Research Area: Neurotechnology

​optogenetics, expansion microscopy, robotic technologies, protein engineering, nanoparticles, probes, apps, sensors, nanomagnetics, drug delivery

Microscopy technique reveals hidden nanostructures in cells and tissues

Anne Trafton |

Press Mentions

Making the invisible visible

The Economist

Inside a living 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 in between the molecules.

MIT researchers have now developed a novel way to overcome this limitation and make those “invisible” molecules visible. Their technique allows them to “de-crowd” the molecules by expanding a cell or tissue sample before labeling the molecules, which makes the molecules more accessible to fluorescent tags.

This method, which builds on a widely used technique known as expansion microscopy previously developed at MIT, should allow scientists to visualize molecules and cellular structures that have never been seen before.

“It’s becoming clear that the expansion process will reveal many new biological discoveries. If biologists and clinicians have been studying a protein in the brain or another biological specimen, and they’re labeling it the regular way, they might be missing entire categories of phenomena,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and 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.

Using this technique, Boyden and his colleagues showed that they could image a nanostructure found in the synapses of neurons. They also imaged the structure of Alzheimer’s-linked amyloid beta plaques in greater detail than has been possible before.

“Our technology, which we named expansion revealing, enables visualization of these nanostructures, which previously remained hidden, using hardware easily available in academic labs,” says Deblina Sarkar, an assistant professor in the Media Lab and one of the lead authors of the study.

The senior authors of the study are Boyden; Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory; and Thomas Blanpied, a professor of physiology at the University of Maryland. Other lead authors include Jinyoung Kang, an MIT postdoc, and Asmamaw Wassie, a recent MIT PhD recipient. The study appears today in Nature Biomedical Engineering.

De-crowding

Imaging a specific protein or other molecule inside a cell requires labeling it with a fluorescent tag carried by an antibody that binds to the target. Antibodies are about 10 nanometers long, while typical cellular proteins are usually about 2 to 5 nanometers in diameter, so if the target proteins are too densely packed, the antibodies can’t get to them.

This has been an obstacle to traditional imaging and also to the original version of expansion microscopy, which Boyden first developed in 2015. In the original version of expansion microscopy, researchers attached fluorescent labels to molecules of interest before they expanded the tissue. The labeling was done first, in part because the researchers had to use an enzyme to chop up proteins in the sample so the tissue could be expanded. This meant that the proteins couldn’t be labeled after the tissue was expanded.

To overcome that obstacle, the researchers had to find a way to expand the tissue while leaving the proteins intact. They used heat instead of enzymes to soften the tissue, allowing the tissue to expand 20-fold without being destroyed. Then, the separated proteins could be labeled with fluorescent tags after expansion.

With so many more proteins accessible for labeling, the researchers were able to identify tiny cellular structures within synapses, the connections between neurons that are densely packed with proteins. They labeled and imaged seven different synaptic proteins, which allowed them to visualize, in detail, “nanocolumns” consisting of calcium channels aligned with other synaptic proteins. These nanocolumns, which are believed to help make synaptic communication more efficient, were first discovered by Blanpied’s lab in 2016.

“This technology can be used to answer a lot of biological questions about dysfunction in synaptic proteins, which are involved in neurodegenerative diseases,” Kang says. “Until now there has been no tool to visualize synapses very well.”

New patterns

The researchers also used their new technique to image beta amyloid, a peptide that forms plaques in the brains of Alzheimer’s patients. Using brain tissue from mice, the researchers found that amyloid beta forms periodic nanoclusters, which had not been seen before. These clusters of amyloid beta also include potassium channels. The researchers also found amyloid beta molecules that formed helical structures along axons.

“In this paper, we don’t speculate as to what that biology might mean, but we show that it exists. That is just one example of the new patterns that we can see,” says Margaret Schroeder, an MIT graduate student who is also an author of the paper.

Sarkar says that she is fascinated by the nanoscale biomolecular patterns that this technology unveils. “With a background in nanoelectronics, I have developed electronic chips that require extremely precise alignment, in the nanofab. But when I see that in our brain Mother Nature has arranged biomolecules with such nanoscale precision, that really blows my mind,” she says.

Boyden and his group members are now working with other labs to study cellular structures such as protein aggregates linked to Parkinson’s and other diseases. In other projects, they are studying pathogens that infect cells and molecules that are involved in aging in the brain. Preliminary results from these studies have also revealed novel structures, Boyden says.

“Time and time again, you see things that are truly shocking,” he says. “It shows us how much we are missing with classical unexpanded staining.”

The researchers are also working on modifying the technique so they can image up to 20 proteins at a time. They are also working on adapting their process so that it can be used on human tissue samples.

Sarkar and her team, on the other hand, are developing tiny wirelessly powered nanoelectronic devices which could be distributed in the brain. They plan to integrate these devices with expansion revealing. “This can combine the intelligence of nanoelectronics with the nanoscopy prowess of expansion technology, for an integrated functional and structural understanding of the brain,” Sarkar says.

The research was funded by the National Institutes of Health, the National Science Foundation, the Ludwig Family Foundation, the JPB Foundation, the Open Philanthropy Project, John Doerr, Lisa Yang and the Tan-Yang Center for Autism Research at MIT, the U.S. Army Research Office, Charles Hieken, Tom Stocky, Kathleen Octavio, Lore McGovern, Good Ventures, and HHMI.

New research center focused on brain-body relationship established at MIT

by Julie Pryor |

The inextricable link between our brains and our bodies has been gaining increasing recognition among researchers and clinicians over recent years. Studies have shown that the brain-body pathway is bidirectional — meaning that our mental state can influence our physical health and vice versa. But exactly how the two interact is less clear.

A new research center at MIT, funded by a $38 million gift to the McGovern Institute for Brain Research from philanthropist K. Lisa Yang, aims to unlock this mystery by creating and applying novel tools to explore the multidirectional, multilevel interplay between the brain and other body organ systems. This gift expands Yang’s exceptional philanthropic support of human health and basic science research at MIT over the past five years.

“Lisa Yang’s visionary gift enables MIT scientists and engineers to pioneer revolutionary technologies and undertake rigorous investigations into the brain’s complex relationship with other organ systems,” says MIT President L. Rafael Reif.  “Lisa’s tremendous generosity empowers MIT scientists to make pivotal breakthroughs in brain and biomedical research and, collectively, improve human health on a grand scale.”

The K. Lisa Yang Brain-Body Center will be directed by Polina Anikeeva, professor of materials science and engineering and brain and cognitive sciences at MIT and an associate investigator at the McGovern Institute. The center will harness the power of MIT’s collaborative, interdisciplinary life sciences research and engineering community to focus on complex conditions and diseases affecting both the body and brain, with a goal of unearthing knowledge of biological mechanisms that will lead to promising therapeutic options.

“Under Professor Anikeeva’s brilliant leadership, this wellspring of resources will encourage the very best work of MIT faculty, graduate fellows, and research — and ultimately make a real impact on the lives of many,” Reif adds.

microscope image of gut
Mouse small intestine stained to reveal cell nucleii (blue) and peripheral nerve fibers (red).
Image: Polina Anikeeva, Marie Manthey, Kareena Villalobos

Center goals  

Initial projects in the center will focus on four major lines of research:

  • Gut-Brain: Anikeeva’s group will expand a toolbox of new technologies and apply these tools to examine major neurobiological questions about gut-brain pathways and connections in the context of autism spectrum disorders, Parkinson’s disease, and affective disorders.
  • Aging: CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and investigator at the McGovern Institute, will lead a group in developing molecular tools for precision epigenomic editing and erasing accumulated “errors” of time, injury, or disease in various types of cells and tissues.
  • Pain: The lab of Fan Wang, investigator at the McGovern Institute and professor of brain and cognitive sciences, will design new tools and imaging methods to study autonomic responses, sympathetic-parasympathetic system balance, and brain-autonomic nervous system interactions, including how pain influences these interactions.
  • Acupuncture: Wang will also collaborate with Hilda (“Scooter”) Holcombe, a veterinarian in MIT’s Division of Comparative Medicine, to advance techniques for documenting changes in brain and peripheral tissues induced by acupuncture in mouse models. If successful, these techniques could lay the groundwork for deeper understandings of the mechanisms of acupuncture, specifically how the treatment stimulates the nervous system and restores function.

A key component of the K. Lisa Yang Brain-Body Center will be a focus on educating and training the brightest young minds who aspire to make true breakthroughs for individuals living with complex and often devastating diseases. A portion of center funding will endow the new K. Lisa Yang Brain-Body Fellows Program, which will support four annual fellowships for MIT graduate students and postdocs working to advance understanding of conditions that affect both the body and brain.

Mens sana in corpore sano

“A phrase I remember reading in secondary school has always stuck with me: ‘mens sana in corpore sano’ — ‘a healthy mind in a healthy body,’” says Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities. “When we look at how stress, nutrition, pain, immunity, and other complex factors impact our health, we truly see how inextricably linked our brains and bodies are. I am eager to help MIT scientists and engineers decode these links and make real headway in creating therapeutic strategies that result in longer, healthier lives.”

“This center marks a once-in-a-lifetime opportunity for labs like mine to conduct bold and risky studies into the complexities of brain-body connections,” says Anikeeva, who works at the intersection of materials science, electronics, and neurobiology. “The K. Lisa Yang Brain-Body Center will offer a pathbreaking, holistic approach that bridges multiple fields of study. I have no doubt that the center will result in revolutionary strides in our understanding of the inextricable bonds between the brain and the body’s peripheral organ systems, and a bold new way of thinking in how we approach human health overall.”

New MRI probe can reveal more of the brain’s inner workings

Anne Trafton |

Using a novel probe for functional magnetic resonance imaging (fMRI), MIT biological engineers have devised a way to monitor individual populations of neurons and reveal how they interact with each other.

Similar to how the gears of a clock interact in specific ways to turn the clock’s hands, different parts of the brain interact to perform a variety of tasks, such as generating behavior or interpreting the world around us. The new MRI probe could potentially allow scientists to map those networks of interactions.

“With regular fMRI, we see the action of all the gears at once. But with our new technique, we can pick up individual gears that are defined by their relationship to the other gears, and that’s critical for building up a picture of the mechanism of the brain,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.

Using this technique, which involves genetically targeting the MRI probe to specific populations of cells in animal models, the researchers were able to identify neural populations involved in a circuit that responds to rewarding stimuli. The new MRI probe could also enable studies of many other brain circuits, the researchers say.

Jasanoff, who is also an associate investigator at the McGovern Institute, is the senior author of the study, which appears today in Nature Neuroscience. The lead authors of the paper are recent MIT PhD recipient Souparno Ghosh and former MIT research scientist Nan Li.

Tracing connections

Traditional fMRI imaging measures changes to blood flow in the brain, as a proxy for neural activity. When neurons receive signals from other neurons, it triggers an influx of calcium, which causes a diffusible gas called nitric oxide to be released. Nitric oxide acts in part as a vasodilator that increases blood flow to the area.

Imaging calcium directly can offer a more precise picture of brain activity, but that type of imaging usually requires fluorescent chemicals and invasive procedures. The MIT team wanted to develop a method that could work across the brain without that type of invasiveness.

“If we want to figure out how brain-wide networks of cells and brain-wide mechanisms function, we need something that can be detected deep in tissue and preferably across the entire brain at once,” Jasanoff says. “The way that we chose to do that in this study was to essentially hijack the molecular basis of fMRI itself.”

The researchers created a genetic probe, delivered by viruses, that codes for a protein that sends out a signal whenever the neuron is active. This protein, which the researchers called NOSTIC (nitric oxide synthase for targeting image contrast), is an engineered form of an enzyme called nitric oxide synthase. The NOSTIC protein can detect elevated calcium levels that arise during neural activity; it then generates nitric oxide, leading to an artificial fMRI signal that arises only from cells that contain NOSTIC.

The probe is delivered by a virus that is injected into a particular site, after which it travels along axons of neurons that connect to that site. That way, the researchers can label every neural population that feeds into a particular location.

“When we use this virus to deliver our probe in this way, it causes the probe to be expressed in the cells that provide input to the location where we put the virus,” Jasanoff says. “Then, by performing functional imaging of those cells, we can start to measure what makes input to that region take place, or what types of input arrive at that region.”

Turning the gears

In the new study, the researchers used their probe to label populations of neurons that project to the striatum, a region that is involved in planning movement and responding to reward. In rats, they were able to determine which neural populations send input to the striatum during or immediately following a rewarding stimulus — in this case, deep brain stimulation of the lateral hypothalamus, a brain center that is involved in appetite and motivation, among other functions.

One question that researchers have had about deep brain stimulation of the lateral hypothalamus is how wide-ranging the effects are. In this study, the MIT team showed that several neural populations, located in regions including the motor cortex and the entorhinal cortex, which is involved in memory, send input into the striatum following deep brain stimulation.

“It’s not simply input from the site of the deep brain stimulation or from the cells that carry dopamine. There are these other components, both distally and locally, that shape the response, and we can put our finger on them because of the use of this probe,” Jasanoff says.

During these experiments, neurons also generate regular fMRI signals, so in order to distinguish the signals that are coming specifically from the genetically altered neurons, the researchers perform each experiment twice: once with the probe on, and once following treatment with a drug that inhibits the probe. By measuring the difference in fMRI activity between these two conditions, they can determine how much activity is present in probe-containing cells specifically.

The researchers now hope to use this approach, which they call hemogenetics, to study other networks in the brain, beginning with an effort to identify some of the regions that receive input from the striatum following deep brain stimulation.

“One of the things that’s exciting about the approach that we’re introducing is that you can imagine applying the same tool at many sites in the brain and piecing together a network of interlocking gears, which consist of these input and output relationships,” Jasanoff says. “This can lead to a broad perspective on how the brain works as an integrated whole, at the level of neural populations.”

The research was funded by the National Institutes of Health and the MIT Simons Center for the Social Brain.

Augmented: The journey of Hugh Herr

by Julie Pryor |

Augmented is a Nova PBS documentary that premiered in February 2022, featuring Hugh Herr, the co-director of the K. Lisa Yang Center for Bionics at MIT.

Follow the dramatic personal journey of Hugh Herr, a biophysicist working to create brain-controlled robotic limbs. At age 17, Herr’s legs were amputated after a climbing accident. Frustrated by the crude prosthetic limbs he was given, Herr set out to remedy their design, leading him to a career as an inventor of innovative prosthetic devices. Now, Herr is teaming up with an injured climber and a surgeon at a leading Boston hospital to test a new approach to surgical amputation that allows prosthetic limbs to move and feel like the real thing. Herr’s journey is a powerful tale of innovation and the inspiring story of a personal tragedy transformed into a life-long quest to help others.

Read more at PBS.org.

The craving state

by Jennifer Michalowski |

This story originally appeared in the Winter 2022 issue of BrainScan.

***

For people struggling with substance use disorders — and there are about 35 million of them worldwide — treatment options are limited. Even among those who seek help, relapse is common. In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A 2019 survey found that 1.6 million people nationwide had an opioid use disorder, and the crisis has surged since the start of the COVID-19 pandemic. The Centers for Disease Control and Prevention estimates that more than 100,000 people died of drug overdose between April 2020 and April 2021 — nearly 30 percent more overdose deaths than occurred during the same period the previous year.

In the United States, an epidemic of opioid addiction has been declared a public health emergency.

A deeper understanding of what addiction does to the brain and body is urgently needed to pave the way to interventions that reliably release affected individuals from its grip. At the McGovern Institute, researchers are turning their attention to addiction’s driving force: the deep, recurring craving that makes people prioritize drug use over all other wants and needs.

McGovern Institute co-founder, Lore Harp McGovern.

“When you are in that state, then it seems nothing else matters,” says McGovern Investigator Fan Wang. “At that moment, you can discard everything: your relationship, your house, your job, everything. You only want the drug.”

With a new addiction initiative catalyzed by generous gifts from Institute co-founder Lore Harp McGovern and others, McGovern scientists with diverse expertise have come together to begin clarifying the neurobiology that underlies the craving state. They plan to dissect the neural transformations associated with craving at every level — from the drug-induced chemical changes that alter neuronal connections and activity to how these modifications impact signaling brain-wide. Ultimately, the McGovern team hopes not just to understand the craving state, but to find a way to relieve it — for good.

“If we can understand the craving state and correct it, or at least relieve a little bit of the pressure,” explains Wang, who will help lead the addiction initiative, “then maybe we can at least give people a chance to use their top-down control to not take the drug.”

The craving cycle

For individuals suffering from substance use disorders, craving fuels a cyclical pattern of escalating drug use. Following the euphoria induced by a drug like heroin or cocaine, depression sets in, accompanied by a drug craving motivated by the desire to relieve that suffering. And as addiction progresses, the peaks and valleys of this cycle dip lower: the pleasant feelings evoked by the drug become weaker, while the negative effects a person experiences in its absence worsen. The craving remains, and increasing use of the drug are required to relieve it.

By the time addiction sets in, the brain has been altered in ways that go beyond a drug’s immediate effects on neural signaling.

These insidious changes leave individuals susceptible to craving — and the vulnerable state endures. Long after the physical effects of withdrawal have subsided, people with substance use disorders can find their craving returns, triggered by exposure to a small amount of the drug, physical or social cues associated with previous drug use, or stress. So researchers will need to determine not only how different parts of the brain interact with one another during craving and how individual cells and the molecules within them are affected by the craving state — but also how things change as addiction develops and progresses.

Circuits, chemistry and connectivity

One clear starting point is the circuitry the brain uses to control motivation. Thanks in part to decades of research in the lab of McGovern Investigator Ann Graybiel, neuroscientists know a great deal about how these circuits learn which actions lead to pleasure and which lead to pain, and how they use that information to establish habits and evaluate the costs and benefits of complex decisions.

Graybiel’s work has shown that drugs of abuse strongly activate dopamine-responsive neurons in a part of the brain called the striatum, whose signals promote habit formation. By increasing the amount of dopamine that neurons release, these drugs motivate users to prioritize repeated drug use over other kinds of rewards, and to choose the drug in spite of pain or other negative effects. Her group continues to investigate the naturally occurring molecules that control these circuits, as well as how they are hijacked by drugs of abuse.

Distribution of opioid receptors targeted by morphine (shown in blue) in two regions in the dorsal striatum and nucleus accumbens of the mouse brain. Image: Ann Graybiel

In Fan Wang’s lab, work investigating the neural circuits that mediate the perception of physical pain has led her team to question the role of emotional pain in craving. As they investigated the source of pain sensations in the brain, they identified neurons in an emotion-regulating center called the central amygdala that appear to suppress physical pain in animals. Now, Wang wants to know whether it might be possible to modulate neurons involved in emotional pain to ameliorate the negative state that provokes drug craving.

These animal studies will be key to identifying the cellular and molecular changes that set the brain up for recurring cravings. And as McGovern scientists begin to investigate what happens in the brains of rodents that have been trained to self-administer addictive drugs like fentanyl or cocaine, they expect to encounter tremendous complexity.

McGovern Associate Investigator Polina Anikeeva, whose lab has pioneered new technologies that will help the team investigate the full spectrum of changes that underlie craving, says it will be important to consider impacts on the brain’s chemistry, firing patterns, and connectivity. To that end, multifunctional research probes developed in her lab will be critical to monitoring and manipulating neural circuits in animal models.

Imaging technology developed by investigator Ed Boyden will also enable nanoscale protein visualization brain-wide. An important goal will be to identify a neural signature of the craving state. With such a signal, researchers can begin to explore how to shut off that craving — possibly by directly modulating neural signaling.

Targeted treatments

“One of the reasons to study craving is because it’s a natural treatment point,” says McGovern Associate Investigator Alan Jasanoff. “And the dominant kind of approaches that people in our team think about are approaches that relate to neural circuits — to the specific connections between brain regions and how those could be changed.” The hope, he explains, is that it might be possible to identify a brain region whose activity is disrupted during the craving state, then use clinical brain stimulation methods to restore normal signaling — within that region, as well as in other connected parts of the brain.

To identify the right targets for such a treatment, it will be crucial to understand how the biology uncovered in laboratory animals reflects what’s happens in people with substance use disorders. Functional imaging in John Gabrieli’s lab can help bridge the gap between clinical and animal research by revealing patterns of brain activity associated with the craving state in both humans and rodents. A new technique developed in Jasanoff’s lab makes it possible to focus on the activity between specific regions of an animal’s brain. “By doing that, we hope to build up integrated models of how information passes around the brain in craving states, and of course also in control states where we’re not experiencing craving,” he explains.

In delving into the biology of the craving state, McGovern scientists are embarking on largely unexplored territory — and they do so with both optimism and urgency. “It’s hard to not appreciate just the size of the problem, and just how devastating addiction is,” says Anikeeva. “At this point, it just seems almost irresponsible to not work on it, especially when we do have the tools and we are interested in the general brain regions that are important for that problem. I would say that there’s almost a civic duty.”

MIT Future Founders Initiative announces prize competition to promote female entrepreneurs in biotech

Anne Trafton |

In a fitting sequel to its entrepreneurship “boot camp” educational lecture series last fall, the MIT Future Founders Initiative has announced the MIT Future Founders Prize Competition, supported by Northpond Ventures, and named the MIT faculty cohort that will participate in this year’s competition. The Future Founders Initiative was established in 2020 to promote female entrepreneurship in biotech.

Despite increasing representation at MIT, female science and engineering faculty found biotech startups at a disproportionately low rate compared with their male colleagues, according to research led by the initiative’s founders, MIT Professor Sangeeta Bhatia, MIT Professor and President Emerita Susan Hockfield, and MIT Amgen Professor of Biology Emerita Nancy Hopkins. In addition to highlighting systemic gender imbalances in the biotech pipeline, the initiative’s founders emphasize that the dearth of female biotech entrepreneurs represents lost opportunities for society as a whole — a bottleneck in the proliferation of publicly accessible medical and technological innovation.

“A very common myth is that representation of women in the pipeline is getting better with time … We can now look at the data … and simply say, ‘that’s not true’,” said Bhatia, who is the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science, in an interview for the March/April 2021 MIT Faculty Newsletter. “We need new solutions. This isn’t just about waiting and being optimistic.”

Inspired by generous funding from Northpond Labs, the research and development-focused affiliate of Northpond Ventures, and by the success of other MIT prize incentive competitions such as the Climate Tech and Energy Prize, the Future Founders Initiative Prize Competition will be structured as a learning cohort in which participants will be supported in commercializing their existing inventions with instruction in market assessments, fundraising, and business capitalization, as well as other programming. The program, which is being run as a partnership between the MIT School of Engineering and the Martin Trust Center for MIT Entrepreneurship, provides hands-on opportunities to learn from industry leaders about their experiences, ranging from licensing technology to creating early startup companies. Bhatia and Kit Hickey, an entrepreneur-in-residence at the Martin Trust Center and senior lecturer at the MIT Sloan School of Management, are co-directors of the program.

“The competition is an extraordinary effort to increase the number of female faculty who translate their research and ideas into real-world applications through entrepreneurship,” says Anantha Chandrakasan, dean of the MIT School of Engineering and Vannevar Bush Professor of Electrical Engineering and Computer Science. “Our hope is that this likewise serves as an opportunity for participants to gain exposure and experience to the many ways in which they could achieve commercial impact through their research.”

At the end of the program, the cohort members will pitch their ideas to a selection committee composed of MIT faculty, biotech founders, and venture capitalists. The grand prize winner will receive $250,000 in discretionary funds, and two runners-up will receive $100,000. The winners will be announced at a showcase event, at which the entire cohort will present their work. All participants will also receive a $10,000 stipend for participating in the competition.

“The biggest payoff is not identifying the winner of the competition,” says Bhatia. “Really, what we are doing is creating a cohort … and then, at the end, we want to create a lot of visibility for these women and make them ‘top of mind’ in the community.”

The Selection Committee members for the MIT Future Founders Prize Competition are:

  • Bill Aulet, professor of the practice in the MIT Sloan School of Management and managing director of the Martin Trust Center for MIT Entrepreneurship
  • Sangeeta Bhatia, the John and Dorothy Wilson Professor of Electrical Engineering and Computer Science at MIT; a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science; and founder of Hepregen, Glympse Bio, and Satellite Bio
  • Kit Hickey, senior lecturer in the MIT Sloan School of Management and entrepreneur-in-residence at the Martin Trust Center
  • Susan Hockfield, MIT president emerita and professor of neuroscience
  • Andrea Jackson, director at Northpond Ventures
  • Harvey Lodish, professor of biology and biomedical engineering at MIT and founder of Genzyme, Millennium, and Rubius
  • Fiona Murray, associate dean for innovation and inclusion in the MIT Sloan School of Management; the William Porter Professor of Entrepreneurship; co-director of the MIT Innovation Initiative; and faculty director of the MIT Legatum Center
  • Amy Schulman, founding CEO of Lyndra Therapeutics and partner at Polaris Partners
  • Nandita Shangari, managing director at Novartis Venture Fund

“As an investment firm dedicated to supporting entrepreneurs, we are acutely aware of the limited number of companies founded and led by women in academia. We believe humanity should be benefiting from brilliant ideas and scientific breakthroughs from women in science, which could address many of the world’s most pressing problems. Together with MIT, we are providing an opportunity for women faculty members to enhance their visibility and gain access to the venture capital ecosystem,” says Andrea Jackson, director at Northpond Ventures.

“This first cohort is representative of the unrealized opportunity this program is designed to capture. While it will take a while to build a robust community of connections and role models, I am pleased and confident this program will make entrepreneurship more accessible and inclusive to our community, which will greatly benefit society,” says Susan Hockfield, MIT president emerita.

The MIT Future Founders Prize Competition cohort members were selected from schools across MIT, including the School of Science, the School of Engineering, and Media Lab within the School of Architecture and Planning. They are:

Polina Anikeeva is professor of materials science and engineering and brain and cognitive sciences, an associate member of the McGovern Institute for Brain Research, and the associate director of the Research Laboratory of Electronics. She is particularly interested in advancing the possibility of future neuroprosthetics, through biologically-informed materials synthesis, modeling, and device fabrication. Anikeeva earned her BS in biophysics from St. Petersburg State Polytechnic University and her PhD in materials science and engineering from MIT.

Natalie Artzi is principal research scientist in the Institute of Medical Engineering and Science and an assistant professor in the department of medicine at Brigham and Women’s Hospital. Through the development of smart materials and medical devices, her research seeks to “personalize” medical interventions based on the specific presentation of diseased tissue in a given patient. She earned both her BS and PhD in chemical engineering from the Technion-Israel Institute of Technology.

Laurie A. Boyer is professor of biology and biological engineering in the Department of Biology. By studying how diverse molecular programs cross-talk to regulate the developing heart, she seeks to develop new therapies that can help repair cardiac tissue. She earned her BS in biomedical science from Framingham State University and her PhD from the University of Massachusetts Medical School.

Tal Cohen is associate professor in the departments of Civil and Environmental Engineering and Mechanical Engineering. She wields her understanding of how materials behave when they are pushed to their extremes to tackle engineering challenges in medicine and industry. She earned her BS, MS, and PhD in aerospace engineering from the Technion-Israel Institute of Technology.

Canan Dagdeviren is assistant professor of media arts and sciences and the LG Career Development Professor of Media Arts and Sciences. Her research focus is on creating new sensing, energy harvesting, and actuation devices that can be stretched, wrapped, folded, twisted, and implanted onto the human body while maintaining optimal performance. She earned her BS in physics engineering from Hacettepe University, her MS in materials science and engineering from Sabanci University, and her PhD in materials science and engineering from the University of Illinois at Urbana-Champaign.

Ariel Furst is the Raymond (1921) & Helen St. Laurent Career Development Professor in the Department of Chemical Engineering. Her research addresses challenges in global health and sustainability, utilizing electrochemical methods and biomaterials engineering. She is particularly interested in new technologies that detect and treat disease. Furst earned her BS in chemistry at the University of Chicago and her PhD at Caltech.

Kristin Knouse is assistant professor in the Department of Biology and the Koch Institute for Integrative Cancer Research. She develops tools to investigate the molecular regulation of organ injury and regeneration directly within a living organism with the goal of uncovering novel therapeutic avenues for diverse diseases. She earned her BS in biology from Duke University, her PhD and MD through the Harvard and MIT MD-PhD program.

Elly Nedivi is the William R. (1964) & Linda R. Young Professor of Neuroscience at the Picower Institute for Learning and Memory with joint appointments in the departments of Brain and Cognitive Sciences and Biology. Through her research of neurons, genes, and proteins, Nedivi focuses on elucidating the cellular mechanisms that control plasticity in both the developing and adult brain. She earned her BS in biology from Hebrew University and her PhD in neuroscience from Stanford University.

Ellen Roche is associate professor in the Department of Mechanical Engineering and Institute of Medical Engineering and Science, and the W.M. Keck Career Development Professor in Biomedical Engineering. Borrowing principles and design forms she observes in nature, Roche works to develop implantable therapeutic devices that assist cardiac and other biological function. She earned her bachelor’s degree in biomedical engineering from the National University of Ireland at Galway, her MS in bioengineering from Trinity College Dublin, and her PhD from Harvard University.

Seven from MIT receive National Institutes of Health awards

by MIT School of Science |

On Oct. 5, the National Institutes of Health announced the names of 106 scientists who have been awarded grants through the High-Risk, High-Reward Research program to advance highly innovative biomedical and behavioral research. Seven of the recipients are MIT faculty members.

The High-Risk, High-Reward Research program catalyzes scientific discovery by supporting research proposals that, due to their inherent risk, may struggle in the traditional peer-review process despite their transformative potential. Program applicants are encouraged to pursue trailblazing ideas in any area of research relevant to the NIH’s mission to advance knowledge and enhance health.

“The science put forward by this cohort is exceptionally novel and creative and is sure to push at the boundaries of what is known,” says NIH Director Francis S. Collins. “These visionary investigators come from a wide breadth of career stages and show that groundbreaking science can happen at any career level given the right opportunity.”

New innovators

Four MIT researchers received New Innovator Awards, which recognize “unusually innovative research from early career investigators.” They are:

  • Pulin Li is a member at the Whitehead Institute for Biomedical Research and an assistant professor in the Department of Biology. Li combines approaches from synthetic biology, developmental biology, biophysics and systems biology to quantitatively understand the genetic circuits underlying cell-cell communication that creates multicellular behaviors.
  • Seychelle Vos, the Robert A. Swanson (1969) Career Development Professor of Life Sciences in the Department of Biology, studies the interplay of gene expression and genome organization. Her work focuses on understanding how large molecular machineries involved in genome organization and gene transcription regulate each others’ function to ultimately determine cell fate and identity.
  • Xiao Wang, the Thomas D. and Virginia Cabot Assistant Professor of Chemistry and a member of the Broad Institute of MIT and Harvard, aims to develop high-resolution and highly-multiplexed molecular imaging methods across multiple scales toward understanding the physical and chemical basis of brain wiring and function.
  • Alison Wendlandt is a Cecil and Ida Green Career Development Assistant Professor of Chemistry. Wendlandt focuses on the development of selective, catalytic reactions using the tools of organic and organometallic synthesis and physical organic chemistry. Mechanistic study plays a central role in the development of these new transformations.

Transformative researchers

Two MIT researchers have received Transformative Research Awards, which “promote cross-cutting, interdisciplinary approaches that could potentially create or challenge existing paradigms.” The recipients are:

  • Manolis Kellis is a professor of computer science at MIT in the area of computational biology, an associate member of the Broad Institute, and a principal investigator with MIT’s Computer Science and Artificial Intelligence Laboratory. He aims to further our understanding of the human genome by computational integration of large-scale functional and comparative genomics datasets.
  • Myriam Heiman is the Latham Family Career Development Associate Professor of Neuroscience in the Department of Brain and Cognitive Sciences and an investigator in the Picower Institute for Learning and Memory. Heiman studies the selective vulnerability and pathophysiology seen in two neurodegenerative diseases of the basal ganglia, Huntington’s disease, and Parkinson’s disease.

Together, Heiman, Kellis and colleagues will launch a five-year investigation to pinpoint what may be going wrong in specific brain cells and to help identify new treatment approaches for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD/MND). The project will bring together four labs, including Heiman and Kellis’ labs at MIT, to apply innovative techniques ranging from computational, genomic, and epigenomic analyses of cells from a rich sample of central nervous system tissue, to precision genetic engineering of stem cells and animal models.

Pioneering researchers

  • Polina Anikeeva received a Pioneer Award, which “challenges investigators at all career levels to pursue new research directions and develop groundbreaking, high-impact approaches to a broad area of biomedical, behavioral, or social science.” Anikeeva is an MIT professor of materials science and engineering, a professor of brain and cognitive sciences, and a McGovern Institute for Brain Research associate investigator. She has established a research program that uniquely combines materials synthesis, device fabrication, neurophysiology, and animal models of behavior. Her group carries out projects that understand, invent, and design materials from the level of atoms to functional devices with applications in fundamental neuroscience.

The program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps throughout the research enterprise that are of great importance to NIH and require collaboration across the agency to succeed. It issues four awards each year: the Pioneer Award, the New Innovator Award, the Transformative Research Award, and the Early Independence Award.

This year, NIH issued 10 Pioneer awards, 64 New Innovator awards, 19 Transformative Research awards (10 general, four ALS-related, and five Covid-19-related), and 13 Early Independence awards for 2021. Funding for the awards comes from the NIH Common Fund, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke.

New bionics center established at MIT with $24 million gift

by Jennifer Michalowski |

A deepening understanding of the brain has created unprecedented opportunities to alleviate the challenges posed by disability. Scientists and engineers are taking design cues from biology itself to create revolutionary technologies that restore the function of bodies affected by injury, aging, or disease – from prosthetic limbs that effortlessly navigate tricky terrain to digital nervous systems that move the body after a spinal cord injury.

With the establishment of the new K. Lisa Yang Center for Bionics, MIT is pushing forward the development and deployment of enabling technologies that communicate directly with the nervous system to mitigate a broad range of disabilities. The center’s scientists, clinicians, and engineers will work together to create, test, and disseminate bionic technologies that integrate with both the body and mind.

The center is funded by a $24 million gift to MIT’s McGovern Institute for Brain Research from philanthropist Lisa Yang, a former investment banker committed to advocacy for individuals with visible and invisible disabilities.

Portait of philanthropist Lisa Yang.
Philanthropist Lisa Yang is committed to advocacy for individuals with visible and invisible disabilities. Photo: Caitlin Cunningham

Her previous gifts to MIT have also enabled the establishment of the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience, Hock E. Tan and K. Lisa Yang Center for Autism Research, Y. Eva Tan Professorship in Neurotechnology, and the endowed K. Lisa Yang Post-Baccalaureate Program.

“The K. Lisa Yang Center for Bionics will provide a dynamic hub for scientists, engineers and designers across MIT to work together on revolutionary answers to the challenges of disability,” says MIT President L. Rafael Reif. “With this visionary gift, Lisa Yang is unleashing a powerful collaborative strategy that will have broad impact across a large spectrum of human conditions – and she is sending a bright signal to the world that the lives of individuals who experience disability matter deeply.”

An interdisciplinary approach

To develop prosthetic limbs that move as the brain commands or optical devices that bypass an injured spinal cord to stimulate muscles, bionic developers must integrate knowledge from a diverse array of fields—from robotics and artificial intelligence to surgery, biomechanics, and design. The K. Lisa Yang Center for Bionics will be deeply interdisciplinary, uniting experts from three MIT schools: Science, Engineering, and Architecture and Planning. With clinical and surgical collaborators at Harvard Medical School, the center will ensure that research advances are tested rapidly and reach people in need, including those in traditionally underserved communities.

To support ongoing efforts to move toward a future without disability, the center will also provide four endowed fellowships for MIT graduate students working in bionics or other research areas focused on improving the lives of individuals who experience disability.

“I am thrilled to support MIT on this major research effort to enable powerful new solutions that improve the quality of life for individuals who experience disability,” says Yang. “This new commitment extends my philanthropic investment into the realm of physical disabilities, and I look forward to the center’s positive impact on countless lives, here in the US and abroad.”

The center will be led by Hugh Herr, a professor of media arts and sciences at MIT’s Media Lab, and Ed Boyden, the Y. Eva Tan Professor of Neurotechnology at MIT, a professor of biological engineering, brain and cognitive sciences, and media arts and sciences, and an investigator at MIT’s McGovern Institute and the Howard Hughes Medical Institute.

A double amputee himself, Herr is a pioneer in the development of bionic limbs to improve mobility for those with physical disabilities. “The world profoundly needs relief from the disabilities imposed by today’s nonexistent or broken technologies. We must continually strive towards a technological future in which disability is no longer a common life experience,” says Herr. “I am thrilled that the Yang Center for Bionics will help to measurably improve the human experience for so many.”

Boyden, who is a renowned creator of tools to analyze and control the brain, will play a key role in merging bionics technologies with the nervous system. “The Yang Center for Bionics will be a research center unlike any other in the world,” he says. “A deep understanding of complex biological systems, coupled with rapid advances in human-machine bionic interfaces, mean we will soon have the capability to offer entirely new strategies for individuals who experience disability. It is an honor to be part of the center’s founding team.”

Center priorities

In its first four years, the K. Lisa Yang Center for Bionics will focus on developing and testing three bionic technologies:

  • Digital nervous system: to eliminate movement disorders caused by spinal cord injuries, using computer-controlled muscle activations to control limb movements while simultaneously stimulating spinal cord repair
  • Brain-controlled limb exoskeletons: to assist weak muscles and enable natural movement for people affected by stroke or musculoskeletal disorders
  • Bionic limb reconstruction: to restore natural, brain-controlled movements as well as the sensation of touch and proprioception (awareness of position and movement) from bionic limbs

A fourth priority will be developing a mobile delivery system to ensure patients in medically underserved communities have access to prosthetic limb services. Investigators will field test a system that uses a mobile clinic to conduct the medical imaging needed to design personalized, comfortable prosthetic limbs and to fit the prostheses to patients where they live. Investigators plan to initially bring this mobile delivery system to Sierra Leone, where thousands of people suffered amputations during the country’s 11-year civil war. While the population of persons with amputation continues to increase each year in Sierra Leone, today less than 10% of persons in need benefit from functional prostheses. Through the mobile delivery system, a key center objective is to scale up production and access of functional limb prostheses for Sierra Leoneans in dire need.

Portrait of Lisa Yang, Hugh Herr, Julius Maada Bio, and David Moinina Sengeh (from left to right).
Philanthropist Lisa Yang (far left) and MIT bionics researcher Hugh Herr (second from left) met with Sierra Leone’s President Julius Maada Bio (second from right) and Chief Innovation Officer for the Directorate of Science, Technology and Innovation, David Moinina Sengeh, to discuss the mobile clinic component of the new K. Lisa Yang Center for Bionics at MIT. Photo: David Moinina Sengeh

“The mobile prosthetics service fueled by the K. Lisa Yang Center for Bionics at MIT is an innovative solution to a global problem,” said Julius Maada Bio, President of Sierra Leone. “I am proud that Sierra Leone will be the first site for deploying this state-of-the-art digital design and fabrication process. As leader of a government that promotes innovative technologies and prioritizes human capital development, I am overjoyed that this pilot project will give Sierra Leoneans (especially in rural areas) access to quality limb prostheses and thus improve their quality of life.”

Together, Herr and Boyden will launch research at the bionics center with three other MIT faculty: Assistant Professor of Media Arts and Sciences Canan Dagdeviren, Walter A. Rosenblith Professor of Cognitive Neuroscience Nancy Kanwisher, and David H. Koch (1962) Institute Professor Robert Langer. They will work closely with three clinical collaborators at Harvard Medical School: orthopedic surgeon Marco Ferrone, plastic surgeon Matthew Carty, and Nancy Oriol, Faculty Associate Dean for Community Engagement in Medical Education.

“Lisa Yang and I share a vision for a future in which each and every person in the world has the right to live without a debilitating disability if they so choose,” adds Herr. “The Yang Center will be a potent catalyst for true innovation and impact in the bionics space, and I am overjoyed to work with my colleagues at MIT, and our accomplished clinical partners at Harvard, to make important steps forward to help realize this vision.”

Squishy, stealthy neural probes

by Jennifer Michalowski |

Slender probes equipped with electrodes, optical channels, and other tools are widely used by neuroscientists to monitor and manipulate brain activity in animal studies. Now, scientists at MIT have devised a way to make these usually rigid devices become as soft and pliable as their surroundings when they are implanted in the brain. Their new multifunctional devices are less intrusive than traditional neuroscience probes and remain functional for months after implantation, enabling long-term studies of neural circuits in animal models.

Researchers led by McGovern Institute scientist Polina Anikeeva built the new devices by embedding their functional components in a water-absorbing hydrogel. Each device begins as stiff probe able to penetrate brain tissue. But once it is in place, the hydrogel absorbs water and the device transforms.

“When it’s dry, it’s completely rigid. Its mechanics are dominated by mechanics of the polymers and metals that went into it,” explains Anikeeva, who is also an associate professor in the Departments of Materials Science and Engineering and Brain and Cognitive Sciences. “When it’s fully hydrated, it has the [mechanical] properties of the brain.”

Anikeeva and colleagues reported on the new devices in the June 8 issue of Nature Communications.

Stealthy probes

Neural probes made out of metal or hard plastics have been invaluable in neuroscience research, allowing scientists to sense electrical activity within the brain, supply drugs to specific locations, or deliver neuron-activating pulses of light.

In 2015, Anikeeva and her group developed multifunctional probes, which are equipped with the tools to do all of these things. Although these polymer based devices were more biocompatible than metals and semiconductors, which can cut like tiny knives through the soft, jiggly tissue of the brain, their mechanics were still orders of magnitude away from those of neural tissue. Most neural probes can be used for a few weeks, until scar tissue forms around them and interferes with their function.

“For some experiments, this may not matter,” Anikeeva says. “But for other experiments, it does. If, for example, you’re interested in how a neuron evolves over the course of long-term behavior, or aging, or development, it’s important to keep track of the same tissue or the same cells. And that was challenging [with rigid probes].”

To enable longer experiments, Anikeeva’s team began to think about making multifunctional probes out of a material that is more compatible with the brain. “We wanted to create a device that would be stealthy, so the brain wouldn’t know that it’s there,” she says. To be useful, the device would still need some amount of hard material. But electrodes, microfluidic chambers, and optical channels can be tiny—just a fraction of the width of a human hair. “Even if they’re made out of polymer or soft metal, if you make them that small, they become sufficiently soft that they will be able to move with the brain and not cause damage,” Anikeeva says. It is the polymer matrix that surrounds these functional components that gives neural probes their shape and rigidity, which despite causing problems once inside the brain, is essential for implantation.

 

Seongjun Park, a graduate student in Anikeeva’s group, and Hyunwoo Yuk, another MIT graduate student who had been working with hydrogels in Xuanhe Zhao’s mechanical engineering lab, discussed the problem and proposed a probe that took advantage of that material. Because of hydrogels’ tunable nature, they could be used to build a device that was both stealthily squishy and piercingly rigid. By fine-tuning the chemistry, the team could ensure that after the device was implanted, its hydrogel would absorb just enough water to closely match the mechanics of the brain.

Hydrogel glue

Other researchers had previously developed neural probes wrapped in a hydrogel covering, but Anikeeva’s team wanted the hydrogel to be the bulk of the device. They would use the swellable material to bundle together the functional elements and fill the space between them.

To do so, they assembled the fibers that would give their device its desired function—an electrode array fiber for sensing neural activity, an optical fiber for delivering light to manipulate signaling, and a fluidic fiber for delivering drugs and genes—and chemically treated them so that they would adhere directly to the components of a hydrogel.

 

They then dipped the treated fibers into a solution of a hydrogel-forming compound called alginate. By exposing the solution to light, they triggered the alginate to polymerize, ultimately creating a thin strand of the hydrogel with the functional fibers embedded within it.

When it is first pulled out of the solution, Anikeeva says, the hydrogel-based device is like a wet noodle, with its components moving freely within it like the bendable bristles of a wet paintbrush. As the hydrogel dries, the fibers become firmly affixed to one another and the entire device stiffens—much like a drying paintbrush.

Long-term tracking

To test the devices, Anikeeva’s team implanted them into mice, targeting anxiety circuits deep within the brain. They behaved exactly as they had hoped—easily penetrating into the tissue, then returning to their “wet noodle” state and remaining in place without triggering a foreign body response in the brain. After more than six months of recording neural activity, the probes remained fully functional.

Anikeeva says her team’s squishy new probes are the first multifunctional neural devices to remain effective in living animals for this prolonged period. The improved longevity of the devices compared to their predecessors means researchers will be able to use them to track and manipulate neuronal behavior during long-term processes such as learning, disease progression, and aging.

The team is already working on the next-generation of hydrogel probes, which will further take advantage of the material’s unique properties to control the release of drugs or other compounds within the brain and improve the devices’ biocompatibility. And with a simplified fabrication process in development, Anikeeva says it may soon be possible for neuroscientists to manufacture the stealthy probes in their own labs.

Exploring the unknown

by Jennifer Michalowski |

View the interactive version of this story in our Summer 2021 issue of BrainScan.

 

McGovern Investigator Ed Boyden.

McGovern Investigator Ed Boyden says his lab’s vision is clear.

“We want to understand how our brains take our sensory inputs, generate emotions and memories and decisions, and ultimately result in motor outputs. We want to be able to see the building blocks of life, and how they go into disarray in brain diseases. We want to be able to control the signals of the brain, so we can repair it,” Boyden says.

To get there, he and his team are exploring the brain’s complexity at every scale, from the function and architecture of its neural networks to the molecules that work together to process information.

And when they don’t have the tools to take them where they want to go, they create them, opening new frontiers for neuroscientists everywhere.

Open to discovery

Boyden’s team is highly interdisciplinary and collaborative. Its specialty, Boyden says, is problem solving. Creativity, adaptability, and deep curiosity are essential, because while many of neuroscience’s challenges are clear, the best way to address them is not. In its search for answers, Boyden’s lab is betting that an important path to discovery begins with finding new ways to explore.

They’ve made that possible with an innovative imaging approach called expansion microscopy (ExM). ExM physically enlarges biological samples so that minute details become visible under a standard laboratory microscope, enabling researchers everywhere to peer into spaces that once went unseen (see video below).

To use the technique, researchers permeate a biological sample with an absorbent gel, then add water, causing the components of the gel to spread apart and the tissue to expand.

This year, postdoctoral researcher Ruixuan Gao and graduate student Chih-Chieh (Jay) Yu made the method more precise, with a new material that anchors a sample’s molecules within a crystal-like lattice, better preserving structure during expansion than the irregular mesh-like composition of the original gel. The advance is an important step toward being able to image expanded samples with single-molecule precision, Gao says.

A revealing look

By opening space within the brain, ExM has let Boyden’s team venture into those spaces in new ways.

Areas of research and brain disorders page
Graduate student Oz Wassie examines expanded brain tissue. Photo: Justin Knight

In work led by Deblina Sarkar (who is now an assistant professor at MIT’s Media Lab), Jinyoung Kang, and Asmamaw (Oz) Wassie, they showed that they can pull apart proteins in densely packed regions like synapses so that it is easier to introduce fluorescent labels, illuminating proteins that were once too crowded to see. The process, called expansion revealing, has made it possible to visualize in intact brain tissue important structures such as ion channels that help transmit signals and fine-scale amyloid clusters in Alzheimer’s model mice.

Another reaction the lab has adapted to the expanded-brain context is RNA sequencing—an important tool for understanding cellular diversity. “Typically, the first thing you do in a sequencing project is you grind up the tissue, and you lose the spatial dimension,” explains Daniel Goodwin, a graduate student in Boyden’s lab. But when sequencing reactions are performed inside cells instead, new information is revealed.

Confocal image showing targeted ExSeq of a 34-panel gene set across a slice of mouse hippocampus. Green indicates YFP, magenta indicates reads identified with ExSeq, and white indicates reads localized within YFP-expressing cells. Image courtesy of the researchers.

Goodwin and fellow Boyden lab members Shahar Alon, Anubhav Sinha, Oz Wassie, and Fei Chen developed expansion sequencing (ExSeq), which copies RNA molecules, nucleotide by nucleotide, directly inside expanded tissue, using fluorescent labels that spell out the molecules’ codes just as they would in a sequencer.

The approach shows researchers which genes are turned on in which cells, as well as where those RNA molecules are—revealing, for example, which genes are active in the neuronal projections that carry out the brain’s communications. A next step, Sinha says, is to integrate expansion sequencing with other technologies to obtain even deeper insights.

That might include combining information revealed with ExSeq with a topographical map of the same cells’ genomes, using a method Boyden’s lab and collaborators Chen (who is now a core member of the Broad Institute) and Jason Buenrostro at Harvard have developed for DNA sequencing. That information is important because the shape of the genome varies across cells and circumstances, and that has consequences for how the genetic code is used.

Using similar techniques to those that make ExSeq possible, graduate students Andrew Payne, Zachary Chiang, and Paul Reginato figured out how to recreate the steps of commercial DNA sequencing within the genome’s natural environment.

By pinpointing the location of specific DNA sequences inside cells, the new method, called in situ genome sequencing (IGS) allows researchers to watch a genome reorganize itself in a developing embryo.

They haven’t yet performed this analysis inside expanded tissue, but Payne says integrating in situ genome sequencing (IGS) with ExM should open up new opportunities to study genomes’ structure.

Signaling clusters

Alongside these efforts, Boyden’s team is working to give researchers better tools to explore how molecules move, change, and interact, including a modular system that lets users assemble sets of sensors into clusters to simultaneously monitor multiple cellular activities.

Molecular sensors use fluorescence to report on certain changes inside cells, such as the calcium that surges into a neuron after it fires. But they come in a limited palette, so in most experiments only one or two things can be seen at once.

Graduate student Shannon Johnson and postdoctoral fellow Changyang Linghu solved this problem by putting different sensors at different points throughout a cell so they can report on different signals. Their technique, called spatial multiplexing, links sensors to molecular scaffolds designed to cling to their own kind. Sensors built on the same scaffold form islands inside cells, so when they light up their signals are distinct from those produced by other sensor islands.

Eventually, as new sensors and scaffolds become available, Johnson says the technique might be used to simultaneously follow dozens of molecular signals in living cells. The more precise information they can help people uncover, the better, Boyden says.

“The brain is so full of surprises, we don’t know where the next big discovery will come from,” he says. With new support from the recently established K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience, the Boyden lab is positioned to make these big discoveries.

“My dream would be to image the signaling dynamics of the brain, and then perturb the dynamics, and then use expansion methods to make a map of the brain. If we can get those three data sets—the dynamics, the causality, and the molecular organization—I think stitching those together could potentially yield deep insights into how the brain works, and how we can repair it in disease states.”