Category: Uncategorized

A new way to see the activity inside a living cell

Anne Trafton |

Living cells are bombarded with many kinds of incoming molecular signal that influence their behavior. Being able to measure those signals and how cells respond to them through downstream molecular signaling networks could help scientists learn much more about how cells work, including what happens as they age or become diseased.

Right now, this kind of comprehensive study is not possible because current techniques for imaging cells are limited to just a handful of different molecule types within a cell at one time. However, MIT researchers have developed an alternative method that allows them to observe up to seven different molecules at a time, and potentially even more than that.

“There are many examples in biology where an event triggers a long downstream cascade of events, which then causes a specific cellular function,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology. “How does that occur? It’s arguably one of the fundamental problems of biology, and so we wondered, could you simply watch it happen?”

It’s arguably one of the fundamental problems of biology, and so we wondered, could you simply watch it happen? – Ed Boyden

The new approach makes use of green or red fluorescent molecules that flicker on and off at different rates. By imaging a cell over several seconds, minutes, or hours, and then extracting each of the fluorescent signals using a computational algorithm, the amount of each target protein can be tracked as it changes over time.

Boyden, who is also a professor of biological engineering and of brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research, as well as the co-director of the K. Lisa Yang Center for Bionics, is the senior author of the study, which appears today in Cell. MIT postdoc Yong Qian is the lead author of the paper.

Fluorescent signals

Labeling molecules inside cells with fluorescent proteins has allowed researchers to learn a great deal about the functions of many cellular molecules. This type of study is often done with green fluorescent protein (GFP), which was first deployed for imaging in the 1990s. Since then, several fluorescent proteins that glow in other colors have been developed for experimental use.

However, a typical light microscope can only distinguish two or three of these colors, allowing researchers only a tiny glimpse of the overall activity that is happening inside a cell. If they could track a greater number of labeled molecules, researchers could measure a brain cell’s response to different neurotransmitters during learning, for example, or investigate the signals that prompt a cancer cell to metastasize.

“Ideally, you would be able to watch the signals in a cell as they fluctuate in real time, and then you could understand how they relate to each other. That would tell you how the cell computes,” Boyden says. “The problem is that you can’t watch very many things at the same time.”

In 2020, Boyden’s lab developed a way to simultaneously image up to five different molecules within a cell, by targeting glowing reporters to distinct locations inside the cell. This approach, known as “spatial multiplexing,” allows researchers to distinguish signals for different molecules even though they may all be fluorescing the same color.

In the new study, the researchers took a different approach: Instead of distinguishing signals based on their physical location, they created fluorescent signals that vary over time. The technique relies on “switchable fluorophores” — fluorescent proteins that turn on and off at a specific rate. For this study, Boyden and his group members identified four green switchable fluorophores, and then engineered two more, all of which turn on and off at different rates. They also identified two red fluorescent proteins that switch at different rates, and engineered one additional red fluorophore.

Using four switchable fluorophores, MIT researchers were able to label and image four different kinases inside these cells (top four rows). In the bottom row, the cell nuclei are labeled in blue.
Image: Courtesy of the researchers

Each of these switchable fluorophores can be used to label a different type of molecule within a living cell, such an enzyme, signaling protein, or part of the cell cytoskeleton. After imaging the cell for several minutes, hours, or even days, the researchers use a computational algorithm to pick out the specific signal from each fluorophore, analogous to how the human ear can pick out different frequencies of sound.

“In a symphony orchestra, you have high-pitched instruments, like the flute, and low-pitched instruments, like a tuba. And in the middle are instruments like the trumpet. They all have different sounds, and our ear sorts them out,” Boyden says.

The mathematical technique that the researchers used to analyze the fluorophore signals is known as linear unmixing. This method can extract different fluorophore signals, similar to how the human ear uses a mathematical model known as a Fourier transform to extract different pitches from a piece of music.

Once this analysis is complete, the researchers can see when and where each of the fluorescently labeled molecules were found in the cell during the entire imaging period. The imaging itself can be done with a simple light microscope, with no specialized equipment required.

Biological phenomena

In this study, the researchers demonstrated their approach by labeling six different molecules involved in the cell division cycle, in mammalian cells. This allowed them to identify patterns in how the levels of enzymes called cyclin-dependent kinases change as a cell progresses through the cell cycle.

The researchers also showed that they could label other types of kinases, which are involved in nearly every aspect of cell signaling, as well as cell structures and organelles such as the cytoskeleton and mitochondria. In addition to their experiments using mammalian cells grown in a lab dish, the researchers showed that this technique could work in the brains of zebrafish larvae.

This method could be useful for observing how cells respond to any kind of input, such as nutrients, immune system factors, hormones, or neurotransmitters, according to the researchers. It could also be used to study how cells respond to changes in gene expression or genetic mutations. All of these factors play important roles in biological phenomena such as growth, aging, cancer, neurodegeneration, and memory formation.

“You could consider all of these phenomena to represent a general class of biological problem, where some short-term event — like eating a nutrient, learning something, or getting an infection — generates a long-term change,” Boyden says.

In addition to pursuing those types of studies, Boyden’s lab is also working on expanding the repertoire of switchable fluorophores so that they can study even more signals within a cell. They also hope to adapt the system so that it could be used in mouse models.

The research was funded by an Alana Fellowship, K. Lisa Yang, John Doerr, Jed McCaleb, James Fickel, Ashar Aziz, the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, the Howard Hughes Medical Institute, and the National Institutes of Health.

Search algorithm reveals nearly 200 new kinds of CRISPR systems

by Allessandra DiCorato | Broad Institute |

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

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

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

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

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

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

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

Searching for CRISPR

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

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

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

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

New systems

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

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

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

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

Mining data

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

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

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

The brain may learn about the world the same way some computational models do

Anne Trafton |

To make our way through the world, our brain must develop an intuitive understanding of the physical world around us, which we then use to interpret sensory information coming into the brain.

How does the brain develop that intuitive understanding? Many scientists believe that it may use a process similar to what’s known as “self-supervised learning.” This type of machine learning, originally developed as a way to create more efficient models for computer vision, allows computational models to learn about visual scenes based solely on the similarities and differences between them, with no labels or other information.

A pair of studies from researchers at the K. Lisa Yang Integrative Computational Neuroscience (ICoN) Center at MIT offers new evidence supporting this hypothesis. The researchers found that when they trained models known as neural networks using a particular type of self-supervised learning, the resulting models generated activity patterns very similar to those seen in the brains of animals that were performing the same tasks as the models.

The findings suggest that these models are able to learn representations of the physical world that they can use to make accurate predictions about what will happen in that world, and that the mammalian brain may be using the same strategy, the researchers say.

“The theme of our work is that AI designed to help build better robots ends up also being a framework to better understand the brain more generally,” says Aran Nayebi, a postdoc in the ICoN Center. “We can’t say if it’s the whole brain yet, but across scales and disparate brain areas, our results seem to be suggestive of an organizing principle.”

Nayebi is the lead author of one of the studies, co-authored with Rishi Rajalingham, a former MIT postdoc now at Meta Reality Labs, and senior authors Mehrdad Jazayeri, an associate professor of brain and cognitive sciences and a member of the McGovern Institute for Brain Research; and Robert Yang, an assistant professor of brain and cognitive sciences and an associate member of the McGovern Institute. Ila Fiete, director of the ICoN Center, a professor of brain and cognitive sciences, and an associate member of the McGovern Institute, is the senior author of the other study, which was co-led by Mikail Khona, an MIT graduate student, and Rylan Schaeffer, a former senior research associate at MIT.

Both studies will be presented at the 2023 Conference on Neural Information Processing Systems (NeurIPS) in December.

Modeling the physical world

Early models of computer vision mainly relied on supervised learning. Using this approach, models are trained to classify images that are each labeled with a name — cat, car, etc. The resulting models work well, but this type of training requires a great deal of human-labeled data.

To create a more efficient alternative, in recent years researchers have turned to models built through a technique known as contrastive self-supervised learning. This type of learning allows an algorithm to learn to classify objects based on how similar they are to each other, with no external labels provided.

“This is a very powerful method because you can now leverage very large modern data sets, especially videos, and really unlock their potential,” Nayebi says. “A lot of the modern AI that you see now, especially in the last couple years with ChatGPT and GPT-4, is a result of training a self-supervised objective function on a large-scale dataset to obtain a very flexible representation.”

These types of models, also called neural networks, consist of thousands or millions of processing units connected to each other. Each node has connections of varying strengths to other nodes in the network. As the network analyzes huge amounts of data, the strengths of those connections change as the network learns to perform the desired task.

As the model performs a particular task, the activity patterns of different units within the network can be measured. Each unit’s activity can be represented as a firing pattern, similar to the firing patterns of neurons in the brain. Previous work from Nayebi and others has shown that self-supervised models of vision generate activity similar to that seen in the visual processing system of mammalian brains.

In both of the new NeurIPS studies, the researchers set out to explore whether self-supervised computational models of other cognitive functions might also show similarities to the mammalian brain. In the study led by Nayebi, the researchers trained self-supervised models to predict the future state of their environment across hundreds of thousands of naturalistic videos depicting everyday scenarios.

“For the last decade or so, the dominant method to build neural network models in cognitive neuroscience is to train these networks on individual cognitive tasks. But models trained this way rarely generalize to other tasks,” Yang says. “Here we test whether we can build models for some aspect of cognition by first training on naturalistic data using self-supervised learning, then evaluating in lab settings.”

Once the model was trained, the researchers had it generalize to a task they call “Mental-Pong.” This is similar to the video game Pong, where a player moves a paddle to hit a ball traveling across the screen. In the Mental-Pong version, the ball disappears shortly before hitting the paddle, so the player has to estimate its trajectory in order to hit the ball.

The researchers found that the model was able to track the hidden ball’s trajectory with accuracy similar to that of neurons in the mammalian brain, which had been shown in a previous study by Rajalingham and Jazayeri to simulate its trajectory — a cognitive phenomenon known as “mental simulation.” Furthermore, the neural activation patterns seen within the model were similar to those seen in the brains of animals as they played the game — specifically, in a part of the brain called the dorsomedial frontal cortex. No other class of computational model has been able to match the biological data as closely as this one, the researchers say.

“There are many efforts in the machine learning community to create artificial intelligence,” Jazayeri says. “The relevance of these models to neurobiology hinges on their ability to additionally capture the inner workings of the brain. The fact that Aran’s model predicts neural data is really important as it suggests that we may be getting closer to building artificial systems that emulate natural intelligence.”

Navigating the world

The study led by Khona, Schaeffer, and Fiete focused on a type of specialized neurons known as grid cells. These cells, located in the entorhinal cortex, help animals to navigate, working together with place cells located in the hippocampus.

While place cells fire whenever an animal is in a specific location, grid cells fire only when the animal is at one of the vertices of a triangular lattice. Groups of grid cells create overlapping lattices of different sizes, which allows them to encode a large number of positions using a relatively small number of cells.

In recent studies, researchers have trained supervised neural networks to mimic grid cell function by predicting an animal’s next location based on its starting point and velocity, a task known as path integration. However, these models hinged on access to privileged information about absolute space at all times — information that the animal does not have.

Inspired by the striking coding properties of the multiperiodic grid-cell code for space, the MIT team trained a contrastive self-supervised model to both perform this same path integration task and represent space efficiently while doing so. For the training data, they used sequences of velocity inputs. The model learned to distinguish positions based on whether they were similar or different — nearby positions generated similar codes, but further positions generated more different codes.

“It’s similar to training models on images, where if two images are both heads of cats, their codes should be similar, but if one is the head of a cat and one is a truck, then you want their codes to repel,” Khona says. “We’re taking that same idea but applying it to spatial trajectories.”

Once the model was trained, the researchers found that the activation patterns of the nodes within the model formed several lattice patterns with different periods, very similar to those formed by grid cells in the brain.

“What excites me about this work is that it makes connections between mathematical work on the striking information-theoretic properties of the grid cell code and the computation of path integration,” Fiete says. “While the mathematical work was analytic — what properties does the grid cell code possess? — the approach of optimizing coding efficiency through self-supervised learning and obtaining grid-like tuning is synthetic: It shows what properties might be necessary and sufficient to explain why the brain has grid cells.”

The research was funded by the K. Lisa Yang ICoN Center, the National Institutes of Health, the Simons Foundation, the McKnight Foundation, the McGovern Institute, and the Helen Hay Whitney Foundation.

A multifunctional tool for cognitive neuroscience

by Jennifer Michalowski |

A team of researchers at MIT’s McGovern and Picower Institutes has advanced the clinical potential of a thin, flexible fiber designed to simultaneously monitor and manipulate neural activity at targeted sites in the brain. The collaborative team improved upon an earlier model of the multifunctional fiber, developed in the lab of McGovern Institute Associate Investigator Polina Anikeeva, to explore dynamic changes to neural signaling as large animals engage in a working memory task. The results appear Oct. 6 in Science Advances.

The new device, developed by Indie Garwood, who recently received her PhD in the Harvard-MIT Program in Health Sciences and Technology, includes four microelectrodes for detecting neural activity and two microfluidic channels through which drugs can be delivered. This means scientists can deliver a drug that alters neural signaling within a particular part of the brain, then monitor the consequences for local brain activity. This technology was a collaborative effort between Anikeeva, who is also the Matoula S. Salapatas Professor in Materials Science and Engineering and a professor of brain and cognitive sciences, and Picower Institute Investigators Emery Brown and Earl Miller, who jointly supervised Garwood to develop a multifunctional neurotechnology for larger and translational animal models, which are necessary to investigate the neural circuits that underlie high-level cognitive functions.  With further development and testing, similar devices might one day be deployed to diagnose or treat brain disorders in human patients.

Brown is the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience in the Picower Institute, the Institute for Medical Engineering and Science, and the Department of Brain and Cognitive Sciences, as well as an anesthesiologist at Massachusetts General Hospital and Harvard Medical School. Miller is the Picower Professor of Neuroscience and a professor of brain and cognitive sciences at MIT.

The new multifunctional fiber is not the first produced by Anikeeva and her team. An earlier model engineered in their lab has already reached the neuroscience community, whose members use it to simultaneously monitor and manipulate neural activity in the brains of mice and rats. But for studies in larger animals, the existing tools for delivering drugs to the brains were rigid, bulky devices, which were both fragile and prone to causing tissue damage. A better tool was needed, both to advance cognitive neuroscience research and to set the stage for developing devices that can deliver drugs directly to the brains of patients and monitor the effects.

Like the devices that Anikeeva’s team designed for rodent studies, the new tool is created by first assembling a larger version of the fiber—a preform cylinder with multiple channels that is then heated and stretched until it is thin and long. As the channels narrow, microelectrodes are incorporated into to the fiber. The final step is to link the electrodes in the fiber to a connector that will relay data collected inside the brain to a unit in the lab.

The final device is long enough to access areas deep in the brain of a large animal. It is built to withstand rigorous sterilization procedures and to stay in place even in an active animal. And it integrates directly with experimental systems that cognitive neuroscientists already use in their labs. “We really wanted this to be something that we could easily hand somebody and they’re going to know how to implement it in their system,” says Garwood, who led development of the device as a graduate student in Anikeeva’s lab.

Once the new device was developed, Garwood and colleagues in the Miller and Brown labs put it to work.  They used the tool to study changes in neural activity as an animal completed a task requiring working memory. The fluid channels in the fiber were used to deliver small amounts of GABA, a neurotransmitter that dampens neuronal activity, to the animal’s premotor cortex, a part of the brain that helps plan movement. At the same time, the device recorded electrical activity from individual neurons, as well as broader patterns of activity in this part of the brain. By monitoring these signals over time, the team learned how neural circuits adapted to the local inhibition they had applied. In another experiment, the team used the device to record neural activity from the putamen, a region deep in the brain involved in reward processing and motivation.

The data collected by the device was extensive and complex, tracking changes that unfolded in the brain over seconds to hours. Interpreting those data required the team to devise new methods of data analysis, which Garwood worked on closely with the Brown lab. Garwood says these methods will be shared with users of the new devices, providing “a roadmap for extracting all of these rich dynamics that you can get out of them.”

These successes, the researchers say, are an important step toward the development of tools to modulate and manipulate neuronal activity in the human brain to benefit patients. For example, they say, a multifunctional fiber might one day be used to more accurately pinpoint the origin of seizures in people with epilepsy, by testing the effects of activating or inhibiting specific brain cells.

 

Soft optical fibers block pain while moving and stretching with the body

by Jennifer Chu |

Scientists have a new tool to precisely illuminate the roots of nerve pain.

Engineers at MIT have developed soft and implantable fibers that can deliver light to major nerves through the body. When these nerves are genetically manipulated to respond to light, the fibers can send pulses of light to the nerves to inhibit pain. The optical fibers are flexible and stretch with the body.

The new fibers are meant as an experimental tool that can be used by scientists to explore the causes and potential treatments for peripheral nerve disorders in animal models. Peripheral nerve pain can occur when nerves outside the brain and spinal cord are damaged, resulting in tingling, numbness, and pain in affected limbs. Peripheral neuropathy is estimated to affect more than 20 million people in the United States.

“Current devices used to study nerve disorders are made of stiff materials that constrain movement, so that we can’t really study spinal cord injury and recovery if pain is involved,” says Siyuan Rao, assistant professor of biomedical engineering at the University of Massachusetts at Amherst, who carried out part of the work as a postdoc at MIT. “Our fibers can adapt to natural motion and do their work while not limiting the motion of the subject. That can give us more precise information.”

“Now, people have a tool to study the diseases related to the peripheral nervous system, in very dynamic, natural, and unconstrained conditions,” adds Xinyue Liu PhD ’22, who is now an assistant professor at Michigan State University (MSU).

Details of their team’s new fibers are reported today in a study appearing in Nature Methods. Rao’s and Liu’s MIT co-authors include Atharva Sahasrabudhe, a graduate student in chemistry; Xuanhe Zhao, professor of mechanical engineering and civil and environmental engineering; and Polina Anikeeva, professor of materials science and engineering, along with others at MSU, UMass-Amherst, Harvard Medical School, and the National Institutes of Health.

Beyond the brain

The new study grew out of the team’s desire to expand the use of optogenetics beyond the brain. Optogenetics is a technique by which nerves are genetically engineered to respond to light. Exposure to that light can then either activate or inhibit the nerve, which can give scientists information about how the nerve works and interacts with its surroundings.

Neuroscientists have applied optogenetics in animals to precisely trace the neural pathways underlying a range of brain disorders, including addiction, Parkinson’s disease, and mood and sleep disorders — information that has led to targeted therapies for these conditions.

To date, optogenetics has been primarily employed in the brain, an area that lacks pain receptors, which allows for the relatively painless implantation of rigid devices. However, the rigid devices can still damage neural tissues. The MIT team wondered whether the technique could be expanded to nerves outside the brain. Just as with the brain and spinal cord, nerves in the peripheral system can experience a range of impairment, including sciatica, motor neuron disease, and general numbness and pain.

Optogenetics could help neuroscientists identify specific causes of peripheral nerve conditions as well as test therapies to alleviate them. But the main hurdle to implementing the technique beyond the brain is motion. Peripheral nerves experience constant pushing and pulling from the surrounding muscles and tissues. If rigid silicon devices were used in the periphery, they would constrain an animal’s natural movement and potentially cause tissue damage.

Crystals and light

The researchers looked to develop an alternative that could work and move with the body. Their new design is a soft, stretchable, transparent fiber made from hydrogel — a rubbery, biocompatible mix of polymers and water, the ratio of which they tuned to create tiny, nanoscale crystals of polymers scattered throughout a more Jell-O-like solution.

The fiber embodies two layers — a core and an outer shell or “cladding.” The team mixed the solutions of each layer to generate a specific crystal arrangement. This arrangement gave each layer a specific, different refractive index, and together the layers kept any light traveling through the fiber from escaping or scattering away.

The team tested the optical fibers in mice whose nerves were genetically modified to respond to blue light that would excite neural activity or yellow light that would inhibit their activity. They found that even with the implanted fiber in place, mice were able to run freely on a wheel. After two months of wheel exercises, amounting to some 30,000 cycles, the researchers found the fiber was still robust and resistant to fatigue, and could also transmit light efficiently to trigger muscle contraction.

The team then turned on a yellow laser and ran it through the implanted fiber. Using standard laboratory procedures for assessing pain inhibition, they observed that the mice were much less sensitive to pain than rodents that were not stimulated with light. The fibers were able to significantly inhibit sciatic pain in those light-stimulated mice.

The researchers see the fibers as a new tool that can help scientists identify the roots of pain and other peripheral nerve disorders.

“We are focusing on the fiber as a new neuroscience technology,” Liu says. “We hope to help dissect mechanisms underlying pain in the peripheral nervous system. With time, our technology may help identify novel mechanistic therapies for chronic pain and other debilitating conditions such as nerve degeneration or injury.”

This research was supported, in part, by the National Institutes of Health, the National Science Foundation, the U.S. Army Research Office, the McGovern Institute for Brain Research, the Hock E. Tan and K. Lisa Yang Center for Autism Research, the K. Lisa Yang Brain-Body Center, and the Brain and Behavior Research Foundation.

Ariel Furst and Fan Wang receive 2023 National Institutes of Health awards

by MIT School of Science |

The National Institutes of Health (NIH) has awarded grants to MIT’s Ariel Furst and Fan Wang, through its High-Risk, High-Reward Research program. The NIH High-Risk, High-Reward Research program awarded 85 new research grants to support exceptionally creative scientists pursuing highly innovative behavioral and biomedical research projects.

Ariel Furst was selected as the recipient of the NIH Director’s New Innovator Award, which has supported unusually innovative research since 2007. Recipients are early-career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Furst, the Paul M. Cook Career Development Assistant Professor of Chemical Engineering at MIT, invents technologies to improve human and environmental health by increasing equitable access to resources. Her lab develops transformative technologies to solve problems related to health care and sustainability by harnessing the inherent capabilities of biological molecules and cells. She is passionate about STEM outreach and increasing the participation of underrepresented groups in engineering.

After completing her PhD at Caltech, where she developed noninvasive diagnostics for colorectal cancer, Furst became an A. O. Beckman Postdoctoral Fellow at the University of California at Berkeley. There she developed sensors to monitor environmental pollutants. In 2022, Furst was awarded the MIT UROP Outstanding Faculty Mentor Award for her work with undergraduate researchers. She is a now a 2023 Marion Milligan Mason Awardee, a CIFAR Azrieli Global Scholar for Bio-Inspired Solar Energy, and an ARO Early Career Grantee. She is also a co-founder of the regenerative agriculture company, Seia Bio.

Fan Wang received the Pioneer Award, which has been challenging researchers at all career levels to pursue new directions and develop groundbreaking, high impact approaches to a broad area of biomedical and behavioral sciences since 2004.

Wang, a professor in the Department of Brain and Cognitive Sciences and an investigator in the McGovern Institute for Brain Research, is uncovering the neural circuit mechanisms that govern bodily sensations, like touch, pain, and posture, as well as the mechanisms that control sensorimotor behaviors. Researchers in the Wang lab aim to generate an integrated understanding of the sensation-perception-action process, hoping to find better treatments for diseases like chronic pain, addiction, and movement disorders. Wang’s lab uses genetic, viral, in vivo large-scale electrophysiology and imaging techniques to gain traction in these pursuits.

Wang obtained her PhD at Columbia University, working with Professor Richard Axel. She conducted her postdoctoral work at Stanford University with Mark Tessier-Lavigne, and then subsequently joined Duke University as faculty in 2003. Wang was later appointed as the Morris N. Broad Distinguished Professor of Neurobiology at the Duke University School of Medicine. In January 2023, she joined the faculty of the MIT School of Science and the McGovern Institute.

The High-Risk, High-Reward Research program is funded through the NIH Common Fund, which supports a series of exceptionally high-impact programs that cross NIH Institutes and Centers.

“The HRHR program is a pillar for innovation here at NIH, providing support to transformational research, with advances in biomedical and behavioral science,” says Robert W. Eisinger, acting director of the Division of Program Coordination, Planning, and Strategic Initiatives, which oversees the NIH Common Fund. “These awards align with the Common Fund’s mandate to support science expected to have exceptionally high and broadly applicable impact.”

NIH issued eight Pioneer Awards, 58 New Innovator Awards, six Transformative Research Awards, and 13 Early Independence Awards in 2023. Funding for the awards comes from the NIH Common Fund; the National Institute of General Medical Sciences; the National Institute of Mental Health; the National Library of Medicine; the National Institute on Aging; the National Heart, Lung, and Blood Institute; and the Office of Dietary Supplements.

New cellular census maps the complexity of a primate brain

by Jennifer Michalowski |

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

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

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

Cellular diversity

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

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

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

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

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

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

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

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

Expanding the cell census

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

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

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

Practicing mindfulness with an app may improve children’s mental health

Anne Trafton |

Many studies have found that practicing mindfulness — defined as cultivating an open-minded attention to the present moment — has benefits for children. Children who receive mindfulness training at school have demonstrated improvements in attention and behavior, as well as greater mental health.

When the Covid-19 pandemic began in 2020, sending millions of students home from school, a group of MIT researchers wondered if remote, app-based mindfulness practices could offer similar benefits. In a study conducted during 2020 and 2021, they report that children who used a mindfulness app at home for 40 days showed improvements in several aspects of mental health, including reductions in stress and negative emotions such as loneliness and fear.

The findings suggest that remote, app-based mindfulness interventions, which could potentially reach a larger number of children than school-based approaches, could offer mental health benefits, the researchers say.

“There is growing and compelling scientific evidence that mindfulness can support mental well-being and promote mental health in diverse children and adults,” says John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology, a professor of brain and cognitive sciences at MIT, and the senior author of the study, which appears this week in the journal Mindfulness.

Researchers in Gabrieli’s lab also recently reported that children who showed higher levels of mindfulness were more emotionally resilient to the negative impacts of the Covid-19 pandemic.

“To some extent, the impact of Covid is out of your control as an individual, but your ability to respond to it and to interpret it may be something that mindfulness can help with,” says MIT graduate student Isaac Treves, who is the lead author of both studies.

Pandemic resilience

After the pandemic began in early 2020, Gabrieli’s lab decided to investigate the effects of mindfulness on children who had to leave school and isolate from friends. In a study that appeared in the journal PLOS One in July, the researchers explored whether mindfulness could boost children’s resilience to negative emotions that the pandemic generated, such as frustration and loneliness.

Working with students between 8 and 10 years old, the researchers measured the children’s mindfulness using a standardized assessment that captures their tendency to blame themselves, ruminate on negative thoughts, and suppress their feelings.

The researchers also asked the children questions about how much the pandemic had affected different aspects of their lives, as well as questions designed to assess their levels of anxiety, depression, stress, and negative emotions such as worry or fear.

Among children who showed the highest levels of mindfulness, there was no correlation between how much the pandemic impacted them and negative feelings. However, in children with lower levels of mindfulness, there was a strong correlation between Covid-19 impact and negative emotions.

The children in this study did not receive any kind of mindfulness training, so their responses reflect their tendency to be mindful at the time they answered the researchers’ questions. The findings suggest that children with higher levels of mindfulness were less likely to get caught up in negative emotions or blame themselves for the negative things they experienced during the pandemic.

“This paper was our best attempt to look at mindfulness specifically in the context of Covid and to think about what are the factors that may help children adapt to the changing circumstances,” Treves says. “The takeaway is not that we shouldn’t worry about pandemics because we can just help the kids with mindfulness. People are able to be resilient when they’re in systems that support them, and in families that support them.”

Remote interventions

The researchers then built on that study by exploring whether a remote, app-based intervention could effectively increase mindfulness and improve mental health. Researchers in Gabrieli’s lab have previously shown that students who received mindfulness training in middle school showed better academic performance, received fewer suspensions, and reported less stress than those who did not receive the training.

For the new study, reported today in Mindfulness, the researchers worked with the same children they had recruited for the PLOS One study and divided them into three groups of about 80 students each.

One group received mindfulness training through an app created by Inner Explorer, a nonprofit that also develops school-based meditation programs. Those children were instructed to engage in mindfulness training five days a week, including relaxation exercises, breathing exercises, and other forms of meditation.

For comparison purposes, the other two groups were asked to use an app for listening to audiobooks (not related to mindfulness). One group was simply given the audiobook app and encouraged to listen at their own pace, while the other group also had weekly one-on-one virtual meetings with a facilitator.

At the beginning and end of the study, the researchers evaluated each participant’s levels of mindfulness, along with measures of mental health such as anxiety, stress, and depression. They found that in all three groups, mental health improved over the course of the eight-week study, and each group also showed increases in mindfulness and prosociality (engaging in helpful behavior).

Additionally, children in the mindfulness group showed some improvements that the other groups didn’t, including a more significant decrease in stress. They also found that parents in the mindfulness group reported that their children experienced more significant decreases in negative emotions such as anger and sadness. Students who practiced the mindfulness exercises the most days showed the greatest benefits.

The researchers were surprised to see that there were no significant differences in measures of anxiety and depression between the mindfulness group and audiobook groups; they hypothesize that may be because students who interacted with a facilitator in one of the audiobook groups also experienced beneficial effects on their mental health.

Overall, the findings suggest that there is value in remote, app-based mindfulness training, especially if children engage with the exercises consistently and receive encouragement from parents, the researchers say. Apps also offer the ability to reach a larger number of children than school-based programs, which require more training and resources.

“There are a lot of great ways to incorporate mindfulness training into schools, but in general, it’s more resource-intensive than having people download an app. So, in terms of pure scalability and cost-effectiveness, apps are useful,” Treves says. “Another good thing about apps is that the kids can go at their own pace and repeat practices that they like, so there’s more freedom of choice.”

The research was funded by the Chan Zuckerberg Initiative as part of the Reach Every Reader Project, the National Institutes of Health, and the National Science Foundation.

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

by MIT School of Science |

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

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

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

MIT faculty

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

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

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

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

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

Additional MIT affiliates

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

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

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

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

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

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

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

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

Thousands of programmable DNA-cutters found in algae, snails, and other organisms

by Jennifer Michalowski |

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.)

Structural illustration of Fanzors.
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.