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.
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.
Genetic engineer Joseph Kreitz looks to the microscopic world for inspiration in Feng Zhang’s lab at the McGovern Institute. Photo: Steph Steve
In their quest to deepen their understanding of the brain, McGovern scientists take inspiration wherever it comes — and sometimes it comes from surprising sources. To develop new tools for research and innovative strategies for treating disease, they’ve drawn on proteins that organisms have been making for billions of years as well as sophisticated materials engineered for modern technology.
For McGovern investigator Feng Zhang, the natural world provides a rich source of molecules with remarkable and potentially useful functions.
Zhang is one of the pioneers of CRISPR, a programmable system for gene editing that is built from the components of a bacterial adaptive immune system. Scientists worldwide use CRISPR to modify genetic sequences in their labs, and many CRISPR-based therapies, which aim to treat disease through gene editing, are now in development. Meanwhile, Zhang and his team have continued to explore CRISPR-like systems beyond the bacteria in which they were originally discovered.
Turning to nature
This year, the search for evolutionarily related systems led Zhang’s team to a set of enzymes made by more complex organisms, including single-celled algae and hard-shell clams. Like the enzymes that power CRISPR, these newly discovered enzymes, called Fanzors, can be directed to cut DNA at specific sites by programming an RNA molecule as a guide.
Rhiannon Macrae, a scientific advisor in Zhang’s lab, says the discovery was surprising because Fanzors don’t seem to play the same role in immunity that CRISPR systems do. In fact, she says it’s not clear what Fanzors do at all. But as programmable gene editors, Fanzors might have an important advantage over current CRISPR tools — particularly for clinical applications. “Fanzor proteins are much smaller than the workhorse CRISPR tool, Cas9,” Macrae says. “This really matters when you actually want to be able to use one of these tools in a patient, because the bigger the tool, the harder it is to package and deliver to patients’ cells.”
Cryo-EM map of a Fanzor protein (gray, yellow, light blue, and pink) in complex with ωRNA (purple) and its target DNA (red). Non-target DNA strand in blue. Image: Zhang lab
Zhang’s team has thought a lot about how to get therapies to patients’ cells, and size is only one consideration. They’ve also been looking for ways to direct drugs, gene-editing tools, or other therapies to specific cells and tissues in the body. One of the lab’s leading strategies comes from another unexpected natural source: a microscopic syringe produced by certain insect-infecting bacteria.
In their search for an efficient system for targeted drug delivery, Zhang and graduate student Joseph Kreitz first considered the injection systems of bacteria-infecting viruses: needle-like structures that pierce the outer membrane of their host to deliver their own genetic material. But these viral injection systems can’t easily be freed from the rest of the virus.
Then Zhang learned that some bacteria have injection systems of their own, which they release inside their hosts after packing them with toxins. They reengineered the bacterial syringe, devising a delivery system that works on human cells. Their current system can be programmed to inject proteins — including those used for gene editing — directly into specified cell types. With further development, Zhang hopes it will work with other types of therapies, as well.
Magnetic imaging
In McGovern Associate Investigator Alan Jasanoff’s lab, researchers are designing sensors that can track the activity of specific neurons or molecules in the brain, using magnetic resonance imaging (MRI) or related forms of non-invasive imaging. These tools are essential for understanding how the brain’s cells and circuits work together to process information. “We want to give MRI a suite of metaphorical colors: sensitivities that enable us to dissect the different kinds of mechanistically significant contributors to neural activity,” he explains.
Jasanoff can tick off a list of molecules with notable roles in biology and industry that his lab has repurposed to glean more information from brain imaging. These include manganese — a metal once used to tint ancient glass; nitric oxide synthase — the enzyme that causes blushing; and iron oxide nanoparticles — tiny magnets that enable compact data storage inside computers. But Jasanoff says none of these should be considered out of place in the imaging world. “Most are pretty logical choices,” he says. “They all do different things and we use them in pretty different ways, but they are either magnetic or interact with magnetic molecules to serve our purposes for brain imaging.”
Manganese, a metal that interacts weakly with magnetic fields, is a key component in new MRI sensors being developed in Alan Jasanoff’s lab at the McGovern Institute.
The enzyme nitric oxide synthase, for example, plays an important role in most functional MRI scans. The enzyme produces nitric oxide, which causes blood vessels to expand. This can bring a blush to the cheeks, but in the brain, it increases blood flow to bring more oxygen to busy neurons. MRI can detect this change because it is sensitive to the magnetic properties of blood.
By using blood flow as a proxy for neural activity, functional MRI scans light up active regions of the brain, but they can’t pinpoint the activity of specific cells. So Jasanoff and his team devised a more informative MRI sensor by reengineering nitric oxide synthase. Their modified enzyme, which they call NOSTIC, can be introduced into a select group of cells, where it will produce nitric oxide in response to neural activity — triggering increased blood flow and strengthening the local MRI signal. Researchers can deliver it to specific kinds of brain cells, or they can deliver it exclusively to neurons that communicate directly with one another. Then they can watch for an elevated MRI signal when those cells fire. This lets them see how information flows through the brain and tie specific cells to particular tasks.
Miranda Dawson, a graduate student in Jasanoff’s lab, is using NOSTIC to study the brain circuits that fuel addiction. She’s interested in the involvement of a brain region called the insula, which may mediate the physical sensations that people with addiction experience during drug cravings or withdrawal. With NOSTIC, Dawson can follow how the insula communicates to other parts of the brain as a rat experiences these MITstages of addiction. “We give our sensor to the insula, and then it projects to anatomically connected brain regions,” she explains. “So we’re able to delineate what circuits are being activated at different points in the addiction cycle.”
Miranda Dawson uses her lab’s novel MRI sensor, NOSTIC, to illuminate the brain circuits involved in fentanyl craving and withdrawal. Photo: Steph Stevens; MRI scan: Nan Li, Souparno Ghosh, Jasanoff lab
Mining biodiversity
McGovern investigators know that good ideas and useful tools can come from anywhere. Sometimes, the key to harnessing those tools is simply recognizing their potential. But there are also opportunities for a more deliberate approach to finding them.
McGovern Investigator Ed Boyden is leading a program that aims to accelerate the discovery of valuable natural products. Called the Biodiversity Network (BioNet), the project is collecting biospecimens from around the world and systematically analyzing them, looking for molecular tools that could be applied to major challenges in science and medicine, from brain research to organ preservation. “The idea behind BioNet,” Boyden explains, “is rather than wait for chance to give us these discoveries, can we go look for them on purpose?”
The lab of Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, has developed a powerful technology called Expansion Revealing (ExR) that makes visible molecular structures that were previously too hidden to be seen with even the most powerful microscopes. It “reveals” the nanoscale alterations in synapses, neural wiring, and other molecular assemblies using ordinary lab microscopes. It does so this way: Inside a cell, proteins and other molecules are often tightly packed together. These dense clusters can be difficult to image because the fluorescent labels used to make them visible can’t wedge themselves between the molecules. ExR “de-crowds” the molecules by expanding the cell using a chemical process, making the molecules accessible to fluorescent tags.
Jinyoung Kang is a J. Douglas Tan Postdoctoral Fellow in the Boyden and Feng labs. Photo: Steph Stevens
“This technology can be used to answer a lot of biological questions about dysfunction in synaptic proteins, which are involved in neurodegenerative diseases,” says Jinyoung Kang, a J. Douglas Tan Postdoctoral Fellow in the labs of Boyden and Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences. “Until now, there has been no tool to visualize synapses very well at nanoscale.”
Over the past year, the Boyden team has been using ExR to explore the underlying mechanisms of brain disorders, including autism spectrum disorder (ASD) and Alzheimer’s disease. Since the method can be applied iteratively, Boyden imagines it may one day succeed in creating a 100-fold magnification of molecular structures.
“Using earlier technology, researchers may be missing entire categories of molecular phenomena, both functional and dysfunctional,” says Boyden. “It’s critical to bring these nanostructures into view so that we can identify potential targets for new therapeutics that can restore functional molecular arrangements.”
The team is applying ExR to the study of mutant-animal-model brain slices to expose complex synapse 3D nanoarchitecture and configuration. Among their questions: How do synapses differ when mutations that cause autism and other neurological conditions are present?
Using the new technology, Kang and her collaborator Menglong Zeng characterized the molecular architecture of excitatory synapses on parvalbumin interneurons, cells that drastically influence the downstream effects of neuronal signaling and ultimately change cognitive behaviors. They discovered condensed AMPAR clustering in parvalbumin interneurons is essential for normal brain function. The next step is to explore their role in the function of parvalbumin interneurons, which are vulnerable to stressors and have been implicated in brain disorders including autism and Alzheimer’s disease.
The researchers are now investigating whether ExR can reveal abnormal protein nanostructures in SHANK3 knockout mice and marmosets. Mutations in the SHANK3 gene lead to one of the most severe types of ASD, Phelan-McDermid syndrome, which accounts for about 2 percent of all ASD patients with intellectual disability.
The brain and the digestive tract are in constant communication, relaying signals that help to control feeding and other behaviors. This extensive communication network also influences our mental state and has been implicated in many neurological disorders.
MIT engineers have designed a new technology for probing those connections. Using fibers embedded with a variety of sensors, as well as light sources for optogenetic stimulation, the researchers have shown that they can control neural circuits connecting the gut and the brain, in mice.
In a new study, the researchers demonstrated that they could induce feelings of fullness or reward-seeking behavior in mice by manipulating cells of the intestine. In future work, they hope to explore some of the correlations that have been observed between digestive health and neurological conditions such as autism and Parkinson’s disease.
“The exciting thing here is that we now have technology that can drive gut function and behaviors such as feeding. More importantly, we have the ability to start accessing the crosstalk between the gut and the brain with the millisecond precision of optogenetics, and we can do it in behaving animals,” says Polina Anikeeva, the Matoula S. Salapatas Professor in Materials Science and Engineering, a professor of brain and cognitive sciences, director of the K. Lisa Yang Brain-Body Center, associate director of MIT’s Research Laboratory of Electronics, and a member of MIT’s McGovern Institute for Brain Research.
McGovern Institute Associate Investigator Polina Anikeeva in her lab. Photo: Steph Stevens
Anikeeva is the senior author of the new study, which appears today in Nature Biotechnology. The paper’s lead authors are MIT graduate student Atharva Sahasrabudhe, Duke University postdoc Laura Rupprecht, MIT postdoc Sirma Orguc, and former MIT postdoc Tural Khudiyev.
The brain-body connection
Last year, the McGovern Institute launched the K. Lisa Yang Brain-Body Center to study the interplay between the brain and other organs of the body. Research at the center focuses on illuminating how these interactions help to shape behavior and overall health, with a goal of developing future therapies for a variety of diseases.
“There’s continuous, bidirectional crosstalk between the body and the brain,” Anikeeva says. “For a long time, we thought the brain is a tyrant that sends output into the organs and controls everything. But now we know there’s a lot of feedback back into the brain, and this feedback potentially controls some of the functions that we have previously attributed exclusively to the central neural control.”
As part of the center’s work, Anikeeva set out to probe the signals that pass between the brain and the nervous system of the gut, also called the enteric nervous system. Sensory cells in the gut influence hunger and satiety via both the neuronal communication and hormone release.
Untangling those hormonal and neural effects has been difficult because there hasn’t been a good way to rapidly measure the neuronal signals, which occur within milliseconds.
“We needed a device that didn’t exist. So, we decided to make it,” says Atharva Sahasrabudhe.
“To be able to perform gut optogenetics and then measure the effects on brain function and behavior, which requires millisecond precision, we needed a device that didn’t exist. So, we decided to make it,” says Sahasrabudhe, who led the development of the gut and brain probes.
The electronic interface that the researchers designed consists of flexible fibers that can carry out a variety of functions and can be inserted into the organs of interest. To create the fibers, Sahasrabudhe used a technique called thermal drawing, which allowed him to create polymer filaments, about as thin as a human hair, that can be embedded with electrodes and temperature sensors.
The filaments also carry microscale light-emitting devices that can be used to optogenetically stimulate cells, and microfluidic channels that can be used to deliver drugs.
The mechanical properties of the fibers can be tailored for use in different parts of the body. For the brain, the researchers created stiffer fibers that could be threaded deep into the brain. For digestive organs such as the intestine, they designed more delicate rubbery fibers that do not damage the lining of the organs but are still sturdy enough to withstand the harsh environment of the digestive tract.
“To study the interaction between the brain and the body, it is necessary to develop technologies that can interface with organs of interest as well as the brain at the same time, while recording physiological signals with high signal-to-noise ratio,” Sahasrabudhe says. “We also need to be able to selectively stimulate different cell types in both organs in mice so that we can test their behaviors and perform causal analyses of these circuits.”
The fibers are also designed so that they can be controlled wirelessly, using an external control circuit that can be temporarily affixed to the animal during an experiment. This wireless control circuit was developed by Orguc, a Schmidt Science Fellow, and Harrison Allen ’20, MEng ’22, who were co-advised between the Anikeeva lab and the lab of Anantha Chandrakasan, dean of MIT’s School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science.
Driving behavior
Using this interface, the researchers performed a series of experiments to show that they could influence behavior through manipulation of the gut as well as the brain.
First, they used the fibers to deliver optogenetic stimulation to a part of the brain called the ventral tegmental area (VTA), which releases dopamine. They placed mice in a cage with three chambers, and when the mice entered one particular chamber, the researchers activated the dopamine neurons. The resulting dopamine burst made the mice more likely to return to that chamber in search of the dopamine reward.
Then, the researchers tried to see if they could also induce that reward-seeking behavior by influencing the gut. To do that, they used fibers in the gut to release sucrose, which also activated dopamine release in the brain and prompted the animals to seek out the chamber they were in when sucrose was delivered.
Next, working with colleagues from Duke University, the researchers found they could induce the same reward-seeking behavior by skipping the sucrose and optogenetically stimulating nerve endings in the gut that provide input to the vagus nerve, which controls digestion and other bodily functions.
Duke University postdoc Laura Rupprecht, MIT graduate student Atharva Sahasrabudhe, and MIT postdoc Sirma Orguc holding their engineered flexible fiber in Polina Anikeeva’s lab at MIT. Photo: Courtesy of the researchers
“Again, we got this place preference behavior that people have previously seen with stimulation in the brain, but now we are not touching the brain. We are just stimulating the gut, and we are observing control of central function from the periphery,” Anikeeva says.
Sahasrabudhe worked closely with Rupprecht, a postdoc in Professor Diego Bohorquez’ group at Duke, to test the fibers’ ability to control feeding behaviors. They found that the devices could optogenetically stimulate cells that produce cholecystokinin, a hormone that promotes satiety. When this hormone release was activated, the animals’ appetites were suppressed, even though they had been fasting for several hours. The researchers also demonstrated a similar effect when they stimulated cells that produce a peptide called PYY, which normally curbs appetite after very rich foods are consumed.
The researchers now plan to use this interface to study neurological conditions that are believed to have a gut-brain connection. For instance, studies have shown that autistic children are far more likely than their peers to be diagnosed with GI dysfunction, while anxiety and irritable bowel syndrome share genetic risks.
“We can now begin asking, are those coincidences, or is there a connection between the gut and the brain? And maybe there is an opportunity for us to tap into those gut-brain circuits to begin managing some of those conditions by manipulating the peripheral circuits in a way that does not directly ‘touch’ the brain and is less invasive,” Anikeeva says.
The research was funded, in part, by the Hock E. Tan and K. Lisa Yang Center for Autism Research and the K. Lisa Yang Brain-Body Center, the National Institute of Neurological Disorders and Stroke, the National Science Foundation (NSF) Center for Materials Science and Engineering, the NSF Center for Neurotechnology, the National Center for Complementary and Integrative Health, a National Institutes of Health Director’s Pioneer Award, the National Institute of Mental Health, and the National Institute of Diabetes and Digestive and Kidney Diseases.
MIT scientists have developed tiny, soft-bodied robots that can be controlled with a weak magnet. The robots, formed from rubbery magnetic spirals, can be programmed to walk, crawl, swim—all in response to a simple, easy-to-apply magnetic field.
“This is the first time this has been done, to be able to control three-dimensional locomotion of robots with a one-dimensional magnetic field,” says McGovern associate investigator Polina Anikeeva, whose team reported on the magnetic robots June 3, 2023, in the journal Advanced Materials. “And because they are predominantly composed of polymer and polymers are soft, you don’t need a very large magnetic field to activate them. It’s actually a really tiny magnetic field that drives these robots,” says Anikeeva, who is also the Matoula S. Salapatas Professor in Materials Science and Engineering and a professor of brain and cognitive sciences at MIT, as well as the associate director of MIT’s Research Laboratory of Electronics and director of MIT’s K. Lisa Yang Brain-Body Center.
McGovern Institute Associate Investigator Polina Anikeeva in her lab. Photo: Steph Stevens
The new robots are well suited to transport cargo through confined spaces and their rubber bodies are gentle on fragile environments, opening the possibility that the technology could be developed for biomedical applications. Anikeeva and her team have made their robots millimeters long, but she says the same approach could be used to produce much smaller robots.
Engineering magnetic robots
Anikeeva says that until now, magnetic robots have moved in response to moving magnetic fields. She explains that for these models, “if you want your robot to walk, your magnet walks with it. If you want it to rotate, you rotate your magnet.” That limits the settings in which such robots might be deployed. “If you are trying to operate in a really constrained environment, a moving magnet may not be the safest solution. You want to be able to have a stationary instrument that just applies magnetic field to the whole sample,” she explains.
Youngbin Lee, a former graduate student in Anikeeva’s lab, engineered a solution to this problem. The robots he developed in Anikeeva’s lab are not uniformly magnetized. Instead, they are strategically magnetized in different zones and directions so a single magnetic field can enable a movement-driving profile of magnetic forces.
Before they are magnetized, however, the flexible, lightweight bodies of the robots must be fabricated. Lee starts this process with two kinds of rubber, each with a different stiffness. These are sandwiched together, then heated and stretched into a long, thin fiber. Because of the two materials’ different properties, one of the rubbers retains its elasticity through this stretching process, but the other deforms and cannot return to its original size. So when the strain is released, one layer of the fiber contracts, tugging on the other side and pulling the whole thing into a tight coil. Anikeeva says the helical fiber is modeled after the twisty tendrils of a cucumber plant, which spiral when one layer of cells loses water and contracts faster than a second layer.
A third material—one whose particles have the potential to become magnetic—is incorporated in a channel that runs through the rubbery fiber. So once the spiral has been made, a magnetization pattern that enables a particular type of movement can be introduced.
“Youngbin thought very carefully about how to magnetize our robots to make them able to move just as he programmed them to move,” Anikeeva says. “He made calculations to determine how to establish such a profile of forces on it when we apply a magnetic field that it will actually start walking or crawling.”
To form a caterpillar-like crawling robot, for example, the helical fiber is shaped into gentle undulations, and then the body, head, and tail are magnetized so that a magnetic field applied perpendicular to the robot’s plane of motion will cause the body to compress. When the field is reduced to zero, the compression is released, and the crawling robot stretches. Together, these movements propel the robot forward. Another robot in which two foot-like helical fibers are connected with a joint is magnetized in a pattern that enables a movement more like walking.
Biomedical potential
This precise magnetization process generates a program for each robot and ensures that that once the robots are made, they are simple to control. A weak magnetic field activates each robot’s program and drives its particular type of movement. A single magnetic field can even send multiple robots moving in opposite directions, if they have been programmed to do so. The team found that one minor manipulation of the magnetic field has a useful effect: With the flip of a switch to reverse the field, a cargo-carrying robot can be made to gently shake and release its payload.
Anikeeva says she can imagine these soft-bodied robots—whose straightforward production will be easy to scale up—delivering materials through narrow pipes or even inside the human body. For example, they might carry a drug through narrow blood vessels, releasing it exactly where it is needed. She says the magnetically-actuated devices have biomedical potential beyond robots as well, and might one day be incorporated into artificial muscles or materials that support tissue regeneration.
In Sierra Leone, war and illness have left up to 40,000 people requiring orthotics and prosthetics services, but there is a profound lack of access to specialized care, says Francesca Riccio-Ackerman, a biomedical engineer and PhD student studying health equity and health systems. There is just one fully certified prosthetist available for the thousands of patients in the African nation who are living with amputation, she notes. The ideal number is one for every 250, according to the World Health Organization and the International Society of Orthotics and Prosthetics.
The data point is significant for Riccio-Ackerman, who conducts research in the MIT Media Lab’s Biomechatronics Group and in the K. Lisa Yang Center for Bionics, both of which aim to improve translation of assistive technologies to people with disabilities. “We’re really focused on improving and augmenting human mobility,” she says. For Riccio-Ackerman, part of the quest to improve human mobility means ensuring that the people who need access to prosthetic care can get it—for the duration of their lives.
“We’re really focused on improving and augmenting human mobility,” says Riccio-Ackerman.
In September 2021, the Yang Center provided funding for Riccio-Ackerman to travel to Sierra Leone, where she witnessed the lingering physical effects of a brutal decade-long civil war that ended in 2002. Prosthetic and orthotic care in the country, where a vast number of patients are also disabled by untreated polio or diabetes, has become more elusive, she says, as global media attention on the war’s aftermath has subsided. “People with amputation need low-level, consistent care for years. There really needs to be a long-term investment in improving this.”
Through the Yang Center and supported by a fellowship from the new MIT Morningside Academy for Design, Riccio-Ackerman is designing and building a sustainable care and delivery model in Sierra Leone that aims to multiply the production of prosthetic limbs and strengthen the country’s prosthetic sector. “[We’re working] to improve access to orthotic and prosthetic services,” she says.
She is also helping to establish a supply chain for prosthetic limb and orthotic brace parts and equipping clinics with machines and infrastructure to serve more patients. In January 2023, her team launched a four-year collaboration with the Sierra Leone Ministry of Health and Sanitation. One of the goals of the joint effort is to enable Sierra Leoneans to obtain professional prosthetics training, so they can care for their own community without leaving home.
From engineering to economics
Riccio-Ackerman was drawn to issues around human mobility after witnessing her aunt suffer from rheumatoid arthritis. “My aunt was young, but she looked like she was 80 or 90. She was sick, in pain, in a wheelchair— a young spirit in an old body,” she says.
As a biomedical engineering undergraduate student at Florida International University, Riccio-Ackerman worked on clinical trials for neural-enabled myoelectric arms controlled by nerves in the body. She says that the technology was thrilling yet heartbreaking. She would often have to explain to patients who participated in testing that they couldn’t take the devices home and that they may never be covered by insurance.
Riccio-Ackerman began asking questions: “What factors determine who gets an amputation? Why are we making devices that are so expensive and inaccessible?” This sense of injustice inspired her to pivot away from device design and toward a master’s degree in health economics and policy at the SDA Bocconi School of Management in Milan.
She began work as a research specialist with Hugh Herr SM ’93, professor of arts and sciences at the MIT Media Lab and codirector of the Yang Center, helping to study communities that were medically neglected in prosthetic care. “I knew that the devices weren’t getting to the people who need them, and I didn’t know if the best way to solve it was through engineering,” Riccio-Ackerman explains.
While Riccio-Ackerman’s PhD should be finished within three years, she’s only at the beginning of her health care equity work. “We’re forging ahead in Sierra Leone and thinking about translating our strategy and methodologies to other communities around the globe that could benefit,” she says. “We hope to be able to do this in many, many countries in the future.”
In early December 2022, a middle-aged woman from California arrived at Boston’s Brigham and Women’s Hospital for the amputation of her right leg below the knee following an accident. This was no ordinary procedure. At the end of her remaining leg, surgeons attached a titanium fixture through which they threaded eight thin, electrically conductive wires. These flexible leads, implanted on her leg muscles, would, in the coming months, connect to a robotic, battery-powered prosthetic ankle and foot.
The goal of this unprecedented surgery, driven by MIT researchers from the K. Lisa Yang Center for Bionics at MIT, was the restoration of near-natural function to the patient, enabling her to sense and control the position and motion of her ankle and foot—even with her eyes closed.
In the K. Lisa Yang Center for Bionics, codirector Hugh Herr SM ’93 and graduate student Christopher Shallal are working to return mobility to people disabled by disease or physical trauma. Photo: Tony Luong
“The brain knows exactly how to control the limb, and it doesn’t matter whether it is flesh and bone or made of titanium, silicon, and carbon composite,” says Hugh Herr SM ’93, professor of media arts and sciences, head of the MIT Media Lab’s Biomechatronics Group, codirector of the Yang Center, and an associate member of MIT’s McGovern Institute for Brain Research.
For Herr, in attendance during that long day, the surgery represented a critical milestone in a decades-long mission to develop technologies returning mobility to people disabled by disease or physical trauma. His research combines a dizzying range of disciplines—electrical, mechanical, tissue, and biomedical engineering, as well as neuroscience and robotics—and has yielded pathbreaking results. Herr’s more than 100 patents include a computer-controlled knee and powered ankle-foot prosthesis and have enabled thousands of people around the world to live more on their own terms, including Herr.
Surmounting catastrophe
For much of Herr’s life, “go” meant “up.”
“Starting when I was eight, I developed an extraordinary passion, an absolute obsession, for climbing; it’s all I thought about in life,” says Herr. He aspired “to be the best climber in the world,” a goal he nearly achieved in his teenage years, enthralled by the “purity” of ascending mountains ropeless and solo in record times, by “a vertical dance, a balance between physicality and mind control.”
McGovern Institute Associate Investigator Hugh Herr. Photo: Jimmy Day / MIT Media Lab
At 17, Herr became disoriented while climbing New Hampshire’s Mt. Washington during a blizzard. Days in the cold permanently damaged his legs, which had to be amputated below his knees. His rescue cost another man’s life, and Herr was despondent, disappointed in himself, and fearful for his future.
Then, following months of rehabilitation, he felt compelled to test himself. His first weekend home, when he couldn’t walk without canes and crutches, he headed back to the mountains. “I hobbled to the base of this vertical cliff and started ascending,” he recalls. “It brought me joy to realize that I was still me, the same person.”
But he also recognized that as a person with amputated limbs, he faced severe disadvantages. “Society doesn’t look kindly on people with unusual bodies; we are viewed as crippled and weak, and that did not sit well with me.” Unable to tolerate both the new physical and social constraints on his life, Herr determined to view his disability not as a loss but as an opportunity. “I think the rage was the catapult that led me to do something that was without precedent,” he says.
Lifelike limb
On hand in the surgical theater in December was a member of Herr’s Biomechatronics Group for whom the bionic limb procedure also held special resonance. Christopher Shallal, a second-year graduate student in the Harvard-MIT Health Sciences and Technology program who received bilateral lower limb amputations at birth, worked alongside surgeon Matthew Carty testing the electric leads before implantation in the patient. Shallal found this, his first direct involvement with a reconstruction surgery, deeply fulfilling.
“Ever since I was a kid, I’ve wanted to do medicine plus engineering,” says Shallal. “I’m really excited to work on this bionic limb reconstruction, which will probably be one of the most advanced systems yet in terms of neural interfacing and control, with a far greater range of motion possible.”
Hugh and Shallal are working on a next-generation, biomimetic limb with implanted sensors that can relay signals between the external prosthesis and muscles in the remaining limb. Photo: Tony Luong
Like other Herr lab designs, the new prosthesis features onboard, battery-powered propulsion, microprocessors, and tunable actuators. But this next-generation, biomimetic limb represents a major leap forward, replacing electrodes sited on a patient’s skin, subject to sweat and other environmental threats, with implanted sensors that can relay signals between the external prosthesis and muscles in the remaining limb.
This system takes advantage of a breakthrough technique invented several years ago by the Herr lab called CMI (for cutaneous mechanoneural interface), which constructs muscle-skin-nerve bundles at the amputation site. Muscle actuators controlled by computers on board the external prosthesis apply forces on skin cells implanted within the amputated residuum when a person with amputation touches an object with their prosthesis.
With CMI and electric leads connecting the prosthesis to these muscle actuators within the residual limb, the researchers hypothesize that a person with an amputation will be able to “feel” their prosthetic leg step onto the ground. This sensory capability is the holy grail for persons with major limb loss. After recovery from her surgery, the woman from California will be wearing Herr’s latest state-of-the-art prosthetic system in the lab.
‘Tinkering’ with the body
Not all artificial limbs emulate those that humans are born with. “You can make them however you want, swapping them in and out depending on what you want to do, and they can take you anywhere,” Herr says. Committed to extreme climbing even after his accident, Herr came up with special limbs that became a commercial hit early in his career. His designs made it possible for someone with amputated legs to run and dance.
But he also knew the day-to-day discomfort of navigating on flatter earth with most prostheses. He won his first patent during his senior year of college for a fluid-controlled socket attachment designed to reduce the pain of walking. Growing up in a Mennonite family skilled in handcrafting things they needed, and in a larger community that was disdainful of technology, Herr says he had “difficulty trusting machines.” Yet by the time he began his master’s program at MIT, intent on liberating persons with limb amputation to live more fully in the world, he had embraced the tools of science and engineering as the means to this end.
“I want to be in the business of designing not more and more powerful tools but designing new bodies,” says Hugh Herr.
For Shallal, Herr was an early icon, and his inventions and climbing exploits served as inspiration. “I’d known about Hugh since middle school; he was famous among those with amputations,” he says. “As a kid, I liked tinkering with things, and I kind of saw my body as a canvas, a place where I could explore different boundaries and expand possibilities for myself and others with amputations.” In school, Shallal sometimes encountered resistance to his prostheses. “People would say I couldn’t do certain things, like running and playing different sports, and I found these barriers frustrating,” he says. “I did things in my own way and didn’t want people to pity me.”
In fact, Shallal felt he could do some things better than his peers. In high school, he used a 3-D printer to make a mobile phone charger case he could plug into his prosthesis. “As a kid, I would wear long pants to hide my legs, but as the technology got cooler, I started wearing shorts,” he says. “I got comfortable and liked kind of showing off my legs.”
Global impact
December’s surgery was the first phase in the bionic limb project. Shallal will be following up with the patient over many months, ensuring that the connections between her limb and implanted sensors function and provide appropriate sensorimotor data for the built-in processor. Research on this and other patients to determine the impact of these limbs on gait and ease of managing slopes, for instance, will form the basis for Shallal’s dissertation.
“After graduation, I’d be really interested in translating technology out of the lab, maybe doing a startup related to neural interfacing technology,” he says. “I watched Inspector Gadget on television when I was a kid. Making the tool you need at the time you need it to fix problems would be my dream.”
Herr will be overseeing Shallal’s work, as well as a suite of research efforts propelled by other graduate students, postdocs, and research scientists that together promise to strengthen the technology behind this generation of biomimetic prostheses.
One example: devising an innovative method for measuring muscle length and velocity with tiny implanted magnets. In work published in November 2022, researchers including Herr; project lead Cameron Taylor SM ’16, PhD ’20, a research associate in the Biomechatronics Group; and Brown University partners demonstrated that this new tool, magnetomicrometry, yields the kind of high-resolution data necessary for even more precise bionic limb control. The Herr lab awaits FDA approval on human implantation of the magnetic beads.
These intertwined initiatives are central to the ambitious mission of the K. Lisa Yang Center for Bionics, established with a $24 million gift from Yang in 2021 to tackle transformative bionic interventions to address an extensive range of human limitations.
Herr is committed to making the broadest possible impact with his technologies. “Shoes and braces hurt, so my group is developing the science of comfort—designing mechanical parts that attach to the body and transfer loads without causing pain.” These inventions may prove useful not just to people living with amputation but to patients suffering from arthritis or other diseases affecting muscles, joints, and bones, whether in lower limbs or arms and hands.
The Yang Center aims to make prosthetic and orthotic devices more accessible globally, so Herr’s group is ramping up services in Sierra Leone, where civil war left tens of thousands missing limbs after devastating machete attacks. “We’re educating clinicians, helping with supply chain infrastructure, introducing novel assistive technology, and developing mobile delivery platforms,” he says.
In the end, says Herr, “I want to be in the business of designing not more and more powerful tools but designing new bodies.” Herr uses himself as an example: “I walk on two very powerful robots, but they’re not linked to my skeleton, or to my brain, so when I walk it feels like I’m on powerful machines that are not me. What I want is such a marriage between human physiology and electromechanics that a person feels at one with the synthetic, designed content of their body.” and control, with a far greater range of motion possible.”
What does a healthy relationship between neuroscience and society look like? How do we set the conditions for that relationship to flourish? Researchers and staff at the McGovern Institute and the MIT Museum have been exploring these questions with a five-month planning grant from the Dana Foundation.
Between October 2022 and March 2023, the team tested the potential for an MIT Center for Neuroscience and Society through a series of MIT-sponsored events that were attended by students and faculty of nearby Cambridge Public Schools. The goal of the project was to learn more about what happens when the distinct fields of neuroscience, ethics, and public engagement are brought together to work side-by-side.
Gabrieli lab members Sadie Zacharek (left) and Shruti Nishith (right) demonstrate how the MRI mock scanner works with a student volunteer from the Cambridge Public Schools. Photo: Emma Skakel, MIT Museum
Middle schoolers visit McGovern
Over four days in February, more than 90 sixth graders from Rindge Avenue Upper Campus (RAUC) in Cambridge, Massachusetts, visited the McGovern Institute and participated in hands-on experiments and discussions about the ethical, legal, and social implications of neuroscience research. RAUC is one of four middle schools in the city of Cambridge with an economically, racially, and culturally diverse student population. The middle schoolers interacted with an MIT team led by McGovern Scientific Advisor Jill R. Crittenden, including seventeen McGovern neuroscientists, three MIT Museum outreach coordinators, and neuroethicist Stephanie Bird, a member of the Dana Foundation planning grant team.
“It is probably the only time in my life I will see a real human brain.” – RAUC student
The students participated in nine activities each day, including trials of brain-machine interfaces, close-up examinations of preserved human brains, a tour of McGovern’s imaging center in which students watched as their teacher’s brain was scanned, and a visit to the MIT Museum’s interactive Artificial Intelligence Gallery.
Imagine-IT, a brain-machine interface designed by a team of middle school students during a visit to the McGovern Institute.
To close out their visit, students worked in groups alongside experts to invent brain-computer interfaces designed to improve or enhance human abilities. At each step, students were introduced to ethical considerations through consent forms, questions regarding the use of animal and human brains, and the possible impacts of their own designs on individuals and society.
“I admit that prior to these four days, I would’ve been indifferent to the inclusion of children’s voices in a discussion about technically complex ethical questions, simply because they have not yet had any opportunity to really understand how these technologies work,” says one researcher involved in the visit. “But hearing the students’ questions and ideas has changed my perspective. I now believe it is critically important that all age groups be given a voice when discussing socially relevant issues, such as the ethics of brain computer interfaces or artificial intelligence.”
For more information on the proposed MIT Center for Neuroscience and Society, visit the MIT Museum website.
MIT’s K. Lisa Yang Center for Bionics has entered into a collaboration with the Government of Sierra Leone to strengthen the capabilities and services of that country’s orthotic and prosthetic (O&P) sector. Tens of thousands of people in Sierra Leone are in need of orthotic braces and artificial limbs, but access to such specialized medical care in this African nation is limited.
The agreement, reached between MIT, the Center for Bionics, and Sierra Leone’s Ministry of Health and Sanitation (MoHS), provides a detailed memorandum of understanding and intentions that will begin as a four-year program. The collaborators aim to strengthen Sierra Leone’s O&P sector through six key objectives: data collection and clinic operations, education, supply chain, infrastructure, new technologies and mobile delivery of services.
Project Objectives
Data Collection and Clinic Operations: collect comprehensive data on epidemiology, need, utilization, and access for O&P services across the country
Education: create an inclusive education and training program for the people of Sierra Leone, to enable sustainable and independent operation of O&P services
Supply Chain: establish supply chains for prosthetic and orthotic components, parts, and materials for fabrication of devices
Infrastructure: prepare infrastructure (e.g., physical space, sufficient water, power and internet) to support increased production and services
New Technologies: develop and translate innovative technologies with potential to improve O&P clinic operations and management, patient mobility, and the design or fabrication of devices
Mobile Delivery: support outreach services and mobile delivery of care for patients in rural and difficult-to-reach areas
Working together, MIT’s bionics center and Sierra Leone’s MoHS aim to sustainably double the production and distribution of O&P services at Sierra Leone’s National Rehabilitation Centre and Bo Clinics over the next four years.
The team of MIT scientists who will be implementing this novel collaboration is led by Hugh Herr, MIT Professor of Media Arts and Sciences. Herr, himself a double amputee, serves as co-director of the K. Lisa Yang Center for Bionics, and heads the renowned Biomechatronics research group at the MIT Media Lab.
“From educational services, to supply chain, to new technology, this important MOU with the government of Sierra Leone will enable the Center to develop a broad, integrative approach to the orthotic and prosthetic sector within Sierra Leone, strengthening services and restoring much needed care to its citizens,” notes Professor Herr.
Sierra Leone’s Honorable Minister of Health Dr. Austin Demby also states: “As the Ministry of Health and Sanitation continues to galvanize efforts towards the attainment of Universal Health Coverage through the life stages approach, this collaboration will foster access, innovation and capacity building in the Orthotic and Prosthetic division. The ministry is pleased to work with and learn from MIT over the next four years in building resilient health systems, especially for vulnerable groups.”
“Our team at MIT brings together expertise across disciplines from global health systems to engineering and design,” added Francesca Riccio-Ackerman, the graduate student lead for the MIT Sierra Leone project. “This allows us to craft an innovative strategy with Sierra Leone’s Ministry of Health and Sanitation. Together we aim to improve available orthotic and prosthetic care for people with disabilities.”
The K. Lisa Yang Center for Bionics at the Massachusetts Institute of Technology pioneers transformational bionic interventions across a broad range of conditions affecting the body and mind. Based on fundamental scientific principles, the Center seeks to develop neural and mechanical interfaces for human-machine communications; integrate these interfaces into novel bionic platforms; perform clinical trials to accelerate the deployment of bionic products by the private sector; and leverage novel and durable, but affordable, materials and manufacturing processes to ensure equitable access to the latest bionic technology by all impacted individuals, especially those in developing countries.
Sierra Leone’s Ministry of Health and Sanitation is responsible for health service delivery across the country, as well as regulation of the health sector to meet the health needs of its citizenry.