responsive and non-responsive T cells. These differences, which are determined when the T cells assume their specialized functional states, may be the underlying cause of ICB resistance.

Now that Horton and his colleagues had a possible explanation for why some T cells did not respond to ICB, they decided to see if they could help the ICB-resistant T cells kill the tumor cells. When analyzing the gene expression patterns of the non-responsive T cells, the researchers had noticed that these T cells had a lower expression of receptors for certain cytokines, small proteins that control immune system activity. To counteract this, the researchers treated lung tumors in murine models with extra cytokines. As a result, the previously non-responsive T cells were then able to fight the tumors — meaning that the cytokine therapy prevented, and potentially even reversed, the dysfunctionality.

Administering cytokine therapy to human patients is not currently safe, because cytokines can cause serious side effects as well as a reaction called a “cytokine storm,” which can produce severe fevers, inflammation, fatigue, and nausea. However, there are ongoing efforts to figure out how to safely administer cytokines to specific tumors. In the future, Spranger and Horton suspect that cytokine therapy could be used in combination with ICB.

“This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer,” Horton says.

Spranger agrees that this work will help researchers develop more innovative cancer therapies, especially because researchers have historically focused on T cell exhaustion rather than the earlier role that T cell functional states might play in cancer.

“If T cells are rendered dysfunctional early on, ICB is not going to be effective, and we need to think outside the box,” she says. “There’s more evidence, and other labs are now showing this as well, that the functional state of the T cell actually matters quite substantially in cancer therapies.” To Spranger, this means that cytokine therapy “might be a therapeutic avenue” for NSCLC patients beyond ICB.

Jeffrey Bluestone, the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the University of California-San Francisco, who was not involved with the paper, agrees. “The study provides a potential opportunity to ‘rescue’ immunity in the NSCLC non-responder patients with appropriate combination therapies,” he says.

This research was funded by the Pew-Stewart Scholars for Cancer Research, the Ludwig Center for Molecular Oncology, the Koch Institute Frontier Research Program through the Kathy and Curt Mable Cancer Research Fund, and the National Cancer Institute.