A diverse set of species, from snails to algae to amoebas, make programmable DNA-cutting enzymes called Fanzors—and a new study from scientists at MIT’s McGovern Institute has identified thousands of them. Fanzors are RNA-guided enzymes that can be programmed to cut DNA at specific sites, much like the bacterial enzymes that power the widely used gene-editing system known as CRISPR. The newly recognized diversity of natural Fanzor enzymes, reported September 27, 2023, in the journal Science Advances, gives scientists an extensive set of programmable enzymes that might be adapted into new tools for research or medicine.
“RNA-guided biology is what lets you make programmable tools that are really easy to use. So the more we can find, the better,” says McGovern fellow Omar Abudayyeh, who led the research with McGovern fellow Jonathan Gootenberg.
CRISPR, an ancient bacterial defense system, has made it clear how useful RNA-guided enzymes can be when they are adapted for use in the lab. CRISPR-based genome editing tools developed by McGovern investigator Feng Zhang, Abudayyeh, Gootenberg and others have changed the way scientists modify DNA, accelerating research and enabling the development of many experimental gene therapies.
Researchers have since uncovered other RNA-guide enzymes throughout the bacterial world, many with features that make them valuable in the lab. The discovery of Fanzors, whose ability to cut DNA in an RNA-guided manner was reported by Zhang’s group earlier this year, opens a new frontier of RNA-guided biology. Fanzors were the first such enzymes to be found in eukaryotic organisms—a wide group of lifeforms, including plants, animals, and fungi, defined by the membrane-bound nucleus that holds each cell’s genetic material. (Bacteria, which lack nuclei, belong to a group known as prokaryotes.)
Predicted structural image of Fanzors. Image: Jonathan Gootenberg and Omar Abudayyeh
“People have been searching for interesting tools in prokaryotic systems for a long time, and I think that that has been incredibly fruitful,” says Gootenberg. “Eukaryotic systems are really just a whole new kind of playground to work in.”
One hope, Abudayyeh and Gootenberg say, is that enzymes that naturally evolved in eukaryotic organisms might be better suited to function safely and efficiently in the cells of other eukaryotic organisms, including humans. Zhang’s group has shown that Fanzor enzymes can be engineered to precisely cut specific DNA sequences in human cells. In the new work, Abudayyeh and Gootenberg discovered that some Fanzors can target DNA sequences in human cells even without optimization. “The fact that they work quite efficiently in mammalian cells was really fantastic to see,” Gootenberg says.
Prior to the current study, hundreds of Fanzors had been found among eukaryotic organisms. Through an extensive search of genetic databases led by lab member Justin Lim, Gootenberg and Abudayyeh’s team has now expanded the known diversity of these enzymes by an order of magnitude.
Among the more than 3,600 Fanzors that the team found in eukaryotes and the viruses that infect them, the researchers were able to identify five different families of the enzymes. By comparing these enzymes’ precise makeup, they found evidence of a long evolutionary history.
Fanzors likely evolved from RNA-guided DNA-cutting bacterial enzymes called TnpBs. In fact, it was Fanzors’ genetic similarities to these bacterial enzymes that first caught the attention of both Zhang’s group and Gootenberg and Abudayyeh’s team.
The evolutionary connections that Gootenberg and Abudayyeh traced suggest that these bacterial predecessors of Fanzors probably entered eukaryotic cells, initiating their evolution, more than once. Some were likely transmitted by viruses, while others may have been introduced by symbiotic bacteria. The research also suggests that after they were taken up by eukaryotes, the enzymes evolved features suited to their new environment, such as a signal that allows them to enter a cell nucleus, where they have access to DNA.
Through genetic and biochemical experiments led by graduate student Kaiyi Jiang, the team determined that Fanzors have evolved a DNA-cutting active site that is distinct from that of their bacterial predecessors. This seems to allow the enzyme to cut its target sequence more precisely the ancestors of TnpB, when targeted to a sequence of DNA in a test tube, become activated and cut other sequences in the tube; Fanzors lack this promiscuous activity. When they used an RNA guide to direct the enzymes to cut specific sites in the genome of human cells, they found that certain Fanzors were able to cut these target sequences with about 10 to 20 percent efficiency.
With further research, Abudayyeh and Gootenberg hope that a variety of sophisticated genome editing tools can be developed from Fanzors. “It’s a new platform, and they have many capabilities,” says Gootenberg. “Opening up the whole eukaryotic world to these types of RNA-guided systems is going to give us a lot to work on,” Abudayyeh adds.
In the human brain, 86 billion neurons form more than 100 trillion connections with other neurons at junctions called synapses. Scientists at the McGovern Institute are working with their collaborators to develop technologies to map these connections across the brain, from mice to humans.
Today, the National Institutes of Health (NIH) announced a new program to support research projects that have the potential to reveal an unprecedented and dynamic picture of the connected networks in the brain. Four of these NIH-funded research projects will take place in McGovern labs.
Today, the NIH announced its third project supported by the BRAIN Initiative, called BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS). The new project complements two previous large-scale projects, which together aim to transform neuroscience research by generating wiring diagrams that can span entire brains across multiple species. These detailed wiring diagrams can help uncover the logic of the brain’s neural code, leading to a better understanding of how this circuitry makes us who we are and how it could be rewired to treat brain diseases.
BRAIN CONNECTS at McGovern
The initial round of BRAIN CONNECTS awards will support researchers at more than 40 university and research institutions across the globe with 11 grants totaling $150 million over five years. Four of these grants have been awarded to McGovern researchers Guoping Feng, Ila Fiete, Satra Ghosh, and Ian Wickersham, whose projects are outlined below:
Summary: This project will establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate (NHP), the common marmoset (Callithrix jacchus). It will do so by tracing axonal projections of RNA barcode-identified neurons brain-wide in the marmoset, utilizing a sequencing-based imaging method that also permits simultaneous transcriptomic cell typing of the identified neurons. This work will help bridge the gap between brain-wide mesoscale connectivity data available for the mouse from a decade of mapping efforts using modern techniques and the absence of comparable data in humans and NHPs.
BRAIN CONNECTS: A center for high-throughput integrative mouse connectomics
Team: Jeff Lichtman (Harvard University), Ila Fiete (McGovern Institute, MIT), Sebastian Seung (Princeton University), David Tank (Princeton University), Hongkui Zeng (Allen Institute), Viren Jain (Google), Greg Jeffries (Oxford University)
Summary: This project aims to produce a large-scale synapse-level brain map (connectome) that includes all the main areas of the mouse hippocampus. This region is of clinical interest because it is an essential part of the circuit underlying spatial navigation and memory and the earliest impairments and degeneration related to Alzheimer’s disease.
Summary: This project will generate connectional diagrams of the monkey and human brain at unprecedented resolutions. These diagrams will be linked both to the neuroanatomic literature and to in vivo neuroimaging techniques, bridging between the rigor of the former and the clinical relevance of the latter. The data to be generated by this project will advance our understanding of brain circuits that are implicated in motor and psychiatric disorders, and that are targeted by deep-brain stimulation to treat these disorders.
Summary: This project aims to optimize and develop barcode sequencing-based neuroanatomical techniques to achieve brain-wide, high-throughput, highly multiplexed mapping of axonal projections and synaptic connectivity of neuronal types at cellular resolution in primate brains. The team will work together to apply these techniques to generate an unprecedented multi-resolution map of brain-wide projections and synaptic inputs of neurons in the macaque visual cortex at cellular resolution.
Sylvia Abente, neuróloga clínica de la Universidad Nacional de Asunción (Paraguay), investiga la variedad de síntomas que son característicos de la epilepsia. Trabaja con los pueblos indígenas de Paraguay, y su dominio del español y el guaraní, los dos idiomas oficiales de Paraguay, le permite ayudar a los pacientes a encontrar las palabras que ayuden a describir sus síntomas de epilepsia para poder tratarlos.
Juan Carlos Caicedo Mera, neurocientífico de la Universidad Externado de Colombia, utiliza modelos de roedores para investigar los efectos neurobiológicos del estrés en los primeros años de vida. Ha desempeñado un papel decisivo en despertar la conciencia pública sobre los efectos biológicos y conductuales del castigo físico a edades tempranas, lo que ha propiciado cambios políticos encaminados a reducir su prevalencia como práctica cultural en Colombia.
Jessica Chomik-Morales (right) interviews Pedro Maldonado at the Biomedical Neuroscience Institute of Chile at the University of Chile. Photo: Jessica Chomik-Morales
Estos son solo dos de los 33 neurocientíficos de siete países latinoamericanos que Jessica Chomik-Morales entrevistó durante 37 días para la tercera temporada de su podcast en español “Mi Última Neurona,” que se estrenará el 18 de septiembre a las 5:00 p. m. en YouTube. Cada episodio dura entre 45 y 90 minutos.
“Quise destacar sus historias para disipar la idea errónea de que la ciencia de primer nivel solo puede hacerse en Estados Unidos y Europa,” dice Chomik-Morales, “o que no se consigue en Sudamérica debido a barreras financieras y de otro tipo.”
Chomik-Morales, graduada universitaria de primera generación que creció en Asunción (Paraguay) y Boca Ratón (Florida), es ahora investigadora académica de post licenciatura en el MIT. Aquí trabaja con Laura Schulz, profesora de Ciencia Cognitiva, y Nancy Kanwisher, investigadora del McGovern Institute y la profesora Walter A. Rosenblith de Neurociencia Cognitiva, utilizando imágenes cerebrales funcionales para investigar de qué forma el cerebro explica el pasado, predice el futuro e interviene sobre el presente a traves del razonamiento causal.
“El podcast está dirigido al público en general y es apto para todas las edades,” afirma. “Se explica la neurociencia de forma fácil para inspirar a los jóvenes en el sentido de que ellos también pueden llegar a ser científicos y para mostrar la amplia variedad de investigaciones que se realizan en los países de origen de los escuchas.”
El viaje de toda una vida
“Mi Última Neurona” comenzó como una idea en 2021 y creció rápidamente hasta convertirse en una serie de conversaciones con destacados científicos hispanos, entre ellos L. Rafael Reif, ingeniero electricista venezolano-estadounidense y 17.º presidente del MIT.
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
Con las relaciones profesionales que estableció en las temporadas uno y dos, Chomik-Morales amplió su visión y reunió una lista de posibles invitados en América Latina para la tercera temporada. Con la ayuda de su asesor científico, Héctor De Jesús-Cortés, un investigador Boricua de posdoctorado del MIT, y el apoyo financiero del McGovern Institute, el Picower Institute for Learning and Memory, el Departamento de Ciencias Cerebrales y Cognitivas, y las Iniciativas Internacionales de Ciencia y Tecnología del MIT, Chomik-Morales organizó entrevistas con científicos en México, Perú, Colombia, Chile, Argentina, Uruguay y Paraguay durante el verano de 2023.
Viajando en avión cada cuatro o cinco días, y consiguiendo más posibles participantes de una etapa del viaje a la siguiente por recomendación, Chomik-Morales recorrió más de 10,000 millas y recopiló 33 historias para su tercera temporada. Las áreas de especialización de los científicos abarcan toda una variedad de temas, desde los aspectos sociales de los ciclos de sueño y vigilia hasta los trastornos del estado de ánimo y la personalidad, pasando por la lingüística y el lenguaje en el cerebro o el modelado por computadoras como herramienta de investigación.
“Si alguien estudia la depresión y la ansiedad, quiero hablar sobre sus opiniones con respecto a diversas terapias, incluidos los fármacos y también las microdosis con alucinógenos,” dice Chomik-Morales. “Estas son las cosas de las que habla la gente.” No le teme a abordar temas delicados, como la relación entre las hormonas y la orientación sexual, porque “es importante que la gente escuche a los expertos hablar de estas cosas,” comenta.
El tono de las entrevistas va de lo informal (“el investigador y yo somos como amigos”, dice) a lo pedagógico (“de profesor a alumno”). Lo que no cambia es la accesibilidad (se evitan términos técnicos) y las preguntas iniciales y finales en cada entrevista. Para empezar: “¿Cómo ha llegado hasta aquí? ¿Qué le atrajo de la neurociencia?”. Para terminar: “¿Qué consejo le daría a un joven estudiante latino interesado en Ciencias, Ingeniería, Tecnología y Matemáticas[1]?
Permite que el marco de referencia de sus escuchas sea lo que la guíe. “Si no entendiera algo o pensara que se podría explicar mejor, diría: ‘Hagamos una pausa’. ¿Qué significa esta palabra?”, aunque ella conociera la definición. Pone el ejemplo de la palabra “MEG” (magnetoencefalografía): la medición del campo magnético generado por la actividad eléctrica de las neuronas, que suele combinarse con la resonancia magnética para producir imágenes de fuentes magnéticas. Para aterrizar el concepto, preguntaría: “¿Cómo funciona? ¿Este tipo de exploración hace daño al paciente?”.
Allanar el camino para la creación de redes globales
El equipo de Chomik-Morales era escaso: tres micrófonos Yeti y una cámara de video Canon conectada a su computadora portátil. Las entrevistas se realizaban en salones de clase, oficinas universitarias, en la casa de los investigadores e incluso al aire libre, ya que no había estudios insonorizados disponibles. Ha estado trabajando con el ingeniero de sonido David Samuel Torres, de Puerto Rico, para obtener un sonido más claro.
Ninguna limitación tecnológica podía ocultar la importancia del proyecto para los científicos participantes.
Jessica Chomik-Morales (left) interviews Josefina Cruzat (right) at Adolfo Ibañez University in Chile. Photo: Jessica Chomik-Morales
“Mi Última Neurona” muestra nuestro conocimiento diverso en un escenario global, proporcionando un retrato más preciso del panorama científico en América Latina,” dice Constanza Baquedano, originaria de Chile. “Es un avance hacia la creación de una representación más inclusiva en la ciencia”. Baquendano es profesora adjunta de psicología en la Universidad Adolfo Ibáñez, en donde utiliza electrofisiología y mediciones electroencefalográficas y conductuales para investigar la meditación y otros estados contemplativos. “Estaba ansiosa por ser parte de un proyecto que buscara brindar reconocimiento a nuestras experiencias compartidas como mujeres latinoamericanas en el campo de la neurociencia.”
“Comprender los retos y las oportunidades de los neurocientíficos que trabajan en América Latina es primordial,” afirma Agustín Ibáñez, profesor y director del Instituto Latinoamericano de Salud Cerebral (BrainLat) de la Universidad Adolfo Ibáñez de Chile. “Esta región, que se caracteriza por tener importantes desigualdades que afectan la salud cerebral, también presenta desafíos únicos en el campo de la neurociencia,” afirma Ibáñez, quien se interesa principalmente en la intersección de la neurociencia social, cognitiva y afectiva. “Al centrarse en América Latina, el podcast da a conocer las historias que frecuentemente no se cuentan en la mayoría de los medios. Eso tiende puentes y allana el camino para la creación de redes globales.”
Por su parte, Chomik-Morales confía en que su podcast generará un gran número de seguidores en América Latina. “Estoy muy agradecida por el espléndido patrocinio del MIT,” dice Chomik-Morales. “Este es el proyecto más gratificante que he hecho en mi vida.”
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[1] En inglés Science, Technology, Engineering and Mathematics (STEM)
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.
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.
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.
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.”
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.
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.”
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.”
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.
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
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.”
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.”
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.
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.”
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.”
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.”
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.”
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?”
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.
