The Pew Charitable Trusts has selected Whitehead Institute Member Ankur Jain to be a 2022 Pew Scholar in the Biomedical Sciences. The Pew program provides funding to young investigators of outstanding promise who work in areas of science relevant to the advancement of human health.
Jain, who joined the Whitehead Institute faculty in 2019, is one of 22 scientists selected to receive this year’s honor, chosen from among 197 nominations submitted by leading U.S. academic and research institutions. “I am grateful to the Pew Trusts for funding our work, and thrilled to be a part of the Pew community,” says Jain, who is also an assistant professor of biology and the Thomas D. and Virginia W. Cabot Career Development Professor at Massachusetts Institute of Technology.
The Pew award will provide research support for the next four years, enabling him to study the role of evolutionarily ancient metabolites called polyamines, which are essential for cell growth and survival.
“Polyamine concentrations within cells are carefully regulated, and disruptions in polyamine production are known to be associated with conditions ranging from cancer and aging to neurological disorders such as Parkinson’s disease” Jain explains. “But, despite being studied for more than a century, the specific role polyamines play in both healthy and diseased cells remains obscure. This is due, in part, to a lack of technologies effective in probing polyamines.”
Jain’s lab will harness the cell’s own polyamine detection machinery to build new tools to inspect polyamines. Those tools will allow his team to measure and track polyamines in individual cells, study how cells maintain their polyamine content, and explore how changing polyamine levels affect cellular functions. “Ultimately, this work could provide the basis for novel strategies for treating cancer or promoting healthy aging,” Jain observes.
Previously, Jain received a 2017 NIH Pathway to Independence Award and was named a 2019 Packard Fellow for Science and Engineering. He is the third current Whitehead Member to be named a Pew Scholar, following in the steps of Mary Gehring (2010) and Jing-Ke Weng (2014). Former Whitehead Fellow Fernando Camargo, now professor of stem cell and regenerative biology at Harvard University, also became a Pew Scholar in 2010.
Launched in 1985, the Pew Scholars in the Biomedical Sciences program supports top U.S. scientists at the assistant professor level and has, since inception, provided nearly 1000 young investigators with funding for research projects that, though seemingly risky, have the potential to benefit human health. Pew Scholars are selected by a national advisory committee of eminent scientists, who evaluate candidates on the basis of proven creativity.
More information about Jain’s selection, the 2022 class of Pew Scholars, and the Pew Scholars program is available here.
Tenth anniversary of the program rewards three innovative projects.
Aaron Braddock | Office of the Provost
June 13, 2022
MIT Provost Cynthia Barnhart has announced three Professor Amar G. Bose Research Grants to support bold research projects across diverse areas of study including biology, engineering, and the humanities.
The three grants honor the visionary and bold thinking in the winning proposals of the following nine researchers: John J. and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science Sangeeta Bhatia; Carl Richard Soderberg Professor of Power Engineering Gang Chen; professor of biology Jianzhu Chen; associate professor of biology Michael Hemann; professor of anthropology and Margaret MacVicar Faculty Fellow Graham Jones; Latham Family Career Development Professor Sebastian Lourido; assistant professor of computer science Arvind Satayanaryan; Howard Hughes Medical Institute Professor Graham Walker; and David H. Koch Professor in Science Michael Yaffe;
“Innovation is born when a unique vision drives daring researchers to take on risky and adventurous projects, a notion that Amar Bose understood well,” says Barnhart. “With support and recognition from this program, these nine talented and forward-thinking faculty have the freedom to explore and study areas not typically backed by conventional funding sources.”
The program was named for the visionary founder of the Bose Corporation and MIT alumnus, Amar G. Bose ’51, SM ’52, ScD ’56. After gaining admission to MIT, Bose became a top math student and a Fulbright Scholarship recipient. He spent 46 years as a professor at MIT, led innovations in sound design, and founded the Bose Corporation in 1964. MIT launched the program a decade ago.
“The legendary explorations and innovations of Professor Amar Bose inspire the Bose Research Grant program,” says President Emerita and Professor Susan Hockfield. “The grants support projects that reach beyond the horizon and so would not receive funding from standard sources. Since its inception, the program has supported 49 MIT faculty to pursue their most compelling ideas and, in doing so, to join the Bose Fellows community of like-minded adventurers.”
The program, which has honored 35 projects to date, is a tribute to the legacy of Bose, who believed that passion and curiosity drive innovation. With that spirit in mind, the projects typically supported by the program are original, cross-disciplinary, and high-risk. The program has encouraged collaborative projects, as reflected in this year’s winners.
This year’s recipients are:
Gang Chen of the Department of Mechanical Engineering. With his proposal, “Photomolecular Effect and Clouds Thinning,” Chen will advance research into his discovery of a way in which photons can be absorbed by cleaving off water clusters from the water-air surface, significantly impacting technologies related to energy and water and climate models.
Graham Jones of the Anthropology Section and Arvind Satayanaryan of the Department of Electrical Engineering and Computer Science (EECS). Their “Magical Data Visualization” proposal uses performance magic to create new visualizations that are responsive to the users’ intent, potentially impacting how misinformation spreads.
Graham Walker, Michael Hemann, Michael Yaffe, Sebastian Lourido, Jianzhu Chen of the Department of Biology and Sangeeta Bhatia of EECS and the Institute of Medical Engineering and Science. Their proposal, “Addressing Critical Human Health Problems with a Special Heme-binding Peptide,” uses a recently discovered plant peptide that binds and sequesters a molecule critical in hemoglobin oxygen binding in a new way, which has significant implications on many health issues.
“This year, more than a dozen faculty members from departments across all five schools and the college participated in the evaluations,” says Chancellor for Academic Advancement Eric Grimson. NetBet sport“Their diverse perspectives were critical in assessing what was a very strong field of interesting proposals. We are grateful for their generous commitment of time and energy and the thoughtfulness with which they approached the selection process.”
The program explores out-of-the-box ideas that would face difficulty in acquiring funding through traditional means but have the potential for strong impacts on the scientific community. Any member of the faculty in any discipline in MIT’s five schools and college is eligible to submit a proposal for a Bose Research Grant, which provides funding over three years.
Jonathan Weissman and collaborators used their single-cell sequencing tool Perturb-seq on every expressed gene in the human genome, linking each to its job in the cell.
Eva Frederick | Whitehead Institute
June 9, 2022
The Human Genome Project was an ambitious initiative to sequence every piece of human DNA. The project drew together collaborators from research institutions around the world, including MIT’s Whitehead Institute for Biomedical Research, and was finally completed in 2003. Now, over two decades later, MIT Professor Jonathan Weissman and colleagues have gone beyond the sequence to present the first comprehensive functional map of genes that are expressed in human cells. The data from this project, published online June 9 in Cell, ties each gene to its job in the cell, and is the culmination of years of collaboration on the single-cell sequencing method Perturb-seq.
The data are available for other scientists to use. “It’s a big resource in the way the human genome is a big resource, in that you can go in and do discovery-based research,” says Weissman, who is also a member of the Whitehead Institute and an investigator with the Howard Hughes Medical Institute. “Rather than defining ahead of time what biology you’re going to be looking at, you have this map of the genotype-phenotype relationships and you can go in and screen the database without having to do any experiments.”
The screen allowed the researchers to delve into diverse biological questions. They used it to explore the cellular effects of genes with unknown functions, to investigate the response of mitochondria to stress, and to screen for genes that cause chromosomes to be lost or gained, a phenotype that has proved difficult to study in the past. “I think this dataset is going to enable all sorts of analyses that we haven’t even thought up yet by people who come from other parts of biology, and suddenly they just have this available to draw on,” says former Weissman Lab postdoc Tom Norman, a co-senior author of the paper.
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The project takes advantage of the Perturb-seq approach that makes it possible to follow the impact of turning on or off genes with unprecedented depth. This method was first published in 2016 by a group of researchers including Weissman and fellow MIT professor Aviv Regev, but could only be used on small sets of genes and at great expense.
The massive Perturb-seq map was made possible by foundational work from Joseph Replogle, an MD-PhD student in Weissman’s lab and co-first author of the present paper. Replogle, in collaboration with Norman, who now leads a lab at Memorial Sloan Kettering Cancer Center; Britt Adamson, an assistant professor in the Department of Molecular Biology at Princeton University; and a group at 10x Genomics, set out to create a new version of Perturb-seq that could be scaled up. The researchers published a proof-of-concept paper in Nature Biotechnology in 2020.
The Perturb-seq method uses CRISPR-Cas9 genome editing to introduce genetic changes into cells, and then uses single-cell RNA sequencing to capture information about the RNAs that are expressed resulting from a given genetic change. Because RNAs control all aspects of how cells behave, this method can help decode the many cellular effects of genetic changes.
Since their initial proof-of-concept paper, Weissman, Regev, and others have used this sequencing method on smaller scales. For example, the researchers used Perturb-seq in 2021 to explore how human and viral genes interact over the course of an infection with HCMV, a common herpesvirus.
In the new study, Replogle and collaborators including Reuben Saunders, a graduate student in Weissman’s lab and co-first author of the paper, scaled up the method to the entire genome. Using human blood cancer cell lines as well noncancerous cells derived from the retina, he performed Perturb-seq across more than 2.5 million cells, and used the data to build a comprehensive map tying genotypes to phenotypes.
Delving into the data
Upon completing the screen, the researchers decided to put their new dataset to use and examine a few biological questions. “The advantage of Perturb-seq is it lets you get a big dataset in an unbiased way,” says Tom Norman. “No one knows entirely what the limits are of what you can get out of that kind of dataset. Now, the question is, what do you actually do with it?”
The first, most obvious application was to look into genes with unknown functions. Because the screen also read out phenotypes of many known genes, the researchers could use the data to compare unknown genes to known ones and look for similar transcriptional outcomes, which could suggest the gene products worked together as part of a larger complex.
The mutation of one gene called C7orf26 in particular stood out. Researchers noticed that genes whose removal led to a similar phenotype were part of a protein complex called Integrator that played a role in creating small nuclear RNAs. The Integrator complex is made up of many smaller subunits — previous studies had suggested 14 individual proteins — and the researchers were able to confirm that C7orf26 made up a 15th component of the complex.
They also discovered that the 15 subunits worked together in smaller modules to perform specific functions within the Integrator complex. “Absent this thousand-foot-high view of the situation, it was not so clear that these different modules were so functionally distinct,” says Saunders.
Another perk of Perturb-seq is that because the assay focuses on single cells, the researchers could use the data to look at more complex phenotypes that become muddied when they are studied together with data from other cells. “We often take all the cells where ‘gene X’ is knocked down and average them together to look at how they changed,” Weissman says. “But sometimes when you knock down a gene, different cells that are losing that same gene behave differently, and that behavior may be missed by the average.”
The researchers found that a subset of genes whose removal led to different outcomes from cell to cell were responsible for chromosome segregation. Their removal was causing cells to lose a chromosome or pick up an extra one, a condition known as aneuploidy. “You couldn’t predict what the transcriptional response to losing this gene was because it depended on the secondary effect of what chromosome you gained or lost,” Weissman says. “We realized we could then turn this around and create this composite phenotype looking for signatures of chromosomes being gained and lost. In this way, we’ve done the first genome-wide screen for factors that are required for the correct segregation of DNA.”
“I think the aneuploidy study is the most interesting application of this data so far,” Norman says. “It captures a phenotype that you can only get using a single-cell readout. You can’t go after it any other way.”
The researchers also used their dataset to study how mitochondria responded to stress. Mitochondria, which evolved from free-living bacteria, carry 13 genes in their genomes. Within the nuclear DNA, around 1,000 genes are somehow related to mitochondrial function. “People have been interested for a long time in how nuclear and mitochondrial DNA are coordinated and regulated in different cellular conditions, especially when a cell is stressed,” Replogle says.
The researchers found that when they perturbed different mitochondria-related genes, the nuclear genome responded similarly to many different genetic changes. However, the mitochondrial genome responses were much more variable.
“There’s still an open question of why mitochondria still have their own DNA,” said Replogle. “A big-picture takeaway from our work is that one benefit of having a separate mitochondrial genome might be having localized or very specific genetic regulation in response to different stressors.”
“If you have one mitochondria that’s broken, and another one that is broken in a different way, those mitochondria could be responding differentially,” Weissman says.
In the future, the researchers hope to use Perturb-seq on different types of cells besides the cancer cell line they started in. They also hope to continue to explore their map of gene functions, and hope others will do the same. “This really is the culmination of many years of work by the authors and other collaborators, and I’m really pleased to see it continue to succeed and expand,” says Norman.
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Twenty winning projects will link industry member priorities with research groups across campus to develop scalable climate solutions.
Molly Chase | Climate and Sustainability Consortium
May 23, 2022
The MIT Climate and Sustainability Consortium (MCSC) has awarded 20 projects a total of $5 million over two years in its first-ever 2022 MCSC Seed Awards program. The winning projects are led by principal investigators across all five of MIT’s schools.
The goal of the MCSC Seed Awards is to engage MIT researchers and link the economy-wide work of the consortium to ongoing and emerging climate and sustainability efforts across campus. The program offers further opportunity to build networks among the awarded projects to deepen the impact of each and ensure the total is greater than the sum of its parts.
For example, to drive progress under the awards category Circularity and Materials, the MCSC can facilitate connections between the technologists at MIT who are developing recovery approaches for metals, plastics, and fiber; the urban planners who are uncovering barriers to reuse; and the engineers, who will look for efficiency opportunities in reverse supply chains.
“The MCSC Seed Awards are designed to complement actions previously outlined in Fast Forward: MIT’s Climate Action Plan for the Decade and, more specifically, the Climate Grand Challenges,” says Anantha P. Chandrakasan, dean of the MIT School of Engineering, Vannevar Bush Professor of Electrical Engineering and Computer Science, and chair of the MIT Climate and Sustainability Consortium. “In collaboration with seed award recipients and MCSC industry members, we are eager to engage in interdisciplinary exploration and propel urgent advancements in climate and sustainability.”
By supporting MIT researchers with expertise in economics, infrastructure, community risk assessment, mobility, and alternative fuels, the MCSC will accelerate implementation of cross-disciplinary solutions in the awards category Decarbonized and Resilient Value Chains. Enhancing Natural Carbon Sinks and building connections to local communities will require associations across experts in ecosystem change, biodiversity, improved agricultural practice and engagement with farmers, all of which the consortium can begin to foster through the seed awards.
“Funding opportunities across campus has been a top priority since launching the MCSC,” says Jeremy Gregory, MCSC executive director. “It is our honor to support innovative teams of MIT researchers through the inaugural 2022 MCSC Seed Awards program.”
The winning projects are tightly aligned with the MCSC’s areas of focus, which were derived from a year of highly engaged collaborations with MCSC member companies. The projects apply across the member’s climate and sustainability goals.
The MCSC’s 16 member companies span many industries, and since early 2021, have met with members of the MIT community to define focused problem statements for industry-specific challenges, identify meaningful partnerships and collaborations, and develop clear and scalable priorities. Outcomes from these collaborations laid the foundation for the focus areas, which have shaped the work of the MCSC. Specifically, the MCSC Industry Advisory Board engaged with MIT on key strategic directions, and played a critical role in the MCSC’s series of interactive events. These included virtual workshops hosted last summer, each on a specific topic that allowed companies to work with MIT and each other to align key assumptions, identify blind spots in corporate goal-setting, and leverage synergies between members, across industries. The work continued in follow-up sessions and an annual symposium.
“We are excited to see how the seed award efforts will help our member companies reach or even exceed their ambitious climate targets, find new cross-sector links among each other, seek opportunities to lead, and ripple key lessons within their industry, while also deepening the Institute’s strong foundation in climate and sustainability research,” says Elsa Olivetti, the Esther and Harold E. Edgerton Associate Professor in Materials Science and Engineering and MCSC co-director.
As the seed projects take shape, the MCSC will provide ongoing opportunities for awardees to engage with the Industry Advisory Board and technical teams from the MCSC member companies to learn more about the potential for linking efforts to support and accelerate their climate and sustainability goals. Awardees will also have the chance to engage with other members of the MCSC community, including its interdisciplinary Faculty Steering Committee.
“One of our mantras in the MCSC is to ‘amplify and extend’ existing efforts across campus; we’re always looking for ways to connect the collaborative industry relationships we’re building and the work we’re doing with other efforts on campus,” notes Jeffrey Grossman, the Morton and Claire Goulder and Family Professor in Environmental Systems, head of the Department of Materials Science and Engineering, and MCSC co-director. “We feel the urgency as well as the potential, and we don’t want to miss opportunities to do more and go faster.”
The MCSC Seed Awards complement the Climate Grand Challenges, a new initiative to mobilize the entire MIT research community around developing the bold, interdisciplinary solutions needed to address difficult, unsolved climate problems. The 27 finalist teams addressed four broad research themes, which align with the MCSC’s focus areas. From these finalist teams, five flagship projects were announced in April 2022.
The parallels between MCSC’s focus areas and the Climate Grand Challenges themes underscore an important connection between the shared long-term research interests of industry and academia. The challenges that some of the world’s largest and most influential companies have identified are complementary to MIT’s ongoing research and innovation — highlighting the tremendous opportunity to develop breakthroughs and scalable solutions quickly and effectively. Special Presidential Envoy for Climate John Kerry underscored the importance of developing these scalable solutions, including critical new technology, during a conversation with MIT President L. Rafael Reif at MIT’s first Climate Grand Challenges showcase event last month.
Both the MCSC Seed Awards and the Climate Grand Challenges are part of MIT’s larger commitment and initiative to combat climate change. Underscored in “Fast Forward: MIT’s Climate Action Plan for the Decade,” which the Institute published in May 2021.
The project titles and research leads for each of the 20 awardees listed below are categorized by MCSC focus area.
Decarbonized and resilient value chains
“Collaborative community mapping toolkit for resilience planning,” led by Miho Mazereeuw, associate professor of architecture and urbanism in the Department of Architecture and director of the Urban Risk Lab (a research lead on Climate Grand Challenges flagship project) and Nicholas de Monchaux, professor and department head in the Department of Architecture
“CP4All: Fast and local climate projections with scientific machine learning — towards accessibility for all of humanity,” led by Chris Hill, principal research scientist in the Department of Earth, Atmospheric and Planetary Sciences and Dava Newman, director of the MIT Media Lab and the Apollo Program Professor in the Department of Aeronautics and Astronautics
“Emissions reductions and productivity in U.S. manufacturing,” led by Mert Demirer, assistant professor of applied economics at the MIT Sloan School of Management and Jing Li, assistant professor and William Barton Rogers Career Development Chair of Energy Economics in the MIT Sloan School of Management
“Logistics electrification through scalable and inter-operable charging infrastructure: operations, planning, and policy,” led by Alex Jacquillat, the 1942 Career Development Professor and assistant professor of operations research and statistics in the MIT Sloan School of Management
“Powertrain and system design for LOHC-powered long-haul trucking,” led by William Green, the Hoyt Hottel Professor in Chemical Engineering in the Department of Chemical Engineering and postdoctoral officer, and Wai K. Cheng, professor in the Department of Mechanical Engineering and director of the Sloan Automotive Laboratory
“Sustainable Separation and Purification of Biochemicals and Biofuels using Membranes,” led by John Lienhard, the Abdul Latif Jameel netbet sports betting appProfessor of Water in the Department of Mechanical Engineering, director of the Abdul Latif Jameel Water and Food Systems Lab, and director of the Rohsenow Kendall Heat Transfer Laboratory; and Nicolas Hadjiconstantinou, professor in the Department of Mechanical Engineering, co-director of the Center for Computational Science and Engineering, associate director of the Center for Exascale Simulation of Materials in Extreme Environments, and graduate officer
“Toolkit for assessing the vulnerability of industry infrastructure siting to climate change,” led by Michael Howland, assistant professor in the Department of Civil and Environmental Engineering
Circularity and Materials
“Colorimetric Sulfidation for Aluminum Recycling,” led by Antoine Allanore, associate professor of metallurgy in the Department of Materials Science and Engineering
“Double Loop Circularity in Materials Design Demonstrated on Polyurethanes,” led by Brad Olsen, the Alexander and I. Michael Kasser (1960) Professor and graduate admissions co-chair in the Department of Chemical Engineering, and Kristala Prather, the Arthur Dehon Little Professor and department executive officer in the Department of Chemical Engineering
“Engineering of a microbial consortium to degrade and valorize plastic waste,” led by Otto Cordero, associate professor in the Department of Civil and Environmental Engineering, and Desiree Plata, the Gilbert W. Winslow (1937) Career Development Professor in Civil Engineering and associate professor in the Department of Civil and Environmental Engineering
“Fruit-peel-inspired, biodegradable packaging platform with multifunctional barrier properties,” led by Kripa Varanasi, professor in the Department of Mechanical Engineering
“High Throughput Screening of Sustainable Polyesters for Fibers,” led by Gregory Rutledge, the Lammot du Pont Professor in the Department of Chemical Engineering, and Brad Olsen, Alexander and I. Michael Kasser (1960) Professor and graduate admissions co-chair in the Department of Chemical Engineering
“Short-term and long-term efficiency gains in reverse supply chains,” led by Yossi Sheffi, the Elisha Gray II Professor of Engineering Systems, professor in the Department of Civil and Environmental Engineering, and director of the Center for Transportation and Logistics
The costs and benefits of circularity in building construction, led by Siqi Zheng, the STL Champion Professor of Urban and Real Estate Sustainability at the MIT Center for Real Estate and Department of Urban Studies and Planning, faculty director of the MIT Center for Real Estate, and faculty director for the MIT Sustainable Urbanization Lab; and Randolph Kirchain, principal research scientist and co-director of MIT Concrete Sustainability Hub
Natural carbon sinks
“Carbon sequestration through sustainable practices by smallholder farmers,” led by Joann de Zegher, the Maurice F. Strong Career Development Professor and assistant professor of operations management in the MIT Sloan School of Management, and Karen Zheng the George M. Bunker Professor and associate professor of operations management in the MIT Sloan School of Management
“Coatings to protect and enhance diverse microbes for improved soil health and crop yields,” led by Ariel Furst, the Raymond A. (1921) And Helen E. St. Laurent Career Development Professor of Chemical Engineering in the Department of Chemical Engineering, and Mary Gehring, associate professor of biology in the Department of Biology, core member of the Whitehead Institute for Biomedical Research, and graduate officer
“ECO-LENS: Mainstreaming biodiversity data through AI,” led by John Fernández, professor of building technology in the Department of Architecture and director of MIT Environmental Solutions Initiative
“Growing season length, productivity, and carbon balance of global ecosystems under climate change,” led by Charles Harvey, professor in the Department of Civil and Environmental Engineering, and César Terrer, assistant professor in the Department of Civil and Environmental Engineering
Social dimensions and adaptation
“Anthro-engineering decarbonization at the million-person scale,” led by Manduhai Buyandelger, professor in the Anthropology Section, and Michael Short, the Class of ’42 Associate Professor of Nuclear Science and Engineering in the Department of Nuclear Science and Engineering
“Sustainable solutions for climate change adaptation: weaving traditional ecological knowledge and STEAM,” led by Janelle Knox-Hayes, the Lister Brothers Associate Professor of Economic Geography and Planning and head of the Environmental Policy and Planning Group in the Department of Urban Studies and Planning, and Miho Mazereeuw, associate professor of architecture and urbanism in the Department of Architecture and director of the Urban Risk Lab (a research lead on a Climate Grand Challenges flagship project)
In a whirlwind team project, undergraduates Aniket Dehadrai SB ’22 and Brindha Rathinasabapathi SB ’24 of the Boyer lab pioneered a new method to study how hearts are built.
Celina Zhao
May 23, 2022
Can’t miss a beat
The lab was bustling with activity, with everyone working together on a team project comprised of many moving parts. Once one person finished a step of the experiment, it was whisked off to the next person. There was no time to lose.
During MIT’s Independent Activities Period (IAP) in January of 2022, several members of the Boyer Lab were hard at work — among them, Aniket Dehadrai, a junior studying Course 5-7 (Chemistry and Biology), and Brindha Rathinasabapathi, a sophomore studying Course 7 (Biology). Fueled with coffee every morning from the lab’s handy Keurig, the team was on a time crunch.
Working alongside Dehadrai and Rathinasabapathi were research scientist Vera Koledova, lab manager Kirsten Schneider, and fellow undergraduate researcher Caroline Zhang. They had a hard deadline at the end of the month to finish the project: studying how the absence of a certain protein affects the growth of cardiomyocytes, the cells responsible for pumping blood around the heart.
The Boyer lab — headed by Professor Laurie Boyer, the “Queen of Hearts” — specializes in heart cells. The lab is particularly interested in one intriguing question: Is it possible to heal the heart? Injuries like heart attacks often cause permanent damage that can eventually lead to heart failure. Scientists have found that at birth, injured heart cells are able to repair or replace themselves after such an event. However, that ability shuts off just a few days post-birth. Afterwards, heart cells, once damaged, are unfixable.
But what if adult cardiomyocytes could regain the ability to repair themselves, and thus repair trauma in heart tissue? The Boyer lab is intrigued by this possibility. But in order to answer that question, they must start from ground zero: learning how cardiomyocytes themselves develop.
The operation
Dehadrai, Rathinasabapathi, and the rest of the team were studying one part of that puzzle — the role histones play in cardiomyocyte growth. Histones are proteins that act as spools for DNA to wind around. DNA is extremely long, so histones help fit all this genetic information into the tiny space of a nucleus.
There are many types of histones (called “variants”), each of which has a unique effect on how DNA is wrapped. The tighter the DNA is packed, the more difficult it is for proteins to access the DNA — all of which affects how genes are expressed. As a result, each variant has a unique effect on how certain genes are regulated.
For the IAP project, the Boyer lab’s team focused on one histone variant called H2AZ.1. Prior studies have shown that H2AZ.1 is essential in most organisms, particularly when it comes to gene expression in stem cells. Stem cells are cells that essentially begin as blank slates, with the ability to form the many different cell types in the body. But through a differentiation process, they develop specific identities: skin, brain, or heart, to name a few.
By the end of the four weeks, the team planned to create and streamline a completely new process to “knock out,” or entirely remove, H2AZ.1 by degrading it during cardiomyocyte differentiation — the process where stem cells become specialized heart cells. Building this procedure to remove H2AZ.1 could later help identify what role H2AZ.1 plays in cardiomyocyte differentiation, a key step in both heart development and regeneration.
The histone variant H2A.Z.1 (red) is located in the nucleus (blue) of cardiac muscle cells. Actin, a component of the sarcomere, is shown in green. The striated structure of the muscle cells gives them strength to beat throughout our entire lives. Credit: Boyer lab
To begin creating the knockout procedure, the team started by culturing stem cells from a cell line specifically developed by the Boyer lab to study the H2AZ.1 histone. The goal was to see if removing H2AZ.1 would have a visible effect on how stem cells eventually become mature cardiomyocytes.
The amount of careful planning and execution to do in just one month — simply running through one full differentiation cycle took 15 days at a time — meant working together as a team was critical. “There was one late night with all five people in the lab, doing this giant experiment as well as we could without mixing up the different variables in play,” Rathinasabapathi netbet sports betting appsays. “It was really critical for us to look over each other’s shoulders and double check each other.”
In all, the team tested out 10 different variations of a method to optimize the experimental procedure. Despite the time crunch, they succeeded in pioneering a procedure to efficiently remove H2AZ.1 during cardiac differentiation. It turns out that H2AZ.1 does, in fact, have a functional impact on heart cells.
Without H2AZ.1, the beating rate of mature cardiomyocytes was notably different, changing from rhythmic to arrhythmic. The research team also found varying levels of maturity in the cells, suggesting that the progression through the differentiation process was also changed.
All of this suggests that H2AZ.1 has a significant influence in gene regulation, which they plan to continue studying in greater detail in the future.
“We’re breaking new ground,” Dehadrai says. “And importantly, it’s a great framework for future work in this field.”
With the procedure the team developed, the lab is now able to ask and answer more questions. For one, they can zoom in on certain parts of cardiomyocyte differentiation to see when H2AZ.1 has the greatest impact on gene expression. They can also use this procedure as a model to study how other histone variants affect heart cell growth. Ultimately, they can begin piecing together how histones, their effect on gene regulation, and cardiomyocyte development unite to build the heart.
“The better we can understand how heart cell development works, the better we can understand heart development, injury, and response — all of which have a lot of different implications in the medical field,” Rathinasabapathi says.
Following their hearts
The two credit the cohesiveness of the team as a big part of their success. “Brindha is really responsible, helpful, and willing to put in the hours,” Dehadrai says . “You can’t take stuff like that for granted.”
“Ani is just as dependable, and I’ve learned a lot from him as a senior with a lot of experience in the lab,” Rathinasabapathi says.
Another strength of the team was their ability to draw upon many different academic areas: a hallmark of the Boyer lab, which is known for its interdisciplinary approach to heart research. Members come from all sorts of backgrounds: biology, chemistry, biological engineering, mechanical engineering, and more. Research in the lab also spans a wide expanse, from uncovering the secrets of heart regeneration to building better microscopy techniques to study the heart. In fact, that was one of the reasons why Dehadrai initially chose to join the lab. “Here, there’s people who pretty much know how to do everything,” he says.
Although the IAP project has concluded, both Dehadrai and Rathinasabapathi are committed to continuing their passion for medical research. Dehadrai, who is graduating in the spring, is planning to take a gap year to work on clinical research projects before applying to medical school.
Rathinasabapathi, on the other hand, still has two years at MIT. She plans to stay in the Boyer Lab and is eager to take more advanced courses in the Department of Biology. “I’m impatient — I wish I already had the solid foundation to attack the research at different angles and come up with more cool new things,” she says. “There’s just so much more that I want to know.”
Greta Friar | Whitehead Institute
May 18, 2022
When animals experience a large injury, such as the loss of a limb, the body immediately begins a wound healing response that includes sealing the wound site and repairing local damage. In many animals, including humans, when the local wound site is taken care of, this response ends. However, in some animals, the initial wound response soon transitions into another stage of healing: regeneration, regrowing the parts that were lost.
Whitehead Institute Member Peter Reddien, also a professor of biology at MIT and a Howard Hughes Medical Investigator (HHMI), has long studied a flatworm known as the planarian (Schmidtea mediterranea), capable of regrowing any part of its body, to understand the mechanisms underlying regeneration. New research from staff scientist M. Lucila Scimone, graduate students Jennifer Cloutier and Chloe Maybrun, and Reddien identifies a previously undescribed gene, equinox, as playing a key role in initiating the transition from the initial wound healing stage into the regeneration stage in planarians. The work, published in Nature Communications on May 18, also reveals an important role for the wound epidermis, the skin that grows to cover a wound site, in initiating regeneration. Discovering what enables animals like planarians to regrow lost body parts can inform the field of regenerative medicine, which seeks to understand the limits of wound healing in humans and to improve our capacity for recovery and regeneration.
“The more we understand about the genes and mechanisms that play key roles in regeneration in animals that are capable of it, the better we may understand why humans lack that ability and, perhaps, the feasibility of future approaches to improve human wound healing,” says co-first author Scimone.
The case of the mystery gene
When the researchers began this project, they had no idea that it would lead them to identify a new gene that was crucial for regeneration. They originally set out to learn more about bmp4, a gene they had previously studied. BMP signaling, which includes bmp4, is involved in dorsal-ventral patterning, or the formation of the body around an axis between its top (dorsal) and bottom (ventral) sides. Previously, Reddien had found that bmp4 was necessary for regeneration after injuries to an animal’s side. Using new technologies that had not been around when they first studied the gene, the researchers now found that planarians without bmp4 failed to regenerate after large injuries anywhere on the body. This suggested a much more fundamental role for bmp4 in regeneration than the researchers expected, given that its main function relates to only one body axis. The researchers hypothesized that along with its role in dorsal-ventral patterning, bmp4 might help to activate an unknown gene that played some important, as yet unidentified role in regeneration. Bmp4 would therefore be necessary for regeneration because of its connection to this mystery gene.
The researchers started looking at genes regulated by bmp4 and found a promising candidate. They learned that bmp4 was needed to activate their mystery gene during the initial wound healing response, and that the mystery gene was crucial for wound healing to progress into regeneration after large injuries. When the gene was not activated, the steps that usually follow the initial wound healing response to prepare the body for regeneration would not occur. The wound would heal but the missing parts would never regrow, much like what would happen in a human. The researchers named the mystery gene equinox in honor of its appearance during a key transition period to move the body towards renewal.
“We know of a few genes that, when they are inactivated, the hallmarks of regeneration do not occur,” says co-first author Cloutier. “When equinox is not activated, we see an even more powerful inhibition of regeneration at an early phase. It appears to be required early on to allow for the other steps to proceed.”
Skin gets a starring role
The researchers found that equinox is expressed, or active in, wound epidermis, a skin tissue that is integral to regeneration after large injuries in a number of animals and yet had not been known to play a role in the signaling that initiates regeneration in planarians. After an injury, the wound epidermis covers and protects the wound site. As animals begin regeneration, the wound epidermis facilitates the formation of an outgrowth of cells called a blastema, in which the body produces the cell types it needs to replace the parts lost in the injury. Correspondingly, the researchers found that equinox is needed for regeneration in any injury that requires a blastema—essentially any large external injury where the replacement tissues grow out from the body.
Previously, the Reddien lab had found key genes required for regeneration expressed largely in muscle. Muscle in planarians maintains an active blueprint of the body, a network of positional genes that lets cells and tissues know where they are supposed to be. After an injury requiring regeneration, these positional genes rescale their body map near the wound site and guide new cells in building replacement tissues in the correct places. However, if equinox is not expressed, then the muscle tissue does not rescale its map. The body also fails to ramp up production of planarian stem cells or to begin differentiating stem cells into the cell types that were lost. Together, these findings flesh out the researchers’ understanding of the complete steps needed for regeneration to occur, revealing an early key NetBet live casinorole for wound epidermis, through its expression of equinox, in the signaling sequence that enables regrowth after an injury.
“There’s a cascade of events in which wound signaling activates, among other genes, equinox; equinox promotes wound-induced gene expression in muscle; and that promotes positional information resetting that can then lead to regeneration,” Reddien says. “What’s exciting about filling in this picture is that we’re identifying the key regulatory logic that can bring about regeneration.”
HMS grad Jennifer Cloutier has a habit of pushing limits
Christine Paul | Harvard Medical School News
May 17, 2022
When Jennifer Cloutier receives her MD from Harvard Medical School in May, it will be 12 years since she won a Canadian national waterskiing championship.
Although that feat alone is impressive, it’s even more extraordinary because the competition was designed for individuals with disabilities, and because of her lower-body paralysis, Cloutier, now 30, performed tricky slalom turns and acrobatics from a special seat bolted to her skis.
But then, pushing limits has been Cloutier’s signature style.
“In the 20-second period allowed for trick skiing, if you fall off the seat, your performance is over,” she said. “So, my goal was to always perform the hardest trick I could do without falling.”
Skiing triumphs were just the beginning of many of Cloutier’s achievements, demonstrating her refusal to be deterred by the spinal-cord injury she experienced at age 6 in a car accident, which also left her younger brother paralyzed.
Pushing limits
Cloutier was encouraged by her parents not to let her injury impede her future ambitions, and during the six months she was initially hospitalized after the accident, she gained firsthand appreciation of the marvels of rehabilitative medicine, which she says helped inspire her to become a doctor.
But childhood came first. At age 10, the Ottawa, Ontario, native also embraced alpine skiing, becoming a ski instructor during high school.
Then, turning to watersports, she competed internationally and became a volunteer administrator for SkiAbility Ottawa, a waterskiing organization for people with chronic illnesses and disabilities.
Winning medal after medal, Cloutier’s athletic successes and volunteer work with disabled people culminated in her being selected in 2011 to Canada’s Top 20 Under 20, a prestigious list published by Youth in Motion.
At the time, Cloutier was already at Harvard College, graduating with a bachelor’s in human developmental and regenerative biology in 2013, and serving as president of Women in Science at Harvard-Radcliffe from 2011 to 2013.
She says her early traumatic injury was pivotal in defining her research goal—to understand how tissues regenerate after they are damaged. HMS and the Massachusetts Institute of Technology (MIT) have given her a unique opportunity to pursue this goal.
Enrolled in the joint Harvard-MIT Program in Health Sciences and Technology (HST), which immerses students in rigorous interdisciplinary studies on both campuses, Cloutier will receive an MD in 2022 from HMS, complementing the PhD in biology she received from MIT in 2020.
Compressed into overlapping years, HST students on the MD track receive training to become physician-scientists. In addition to classroom studies on the HMS campus and clinical rotations at HMS-affiliated hospitals, they spend long hours in HMS or MIT laboratories, working with leading scientists on critical questions.
“As a physician-scientist, I am very interested in how organs and tissues re-form in adult organisms that are attempting to regenerate from injury,” Cloutier said.
She has studied the regenerative ability of a tiny planarian, or flatworm, named Schmidtea mediterranea.
For two centuries, this freshwater planarian has been a model organism for studying development and regeneration, because of its distinct anatomical features—eyes, gut, brain, central nervous system, and more—and its capacity to regenerate any missing body region, even the whole body, from minuscule body parts.
Working in the lab of Peter Reddien, professor and associate head of the MIT Department of Biology, Cloutier’s research has focused on planarian signaling pathways that recruit stem cells for regenerating tissues.
“Our research team is seeking to identify the genes and signals involved in initiating regeneration,” Cloutier said. “We are converging on a promising regulator that is expressed within hours of injury in the planarian wound epidermis. Such a discovery would offer key insights to the cellular signals that drive regeneration and could potentially lead someday to therapeutic strategies for better repair after injury,” she said.
Precursor cells
While at Harvard College, she worked as an undergraduate in the labs of Konrad Hochedlinger, HMS professor of genetics at Massachusetts General Hospital, and Guillermo Garcia-Cardeña, HMS associate professor of pathology at Brigham and Women’s Hospital, again focusing on questions of cell fate.
Before beginning her research at MIT, Cloutier gained experience as a doctoral student in the laboratory of HMS Dean George Q. Daley, well known for his research on hematopoietic stem cells, precursor cells in the blood and bone marrow that give rise to mature blood cells which are often used in therapies designed to replace or rebuild a patient’s hematopoietic system.
Then, in 2018, something besides regenerative biology caught her eye. Crossing the MIT campus one day, Cloutier noticed a group of mechanical engineering students designing their capstone project—a wheelchair with an adjustable seat that could be raised 12 inches.
Recognizing the potential benefit of this device for physicians with disabilities when they are performing patient procedures and physical exams, she provided valuable feedback to the group of 20 students.
Feeling at home
On-campus mobility was essential to her studies, and Cloutier credits Harvard for striving to make its facilities accessible. One of her favorite aspects of Harvard life was living as an undergrad at Quincy House in Cambridge, where she later returned during her time as an HST student to serve as resident tutor and mentor.
“Harvard’s house system is incredible and unique,” she said. “It feels like home.”
Even after Cloutier graduates from HMS, she’s not planning on going far. Her residency assignment is at Mass General, an HMS affiliate, where she’ll train in internal medicine.
Again, her primary interest is tissue regeneration, particularly the liver, which has the greatest regenerative capacity of any organ in the body. But if the liver is injured beyond its ability to regenerate itself, a transplant is often called for.
“During my principal clinical experience at HMS, I realized how much liver disease affects a patient,” Cloutier said, which led to more questions. “With the current shortage of livers available for transplant, is there a way to prolong the liver’s regeneration capacity and extend the bridge to transplant?”
Harkening back to the accident that changed her life, Cloutier’s also concerned about people who cope daily with chronic illnesses and pain, like her father, whose leg injury from that car accident that injured her still causes him significant discomfort.
“As physicians, we can’t fix all problems,” she said. “But we can focus on what matters to our patients and try to improve their quality of life.”
With her future before her, Cloutier is reminded of the powerful life lesson she learned at an early age.
“One day you may wake up, and things might be quite different,” she said. “But you still can do really cool things.”
Image: Gretchen Ertl
MIT cell biologist and computational neuroscientist recognized for their innovative research contributions.
Raleigh McElvery | Julie Pryor | McGovern Institute for Brain Research | Department of Biology
May 13, 2022
MIT cell biologist Lindsay Case and computational neuroscientist Guangyu Robert Yang have been named 2022 Searle Scholars, an award given annually to 15 outstanding U.S. assistant professors who have high potential for ongoing innovative research contributions in medicine, chemistry, or the biological sciences.
Case is an assistant professor of biology, while Yang is an assistant professor of brain and cognitive sciences and electrical engineering and computer science, and an associate investigator at the McGovern Institute for Brain Research. They will each receive $300,000 in flexible funding to support their high-risk, high-reward work over the next three years.
Lindsay Case
Case arrived at MIT in 2021, after completing a postdoc at the University of Texas Southwestern Medical Center in the lab of Michael Rosen. Prior to that, she earned her PhD from the University of North Carolina at Chapel Hill, working in the lab of Clare Waterman at the National Heart Lung and Blood Institute.
Situated in MIT’s Building 68, Case’s lab studies how molecules within cells organize themselves, and how such organization begets cellular function. Oftentimes, molecules will assemble at the cell’netbet online sports bettings plasma membrane — a complex signaling platform where hundreds of receptors sense information from outside the cell and initiate cellular changes in response. Through her experiments, Case has found that molecules at the plasma membrane can undergo a process known as phase separation, condensing to form liquid-like droplets.
As a Searle Scholar, Case is investigating the role that phase separation plays in regulating a specific class of signaling molecules called kinases. Her team will take a multidisciplinary approach to probe what happens when kinases phase separate into signaling clusters, and what cellular changes occur as a result. Because phase separation is emerging as a promising new target for small molecule therapies, this work will help identify kinases that are strong candidates for new therapeutic interventions to treat diseases such as cancer.
“I am honored to be recognized by the Searle Scholars Program, and thrilled to join such an incredible community of scientists,” Case says. “This support will enable my group to broaden our research efforts and take our preliminary findings in exciting new directions. I look forward to better understanding how phase separation impacts cellular function.”
His research team at MIT, the MetaConscious Group, develops models of mental functions by incorporating multiple interacting modules. They are designing pipelines to process and compare large-scale experimental datasets that span modalities ranging from behavioral data to neural activity data to molecular data. These datasets are then be integrated to train individual computational modules based on the experimental tasks that were evaluated such as vision, memory, or movement.
Ultimately, Yang seeks to combine these modules into a “network of networks” that models higher-level brain functions such as the ability to flexibly and rapidly learn a variety of tasks. Such integrative models are rare because, until recently, it was not possible to acquire data that spans modalities and brain regions in real time as animals perform tasks. The time is finally right for integrative network models. Computational models that incorporate such multisystem, multilevel datasets will allow scientists to make new predictions about the neural basis of cognition and open a window to a mathematical understanding the mind.
“This is a new research direction for me, and I think for the field too. It comes with many exciting opportunities as well as challenges. Having this recognition from the Searle Scholars program really gives me extra courage to take on the uncertainties and challenges,” says Yang.
Since 1981, 647 scientists have been named Searle Scholars. Including this year, the program has awarded more than $147 million. Eighty-five Searle Scholars have been inducted into the National Academy of Sciences. Twenty scholars have been recognized with a MacArthur Fellowship, known as the “genius grant,” and two Searle Scholars have been awarded the Nobel Prize in Chemistry. The Searle Scholars Program is funded through the Searle Funds at The Chicago Community Trust and administered by Kinship Foundation.
