Researcher: Guoping Feng

New MIT initiative seeks to transform rare brain disorders research

by Rubina Veerakone |

More than 300 million people worldwide are living with rare disorders — many of which have a genetic cause and affect the brain and nervous system — yet the vast majority of these conditions lack an approved therapy. Because each rare disorder affects fewer than 65 out of every 100,000 people, studying these disorders and creating new treatments for them is especially challenging.

Thanks to a generous philanthropic gift from Ana Méndez ’91 and Rajeev Jayavant ’86, EE ’88, SM ’88, MIT is now poised to fill the gaps in this research landscape. By establishing the Rare Brain Disorders Nexus — or RareNet — at MIT’s McGovern Institute, the alumni aim to convene leaders in neuroscience research, clinical medicine, patient advocacy, and industry to streamline the lab-to-clinic pipeline for rare brain disorder treatments.

“Ana and Rajeev’s commitment to MIT will form crucial partnerships to propel the translation of scientific discoveries into promising therapeutics and expand the Institute’s impact on the rare brain disorders community,” says MIT President Sally Kornbluth. “We are deeply grateful for their pivotal role in advancing such critical science and bringing attention to conditions that have long been overlooked.”

Building new coalitions

Several hurdles have slowed the lab-to-clinic pipeline for rare brain disorder research. It is difficult to secure a sufficient number of patients per study, and current research efforts are fragmented since each study typically focuses on a single disorder (there are more than 7,000 known rare disorders, according to the World Health Organization). Pharmaceutical companies are often reluctant to invest in emerging treatments due to a limited market size and the high costs associated with preparing drugs for commercialization.

Méndez and Jayavant envision that RareNet will finally break down these barriers. “Our hope is that RareNet will allow leaders in the field to come together under a shared framework and ignite scientific breakthroughs across multiple conditions. A discovery for one rare brain disorder could unlock new insights that are relevant to another,” says Jayavant. “By congregating the best minds in the field, we are confident that MIT will create the right scientific climate to produce drug candidates that may benefit a spectrum of uncommon conditions.”

Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor in Neuroscience and associate director of the McGovern Institute for Brain Research at MIT, will serve as RareNet’s inaugural faculty director. Feng holds a strong record of advancing studies on therapies for neurodevelopmental disorders, including autism spectrum disorders, Williams syndrome, and uncommon forms of epilepsy. His team’s gene therapy for Phelan-McDermid syndrome, a rare and profound autism spectrum disorder, has been licensed to Jaguar Gene Therapy and is currently undergoing clinical trials. “RareNet pioneers a unique model for biomedical research — one that is reimagining the role academia can play in developing therapeutics,” says Feng.

Image of SHANK3 therapy correctly finding its way to dendrites. Image: Guoping Feng
An early version of a gene therapy for SHANK3 mutations — linked to a rare brain disorder called Phelan-McDermid syndrome — correctly finds its way to neurons. Image: Feng lab

RareNet plans to deploy two major initiatives: a global consortium and a therapeutic pipeline accelerator. The consortium will form an international network of researchers, clinicians, and patient groups from the outset. It seeks to connect siloed research efforts, secure more patient samples, promote data sharing, and drive a strong sense of trust and goal alignment across the RareNet community. Partnerships within the consortium will support the aim of the therapeutic pipeline accelerator: to de-risk early lab discoveries and expedite their translation to clinic. By fostering more targeted collaborations — especially between academia and industry — the accelerator will prepare potential treatments for clinical use as efficiently as possible.

MIT labs are focusing on four uncommon conditions in the first wave of RareNet projects: Rett syndrome, prion disease, disorders linked to SYNGAP1 mutations, and Sturge-Weber syndrome. The teams are working to develop novel therapies that can slow, halt, or reverse dysfunctions in the brain and nervous system.

These efforts will build new bridges to connect key stakeholders across the rare brain disorders community and disrupt conventional research approaches. “Rajeev and I are motivated to seed powerful collaborations between MIT researchers, clinicians, patients, and industry,” says Méndez. “Guoping Feng clearly understands our goal to create an environment where foundational studies can thrive and seamlessly move toward clinical impact.”

“Patient and caregiver experiences, and our foreseeable impact on their lives, will guide us and remain at the forefront of our work,” Feng adds. “For far too long has the rare brain disorders community been deprived of life-changing treatments — and, importantly, hope. RareNet gives us the opportunity to transform how we study these conditions and to do so at a moment when it’s needed more than ever.”

 

New gift expands mental illness studies at Poitras Center for Psychiatric Disorders Research

by Julie Pryor |

One in every eight people—970 million globally—live with mental illness, according to the World Health Organization, with depression and anxiety being the most common mental health conditions worldwide. Existing therapies for complex psychiatric disorders like depression, anxiety, and schizophrenia have limitations, and federal funding to address these shortcomings is growing increasingly uncertain.

Jim and Pat Poitras
James and Patricia Poitras at an event co-hosted by the McGovern Institute and Autism Speaks. Photo: Justin Knight

Patricia and James Poitras ’63 have committed $8 million to the Poitras Center for Psychiatric Disorders Research to launch pioneering research initiatives aimed at uncovering the brain basis of major mental illness and accelerating the development of novel treatments.

“Federal funding rarely supports the kind of bold, early-stage research that has the potential to transform our understanding of psychiatric illness. Pat and I want to help fill that gap—giving researchers the freedom to follow their most promising leads, even when the path forward isn’t guaranteed,” says James Poitras, who is chair of the McGovern Institute Board.

Their latest gift builds upon their legacy of philanthropic support for psychiatric disorders research at MIT, which now exceeds $46 million.

“With deep gratitude for Jim and Pat’s visionary support, we are eager to launch a bold set of studies aimed at unraveling the neural and cognitive underpinnings of major mental illnesses,” says Robert Desimone, director of the McGovern Institute, home to the Poitras Center. “Together, these projects represent a powerful step toward transforming how we understand and treat mental illness.”

A legacy of support

Soon after joining the McGovern Institute Leadership Board in 2006, the Poitrases made a $20 million commitment to establish the Poitras Center for Psychiatric Disorders Research at MIT. The center’s goal, to improve human health by addressing the root causes of complex psychiatric disorders, is deeply personal to them both.

“We had decided many years ago that our philanthropic efforts would be directed towards psychiatric research. We could not have imagined then that this perfect synergy between research at MIT’s McGovern Institute and our own philanthropic goals would develop,” recalls Patricia.

The center supports research at the McGovern Institute and collaborative projects with institutions such as the Broad Institute, McLean Hospital, Mass General Brigham and other clinical research centers. Since its establishment in 2007, the center has enabled advances in psychiatric research including the development of a machine learning “risk calculator” for bipolar disorder, the use of brain imaging to predict treatment outcomes for anxiety, and studies demonstrating that mindfulness can improve mental health in adolescents.

A scientist speaks at a podium with an image of DNA on the wall behind him.
Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, delivers a lecture at the Poitras Center’s 10th anniversary celebration in 2017. Photo: Justin Knight

For the past decade, the Poitrases have also fueled breakthroughs in McGovern Investigator Feng Zhang’s lab, backing the invention of powerful CRISPR systems and other molecular tools that are transforming biology and medicine. Their support has enabled the Zhang team to engineer new delivery vehicles for gene therapy, including vehicles capable of carrying genetic payloads that were once out of reach. The lab has also advanced innovative RNA-guided gene engineering tools such as NovaIscB, published in Nature Biotechnology in May 2025. These revolutionary genome editing and delivery technologies hold promise for the next generation of therapies needed for serious psychiatric illness.

In addition to fueling research in the center, the Poitras family has gifted two endowed professorships—the James and Patricia Poitras Professor of Neuroscience at MIT, currently held by Feng Zhang, and the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT, held by Guoping Feng—and an annual postdoctoral fellowship at the McGovern Institute.

New initiatives at the Poitras Center

The Poitras family’s latest commitment to the Poitras Center will launch an ambitious set of new projects that bring together neuroscientists, clinicians, and computational experts to probe underpinnings of complex psychiatric disorders including schizophrenia, anxiety, and depression. These efforts reflect the center’s core mission: to speed scientific discovery and therapeutic innovation in the field of psychiatric brain disorders research.

McGovern cognitive neuroscientists Evelina Fedorenko PhD ‘07 and Nancy Kanwisher ’80, PhD ’86, the Walter A. Rosenblith Professor of Cognitive Neuroscience—in collaboration with psychiatrist Ann Shinn of McLean Hospital—will explore how altered inner speech and reasoning contribute to the symptoms of schizophrenia. They will collect functional MRI data from individuals diagnosed with schizophrenia and matched controls as they perform reasoning tasks. The goal is to identify the brain activity patterns that underlie impaired reasoning in schizophrenia, a core cognitive disruption in the disorder.

Three women wearing name tags smile for hte camera.
Patricia Poitras (center) with McGovern Investigators Nancy Kanwisher ’80, PhD ’86 (left) and Martha Constantine-Paton (right) at the Poitras Center’s 10th anniversary celebration in 2017. Photo: Justin Knight

A complementary line of investigation will focus on the role of inner speech—the “voice in our head” that shapes thought and self-awareness. The team will conduct a large-scale online behavioral study of neurotypical individuals to analyze how inner speech characteristics correlate with schizophrenia-spectrum traits. This will be followed by neuroimaging work comparing brain architecture among individuals with strong or weak inner voices and people with schizophrenia, with the aim of discovering neural markers linked to self-talk and disrupted cognition.

A different project led by McGovern neuroscientist Mark Harnett and 2024–2026 Poitras Center Postdoctoral Fellow Cynthia Rais focuses on how ketamine—an increasingly used antidepressant—alters brain circuits to produce rapid and sustained improvements in mood. Despite its clinical success, ketamine’s mechanisms of action remain poorly understood. The Harnett lab is using sophisticated tools to track how ketamine affects synaptic communication and large-scale brain network dynamics, particularly in models of treatment-resistant depression. By mapping these changes at both the cellular and systems levels, the team hopes to reveal how ketamine lifts mood so quickly—and inform the development of safer, longer-lasting antidepressants.

Guoping Feng is leveraging a new animal model of depression to uncover the brain circuits that drive major depressive disorder. The new animal model provides a powerful system for studying the intricacies of mood regulation. Feng’s team is using state-of-the-art molecular tools to identify the specific genes and cell types involved in this circuit, with the goal of developing targeted treatments that can fine-tune these emotional pathways.

“This is one of the most promising models we have for understanding depression at a mechanistic level,” says Feng, who is also associate director of the McGovern Institute. “It gives us a clear target for future therapies.”

Another novel approach to treating mood disorders comes from the lab of James DiCarlo, the Peter de Florez Professor of Neuroscience at MIT, who is exploring the brain’s visual-emotional interface as a therapeutic tool for anxiety. The amygdala, a key emotional center in the brain, is heavily influenced by visual input. DiCarlo’s lab is using advanced computational models to design visual scenes that may subtly shift emotional processing in the brain—essentially using sight to regulate mood. Unlike traditional therapies, this strategy could offer a noninvasive, drug-free option for individuals suffering from anxiety.

Together, these projects exemplify the kind of interdisciplinary, high-impact research that the Poitras Center was established to support.

“Mental illness affects not just individuals, but entire families who often struggle in silence and uncertainty,” adds Patricia. “Our hope is that Poitras Center scientists will continue to make important advancements and spark novel treatments for complex mental health disorders and most of all, give families living with these conditions a renewed sense of hope for the future.”

Five MIT faculty elected to the National Academy of Sciences for 2024

by School of Science, MIT |

The National Academy of Sciences has elected 120 members and 24 international members, including five faculty members from MIT. Guoping Feng, Piotr Indyk, Daniel J. Kleitman, Daniela Rus, and Senthil Todadri were elected in recognition of their “distinguished and continuing achievements in original research.” Membership to the National Academy of Sciences is one of the highest honors a scientist can receive in their career.

Among the new members added this year are also nine MIT alumni, including Zvi Bern ’82; Harold Hwang ’93, SM ’93; Leonard Kleinrock SM ’59, PhD ’63; Jeffrey C. Lagarias ’71, SM ’72, PhD ’74; Ann Pearson PhD ’00; Robin Pemantle PhD ’88; Jonas C. Peters PhD ’98; Lynn Talley PhD ’82; and Peter T. Wolczanski ’76. Those elected this year bring the total number of active members to 2,617, with 537 international members.

The National Academy of Sciences is a private, nonprofit institution that was established under a congressional charter signed by President Abraham Lincoln in 1863. It recognizes achievement in science by election to membership, and — with the National Academy of Engineering and the National Academy of Medicine — provides science, engineering, and health policy advice to the federal government and other organizations.

Guoping Feng

Guoping Feng is the James W. (1963) and Patricia T. Poitras Professor in the Department of Brain and Cognitive Sciences. He is also associate director and investigator in the McGovern Institute for Brain Research, a member of the Broad Institute of MIT and Harvard, and director of the Hock E. Tan and K. Lisa Yang Center for Autism Research.

His research focuses on understanding the molecular mechanisms that regulate the development and function of synapses, the places in the brain where neurons connect and communicate. He’s interested in how defects in the synapses can contribute to psychiatric and neurodevelopmental disorders. By understanding the fundamental mechanisms behind these disorders, he’s producing foundational knowledge that may guide the development of new treatments for conditions like obsessive-compulsive disorder and schizophrenia.

Feng received his medical training at Zhejiang University Medical School in Hangzhou, China, and his PhD in molecular genetics from the State University of New York at Buffalo. He did his postdoctoral training at Washington University at St. Louis and was on the faculty at Duke University School of Medicine before coming to MIT in 2010. He is a member of the American Academy of Arts and Sciences, a fellow of the American Association for the Advancement of Science, and was elected to the National Academy of Medicine in 2023.

Piotr Indyk

Piotr Indyk is the Thomas D. and Virginia W. Cabot Professor of Electrical Engineering and Computer Science. He received his magister degree from the University of Warsaw and his PhD from Stanford University before coming to MIT in 2000.

Indyk’s research focuses on building efficient, sublinear, and streaming algorithms. He’s developed, for example, algorithms that can use limited time and space to navigate massive data streams, that can separate signals into individual frequencies faster than other methods, and can address the “nearest neighbor” problem by finding highly similar data points without needing to scan an entire database. His work has applications on everything from machine learning to data mining.

He has been named a Simons Investigator and a fellow of the Association for Computer Machinery. In 2023, he was elected to the American Academy of Arts and Sciences.

Daniel J. Kleitman

Daniel Kleitman, a professor emeritus of applied mathematics, has been at MIT since 1966. He received his undergraduate degree from Cornell University and his master’s and PhD in physics from Harvard University before doing postdoctoral work at Harvard and the Niels Bohr Institute in Copenhagen, Denmark.

Kleitman’s research interests include operations research, genomics, graph theory, and combinatorics, the area of math concerned with counting. He was actually a professor of physics at Brandeis University before changing his field to math, encouraged by the prolific mathematician Paul Erdős. In fact, Kleitman has the rare distinction of having an Erdős number of just one. The number is a measure of the “collaborative distance” between a mathematician and Erdős in terms of authorship of papers, and studies have shown that leading mathematicians have particularly low numbers.

He’s a member of the American Academy of Arts and Sciences and has made important contributions to the MIT community throughout his career. He was head of the Department of Mathematics and served on a number of committees, including the Applied Mathematics Committee. He also helped create web-based technology and an online textbook for several of the department’s core undergraduate courses. He was even a math advisor for the MIT-based film “Good Will Hunting.”

Daniela Rus

Daniela Rus, the Andrew (1956) and Erna Viterbi Professor of Electrical Engineering and Computer Science, is the director of the Computer Science and Artificial Intelligence Laboratory (CSAIL). She also serves as director of the Toyota-CSAIL Joint Research Center.

Her research on robotics, artificial intelligence, and data science is geared toward understanding the science and engineering of autonomy. Her ultimate goal is to create a future where machines are seamlessly integrated into daily life to support people with cognitive and physical tasks, and deployed in way that ensures they benefit humanity. She’s working to increase the ability of machines to reason, learn, and adapt to complex tasks in human-centered environments with applications for agriculture, manufacturing, medicine, construction, and other industries. She’s also interested in creating new tools for designing and fabricating robots and in improving the interfaces between robots and people, and she’s done collaborative projects at the intersection of technology and artistic performance.

Rus received her undergraduate degree from the University of Iowa and her PhD in computer science from Cornell University. She was a professor of computer science at Dartmouth College before coming to MIT in 2004. She is part of the Class of 2002 MacArthur Fellows; was elected to the National Academy of Engineering and the American Academy of Arts and Sciences; and is a fellow of the Association for Computer Machinery, the Institute of Electrical and Electronics Engineers, and the Association for the Advancement of Artificial Intelligence.

Senthil Todadri

Senthil Todadri, a professor of physics, came to MIT in 2001. He received his undergraduate degree from the Indian Institute of Technology in Kanpur and his PhD from Yale University before working as a postdoc at the Kavli Institute for Theoretical Physics in Santa Barbara, California.

Todadri’s research focuses on condensed matter theory. He’s interested in novel phases and phase transitions of quantum matter that expand beyond existing paradigms. Combining modeling experiments and abstract methods, he’s working to develop a theoretical framework for describing the physics of these systems. Much of that work involves understanding the phenomena that arise because of impurities or strong interactions between electrons in solids that don’t conform with conventional physical theories. He also pioneered the theory of deconfined quantum criticality, which describes a class of phase transitions, and he discovered the dualities of quantum field theories in two dimensional superconducting states, which has important applications to many problems in the field.

Todadri has been named a Simons Investigator, a Sloan Research Fellow, and a fellow of the American Physical Society. In 2023, he was elected to the American Academy of Arts and Sciences

The promise of gene therapy

by Robert Desimone |

Portrait of Bob Desimone wearing a suit and tie.
McGovern Institute Director Robert Desimone. Photo: Steph Stevens

As we start 2024, I hope you can join me in celebrating a historic recent advance: the FDA approval of Casgevy, a bold new treatment for devastating sickle cell disease and the world’s first approved CRISPR gene therapy.

Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, we are proud to share that this pioneering therapy licenses the CRISPR discoveries of McGovern scientist and Poitras Professor of Neuroscience Feng Zhang.

It is amazing to think that Feng’s breakthrough work adapting CRISPR-Cas9 for genome editing in eukaryotic cells was published only 11 years ago today in Science.

Incredibly, CRISPR-Cas9 rapidly transitioned from proof-of-concept experiments to an approved treatment in just over a decade.

McGovern scientists are determined to maintain the momentum!

 

Incredibly, CRISPR-Cas9 rapidly transitioned from proof-of-concept experiments to an approved treatment in just over a decade.

Our labs are creating new gene therapies that are already in clinical trials or preparing to enroll patients in trials. For instance, Feng Zhang’s team has developed therapies currently in clinical trials for lymphoblastic leukemia and beta thalassemia, while another McGovern researcher, Guoping Feng, the Poitras Professor of Brain and Cognitive Sciences at MIT, has made advancements that lay the groundwork for a new gene therapy to treat a severe form of autism spectrum disorder. It is expected to enter clinical trials later this year. Moreover, McGovern fellows Omar Abudayyeh and Jonathan Gootenberg created programmable genomic tools that are now licensed for use in monogenic liver diseases and autoimmune disorders.

These exciting innovations stem from your steadfast support of our high-risk, high-reward research. Your generosity is enabling our scientists to pursue basic research in other areas with potential therapeutic applications in the future, such as mechanisms of pain, addiction, the connections between the brain and gut, the workings of memory and attention, and the bi-directional influence of artificial intelligence on brain research. All of this fundamental research is being fueled by major new advances in technology, many of them developed here.

As we enter a new year filled with anticipation following our inaugural gene therapy, I want to express my heartfelt gratitude for your invaluable support in advancing our research programs. Your role in pushing our research to new heights is valued by all faculty, students, and researchers at the McGovern Institute. We can’t wait to share our continued progress with you.

Thank you again for partnering with us to make great scientific achievements possible.

With appreciation and best wishes,

Robert Desimone, PhD
Director, McGovern Institute
Doris and Don Berkey Professor of Neuroscience, MIT

K. Lisa Yang Postbaccalaureate Program names new scholars

by Julie Pryor |

Funded by philanthropist Lisa Yang, the K. Lisa Yang Postbaccalaureate Scholar Program provides two years of paid laboratory experience, mentorship, and education to recent college graduates from backgrounds underrepresented in neuroscience. This year, two young researchers in McGovern Institute labs, Joseph Itiat and Sam Merrow, are the recipients of the Yang postbac program.

Itiat moved to the United States from Nigeria in 2019 to pursue a degree in psychology and cognitive neuroscience at Temple University. Today, he is a Yang postbac in John Gabrieli’s lab studying the relationship between learning and value processes and their influence on future-oriented decision-making. Ultimately, Itiat hopes to develop models that map the underlying mechanisms driving these processes.

“Being African, with limited research experience and little representation in the domain of neuroscience research,” Itiat says, “I chose to pursue a postbaccalaureate
research program to prepare me for a top graduate school and a career in cognitive neuroscience.”

Merrow first fell in love with science while working at the Barrow Neurological Institute in Arizona during high school. After graduating from Simmons University in Boston, Massachusetts, Merrow joined Guoping Feng’s lab as a Yang postbac to pursue research on glial cells and brain disorders. “As a queer, nonbinary, LatinX person, I have not met anyone like me in my field, nor have I had role models that hold a similar identity to myself,” says Merrow.

“My dream is to one day become a professor, where I will be able to show others that science is for anyone.”

Previous Yang postbacs include Alex Negron, Zoe Pearce, Ajani Stewart, and Maya Taliaferro.

New cellular census maps the complexity of a primate brain

by Jennifer Michalowski |

A new atlas developed by researchers at MIT’s McGovern Institute and Harvard Medical School catalogs a diverse array of brain cells throughout the marmoset brain. The atlas helps establish marmosets—small monkeys whose brains share many functional and structural features with the human brain—as a valuable model for neuroscience research.

Data from more than two million brain cells are included in the atlas, which spans 18 regions of the marmoset brain. A research team led by Guoping Feng, associate director of the McGovern Institute and member of the Broad Institute of Harvard and MIT, Harvard biologist and member of the Broad Institute of Harvard and MIT Steven McCarroll, and Princeton neurobiologist Fenna Krienen classified each cell according to its particular pattern of genetic activity, providing an important reference for studies of the marmoset brain. The team’s analysis, reported October 13, 2023, in the journal Science Advances, also reveals the profound influence of a cell’s developmental origin on its identity in the primate brain.

Regional variation in neocortical cell types and expression patterns. Image courtesy of the researchers.

Cellular diversity

Brains are made up of a tremendous diversity of cells. Neurons with dramatically different gene expression, shapes, and activities work together to process information and drive behavior, supported by an assortment of immune cells and other cell types. Scientists have only recently begun to catalog this cellular diversity—first in mice, and now in primates.

The marmoset is a quick-breeding monkey whose small brain has many of features similar to those that enable higher cognitive processes in humans. Feng says neuroscientists have begun turning to marmosets as a research model in recent years because new gene editing technology has made it easier to modify the animal’s DNA, so scientists can now study the genetic factors that shape marmosets’ brains and behavior. Feng, McCarroll, Krienen and others hope these animals will offer insights into how primate brains handle complex decision-making, social interactions, and other higher brain functions that are difficult to study in mice. Likewise, Feng says, the monkeys will help scientists investigate the impact of genetic mutations associated with brain disorders and explore potential therapeutic strategies.

To make marmosets a practical model for neuroscience, scientists need to understand the fundamental composition of their brains. Feng and McCarroll’s team have begun that characterization with their cell census, which was supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative’s Cell Census Network (BICCN), as part a larger effort to map cellular features in the brains of mice, non-human primates, and humans. It is an essential first step in the creation of a comprehensive atlas charting the molecular, anatomical, and functional features of cells in the marmoset brain.

“Hopefully, when the BRAIN Initiative is complete, we will have a very complete map of these cells: where they are located, their abundance, their functional properties,” says Feng. “This not only gives you knowledge of the normal brain, but you can also look at what aspects change in diseases of the brain. So it’s a really powerful database.”

To catalog the diversity of cells in the marmoset brain, the researchers undertook an expansive analysis of the molecular contents of 2.4 million brain cells from adult marmosets. For each of these cells, they analyzed the complete set of RNA copies of its genes that the cell had produced, known as the cell’s transcriptome. Because the transcriptome captures patterns of genetic activity inside a cell, it is an indication of the cell’s function and can be used to assess cellular identity.

Gene expression across neural populations. Image courtesy of the researchers.

The team’s analysis is one of the first to compare patterns of gene activity in cells from disparate regions of the marmoset brain. Doing so yielded surprising insights into the factors that shape brain cells’ transcriptomic identities. “What we found is that the cell’s transcriptome contains breadcrumbs that link back to the developmental origin of that cell type,” says Krienen, who led the cellular census as a postdoctoral researcher in McCarroll’s lab. That suggests that comparing cells’ transcriptomes can help scientists figure out how primate brains are assembled, which might lead to insights into neurodevelopmental disorders, she says.

The team also learned that a cell’s location in the brain was critical to shaping its transcriptomic identity. For example, Krienen says, “it turns out that an inhibitory neuron in the cortex doesn’t look very anything like an inhibitory neuron in the thalamus, probably because they have distinct embryonic origins.”

Expanding the cell census

This new picture of cellular diversity in the marmoset brain will help researchers understand how genetic perturbations affect different brain cells and interpret the results of future experiments. Importantly, Krienen says, it could help researchers pinpoint exactly which cells are affected in brain disorders, and how the effects of a disease might localize to specific brain regions.

Krienen, McCarroll, and Feng went beyond their initial survey of cellular diversity with analyses of specific subsets of cells, charting the spatial distribution of interneurons in a key region of the prefrontal cortex and visualizing the shapes of several molecularly-defined cell types. Now, they have begun expanding their cell census beyond the 18 brain structures represented in the reported work. As part of the BRAIN Initiative’s Brain Cell Atlas Network (BICAN), the team will profile cells throughout the entire adult marmoset brain, including multiple data types in their analysis. Building on cell census data, NIH BRAIN Initiative has also launched BRAIN CONNECTS projects to map cellular connectivity in the brain.

This work was supported by the National Institutes of Health, the National Science Foundation, MathWorks, MIT, Harvard Medical School, the Broad Institute’s Stanley Center for Psychiatric Research, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the Poitras Center for Psychiatric Disorders Research at MIT, and the McGovern Institute for Brain Research at MIT.

Twelve with MIT ties elected to the National Academy of Medicine for 2023

by MIT School of Science |

The National Academy of Medicine announced the election of 100 new members to join their esteemed ranks in 2023, among them five MIT faculty members and seven additional affiliates.

MIT professors Daniel Anderson, Regina Barzilay, Guoping Feng, Darrell Irvine, and Morgen Shen were among the new members. Justin Hanes PhD ’96, Said Ibrahim MBA ’16, and Jennifer West ’92, along with three former students in the Harvard-MIT Program in Health Sciences and Technology (HST) — Michael Chiang, Siddhartha Mukherjee, and Robert Vonderheide — were also elected, as was Yi Zhang, an associate member of The Broad Institute of MIT and Harvard.

Election to the academy is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service, the academy noted in announcing the election of its new members.

MIT faculty

Daniel G. Anderson, professor in the Department of Chemical Engineering and the Institute for Medical Engineering and Science, was elected “for pioneering the area of non-viral gene therapy and cellular delivery. His work has resulted in fundamental scientific advances; over 500 papers, patents, and patent applications; and the creation of companies, products, and technologies that are now in the clinic.” Anderson is an affiliate of the Broad Institute of MIT and Harvard and of the Ragon Institute at MGH, MIT and Harvard.

Regina Barzilay, the School of Engineering Distinguished Professor for AI and Health within the Department of Electrical Engineering and Computer Science at MIT, was elected “for the development of machine learning tools that have been transformational for breast cancer screening and risk assessment, and for the development of molecular design tools broadly utilized for drug discovery.” Barzilay is the AI faculty lead within the MIT Abdul Latif Jameel Clinic for Machine Learning in Health and an affiliate of the Computer Science and Artificial Intelligence Laboratory and Institute for Medical Engineering and Science.

Guoping Feng, the associate director of the McGovern Institute for Brain Research, James W. (1963) and Patricia T. Professor of Neuroscience in MIT’s Department of Brain and Cognitive Sciences, and an affiliate of the Broad Institute of MIT and Harvard, was elected “for his breakthrough discoveries regarding the pathological mechanisms of neurodevelopmental and psychiatric disorders, providing foundational knowledges and molecular targets for developing effective therapeutics for mental illness such as OCD, ASD, and ADHD.”

Darrell J. Irvine ’00, the Underwood-Prescott Professor of Biological Engineering and Materials Science at MIT and a member of the Koch Institute for Integrative Cancer Research, was elected “for the development of novel methods for delivery of immunotherapies and vaccines for cancer and infectious diseases.”

Morgan Sheng, professor of neuroscience in the Department of Brain and Cognitive Sciences, with affiliations in the McGovern Institute and The Picower Institute for Learning and Memory at MIT, as well as the Broad Institute of MIT and Harvard, was elected “for transforming the understanding of excitatory synapses. He revealed the postsynaptic density as a protein network controlling synaptic signaling and morphology; established the paradigm of signaling complexes organized by PDZ scaffolds; and pioneered the concept of localized regulation of mitochondria, apoptosis, and complement for targeted synapse elimination.”

Additional MIT affiliates

Michael F. Chiang, a former student in the Harvard-MIT Program in Health Sciences and Technology (HST) who is now director of the National Eye Institute of the National Institutes of Health, was honored “for pioneering applications of biomedical informatics to ophthalmology in artificial intelligence, telehealth, pediatric retinal disease, electronic health records, and data science, including methodological and diagnostic advances in AI for pediatric retinopathy of prematurity, and for contributions to developing and implementing the largest ambulatory care registry in the United States.”

Justin Hanes PhD ’96, who earned his PhD from the MIT Department of Chemical Engineering and is now a professor at Johns Hopkins University, was honored “for pioneering discoveries and inventions of innovative drug delivery technologies, especially mucosal, ocular, and central nervous system drug delivery systems; and for international leadership in research and education at the interface of engineering, medicine, and entrepreneurship, leading to clinical translation of drug delivery technologies.”

Said Ibrahim MBA ’16, a graduate of the MIT Sloan School of Management who is now a senior vice president and chair, department of medicine at the Zucker School of Medicine at Hofstra/Northwell, was honored for influential “health services research on racial disparities in elective joint replacement that has provided a national model for advancing health equity research beyond the identification of inequities and toward their remediation, and for his research that has been leveraged to engage diverse and innovative emerging scholars.”

Siddhartha Mukherjee, a former student in HST who is now an associate professor of medicine at Columbia University School of Medicine, was honored “for contributing important research in the immunotherapy of myeloid malignancies, such as acute myeloid leukemia, for establishing international centers for immunotherapy for childhood cancers, and for the discovery of tissue-resident stem cells.”

Robert H. Vonderheide, a former student in HST who is now a professor and vice dean at the Perelman School of Medicine and vice president of cancer programs at the University of Pennsylvania Health System, was honored “for developing immune combination therapies for patients with pancreatic cancer by driving proof-of-concept from lab to clinic, then leading national, randomized clinical trials for therapy, maintenance, and interception; and for improving access of minority individuals to clinical trials while directing an NCI comprehensive cancer center.”

Jennifer West ’92, a graduate of the MIT Department of Chemical Engineering who is now a professor of biomedical engineering and dean of the School of Engineering and Applied Science at the University of Virginia at Charlottesville, was honored “for the invention, development, and translation of novel biomaterials including bioactive, photopolymerizable hydrogels and theranostic nanoparticles.”

Yi Zhang, associate member of the Broad Institute, was honored “for making fundamental contributions to the epigenetics field through systematic identification and characterization of chromatin modifying enzymes, including EZH2, JmjC, and Tet. His proof-of-principle work on EZH2 inhibitors led to the founding of Epizyme and eventual making of tazemetostat, a drug approved for epithelioid sarcoma and follicular lymphoma.”

“It is my honor to welcome this truly exceptional class of new members to the National Academy of Medicine,” said NAM President Victor J. Dzau. “Their contributions to health and medicine are unparalleled, and their leadership and expertise will be essential to helping the NAM tackle today’s urgent health challenges, inform the future of health care, and ensure health equity for the benefit of all around the globe.”

Four McGovern Investigators receive NIH BRAIN Initiative grants

by Julie Pryor |

In the human brain, 86 billion neurons form more than 100 trillion connections with other neurons at junctions called synapses. Scientists at the McGovern Institute are working with their collaborators to develop technologies to map these connections across the brain, from mice to humans.

Today, the National Institutes of Health (NIH) announced a new program to support research projects that have the potential to reveal an unprecedented and dynamic picture of the connected networks in the brain. Four of these NIH-funded research projects will take place in McGovern labs.

BRAIN Initiative

In 2013, the Obama administration announced the Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, a public-private research effort to support the development and application of new technologies to understand brain function.

Today, the NIH announced its third project supported by the BRAIN Initiative, called BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS). The new project complements two previous large-scale projects, which together aim to transform neuroscience research by generating wiring diagrams that can span entire brains across multiple species. These detailed wiring diagrams can help uncover the logic of the brain’s neural code, leading to a better understanding of how this circuitry makes us who we are and how it could be rewired to treat brain diseases.

BRAIN CONNECTS at McGovern

The initial round of BRAIN CONNECTS awards will support researchers at more than 40 university and research institutions across the globe with 11 grants totaling $150 million over five years. Four of these grants have been awarded to McGovern researchers Guoping Feng, Ila Fiete, Satra Ghosh, and Ian Wickersham, whose projects are outlined below:

BRAIN CONNECTS: Comprehensive regional projection map of marmoset with single axon and cell type resolution
Team: Guoping Feng (McGovern Institute, MIT), Partha Mitra (Cold Spring Harbor Laboratory), Xiao Wang (Broad Institute), Ian Wickersham (McGovern Institute, MIT)

Summary: This project will establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate (NHP), the common marmoset (Callithrix jacchus). It will do so by tracing axonal projections of RNA barcode-identified neurons brain-wide in the marmoset, utilizing a sequencing-based imaging method that also permits simultaneous transcriptomic cell typing of the identified neurons. This work will help bridge the gap between brain-wide mesoscale connectivity data available for the mouse from a decade of mapping efforts using modern techniques and the absence of comparable data in humans and NHPs.

BRAIN CONNECTS: A center for high-throughput integrative mouse connectomics
Team: Jeff Lichtman (Harvard University), Ila Fiete (McGovern Institute, MIT), Sebastian Seung (Princeton University), David Tank (Princeton University), Hongkui Zeng (Allen Institute), Viren Jain (Google), Greg Jeffries (Oxford University)

Summary: This project aims to produce a large-scale synapse-level brain map (connectome) that includes all the main areas of the mouse hippocampus. This region is of clinical interest because it is an essential part of the circuit underlying spatial navigation and memory and the earliest impairments and degeneration related to Alzheimer’s disease.

BRAIN CONNECTS: The center for Large-scale Imaging of Neural Circuits (LINC)
Team: Anastasia Yendiki (MGH), Satra Ghosh (McGovern, MIT), Suzanne Haber (University of Rochester), Elizabeth Hillman (Columbia University)

Summary: This project will generate connectional diagrams of the monkey and human brain at unprecedented resolutions. These diagrams will be linked both to the neuroanatomic literature and to in vivo neuroimaging techniques, bridging between the rigor of the former and the clinical relevance of the latter. The data to be generated by this project will advance our understanding of brain circuits that are implicated in motor and psychiatric disorders, and that are targeted by deep-brain stimulation to treat these disorders.

BRAIN CONNECTS: Mapping brain-wide connectivity of neuronal types using barcoded connectomics
Team: Xiaoyin Chen (Allen Institute), Ian Wickersham (McGovern Institute, MIT), and Justus Kebschull of JHU

Summary: This project aims to optimize and develop barcode sequencing-based neuroanatomical techniques to achieve brain-wide, high-throughput, highly multiplexed mapping of axonal projections and synaptic connectivity of neuronal types at cellular resolution in primate brains. The team will work together to apply these techniques to generate an unprecedented multi-resolution map of brain-wide projections and synaptic inputs of neurons in the macaque visual cortex at cellular resolution.

 

One scientist’s journey from the Middle East to MIT

by Thea Singer |

Smiling man holidng paper in a room.
Ubadah Sabbagh, soon after receiving his US citizenship papers, in April 2023. Photo: Ubadah Sabbagh

“I recently exhaled a breath I’ve been holding in for nearly half my life. After applying over a decade ago, I’m finally an American. This means so many things to me. Foremost, it means I can go back to the the Middle East, and see my mama and the family, for the first time in 14 years.” — McGovern Institute Postdoctoral Associate Ubadah Sabbagh, X (formerly Twitter) post, April 27, 2023

The words sit atop a photo of Ubadah Sabbagh, who joined the lab of Guoping Feng, James W. (1963) and Patricia T. Poitras Professor at MIT, as a postdoctoral associate in 2021. Sabbagh, a Syrian national, is dressed in a charcoal grey jacket, a keffiyeh loose around his neck, and holding his US citizenship papers, which he began applying for when he was 19 and an undergraduate at the University of Missouri-Kansas City (UMKC) studying biology and bioinformatics.

In the photo he is 29.

A clarity of vision

Sabbagh’s journey from the Middle East to his research position at MIT has been marked by determination and courage, a multifaceted curiosity, and a role as a scientist-writer/scientist-advocate.  He is particularly committed to the importance of humanity in science.

“For me, a scientist is a person who is not only in the lab but also has a unique perspective to contribute to society,” he says. “The scientific method is an idea, and that can be objective. But the process of doing science is a human endeavor, and like all human endeavors, it is inherently both social and political.”

At just 30 years of age, some of Sabbagh’s ideas have disrupted conventional thinking about how science is done in the United States. He believes nations should do science not primarily to compete, for example, but to be aspirational.

“It is our job to make our work accessible to the public, to educate and inform, and to help ground policy,” he says. “In our technologically advanced society, we need to raise the baseline for public scientific intuition so that people are empowered and better equipped to separate truth from myth.”

Two men sitting at a booth wearing headphones.
Ubadah Sabbagh is interviewed for Max Planck Forida’s Neurotransmissions podcast at the 2023 Society for Neuroscience conference in San Diego. Photo: Max Planck Florida

His research and advocacy work have won him accolades, including the 2023 Young Arab Pioneers Award from the Arab Youth Center and the 2020 Young Investigator Award from the American Society of Neurochemistry. He was also named to the 2021 Forbes “30 under 30” list, the first Syrian to be selected in the Science category.

A path to knowledge

Sabbagh’s path to that knowledge began when, living on his own at age 16, he attended Longview Community College, in Kansas City, often juggling multiple jobs. It continued at UMKC, where he fell in love with biology and had his first research experience with bioinformatician Gerald Wyckoff at the same time the civil war in Syria escalated, with his family still in the Middle East. “That was a rough time for me,” he says. “I had a lot of survivor’s guilt: I am here, I have all of this stability and security compared to what they have, and while they had suffocation, I had opportunity. I need to make this mean something positive, not just for me, but in as broad a way as possible for other people.”

Child smiles in front of scientific poster.
Ubadah Sabbagh, age 9, presents his first scientific poster. Photo: Ubadah Sabbagh

The war also sparked Sabbagh’s interest in human behavior—“where it originates, what motivates people to do things, but in a biological, not a psychological way,” he says. “What circuitry is engaged? What is the infrastructure of the brain that leads to X, Y, Z?”

His passion for neuroscience blossomed as a graduate student at Virginia Tech, where he earned his PhD in translational biology, medicine, and health. There, he received a six-year NIH F99/K00 Award, and under the mentorship of neuroscientist at the Fralin Biomedical Research Institute he researched the connections between the eye and the brain, specifically, mapping the architecture of the principle neurons in a region of the thalamus essential to visual processing.

“The retina, and the entire visual system, struck me as elegant, with beautiful layers of diverse cells found at every node,” says Sabbagh, his own eyes lighting up.

His research earned him a coveted spot on the Forbes “30 under 30” list, generating enormous visibility, including in the Arab world, adding visitors to his already robust X (formerly Twitter) account, which has more than 9,200 followers. “The increased visibility lets me use my voice to advocate for the things I care about,” he says.

“I need to make this mean something positive, not just for me, but in as broad a way as possible for other people.” — Ubadah Sabbagh

Those causes range from promoting equity and inclusion in science to transforming the American system of doing science for the betterment of science and the scientists themselves. He cofounded the nonprofit Black in Neuro to celebrate and empower Black scholars in neuroscience, and he continues to serve on the board. He is the chair of an advisory committee for the Society for Neuroscience (SfN), recommending ways SfN can better address the needs of its young members, and a member of the Advisory Committee to the National Institutes of Health (NIH) Director working group charged with re-envisioning postdoctoral training. He serves on the advisory board of Community for Rigor, a new NIH initiative that aims to teach scientific rigor at national scale and, in his spare time, he writes articles about the relationship of science and policy for publications including Scientific American and the Washington Post.

Still, there have been obstacles. The same year Sabbagh received the NIH F99/K00 Award, he faced major setbacks in his application to become a citizen. He would not try again until 2021, when he had his PhD in hand and had joined the McGovern Institute.

An MIT postdoc and citizenship

Sabbagh dove into his research in Guoping Feng’s lab with the same vigor and outside-the-box thinking that characterized his previous work. He continues to investigate the thalamus, but in a region that is less involved in processing pure sensory signals, such as light and sound, and more focused on cognitive functions of the brain. He aims to understand how thalamic brain areas orchestrate complex functions we carry out every day, including working memory and cognitive flexibility.

“This is important to understand because when this orchestra goes out of tune it can lead to a range of neurological disorders, including autism spectrum disorder and schizophrenia,” he says. He is also developing new tools for studying the brain using genome editing and viral engineering to expand the toolkit available to neuroscientists.

Microscopic image of mouse brain
Neurons in a transgenic mouse brain labeled by Sabbagh using genome editing technology in the Feng lab. Image: Ubadah Sabbagh

The environment at the McGovern Institute is also a source of inspiration for Sabbagh’s research. “The scale and scope of work being done at McGovern is remarkable. It’s an exciting place for me to be as a neuroscientist,” said Sabbagh. “Besides being intellectually enriching, I’ve found great community here – something that’s important to me wherever I work.”

Returning to the Middle East

Profile of scientist Ubadah Sabbagh speaking at a table.
McGovern postdoc Ubadah Sabbagh at the 2023 Young Arab Pioneers Award ceremony in Abu Dhabi. Photo: Arab Youth Center

While at an advisory meeting at the NIH, Sabbagh learned he had been selected as a Young Arab Pioneer by the Arab Youth Center and was flown the next day to Abu Dhabi for a ceremony overseen by Her Excellency Shamma Al Mazrui, Cabinet Member and Minister of Community Development in the United Arab Emirates. The ceremony recognized 20 Arab youth from around the world in sectors ranging from scientific research to entrepreneurship and community development. Sabbagh’s research “presented a unique portrayal of creative Arab youth and an admirable representation of the values of youth beyond the Arab world,” said Sadeq Jarrar, executive director of the center.

“There I was, among other young Arab leaders, learning firsthand about their efforts, aspirations, and their outlook for the future,” says Sabbagh, who was deeply inspired by the experience.

Just a month earlier, his passport finally secured, Sabbagh had reunited with his family in the Middle East after more than a decade in the United States. “I had been away for so long,” he said, describing the experience as a “cultural reawakening.”

Woman hands man an award on stage.
Ubadah Sabbagh receives a Young Arab Pioneer Award by Her Excellency Shamma Al Mazrui, Cabinet Member and Minister of Community Development in the United Arab Emirates. Photo: Arab Youth Center

Sabbagh saw a gaping need he had not been aware of when he left 14 years earlier, as a teen. “The Middle East had such a glorious intellectual past,” he says. “But for years people have been leaving to get their advanced scientific training, and there is no adequate infrastructure to support them if they want to go back.” He wondered: What if there were a scientific renaissance in the region? How would we build infrastructure to cultivate local minds and local talent? What if the next chapter of the Middle East included being a new nexus of global scientific advancements?

“I felt so inspired,” he says. “I have a longing, someday, to meaningfully give back.”

Making invisible therapy targets visible

by Thea Singer |

The lab of Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, has developed a powerful technology called Expansion Revealing (ExR) that makes visible molecular structures that were previously too hidden to be seen with even the most powerful microscopes. It “reveals” the nanoscale alterations in synapses, neural wiring, and other molecular assemblies using ordinary lab microscopes. It does so this way: Inside a cell, proteins and other molecules are often tightly packed together. These dense clusters can be difficult to image because the fluorescent labels used to make them visible can’t wedge themselves between the molecules. ExR “de-crowds” the molecules by expanding the cell using a chemical process, making the molecules accessible to fluorescent tags.

Jinyoung Kang is a J. Douglas Tan Postdoctoral Fellow in the Boyden and Feng labs. Photo: Steph Stevens

“This technology can be used to answer a lot of biological questions about dysfunction in synaptic proteins, which are involved in neurodegenerative diseases,” says Jinyoung Kang, a J. Douglas Tan Postdoctoral Fellow in the labs of Boyden and Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences. “Until now, there has been no tool to visualize synapses very well at nanoscale.”

Over the past year, the Boyden team has been using ExR to explore the underlying mechanisms of brain disorders, including autism spectrum disorder (ASD) and Alzheimer’s disease. Since the method can be applied iteratively, Boyden imagines it may one day succeed in creating a 100-fold magnification of molecular structures.

“Using earlier technology, researchers may be missing entire categories of molecular phenomena, both functional and dysfunctional,” says Boyden. “It’s critical to bring these nanostructures into view so that we can identify potential targets for new therapeutics that can restore functional molecular arrangements.”

The team is applying ExR to the study of mutant-animal-model brain slices to expose complex synapse 3D nanoarchitecture and configuration. Among their questions: How do synapses differ when mutations that cause autism and other neurological conditions are present?

Using the new technology, Kang and her collaborator Menglong Zeng characterized the molecular architecture of excitatory synapses on parvalbumin interneurons, cells that drastically influence the downstream effects of neuronal signaling and ultimately change cognitive behaviors. They discovered condensed AMPAR clustering in parvalbumin interneurons is essential for normal brain function. The next step is to explore their role in the function of parvalbumin interneurons, which are vulnerable to stressors and have been implicated in brain disorders including autism and Alzheimer’s disease.

The researchers are now investigating whether ExR can reveal abnormal protein nanostructures in SHANK3 knockout mice and marmosets. Mutations in the SHANK3 gene lead to one of the most severe types of ASD, Phelan-McDermid syndrome, which accounts for about 2 percent of all ASD patients with intellectual disability.