Research Area: Neurotechnology

expansion microscopy, bionic limbs, hydrogel fibers, magnetic nanodiscs, soft-bodied robots, protein engineering, molecular syringes, switchable fluorophores, stealthy probes, apps, MRI sensors, drug delivery systems

Michale Fee receives McKnight Technological Innovations in Neuroscience Award

by Julie Pryor |

McGovern Institute investigator Michale Fee has been selected to receive a 2018 McKnight Technological Innovations in Neuroscience Award for his research on “new technologies for imaging and analyzing neural state-space trajectories in freely-behaving small animals.”

“I am delighted to get support from the McKnight Foundation,” says Fee, who is also the Glen V. and Phyllis F. Dorflinger Professor in the Department of Brain and Cognitive Neurosciences at MIT. “We’re very excited about this project which aims to develop technology that will be a great help to the broader neuroscience community.”

Fee studies the neural mechanisms by which the brain, specifically that of juvenile songbirds, learns complex sequential behaviors. The way that songbirds learn a song through trial and error is analogous to humans learning complex behaviors, such as riding a bicycle. While it would be insightful to link such learning to neural activity, current methods for monitoring neurons can only monitor a limited field of neurons, a big issue since such learning and behavior involve complex interactions between larger circuits. While a wider field of view for recordings would help decipher neural changes linked to this learning paradigm, current microscopy equipment is large relative to a juvenile songbird, and microscopes that can record neural activity generally constrain the behavior of small animals. Ideally, technologies need to be lightweight (about 1 gram) and compact in size (the size of a dime), a far cry from current larger microscopes that weigh in at 3 grams. Fee hopes to be able to break these technical boundaries and miniaturize the recording equipment thus allowing recording of more neurons in naturally behaving small animals.

“We are thrilled that the McKnight Foundation has chosen to support this project. The technology that Michale’s developing will help to better visualize and understand the circuits underlying learning,” says Robert Desimone, director of MIT’s McGovern Institute for Brain Research.

In addition to development and miniaturization of the microscopy hardware itself, the award will support the development of technology that helps analyze the resulting images, so that the neuroscience community at large can more easily deploy and use the technology.

Chronic neural implants modulate microstructures in the brain with pinpoint accuracy

Anne Trafton |

Post by Windy Pham

The diversity of structures and functions of the brain is becoming increasingly realized in research today. Key structures exist in the brain that regulate emotion, anxiety, happiness, memory, and mobility. These structures can come in a huge variety of shapes and sizes and can all be physically near one another. Dysfunction of these structures and circuits linking them are common causes of many neurologic and neuropsychiatric diseases. For example, the substantia nigra is only a few millimeters in size yet is crucial for movement and coordination. Destruction of substantia nigra neurons is what causes motor symptoms in Parkinson’s disease.

New technologies such as optogenetics have allowed us to identify similar microstructures in the brain. However, these techniques rely on liquid infusions into the brain, which prepare the regions to be studied to respond to light. These infusions are done with large needles, which do not have the fine control to target specific regions. Clinical therapy has also lagged behind. New drug therapies aimed at treating these conditions are delivered orally, which results in drug distribution throughout the brain, or through large needle-cannulas, which do not have the fine control to accurately dose specific regions. As a result, patients of neurologic and psychiatric disorders frequently fail to respond to therapies due to poor drug delivery to diseased regions.

A new study addressing this problem has been published in Proceedings of the National Academy of Sciences. The lead author is Khalil Ramadi, a medical engineering and medical physics (MEMP) PhD candidate in the Harvard-MIT Program in Health Sciences and Technology (HST). For this study, Khalil and his thesis advisor, Michael Cima, the David H. Koch Professor of Engineering within the Department of Materials Science and Engineering and the Koch Institute for Integrative Cancer Research, and associate dean of innovation in the School of Engineering, collaborated with Institute Professors Robert Langer and Ann Graybiel, an Investigator at the McGovern Institute of Brain Research to tackle this issue.

The team developed tools to enable targeted delivery of nanoliters of drugs to deep brain structures through chronically implanted microprobes. They also developed nuclear imaging techniques using positron emission tomography (PET) to measure the volume of the brain region targeted with each infusion. “Drugs for disorders of the central nervous system are nonspecific and get distributed throughout the brain,” Cima says. “Our animal studies show that volume is a critical factor when delivering drugs to the brain, as important as the total dose delivered. Using microcannulas and microPET imaging, we can control the area of brain exposed to these drugs, improving targeting accuracy double time comparing to the traditional methods used today.”

The researchers were also able to design cannulas that are MRI-compatible and implanted up to one year in rats. Implanting these cannulas with micropumps allowed the researchers to remotely control the behavior of animals. Significantly, they found that varying the volume infused alone had a profound effect on behavior induced, even if the total drug dose delivered stayed constant. These results show that regulation of volume delivery to brain region is extremely important in influencing brain activity. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more effective treatment in human patients.

 

 

Ed Boyden and Feng Zhang named Howard Hughes Medical Institute Investigators

Anne Trafton |

Two members of the MIT faculty were named Howard Hughes Medical Institute (HHMI) investigators today. Ed Boyden and Feng Zhang join a community of 300 HHMI scientists who are “transforming biology and medicine, one discovery at a time.” Both researchers have been instrumental in recognizing, developing, and sharing robust tools with broad utility that have revolutionized the life sciences.

“We are thrilled that Ed and Feng are being recognized in this way” says Robert Desimone, director of the McGovern Institute for Brain Research at MIT. “Being named to the investigator program recognizes their previous achievements and allows them to follow the innovative path that is a trait of their research.”

HHMI selects new Investigators to join its flagship program through periodic competitions. In choosing researchers to join its investigator program, HHMI specifically aims to select ‘people, not projects’ and identifies trail blazers in the biomedical sciences. The organization provides support for an unusual length of time, seven years with a renewal process at the end of that period, thus giving selected scientists the time and freedom to tackle difficult and important biological questions. HHMI-affiliated scientists continue to work at their home institution. The HHMI Investigator program currently funds 300 scientists at 60 research institutions across the United States.

Ed Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT, has pioneered a number of technologies that allow visualization and manipulation of complex biological systems. Boyden worked, along with Karl Deisseroth and Feng Zhang, on optogenetics, a system that leverages microbial opsins to manipulate neuronal activity using light. This technology has transformed our ability to examine neuronal function in vivo. Boyden’s work initiated optogenetics, then extended it into a multicolor, high-speed, and noninvasive toolbox. Subsequent technological advances developed by Boyden and his team include expansion microscopy, an imaging strategy that overcomes the limits of light microscopy by expanding biological specimens in a controlled fashion. Boyden’s team also recently developed a directed evolution system that is capable of robotically screening hundreds of thousands of mutated proteins for specific properties within hours. He and his team recently used the system to develop a high-performance fluorescent voltage indicator.

“I am honored and excited to become an HHMI investigator,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research and an associate professor in the Program in Media Arts and Sciences at the MIT Media Lab; the MIT Department of Brain and Cognitive Sciences; and the MIT Department of Biological Engineering. “This will give my group the ability to open up completely new areas of science, in a way that would not be possible with traditional funding.”

Feng Zhang is a molecular biologist focused on building new tools for probing the human brain. As a graduate student, Zhang was part of the team that developed optogenetics. Zhang went on to develop other innovative tools. These achievements include the landmark deployment of the microbial CRISPR-Cas9 system for genome engineering in eukaryotic cells. The ease and specificity of the system has led to its widespread use. Zhang has continued to mine bacterial CRISPR systems for additional enzymes with useful properties, leading to the discovery of Cas13, which targets RNA, rather than DNA. By leveraging the unique properties of Cas13, Zhang and his team created a precise RNA editing tool, which may potentially be a safer way to treat genetic diseases because the genome does not need to be cut, as well as a molecular detection system, termed SHERLOCK, which can sense trace amounts of genetic material, such as viruses.

“It is so exciting to join this exceptional scientific community,” says Zhang, “and be given this opportunity to pursue our research into engineering natural systems.”

Zhang is the James and Patricia Poitras Professor of Neuroscience at MIT, an associate professor in the MIT departments of Brain and Cognitive Sciences and Biological Engineering, an investigator at the McGovern Institute for Brain Research, and a core member of the Broad Institute of MIT and Harvard.

The MIT Media Lab, Broad Institute of MIT and Harvard, and MIT departments of Brain and Cognitive Sciences and Biological Engineering contributed to this article.

Calcium-based MRI sensor enables more sensitive brain imaging

Anne Trafton |

MIT neuroscientists have developed a new magnetic resonance imaging (MRI) sensor that allows them to monitor neural activity deep within the brain by tracking calcium ions.

Because calcium ions are directly linked to neuronal firing — unlike the changes in blood flow detected by other types of MRI, which provide an indirect signal — this new type of sensing could allow researchers to link specific brain functions to their pattern of neuron activity, and to determine how distant brain regions communicate with each other during particular tasks.

“Concentrations of calcium ions are closely correlated with signaling events in the nervous system,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering, an associate member of MIT’s McGovern Institute for Brain Research, and the senior author of the study. “We designed a probe with a molecular architecture that can sense relatively subtle changes in extracellular calcium that are correlated with neural activity.”

In tests in rats, the researchers showed that their calcium sensor can accurately detect changes in neural activity induced by chemical or electrical stimulation, deep within a part of the brain called the striatum.

MIT research associates Satoshi Okada and Benjamin Bartelle are the lead authors of the study, which appears in the April 30 issue of Nature Nanotechnology. Other authors include professor of brain and cognitive sciences and Picower Institute for Learning and Memory member Mriganka Sur, Research Associate Nan Li, postdoc Vincent Breton-Provencher, former postdoc Elisenda Rodriguez, Wellesley College undergraduate Jiyoung Lee, and high school student James Melican.

Tracking calcium

A mainstay of neuroscience research, MRI allows scientists to identify parts of the brain that are active during particular tasks. The most commonly used type, known as functional MRI, measures blood flow in the brain as an indirect marker of neural activity. Jasanoff and his colleagues wanted to devise a way to map patterns of neural activity with specificity and resolution that blood-flow-based MRI techniques can’t achieve.

“Methods that are able to map brain activity in deep tissue rely on changes in blood flow, and those are coupled to neural activity through many different physiological pathways,” Jasanoff says. “As a result, the signal you see in the end is often difficult to attribute to any particular underlying cause.”

Calcium ion flow, on the other hand, can be directly linked with neuron activity. When a neuron fires an electrical impulse, calcium ions rush into the cell. For about a decade, neuroscientists have been using fluorescent molecules to label calcium in the brain and image it with traditional microscopy. This technique allows them to precisely track neuron activity, but its use is limited to small areas of the brain.

The MIT team set out to find a way to image calcium using MRI, which enables much larger tissue volumes to be analyzed. To do that, they designed a new sensor that can detect subtle changes in calcium concentrations outside of cells and respond in a way that can be detected with MRI.

The new sensor consists of two types of particles that cluster together in the presence of calcium. One is a naturally occurring calcium-binding protein called synaptotagmin, and the other is a magnetic iron oxide nanoparticle coated in a lipid that can also bind to synaptotagmin, but only when calcium is present.

Calcium binding induces these particles to clump together, making them appear darker in an MRI image. High levels of calcium outside the neurons correlate with low neuron activity; when calcium concentrations drop, it means neurons in that area are firing electrical impulses.

Detecting brain activity

To test the sensors, the researchers injected them into the striatum of rats, a region that is involved in planning movement and learning new behaviors. They then gave the rats a chemical stimulus that induces short bouts of neural activity, and found that the calcium sensor reflected this activity.

They also found that the sensor picked up activity induced by electrical stimulation in a part of the brain involved in reward.

This approach provides a novel way to examine brain function, says Xin Yu, a research group leader at the Max Planck Institute for Biological Cybernetics in Tuebingen, Germany, who was not involved in the research.

“Although we have accumulated sufficient knowledge on intracellular calcium signaling in the past half-century, it has seldom been studied exactly how the dynamic changes in extracellular calcium contribute to brain function, or serve as an indicator of brain function,” Yu says. “When we are deciphering such a complicated and self-adapted system like the brain, every piece of information matters.”

The current version of the sensor responds within a few seconds of the initial brain stimulation, but the researchers are working on speeding that up. They are also trying to modify the sensor so that it can spread throughout a larger region of the brain and pass through the blood-brain barrier, which would make it possible to deliver the particles without injecting them directly to the test site.

With this kind of sensor, Jasanoff hopes to map patterns of neural activity with greater precision than is now possible. “You could imagine measuring calcium activity in different parts of the brain and trying to determine, for instance, how different types of sensory stimuli are encoded in different ways by the spatial pattern of neural activity that they induce,” he says.

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

Ed Boyden receives 2018 Canada Gairdner International Award

Anne Trafton |

Ed Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT has been named a recipient of the 2018 Canada Gairdner International Award — Canada’s most prestigious scientific prize — for his role in the discovery of light-gated ion channels and optogenetics, a technology to control brain activity with light.

Boyden’s work has given neuroscientists the ability to precisely activate or silence brain cells to see how they contribute to — or possibly alleviate — brain disease. By optogenetically controlling brain cells, it has become possible to understand how specific patterns of brain activity might be used to quiet seizures, cancel out Parkinsonian tremors, and make other improvements to brain health.

Boyden is one of three scientists the Gairdner Foundation is honoring for this work. He shares the prize with Peter Hegemann from Humboldt University of Berlin and Karl Deisseroth from Stanford University.

“I am honored that the Gairdner Foundation has chosen our work in optogenetics for one of the most prestigious biology prizes awarded today,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research and an associate professor in the Media Lab, the Department of Brain and Cognitive Sciences, and the Department of Biological Engineering at MIT. “It represents a great collaborative body of work, and I feel excited that my angle of thinking like a physicist was able to contribute to biology.”

Boyden, along with fellow laureate Karl Deisseroth, brainstormed about how microbial opsins could be used to mediate optical control of neural activity, while both were students in 2000. Together, they collaborated to demonstrate the first optical control of neural activity using microbial opsins in the summer of 2004, when Boyden was at Stanford. At MIT, Boyden’s team developed the first optogenetic silencing (2007), the first effective optogenetic silencing in live mammals (2010), noninvasive optogenetic silencing (2014), multicolor optogenetic control (2014), and temporally precise single-cell optogenetic control (2017).

In addition to his work with optogenetics, Boyden has pioneered the development of many transformative technologies that image, record, and manipulate complex systems, including expansion microscopy and robotic patch clamping. He has received numerous awards for this work, including the Breakthrough Prize in Life Sciences (2016), the BBVA Foundation Frontiers of Knowledge Award (2015), the Carnegie Prize in Mind and Body Sciences (2015), the Grete Lundbeck European Brain Prize (2013), and the Perl-UNC Neuroscience prize (2011). Boyden is an elected member of the American Academy of Arts and Sciences and the National Academy of Inventors.

“We are thrilled Ed has been recognized with the prestigious Gairdner Award for his work in developing optogenetics,” says Robert Desimone, director of the McGovern Institute. “Ed’s body of work has transformed neuroscience and biomedicine, and I am exceedingly proud of the contributions he has made to MIT and to the greater community of scientists worldwide.”

The Canada Gairdner International Awards, created in 1959, are given annually to recognize and reward the achievements of medical researchers whose work contributes significantly to the understanding of human biology and disease. The awards provide a $100,000 (CDN) prize to each scientist for their work. Each year, the five honorees of the International Awards are selected after a rigorous two-part review, with the winners voted by secret ballot by a medical advisory board composed of 33 eminent scientists from around the world.

Viral tool traces long-term neuron activity

Anne Trafton |

For the past decade, neuroscientists have been using a modified version of the rabies virus to label neurons and trace the connections between them. Although this technique has proven very useful, it has one major drawback: The virus is toxic to cells and can’t be used for studies longer than about two weeks.

Researchers at MIT and the Allen Institute for Brain Science have now developed a new version of this virus that stops replicating once it infects a cell, allowing it to deliver its genetic cargo without harming the cell. Using this technique, scientists should be able to study the infected neurons for several months, enabling longer-term studies of neuron functions and connections.

“With the first-generation vectors, the virus is replicating like crazy in the infected neurons, and that’s not good for them,” says Ian Wickersham, a principal research scientist at MIT’s McGovern Institute for Brain Research and the senior author of the new study. “With the second generation, infected cells look normal and act normal for at least four months — which was as long as we tracked them — and probably for the lifetime of the animal.”

Soumya Chatterjee of the Allen Institute is the lead author of the paper, which appears in the March 5 issue of Nature Neuroscience.

Viral tracing

Rabies viruses are well-suited for tracing neural connections because they have evolved to spread from neuron to neuron through junctions known as synapses. The viruses can also spread from the terminals of axons back to the cell body of the same neuron. Neuroscientists can engineer the viruses to carry genes for fluorescent proteins, which are useful for imaging, or for light-sensitive proteins that can be used to manipulate neuron activity.

In 2007, Wickersham demonstrated that a modified version of the rabies virus could be used to trace synapses between only directly connected neurons. Before that, researchers had been using the rabies virus for similar studies, but they were unable to keep it from spreading throughout the entire brain.

By deleting one of the virus’ five genes, which codes for a glycoprotein normally found on the surface of infected cells, Wickersham was able to create a version that can only spread to neurons in direct contact with the initially infected cell. This 2007 modification enabled scientists to perform “monosynaptic tracing,” a technique that allows them to identify connections between the infected neuron and any neuron that provides input to it.

This first generation of the modified rabies virus is also used for a related technique known as retrograde targeting, in which the virus can be injected into a cluster of axon terminals and then travel back to the cell bodies of those axons. This can help researchers discover the location of neurons that send impulses to the site of the virus injection.

Researchers at MIT have used retrograde targeting to identify populations of neurons of the basolateral amygdala that project to either the nucleus accumbens or the central medial amygdala. In that type of study, researchers can deliver optogenetic proteins that allow them to manipulate the activity of each population of cells. By selectively stimulating or shutting off these two separate cell populations, researchers can determine their functions.

Reduced toxicity

To create the second-generation version of this viral tool, Wickersham and his colleagues deleted the gene for the polymerase enzyme, which is necessary for transcribing viral genes. Without this gene, the virus becomes less harmful and infected cells can survive much longer. In the new study, the researchers found that neurons were still functioning normally for up to four months after infection.

“The second-generation virus enters a cell with its own few copies of the polymerase protein and is able to start transcribing its genes, including the transgene that we put into it. But then because it’s not able to make more copies of the polymerase, it doesn’t have this exponential takeover of the cell, and in practice it seems to be totally nontoxic,” Wickersham says.

The lack of polymerase also greatly reduces the expression of whichever gene the researchers engineer into the virus, so they need to employ a little extra genetic trickery to achieve their desired outcome. Instead of having the virus deliver a gene for a fluorescent or optogenetic protein, they engineer it to deliver a gene for an enzyme called Cre recombinase, which can delete target DNA sequences in the host cell’s genome.

This virus can then be used to study neurons in mice whose genomes have been engineered to include a gene that is turned on when the recombinase cuts out a small segment of DNA. Only a small amount of recombinase enzyme is needed to turn on the target gene, which could code for a fluorescent protein or another type of labeling molecule. The second-generation viruses can also work in regular mice if the researchers simultaneously inject another virus carrying a recombinase-activated gene for a fluorescent protein.

The new paper shows that the second-generation virus works well for retrograde labeling, not tracing synapses between cells, but the researchers have also now begun using it for monosynaptic tracing.

The research was funded by the National Institute of Mental Health, the National Institute on Aging, and the National Eye Institute.

Edward Boyden named inaugural Y. Eva Tan Professor in Neurotechnology

Anne Trafton |

Edward S. Boyden, a member of MIT’s McGovern Institute for Brain Research and the Media Lab, and an associate professor of brain and cognitive sciences and biological engineering at MIT, has been appointed the inaugural Y. Eva Tan Professor in Neurotechnology. The new professorship has been established at the McGovern Institute by K. Lisa Yang in honor of her daughter Y. Eva Tan.

“We are thrilled Lisa has made a generous investment in neurotechnology and the McGovern Institute by creating this new chair,” says Robert Desimone, director of the McGovern Institute. “Ed’s body of work has already transformed neuroscience and biomedicine, and this chair will help his team to further develop revolutionary tools that will have a profound impact on research worldwide.”

In 2017, Yang co-founded the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute. The center catalyzes interdisciplinary and cutting-edge research into the genetic, biological, and brain bases of autism spectrum disorders. In late 2017, Yang grew the center with the establishment of the endowed J. Douglas Tan Postdoctoral Research Fund, which supports talented postdocs in the lab of Poitras Professor of Neuroscience Guoping Feng.

“I am excited to further expand the Hock E. Tan and K. Lisa Yang Center for Autism Research and to support Ed and his team’s critical work,” says Yang. “Novel technology is the driving force behind much-needed breakthroughs in brain research — not just for individuals with autism, but for those living with all brain disorders. My daughter Eva and I are greatly pleased to recognize Ed’s talent and to contribute toward his future successes.”

Yang’s daughter agrees. “I’m so pleased this professorship will have a significant and lasting impact on MIT’s pioneering work in neurotechnology,” says Tan. “My family and I have always believed that advances in technology are what make all scientific progress possible, and I’m overjoyed that we can help enable amazing discoveries in the Boyden Lab through Ed’s appointment to this chair.”

Boyden has pioneered the development of many transformative technologies that image, record, and manipulate complex systems, including optogenetics, expansion microscopy, and robotic patch clamping. He has received numerous awards for this work, including the Breakthrough Prize in Life Sciences (2016), the BBVA Foundation Frontiers of Knowledge Award (2015), the Carnegie Prize in Mind and Body Sciences (2015), the Grete Lundbeck European Brain Prize (2013), and the Perl-UNC Neuroscience prize (2011). Boyden is an elected member of the American Academy of Arts and Sciences and the National Academy of Inventors.

“I deeply appreciate the honor that comes with being named the first Y. Eva Tan Professor in Neurotechnology,” says Boyden. “This is a tremendous recognition of not only my team’s work, but the groundbreaking impact of the neurotechnology field.”

Boyden joined MIT in 2007 as an assistant professor at the Media Lab, and later was appointed as a joint professor in the departments of Brain and Cognitive Sciences and Biological Engineering and an investigator in the McGovern Institute. In 2011, he was named the Benesse Career Development Professor, and in 2013 he was awarded the AT&T Career Development Professorship. Seven years after arriving at MIT, he was awarded tenure. Boyden earned his BS and MEng from MIT in 1999 and his PhD in Neuroscience from Stanford University in 2005.

Seeing the brain’s electrical activity

Anne Trafton |

Neurons in the brain communicate via rapid electrical impulses that allow the brain to coordinate behavior, sensation, thoughts, and emotion. Scientists who want to study this electrical activity usually measure these signals with electrodes inserted into the brain, a task that is notoriously difficult and time-consuming.

MIT researchers have now come up with a completely different approach to measuring electrical activity in the brain, which they believe will prove much easier and more informative. They have developed a light-sensitive protein that can be embedded into neuron membranes, where it emits a fluorescent signal that indicates how much voltage a particular cell is experiencing. This could allow scientists to study how neurons behave, millisecond by millisecond, as the brain performs a particular function.

“If you put an electrode in the brain, it’s like trying to understand a phone conversation by hearing only one person talk,” says Edward Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT. “Now we can record the neural activity of many cells in a neural circuit and hear them as they talk to each other.”

Boyden, who is also a member of MIT’s Media Lab, McGovern Institute for Brain Research, and Koch Institute for Integrative Cancer Research, and an HHMI-Simons Faculty Scholar, is the senior author of the study, which appears in the Feb. 26 issue of Nature Chemical Biology. The paper’s lead authors are MIT postdocs Kiryl Piatkevich and Erica Jung.

Imaging voltage

For the past two decades, scientists have sought a way to monitor electrical activity in the brain through imaging instead of recording with electrodes. Finding fluorescent molecules that can be used for this kind of imaging has been difficult; not only do the proteins have to be very sensitive to changes in voltage, they must also respond quickly and be resistant to photobleaching (fading that can be caused by exposure to light).

Boyden and his colleagues came up with a new strategy for finding a molecule that would fulfill everything on this wish list: They built a robot that could screen millions of proteins, generated through a process called directed protein evolution, for the traits they wanted.

“You take a gene, then you make millions and millions of mutant genes, and finally you pick the ones that work the best,” Boyden says. “That’s the way that evolution works in nature, but now we’re doing it in the lab with robots so we can pick out the genes with the properties we want.”

The researchers made 1.5 million mutated versions of a light-sensitive protein called QuasAr2, which was previously engineered by Adam Cohen’s lab at Harvard University. (That work, in turn, was based on the molecule Arch, which the Boyden lab reported in 2010.) The researchers put each of those genes into mammalian cells (one mutant per cell), then grew the cells in lab dishes and used an automated microscope to take pictures of the cells. The robot was able to identify cells with proteins that met the criteria the researchers were looking for, the most important being the protein’s location within the cell and its brightness.

The research team then selected five of the best candidates and did another round of mutation, generating 8 million new candidates. The robot picked out the seven best of these, which the researchers then narrowed down to one top performer, which they called Archon1.

Mapping the brain

A key feature of Archon1 is that once the gene is delivered into a cell, the Archon1 protein embeds itself into the cell membrane, which is the best place to obtain an accurate measurement of a cell’s voltage.

Using this protein, the researchers were able to measure electrical activity in mouse brain tissue, as well as in brain cells of zebrafish larvae and the worm Caenorhabditis elegans. The latter two organisms are transparent, so it is easy to expose them to light and image the resulting fluorescence. When the cells are exposed to a certain wavelength of reddish-orange light, the protein sensor emits a longer wavelength of red light, and the brightness of the light corresponds to the voltage of that cell at a given moment in time.

The researchers also showed that Archon1 can be used in conjunction with light-sensitive proteins that are commonly used to silence or stimulate neuron activity — these are known as optogenetic proteins — as long as those proteins respond to colors other than red. In experiments with C. elegans, the researchers demonstrated that they could stimulate one neuron using blue light and then use Archon1 to measure the resulting effect in neurons that receive input from that cell.

Cohen, the Harvard professor who developed the predecessor to Archon1, says the new MIT protein brings scientists closer to the goal of imaging millisecond-timescale electrical activity in live brains.

“Traditionally, it has been excruciatingly labor-intensive to engineer fluorescent voltage indicators, because each mutant had to be cloned individually and then tested through a slow, manual patch-clamp electrophysiology measurement. The Boyden lab developed a very clever high-throughput screening approach to this problem,” says Cohen, who was not involved in this study. “Their new reporter looks really great in fish and worms and in brain slices. I’m eager to try it in my lab.”

The researchers are now working on using this technology to measure brain activity in mice as they perform various tasks, which Boyden believes should allow them to map neural circuits and discover how they produce specific behaviors.

“We will be able to watch a neural computation happen,” he says. “Over the next five years or so we’re going to try to solve some small brain circuits completely. Such results might take a step toward understanding what a thought or a feeling actually is.”

The research was funded by the HHMI-Simons Faculty Scholars Program, the IET Harvey Prize, the MIT Media Lab, the New York Stem Cell Foundation Robertson Award, the Open Philanthropy Project, John Doerr, the Human Frontier Science Program, the Department of Defense, the National Science Foundation, and the National Institutes of Health, including an NIH Director’s Pioneer Award.

Polina Anikeeva and Feng Zhang awarded 2018 Vilcek Prize

Anne Trafton |

Polina Anikeeva, the Class of 1942 Associate Professor in the Department of Materials Science and Engineering and associate director of the Research Laboratory of Electronics, and Feng Zhang, the James and Patricia Poitras ’63 Professor in Neuroscience at the McGovern Institute, have each been awarded a 2018 Vilcek Prize for Creative Promise in Biomedical Science. Awarded annually by the Vilcek Foundation, the $50,000 prizes recognize younger immigrants who have demonstrated exceptional promise early in their careers.

“The Vilcek Prizes were established in appreciation of the immigrants who chose to dedicate their vision and talent to bettering American society,” says Rick Kinsel, president of the Vilcek Foundation. “This year’s prizewinners honor and continue that legacy with works of astounding, revolutionary importance.”

Polina Anikeeva, who was born in the former Soviet Union, earned her PhD in materials science and engineering at MIT in 2009 and now runs her own bioelectronics lab in the same department focused on the development of materials and devices that enable recording and manipulation of signaling processes within the nervous system. The Vilcek Foundation recognizes Anikeeva for “fashioning ingenious solutions to long-standing challenges in biomedical engineering” including the design of therapeutic devices for conditions such as Parkinson’s disease and spinal cord injury.

Feng Zhang, who is also a core member of the Broad Institute and an associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering, is being recognized for his role in advancing optogenetics (a method for controlling brain activity with light) and developing molecular tools to edit the genome. Thanks to his leadership in inventing precise and efficient gene-editing technologies using CRISPR, Zhang’s work has resulted in a “growing array of applications, such as uncovering the genetic underpinnings of diseases, ushering in gene therapies to cure heritable diseases, and improving agriculture.” Zhang’s family immigrated to the United States from China when he was 11 years of age.

Anikeeva and Zhang will be among eight Vilcek prizewinners honored at an awards gala in New York City in April 2018.

The Vilcek Foundation was established in 2000 by Jan and Marica Vilcek, immigrants from the former Czechoslovakia. The mission of the foundation, to honor the contributions of immigrants to the United States and to foster appreciation of the arts and sciences, was inspired by the couple’s respective careers in biomedical science and art history, as well as their personal experiences and appreciation of the opportunities they received as newcomers to this country.

Ultrathin needle can deliver drugs directly to the brain

Anne Trafton |

MIT researchers have devised a miniaturized system that can deliver tiny quantities of medicine to brain regions as small as 1 cubic millimeter. This type of targeted dosing could make it possible to treat diseases that affect very specific brain circuits, without interfering with the normal function of the rest of the brain, the researchers say.

Using this device, which consists of several tubes contained within a needle about as thin as a human hair, the researchers can deliver one or more drugs deep within the brain, with very precise control over how much drug is given and where it goes. In a study of rats, they found that they could deliver targeted doses of a drug that affects the animals’ motor function.

“We can infuse very small amounts of multiple drugs compared to what we can do intravenously or orally, and also manipulate behavioral changes through drug infusion,” says Canan Dagdeviren, the LG Electronics Career Development Assistant Professor of Media Arts and Sciences and the lead author of the paper, which appears in the Jan. 24 issue of Science Translational Medicine.

“We believe this tiny microfabricated device could have tremendous impact in understanding brain diseases, as well as providing new ways of delivering biopharmaceuticals and performing biosensing in the brain,” says Robert Langer, the David H. Koch Institute Professor at MIT and one of the paper’s senior authors.

Michael Cima, the David H. Koch Professor of Engineering in the Department of Materials Science and Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, is also a senior author of the paper.

Targeted action

Drugs used to treat brain disorders often interact with brain chemicals called neurotransmitters or the cell receptors that interact with neurotransmitters. Examples include l-dopa, a dopamine precursor used to treat Parkinson’s disease, and Prozac, used to boost serotonin levels in patients with depression. However, these drugs can have side effects because they act throughout the brain.

“One of the problems with central nervous system drugs is that they’re not specific, and if you’re taking them orally they go everywhere. The only way we can limit the exposure is to just deliver to a cubic millimeter of the brain, and in order to do that, you have to have extremely small cannulas,” Cima says.

The MIT team set out to develop a miniaturized cannula (a thin tube used to deliver medicine) that could target very small areas. Using microfabrication techniques, the researchers constructed tubes with diameters of about 30 micrometers and lengths up to 10 centimeters. These tubes are contained within a stainless steel needle with a diameter of about 150 microns. “The device is very stable and robust, and you can place it anywhere that you are interested,” Dagdeviren says.

The researchers connected the cannulas to small pumps that can be implanted under the skin. Using these pumps, the researchers showed that they could deliver tiny doses (hundreds of nanoliters) into the brains of rats. In one experiment, they delivered a drug called muscimol to a brain region called the substantia nigra, which is located deep within the brain and helps to control movement.

Previous studies have shown that muscimol induces symptoms similar to those seen in Parkinson’s disease. The researchers were able to generate those effects, which include stimulating the rats to continually turn in a clockwise direction, using their miniaturized delivery needle. They also showed that they could halt the Parkinsonian behavior by delivering a dose of saline through a different channel, to wash the drug away.

“Since the device can be customizable, in the future we can have different channels for different chemicals, or for light, to target tumors or neurological disorders such as Parkinson’s disease or Alzheimer’s,” Dagdeviren says.

This device could also make it easier to deliver potential new treatments for behavioral neurological disorders such as addiction or obsessive compulsive disorder, which may be caused by specific disruptions in how different parts of the brain communicate with each other.

“Even if scientists and clinicians can identify a therapeutic molecule to treat neural disorders, there remains the formidable problem of how to delivery the therapy to the right cells — those most affected in the disorder. Because the brain is so structurally complex, new accurate ways to deliver drugs or related therapeutic agents locally are urgently needed,” says Ann Graybiel, an MIT Institute Professor and a member of MIT’s McGovern Institute for Brain Research, who is also an author of the paper.

Measuring drug response

The researchers also showed that they could incorporate an electrode into the tip of the cannula, which can be used to monitor how neurons’ electrical activity changes after drug treatment. They are now working on adapting the device so it can also be used to measure chemical or mechanical changes that occur in the brain following drug treatment.

The cannulas can be fabricated in nearly any length or thickness, making it possible to adapt them for use in brains of different sizes, including the human brain, the researchers say.

“This study provides proof-of-concept experiments, in large animal models, that a small, miniaturized device can be safely implanted in the brain and provide miniaturized control of the electrical activity and function of single neurons or small groups of neurons. The impact of this could be significant in focal diseases of the brain, such as Parkinson’s disease,” says Antonio Chiocca, neurosurgeon-in-chief and chairman of the Department of Neurosurgery at Brigham and Women’s Hospital, who was not involved in the research.

The research was funded by the National Institutes of Health and the National Institute of Biomedical Imaging and Bioengineering.