Ed Boyden wins prestigious entrepreneurial science award

The Austrian Association of Entrepreneurs announced today that Edward S. Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT, has been awarded the 2020 Wilhelm Exner Medal.

Named after Austrian businessman Wilhelm Exner, the medal has been awarded annually since 1921 to scientists, inventors, and designers that are “promoting the economy directly or indirectly in an outstanding manner.” Past honorees include 22 Nobel laureates.

“It’s a great honor to receive this award, which recognizes not only the basic science impact of our group’s work, but the impact of the work in the industrial and startup worlds,” says Boyden, who is a professor of biological engineering and of brain and cognitive sciences at MIT.

Boyden is a leading scientist whose work is widely used in industry, both in his own startup companies and in existing companies. Boyden is also a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research.

“I am so thrilled that Ed has received this honor,” says Robert Desimone, director of the McGovern Institute. “Ed’s work has transformed neuroscience, through optogenetics, expansion microscopy, and other findings that are pushing biotechnology forward too.”

He is interested in understanding the brain as a computational system, and builds and applies tools for the analysis of neural circuit structure and dynamics, in behavioral and disease contexts. He played a critical role in the development of optogenetics, a revolutionary tool where the activity of neurons can be controlled using light. Boyden also led the team that invented expansion microscopy, which gives an unprecedented view of the nanoscale structures of cells, even in the absence of special super resolution microscopy equipment. Exner Medal laureates include notable luminaries of science, including Robert Langer of MIT. In addition, Boyden has founded a number of companies based on his inventions in the busy biotech hub of Kendall Square, Cambridge. These include a startup that is seeking to apply expansion microscopy to medical problems.

Boyden will deliver his prize lecture at the Exner symposium in November 2020, during which economists and scientists come together to hear about the winner’s research.

McGovern scientists named STAT Wunderkinds

McGovern researchers Sam Rodriques and Jonathan Strecker have been named to the class of 2019 STAT wunderkinds. This group of 22 researchers was selected from a national pool of hundreds of nominees, and aims to recognize trail-blazing scientists that are on the cusp of launching their careers but not yet fully independent.

“We were thrilled to receive this news,” said Robert Desimone, director of the McGovern Institute. “It’s great to see the remarkable progress being made by young scientists in McGovern labs be recognized in this way.”

Finding context

Sam Rodriques works in Ed Boyden’s lab at the McGovern Institute, where he develops new technologies that enable researchers to understand the behaviors of cells within their native spatial and temporal context.

“Psychiatric disease is a huge problem, but only a handful of first-in-class drugs for psychiatric diseases approved since the 1960s,” explains Rodriques, also affiliated with the MIT Media Lab and Broad Institute. “Coming up with novel cures is going to require new ways to generate hypotheses about the biological processes that underpin disease.”

Rodriques also works on several technologies within the Boyden lab, including preserving spatial information in molecular mapping technologies, finding ways of following neural connectivity in the brain, and Implosion Fabrication, or “Imp Fab.” This nanofabrication technology allows objects to be evenly shrunk to the nanoscale and has a wide range of potential applications, including building new miniature devices for examining neural function.

“I was very surprised, not expecting it at all!” explains Rodriques when asked about becoming a STAT Wunderkind, “I’m sure that all of the hundreds of applicants are very accomplished scientists, and so to be chosen like this is really an honor.”

New tools for gene editing

Jonathan Strecker is currently a postdoc working in Feng Zhang’s lab, and associated with both the McGovern Institute and Broad Institute. While CRISPR-Cas9 continues to have a profound effect and huge potential for research and biomedical, and agricultural applications, the ability to move entire genes into specific target locations remained out reach.

“Genome editing with CRISPR-Cas enzymes typically involves cutting and disrupting genes, or making certain base edits,” explains Strecker, “however, inserting large pieces of DNA is still hard to accomplish.”

As a postdoctoral researcher in the lab of CRISPR pioneer Feng Zhang, Strecker led research that showed how large sequences could be inserted into a genome at a given location.

“Nature often has interesting solutions to these problems and we were fortunate to identify and characterize a remarkable CRISPR system from cyanobacteria that functions as a programmable transposase.”

Importantly, the system he discovered, called CAST, doesn’t require cellular machinery to insert DNA. This is important as it means that CAST could work in many cell types, including those that have stopped dividing such as neurons, something that is being pursued.

By finding new sources of inspiration, be it nature or art, both Rodriques and Strecker join a stellar line up of young investigators being recognized for creativity and innovation.

 

New method visualizes groups of neurons as they compute

Using a fluorescent probe that lights up when brain cells are electrically active, MIT and Boston University researchers have shown that they can image the activity of many neurons at once, in the brains of mice.

McGovern Investigator Ed Boyden has developed a technology that allows neuroscientists to visualize the activity of circuits within the brain and link them to specific behaviors.

This technique, which can be performed using a simple light microscope, could allow neuroscientists to visualize the activity of circuits within the brain and link them to specific behaviors, says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology and a professor of biological engineering and of brain and cognitive sciences at MIT.

“If you want to study a behavior, or a disease, you need to image the activity of populations of neurons because they work together in a network,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research.

Using this voltage-sensing molecule, the researchers showed that they could record electrical activity from many more neurons than has been possible with any existing, fully genetically encoded, fluorescent voltage probe.

Boyden and Xue Han, an associate professor of biomedical engineering at Boston University, are the senior authors of the study, which appears in the Oct. 9 online edition of Nature. The lead authors of the paper are MIT postdoc Kiryl Piatkevich, BU graduate student Seth Bensussen, and BU research scientist Hua-an Tseng.

Seeing connections

Neurons compute using rapid electrical impulses, which underlie our thoughts, behavior, and perception of the world. Traditional methods for measuring this electrical activity require inserting an electrode into the brain, a process that is labor-intensive and usually allows researchers to record from only one neuron at a time. Multielectrode arrays allow the monitoring of electrical activity from many neurons at once, but they don’t sample densely enough to get all the neurons within a given volume.  Calcium imaging does allow such dense sampling, but it measures calcium, an indirect and slow measure of neural electrical activity.

In 2018, MIT researchers 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. Image courtesy of the researchers

In 2018, Boyden’s team developed an alternative way to monitor electrical activity by labeling neurons with a fluorescent probe. Using a technique known as directed protein evolution, his group engineered a molecule called Archon1 that can be genetically inserted into neurons, where it becomes embedded in the cell membrane. When a neuron’s electrical activity increases, the molecule becomes brighter, and this fluorescence can be seen with a standard light microscope.

In the 2018 paper, Boyden and his colleagues showed that they could use the molecule to image electrical activity in the brains of transparent worms and zebrafish embryos, and also in mouse brain slices. In the new study, they wanted to try to use it in living, awake mice as they engaged in a specific behavior.

To do that, the researchers had to modify the probe so that it would go to a subregion of the neuron membrane. They found that when the molecule inserts itself throughout the entire cell membrane, the resulting images are blurry because the axons and dendrites that extend from neurons also fluoresce. To overcome that, the researchers attached a small peptide that guides the probe specifically to membranes of the cell bodies of neurons. They called this modified protein SomArchon.

“With SomArchon, you can see each cell as a distinct sphere,” Boyden says. “Rather than having one cell’s light blurring all its neighbors, each cell can speak by itself loudly and clearly, uncontaminated by its neighbors.”

The researchers used this probe to image activity in a part of the brain called the striatum, which is involved in planning movement, as mice ran on a ball. They were able to monitor activity in several neurons simultaneously and correlate each one’s activity with the mice’s movement. Some neurons’ activity went up when the mice were running, some went down, and others showed no significant change.

“Over the years, my lab has tried many different versions of voltage sensors, and none of them have worked in living mammalian brains until this one,” Han says.

Using this fluorescent probe, the researchers were able to obtain measurements similar to those recorded by an electrical probe, which can pick up activity on a very rapid timescale. This makes the measurements more informative than existing techniques such as imaging calcium, which neuroscientists often use as a proxy for electrical activity.

“We want to record electrical activity on a millisecond timescale,” Han says. “The timescale and activity patterns that we get from calcium imaging are very different. We really don’t know exactly how these calcium changes are related to electrical dynamics.”

With the new voltage sensor, it is also possible to measure very small fluctuations in activity that occur even when a neuron is not firing a spike. This could help neuroscientists study how small fluctuations impact a neuron’s overall behavior, which has previously been very difficult in living brains, Han says.

Mapping circuits

The researchers also showed that this imaging technique can be combined with optogenetics — a technique developed by the Boyden lab and collaborators that allows researchers to turn neurons on and off with light by engineering them to express light-sensitive proteins. In this case, the researchers activated certain neurons with light and then measured the resulting electrical activity in these neurons.

This imaging technology could also be combined with expansion microscopy, a technique that Boyden’s lab developed to expand brain tissue before imaging it, make it easier to see the anatomical connections between neurons in high resolution.

“One of my dream experiments is to image all the activity in a brain, and then use expansion microscopy to find the wiring between those neurons,” Boyden says. “Then can we predict how neural computations emerge from the wiring.”

Such wiring diagrams could allow researchers to pinpoint circuit abnormalities that underlie brain disorders, and may also help researchers to design artificial intelligence that more closely mimics the human brain, Boyden says.

The MIT portion of the research was funded by Edward and Kay Poitras, the National Institutes of Health, including a Director’s Pioneer Award, Charles Hieken, John Doerr, the National Science Foundation, the HHMI-Simons Faculty Scholars Program, the Human Frontier Science Program, and the U.S. Army Research Office.

Ed Boyden wins premier Royal Society honor

Edward S. Boyden, the Y. Eva Tan Professor in Neurotechnology at MIT, has been awarded the 2019 Croonian Medal and Lecture by the Royal Society. Twenty-four medals and awards are announced by the Royal Society each year, honoring exceptional researchers who are making outstanding contributions to science.

“The Royal Society gives an array of medals and awards to scientists who have done exceptional, ground-breaking work,” explained Sir Venki Ramakrishnan, President of the Royal Society. “This year, it is again a pleasure to see these awards bestowed on scientists who have made such distinguished and far-reaching contributions in their fields. I congratulate and thank them for their efforts.”

Boyden wins the medal and lecture in recognition of his research that is expanding our understanding of the brain. This includes his critical role in the development of optogenetics, a technique for controlling brain activity with light, and his invention of expansion microscopy. Croonian Medal laureates include notable luminaries of science and neurobiology.

“It is a great honor to be selected to receive this medal, especially
since it was also given to people such as Santiago Ramon y Cajal, the
founder of modern neuroscience,” says Boyden. “This award reflects the great work of many fantastic students, postdocs, and collaborators who I’ve had the privilege to work with over the years.”

The award includes an invitation to deliver the premier British lecture in the biological sciences, given annually at the Royal Society in London. At the lecture, the winner is awarded a medal and a gift of £10,000. This announcement comes shortly after Boyden was co-awarded the Warren Alpert Prize for his role in developing optogenetics.

History of the Croonian Medal and Lecture

William Croone, pictured, envisioned an annual lecture that is the premier biological sciences medal and lecture at the Royal Society
William Croone, FRS Photo credit: Royal College of Physicians, London

The lectureship was conceived by William Croone FRS, one of the original Fellows of the Society based in London. Among the papers left on his death in 1684 were plans to endow two lectureships, one at the Royal Society and the other at the Royal College of Physicians. His widow later bequeathed the means to carry out the scheme. The lecture series began in 1738.

 

 

Ed Boyden holds the titles of Investigator, McGovern Institute; Y. Eva Tan Professor in Neurotechnology at MIT; Leader, Synthetic Neurobiology Group, MIT Media Lab; Professor, Biological Engineering, Brain and Cognitive Sciences, MIT Media Lab; Co-Director, MIT Center for Neurobiological Engineering; Member, MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute.

Ed Boyden receives 2019 Warren Alpert Prize

The 2019 Warren Alpert Foundation Prize has been awarded to four scientists, including Ed Boyden, for pioneering work that launched the field of optogenetics, a technique that uses light-sensitive channels and pumps to control the activity of neurons in the brain with a flick of a switch. He receives the prize alongside Karl Deisseroth, Peter Hegemann, and Gero Miesenböck, as outlined by The Warren Alpert Foundation in their announcement.

Harnessing light and genetics, the approach illuminates and modulates the activity of neurons, enables study of brain function and behavior, and helps reveal activity patterns that can overcome brain diseases.

Boyden’s work was key to envisioning and developing optogenetics, now a core method in neuroscience. The method allows brain circuits linked to complex behavioral processes, such as those involved in decision-making, feeding, and sleep, to be unraveled in genetic models. It is also helping to elucidate the mechanisms underlying neuropsychiatric disorders, and has the potential to inspire new strategies to overcome brain disorders.

“It is truly an honor to be included among the extremely distinguished list of winners of the Alpert Award,” says Boyden, the Y. Eva Tan Professor in Neurotechnology at the McGovern Institute, MIT. “To me personally, it is exciting to see the relatively new field of neurotechnology recognized. The brain implements our thoughts and feelings. It makes us who we are. This mysteries and challenge requires new technologies to make the brain understandable and repairable. It is a great honor that our technology of optogenetics is being thus recognized.”

While they were students, Boyden, and fellow awardee Karl Deisseroth, brainstormed about how microbial opsins could be used to mediate optical control of neural activity. In mid-2004, the pair collaborated to show that microbial opsins can be used to optically control neural activity. Upon launching his lab at MIT, Boyden’s team developed the first optogenetic silencing tool, the first effective optogenetic silencing in live mammals, noninvasive optogenetic silencing, and single-cell optogenetic control.

“The discoveries made by this year’s four honorees have fundamentally changed the landscape of neuroscience,” said George Q. Daley, dean of Harvard Medical School. “Their work has enabled scientists to see, understand and manipulate neurons, providing the foundation for understanding the ultimate enigma—the human brain.”

Beyond optogenetics, Boyden has pioneered transformative technologies that image, record, and manipulate complex systems, including expansion microscopy, robotic patch clamping, and even shrinking objects to the nanoscale. He was elected this year to the ranks of the National Academy of Sciences, and selected as an HHMI Investigator. Boyden has received numerous awards for this work, including the 2018 Gairdner International Prize and the 2016 Breakthrough Prize in Life Sciences.

The Warren Alpert Foundation, in association with Harvard Medical School, honors scientists whose work has improved the understanding, prevention, treatment or cure of human disease. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School. The honorees will share a $500,000 prize and will be recognized at a daylong symposium on Oct. 3 at Harvard Medical School.

Ed Boyden holds the titles of Investigator, McGovern Institute; Y. Eva Tan Professor in Neurotechnology at MIT; Leader, Synthetic Neurobiology Group, Media Lab; Associate Professor, Biological Engineering, Brain and Cognitive Sciences, Media Lab; Co-Director, MIT Center for Neurobiological Engineering; Member, MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute.

Ed Boyden elected to National Academy of Sciences

Ed Boyden has been elected to join the National Academy of Sciences (NAS). The organization, established by an act of Congress during the height of the Civil War, was founded to provide independent and objective advice on scientific matters to the nation, and is actively engaged in furthering science in the United States. Each year NAS members recognize fellow scientists through election to the academy based on their distinguished and continuing achievements in original research.

“I’m very honored and grateful to have been elected to the NAS,” says Boyden. “This is a testament to the work of many graduate students, postdoctoral scholars, research scientists, and staff at MIT who have worked with me over the years, and many collaborators and friends at MIT and around the world who have helped our group on this mission to advance neuroscience through new tools and ways of thinking.”

Boyden’s research creates and applies technologies that aim to expand our understanding of the brain. He notably co-invented optogenetics as an independent side collaboration, conducted in parallel to his PhD studies, a game-changing technology that has revolutionized neurobiology. This technology uses targeted expression of light-sensitive channels and pumps to activate or suppress neuronal activity in vivo using light. Optogenetics quickly swept the field of neurobiology and has been leveraged to understand how specific neurons and brain regions contribute to behavior and to disease.

His research since has an overarching focus on understanding the brain. To this end, he and his lab have the ambitious goal of developing technologies that can map, record, and manipulate the brain. This has led, as selected examples, to the invention of expansion microscopy, a super-resolution imaging technology that can capture neuron’s microstructures and reveal their complex connections, even across large-scale neural circuits; voltage-sensitive fluorescent reporters that allow neural activity to be monitored in vivo; and temporal interference stimulation, a non-invasive brain stimulation technique that allows selective activation of subcortical brain regions.

“We are all incredibly happy to see Ed being elected to the academy,” says Robert Desimone, director of the McGovern Institute for Brain Research at MIT. “He has been consistently innovative, inventing new ways of manipulating and observing neurons that are revolutionizing the field of neuroscience.”

This year the NAS, an organization that includes over 500 Nobel Laureates, elected 100 new members and 25 foreign associates. Three MIT professors were elected this year, with Paula T. Hammond (David H. Koch (1962) Professor of Engineering and Department Head, Chemical Engineering) and Aviv Regev (HHMI Investigator and Professor in the Department of Biology) being elected alongside Boyden. Boyden becomes the seventh member of the McGovern Institute faculty to join the National Academy of Sciences.

The formal induction ceremony for new NAS members, during which they sign the ledger whose first signatory is Abraham Lincoln, will be held at the Academy’s annual meeting in Washington D.C. next spring.

 

 

 

 

 

 

 

 

Mapping the brain at high resolution

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 Matter and Mind

Ed Boyden develops new tools for probing, analyzing, and engineering brain circuits. He uses a range of approaches, including synthetic biology, nanotechnology, chemistry, electrical engineering, and optics to develop tools capable of revealing fundamental mechanisms underlying complex brain processes.

Boyden may be best known for pioneering the development of optogenetics, a powerful method that enables neuronal activity to be controlled with light. He also led the team that invented expansion microscopy, in which a specimen is embedded in a gel that swells as it absorbs water, thereby expanding nanoscale features to a size where they can be seen using conventional microscopes. He is now seeking to systematically integrate these technologies to create detailed maps and models of brain circuitry.

Virtual Tour of Boyden Lab

Team invents method to shrink objects to the nanoscale

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

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.