Researcher: Ed Boyden

Mapping the brain at high resolution

Anne Trafton |

Researchers have developed a new way to image the brain with unprecedented resolution and speed. Using this approach, they can locate individual neurons, trace connections between them, and visualize organelles inside neurons, over large volumes of brain tissue.

The new technology combines a method for expanding brain tissue, making it possible to image at higher resolution, with a rapid 3-D microscopy technique known as lattice light-sheet microscopy. In a paper appearing in Science Jan. 17, the researchers showed that they could use these techniques to image the entire fruit fly brain, as well as large sections of the mouse brain, much faster than has previously been possible. The team includes researchers from MIT, the University of California at Berkeley, the Howard Hughes Medical Institute, and Harvard Medical School/Boston Children’s Hospital.

This technique allows researchers to map large-scale circuits within the brain while also offering unique insight into individual neurons’ functions, says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, an associate professor of biological engineering and of brain and cognitive sciences at MIT, and a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research.

“A lot of problems in biology are multiscale,” Boyden says. “Using lattice light-sheet microscopy, along with the expansion microscopy process, we can now image at large scale without losing sight of the nanoscale configuration of biomolecules.”

Boyden is one of the study’s senior authors, along with Eric Betzig, a senior fellow at the Janelia Research Campus and a professor of physics and molecular and cell biology at UC Berkeley. The paper’s lead authors are MIT postdoc Ruixuan Gao, former MIT postdoc Shoh Asano, and Harvard Medical School Assistant Professor Srigokul Upadhyayula.

Large-scale imaging

In 2015, Boyden’s lab developed a way to generate very high-resolution images of brain tissue using an ordinary light microscope. Their technique relies on expanding tissue before imaging it, allowing them to image the tissue at a resolution of about 60 nanometers. Previously, this kind of imaging could be achieved only with very expensive high-resolution microscopes, known as super-resolution microscopes.

In the new study, Boyden teamed up with Betzig and his colleagues at HHMI’s Janelia Research Campus to combine expansion microscopy with lattice light-sheet microscopy. This technology, which Betzig developed several years ago, has some key traits that make it ideal to pair with expansion microscopy: It can image large samples rapidly, and it induces much less photodamage than other fluorescent microscopy techniques.

“The marrying of the lattice light-sheet microscope with expansion microscopy is essential to achieve the sensitivity, resolution, and scalability of the imaging that we’re doing,” Gao says.

Imaging expanded tissue samples generates huge amounts of data — up to tens of terabytes per sample — so the researchers also had to devise highly parallelized computational image-processing techniques that could break down the data into smaller chunks, analyze it, and stitch it back together into a coherent whole.

In the Science paper, the researchers demonstrated the power of their new technique by imaging layers of neurons in the somatosensory cortex of mice, after expanding the tissue volume fourfold. They focused on a type of neuron known as pyramidal cells, one of the most common excitatory neurons found in the nervous system. To locate synapses, or connections, between these neurons, they labeled proteins found in the presynaptic and postsynaptic regions of the cells. This also allowed them to compare the density of synapses in different parts of the cortex.

Using this technique, it is possible to analyze millions of synapses in just a few days.

“We counted clusters of postsynaptic markers across the cortex, and we saw differences in synaptic density in different layers of the cortex,” Gao says. “Using electron microscopy, this would have taken years to complete.”

The researchers also studied patterns of axon myelination in different neurons. Myelin is a fatty substance that insulates axons and whose disruption is a hallmark of multiple sclerosis. The researchers were able to compute the thickness of the myelin coating in different segments of axons, and they measured the gaps between stretches of myelin, which are important because they help conduct electrical signals. Previously, this kind of myelin tracing would have required months to years for human annotators to perform.

This technology can also be used to image tiny organelles inside neurons. In the new paper, the researchers identified mitochondria and lysosomes, and they also measured variations in the shapes of these organelles.

Circuit analysis

The researchers demonstrated that this technique could be used to analyze brain tissue from other organisms as well; they used it to image the entire brain of the fruit fly, which is the size of a poppy seed and contains about 100,000 neurons. In one set of experiments, they traced an olfactory circuit that extends across several brain regions, imaged all dopaminergic neurons, and counted all synapses across the brain. By comparing multiple animals, they also found differences in the numbers and arrangements of synaptic boutons within each animal’s olfactory circuit.

In future work, Boyden envisions that this technique could be used to trace circuits that control memory formation and recall, to study how sensory input leads to a specific behavior, or to analyze how emotions are coupled to decision-making.

“These are all questions at a scale that you can’t answer with classical technologies,” he says.

The system could also have applications beyond neuroscience, Boyden says. His lab is planning to work with other researchers to study how HIV evades the immune system, and the technology could also be adapted to study how cancer cells interact with surrounding cells, including immune cells.

The research was funded by John Doerr, K. Lisa Yang and Y. Eva Tan, the Open Philanthropy Project, the National Institutes of Health, the Howard Hughes Medical Institute, the HHMI-Simons Faculty Scholars Program, the U.S. Army Research Laboratory and Army Research Office, the US-Israel Binational Science Foundation, Biogen, and Ionis Pharmaceuticals.

Ed Boyden

Engineering the Brain

Ed Boyden develops advanced technologies for analyzing, engineering, and simulating brain circuits to reveal and repair the fundamental mechanisms behind complex brain processes.

Boyden may be best known for pioneering optogenetics, a powerful method that enables scientists to control neurons using light. He also led the team that created expansion microscopy, which expands nanoscale features in a cell to make them visible using conventional microscopes. In addition, his lab develops methods so that many signals can be imaged in living cells at the same time. He continues to invent new tools, and works to systematically integrate these tools to enable biologically accurate computer simulations of the brain.

Team invents method to shrink objects to the nanoscale

Anne Trafton |

MIT researchers have invented a way to fabricate nanoscale 3-D objects of nearly any shape. They can also pattern the objects with a variety of useful materials, including metals, quantum dots, and DNA.

“It’s a way of putting nearly any kind of material into a 3-D pattern with nanoscale precision,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology and an associate professor of biological engineering and of brain and cognitive sciences at MIT.

Using the new technique, the researchers can create any shape and structure they want by patterning a polymer scaffold with a laser. After attaching other useful materials to the scaffold, they shrink it, generating structures one thousandth the volume of the original.

These tiny structures could have applications in many fields, from optics to medicine to robotics, the researchers say. The technique uses equipment that many biology and materials science labs already have, making it widely accessible for researchers who want to try it.

Boyden, who is also a member of MIT’s Media Lab, McGovern Institute for Brain Research, and Koch Institute for Integrative Cancer Research, is one of the senior authors of the paper, which appears in the Dec. 13 issue of Science. The other senior author is Adam Marblestone, a Media Lab research affiliate, and the paper’s lead authors are graduate students Daniel Oran and Samuel Rodriques.

Implosion fabrication

Existing techniques for creating nanostructures are limited in what they can accomplish. Etching patterns onto a surface with light can produce 2-D nanostructures but doesn’t work for 3-D structures. It is possible to make 3-D nanostructures by gradually adding layers on top of each other, but this process is slow and challenging. And, while methods exist that can directly 3-D print nanoscale objects, they are restricted to specialized materials like polymers and plastics, which lack the functional properties necessary for many applications. Furthermore, they can only generate self-supporting structures. (The technique can yield a solid pyramid, for example, but not a linked chain or a hollow sphere.)

To overcome these limitations, Boyden and his students decided to adapt a technique that his lab developed a few years ago for high-resolution imaging of brain tissue. This technique, known as expansion microscopy, involves embedding tissue into a hydrogel and then expanding it, allowing for high resolution imaging with a regular microscope. Hundreds of research groups in biology and medicine are now using expansion microscopy, since it enables 3-D visualization of cells and tissues with ordinary hardware.

By reversing this process, the researchers found that they could create large-scale objects embedded in expanded hydrogels and then shrink them to the nanoscale, an approach that they call “implosion fabrication.”

As they did for expansion microscopy, the researchers used a very absorbent material made of polyacrylate, commonly found in diapers, as the scaffold for their nanofabrication process. The scaffold is bathed in a solution that contains molecules of fluorescein, which attach to the scaffold when they are activated by laser light.

Using two-photon microscopy, which allows for precise targeting of points deep within a structure, the researchers attach fluorescein molecules to specific locations within the gel. The fluorescein molecules act as anchors that can bind to other types of molecules that the researchers add.

“You attach the anchors where you want with light, and later you can attach whatever you want to the anchors,” Boyden says. “It could be a quantum dot, it could be a piece of DNA, it could be a gold nanoparticle.”

“It’s a bit like film photography — a latent image is formed by exposing a sensitive material in a gel to light. Then, you can develop that latent image into a real image by attaching another material, silver, afterwards. In this way implosion fabrication can create all sorts of structures, including gradients, unconnected structures, and multimaterial patterns,” Oran says.

Once the desired molecules are attached in the right locations, the researchers shrink the entire structure by adding an acid. The acid blocks the negative charges in the polyacrylate gel so that they no longer repel each other, causing the gel to contract. Using this technique, the researchers can shrink the objects 10-fold in each dimension (for an overall 1,000-fold reduction in volume). This ability to shrink not only allows for increased resolution, but also makes it possible to assemble materials in a low-density scaffold. This enables easy access for modification, and later the material becomes a dense solid when it is shrunk.

“People have been trying to invent better equipment to make smaller nanomaterials for years, but we realized that if you just use existing systems and embed your materials in this gel, you can shrink them down to the nanoscale, without distorting the patterns,” Rodriques says.

Currently, the researchers can create objects that are around 1 cubic millimeter, patterned with a resolution of 50 nanometers. There is a tradeoff between size and resolution: If the researchers want to make larger objects, about 1 cubic centimeter, they can achieve a resolution of about 500 nanometers. However, that resolution could be improved with further refinement of the process, the researchers say.

Better optics

The MIT team is now exploring potential applications for this technology, and they anticipate that some of the earliest applications might be in optics — for example, making specialized lenses that could be used to study the fundamental properties of light. This technique might also allow for the fabrication of smaller, better lenses for applications such as cell phone cameras, microscopes, or endoscopes, the researchers say. Farther in the future, the researchers say that this approach could be used to build nanoscale electronics or robots.

“There are all kinds of things you can do with this,” Boyden says. “Democratizing nanofabrication could open up frontiers we can’t yet imagine.”

Many research labs are already stocked with the equipment required for this kind of fabrication. “With a laser you can already find in many biology labs, you can scan a pattern, then deposit metals, semiconductors, or DNA, and then shrink it down,” Boyden says.

The research was funded by the Kavli Dream Team Program, the HHMI-Simons Faculty Scholars Program, the Open Philanthropy Project, John Doerr, the Office of Naval Research, the National Institutes of Health, the New York Stem Cell Foundation-Robertson Award, the U.S. Army Research Office, K. Lisa Yang and Y. Eva Tan, and the MIT Media Lab.

Meeting of the minds

Anne Trafton |

In the summer of 2006, before their teenage years began, Mahdi Ramadan and Alexi Choueiri were spirited from their homes amid political unrest in Lebanon. Evacuated on short notice by the U.S. Marines, they were among 2,000 refugees transported to the U.S. on the aircraft carrier USS Nashville.

The two never met in their homeland, nor on the transatlantic journey, and after arriving in the U.S. they went their separate ways. Ramadan and his family moved to Seattle, Washington. Choueiri’s family settled in Chandler, Arizona, where they already had some extended family.

Yet their paths converged 11 years later as graduate students in MIT’s Department of Brain and Cognitive Sciences (BCS). One day last fall, on a walk across campus, Ramadan and Choueiri slowly unraveled their connection. With increasing excitement, they narrowed it down by year, by month, and eventually, by boat, to discover just how closely their lives had once come to one another.

Lebanon, the only Middle Eastern country without a desert, enjoys a lush, Mediterranean climate. Amid this natural beauty, though, the country struggles under the weight of deep political and cultural divides that sometimes erupt into conflict.

Despite different Lebanese cultural backgrounds — Ramadan’s family is Muslim and Choueiri’s Christian — they have had remarkably similar experiences as refugees from Lebanon. Both credit those experiences with motivating their interest in neuroscience. Questions about human behavior — How do people form beliefs about the world? Can those beliefs really change? — led them to graduate work at MIT.

In pursuit of knowledge

When they first immigrated to the U.S., school symbolized survival for Ramadan and Choueiri. Not only was education a mode of improving their lives and supporting their families, it was a search for objectivity in their recently upended worlds.

As the family’s primary English speaker, Ramadan became a bulwark for his family in their new country, especially in medical matters; his little sister, Ghida, has cerebral palsy. Though his family has limited financial resources, he emphasizes that both he and his sister have been constantly supported by their parents in pursuit of their educations.

In fact, Ramadan feels motivated by Ghida’s determination to complete her degree in occupational therapy: “That to me is really inspirational, her resilience in the face of her disability and in the face of assumptions that people make about capability. She’s really sassy, she’s really witty, she’s really funny, she’s really intelligent, and she doesn’t see her disability as a disability. She actually thinks it’s an advantage — it actually motivated her to pursue [her education] even more.”

Ramadan hopes his own educational journey, from a low-income evacuee to a neuroscience PhD, can show others like him that success is possible.

Choueiri also relied on academics to adapt to his new world in Arizona. Even in Lebanon, he remembers taking solace from a chaotic world in his education, and once in the U.S., he dove headfirst into his studies.

Choueiri’s hometown in Arizona sometimes felt homogenous, so coming to MIT has been a staggering — and welcome — experience. “The diversity here is phenomenal: meeting people from different cultures, upbringings, countries,” he says. “I love making friends from all over and learning their stories. Being a neuroscientist, I like to know how they were brought up and how their ideas were formed. … It’s like Disneyland for me. I feel like I’m coming to Disneyland every day and high-fiving Mickey Mouse.”

At home at MIT

Ramadan and Choueiri revel in the freedom of thought they have found in their academic home here. They say they feel taken seriously as students and, more importantly, as thinkers. The BCS department values interdisciplinary thought, and cultivates extracurricular student activities like philosophy discussion groups, the development of neuroscience podcasts, and independent, student-led lectures on myriad neuroscience-adjacent topics.

Both students were drawn to neuroscience not only by their experiences as Lebanese-Americans, but by trying to make sense of what happened to them at a young age.

Ramadan became interested in neuroplasticity through self-observation. “You know that feeling of childhood you have where everything is magical and you’re not really aware of things around you? I feel like when I immigrated to the U.S., that feeling went away and I had to become extra-aware of everything because I had to adapt so quickly. So, something that intrigued me about neuroscience is how the brain is able to adapt so quickly and how different experiences can shape and rewire your brain.”

Now in his second year, Ramadan plans to pursue his interest in neuroplasticity in Professor Mehrdad Jazayeri’s lab at the McGovern Institute by investigating how learning changes the brain’s underlying neural circuits; understanding the physical mechanism of plasticity has application to both disease states and artificial intelligence.

Choueiri, a third-year student in the program, is a member of Professor Ed Boyden’s lab at the McGovern Institute. While his interest in neuroscience was similarly driven by his experience as an evacuee, his approach is outward-looking, focused on making sense of people’s choices. Ultimately, the brain controls human ability to perceive, learn, and choose through physiological changes; Choueiri wants to understand not just the human brain, but also the human condition — and to use that understanding to alleviate pain and suffering.

“Growing up in Lebanon, with different religions and war … I became fundamentally interested in human behavior, irrationality, and conflict, and how can we resolve those things … and maybe there’s an objective way to really make sense of where these differences are coming from,” he says. In the Synthetic Neurobiology Group, Choueiri’s research involves developing neurotechnologies to map the molecular interactions of the brain, to reveal the fundamental mechanisms of brain function and repair dysfunction.

Shared identities

As evacuees, Ramadan and Choueiri left their country without notice and without saying goodbye. However, in other ways, their experience was not unlike an immigrant experience. This sometimes makes identifying as a refugee in the current political climate complex, as refugees from Syria and other war-ravaged regions struggle to make a home in the U.S. Still, both believe that sharing their personal experience may help others in difficult positions to see that they do belong in the U.S., and at MIT.

Despite their American identity, Ramadan and Choueiri also share a palpable love for Lebanese culture. They extol the diversity of Lebanese cuisine, which is served mezze-style, making meals an experience full of variety, grilled food, and yogurt dishes. The Lebanese diaspora is another source of great pride for them. Though the population of Lebanon is less than 5 million, as many as 14 million live abroad.

It’s all the more remarkable, then, that Ramadan and Choueiri intersected at MIT, some 6,000 miles from their homeland. The bond they have forged since, through their common heritage, experiences, and interests, is deeply meaningful to both of them.

“I was so happy to find another student who has this story because it allows me to reflect back on those experiences and how they changed me,” says Ramadan. “It’s like a mirror image. … Was it a coincidence, or were our lives so similar that they led to this point?”

This story was written by Bridget E. Begg at MIT’s Office of Graduate Education.

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.

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.

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.

Next-generation optogenetic molecules control single neurons

Anne Trafton |

Researchers at MIT and Paris Descartes University have developed a new optogenetic technique that sculpts light to target individual cells bearing engineered light-sensitive molecules, so that individual neurons can be precisely stimulated.

Until now, it has been challenging to use optogenetics to target single cells with such precise control over both the timing and location of the activation. This new advance paves the way for studies of how individual cells, and connections among those cells, generate specific behaviors such as initiating a movement or learning a new skill.

“Ideally what you would like to do is play the brain like a piano. You would want to control neurons independently, rather than having them all march in lockstep the way traditional optogenetics works, but which normally the brain doesn’t do,” says Ed Boyden, an associate professor of brain and cognitive sciences and biological engineering at MIT, and a member of MIT’s Media Lab and McGovern Institute for Brain Research.

The new technique relies on a new type of light-sensitive protein that can be embedded in neuron cell bodies, combined with holographic light-shaping that can focus light on a single cell.

Boyden and Valentina Emiliani, a research director at France’s National Center for Scientific Research (CNRS) and director of the Neurophotonics Laboratory at Paris Descartes University, are the senior authors of the study, which appears in the Nov. 13 issue of Nature Neuroscience. The lead authors are MIT postdoc Or Shemesh and CNRS postdocs Dimitrii Tanese and Valeria Zampini.

Precise control

More than 10 years ago, Boyden and his collaborators first pioneered the use of light-sensitive proteins known as microbial opsins to manipulate neuron electrical activity. These opsins can be embedded into the membranes of neurons, and when they are exposed to certain wavelengths of light, they silence or stimulate the cells.

Over the past decade, scientists have used this technique to study how populations of neurons behave during brain tasks such as memory recall or habit formation. Traditionally, many cells are targeted simultaneously because the light shining into the brain strikes a relatively large area. However, as Boyden points out, neurons may have different functions even when they are near each other.

“Two adjacent cells can have completely different neural codes. They can do completely different things, respond to different stimuli, and play different activity patterns during different tasks,” he says.

To achieve independent control of single cells, the researchers combined two new advances: a localized, more powerful opsin and an optimized holographic light-shaping microscope.

For the opsin, the researchers used a protein called CoChR, which the Boyden lab discovered in 2014. They chose this molecule because it generates a very strong electric current in response to light (about 10 times stronger than that produced by channelrhodopsin-2, the first protein used for optogenetics).

They fused CoChR to a small protein that directs the opsin into the cell bodies of neurons and away from axons and dendrites, which extend from the neuron body. This helps to prevent crosstalk between neurons, since light that activates one neuron can also strike axons and dendrites of other neurons that intertwine with the target neuron.

Boyden then worked with Emiliani to combine this approach with a light-stimulation technique that she had previously developed, known as two-photon computer-generated holography (CGH). This can be used to create three-dimensional sculptures of light that envelop a target cell.

Traditional holography is based on reproducing, with light, the shape of a specific object, in the absence of that original object. This is achieved by creating an “interferogram” that contains the information needed to reconstruct an object that was previously illuminated by a reference beam. In computer generated holography, the interferogram is calculated by a computer without the need of any original object. Years ago, Emiliani’s research group demonstrated that combined with two-photon excitation, CGH can be used to refocus laser light to precisely illuminate a cell or a defined group of cells in the brain.

In the new study, by combining this approach with new opsins that cluster in the cell body, the researchers showed they could stimulate individual neurons with not only precise spatial control but also great control over the timing of the stimulation. When they target a specific neuron, it responds consistently every time, with variability that is less than one millisecond, even when the cell is stimulated many times in a row.

“For the first time ever, we can bring the precision of single-cell control toward the natural timescales of neural computation,” Boyden says.

Mapping connections

Using this technique, the researchers were able to stimulate single neurons in brain slices and then measure the responses from cells that are connected to that cell. This paves the way for possible diagramming of the connections of the brain, and analyzing how those connections change in real time as the brain performs a task or learns a new skill.

One possible experiment, Boyden says, would be to stimulate neurons connected to each other to try to figure out if one is controlling the others or if they are all receiving input from a far-off controller.

“It’s an open question,” he says. “Is a given function being driven from afar, or is there a local circuit that governs the dynamics and spells out the exact chain of command within a circuit? If you can catch that chain of command in action and then use this technology to prove that that’s actually a causal link of events, that could help you explain how a sensation, or movement, or decision occurs.”

As a step toward that type of study, the researchers now plan to extend this approach into living animals. They are also working on improving their targeting molecules and developing high-current opsins that can silence neuron activity.

Kirill Volynski, a professor at the Institute of Neurology at University College London, who was not involved in the research, plans to use the new technology in his studies of diseases caused by mutations of proteins involved in synaptic communication between neurons.

“This gives us a very nice tool to study those mutations and those disorders,” Volynski says. “We expect this to enable a major improvement in the specificity of stimulating neurons that have mutated synaptic proteins.”

The research was funded by the National Institutes of Health, France’s National Research Agency, the Simons Foundation for the Social Brain, the Human Frontiers Science Program, John Doerr, the Open Philanthropy Project, the Howard Hughes Medical Institute, and the Defense Advanced Research Projects Agency.

Ten researchers from MIT and Broad receive NIH Director’s Awards

Anne Trafton |

The High-Risk, High-Reward Research (HRHR) program, supported by the National Institutes of Health (NIH) Common Fund, has awarded 86 grants to scientists with unconventional approaches to major challenges in biomedical and behavioral research. Ten of the awardees are affiliated with MIT and the Broad Institute of MIT and Harvard.

The NIH typically supports research projects, not individual scientists, but the HRHR program identifies specific researchers with innovative ideas to address gaps in biomedical research. The program issues four types of awards annually — the Pioneer Award, the New Innovator Award, the Transformative Research Award and the Early Independence Award — to “high-caliber investigators whose ideas stretch the boundaries of our scientific knowledge.”

Four researchers who are affiliated with either MIT or the Broad Institute received this year’s New Innovator Awards, which support “unusually innovative research” from early career investigators. They are:

  • Paul Blainey, an MIT assistant professor of biological engineering and a core member of the Broad Institute, is an expert in microanalysis systems for studies of individual molecules and cells. The award will fund the establishment a new technology that enables advanced readout from living cells.
  • Kevin Esvelt, an associate professor of media arts and sciences at MIT’s Media Lab, invents new ways to study and influence the evolution of ecosystems. Esvelt plans to use the NIH grant to develop powerful “daisy drive” systems for more precise genetic alterations of wild organisms. Such an intervention has the potential to serve as a powerful weapon against malaria, Zika, Lyme disease, and many other infectious diseases.
  • Evan Macosko is an associate member of the Broad Institute who develops molecular techniques to more deeply understand the function of cellular specialization in the nervous system. Macosko’s award will fund a novel technology, Slide-seq, which enables genome-wide expression analysis of brain tissue sections at single-cell resolution.
  • Gabriela Schlau-Cohen, an MIT assistant professor of chemistry, combines tools from chemistry, optics, biology, and microscopy to develop new approaches to study the dynamics of biological systems. Her award will be used to fund the development of a new nanometer-distance assay that directly accesses protein motion with unprecedented spatiotemporal resolution under physiological conditions.

Recipients of the Early Independence Award include three Broad Institute Fellows. The award recognizes “exceptional junior scientists” with an opportunity to skip traditional postdoctoral training and move immediately into independent research positions.

  • Ahmed Badran is a Broad Institute Fellow who studies the function of ribosomes and the control of protein synthesis. Ribosomes are important targets for antibiotics, and the NIH award will support the development of a new technology platform for probing ribosome function within living cells.
  • Fei Chen, a Broad Institute Fellow who is also a research affiliate at MIT’s McGovern Institute for Brain Research, has pioneered novel molecular and microscopy tools to illuminate biological pathways and function. He will use one of these tools, expansion microscopy, to explore the molecular basis of glioblastomas, an aggressive form of brain cancer.
  • Hilary Finucane, a Broad Institute Fellow who recently received her PhD from MIT’s Department of Mathematics, develops computational methods for analyzing biological data. She plans to develop methods to analyze large-scale genomic data to identify disease-relevant cell types and tissues, a necessary first step for understanding molecular mechanisms of disease.

Among the recipients of the NIH’s Pioneer Awards are Kay Tye, an assistant professor of brain and cognitive sciences at MIT and a member of MIT’s Picower Institute for Learning and Memory, and Feng Zhang, the James and Patricia Poitras ’63 Professor in Neuroscience, an associate professor of brain and cognitive sciences and biological engineering at MIT, a core member of the Broad Institute, and an investigator at MIT’s McGovern Institute for Brain Research. Recipients of this award are challenged to pursue “groundbreaking, high-impact approaches to a broad area of biomedical or behavioral science. Tye, who studies the brain mechanisms underlying emotion and behavior, will use her award to look at the neural representation of social homeostasis and social rank. Zhang, who pioneered the gene-editing technology known as CRISPR, plans to develop a suite of tools designed to achieve precise genome surgery for repairing disease-causing changes in DNA.

Ed Boyden, an associate professor of brain and cognitive sciences and biological engineering at MIT, and a member of MIT’s Media Lab and McGovern Institute for Brain Research, is a recipient of the Transformative Research Award. This award promotes “cross-cutting, interdisciplinary approaches that could potentially create or challenge existing paradigms.” Boyden, who develops new strategies for understanding and engineering brain circuits, will use the grant to develop high-speed 3-D imaging of neural activity.

This year, the NIH issued a total of 12 Pioneer Awards, 55 New Innovator Awards, 8 Transformative Research Awards, and 11 Early Independence Awards. The awards total $263 million and represent contributions from the NIH Common Fund; National Institute of General Medical Sciences; National Institute of Mental Health; National Center for Complementary and Integrative Health; and National Institute of Dental and Craniofacial Research.

“I continually point to this program as an example of the creative and revolutionary research NIH supports,” said NIH Director Francis S. Collins. “The quality of the investigators and the impact their research has on the biomedical field is extraordinary.”