Coding for health equity

Senior Mercy Oladipo is building tools to address disparities in health care.

Laura Rosado | MIT News correspondent
March 24, 2023

Choosing a major was a long process for Mercy Oladipo. Coming into MIT, she was interested in both computer science and medicine, but a plan for how those passions would intersect took some time to coalesce.

Oladipo finally settled on a joint major in computer science and molecular biology, which allowed her to dive into computer science and also fulfill her pre-med class requirements.

At face value, the classes in her two majors “are very far-removed,” says Oladipo. “You don’t really touch any interaction until your junior or senior year, but it helped me feel like I could do whatever I want and chart my own path.”

Now a senior, Oladipo has pursued a range of opportunities that allow her to apply her coding skills to build tools for health care, with support from MIT’s PKG Center. These include exploring health disparities in end-of-life care with the Clinical Decision-Making Group in MIT’s Computer Science and Artificial Intelligence Laboratory, revamping the webpage for the Boston Medical Center’s Autism Friendly Initiative, and creating websites for studies run by Tufts University’s Maternal Outcomes for Translational Health Equity Research (M.O.T.H.E.R.) Lab.

For Oladipo, the through-line among her interests has always been equity, whether in health care or in education.

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Everything came together when Oladipo participated as a sophomore in Womxn Ignite, a tech incubator for women interested in public interest technology. It was there that she first had the idea for Birth By Us, a startup she co-founded with Ijeoma Uche, a second-year master’s student at the University of California at Berkeley.

Birth By Us is a pregnancy and postpartum app built by and for Black women. The goal is to be a centralized source of information throughout the entire birth experience, from prenatal appointments to postpartum recovery. Every day, users fill out a questionnaire to screen for symptoms that are often overlooked, and will be provided with resources tailored to their personal experience. With Birth By Us, Oladipo hopes to address the racial disparity in maternal deaths while also forging stronger connections between community programs and Black mothers.

Now a senior, Oladipo still sees many paths ahead of her following graduation. Over the next few years, she plans to keep working on and scaling Birth By Us. She’d also like to attend medical school and pursue maternal health research in other contexts.

“Everything is very intertwined,” Oladipo says when asked about what comes next. “It’s all the same topic in different fonts.”

Oladipo also says she isn’t stressed about the uncertainty in her future. She credits that comfort to the support she receives from her family and her faith. Oladipo is grateful for her family’s presence in her life, whether that’s in the form of advice from her parents and two older siblings or daily calls from her younger brother.

A lifelong love of language learning

This year, Oladipo spent Independent Activities Period in Aguascalientes, Mexico, teaching middle schoolers through the MIT International Science and Technology Initiatives’ Global Teaching Labs program. Along with two other MIT students, they tackled coding and building lava lamps, and ended the program by building a Rube Goldberg machine in collaboration with Panamerican University.

To apply for the program, Oladipo needed to be able to speak Spanish, a requirement she easily cleared from studying the language since high school. There were two reasons why she had picked it up. The first was that most of her friends also spoke Spanish and she wanted to be able to converse with them in their native language.

“My best friend in seventh grade didn’t have a phone, so we’d always email back and forth in the mornings,” says Oladipo. “I would try to practice my Spanish with him. I look back and the grammar is not there, the spelling is all off, but it was cute.”

The second reason was that she had studied Latin since second grade and found herself wondering what came next after completing AP Latin.

“Everyone used to tell me it’s a dead language, but I thought it was so cool,” says Oladipo. She adds that she was “such a nerd back then” for enjoying the nuances of the language, such as the rigid grammatical structure and how English derivatives came to be.

Oladipo didn’t plan on taking Portuguese in college — she had originally intended on adding Yoruba to her arsenal but couldn’t work it into her schedule — but decided to take it when it fit her schedule. Now, she’s eyeing a potential Fulbright in São Paolo and has plans to see more of Latin America following graduation.

For now, Oladipo is focusing on finishing up her college career. In between managing her company and balancing her classwork, she’s also a member of the cheerleading team. And, she’s currently the president of the Xi Tau Chapter of the Delta Sigma Theta Sorority, Inc. where she helps plan public service events and other programs throughout the year.

There’s a lot on her plate, and Oladipo acknowledges that. But she’s also looking forward to what comes after graduation.

“I’m a bit of a workaholic, but I’m excited to be more done and focus on what I actually want to put my time toward,” she says.

QS World University Rankings rates MIT No. 1 in 11 subjects for 2023

The Institute also ranks second in five subject areas.

MIT News Office
March 22, 2023

QS World University Rankings has placed MIT in the No. 1 spot in 11 subject areas for 2023, the organization announced today.

The Institute received a No. 1 ranking in the following QS subject areas: Chemical Engineering; Civil and Structural Engineering; Computer Science and Information Systems; Data Science and Artificial Intelligence; Electrical and Electronic Engineering; Linguistics; Materials Science; Mechanical, Aeronautical, and Manufacturing Engineering; Mathematics; Physics and Astronomy; and Statistics and Operational Research.

MIT also placed second in five subject areas: Accounting and Finance; Architecture/Built Environment; Biological Sciences; Chemistry; and Economics and Econometrics.

For 2023, universities were evaluated in 54 specific subjects and five broader subject areas. MIT was ranked No. 1 in the broader subject area of Engineering and Technology and No. 2 in Natural Sciences.

Quacquarelli Symonds Limited subject rankings, published annually, are designed to help prospective students find the leading schools in their field of interest. Rankings are based on research quality and accomplishments, academic reputation, and graduate employment.

MIT has been ranked as the No. 1 university in the world by QS World University Rankings for 11 straight years.

2023 MacVicar Faculty Fellows named

Professors Gabrieli, Gubar, Martin, and Sass are honored for exceptional undergraduate teaching.

Meghan Burke | Office of the Registrar
March 10, 2023

The Office of the Vice Chancellor and the Registrar’s Office have announced this year’s Margaret MacVicar Faculty Fellows: professor of brain and cognitive sciences John Gabrieli, associate professor of literature Marah Gubar, professor of biology Adam C. Martin, and associate professor of architecture Lawrence “Larry” Sass.

For more than 30 years, the MacVicar Faculty Fellows Program has recognized exemplary and sustained contributions to undergraduate education at MIT. The program is named in honor of Margaret MacVicar, the first dean for undergraduate education and founder of the Undergraduate Research Opportunities Program (UROP). New fellows are chosen every year through a competitive nomination process that includes submission of letters of support from colleagues, students, and alumni; review by an advisory committee led by the vice chancellor; and a final selection by the provost. Fellows are appointed to a 10-year term and receive $10,000 per year of discretionary funds.

Gabrieli, Gubar, Martin, and Sass join an elite group of more than 130 scholars from across the Institute who are committed to curricular innovation, excellence in teaching, and supporting students both in and out of the classroom.

John Gabrieli

“When I learned of this wonderful honor, I felt gratitude — for how MIT values teaching and learning, how my faculty colleagues bring such passion to their teaching, and how the students have such great curiosity for learning,” says new MacVicar Fellow John Gabrieli.

Gabrieli PhD ’87 received a bachelor’s degree in English from Yale University and his PhD in behavioral neuroscience from MIT. He is the Grover M. Hermann Professor in the Department of Brain and Cognitive sciences. Gabrieli is also an investigator in the McGovern Institute for Brain Research and the founding director of the MIT Integrated Learning Initiative (MITili). He holds appointments in the Department of Psychiatry at Massachusetts General Hospital and the Harvard Graduate School of Education, and studies the organization of memory, thought, and emotion in the human brain.

He joined Course 9 as a professor in 2005 and since then, he has taught over 3,000 undergraduates through the department’s introductory course, NetBet sport9.00 (Introduction to Psychological Science). Gabrieli was recognized with departmental awards for excellence in teaching in 2009, 2012, and 2015. Highly sought after by undergraduate researchers, the Gabrieli Laboratory (GabLab) hosts five to 10 UROPs each year.

A unique element of Gabrieli’s classes is his passionate, hands-on teaching style and his use of interactive demonstrations, such as optical illusions and personality tests, to help students grasp some of the most fundamental topics in psychology.

His former teaching assistant Daniel Montgomery ’22 writes, “I was impressed by his enthusiasm and ability to keep students engaged throughout the lectures … John clearly has a desire to help students become excited about the material he’s teaching.”

Senior Elizabeth Carbonell agrees: “The excitement professor Gabrieli brought to lectures by starting with music every time made the classroom an enjoyable atmosphere conducive to learning … he always found a way to make every lecture relatable to the students, teaching psychological concepts that would shine a light on our own human emotions.”

Lecturer and 9.00 course coordinator Laura Frawley says, “John constantly innovates … He uses research-based learning techniques in his class, including blended learning, active learning, and retrieval practice.” His findings on blended learning resulted in two MITx offerings including 9.00x (Learning and Memory), which utilizes a nontraditional approach to assignments and exams to improve how students retrieve and remember information.

In addition, he is known for being a devoted teacher who believes in caring for the student as a whole. Through MITili’s Mental Wellness Initiative, Gabrieli, along with a compassionate team of faculty and staff, are working to better understand how mental health conditions impact learning.

Associate department head and associate professor of brain and cognitive sciences Josh McDermott calls him “an exceptional educator who has left his mark on generations of MIT undergraduate students with his captivating, innovative, and thoughtful approach to teaching.”

Mariana Gomez de Campo ’20 concurs: “There are certain professors that make their mark on students’ lives; professor Gabrieli permanently altered the course of mine.”

Laura Schulz, MacVicar Fellow and associate department head of brain and cognitive sciences, remarks, “His approach is visionary … John’s manner with students is unfailingly gracious … he hastens to remind them that they are as good as it gets, the smartest and brightest of their generation … it is the kind of warm, welcoming, inclusive approach to teaching that subtly but effectively reminds students that they belong here at MIT … It is little wonder that they love him.”

Marah Gubar

Marah Gubar joined MIT as an associate professor of literature in 2014. She received her BA in English literature from the University of Michigan at Ann Arbor and a PhD from Princeton University. Gubar taught in the English department at the University of Pittsburgh and served as director of the Children’s Literature Program. She received MIT’s James A. and Ruth Levitan Teaching Award in 2019 and the Teaching with Digital Technology Award in 2020.

Gubar’s research focuses on children’s literature, history of children’s theater, performance, and 19th- and 20th-century representations of childhood. Her research and pedagogies underscore the importance of integrated learning.

Colleagues at MIT note her efficacy in introducing new concepts and new subjects into the literature curriculum during her tenure as curricular chair. Gubar set the stage for wide-ranging curricular improvements, resulting in a host of literature subjects on interrelated topics within and across disciplines.

Gubar teaches several classes, including 21L.452 (Literature and Philosophy) and 21L.500 (How We Got to Hamilton). Her lectures provide uniquely enriching learning experiences in which her students are encouraged to dive into literary texts; craft thoughtful, persuasive arguments; and engage in lively intellectual debate.

Gubar encourages others to bring fresh ideas and think outside the box. For example, her seminar on “Hamilton” challenges students to recontextualize the hip-hop musical in several intellectual traditions. Professor Eric Klopfer, head of the Comparative Media Studies Program/Writing and interim head of literature, calls Gubar “a thoughtful, caring instructor, and course designer … She thinks critically about whose story is being told and by whom.”

MacVicar Fellow and professor of literature Stephen Tapscott praises her experimentation, abstract thinking, and storytelling: “Professor Gubar’s ability to frame intellectual questions in terms of problems, developments, and performance is an important dimension of the genius of her teaching.”

“Marah is hands-down the most enthusiastic, effective, and engaged professor I had the pleasure of learning from at MIT,” writes one student. “She’s one of the few instructors I’ve had who never feels the need to reassert her place in the didactic hierarchy, but approaches her students as intellectual equals.”

Tapscott continues, “She welcomes participation in ways that enrich the conversation, open new modes of communication, and empower students as autonomous literary critics. In professor Gubar’s classroom we learn by doing … and that progress also includes ‘doing’ textual analysis, cultural history, and abstract literary theory.”

Gubar is also a committed mentor and student testimonials highlight her supportive approach. One of her former students remarked that Gubar “has a strong drive to be inclusive, and truly cares about ‘getting it right’ … her passion for literature and teaching, together with her drive for inclusivity, her ability to take accountability, and her compassion and empathy for her students, make [her] a truly remarkable teacher.”

On receiving this award Marah Gubar writes, “The best word I can think of to describe how I reacted to hearing that I had received this very overwhelming honor is ‘plotzing.’ The Yiddish verb ‘to plotz’ literally means to crack, burst, or collapse, so that captures how undone I was. I started to cry, because it suddenly struck me how much joy my father, Edward Gubar, would have taken in this amazing news. He was a teacher, too, and he died during the first phase of this terrible pandemic that we’re still struggling to get through.”

Adam C. Martin

Adam C. Martin is a professor and undergraduate officer in the Department of Biology. He studies the molecular mechanisms that underlie tissue form and function. His research interests include gastrulation, embryotic development, cytoskeletal dynamics, and the coordination of cellular behavior. Martin received his PhD from the University of California at Berkeley and his BS in biology (genetics) from Cornell University. Martin joined the Course 7 faculty in 2011.

“I am overwhelmed with gratitude knowing that this has come from our students. The fact that they spent time to contribute to a nomination is incredibly meaningful to me,” says Martin. “I want to also thank all of my faculty colleagues with whom I have taught, appreciate, and learned immensely from over the past 12 years. I am a better teacher because of them and inspired by their dedication.”

He is committed to undergraduate education, teaching several key department offerings including 7.06 (Cell Biology), 7.016 (Introductory Biology), 7.002 (Fundamentals of Experimental Molecular Biology), and 7.102 (Introduction to Molecular Biology Techniques).

Martin’s style combines academic and scientific expertise with creative elements like props and demonstrations. His “energy and passion for the material” is obvious, writes Iain Cheeseman, associate department head and the Herman and Margaret Sokol Professor of Biology. “In addition to creating engaging lectures, Adam went beyond the standard classroom requirements to develop videos and animations (in collaboration with the Biology MITx team) to illustrate core cell biological approaches and concepts.”

What sets Martin apart is his connection with students, his positive spirit, and his welcoming demeanor. Apolonia Gardner ’22 reflects on the way he helped her outside of class through his running group, which connects younger students with seniors in his lab. “Professor Martin was literally committed to ‘going the extra mile’ by inviting his students to join him on runs around the Charles River on Friday afternoons,” she says.

Amy Keating, department head and Jay A. Stein professor of biology, and professor of biological engineering, goes on to praise Martin’s ability to attract students to Course 7 and guide them through their educational experience in his role as the director of undergraduate studies. “He hosts social events, presides at our undergraduate research symposium and the department’s undergraduate graduation and awards banquet, and works with the Biology Undergraduate Student Association,” she says.

As undergraduate officer, Martin is involved in both advising and curriculum building. He mentors UROP students, serves as a first-year advisor, and is a current member of MIT’s Committee on the Undergraduate Program (CUP).

Martin also brings a commitment to diversity, equity, and inclusion (DEI) as evidenced by his creation of a DEI journal club in his lab so that students have a dedicated space to discuss issues and challenges. Course 7 DEI officer Hallie Dowling-Huppert writes that Martin “thinks deeply about how DEI efforts are created to ensure that department members receive the maximum benefit. Adam considers all perspectives when making decisions, and is extremely empathetic and caring towards his students.”

“He makes our world so much better,” Keating observes. “Adam is a gem.”

Lawrence “Larry” Sass

Larry Sass SM ’94, PhD ’00 is an associate professor in the Department of Architecture. He earned his PhD and SM in architecture at MIT, and has a BArch from Pratt Institute in New York City. Sass joined the faculty in the Department of Architecture in 2002. His work focuses on the delivery of affordable housing for low-income families. He was included in an exhibit titled “Home Delivery: Fabricating the Modern Dwelling” at the Museum of Modern Art in New York City.

Sass’s teaching blends computation with design. His two signature courses, 4.500 (Design Computation: Art, Objects and Space) and 4.501 (Tiny Fab: Advancements in Rapid Design and Fabrication of Small Homes), reflect his specialization in digitally fabricating buildings and furniture from machines.

Professor and head of architecture Nicholas de Monchaux writes, “his classes provide crucial instruction and practice with 3D modeling and computer-generated rendering and animation …  [He] links digital design to fabrication, in a process that invites students to define desirable NetBet sportdesign attributes of an object, develop a digital model, prototype it, and construct it at full scale.”

More generally, Sass’ approach is to help students build confidence in their own design process through hands-on projects. MIT Class of 1942 Professor John Ochsendorf, MacVicar Fellow, and founding director of the Morningside Academy for Design with appointments in the departments of architecture and civil and environmental engineering, confirms, “Larry’s teaching is a perfect embodiment of the ‘mens et manus’ spirit … [he] requires his students to go back and forth from mind and hand throughout each design project.”

Students say that his classes are a journey of self-discovery, allowing them to learn more about themselves and their own abilities. Senior Natasha Hirt notes, “What I learned from Larry was not something one can glean from a textbook, but a new way of seeing space … he tectonically shifted my perspective on buildings. He also shifted my perspective on myself. I’m a better designer for his teachings, and perhaps more importantly, I better understand how I design.”

Senior Izzi Waitz echoes this sentiment: “Larry emphasizes the importance of intentionally thinking through your designs and being confident in your choices … he challenges, questions, and prompts you so that you learn to defend and support yourself on your own.”

As a UROP coordinator, Sass assures students that the “sky is the limit” and all ideas are welcome. Postgraduate teaching fellow and research associate Myles Sampson says, “During the last year of my SM program, I assisted Larry in conducting a year-long UROP project … He structured the learning experience in a way that allowed the students to freely flex their design muscles: no idea was too outrageous.”

Sass is equally devoted to his students outside the classroom. In his role as head of house at MacGregor House, he lives in community with more than 300 undergraduates each year, providing academic guidance, creating residential programs and recreational activities, and ensuring that student wellness and mental health is a No. 1 priority.

Professor of architecture and MacVicar Fellow Les Norford says, “In two significant ways, Larry has been ahead of his time: combining digital representation and design with making and being alert to the well-being of his students.”

“In his kindness, he honors the memory of Margaret MacVicar, as well as the spirit of MIT itself,” Hirt concludes. “He is a designer, a craftsman, and an innovator. He is an inspiration and a compass.”

On receiving this award, Sass is full of excitement: “I love teaching and being part of the MIT community. I am grateful for the opportunity to be part of the MacVicar family of fellows.”

New research supports finding explaining why some patients may test positive for COVID-19 long after recovery

SARS-CoV-2, the virus that causes COVID-19, seems to have become a permanent presence in our lives. Research from Whitehead Institute Founding Member Rudolf Jaenisch’s lab reveals that this may be true on multiple levels.

Greta Friar | Whitehead Institute
February 28, 2023

SARS-CoV-2, the virus that causes COVID-19, seems to have become a permanent presence in our lives. Research from Whitehead Institute Founding Member Rudolf Jaenisch’s lab reveals that this may be true on multiple levels. Jaenisch, postdoc Liguo Zhang, and colleagues have shown that when the virus infects people, it is capable of integrating parts of its genetic code into the human genome through a process called reverse transcription. This genomic integration is rare, but due to how many hundreds of millions of people have been infected, it has likely occurred many times.

In a paper published in the journal Viruses on February 25, the researchers use and compare multiple methods to show that SARS-CoV-2 can integrate into host cells’ genomes. The paper is a follow up to Jaenisch and Zhang’s 2021 paper in the Proceedings of the National Academy of Sciences, which provided initial evidence of SARS-CoV-2 genomic integration. The original paper intended to solve the puzzle of why some people who had had COVID-19 were still testing positive long after recovering from the disease. The answer the researchers found was that parts of the viral genome were reverse transcribed into the human genome, meaning the viral RNA was transcribed or “read” into DNA (a reverse of the usual process) and then that DNA was stitched into the cell’s DNA. Then, when the cells’ genomes were transcribed into RNA, the portion of the virus’ genome that had been incorporated would be included and could be recognized by a PCR test, leading to a positive result.

In order to further substantiate the findings described in the previous paper, Jaenisch and Zhang have now performed additional experiments and analyses. The new paper explains why some experiments testing for viral genomic integration would come up with a negative result, and how this is consistent with Jaenisch and Zhang’s conclusion. Additionally, Jaenisch and Zhang examine whether viral RNA put into cells, as a model of the COVID-19 mRNA vaccines, can also integrate into the human genome, and find initial evidence that it cannot.

“This paper puts our data on a very firm footing,” Jaenisch says. “Hopefully, it will clarify some of the issues raised in the discussion that followed the first paper, and provide some reassurance to people who were worried about the implications for the vaccine.”

Hunting for a needle in a haystack

The main challenge in finding evidence of SARS-CoV-2 integrating into the human genome is that this event appears to be very rare. In the new paper, Jaenisch and Zhang used digital PCR, an approach that can sensitively detect specific DNA sequences in cells, to see how commonly the sequence that they would find in instances of viral RNA being read into DNA appeared in infected cells. Specifically, they looked for reverse transcribed SARS-CoV-2 complementary DNA (cDNA), DNA that is made from the virus’ original mRNA. Digital PCR revealed that for every one thousand cells, reverse transcribed viral cDNA was only present in around four to twenty cells. This number includes all detected instances of viral cDNA, whether integrated into the genome or not, so genomic integration is likely even rarer—indeed, the new research suggests that only a fraction of the total cDNA identified is from genomic integration.

Because genomic viral integration is so rare, Jaenisch and Zhang needed to use multiple complementary methods to test for it. One approach, called whole genome sequencing (WGS), is able to search cells’ genomes in great detail. When it does come across an instance of viral genomic integration, it can identify not only the reverse transcribed viral sequence, but also two sequences near the viral sequence that are added when it is integrated into the genome by a common reverse transcription complex called LINE1, which is encoded in the host cells. The combination of viral cDNA plus the two nearby cellular host sequences provides very strong evidence that viral cDNA is not only present but has been incorporated into the cell’s genome. However, WGS can only search the equivalent of a few cells’ genomes, and so when searching for a rare event, like SARS-CoV-2 integration, it often comes up empty. People skeptical of the first paper performed this type of experiment and came up with a negative result; Jaenisch and Zhang were not surprised by that, and it is consistent with their own findings when using this approach.

“Because the human cell genome coverage by whole genome sequencing is very limited, you would need to run the sequencing experiment many times in order to have a good chance of detecting one viral genome copy,” Zhang says.

In order to make the most of WGS, Jaenisch and Zhang induced their cells to overexpress LINE1, the cellular machinery that reverse transcribes viral RNA into the human genome. This exponentially increases the amount of viral cDNA that gets made; when the researchers performed digital PCR on their cells with overexpression, it detected fourteen to twenty thousand cDNA copies per thousand cells. Consequently, WGS was able to detect instances of viral cDNA plus the two nearby sequences that are the telltale signature of genomic integration in these cells.

“This is unambiguous proof of viral genomic integration,” Zhang says.

This type of experiment is called a positive control. Researchers use it to prove that, in ideal circumstances, the biological phenomenon they are curious about can occur. The question then becomes: does the phenomenon happen in normal circumstances? This was a criticism raised by some researchers in response to the first paper: they were not convinced that viral genomic integration happens in the cells of an infected person, which do not have the same levels of LINE1.

The search gets shallower but wider

Jaenisch and Zhang used another approach to hunt for evidence of viral genomic integration in cells without LINE1 overexpression. The approach, called an enrichment method and performed with the tool TagMap, can analyze thousands of cells—enough cells to reliably find evidence of a rare event. However, it cannot get the same detail as whole genome sequencing; TagMap enriches and captures shorter sequences of DNA, so it can only capture one of the two nearby sequences that act as a signature alongside viral cDNA. However, the smaller stretch of DNA that the researchers focused on still has features that can be used as evidence of integration. With this approach, Jaenisch and Zhang detected many instances of viral cDNA linked to the nearby cellular sequence.

Jaenisch and Zhang argue that the combined results of these experiments show strong proof of viral integration. Whole genome sequencing provides very strong proof that viral genomic integration can occur in the right conditions. Enrichment with TagMap provides reasonably strong proof that viral genomic integration occurs in normal cells.

“Each of these methods has advantages and disadvantages. You have to combine them to get the complete picture,” Jaenisch says.

Turning to the vaccine

After reaffirming their results that genomic integration of SARS-CoV-2 happens following viral infection, the researchers wanted to know whether the same thing happens with mRNA from the COVID-19 vaccines—which had been a concern expressed by many in the wake of the first paper. Jaenisch and Zhang could not get access to the actual vaccine RNA, packaged into a lipid coat, which is used for vaccination. Instead, they created a model of vaccine injection, inserting a bit of SARS-CoV-2 genetic material (mRNA) into cells through transfection, or non-infection “delivery” of genetic content into cells.

The researchers found that transfection of SARS-CoV-2 mRNA did not lead to genomic integration in the same way that infection did. Infection naturally produces a large amount of viral RNA and causes an inflammatory response in cells. Such cellular stresses increase the level of the reverse transcription machinery. Transfection does not do this, and correspondingly, the researchers found no evidence with TagMap that it led to viral genomic integration by LINE1 in normal cells.

The researchers’ model of vaccine injection is missing several key features of the actual vaccine. In the future, Jaenisch hopes to follow up on NetBet live casinothis research using the actual vaccine RNA sequence, and testing in an animal model to more closely match what happens during vaccine injection. In the meantime, the researchers hope that these initial results are reassuring.

“We need to do further testing, but our results are consistent with vaccine RNA not integrating,” Jaenisch says.

Notes

Zhang, Liguo, Punam Bisht, Anthony Flamier, M. Inmaculada Barrasa, Max Friesen, Alexsia Richards, Stephen H. Hughes, and Rudolf Jaenisch. 2023. “LINE1-Mediated Reverse Transcription and Genomic Integration of SARS-CoV-2 mRNA Detected in Virus-Infected but Not in Viral mRNA-Transfected Cells” Viruses 15, no. 3: 629. https://doi.org/10.3390/v15030629

MIT vs. poop

When Greater Boston faced a sewage crisis, the MIT biology department was there to help.

Saima May Sidik, SM ’21
February 21, 2023

View of Neponset River in Mattapan.

In the 1800s, Boston had a problem: it stank, and there was no question why. Modern sewage treatment had not yet been invented, so human waste ran through makeshift drainage systems into the surrounding rivers and bays. “Large territories have been at once, and frequently, enveloped in an atmosphere of stench so strong as to arouse the sleeping, terrify the weak, and nauseate and exasperate everybody,” an official from the City Board of Health wrote in an annual report in 1872.

Nausea and exasperation were the least of Bostonians’ worries: sewage spreads bacteria that cause diseases such as cholera and typhoid fever. In 1849, a major cholera outbreak killed more than 600 Boston residents, prompting city officials to take action. By the 20th century, Boston had a system for pumping waste away from the city and into the ocean.

Hughes House
When heiress Sarah Hughes married, her father gave her a mansion, abutting the Neponset River. She had just one complaint: the river “smells so horribly that you can’t sit near it.” Her anonymous support of MIT’s sewage treatment research helped clean up the river and significantly reduced rates of typhoid fever.
MILTON HISTORICAL SOCIETY

The system improved conditions downtown, but for people living along certain sewage-laden waterways, the problem was far from solved. One of these was Sarah Hughes, daughter of the merchant and railroad stockholder John Murray Forbes, who was known as “the richest man in New England.” In 1889, Forbes gave Hughes an elaborate wedding present: a mansion in Milton, near the Neponset River, that would become known as the Hughes House. There was just one problem: “Neponset River smells so horribly that you can’t sit near it,” Hughes wrote in a letter she sent to MIT president Henry Smith Pritchett in 1902.

Hughes had the means to do more than just complain. So for about 15 years, she anonymously donated thousands of dollars to MIT each year for research on treating human waste. By the 1920s, sewage purification systems—developed partly thanks to Hughes’s support—had reduced rates of typhoid fever significantly. In 1908, the disease struck at least 15 people per 100,000 in 35 US cities. Ten years later, only two or three cities were experiencing such dire problems. Techniques developed during this period underlie today’s methods for treating human waste.

Wryly suggesting that few Bostonians would believe in germs smaller than lobsters, Hughes pushed the researchers to describe their findings in plain language.

At the helm of MIT’s sewage treatment research was William Sedgwick, the founding head of the biology department, who had been working with the Massachusetts State Department of Health to improve water safety since 1888. At an experiment station in Lawrence, he and his colleagues built on European research to devise a method of removing pathogenic microbes by filtering sewage through sand. Harmless microbes that grew in the sand added to the filtering effect and prevented the harmful bacteria from passing through.

William Sedgwick
William Sedgwick, the founding head of the biology department, led MIT’s sewage treatment research.
MIT MUSEUM

Filtering an entire city’s waste would require an unfeasibly large bed of sand, however. Using Hughes’s funding, Sedgwick and his colleagues—including MIT student Anne Rogers, Class of 1904, and recent graduates Charles-Edward Amory Winslow, Class of 1898, SM 1899, and Earle Phelps, Class of 1899—aimed to devise more scalable methods. The work took place on the corner of Albany Street and Massachusetts Avenue in Boston, where they built a station consisting of a series of holding tanks positioned above 25 test tanks and filters divided between two levels. The researchers pumped sewage from a sewer that ran below the street into the holding tanks. They could then control the rate at which sewage ran into the test tanks on the upper level. After being subjected to treatment there, sewage ran into the lower level of tanks, where it underwent one or more additional experimental treatments. In this way, the researchers could test how sewage fared under different combinations of sequential treatments.

After a few years they noted some general trends. Four-foot-deep beds were better than six-foot-deep ones, but the improvement wasn’t enough to offset the smaller capacity and diminished filtration rate. The material filling the beds was less critical—coke, brick, and broken stone all worked. The size of the pieces was important, however; half-inch stone filtered much more effectively than coarser material.

Sewage treatment was an international field of study in the early 1900s, and many of the experiments performed at MIT involved fine-tuning techniques that had been developed elsewhere. For example, other groups had discovered that sewage could be reduced to an odorless liquid if it was left to trickle through a bed of coarse rocks, but this liquid still contained pathogenic bacteria. At the MIT station on Albany Street, researchers tested whether chlorine could kill these bacteria and render the liquid harmless. The experiment was a success, and the researchers estimated that 85 cents’ worth of chlorine could sterilize a million gallons of sewage. Today, chlorine is still part of the strategy at many wastewater facilities, including Boston’s Deer Island plant.

Hughes insisted on remaining anonymous, but rumors circulated about who was funding the station. In 1903, the philanthropist George Foster Peabody offered to pay for printing and distribution of 100,000 copies of an article about it, leading many to speculate that he was the donor. Behind the scenes, meanwhile, Hughes offered advice to the researchers through letters she wrote to Pritchett. Coauthor of the textbook Lessons on Practical Subjects, she believed strongly in the importance of educating the populace on essential topics and pushed the researchers to release pamphlets explaining their findings in plain language so that members of the state board of health, politicians, and the public could understand them. She had very little faith in the ability of the average Bostonian to comprehend the importance of sewage treatment otherwise. “Their slow and bewildered minds must be taught by the plainest language,” she wrote. “Unless a typhoid or diphtheria germ were the size of a lobster they would not believe in it.”

filter house diagram
MIT researchers tested sewage treatment options at its Albany Street station, which had a series of holding tanks positioned above 25 test tanks and filters divided between two levels.
MIT CONTRIBUTIONS FROM THE SANITARY RESEARCH LABORATORY AND SEWAGE EXPERIMENT STATION, VOLUME II

Hughes and Pritchett also discussed the business side of research and grappled with the slow, incremental process of scientific discovery. “We must admit quite frankly that they have not solved the problem which you had in mind, although I think they have made some important contributions toward it. Whether you care to have the work go on further is for you to say,” Pritchett wrote in 1905. Hughes was patient, and she kept sending money.

By 1909, the researchers had outgrown the Albany Street station, and Hughes donated money to erect a new one abutting the Calf Pasture Pumping Station in Dorchester, on what’s now the campus of the University of Massachusetts Boston. At this new location, the researchers could obtain sewage directly from an outflow—a more realistic scenario than using pumps to raise it from below the street. Here they began to move beyond studying how large cities could handle sewage, considering, for example, how rural communities lacking sewers could dispose of their waste. As effective sewage treatment systems became widespread, the MIT biology department shifted its focus toward other important research questions, like how to incorporate pasteurization into the burgeoning ice cream industry.

After Hughes’s death in January of 1917, Sedgwick wrote in a report to MIT’s president that many people would be surprised to learn that the donor was a woman. He went on to say, “We shall long cherish the memory of her alert, original, incisive, and powerful personality; of her determination to uphold whatsoever things are lovely and of good report; and her eagerness to put down all evil, to do away with filth, and to cleanse and purify the dirty places of this too often unclean world.”

School of Science presents 2023 Infinite Expansion Awards

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

Sarah Costello | School of Science
February 24, 2023

The MIT School of Science has announced seven postdocs and research scientists as recipients of the 2023 Infinite Expansion Award. Nominated by their peers and mentors, the awardees are recognized not only for their exceptional science, but for mentoring and advising junior colleagues, supporting educational programs, working with the MIT Postdoctoral Association, or contributing some other way to the Institute.

The 2023 Infinite Expansion award winners in the School of Science are:

  • Kyle Jenks, a postdoc in the Picower Institute for Learning and Memory, nominated by professor and Picower Institute investigator Mriganka Sur;
  • Matheus Victor, a postdoc in the Picower Institute, nominated by professor and Picower Institute director Li-Huei Tsai.

A monetary award is granted to recipients, and a celebratory reception will be held for the winners this spring with family, friends, nominators, and recipients of the Infinite Expansion Award.

Not so inactive X chromosome

Whitehead Institute Member David Page has spent his career understanding how the differences between X and Y contribute to these sex differences, but a recent project is taking his lab in a netbet online sports bettingnew direction: understanding how the differences between X chromosomes contribute to sex differences.

Greta Friar | Whitehead Institute
February 7, 2023

Nearly every cell in our body contains pairs of each of our chromosomes, and these pairs are identical in all but one case: that of our sex chromosomes. Males typically have one X and one Y sex chromosome, while females typically have two X chromosomes. In recent years, research has suggested that these different chromosomes can influence far more than sex determination. Gene expression from the sex chromosomes appears to contribute to sex differences in health and disease, which males and females experience in everything from the incidence of getting certain diseases, to the symptoms of diseases, to responses to drugs, and more. For example, women are more likely to develop autoimmune disorders, while men are more likely to develop heart conditions.

Whitehead Institute Member David Page has spent his career understanding how the differences between X and Y contribute to these sex differences, but a recent project is taking his lab in a netbet online sports bettingnew direction: understanding how the differences between X chromosomes contribute to sex differences. Although females’ pair of X chromosomes contain the same genes, they have different patterns of gene expression. New research from Page and postdoc Adrianna San Roman reveals just how different the two types of X chromosomes are. The findings, published in the journal Cell Genomics on February 8, show that one type of X chromosome, known as the inactive X chromosome, can modulate the gene expression of the other type of X chromosome, known as the active X chromosome. Their work indicates that inactive X chromosomes have underappreciated roles in gene regulation and, most likely, in sex differences in health and disease.

Difference rooted in history

Females’ two X chromosomes have different gene expression activity because of the sex chromosomes’ evolutionary history. The X and Y sex chromosomes evolved from a pair of identical non-sex chromosomes. Because of this ancestry, the sex chromosomes still contain genes that are important outside of regulating sex differences, such as genes that contribute to our immune system or regulate gene expression throughout the body. However, over time the Y chromosome shrank and lost most of its genes. Researchers think that in order to make up for the loss of necessary genes on the Y, expression of the corresponding genes on the X chromosome increased. This ensured that males still had the necessary levels of gene expression from their sex chromosomes, but now females, with two copies of X both working overtime, had levels of gene expression that were too high. To solve this problem, our bodies developed a process called X chromosome inactivation, by which the majority of genes on all but one copy of the X chromosome in each cell are silenced, or turned off. This means that everyone, male and female alike, has one copy of the X chromosome working at full strength–the active X chromosome. In males, the active X chromosome is paired with a Y chromosome, and in females, it is paired with a so-called inactive X chromosome, on which most of the genes are turned off.

In spite of the evolution of X chromosome inactivation, some percentage of genes on the inactive X chromosome are still expressed, such as genes that have an active counterpart on the Y chromosome. Previous research has indicated that about a quarter of the genes on the inactive X are, in fact, active, so researchers have long been aware that the chromosome is not completely silent. However, it’s still often painted as a passive copy playing backup for its more active partner. San Roman’s work shows that the inactive X chromosome’s gene expression is much more potent and complex than that.

A spectrum of sex chromosomes

In order to understand the inactive X chromosome’s contributions to gene expression, San Roman and colleagues in the Page lab collected blood and skin samples from people born with unusual combinations of sex chromosomes—everything from X0 (one X chromosome) to XXXXY. People with these different sets of chromosomes often have health issues; for example, X0 females have Turner syndrome, which can cause heart defects, hearing impairment, and more; and XXY males have Klinefelter syndrome, which can cause infertility, weak muscles, and more. Page and San Roman hope their research could provide useful insights into these health issues as well as into sex differences between XY males and XX females.

In people with more than one X chromosome, every X but one is an inactive X. The researchers graphed sex chromosome gene expression, measuring the change in expression level of each gene with the addition of each inactive X, for people with anything from zero to three inactive X chromosomes, as well as different numbers of Y chromosomes. They also looked at the relative contribution to overall expression from the active versus inactive X chromosomes. One might expect the graphs they made to be relatively straightforward: for genes that are turned off on the inactive X chromosome, the gene expression level would not change at all as the number of copies of the inactive X increased. For genes that are turned on, the gene expression level would double with two X chromosomes, triple with three X chromosomes, and so on. When the researchers looked at chromosomes other than X with extra copies—namely, Y and chromosome 21—this is essentially the pattern they observed. Gene expression from additional X chromosomes, however, was not so straightforward.

Each additional inactive X chromosome changes gene expression by the same amount. However, the researchers found a surprising diversity in expression levels across X chromosome genes. The presence of each additional inactive X might increase one gene’s expression by 20 percent and another’s by 70 percent. Then the results grew more surprising: for some genes, the addition of an inactive X decreased their expression. For some genes that are only expressed on the active X chromosome, and completely silent on the inactive X, additional inactive X chromosomes nonetheless changed their expression level.

These discrepancies led the researchers to a startling finding. The X chromosomes do not function independently of each other. Instead, the inactive X chromosome can modulate expression of genes on the active X chromosome. In other words, some genes on the inactive X chromosome regulate genes on the active X chromosome, dialing their expression up or down. Altogether, the researchers found that 38% of the X chromosome genes in the two cell types that they tested are affected by the presence of inactive X chromosomes, either because the genes are expressed on the inactive X, or because the inactive X regulates their expression on the active X, or through some combination of the two mechanisms.

These findings show that the inactive X plays a much more active role in gene expression and regulation than was previously appreciated. Rather than just playing second fiddle to the active X chromosome, the inactive X is sometimes harmonizing with and sometimes even conducting its partner.

Rethinking the role of the inactive X in health and disease

Page and San Roman hope that their findings will help refocus research into sex differences. Previous research into the mechanisms behind these differences has focused on the effects of having X versus Y chromosomes. Page and San Roman’s work show that researchers also need to consider how the presence (in females) or absence (in males) of an inactive X chromosome contributes to sex differences.

“Everybody on the planet carries one active X chromosome, so that first X chromosome really does not contribute, we think, to differences between males and females,” says Page, who is also a professor of biology at the Massachusetts Institute of Technology and Investigator with the Howard Hughes Medical Institute. “If we transition from saying that females are XX and males are XY, to saying that females are Xi [have an inactive X] and males are Y, that really focuses the question.”

Page lab researchers have already begun using their findings to identify X chromosome genes that are likely to be important for sex differences in health and disease. From their list of genes that change in expression based on the presence of an inactive X, the researchers narrowed in on a top ten list of genes that need to maintain a specific expression level or else there will be severe negative consequences. These genes are also likely to be responsible for causing the health issues associated with different atypical sex chromosome compositions, because changes in their expression level are most likely to have strong effects on cells.

“This is a new way of thinking about how the X chromosome is expressed and how it might be impacting our biology,” San Roman says. “This top ten list will be really interesting to consider in the future in terms of how the level of expression of these genes affects cells and tissues in very fundamental ways.”

Notes

Citation:

Adrianna K. San Roman, Alexander K. Godfrey, Helen Skaletsky, Daniel W. Bellott, Abigail F. Groff, Hannah L. Harris, Laura V. Blanton, Jennifer F. Hughes, Laura Brown, Sidaly Phou, Ashley Buscetta, Paul Kruszka, Nicole Banks, Amalia Dutra, Evgenia Pak, Patricia C. Lasutschinkow, Colleen Keen, Shanlee M. Davis, Nicole R. Tartaglia, Carole Samango-Sprouse, Maximilian Muenke, and David C. Page. (2023). The human inactive X chromosome modulates expression of the active X chromosome. Cell Genomics. https://doi.org/10.1016/j.xgen.2023.100259

Why lung cancer doesn’t respond well to immunotherapy

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

Anne Trafton | MIT News Office
February 2, 2023

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

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

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

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

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

Failure to attack

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

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

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

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

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

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

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

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

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

Microbial influence

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

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

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

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

Sparse, small, but diverse neural connections help make perception reliable, efficient

First detailed mapping and modeling of thalamus inputs onto visual cortex neurons show brain leverages “wisdom of the crowd” to process sensory information.

David Orenstein | Picower Institute for Learning and Memory
February 2, 2023

The brain’s cerebral cortex produces perception based on the sensory information it’s fed through a region called the thalamus.

“How the thalamus communicates with the cortex in a fundamental feature of how the brain interprets the world,” says Elly Nedivi, the William R. and Linda R. Young Professor in The Picower Institute for Learning and Memory at MIT. Despite the importance of thalamic input to the cortex, neuroscientists have struggled to understand how it works so well given the relative paucity of observed connections, or “synapses,” between the two regions.

To help close this knowledge gap, Nedivi assembled a collaboration within and beyond MIT to apply several innovative methods. In a new study described in Nature Neuroscience, the team reports that thalamic inputs into superficial layers of the cortex are not only rare, but also surprisingly weak, and quite diverse in their distribution patterns. Despite this, they are reliable and efficient representatives of information in the aggregate, and their diversity is what underlies these advantages.

Essentially, by meticulously mapping every thalamic synapse on 15 neurons in layer 2/3 of the visual cortex in mice and then modeling how that input affected each neuron’s processing of visual information, the team found that wide variations in the number and arrangement of thalamic synapses made them differentially sensitive to visual stimulus features. While individual neurons therefore couldn’t reliably interpret all aspects of the stimulus, a small population of them could together reliably and efficiently assemble the overall picture.

“It seems this heterogeneity is not a bug; it’s a feature that provides not only a cost benefit, but also confers flexibility and robustness to perturbation” says Nedivi, corresponding author of the study and a member of MIT’s faculty in the departments of Biology and Brain and Cognitive Sciences.

Aygul Balcioglu, the research scientist in Nedivi’s lab who led the work, adds that the research has created a way for neuroscientists to track all the many individual inputs a cell receives as that input is happening.

“Thousands of information inputs pour into a single brain cell. The brain cell then interprets all that information before it communicates its own response to the next brain cell,” Balcioglu says. “What is new, and we feel exciting, is we can now reliably describe the identity and the characteristics of those inputs, as different inputs and characteristics convey different information to a given brain cell. Our techniques give us the ability to describe in living animals where in the structure of the single cell what kind of information gets incorporated. This was not possible until now.”

“MAP”ping and modeling

Nedivi and Balcioglu’s team chose layer 2/3 of the cortex because this layer is where there is relatively high flexibility, or “plasticity,” even in the adult brain. Yet, thalamic innervation there has rarely been characterized. Moreover, Nedivi says, even though the model organism for the study was mice, those layers are the ones that have thickened the most over the course of evolution, and therefore play especially important roles in the human cortex.

Precisely mapping all the thalamic innervation onto entire neurons in living, perceiving mice is so daunting it’s never been done.

To get started, the team used a technique established in Nedivi’s lab that enables observing whole cortical neurons under a two-photon microscope using three different color tags in the same cell simultaneously, except in this case they used one of the colors to label thalamic inputs contacting the labeled cortical neurons. Wherever the color of those thalamic inputs overlapped with the color labeling excitatory synapses on the cortical neurons, that revealed the location of putative thalamic inputs onto the cortical neurons.

Two-photon microscopes offer deep looks into living tissues, but their resolution is not sufficient to confirm that the overlapping labels are indeed synaptic contacts. To confirm their first indications of thalamic inputs, the team turned to a technique called MAP invented in the Picower Institute lab of MIT chemical engineering Associate Professor Kwanghun Chung. MAP physically enlarges tissue in the lab, effectively increasing the resolution of standard microscopes. Rebecca Gillani, a postdoc in the Nedivi lab, with help from Taeyun Ku, a Chung Lab postdoc, was able to combine the new labeling and MAP to definitely resolve, count, map, and even measure the size of all thalamic-cortical synapses onto entire neurons.

The analysis revealed that the thalamic inputs were rather small (typically presumed to also be weak and maybe temporary), and accounted for between 2 and 10 percent of the excitatory synapses on individual visual cortex neurons. The variance in thalamic synapse numbers was not just at a cellular level, but also across different “dendrite” branches of individual cells, accounting for anywhere between zero and nearly half the synapses on a given branch.

“Wisdom of the crowd”

These facts presented Nedivi’s team with a conundrum. If the thalamic inputs were weak, sparse, and widely varying, not only across neurons but even across each neuron’s dendrites, then how good could they be for reliable information transfer?

To help solve the riddle, Nedivi turned to colleague Idan Segev, a professor at Hebrew University in Jerusalem specializing in computational neuroscience. Segev and his student Michael Doron used the Nedivi lab’s detailed anatomical measurements and physiological information from the Allen Brain Atlas to create a biophysically faithful model of the cortical neurons.

Segev’s model showed that when the cells were fed visual information (the simulated signals of watching a grating go past the eyes) their electrical responses varied based on how their thalamic input varied. Some cells perked up more than others in response to different aspects of the visual information, such as contrast or shape, but no single cell revealed much about the overall picture. But with about 20 cells together, the whole visual input could be decoded from their combined activity — a so-called “wisdom of the crowd.”

Notably, Segev compared the performance of cells with the weak, sparse, and varying input akin to what Nedivi’s lab measured, to the performance of a group of cells that all acted like the best single cell of the lot. Up to about 5,000 total synapses, the “best” cell group delivered more informative results, but after that level the small, weak, and diverse group actually performed better. In the race to represent the total visual input with at least 90 percent accuracy, the small, weak, and diverse group reached that level with about 6,700 synapses, while the “best” cell group needed more than 7,900.

“Thus heterogeneity imparts a cost reduction in terms of the number of synapses required for accurate readout of visual features,” the authors wrote.

Nedivi says the study raises tantalizing implications regarding how thalamic input into the cortex works. One, she says, is that given the small size of thalamic synapses they are likely to exhibit significant “plasticity.” Another is that the surprising benefit of diversity may be a general feature, not just a special case for visual input in layer 2/ 3. Further NetBet sportstudies, however, are needed to know for sure.

In addition to Nedivi, Balcioglu, Gillani, Ku, Chung, Segev and Doron, other authors are Kendyll Burnell and Alev Erisir.

The National Eye Institute of the National Institutes of Health, the Office of Naval Research, and the JPB Foundation funded the study.

New instrument lets MIT researchers combine previously disparate microscopy techniques

The first Live μ in the country will reveal fleeting sub-cellular events in high resolution

Saima Sidik
February 1, 2023

Inside cells, events can unfold quickly. Sub-cellular compartments constantly re-arrange while proteins move along structural fibers and membranes fuse and divide. By attaching fluorescent tags to sub-cellular structures, researchers can watch events unfold in real time using light microscopes. But to see the finest details of these processes, scientists need to shift from using light microscopy to using beams of electrons to generate even higher resolution images using a technique called electron microscopy. Using these techniques together is a powerful and rapidly growing strategy called correlative light electron microscopy (CLEM). In CLEM, light microscopy images are used to target regions of interest, and then the same sample is interrogated with electron microscopy to see the same areas at higher resolution.

The Peterson (1957) Nanotechnology Materials Core Facility in the Robert A. Swanson (1969) Biotechnology Center at the Koch Institute for Integrative Cancer Research at MIT recently acquired a high pressure freezer called the Live μ that will let researchers do just that. This instrument allows scientists to image the same biological sample using fluorescent light microscopy and electron microscopy in close succession. These two techniques are usually performed on separate samples, but with the Live μ, researchers will be able to identify fleeting sub-cellular events using light microscopy, then preserve cells and observe the same events in high resolution using electron microscopy — a combination that was not previously available to researchers at MIT. In fact, the Live μ, which is sold by the Paris-based company CryoCapCell, will be the first instrument of its kind in the country.

Although high-pressure freezers like the Live μ have been around for decades, integration with a light microscope is what makes the Live μ special. The instrument itself is a washing machine-sized freezing instrument, equipped with an arm to hold a biological sample under a nearby light microscope. When researchers observe an interesting biological event using the light microscope, they can quickly retract the arm and insert the sample into the Live μ’s inner chamber, exposing it to low temperature and high pressure and freezing it in less than two seconds. Cells must be preserved before they can be observed using an electron microscope, and by freezing samples faster than ice crystals can form, the Live μ creates pristine samples that accurately represent the state of cells before preservation. Superimposing pictures taken using the light microscope on top of images from an electron microscope allows researchers to use the fluorescent signals like a “treasure map,” says Abigail Lytton-Jean, the director of the Peterson Facility.

Exocytosis is a vital sub-cellular event that could be studied using the Live μ. In this cellular process, cells use bubble-like vesicles to ferry proteins from the internal compartments where they’re made to the cell’s surface, where they can sense the external environment, attach cells to one another, or carry information to other cells. Exocytosis is important for many aspects of biology, and a variety of scientists, from ecologists to cancer researchers to microbiologists, would benefit from a greater understanding of this process. With the Live μ, researchers may be able to use light microscopy to catch the vesicles that mediate exocytosis when they dock with the cell’s surface, then use electron microscopy to understand the details of this association.

Researchers creating artificial materials to replace human tissues could also benefit from the Live μ, Lytton-Jean says. These materials are thick and contain a lot of water, but the Live μ is capable of freezing them without generating ice crystals that change their structure. Using this instrument, scientists can examine the internal structure of these synthetic materials and assess their similarities to live tissue.

“People who want to use the Live μ are coming from all sorts of labs,” Lytton-Jean says.

The world of biology and electron microscopy is wildly exciting right now, she adds, thanks in part to instruments like this. “People who have worked with electron microscopes for decades have told me that this is the most exciting time they’ve ever lived in.”

The Live μ recently took its place in the back of the Peterson Facility, under a picture of the Eiffel Tower that Lytton-Jean brought back from Paris when she first went to test the Live μ at CryoCapCell’s headquarters years ago. The Live μ is only the latest addition to a vast suite of instrumentation focused on cutting-edge cryo-electron microscopy and CLEM workflows, expanding the facility’s unusually large portfolio of workflows.

“There aren’t many places in the country that can do all of the different workflows we offer, and all in one place,” said Lytton-Jean. “High pressure freezing is the first step in the preservation process, so having this instrument in our lab will further enable many new workflows with our existing instrumentation. Although these workflows are challenging and sophisticated, our team of dedicated scientists are familiar with conducting this work.”