In 2017 Polina Anikeeva, PhD ’09, was invited to a convention within the Netherlands to offer a discuss magnetic applied sciences that she and her workforce had developed at MIT and the way they is likely to be used for deep mind stimulation to deal with Parkinson’s illness. After sitting by means of an extended day of lectures, she was struck by one discuss particularly, wherein a researcher introduced up the concept that Parkinson’s is likely to be linked to pathogens within the digestive system. And immediately Anikeeva, who had pioneered the event of versatile, multifunction mind probes, discovered herself eager about how she would possibly use these probes to check the intestine.
Whereas the thought of switching gears would possibly give some researchers pause, Anikeeva thrives on venturing past her educational consolation zones. Actually, the trail that led to her turning into the Matoula S. Salapatas Professor in Supplies Science and Engineering—in addition to a professor of mind and cognitive sciences, affiliate director of MIT’s Analysis Laboratory of Electronics, and an affiliate investigator at MIT’s McGovern Institute for Mind Analysis—was hardly ever a transparent or apparent one. There may be, nonetheless, one fixed in every thing she does: an indefatigable curiosity that pushes her towards the sting of threat—or, as she likes to name it, “the mental abyss.”
After the convention within the Netherlands, she quickly dove into finding out the human intestine, a system that doesn’t merely transfer vitamins by means of the physique but in addition has the capability to interpret or ship info. Actually, she has come to consider it as a largely uncharted “distributed nervous system.” In 2022, she grew to become the director of the newly launched Okay. Lisa Yang Mind-Physique Heart at MIT, the place she’s directing analysis into the neural pathways past the mind—work that would make clear the processes implicated in growing older and ache, the mechanisms behind acupuncture, and the methods digestive points is likely to be linked not simply to Parkinson’s however to autism and different circumstances.
Though she hadn’t heard of it earlier than that convention within the Netherlands, the speculation that piqued Anikeeva’s curiosity in finding out the brain-body connection was first posed by the German anatomist Heiko Braak in 2003. He and colleagues posited {that a} kind of Parkinson’s illness has environmental origins: a pathogen that enters the physique by means of the mouth or the nasal cavity and leads to the digestive tract,the place it triggers the formation of irregular, probably poisonous clumps of protein inside neurons. That situation, referred to as Lewy pathology, is the hallmark of the illness.
“The explanation the environmental speculation took place is as a result of these Lewy our bodies even have been discovered within the GI tract of sufferers with Parkinson’s,” Anikeeva explains. “However what’s extra putting is that should you return within the medical historical past, Parkinson’s sufferers—a lot of them, like 80% or so—have been identified with GI dysfunction, mostly constipation, years earlier than they get a Parkinson’s prognosis.”
Capabilities, behaviors, and illnesses lengthy thought to originate within the mind is likely to be influenced by indicators from different components of the physique.
Researchers have debated the speculation and have but to make particular causal connections between the ingestion of pathogens and the development of Parkinson’s illness. However Anikeeva was intrigued.
“It’s fairly controversial and it has seen some makes an attempt at testing, however nothing conclusive,” she says. “I believed that my lab had a singular instrument package to start out testing this speculation.”
microscopic gut-brain interfaces her workforce developed.
On the time, Anikeeva’s lab was targeted on versatile polymer-fiber probes that may interface with the mind and spinal wire. Having developed these fibers, she and her workforce have been testing them in mice, each to stimulate neurons and to report their indicators so they may research the methods wherein these indicators underlie habits. The lab had additionally been engaged on utilizing magnetic nanomaterials to stimulate neurons so their exercise might be regulated remotely—without having to run fibers to a mouse’s mind in any respect.
Braak’s speculation made Anikeeva marvel: May comparable multifunctional probes be used to discover the digestive system? May she and her workforce engineer gut-particular instruments to check the neurons that make up what’s referred to as the enteric nervous system, which regulates sensing, shifting, absorbing, and secreting—the duties that the gastrointestinal tract should carry out to digest meals? And for that matter, might they research any of the physique’s peripheral methods?
“I began eager about interfacing not solely with the central nervous system, but in addition with different organ methods within the physique, and about how these organ methods contribute to mind perform,” she explains.
In the end, this interface might assist researchers perceive the way in which the physique communicates with the mind and vice versa, and to pinpoint the place illnesses, together with Parkinson’s, originate.
“For a few years neuroscience has primarily thought-about the mind in a vacuum. It was this stunning factor floating, disconnected,” Anikeeva says. “Now we all know that it’s not in a vacuum … The physique talks again to the mind. It’s not a strictly downward info move. No matter we expect—our character, our feelings—might not solely come from what we understand because the acutely aware mind.” In different phrases, capabilities, behaviors, and neurodegenerative illnesses lengthy thought to originate within the mind—maybe even the act of pondering itself—is likely to be influenced by indicators from different components of the physique. “These are the indicators that I’m very enthusiastic about finding out,” she says. “And now we’ve the instruments to do this.”
“It’s opened technological floodgates into these neuroscience questions,” she provides. “It is a new frontier.”
Anikeeva grew up in Saint Petersburg, Russia, the kid of engineers, and confirmed brilliance from an early age. She was admitted to a selective science magnet faculty, however she briefly thought-about pursuing a profession in artwork.
“I used to be about 15 years previous once I was selecting between skilled artwork {and professional} physics, and I didn’t wish to be poor,” she says with amusing. “Being good at watercolor doesn’t assist with leaving Russia, which was my goal. I grew up in a really unstable political atmosphere, a really unstable financial atmosphere. No one turns into an artist if they’ll do one thing else that’s extra sensible.” She selected science and earned her undergraduate diploma in biophysics at Saint Petersburg State Polytechnic.
However Anikeeva says her inventive mind, together with the mind-clearing avocations of climbing and long-distance operating, helps her along with her work as we speak: “I exploit that mind-set, the creativeness, to suppose conceptually about how a tool would possibly come collectively. The thought comes first as a picture.”
After graduating, Anikeeva obtained an internship in bodily chemistry with the Los Alamos Nationwide Laboratory in New Mexico and labored on photo voltaic cells utilizing quantum dots. In 2004, she arrived at MIT to start her PhD in supplies science and engineering.
Sirma Orguc, SM ’16, PhD ’21, within the lab.
As a graduate pupil, Anikeeva helped develop quantum-dot LED show expertise that’s now utilized by tv producers and bought in shops world wide. She has coauthored two papers on that analysis along with her major advisor, Vladimir Bulović, the Fariborz Maseeh (1990) Professor of Rising Know-how, affiliate dean for innovation on the Faculty of Engineering, and director of MIT.nano, and 7 with Bulović and Nobel Prize winner Moungi Bawendi, MIT’s Lester Wolfe Professor of Chemistry.
However after incomes her PhD in 2009, Anikeeva says, she obtained bored—as she continuously does. “I wished to work on one thing that didn’t exist,” she says.
That led her to hunt out a postdoctoral fellowship in neuroscience at Stanford College within the lab of Karl Deisseroth, one of many inventors of optogenetics, which makes use of laser gentle to activate proteins in genetically modified mind cells. Optogenetic instruments make it attainable to set off or inhibit neurons in take a look at rodents, creating an on/off swap that lets researchers research how the neurons work.
“I used to be actually lucky to be employed into that lab, even if my PhD, in the end, was not in neuroscience however in optical electronics,” she says. “I noticed all these animals operating round with optical cables popping out of their heads, and it was superb. I wished to discover ways to do this. That’s how I got here to neuroscience.”
Realizing that the instruments neuroscientists used to check advanced organic phenomena within the mind have been insufficient, she began to develop new ones. In Deisseroth’s lab, she discovered a means to enhance upon the fiber-optic probes they have been utilizing. Her model integrated a number of electrodes, permitting them to higher seize neuronal indicators.
Probing the mind is difficult as a result of it’s very gentle—“like pudding,” as she places it—and the instruments researchers used then have been inflexible and probably damaging. So when Anikeeva returned to MIT as an assistant professor, her lab collaborated with Yoel Fink, PhD ’00, a professor of supplies science and engineering in addition to electrical engineering and pc science and director of MIT’s Analysis Laboratory of Electronics, to create very skinny, extremely versatile fibers that may enter the mind and the spinal wire with out doing any hurt (see “A Higher Strategy to Probe the Mind,” MIT Information, Might/June 2015). In contrast to the cumbersome {hardware} that Deisseroth was utilizing to ship gentle for optogenetics, Anikeeva’sfibers are multifunctional. They’re manufactured from an optical core surrounded by polycarbonate and lined with electrodes and microfluidic channels, all of that are heated after which stretched in manufacturing. “You pull, pull, pull and also you get kilometers of fiber which might be fairly tiny,” Anikeeva explains. “In the end it will get drawn right down to a couple of hair-thin construction.”
Utilizing these ultrathin fibers, researchers can report neuronal indicators and ship their very own indicators to neurons within the mind and spinal wire of genetically engineered mice to show them on and off. The fibers supplied a brand new approach to examine neural responses—and earned Anikeeva a spot on our 2015 listing of 35 Innovators Below 35. Additionally they proved to be a helpful therapeutic instrument for drug supply utilizing the fibers’ microfluidic channels.
As this work hummed alongside, Anikeeva heard about Braak’s speculation in 2017 and got down to discover sources to analyze the gut-brain connection. “I promptly wrote an NIH grant, and I promptly obtained rejected,” she says.
However the concept endured.
Later that yr, neural engineers finding out mind interfaces at Duke invited Anikeeva to offer a chat. As she had gotten within the behavior of doing throughout her travels to different universities, she seemed up researchers engaged on GI methods there. She discovered the gut-brain neuroscientist Diego Bohórquez.
Whereas the mind is very advanced, from an engineering and analysis standpoint it’s way more handy to check than the digestive tract.
“I instructed him that I’m actually within the intestine, and he instructed me that they have been … finding out nutrient absorption within the intestine and the way it impacts mind perform,” Anikeeva recollects. “They wished to make use of optogenetics for that.”
However the glass fibers he’d been attempting to make use of for optogenetics within the intestine might do critical injury to the delicate GI system. So Anikeeva proposed a commerce of kinds.
“I believed that we are able to simply clear up Diego’s issues,” she says. “We will make units which might be extremely versatile, principally in change for Diego educating us every thing in regards to the intestine and learn how to work in that basically fascinating system.”
Bohórquez remembers their first assembly, the start of a fruitful collaboration, in some element. “She stated, ‘I see that you’re doing a little actually attention-grabbing work in sensations and the intestine. I’m certain that you simply’re most likely attempting to do one thing with habits,’” he says. “After which she pulls out these fibers and stated, ‘I’ve this versatile fiber. Do you suppose that you are able to do one thing with it?’”
interface.
stretchable organ probes underneath a microscope.
She returned to MIT and, she says, started to “take this lab that could be a quickly shifting plane service and begin reorienting it from engaged on the mind to engaged on the intestine.”
The transfer might have shocked colleagues, however Anikeeva refuses to do something if it loses her curiosity—and whereas the mind is very advanced, from an engineering and analysis standpoint it’s way more handy to check than the digestive tract. “The intestine wall is about 300 microns or so,” Anikeeva says. “It’s like three to 4 hairs caught collectively. And it’s in steady movement and it’s stuffed with stuff: bile, poop, all of the issues.” The challenges of finding out it, in different phrases, are nothing wanting daunting.
The nervous system within the intestine, Anikeeva explains, may be regarded as two socks, one inside the opposite. The one on the skin is the myenteric plexus, which regulates peristalsis—the rhythmic contraction of muscle mass that allows meals to maneuver alongside the gastrointestinal tract, a course of referred to as motility. The one on the within is the submucosal plexus, which is nearer to the mucosa (the mucus-coated interior lining) and facilitates sensing throughout the intestine. However the roles of the plexuses will not be totally understood. “That’s as a result of we are able to’t simply implant the intestine stuffed with {hardware} the identical means we do within the mind,” Anikeeva says. “All of the strategies, like optogenetics and any sort of electrical physiology—all of that was just about inconceivable within the intestine. These have been virtually intractable issues.”
Anikeeva’s work creating instruments for the mind had been so profitable and groundbreaking that it was tough for her to seek out monetary help for her pivot to different components of the physique. However then, she says, got here “one other fateful assembly.”
In 2018, she gave a presentation at a McGovern Institute board assembly, conveying her newest concepts about finding out Parkinson’s illness and engineering instruments to discover the GI system. Lisa Yang, a board member, talked about that many individuals with autism additionally endure from GI dysfunction—from motility problems to meals sensitivities. Yang was already deeply fascinated by autism, and he or she and her husband had simply launched the McGovern Institute’s Hock E. Tan (’75, SM ’75) and Okay. Lisa Yang Heart for Autism Analysis the yr earlier than.
“She was on this gut-brain connection,” Anikeeva remembers. “I used to be introduced into the Heart for Autism Analysis for a small challenge, and that small challenge sort of nucleated my potential to do that analysis—to start creating instruments to check the gut-brain connection.”
As that effort obtained underway, quite a few colleagues at MIT and elsewhere who have been additionally fascinated by brain-body pathways have been drawn to the brand new analysis.
“As our instruments began to mature, I began assembly extra individuals and it grew to become clear to me that I’m not the one individual on this space of inquiry at MIT,” she says. “The instruments opened this frontier, and the Mind-Physique Heart bubbled up from that.”
To launch into their work on the gut-brain connection, Anikeeva and her workforce needed to fully rethink the fibers they’d designed beforehand to check the mind.
In mind probes, all of the purposeful options sit on the tip of the fiber, and when that fiber is threaded into the cranium, the light-emitting tip faces downward, permitting researchers a view of every thing underneath it. That doesn’t work with the GI system. “It’s not the way you wish to interface with the intestine,” Anikeeva says. “The intestine is a lumenal organ—it’s a sock—and the nervous system is distributed within the wall.”
In different phrases, if the probe is trying downward, all it’ll see is matter passing by means of the intestine. To analysis the GI tract, Anikeeva and her colleagues wanted these options to take a seat laterally, alongside the size of the fiber. So with this fabrication problem in thoughts, Anikeeva once more approached Fink, a longtime mentor and collaborator—and a fellow TR35 veteran.
Mice “would usually eat ferociously” when given entry to meals after fasting. “However should you stimulate these cells within the intestine, they might really feel full.”
Collectively they developed a approach to distribute microelectronic elements—LEDs for optogenetic stimulation, temperature sensors, and microfluidic channels that may ship medicine, vitamins, and genetic materials—alongside the fiber by primarily making a collection of pockets to comprise them. Grad pupil Atharva Sahasrabudhe put in numerous hours to make it occur and optimized the method with the assistance of technician Lee Maresco, Anikeeva says. Then, with Anantha P. Chandrakasan, dean of MIT’s Faculty of Engineering, the Vannevar Bush Professor of EECS, and head of MIT’s Power-Environment friendly Circuits and Methods Group, the workforce designed a wi-fi, battery-powered unit that would talk with all these elements.
The outcome was a fiber, about half a millimeter by one-third of a millimeter huge, made out of a rubbery materials that may bend and conform to a mouse’s intestine but face up to its harsh atmosphere. And all of the digital elements housed inside it may be managed wirelessly through Bluetooth.
“We had all of the supplies engineers, after which we collaborated with our wi-fi colleagues, and we made this gadget that might be implanted within the intestine. After which, in fact, comparable ideas can be used within the mind,” Anikeeva explains. “We might do experiments each within the mind and the intestine.”
In one of many first experiments with the brand new fibers, Anikeeva labored with Bohórquez and his workforce, who had decided that sensory cells within the GI tract, referred to as neuropods, ship indicators to the mind that management sensations of satiety. Utilizing mice whose cells are genetically engineered to answer gentle, the MIT and Duke researchers used the specialised fibers to optically stimulate these cells within the intestine.
“We might take mice which might be hungry, which have been fasting for about 18 hours, and we might put them in a cage with entry to meals, which they might usually eat ferociously,” Anikeeva says. “However should you stimulate these cells within the intestine, they might really feel full though they have been hungry, and they’d not eat, or not as a lot.”
This was a breakthrough. “We knew that the expertise works,” she says, “and that we are able to management intestine capabilities from the intestine.”
Subsequent Anikeeva’s workforce wished to discover how these neural connections between the intestine and the mind can affect a mouse’s notion of reward or pleasure. They put the brand new fiber into the world of the mind the place reward notion is processed. It’s filled with neurons that launch dopamine—the “pleased hormone”—when activated.
Then they ran checks wherein mice had a alternative between two compartments in a cage; every time a mouse entered a selected one, the researchers stimulated its dopamine neurons, inflicting the mouse to favor it.
To see if they may replicate that reward-seeking habits by means of the intestine, the researchers used the gut-specific fibers’ microfluidic channels to infuse sucrose into the center of the mice at any time when they entered a selected compartment—and watched as dopamine neurons within the mind started firing quickly in response. These mice quickly tended to favor the sucrose-associated compartment.
However Anikeeva’s group questioned if they may management the intestine with none sucrose in any respect. In collaboration with Bohórquez and his workforce at Duke, the researchers omitted the sucrose infusion and easily stimulated the intestine neurons when the mice entered a delegated compartment. As soon as once more, the mice realized to hunt out that compartment.
“We didn’t contact the mind and we stimulated nerve endings within the intestine, and the mice developed the very same kind of desire—they felt pleased simply once we stimulated the nerve endings of their small intestines utilizing our expertise,” Anikeeva says. “This, in fact, was a technical demonstration that it’s now attainable to manage the nervous system of the intestine.”
The brand new instruments will make it attainable to check how totally different cells within the intestine ship info to the mind, and in the end the researchers hope to know the origins not solely of digestive illnesses, like weight problems, however of autism and neurodegenerative illnesses equivalent to Parkinson’s.
Researchers on the Mind-Physique Heart are already exploring these connections. “We’re notably within the gut-brain connection in autism,” Anikeeva says. “And we’re additionally fascinated by extra affective problems, as a result of there’s a huge genetic hyperlink, as an example, between anxiousness and IBS [or irritable bowel syndrome].”
Sooner or later, the expertise additionally might result in new therapies that may management intestine perform extra exactly and successfully than medicine, together with semaglutides like Ozempic, which have made headlines previously yr for weight management.
Now that Anikeeva has developed and examined the gadget within the GI system and solved loads of technical challenges, different peripheral methods within the physique might be subsequent.
“The intestine is innervated, however so is each organ within the physique. Now we are able to begin asking questions: What’s the connection to the immune system? The connection to the respiratory system?” she says. “All of those issues at the moment are turning into tractable. That is the start.”
Probing the mind-body connection
Based in 2022, the Okay. Lisa Yang Mind-Physique Heart at MIT is specializing in 4 main strains of analysis for its preliminary tasks.
GUT-BRAIN:
Polina Anikeeva’s group is increasing a toolbox of recent applied sciences and making use of these instruments to look at main neurobiological questions about gut-brain pathways and connections within the context of autism spectrum problems, Parkinson’s illness, and affective problems.
AGING:
CRISPR pioneer Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT and an investigator on the McGovern Institute, is main a gaggle in creating molecular instruments for precision epigenomic modifying and erasing amassed “errors” of time, damage, or illness in varied forms of cells and tissues.
PAIN:
The lab of Fan Wang, an investigator on the McGovern Institute and professor of mind and cognitive sciences, is designing new instruments and imaging strategies to check autonomic responses, exercise of the sympathetic and parasympathetic neurons, and interactions between the mind and the autonomic nervous system, together with how ache influences these interactions.
ACUPUNCTURE:
Wang can be collaborating with Kelly Metcalf Pate’s group in MIT’s Division of Comparative Medication, to advance strategies for documenting adjustments in mind and peripheral tissues induced by acupuncture in mouse fashions. If profitable, these strategies might assist make it attainable to higher perceive the mechanisms concerned in acupuncture—particularly, how the remedy stimulates the nervous system and restores perform.
A part of the objective of the Mind-Physique Heart, Wang says, is to dissect how the circuits of the central nervous system work together with the peripheral autonomic system to generate emotional responses to ache. She says her analysis has led her to a deeper understanding of the 2 responses to ache—sensory and emotional. The latter, a perform requiring the autonomic nervous system, is what results in a way of struggling. If researchers can stop the autonomic responses elicited by ache, she explains, then the identical stimulus might produce “a sensation with out ache.” The thought is to develop units to govern autonomic responses in mice, after which in the end develop units that may assist people. —Julie Pryor and Georgina Gustin
