Research Area: Genome Engineering

​CRISPR, SHERLOCK, REPAIR, RNA editing, DNA editing, brain disorders, diagnostics, disease models, therapeutics

RareNet Symposium 2026

by Julie Pryor |

On June 9, the McGovern Institute convened leaders in science, biotechnology, and patient advocacy for RareNet 2026, a first-of-its-kind symposium aimed at dismantling the barriers between laboratory discovery and life-changing treatments for rare brain disorders.

Over 300 million people worldwide live with rare disorders—most affecting the brain and nervous system. Yet the vast majority lack an approved therapy. The Rare Brain Disorders Nexus (RareNet) was established at the McGovern Institute in 2025 by MIT alums Ana Méndez ’91 and Rajeev Jayavant ’86, (EE ’88, SM ’88) to address this need. Led by Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Neuroscience at MIT, RareNet draws together expertise from the MIT community and beyond to expedite the path from lab to clinic.

MIT President Sally Kornbluth set the tone at the inaugural RareNet symposium, thanking founders Méndez and Jayavant for helping MIT focus on this important challenge: “I look forward to watching RareNet dissolve needless barriers, accelerate timelines, and bring new hope to millions of patients and their families for whom hope is long overdue.”

MIT President Sally Kornbluth (third from left) with RareNet founders Rajeev Jayavant (far left) and Ana Méndez (center) at the June 9 symposium at the McGovern Institute. Also pictured are the founders’ son Neal (second from left), RareNet Director Guoping Feng, RareNet Scientific Advisor Xian Gao, and McGovern Institute Director Robert Desimone. Photo: Steph Stevens

RareNet’s collaborative vision came into focus at the symposium, where more than a dozen leading neuroscientists, biotech innovators, and patient advocates shared the podium. The scientific program spanned the full translational pathway, from fundamental discovery to clinical development.

Feng Zhang (McGovern Institute, MIT; HHMI; Broad Institute), Katherine High (RhyGaze AG; Rockefeller University), Kiran Musunuru (University of Pennsylvania), and Timothy Yu (Boston Children’s Hospital; Harvard Medical School) discussed emerging genetic medicines–including genome editing, gene therapy, and individualized therapeutic strategies–and the challenges involved in bringing them safely to patients.

Kevin Bender (University of California San Francisco), Christopher Walsh (Boston Children’s Hospital; Harvard Medical School), Sonia Vallabh (Broad Institute; MGH; Harvard Medical School), and Joseph Buxbaum (Icahn School of Medicine at Mount Sinai) explored how insights into disease mechanisms, human genetics, and patient-derived data are advancing research in neurodevelopmental disorders, autism, and prion disease.

Representatives from the Sturge-Weber and FOXP1 communities–including Karen Ball, Matt Shirley, and Samit Dasgupta–demonstrated how patient foundations can help define research priorities, build essential resources, and drive promising discoveries toward meaningful treatments.

Also among the day’s speakers was Monica Coenraads, who transformed her child’s rare disease into a powerful research initiative. When her daughter Chelsea was diagnosed with Rett syndrome in 1998 at age two, Coenraads faced an uncertain future. Today, as founder and CEO of the Rett Syndrome Research Trust, she is helping to rewrite that story for other families. In a compelling talk with John Sinnamon, Director of Research at RSRT, Coenraads shared both the scientific breakthroughs reshaping Rett syndrome treatment and the deeply personal journey that sparked it all.

“Monica and John’s talks capture the vital connection between patients and families, cutting-edge research, and translational innovation,” says RareNet Executive Director Xian Gao. “It’s a powerful reminder that behind every research breakthrough is a human story demanding progress.”

Tackling rare genetic disorders with patient-focused science

by Stefanie Koperniak | Office of Graduate Education |

Shannon Knight attributes her interest in neuroscience to an experience she had in high school. She and her sister attended a medical day for students at the nearby University of Illinois Chicago. As they were on their way out of the event, they walked past a room with a person holding a brain.

“We stopped and backpedaled into the room, and I was so fascinated,” says Knight. “I was able to hold the brain of a patient who had passed away of Alzheimer’s. The brain holds so much emotion, decision-making — everything. I realized that this man’s entire memory was in my hands, and something clicked for me. I decided that I really wanted to learn much more about this organ.”

Now in her sixth year of doctoral studies at MIT’s McGovern Institute for Brain Research, Knight is working on developing a novel gene therapy for childhood-onset epilepsy, specifically SYNGAP1 haploinsufficiency. This rare genetic disorder is caused by a mutation in the SYNGAP1 gene, rendering one of the two copies of the gene nonfunctional.

SYNGAP1 is important for brain development and neuronal communication, and the disorder leads to seizures in children starting as young as 4 months old. Other symptoms include intellectual disabilities, challenges with eating and sleeping, and difficulties with movement.

While there are currently methods to address the symptoms of the disorder, such as anti-seizure medications and dietary restrictions, as the child ages, the seizures often become resistant to medications. Knight is working to develop a therapeutic using CRISPR, a biotechnology tool used to edit genes. This therapeutic aims to address the root cause of this medication resistance by focusing on the gene itself.

“The idea of leading science with empathy is something that I feel very deeply,” she says. “I hope my efforts in the lab work toward the benefit of the people affected, rather than just for the benefit of my own science.”

Researching gene therapies

Knight’s interest in the brain flourished as a neuroscience major at Bowdoin College, working with Professor Hadley Horch. While she had originally planned to be pre-med, Knight ultimately decided that it wasn’t the best fit. She enjoyed the research she did as part of her honors thesis, exploring the regeneration of neurons in the auditory system of crickets, and decided that she wanted to pursue more research in molecular neuroscience, as well as genetics.

After graduating, Knight worked at the Perrimon Lab at Harvard University, where she first learned about CRISPR, applying it in a fruit fly model. She worked for two years in the lab, co-authoring a few papers and applying to graduate schools.

She ultimately landed in the lab of MIT Professor Guoping Feng, studying the potential of utilizing CRISPR to develop a gene therapy treatment for Phelan-McDermid Syndrome, a rare genetic disorder caused by a deletion or mutation on the 22nd chromosome.

“Many of our graduate students are passionate about making a positive impact to society through cutting-edge research, and Shannon is a perfect example,” says Feng, the James W. and Patricia T. Poitras Professor and associate director at the McGovern Institute. “She is developing gene therapy technologies that have the potential to help many kids with devastating neurodevelopmental disorders.”

Building off of the gene therapy research around Phelan-McDermid syndrome, which is now in clinical trials in patients, Knight is now in the early phases of testing gene therapy for SYNGAP1 disorder. The goal is to go through the same process for the SYNGAP1 gene therapy as for the Phelan-McDermid gene therapy — eventually obtaining U.S. Food and Drug Administration approval and beginning clinical trials.

The testing of the gene therapy on mice with a version of SYNGAP1 disorder has alleviated seizures and all of the behavioral phenotypes. This promising work is being accelerated by the Rare Brain Disorders Nexus, an MIT initiative that launched in the fall of 2025.

“Something I think about a lot is the idea of who ‘deserves’ the attention of a gene therapy. I feel that, regardless of how rare a genetic disorder might be, it still deserves care,” says Knight. “SYNGAP1 disorder is extremely rare, only impacting one to four out of every 10,000 children. I am very fortunate to be at an institution like MIT that has so many labs and brilliant researchers working on diseases that impact large portions of society, and it was really important to me to spend my PhD years helping a small, often unseen population. Although I don’t actually have a relationship with someone who has SYNGAP1 disorder, I know so many people who feel invisible in systems, and it is really important to me to be able to focus on people who feel unseen and give them hope.”

Inspiring others in the lab

In addition to her passion for neuroscience and genetic research, Knight has also developed a love of teaching. She has been a teaching assistant for class 9.12 (Experimental Molecular Neurobiology), leading the lab portion of the course. She has enjoyed working closely with small classes of students, introducing them to the fundamentals of neuroscience lab research.

“We walked through the process of looking at a specific protein in neurons, and talked about how you can go from cell culture all the way up to a mouse brain — and all the steps in between,” she says. “It was so important to me to be able to teach the students and help them to consider all of the different types of experiments they could do.”

Knight received the Goodwin Medal in 2025 in recognition of her commitment to excellent teaching.

“I’ve talked to many of the students since then,” she says, “and many said it was one of their favorite classes.”

Feng Zhang inducted into the National Inventors Hall of Fame

by Julie Pryor |

Fifteen innovation pioneers, including McGovern Investigator Feng Zhang, have been inducted into the 2026 class of the National Inventors Hall of Fame. Zhang is being recognized for his innovations in gene editing and for sharing his resources and expertise broadly with the global scientific community.

In addition to his appointment at the McGovern Institute, Zhang is the James and Patricia Poitras Professor of Neuroscience at MIT and has joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering. He is also an investigator at the McGovern Institute for Brain Research at MIT, an investigator in the Howard Hughes Medical Institute, and co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT.

“The National Inventors Hall of Fame is committed to illuminating the legacies of world-changing inventors and creating opportunities for the next generation to learn from these innovative role models,” said Monica Jones, Chief Executive Officer of the National Inventors Hall of Fame. “The inventors in our 2026 class have made contributions in fields as varied as semiconductor technology and portable inhalers. Induction into the Hall of Fame honors the significance of these advances, which have enhanced our daily lives and well-being.”

Zhang has invented transformative technologies to improve human health, including first demonstrating the use of engineered CRISPR-Cas9 systems for genome editing in human cells. He has co-founded several companies to commercialize these technologies. Through the nonprofit repository Addgene, by 2023 over 75,000 samples of Zhang’s reagents had been shared with researchers in more than 79 countries. He also has trained scientists from around the world in online research forums, in his workshops and in his lab.

“My mother would always emphasize that I should choose to do something useful for the world; to live a life that is meaningful and is adding something to the world, rather than just consuming from the world,” Zhang says. “That has been one of the strongest guiding factors for me.”

In partnership with the United States Patent and Trademark Office (USPTO), the Hall of Fame will honor Zhang and the other 2026 inductees on May 7 at an event in Washington DC.

New study suggests a way to rejuvenate the immune system

by Anne Trafton |

As people age, their immune system function declines. T cell populations become smaller and can’t react to pathogens as quickly, making people more susceptible to a variety of infections.

To try to overcome that decline, researchers at MIT and the Broad Institute have found a way to temporarily program cells in the liver to improve T-cell function. This reprogramming can compensate for the age-related decline of the thymus, where T cell maturation normally occurs.

Using mRNA to deliver three key factors that usually promote T-cell survival, the researchers were able to rejuvenate the immune systems of mice. Aged mice that received the treatment showed much larger and more diverse T cell populations in response to vaccination, and they also responded better to cancer immunotherapy treatments. Their findings are published in the December 17 issue of the journal Nature.

If developed for use in patients, this type of treatment could help people lead healthier lives as they age, the researchers say.

“If we can restore something essential like the immune system, hopefully we can help people stay free of disease for a longer span of their life,” says Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, who has joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.

Zhang, who is also an investigator at the McGovern Institute for Brain Research at MIT, a core institute member at the Broad Institute of MIT and Harvard, an investigator in the Howard Hughes Medical Institute, and co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, is the senior author of the new study. Former MIT postdoc Mirco Friedrich is the lead author of the paper, which appears today in Nature.

A temporary factory

The thymus, a small organ located in front of the heart, plays a critical role in T-cell development. Within the thymus, immature T cells go through a checkpoint process that ensures a diverse repertoire of T cells. The thymus also secretes cytokines and growth factors that help T cells to survive.

However, starting in early adulthood, the thymus begins to shrink. This process, known as thymic involution, leads to a decline in the production of new T cells. By the age of approximately 75, the thymus is greatly reduced.

“As we get older, the immune system begins to decline. We wanted to think about how can we maintain this kind of immune protection for a longer period of time, and that’s what led us to think about what we can do to boost immunity,” Friedrich says.

Previous work on rejuvenating the immune system has focused on delivering T cell growth factors into the bloodstream, but that can have harmful side effects. Researchers are also exploring the possibility of using transplanted stem cells to help regrow functional tissue in the thymus.

The MIT team took a different approach: They wanted to see if they could create a temporary “factory” in the body that would generate the T-cell-stimulating signals that are normally produced by the thymus.

“Our approach is more of a synthetic approach,” Zhang says. “We’re engineering the body to mimic thymic factor secretion.”

For their factory location, they settled on the liver, for several reasons. First, the liver has a high capacity for producing proteins, even in old age. Also, it’s easier to deliver mRNA to the liver than to most other organs of the body. The liver was also an appealing target because all of the body’s circulating blood has to flow through it, including T cells.

To create their factory, the researchers identified three immune cues that are important for T-cell maturation. They encoded these three factors into mRNA sequences that could be delivered by lipid nanoparticles. When injected into the bloodstream, these particles accumulate in the liver and the mRNA is taken up by hepatocytes, which begin to manufacture the proteins encoded by the mRNA.

The factors that the researchers delivered are DLL1, FLT-3, and IL-7, which help immature progenitor T cells mature into fully differentiated T cells.

Immune rejuvenation

Tests in mice revealed a variety of beneficial effects. First, the researchers injected the mRNA particles into 18-month-old mice, equivalent to humans in their 50s. Because mRNA is short-lived, the researchers gave the mice multiple injections over four weeks to maintain a steady production by the liver.

After this treatment, T cell populations showed significant increases in size and function.

The researchers then tested whether the treatment could enhance the animals’ response to vaccination. They vaccinated the mice with ovalbumin, a protein found in egg whites that is commonly used to study how the immune system responds to a specific antigen. In 18-month-old mice that received the mRNA treatment before vaccination, the researchers found that the population of cytotoxic T-cells specific to ovalbumin doubled, compared to mice of the same age that did not receive the mRNA treatment.

The mRNA treatment can also boost the immune system’s response to cancer immunotherapy, the researchers found. They delivered the mRNA treatment to 18-month-old mice, who were then implanted with tumors and treated with a checkpoint inhibitor drug. This drug, which targets the protein PD-L1, is designed to help take the brakes off the immune system and stimulate T cells to attack tumor cells.

Mice that received the treatment showed much higher survival rates and longer lifespan that those that received the checkpoint inhibitor drug but not the mRNA treatment.

The researchers found that all three factors were necessary to induce this immune enhancement; none could achieve all aspects of it on their own. They now plan to study the treatment in other animal models and to identify additional signaling factors that may further enhance immune system function. They also hope to study how the treatment affects other immune cells, including B cells.

Other authors of the paper include Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, and Rhiannon Macrae.

The research was funded, in part, by the Howard Hughes Medical Institute, the K. Lisa Yang Brain-Body Center, part of the Yang Tan Collective at MIT, Broad Institute Programmable Therapeutics Gift Donors, the Pershing Square Foundation, J. and P. Poitras, and an EMBO Postdoctoral Fellowship.

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 the rare brain disorders community has 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.”

Feng Zhang elected to EMBO membership

by Julie Pryor |

The European Molecular Biology Organization (EMBO), a professional non-profit organization dedicated to promoting international research in life sciences, announced its new members today. Among the 69 new members recognized for their outstanding achievements is Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and an investigator at the McGovern Institute.

Zhang, who is also a core member of the Broad Institute, a professor of brain and cognitive sciences and biological engineering at MIT, and a Howard Hughes Medical Institute investigator, is a molecular biologist focused on improving human health. He played an integral role in pioneering the use of CRISPR-Cas9 for genome editing in human cells, including working with Stuart Orkin to develop Casgevy, the first CRISPR-based therapeutic approved for clinical use. His team is currently discovering new ways to modify cellular function and activity—including the restoration of diseased, stressed, or aged cells to a more healthful state.

Zhang has been elected to EMBO as an associate member, where he joins a community of more than 2,100 international life scientists that have demonstrated research excellence in their fields.

“A major strength of EMBO lies in the excellence and dedication of its members,” says EMBO Director Fiona Watt. “Science thrives on global collaboration, and the annual election of the new EMBO members and associate members brings fresh energy and inspiration to our community. We are honoured to welcome this remarkable group of scientists to the EMBO Membership. Their ideas and contributions will enrich the organization and help advance the life sciences internationally.”

The 60 new EMBO members in 2025 are based in 18 member states of the EMBC, the intergovernmental organization that funds the main EMBO programs and activities. The nine new EMBO associate members, including Zhang, are based in six countries outside Europe. In total, 29 (42%) of the new members are women and 40 (58%) are men.

The new members will be formally welcomed at the next EMBO Members’ Meeting in Heidelberg, Germany, on 22-24 October 2025.

Rational engineering generates a compact new tool for gene therapy

by Jennifer Michalowski |

Scientists at the McGovern Institute and the Broad Institute of MIT and Harvard have reengineered a compact RNA-guided enzyme they found in bacteria into an efficient, programmable editor of human DNA. The protein they created, called NovaIscB, can be adapted to make precise changes to the genetic code, modulate the activity of specific genes, or carry out other editing tasks. Because its small size simplifies delivery to cells, NovaIscB’s developers say it is a promising candidate for developing gene therapies to treat or prevent disease.

The study was led by McGovern Institute investigator Feng Zhang, who is also the James and Patricia Poitras Professor of Neuroscience at MIT, a Howard Hughes Medical Institute investigator, and a core member of the Broad Institute. Zhang and his team reported their work today in the journal Nature Biotechnology.

Compact tools

NovaIscB is derived from a bacterial DNA cutter that belongs to a family of proteins called IscBs, which Zhang’s lab discovered in 2021. IscBs are a type of OMEGA system, the evolutionary ancestors to Cas9, which is part of the bacterial CRISPR system that Zhang and others have developed into powerful genome-editing tools. Like Cas9, IscB enzymes cut DNA at sites specified by an RNA guide. By reprogramming that guide, researchers can redirect the enzymes to target sequences of their choosing.

IscBs had caught the team’s attention not only because they share key features of CRISPR’s DNA-cutting Cas9, but also because they are a third of its size. That would be an advantage for potential gene therapies: Compact tools are easier to deliver to cells, and with a small enzyme, researchers would have more flexibility to tinker, potentially adding new functionalities without creating tools that were too bulky for clinical use.

From their initial studies of IscBs, researchers in Zhang’s lab knew that some members of the family could cut DNA targets in human cells. None of the bacterial proteins worked well enough to be deployed therapeutically, however: The team would have to modify an IscB to ensure it could edit targets in human cells efficiently without disturbing the rest of the genome.

To begin that engineering process, Soumya Kannan, a graduate student in Zhang’s lab who is now a junior fellow at the Harvard Society of Fellows, and postdoctoral fellow Shiyou Zhu first searched for an IscB that would make good starting point. They tested nearly 400 different IscB enzymes that can be found in bacteria. Ten were capable of editing DNA in human cells.

Even the most active of those would need to be enhanced to make it a useful genome editing tool. The challenge would be increasing the enzyme’s activity, but only at the sequences specified by its RNA guide. If the enzyme became more active, but indiscriminately so, it would cut DNA in unintended places. “The key is to balance the improvement of both activity and specificity at the same time,” explains Zhu.

Zhu notes that bacterial IscBs are directed to their target sequences by relatively short RNA guides, which makes it difficult to restrict the enzyme’s activity to a specific part of the genome. If an IscB could be engineered to accommodate a longer guide, it would be less likely to act on sequences beyond its intended target.

To optimize IscB for human genome editing, the team leveraged information that graduate student Han Altae-Tran, who is now a postdoctoral fellow at the University of Washington, had learned about the diversity of bacterial IscBs and how they evolved. For instance, the researchers noted that IscBs that worked in human cells included a segment they called REC, which was absent in other IscBs. They suspected the enzyme might need that segment to interact with the DNA in human cells. When they took a closer look at the region, structural modeling suggested that by slightly expanding part of the protein, REC might also enable IscBs to recognize longer RNA guides.

Based on these observations, the team experimented with swapping in parts of REC domains from different IscBs and Cas9s, evaluating how each change impacted the protein’s function. Guided by their understanding of how IscBs and Cas9s interact with both DNA and their RNA guides, the researchers made additional changes, aiming to optimize both efficiency and specificity.

In the end, they generated a protein they called NovaIscB, which was over 100 times more active in human cells than the IscB they had started with and that had demonstrated good specificity for its targets.

Kannan and Zhu constructed and screened hundreds of new IscBs before arriving at NovaIscB—and every change they made to the original protein was strategic. Their efforts were guided by their team’s knowledge of IscBs’ natural evolution as well as predictions of how each alteration would impact the protein’s structure, made using an artificial intelligence tool called AlphaFold2. Compared to traditional methods of introducing random changes into a protein and screening for their effects, this rational engineering approach greatly accelerated the team’s ability to identify a protein with the features they were looking for.

The team demonstrated that NovaIscB is a good scaffold for a variety of genome editing tools. “It biochemically functions very similarly to Cas9, and that makes it easy to port over tools that were already optimized with the Cas9 scaffold,” Kannan says. With different modifications, the researchers used NovaIscB to replace specific letters of the DNA code in human cells and to change the activity of targeted genes.

Importantly, the NovaIscB-based tools are compact enough to be easily packaged inside a single adeno-associated virus (AAV)—the vector most commonly used to safely deliver gene therapy to patients. Because they are bulkier, tools developed using Cas9 can require a more complicated delivery strategy.

Demonstrating NovaIscB’s potential for therapeutic use, Zhang’s team created a tool called OMEGAoff that adds chemical markers to DNA to dial down the activity of specific genes. They programmed OMEGAoff to repress a gene involved in cholesterol regulation, then used AAV to deliver the system to the livers of mice, leading to lasting reductions in cholesterol levels in the animals’ blood.

The team expects that NovaIscB can be used to target genome editing tools to most human genes, and look forward to seeing how other labs deploy the new technology. They also hope others will adopt their evolution-guided approach to rational protein engineering. “Nature has such diversity and its systems have different advantages and disadvantages,” Zhu says. “By learning about that natural diversity, we can make the systems we are trying to engineer better and better.”

This study was funded in part by the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, Broad Institute Programmable Therapeutics Gift Donors, Pershing Square Foundation, William Ackman, Neri Oxman, the Phillips family, and J. and P. Poitras.

Scientists engineer CRISPR enzymes that evade the immune system

by Allessandra DiCorato | Broad Institute |

The core components of CRISPR-based genome-editing therapies are bacterial proteins called nucleases that can stimulate unwanted immune responses in people, increasing the chances of side effects and making these therapies potentially less effective.

Researchers at the Broad Institute of MIT and Harvard and Cyrus Biotechnology have now engineered two CRISPR nucleases, Cas9 and Cas12, to mask them from the immune system. The team identified protein sequences on each nuclease that trigger the immune system and used computational modeling to design new versions that evade immune recognition. The engineered enzymes had similar gene-editing efficiency and reduced immune responses compared to standard nucleases in mice.

Appearing today in Nature Communications, the findings could help pave the way for safer, more efficient gene therapies. The study was led by Feng Zhang, a core institute member at the Broad and an Investigator at the McGovern Institute for Brain Research at MIT.

“As CRISPR therapies enter the clinic, there is a growing need to ensure that these tools are as safe as possible, and this work tackles one aspect of that challenge,” said Zhang, who is also a co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics, the James and Patricia Poitras Professor of Neuroscience, and a professor at MIT. He is an Investigator at the Howard Hughes Medical Institute.

Rumya Raghavan, a graduate student in Zhang’s lab when the study began, and Mirco Julian Friedrich, a postdoctoral scholar in Zhang’s lab, were co-first authors on the study.

“People have known for a while that Cas9 causes an immune response, but we wanted to pinpoint which parts of the protein were being recognized by the immune system and then engineer the proteins to get rid of those parts while retaining its function,” said Raghavan.

“Our goal was to use this information to create not only a safer therapy, but one that is potentially even more effective because it is not being eliminated by the immune system before it can do its job,” added Friedrich.

In search of immune triggers

Many CRISPR-based therapies use nucleases derived from bacteria. About 80 percent of people have pre-existing immunity to these proteins through everyday exposure to these bacteria, but scientists didn’t know which parts of the nucleases the immune system recognized.

To find out, Zhang’s team used a specialized type of mass spectrometry to identify and analyze the Cas9 and Cas 12 protein fragments recognized by immune cells. For each of two nucleases — Cas9 from Streptococcus pyogenes and Cas12 from Staphylococcus aureus — they identified three short sequences, about eight amino acids long, that evoked an immune response. They then partnered with Cyrus Biotechnology, a company co-founded by University of Washington biochemist David Baker that develops structure-based computational tools to design proteins that evade the immune response. After Zhang’s team identified immunogenic sequences in Cas9 and Cas12, Cyrus used these computational approaches to design versions of the nucleases that did not include the immune-triggering sequences.

Zhang’s lab used prediction software to validate that the new nucleases were less likely to trigger immune responses. Next, the team engineered a panel of new nucleases informed by these predictions and tested the most promising candidates in human cells and in mice that were genetically modified to bear key components of the human immune system. In both cases, they found that the engineered enzymes resulted in significantly reduced immune responses compared to the original nucleases, but still cut DNA at the same efficiency.

Minimally immunogenic nucleases are just one part of safer gene therapies, Zhang’s team says. In the future, they hope their methods may also help scientists design delivery vehicles to evade the immune system.

This study was funded in part by the Poitras Center for Psychiatric Disorders Research, the K. Lisa. Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience and the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT.

Feng Zhang awarded 2024 National Medal of Technology

by Julie Pryor |

This post is adapted from an MIT News story.

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Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and an Investigator at the McGovern Institute, has won the National Medal of Technology and Innovation, the nation’s highest recognition for scientists and engineers. The prestigious award recognizes “American innovators whose vision, intellect, creativity, and determination have strengthened America’s economy and improved our quality of life.”

Zhang, who is also a professor of brain and cognitive sciences and biological engineering at MIT, a core member of the Broad Institute of MIT and Harvard, and an investigator with the Howard Hughes Medical Institute, was recognized for his work developing molecular tools, including the CRISPR genome-editing system, that have accelerated biomedical research and led to the first FDA-approved gene editing therapy.

This year, the White House awarded the National Medal of Science to 14 recipients and named nine individual awardees of the National Medal of Technology and Innovation, along with two organizations. Zhang is among four MIT faculty members who were awarded the nation’s highest honors for exemplary achievement and leadership in science and technology.

Designing molecular tools

Zhang, who earned his undergraduate degree from Harvard University in 2004, has contributed to the development of multiple molecular tools to accelerate the understanding of human disease. While a graduate student at Stanford University, from which he received his PhD in 2009, Zhang worked in the lab of Professor Karl Deisseroth. There, he worked on a protein called channelrhodopsin, which he and Deisseroth believed held potential for engineering mammalian cells to respond to light.

The resulting technique, known as optogenetics, is now used widely used in neuroscience and other fields. By engineering neurons to express light-sensitive proteins such as channelrhodopsin, researchers can either stimulate or silence the cells’ electrical impulses by shining different wavelengths of light on them. This has allowed for detailed study of the roles of specific populations of neurons in the brain, and the mapping of neural circuits that control a variety of behaviors.

In 2011, about a month after joining the MIT faculty, Zhang attended a talk by Harvard Medical School Professor Michael Gilmore, who studies the pathogenic bacterium Enteroccocus. The scientist mentioned that these bacteria protect themselves from viruses with DNA-cutting enzymes known as nucleases, which are part of a defense system known as CRISPR.

“I had no idea what CRISPR was, but I was interested in nucleases,” Zhang told MIT News in 2016. “I went to look up CRISPR, and that’s when I realized you might be able to engineer it for use for genome editing.”

In January 2013, Zhang and members of his lab reported that they had successfully used CRISPR to edit genes in mammalian cells. The CRISPR system includes a nuclease called Cas9, which can be directed to cut a specific genetic target by RNA molecules known as guide strands.

Since then, scientists in fields from medicine to plant biology have used CRISPR to study gene function and modify faulty genes that cause disease. More recently, Zhang’s lab has devised many enhancements to the original CRISPR system, such as making the targeting more precise and preventing unintended cuts in the wrong locations. In 2023, the FDA approved Casgevy, a CRISPR gene therapy based on Zhang’s discoveries, for the treatment of sickle cell disease and beta thalassemia.

The National Medal of Technology and Innovation was established in 1980 and is administered for the White House by the U.S. Department of Commerce’s Patent and Trademark Office. The award recognizes those who have made lasting contributions to America’s competitiveness and quality of life and helped strengthen the nation’s technological workforce.