Researcher: Feng Zhang

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.

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.

An ancient RNA-guided system could simplify delivery of gene editing therapies

by Jennifer Michalowski |

A vast search of natural diversity has led scientists at MIT’s McGovern Institute and the Broad Institute of MIT and Harvard to uncover ancient systems with potential to expand the genome editing toolbox. These systems, which the researchers call TIGR (Tandem Interspaced Guide RNA) systems, use RNA to guide them to specific sites on DNA. TIGR systems can be reprogrammed to target any DNA sequence of interest, and they have distinct functional modules that can act on the targeted DNA. In addition to its modularity, TIGR is very compact compared to other RNA-guided systems, like CRISPR, which is a major advantage for delivering it in a therapeutic context.

These findings are reported online February 27, 2025 in the journal Science.

“This is a very versatile RNA-guided system with a lot of diverse functionalities,” says Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT who led the research. The TIGR-associated (Tas) proteins that Zhang’s team found share a characteristic RNA-binding component that interacts with an RNA guide that directs it to a specific site in the genome. Some cut the DNA at that site, using an adjacent DNA-cutting segment of the protein. That modularity could facilitate tool development, allowing researchers to swap useful new features into natural Tas proteins.

“Nature is pretty incredible,” said Zhang who is also an investigator at the McGovern Institute and the Howard Hughes Medical Institute, a core member of the Broad Institute, a professor of brain and cognitive sciences and biological engineering at MIT, and co-director of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT. “It’s got a tremendous amount of diversity, and we have been exploring that natural diversity to find new biological mechanisms and harnessing them for different applications to manipulate biological processes,” he says. Previously, Zhang’s team adapted bacterial CRISPR systems into gene editing tools that have transformed modern biology. His team has also found a variety of programmable proteins, both from CRISPR systems and beyond.

In their new work, to find novel programmable systems, the team began by zeroing in a structural feature of the CRISPR Cas9 protein that binds to the enzyme’s RNA guide. That is a key feature that has made Cas9 such a powerful tool: “Being RNA-guided makes it relatively easy to reprogram, because we know how RNA binds to other DNA or other RNA,” Zhang explains. His team searched hundreds of millions of biological proteins with known or predicted structures, looking for any that shared a similar domain. To find more distantly related proteins, they used an iterative process: from Cas9, they identified a protein called IS110, which had previously been shown by others to bind RNA. They then zeroed in on the structural features of IS110 that enable RNA binding and repeated their search.

At this point, the search had turned up so many distantly related proteins that they team turned to artificial intelligence to make sense of the list. “When you are doing iterative, deep mining, the resulting hits can be so diverse that they are difficult to analyze using standard phylogenetic methods, which rely on conserved sequence,” explains Guilhem Faure, a computational biologist in Zhang’s lab. With a protein large language model, the team was able to cluster the proteins they had found into groups according to their likely evolutionarily relationships. One group set apart from the rest, and its members were particularly intriguing because they were encoded by genes with regularly spaced repetitive sequences reminiscent of an essential component of CRISPR systems. These were the TIGR-Tas systems.

Zhang’s team discovered >20,000 different Tas proteins, mostly occurring in bacteria-infecting viruses. Sequences within each gene’s repetitive region—its TIGR arrays—encode an RNA guide that interacts with the RNA-binding part of the protein. In some, the RNA-binding region is adjacent to a DNA-cutting part of the protein. Others appear to bind to other proteins, which suggests they might help direct those proteins to DNA targets.

Zhang and his team experimented with dozens of Tas proteins, demonstrating that some can be programmed to make targeted cuts to DNA in human cells. As they think about developing TIGR-Tas systems into programmable tools, the researchers are encouraged by features that could make those tools particularly flexible and precise.

They note that CRISPR systems can only be directed to segments of DNA that are flanked by short motifs known as PAMs (protospacer adjacent motifs). TIGR Tas proteins, in contrast, have no such requirement. “This means theoretically, any site in the genome should be targetable,” says scientific advisor Rhiannon Macrae. The team’s experiments also show that TIGR systems have what Faure calls a “dual-guide system,” interacting with both strands of the DNA double helix to home in on their target sequences, which should ensure they act only where they are directed by their RNA guide. What’s more, Tas proteins are compact—a quarter of the size Cas9 on average—making them easier to deliver, which could overcome a major obstacle to therapeutic deployment of gene editing tools.

Excited by their discovery, Zhang’s team is now investigating the natural role of TIGR systems in viruses as well as how they can be adapted for research or therapeutics. They have determined the molecular structure of one of the Tas proteins they found to work in human cells, and will use that information to guide their efforts to make it more efficient. Additionally, they note connections between TIGR-Tas systems and certain RNA-processing proteins in human cells. “I think there’s more there to study in terms of what some of those relationships may be, and it may help us better understand how these systems are used in humans,” Zhang says.

This work was supported by the Helen Hay Whitney Foundation, Howard Hughes Medical Institute, K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics, Broad Institute Programmable Therapeutics Gift Donors, Pershing Square Foundation, William Ackman, and Neri Oxman, the Phillips family, J. and P. Poitras, and the BT Charitable Foundation.

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.

***

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.

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

Search algorithm reveals nearly 200 new kinds of CRISPR systems

by Allessandra DiCorato | Broad Institute |

Microbial sequence databases contain a wealth of information about enzymes and other molecules that could be adapted for biotechnology. But these databases have grown so large in recent years that they’ve become difficult to search efficiently for enzymes of interest.

Now, scientists at the Broad Institute of MIT and Harvard, the McGovern Institute for Brain Research at MIT, and the National Center for Biotechnology Information (NCBI) at the National Institutes of Health have developed a new search algorithm that has identified 188 kinds of new rare CRISPR systems in bacterial genomes, encompassing thousands of individual systems. The work appears today in Science.

The algorithm, which comes from the lab of CRISPR pioneer Feng Zhang, uses big-data clustering approaches to rapidly search massive amounts of genomic data. The team used their algorithm, called Fast Locality-Sensitive Hashing-based clustering (FLSHclust) to mine three major public databases that contain data from a wide range of unusual bacteria, including ones found in coal mines, breweries, Antarctic lakes, and dog saliva. The scientists found a surprising number and diversity of CRISPR systems, including ones that could make edits to DNA in human cells, others that can target RNA, and many with a variety of other functions.

The new systems could potentially be harnessed to edit mammalian cells with fewer off-target effects than current Cas9 systems. They could also one day be used as diagnostics or serve as molecular records of activity inside cells.

The researchers say their search highlights an unprecedented level of diversity and flexibility of CRISPR and that there are likely many more rare systems yet to be discovered as databases continue to grow.

“Biodiversity is such a treasure trove, and as we continue to sequence more genomes and metagenomic samples, there is a growing need for better tools, like FLSHclust, to search that sequence space to find the molecular gems,” said Zhang, a co-senior author on the study and a core institute member at the Broad.

Zhang is also an investigator at the McGovern Institute for Brain Research at MIT, the James and Patricia Poitras Professor of Neuroscience at MIT with joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering, and an investigator at the Howard Hughes Medical Institute. Eugene Koonin, a distinguished investigator at the NCBI, is co-senior author on the study as well.

Searching for CRISPR

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a bacterial defense system that has been engineered into many tools for genome editing and diagnostics.

To mine databases of protein and nucleic acid sequences for novel CRISPR systems, the researchers developed an algorithm based on an approach borrowed from the big data community. This technique, called locality-sensitive hashing, clusters together objects that are similar but not exactly identical. Using this approach allowed the team to probe billions of protein and DNA sequences — from the NCBI, its Whole Genome Shotgun database, and the Joint Genome Institute — in weeks, whereas previous methods that look for identical objects would have taken months. They designed their algorithm to look for genes associated with CRISPR.

“This new algorithm allows us to parse through data in a time frame that’s short enough that we can actually recover results and make biological hypotheses,” said Soumya Kannan, who is a co-first author on the study. Kannan was a graduate student in Zhang’s lab when the study began and is currently a postdoctoral researcher and Junior Fellow at Harvard University. Han Altae-Tran, a graduate student in Zhang’s lab during the study and currently a postdoctoral researcher at the University of Washington, was the study’s other co-first author.

“This is a testament to what you can do when you improve on the methods for exploration and use as much data as possible,” said Altae-Tran. “It’s really exciting to be able to improve the scale at which we search.”

New systems

In their analysis, Altae-Tran, Kannan, and their colleagues noticed that the thousands of CRISPR systems they found fell into a few existing and many new categories. They studied several of the new systems in greater detail in the lab.

They found several new variants of known Type I CRISPR systems, which use a guide RNA that is 32 base pairs long rather than the 20-nucleotide guide of Cas9. Because of their longer guide RNAs, these Type I systems could potentially be used to develop more precise gene-editing technology that is less prone to off-target editing. Zhang’s team showed that two of these systems could make short edits in the DNA of human cells. And because these Type I systems are similar in size to CRISPR-Cas9, they could likely be delivered to cells in animals or humans using the same gene-delivery technologies being used today for CRISPR.

One of the Type I systems also showed “collateral activity” — broad degradation of nucleic acids after the CRISPR protein binds its target. Scientists have used similar systems to make infectious disease diagnostics such as SHERLOCK, a tool capable of rapidly sensing a single molecule of DNA or RNA. Zhang’s team thinks the new systems could be adapted for diagnostic technologies as well.

The researchers also uncovered new mechanisms of action for some Type IV CRISPR systems, and a Type VII system that precisely targets RNA, which could potentially be used in RNA editing. Other systems could potentially be used as recording tools — a molecular document of when a gene was expressed — or as sensors of specific activity in a living cell.

Mining data

The scientists say their algorithm could aid in the search for other biochemical systems. “This search algorithm could be used by anyone who wants to work with these large databases for studying how proteins evolve or discovering new genes,” Altae-Tran said.

The researchers add that their findings illustrate not only how diverse CRISPR systems are, but also that most are rare and only found in unusual bacteria. “Some of these microbial systems were exclusively found in water from coal mines,” Kannan said. “If someone hadn’t been interested in that, we may never have seen those systems. Broadening our sampling diversity is really important to continue expanding the diversity of what we can discover.”

This work was supported by the Howard Hughes Medical Institute; K. Lisa Yang and Hock E. Tan Molecular Therapeutics Center at MIT; Broad Institute Programmable Therapeutics Gift Donors; The Pershing Square Foundation, William Ackman and Neri Oxman; James and Patricia Poitras; BT Charitable Foundation; Asness Family Foundation; Kenneth C. Griffin; the Phillips family; David Cheng; and Robert Metcalfe.

Nature: An unexpected source of innovative tools to study the brain

by Jennifer Michalowski |

This story originally appeared in the Fall 2023 issue of BrainScan.

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Scientist holds 3D printed phage over a natural background.
Genetic engineer Joseph Kreitz looks to the microscopic world for inspiration in Feng Zhang’s lab at the McGovern Institute. Photo: Steph Steve

In their quest to deepen their understanding of the brain, McGovern scientists take inspiration wherever it comes — and sometimes it comes from surprising sources. To develop new tools for research and innovative strategies for treating disease, they’ve drawn on proteins that organisms have been making for billions of years as well as sophisticated materials engineered for modern technology.

For McGovern investigator Feng Zhang, the natural world provides a rich source of molecules with remarkable and potentially useful functions.

Zhang is one of the pioneers of CRISPR, a programmable system for gene editing that is built from the components of a bacterial adaptive immune system. Scientists worldwide use CRISPR to modify genetic sequences in their labs, and many CRISPR-based therapies, which aim to treat disease through gene editing, are now in development. Meanwhile, Zhang and his team have continued to explore CRISPR-like systems beyond the bacteria in which they were originally discovered.

Turning to nature

This year, the search for evolutionarily related systems led Zhang’s team to a set of enzymes made by more complex organisms, including single-celled algae and hard-shell clams. Like the enzymes that power CRISPR, these newly discovered enzymes, called Fanzors, can be directed to cut DNA at specific sites by programming an RNA molecule as a guide.

Rhiannon Macrae, a scientific advisor in Zhang’s lab, says the discovery was surprising because Fanzors don’t seem to play the same role in immunity that CRISPR systems do. In fact, she says it’s not clear what Fanzors do at all. But as programmable gene editors, Fanzors might have an important advantage over current CRISPR tools — particularly for clinical applications. “Fanzor proteins are much smaller than the workhorse CRISPR tool, Cas9,” Macrae says. “This really matters when you actually want to be able to use one of these tools in a patient, because the bigger the tool, the harder it is to package and deliver to patients’ cells.”

Cryo-EM map of a Fanzor protein (gray, yellow, light blue, and pink) in complex with ωRNA (purple) and its target DNA (red). Non-target DNA strand in blue. Image: Zhang lab

Zhang’s team has thought a lot about how to get therapies to patients’ cells, and size is only one consideration. They’ve also been looking for ways to direct drugs, gene-editing tools, or other therapies to specific cells and tissues in the body. One of the lab’s leading strategies comes from another unexpected natural source: a microscopic syringe produced by certain insect-infecting bacteria.

In their search for an efficient system for targeted drug delivery, Zhang and graduate student Joseph Kreitz first considered the injection systems of bacteria-infecting viruses: needle-like structures that pierce the outer membrane of their host to deliver their own genetic material. But these viral injection systems can’t easily be freed from the rest of the virus.

Then Zhang learned that some bacteria have injection systems of their own, which they release inside their hosts after packing them with toxins. They reengineered the bacterial syringe, devising a delivery system that works on human cells. Their current system can be programmed to inject proteins — including those used for gene editing — directly into specified cell types. With further development, Zhang hopes it will work with other types of therapies, as well.

Magnetic imaging

In McGovern Associate Investigator Alan Jasanoff’s lab, researchers are designing sensors that can track the activity of specific neurons or molecules in the brain, using magnetic resonance imaging (MRI) or related forms of non-invasive imaging. These tools are essential for understanding how the brain’s cells and circuits work together to process information. “We want to give MRI a suite of metaphorical colors: sensitivities that enable us to dissect the different kinds of mechanistically significant contributors to neural activity,” he explains.

Jasanoff can tick off a list of molecules with notable roles in biology and industry that his lab has repurposed to glean more information from brain imaging. These include manganese — a metal once used to tint ancient glass; nitric oxide synthase — the enzyme that causes blushing; and iron oxide nanoparticles — tiny magnets that enable compact data storage inside computers. But Jasanoff says none of these should be considered out of place in the imaging world. “Most are pretty logical choices,” he says. “They all do different things and we use them in pretty different ways, but they are either magnetic or interact with magnetic molecules to serve our purposes for brain imaging.”

Close-up picture of manganese metal
Manganese, a metal that interacts weakly with magnetic fields, is a key component in new MRI sensors being developed in Alan Jasanoff’s lab at the McGovern Institute.

The enzyme nitric oxide synthase, for example, plays an important role in most functional MRI scans. The enzyme produces nitric oxide, which causes blood vessels to expand. This can bring a blush to the cheeks, but in the brain, it increases blood flow to bring more oxygen to busy neurons. MRI can detect this change because it is sensitive to the magnetic properties of blood.

By using blood flow as a proxy for neural activity, functional MRI scans light up active regions of the brain, but they can’t pinpoint the activity of specific cells. So Jasanoff and his team devised a more informative MRI sensor by reengineering nitric oxide synthase. Their modified enzyme, which they call NOSTIC, can be introduced into a select group of cells, where it will produce nitric oxide in response to neural activity — triggering increased blood flow and strengthening the local MRI signal. Researchers can deliver it to specific kinds of brain cells, or they can deliver it exclusively to neurons that communicate directly with one another. Then they can watch for an elevated MRI signal when those cells fire. This lets them see how information flows through the brain and tie specific cells to particular tasks.

Miranda Dawson, a graduate student in Jasanoff’s lab, is using NOSTIC to study the brain circuits that fuel addiction. She’s interested in the involvement of a brain region called the insula, which may mediate the physical sensations that people with addiction experience during drug cravings or withdrawal. With NOSTIC, Dawson can follow how the insula communicates to other parts of the brain as a rat experiences these MITstages of addiction. “We give our sensor to the insula, and then it projects to anatomically connected brain regions,” she explains. “So we’re able to delineate what circuits are being activated at different points in the addiction cycle.”

Scientist with folded arms next to a picture of a brain
Miranda Dawson uses her lab’s novel MRI sensor, NOSTIC, to illuminate the brain circuits involved in fentanyl craving and withdrawal. Photo: Steph Stevens; MRI scan: Nan Li, Souparno Ghosh, Jasanoff lab

Mining biodiversity

McGovern investigators know that good ideas and useful tools can come from anywhere. Sometimes, the key to harnessing those tools is simply recognizing their potential. But there are also opportunities for a more deliberate approach to finding them.

McGovern Investigator Ed Boyden is leading a program that aims to accelerate the discovery of valuable natural products. Called the Biodiversity Network (BioNet), the project is collecting biospecimens from around the world and systematically analyzing them, looking for molecular tools that could be applied to major challenges in science and medicine, from brain research to organ preservation. “The idea behind BioNet,” Boyden explains, “is rather than wait for chance to give us these discoveries, can we go look for them on purpose?”