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New Spanish-language neuroscience podcast flourishes in third season

by Thea Singer |

A Spanish version of this news story can be found here. (Una versión en español de esta noticia se puede encontrar aquí.)

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Sylvia Abente, a clinical neurologist at the Universidad Nacional de Asunción in Paraguay, investigates the range of symptoms that characterize epilepsy. She works with indigenous peoples in Paraguay, and her fluency in Spanish and Guarni—the two official languages of Paraguay—allows her to help patients find the words to describe their epilepsy symptoms so she can treat them.

Juan Carlos Caicedo Mera, a neuroscientist at the Universidad Externado de Colombia, uses rodent models to research the neurobiological effects of early life stress. He has been instrumental in raising public awareness about the biological and behavioral effects of early-age physical punishment, leading to policy changes aimed at reducing its prevalence as a cultural practice in Colombia.

Woman interviews a man at a table with a camera recording the interview in the foreground.
Jessica Chomik-Morales (right) interviews Pedro Maldonado at the Biomedical Neuroscience Institute of Chile at the University of Chile. Photo: Jessica Chomik-Morales

Those are just two of the 33 neuroscientists in seven Latin American countries that Jessica Chomik-Morales interviewed over 37 days for the expansive third season of her Spanish-language podcast, “Mi Ultima Neurona” (“My Last Neuron”), which launches Sept. 18 at 5 p.m. on YouTube. Each episode runs between 45 and 90 minutes.

“I wanted to shine a spotlight on their stories to dispel the misconception that excellent science can only be done in America and Europe,” says Chomik-Morales, “or that it isn’t being produced in South America because of financial and other barriers.”

A first-generation college graduate who grew up in Asunción, Paraguay and Boca Raton, Florida, Chomik-Morales is now a postbaccalaureate research scholar at MIT. Here she works with Laura Schulz, professor of cognitive science, and Nancy Kanwisher, McGovern Institute investigator and the Walter A. Rosenblith Professor of Cognitive Neuroscience, using functional brain imaging to investigate how the brain explains the past, predicts the future, and intervenes on the present.

“The podcast is for the general public and is suitable for all ages,” she says. “It explains neuroscience in a digestable way to inspire young people that they, too, can become scientists and to show the rich variety of reseach that is being done in listeners’ home countries.”

Journey of a lifetime

“Mi Ultima Neurona” began as an idea in 2021 and grew rapidly into a collection of conversations with prominent Hispanic scientists, including L. Rafael Reif, a Venezuelan-American electrical engineer and the 17th president of MIT.

Woman interviews man at a table while another man adjusts microphone.
Jessica Chomik-Morales (left) interviews the 17th president of MIT, L. Rafael Reif (right), for her podcast while Héctor De Jesús-Cortés (center) adjusts the microphone. Photo: Steph Stevens

Building upon the professional relationships she built in seasons one and two, Chomik-Morales broadened her vision, and assembled a list of potential guests in Latin America for season three.  With research help from her scientific advisor, Héctor De Jesús-Cortés, an MIT postdoc from Puerto Rico, and financial support from the McGovern Institute, the Picower Institute for Learning and Memory, the Department of Brain and Cognitive Sciences, and MIT International Science and Technology Initiatives, Chomik-Morales lined up interviews with scientists in Mexico, Peru, Colombia, Chile, Argentina, Uruguay, and Paraguay during the summer of 2023.

Traveling by plane every four or five days, and garnering further referrals from one leg of the trip to the next through word of mouth, Chomik-Morales logged over 10,000 miles and collected 33 stories for her third season. The scientists’ areas of specialization run the gamut— from the social aspects of sleep/wake cycles to mood and personality disorders, from linguistics and language in the brain to computational modeling as a research tool.

“This is the most fulfilling thing I’ve ever done.” – Jessica Chomik-Morales

“If somebody studies depression and anxiety, I want to touch on their opinions regarding various therapies, including drugs, even microdosing with hallucinogens,” says Chomik-Morales. “These are the things people are talking about.” She’s not afraid to broach sensitive topics, like the relationship between hormones and sexual orientation, because “it’s important that people listen to experts talk about these things,” she says.

The tone of the interviews range from casual (“the researcher and I are like friends,” she says) to pedagogic (“professor to student”). The only constants are accessibility—avoiding technical terms—and the opening and closing questions in each one. To start: “How did you get here? What drew you to neuroscience?” To end: “What advice would you give a young Latino student who is interested in STEM?”

She lets her listeners’ frame of reference be her guide. “If I didn’t understand something or thought it could be explained better, I’d say, ‘Let’s pause. ‘What does this word mean?’ ” even if she knew the definition herself. She gives the example of the word “MEG” (magnetoencephalography)—the measurement of the magnetic field generated by the electrical activity of neurons, which is usually combined with magnetic resonance imaging to produce magnetic source imaging. To bring the concept down to Earth, she’d ask: “How does it work? Does this kind of scan hurt the patient?’ ”

Paving the way for global networking

Chomik-Morales’s equipment was spare: three Yeti microphones and a Canon video camera connected to her laptop computer. The interviews took place in classrooms, university offices, at researchers’ homes, even outside—no soundproof studios were available. She has been working with sound engineer David Samuel Torres, from Puerto Rico, to clarify the audio.

No technological limitations could obscure the significance of the project for the participating scientists.

Two women talking at a table in front of a camera.
Jessica Chomik-Morales (left) interviews Josefina Cruzat (right) at Adolfo Ibañez University in Chile. Photo: Jessica Chomik-Morales

“‘Mi Ultima Neurona’ showcases our diverse expertise on a global stage, providing a more accurate portrayal of the scientific landscape in Latin America,” says Constanza Baquedano, who is from Chile. “It’s a step toward creating a more inclusive representation in science.” Baquendano is an assistant professor of psychology at Universidad Adolfo Ibáñez, where she uses electrophysiology and electroencephalographic and behavioral measurements to investigate meditation and other contemplative states. “I was eager to be a part of a project that aimed to bring recognition to our shared experiences as Latin American women in the field of neuroscience.”

“Understanding the challenges and opportunities of neuroscientists working in Latin America is vital,”says Agustín Ibañez, professor and director of the Latin American Brain Health Institute (BrainLat) at Universidad Adolfo Ibáñez in Chile. “This region, characterized by significant inequalities affecting brain health, also presents unique challenges in the field of neuroscience,” says Ibañez, who is primarily interested in the intersection of social, cognitive, and affective neuroscience. “By focusing on Latin America, the podcast brings forth the narratives that often remain untold in the mainstream. That bridges gaps and paves the way for global networking.”

For her part, Chomik-Morales is hopeful that her podcast will generate a strong following in Latin America. “I am so grateful for the wonderful sponsorship from MIT,” says Chomik-Morales. “This is the most fulfilling thing I’ve ever done.”

Study decodes surprising approach mice take in learning

by David Orenstein |

Neuroscience discoveries ranging from the nature of memory to treatments for disease have depended on reading the minds of mice, so researchers need to truly understand what the rodents’ behavior is telling them during experiments. In a new study that examines learning from reward, MIT researchers deciphered some initially mystifying mouse behavior, yielding new ideas about how mice think and a mathematical tool to aid future research.

The task the mice were supposed to master is simple: Turn a wheel left or right to get a reward and then recognize when the reward direction switches. When neurotypical people play such “reversal learning” games they quickly infer the optimal approach: stick with the direction that works until it doesn’t and then switch right away. Notably, people with schizophrenia struggle with the task. In the new study in PLOS Computational Biology, mice surprised scientists by showing that while they were capable of learning the “win-stay, lose-shift” strategy, they nonetheless refused to fully adopt it.

“It is not that mice cannot form an inference-based model of this environment—they can,” said corresponding author Mriganka Sur, Newton Professor in The Picower Institute for Learning and Memory and MIT’s Department of Brain and Cognitive Sciences (BCS). “The surprising thing is that they don’t persist with it. Even in a single block of the game where you know the reward is 100 percent on one side, every so often they will try the other side.”

While the mouse motif of departing from the optimal strategy could be due to a failure to hold it in memory, said lead author and Sur Lab graduate student Nhat Le, another possibility is that mice don’t commit to the “win-stay, lose-shift” approach because they don’t trust that their circumstances will remain stable or predictable. Instead, they might deviate from the optimal regime to test whether the rules have changed. Natural settings, after all, are rarely stable or predictable.

“I’d like to think mice are smarter than we give them credit for,” Le said.

But regardless of which reason may cause the mice to mix strategies, added co-senior author Mehrdad Jazayeri, Associate Professor in BCS and the McGovern Institute for Brain Research, it is important for researchers to recognize that they do and to be able to tell when and how they are choosing one strategy or another.

“This study highlights the fact that, unlike the accepted wisdom, mice doing lab tasks do not necessarily adopt a stationary strategy and it offers a computationally rigorous approach to detect and quantify such non-stationarities,” he said. “This ability is important because when researchers record the neural activity, their interpretation of the underlying algorithms and mechanisms may be invalid when they do not take the animals’ shifting strategies into account.”

Tracking thinking

The research team, which also includes co-author Murat Yildirim, a former Sur lab postdoc who is now an assistant professor at the Cleveland Clinic Lerner Research Institute, initially expected that the mice might adopt one strategy or the other. They simulated the results they’d expect to see if the mice either adopted the optimal strategy of inferring a rule about the task, or more randomly surveying whether left or right turns were being rewarded. Mouse behavior on the task, even after days, varied widely but it never resembled the results simulated by just one strategy.

To differing, individual extents, mouse performance on the task reflected variance along three parameters: how quickly they switched directions after the rule switched, how long it took them to transition to the new direction, and how loyal they remained to the new direction. Across 21 mice, the raw data represented a surprising diversity of outcomes on a task that neurotypical humans uniformly optimize. But the mice clearly weren’t helpless. Their average performance significantly improved over time, even though it plateaued below the optimal level.

In the task, the rewarded side switched every 15-25 turns. The team realized the mice were using more than one strategy in each such “block” of the game, rather than just inferring the simple rule and optimizing based on that inference. To disentangle when the mice were employing that strategy or another, the team harnessed an analytical framework called a Hidden Markov Model (HMM), which can computationally tease out when one unseen state is producing a result vs. another unseen state. Le likens it to what a judge on a cooking show might do: inferring which chef contestant made which version of a dish based on patterns in each plate of food before them.

Before the team could use an HMM to decipher their mouse performance results, however, they had to adapt it. A typical HMM might apply to individual mouse choices, but here the team modified it to explain choice transitions over the course of whole blocks. They dubbed their modified model the blockHMM. Computational simulations of task performance using the blockHMM showed that the algorithm is able to infer the true hidden states of an artificial agent. The authors then used this technique to show the mice were persistently blending multiple strategies, achieving varied levels of performance.

“We verified that each animal executes a mixture of behavior from multiple regimes instead of a behavior in a single domain,” Le and his co-authors wrote. “Indeed 17/21 mice used a combination of low, medium and high-performance behavior modes.”

Further analysis revealed that the strategies afoot were indeed the “correct” rule inference strategy and a more exploratory strategy consistent with randomly testing options to get turn-by-turn feedback.

Now that the researchers have decoded the peculiar approach mice take to reversal learning, they are planning to look more deeply into the brain to understand which brain regions and circuits are involved. By watching brain cell activity during the task, they hope to discern what underlies the decisions the mice make to switch strategies.

By examining reversal learning circuits in detail, Sur said, it’s possible the team will gain insights that could help explain why people with schizophrenia show diminished performance on reversal learning tasks. Sur added that some people with autism spectrum disorders also persist with newly unrewarded behaviors longer than neurotypical people, so his lab will also have that phenomenon in mind as they investigate.

Yildirim, too, is interested in examining potential clinical connections.

“This reversal learning paradigm fascinates me since I want to use it in my lab with various preclinical models of neurological disorders,” he said. “The next step for us is to determine the brain mechanisms underlying these differences in behavioral strategies and whether we can manipulate these strategies.”

Funding for the study came from The National Institutes of Health, the Army Research Office, a Paul and Lilah Newton Brain Science Research Award, the Massachusetts Life Sciences Initiative, The Picower Institute for Learning and Memory and The JPB Foundation.

One scientist’s journey from the Middle East to MIT

by Thea Singer |

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

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

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

In the photo he is 29.

A clarity of vision

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

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

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

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

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

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

A path to knowledge

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

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

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

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

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

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

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

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

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

An MIT postdoc and citizenship

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

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

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

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

Returning to the Middle East

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

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

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

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

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

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

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

Unpacking auditory hallucinations

by Thea Singer |

Tamar Regev, the 2022–2024 Poitras Center Postdoctoral Fellow, has identified a new neural system that may shed light on the auditory hallucinations experienced by patients diagnosed with schizophrenia.

Scientist portrait
Tamar Regev is the 2022–2024 Poitras Center Postdoctoral
Fellow in Ev Fedorenko’s lab at the McGovern Institute. Photo: Steph Stevens

“The system appears integral to prosody processing,”says Regev. “‘Prosody’ can be described as the melody of speech — auditory gestures that we use when we’re speaking to signal linguistic, emotional, and social information.” The prosody processing system Regev has uncovered is distinct from the lower-level auditory speech processing system as well as the higher-level language processing system. Regev aims to understand how the prosody system, along with the speech and language processing systems, may be impaired in neuropsychiatric disorders such as schizophrenia, especially when experienced with auditory hallucinations in the form of speech.

“Knowing which neural systems are affected by schizophrenia can lay the groundwork for future research into interventions that target the mechanisms underlying symptoms such as hallucinations,” says Regev. Passionate about bridging gaps between disciplines, she is collaborating with Ann Shinn, MD, MPH, of McLean Hospital’s Schizophrenia and Bipolar Disorder Research Program.

Regev’s graduate work at the Hebrew University of Jerusalem focused on exploring the auditory system with electroencephalography (EEG), which measures electrical activity in the brain using small electrodes attached to the scalp. She came to MIT to study under Evelina Fedorenko, a world leader in researching the cognitive and neural mechanisms underlying language processing. With Fedorenko she has learned to use functional magnetic resonance imaging (fMRI), which reveals the brain’s functional anatomy by measuring small changes in blood flow that occur with brain activity.

“I hope my research will lead to a better understanding of the neural architectures that underlie these disorders—and eventually help us as a society to better understand and accept special populations.”- Tamar Regev

“EEG has very good temporal resolution but poor spatial resolution, while fMRI provides a map of the brain showing where neural signals are coming from,” says Regev. “With fMRI I can connect my work on the auditory system with that on the language system.”

Regev developed a unique fMRI paradigm to do that. While her human subjects are in the scanner, she is comparing brain responses to speech with expressive prosody versus flat prosody to find the role of the prosody system among the auditory, speech, and language regions. She plans to apply her findings to analyze a rich data set drawn from fMRI studies that Fedorenko and Shinn began a few years ago while investigating the neural basis of auditory hallucinations in patients with schizophrenia and bipolar disorder. Regev is exploring how the neural architecture may differ between control subjects and those with and without auditory hallucinations as well as those with schizophrenia and bipolar disorder.

“This is the first time these questions are being asked using the individual-subject approach developed in the Fedorenko lab,” says Regev. The approach provides superior sensitivity, functional resolution, interpretability, and versatility compared with the group analyses of the past. “I hope my research will lead to a better understanding of the neural architectures that underlie these disorders,” says Regev, “and eventually help us as a society to better understand and accept special populations.”

Using the tools of neuroscience to personalize medicine

by Thea Singer |

Profile picture of Sadie Zacharek
Graduate student Sadie Zacharek. Photo: Steph Stevens

From summer internships as an undergraduate studying neuroscience at the University of Notre Dame, Sadie Zacharek developed interests in areas ranging from neuroimaging to developmental psychopathologies, from basic-science research to clinical translation. When she interviewed with John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology and Cognitive Neuroscience, for a position in his lab as a graduate fellow, everything came together.

“The brain provides a window not only into dysfunction but also into response to treatment,” she says. “John and I both wanted to explore how we might use neuroimaging as a step toward personalized medicine.”

Zacharek joined the Gabrieli lab in 2020 and currently holds the Sheldon and Janet Razin’59 Fellowship for 2023-2024. In the Gabrieli lab, she has been designing and helping launch studies focusing on the neural mechanisms driving childhood depression and social anxiety disorder with the aim of developing strategies to predict which treatments will be most effective for individual patients.

Helping children and adults

“Depression in children is hugely understudied,” says Zacharek. “Most of the research has focused on adult and adolescent depression.” But the clinical presentation differs in the two groups, she says. “In children, irritability can be the primary presenting symptom rather than melancholy.” To get to the root of childhood depression, she is exploring both the brain basis of the disorder and how the parent-child relationship might influence symptoms. “Parents help children develop their emotion-regulation skills,” she says. “Knowing the underlying mechanisms could, in family-focused therapy, help them turn a ‘downward spiral’ into irritability, into an ‘upward spiral,’ away from it.”

The studies she is conducting include functional magnetic resonance imaging (fMRI) of children to explore their brain responses to positive and negative stimuli, fMRI of both the child and parent to compare maps of their brains’ functional connectivity, and magnetic resonance spectroscopy to explore the neurochemical environment of both, including quantities of neurometabolites that indicate inflammation (higher levels have been found to correlate with depressive pathology).

“If we could find a normative range for neurochemicals and then see how far someone has deviated in depression, or a neural signature of elevated activity in a brain region, that could serve as a biomarker for future interventions,” she says. “Such a biomarker would be especially relevant for children given that they are less able to articulately convey their symptoms or internal experience.”

“The brain provides a window not only into dysfunction but also into response to treatment.” – Sadie Zacharek

Social anxiety disorder is a chronic and disabling condition that affects about 7.1 percent of U.S. adults. Treatment usually involves cognitive behavior therapy (CBT), and then, if there is limited response, the addition of a selective serotonin reuptake inhibitor (SSRI), as an anxiolytic.

But what if research could reveal the key neurocircuitry of social anxiety disorder as well as changes associated with treatment? That could open the door to predicting treatment outcome.

Zacharek is collecting neuroimaging data, as well as clinical assessments, from participants. The participants diagnosed with social anxiety disorder will then undergo 12 weeks of group CBT, followed by more data collection, and then individual CBT for 12 weeks plus an SSRI for those who do not benefit from the group CBT. The results from those two time points will help determine the best treatment for each person.

“We hope to build a predictive model that could enable clinicians to scan a new patient and select the optimal treatment,” says Zacharek. “John’s many long-standing relationships with clinicians in this area make all of these translational studies possible.”

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?”

Fourteen MIT School of Science professors receive tenure for 2022 and 2023

Anne Trafton |

In 2022, nine MIT faculty were granted tenure in the School of Science:

Gloria Choi examines the interaction of the immune system with the brain and the effects of that interaction on neurodevelopment, behavior, and mood. She also studies how social behaviors are regulated according to sensory stimuli, context, internal state, and physiological status, and how these factors modulate neural circuit function via a combinatorial code of classic neuromodulators and immune-derived cytokines. Choi joined the Department of Brain and Cognitive Sciences after a postdoc at Columbia University. She received her bachelor’s degree from the University of California at Berkeley, and her PhD from Caltech. Choi is also an investigator in The Picower Institute for Learning and Memory.

Nikta Fakhri develops experimental tools and conceptual frameworks to uncover laws governing fluctuations, order, and self-organization in active systems. Such frameworks provide powerful insight into dynamics of nonequilibrium living systems across scales, from the emergence of thermodynamic arrow of time to spatiotemporal organization of signaling protein patterns and discovery of odd elasticity. Fakhri joined the Department of Physics in 2015 following a postdoc at University of Göttingen. She completed her undergraduate degree at Sharif University of Technology and her PhD at Rice University.

Geobiologist Greg Fournier uses a combination of molecular phylogeny insights and geologic records to study major events in planetary history, with the hope of furthering our understanding of the co-evolution of life and environment. Recently, his team developed a new technique to analyze multiple gene evolutionary histories and estimated that photosynthesis evolved between 3.4 and 2.9 billion years ago. Fournier joined the Department of Earth, Atmospheric and Planetary Sciences in 2014 after working as a postdoc at the University of Connecticut and as a NASA Postdoctoral Program Fellow in MIT’s Department of Civil and Environmental Engineering. He earned his BA from Dartmouth College in 2001 and his PhD in genetics and genomics from the University of Connecticut in 2009.

Daniel Harlow researches black holes and cosmology, viewed through the lens of quantum gravity and quantum field theory. His work generates new insights into quantum information, quantum field theory, and gravity. Harlow joined the Department of Physics in 2017 following postdocs at Princeton University and Harvard University. He obtained a BA in physics and mathematics from Columbia University in 2006 and a PhD in physics from Stanford University in 2012. He is also a researcher in the Center for Theoretical Physics.

A biophysicist, Gene-Wei Li studies how bacteria optimize the levels of proteins they produce at both mechanistic and systems levels. His lab focuses on design principles of transcription, translation, and RNA maturation. Li joined the Department of Biology in 2015 after completing a postdoc at the University of California at San Francisco. He earned an BS in physics from National Tsinghua University in 2004 and a PhD in physics from Harvard University in 2010.

Michael McDonald focuses on the evolution of galaxies and clusters of galaxies, and the role that environment plays in dictating this evolution. This research involves the discovery and study of the most distant assemblies of galaxies alongside analyses of the complex interplay between gas, galaxies, and black holes in the closest, most massive systems. McDonald joined the Department of Physics and the Kavli Institute for Astrophysics and Space Research in 2015 after three years as a Hubble Fellow, also at MIT. He obtained his BS and MS degrees in physics at Queen’s University, and his PhD in astronomy at the University of Maryland in College Park.

Gabriela Schlau-Cohen combines tools from chemistry, optics, biology, and microscopy to develop new approaches to probe dynamics. Her group focuses on dynamics in membrane proteins, particularly photosynthetic light-harvesting systems that are of interest for sustainable energy applications. Following a postdoc at Stanford University, Schlau-Cohen joined the Department of Chemistry faculty in 2015. She earned a bachelor’s degree in chemical physics from Brown University in 2003 followed by a PhD in chemistry at the University of California at Berkeley.

Phiala Shanahan’s research interests are focused around theoretical nuclear and particle physics. In particular, she works to understand the structure and interactions of hadrons and nuclei from the fundamental degrees of freedom encoded in the Standard Model of particle physics. After a postdoc at MIT and a joint position as an assistant professor at the College of William and Mary and senior staff scientist at the Thomas Jefferson National Accelerator Facility, Shanahan returned to the Department of Physics as faculty in 2018. She obtained her BS from the University of Adelaide in 2012 and her PhD, also from the University of Adelaide, in 2015.

Omer Yilmaz explores the impact of dietary interventions on stem cells, the immune system, and cancer within the intestine. By better understanding how intestinal stem cells adapt to diverse diets, his group hopes to identify and develop new strategies that prevent and reduce the growth of cancers involving the intestinal tract. Yilmaz joined the Department of Biology in 2014 and is now also a member of Koch Institute for Integrative Cancer Research. After receiving his BS from the University of Michigan in 1999 and his PhD and MD from University of Michigan Medical School in 2008, he was a resident in anatomic pathology at Massachusetts General Hospital and Harvard Medical School until 2013.

In 2023, five MIT faculty were granted tenure in the School of Science:

Physicist Riccardo Comin explores the novel phases of matter that can be found in electronic solids with strong interactions, also known as quantum materials. His group employs a combination of synthesis, scattering, and spectroscopy to obtain a comprehensive picture of these emergent phenomena, including superconductivity, (anti)ferromagnetism, spin-density-waves, charge order, ferroelectricity, and orbital order. Comin joined the Department of Physics in 2016 after postdoctoral work at the University of Toronto. He completed his undergraduate studies at the Universita’ degli Studi di Trieste in Italy, where he also obtained a MS in physics in 2009. Later, he pursued doctoral studies at the University of British Columbia, Canada, earning a PhD in 2013.

Netta Engelhardt researches the dynamics of black holes in quantum gravity and uses holography to study the interplay between gravity and quantum information. Her primary focus is on the black hole information paradox, that black holes seem to be destroying information that, according to quantum physics, cannot be destroyed. Engelhardt was a postdoc at Princeton University and a member of the Princeton Gravity Initiative prior to joining the Department of Physics in 2019. She received her BS in physics and mathematics from Brandeis University and her PhD in physics from the University of California at Santa Barbara. Engelhardt is a researcher in the Center for Theoretical Physics and the Black Hole Initiative at Harvard University.

Mark Harnett studies how the biophysical features of individual neurons endow neural circuits with the ability to process information and perform the complex computations that underlie behavior. As part of this work, his lab was the first to describe the physiological properties of human dendrites. He joined the Department of Brain and Cognitive Sciences and the McGovern Institute for Brain Research in 2015. Prior, he was a postdoc at the Howard Hughes Medical Institute’s Janelia Research Campus. He received his BA in biology from Reed College in Portland, Oregon and his PhD in neuroscience from the University of Texas at Austin.

Or Hen investigates quantum chromodynamic effects in the nuclear medium and the interplay between partonic and nucleonic degrees of freedom in nuclei. Specifically, Hen utilizes high-energy scattering of electron, neutrino, photon, proton and ion off atomic nuclei to study short-range correlations: temporal fluctuations of high-density, high-momentum, nucleon clusters in nuclei with important implications for nuclear, particle, atomic, and astrophysics. Hen was an MIT Pappalardo Fellow in the Department of Physics from 2015 to 2017 before joining the faculty in 2017. He received his undergraduate degree in physics and computer engineering from the Hebrew University and earned his PhD in experimental physics at Tel Aviv University.

Sebastian Lourido is interested in learning about the vulnerabilities of parasites in order to develop treatments for infectious diseases and expand our understanding of eukaryotic diversity. His lab studies many important human pathogens, including Toxoplasma gondii, to model features conserved throughout the phylum. Lourido was a Whitehead Fellow at the Whitehead Institute for Biomedical Research until 2017, when he joined the Department of Biology and became a Whitehead Member. He earned his BS from Tulane University in 2004 and his PhD from Washington University in St. Louis in 2012.

Thirty-four community members receive 2023 MIT Excellence Awards, Collier Medal, and Staff Award for Distinction in Service

Anne Trafton |

Twenty-four individuals and one team were awarded MIT Excellence Awards — the highest awards for staff at the Institute — at a well-attended and energetic ceremony the afternoon of June 8 in Kresge Auditorium. In addition to the Excellence Awards, two community members were honored with the Collier Medal and Staff Award for Distinction in Service.

The Excellence Awards, Collier Medal, and Staff Award for Distinction in Service recognize the extraordinary dedication of staff and community members who represent all areas of the Institute, both on campus and at the Lincoln Laboratory.

The Collier Medal honors the memory of Officer Sean Collier, who gave his life protecting and serving the MIT community, and celebrates an individual or group whose actions demonstrate the importance of community. The Staff Award for Distinction in Service, now in its second year, is presented to a staff member whose service to the Institute results in a positive lasting impact on the community.

The 2023 MIT Excellence Award recipients and their award categories are:

  • Sustaining MIT: Erin Genereux; Rachida Kernis; J. Bradley Morrison, and the Tip Box Recycling Team (John R. Collins, Michael A. DeBerio, Normand J. Desrochers III, Mitchell S. Galanek, David M. Pavone, Ryan Samz, Rosario Silvestri, and Lu Zhong);
  • Innovative Solutions: Abram Barrett, Nicole H. W. Henning
  • Bringing Out the Best: Patty Eames, Suzy Maholchic Nelson
  • Serving Our Community: Mahnaz El-Kouedi, Kara Flyg, Timothy J. Meunier, Marie A. Stuppard, Roslyn R. Wesley
  • Embracing Diversity, Equity, and Inclusion: Farrah A. Belizaire
  • Outstanding Contributor: Diane Ballestas, Robert J. Bicchieri, Lindsey Megan Charles, Benoit Desbiolles, Dennis C. Hamel, Heather Anne Holland, Gregory L. Long, Linda Mar, Mary Ellen Sinkus, Sarah E. Willis, and Phyl A. Winn
  • The 2023 Collier Medal recipient was Martin Eric William Nisser, a graduate student fellow in the Department of Electrical Engineering and Computer Science/Computer Science and Artificial Intelligence Laboratory and the School of Engineering/MIT Schwarzman College of Computing.
  • The 2023 recipient of the Staff Award for Distinction in Service was Kimberly A. Haberlin, chief of staff in the Chancellor’s Office.

Presenters included President Sally Kornbluth; Vice President for Human Resources Ramona Allen; Provost Cynthia Barnhart; School of Engineering Dean Anantha Chandrakasan; MIT Police Chief John DiFava and MIT Police Captain Andrew Turco; Institute Community and Equity Officer John Dozier; Lincoln Laboratory Director Eric Evans; and Chancellor Melissa Nobles. As always, an animated and supportive audience with signs, pompoms, and glow bracelets filled the auditorium with cheers for the honorees.

Visit the MIT Human Resources website for more information about the award categories, selection process, recipients, and to view the archive video of the event.

Making invisible therapy targets visible

by Thea Singer |

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

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

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

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

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

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

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

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

Researchers uncover new CRISPR-like system in animals that can edit the human genome

by Leah Eisenstadt |

A team of researchers led by Feng Zhang at the McGovern Institute and the Broad Institute of MIT and Harvard has uncovered the first programmable RNA-guided system in eukaryotes — organisms that include fungi, plants, and animals.

In a study in Nature, the team describes how the system is based on a protein called Fanzor. They showed that Fanzor proteins use RNA as a guide to target DNA precisely, and that Fanzors can be reprogrammed to edit the genome of human cells. The compact Fanzor systems have the potential to be more easily delivered to cells and tissues as therapeutics than CRISPR/Cas systems, and further refinements to improve their targeting efficiency could make them a valuable new technology for human genome editing.

CRISPR/Cas was first discovered in prokaryotes (bacteria and other single-cell organisms that lack nuclei) and scientists including Zhang’s lab have long wondered whether similar systems exist in eukaryotes. The new study demonstrates that RNA-guided DNA-cutting mechanisms are present across all kingdoms of life.

“This new system is another way to make precise changes in human cells, complementing the genome editing tools we already have.” — Feng Zhang

“CRISPR-based systems are widely used and powerful because they can be easily reprogrammed to target different sites in the genome,” said Zhang, senior author on the study and a core institute member at the Broad, an investigator at MIT’s McGovern Institute, the James and Patricia Poitras Professor of Neuroscience at MIT, and a Howard Hughes Medical Institute investigator. “This new system is another way to make precise changes in human cells, complementing the genome editing tools we already have.”

Searching the domains of life

A major aim of the Zhang lab is to develop genetic medicines using systems that can modulate human cells by targeting specific genes and processes. “A number of years ago, we started to ask, ‘What is there beyond CRISPR, and are there other RNA-programmable systems out there in nature?’” said Zhang.

Feng Zhang with folded arms in lab
McGovern Investigator Feng Zhang in his lab.

Two years ago, Zhang lab members discovered a class of RNA-programmable systems in prokaryotes called OMEGAs, which are often linked with transposable elements, or “jumping genes”, in bacterial genomes and likely gave rise to CRISPR/Cas systems. That work also highlighted similarities between prokaryotic OMEGA systems and Fanzor proteins in eukaryotes, suggesting that the Fanzor enzymes might also use an RNA-guided mechanism to target and cut DNA.

In the new study, the researchers continued their study of RNA-guided systems by isolating Fanzors from fungi, algae, and amoeba species, in addition to a clam known as the Northern Quahog. Co-first author Makoto Saito of the Zhang lab led the biochemical characterization of the Fanzor proteins, showing that they are DNA-cutting endonuclease enzymes that use nearby non-coding RNAs known as ωRNAs to target particular sites in the genome. It is the first time this mechanism has been found in eukaryotes, such as animals.

Unlike CRISPR proteins, Fanzor enzymes are encoded in the eukaryotic genome within transposable elements and the team’s phylogenetic analysis suggests that the Fanzor genes have migrated from bacteria to eukaryotes through so-called horizontal gene transfer.

“These OMEGA systems are more ancestral to CRISPR and they are among the most abundant proteins on the planet, so it makes sense that they have been able to hop back and forth between prokaryotes and eukaryotes,” said Saito.

To explore Fanzor’s potential as a genome editing tool, the researchers demonstrated that it can generate insertions and deletions at targeted genome sites within human cells. The researchers found the Fanzor system to initially be less efficient at snipping DNA than CRISPR/Cas systems, but by systematic engineering, they introduced a combination of mutations into the protein that increased its activity 10-fold. Additionally, unlike some CRISPR systems and the OMEGA protein TnpB, the team found that a fungal-derived Fanzor protein did not exhibit “collateral activity,” where an RNA-guided enzyme cleaves its DNA target as well as degrading nearby DNA or RNA. The results suggest that Fanzors could potentially be developed as efficient genome editors.

Co-first author Peiyu Xu led an effort to analyze the molecular structure of the Fanzor/ωRNA complex and illustrate how it latches onto DNA to cut it. Fanzor shares structural similarities with its prokaryotic counterpart CRISPR-Cas12 protein, but the interaction between the ωRNA and the catalytic domains of Fanzor is more extensive, suggesting that the ωRNA might play a role in the catalytic reactions. “We are excited about these structural insights for helping us further engineer and optimize Fanzor for improved efficiency and precision as a genome editor,” said Xu.

Like CRISPR-based systems, the Fanzor system can be easily reprogrammed to target specific genome sites, and Zhang said it could one day be developed into a powerful new genome editing technology for research and therapeutic applications. The abundance of RNA-guided endonucleases like Fanzors further expands the number of OMEGA systems known across kingdoms of life and suggests that there are more yet to be found.

“Nature is amazing. There’s so much diversity,” said Zhang. “There are probably more RNA-programmable systems out there, and we’re continuing to explore and will hopefully discover more.”

The paper’s other authors include Guilhem Faure, Samantha Maguire, Soumya Kannan, Han Altae-Tran, Sam Vo, AnAn Desimone, and Rhiannon Macrae.

Support for this work was provided by the Howard Hughes Medical Institute; Poitras Center for Psychiatric Disorders Research at MIT; 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; Robert Metcalfe; and Hugo Shong.