Author: MIT News

Gene-editing technology developer Feng Zhang awarded $500,000 Lemelson-MIT Prize

Anne Trafton |

Feng Zhang, a pioneer of the revolutionary CRISPR gene-editing technology, TAL effector proteins, and optogenetics, is the recipient of the 2017 $500,000 Lemelson-MIT Prize, the largest cash prize for invention in the United States. Zhang is a core member of the Broad Institute of MIT and Harvard, an investigator at the McGovern Institute for Brain Research, the James and Patricia Poitras Professor in Neuroscience at MIT, and associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering at MIT.

Zhang and his team were first to develop and demonstrate successful methods for using an engineered CRISPR-Cas9 system to edit genomes in living mouse and human cells and have turned CRISPR technology into a practical and shareable collection of tools for robust gene editing and epigenomic manipulation. CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, has been harnessed by Zhang and his team as a groundbreaking gene-editing tool that is simple and versatile to use. A key tenet of Zhang’s is to encourage further development and research through open sharing of tools and scientific collaboration. Zhang believes that wide use of CRISPR-based tools will further our understanding of biology, allowing scientists to identify genetic differences that contribute to diseases and, eventually, provide the basis for new therapeutic techniques.

Zhang’s lab has trained thousands of researchers to use CRISPR technology, and since 2013 he has shared over 40,000 plasmid samples with labs around the world both directly and through the nonprofit Addgene, enabling wide use of his CRISPR tools in their research.

Zhang began working in a gene therapy laboratory at the age of 16 and has played key roles in the development of multiple technologies. Prior to harnessing CRISPR-Cas9, Zhang engineered microbial TAL effectors (TALEs) for use in mammalian cells, working with colleagues at Harvard University, authoring multiple publications on the subject and becoming a co-inventor on several patents on TALE-based technologies. Zhang was also a key member of the team at Stanford University that harnessed microbial opsins for developing optogenetics, which uses light signals and light-sensitive proteins to monitor and control activity in brain cells. This technology can help scientists understand how cells in the brain affect mental and neurological illnesses. Zhang has co-authored multiple publications on optogenetics and is a co-inventor on several patents related to this technology.

Zhang’s numerous scientific discoveries and inventions, as well as his commitment to mentorship and collaboration, earned him the Lemelson-MIT Prize, which honors outstanding mid-career inventors who improve the world through technological invention and demonstrate a commitment to mentorship in science, technology, engineering and mathematics (STEM).

“Feng’s creativity and dedication to problem-solving impressed us,” says Stephanie Couch, executive director of the Lemelson-MIT Program. “Beyond the breadth of his own accomplishments, Feng and his lab have also helped thousands of scientists across the world access the new technology to advance their own scientific discoveries.”

“It is a tremendous honor to receive the Lemelson-MIT Prize and to join the company of so many incredibly impactful inventors who have won this prize in years past,” says Zhang. “Invention has always been a part of my life; I think about new problems every day and work to solve them creatively. This prize is a testament to the passionate work of my team and the support of my family, teachers, colleagues and counterparts around the world.”

The $500,000 prize, which bears no restrictions in how it can be used, is made possible through the support of The Lemelson Foundation, the world’s leading funder of invention in service of social and economic change.

“We are thrilled to honor Dr. Zhang, who we commend for his advancements in genetics, and more importantly, his willingness to share his discoveries to advance the work of others around the world,” says Dorothy Lemelson, chair of The Lemelson Foundation. “Zhang’s work is inspiring a new generation of inventors to tackle the biggest problems of our time.”

Zhang will speak at EmTech MIT, the annual conference on emerging technologies hosted by MIT Technology Review at the MIT Media Lab on Tuesday, Nov. 7.

The Lemelson-MIT Program is now seeking nominations for the 2018 $500,000 Lemelson-MIT Prize. Please contact the Lemelson-MIT Program at awards-lemelson@mit.edu for more information or visit the MIT-Lemelson Prize website.

Studies help explain link between autism, severe infection during pregnancy

Anne Trafton |

Mothers who experience an infection severe enough to require hospitalization during pregnancy are at higher risk of having a child with autism. Two new studies from MIT and the University of Massachusetts Medical School shed more light on this phenomenon and identify possible approaches to preventing it.

In research on mice, the researchers found that the composition of bacterial populations in the mother’s digestive tract can influence whether maternal infection leads to autistic-like behaviors in offspring. They also discovered the specific brain changes that produce these behaviors.

“We identified a very discrete brain region that seems to be modulating all the behaviors associated with this particular model of neurodevelopmental disorder,” says Gloria Choi, the Samuel A. Goldblith Career Development Assistant Professor of Brain and Cognitive Sciences and a member of MIT’s McGovern Institute for Brain Research.

If further validated in human studies, the findings could offer a possible way to reduce the risk of autism, which would involve blocking the function of certain strains of bacteria found in the maternal gut, the researchers say.

Choi and Jun Huh, formerly an assistant professor at UMass Medical School who is now a faculty member at Harvard Medical School, are the senior authors of both papers, which appear in Nature on Sept. 13. MIT postdoc Yeong Shin Yim is the first author of one paper, and UMass Medical School visiting scholars Sangdoo Kim and Hyunju Kim are the lead authors of the other.

Reversing symptoms

A 2010 study that included all children born in Denmark between 1980 and 2005 found that severe viral infections during the first trimester of pregnancy translated to a threefold risk for autism, and serious bacterial infections during the second trimester were linked with a 1.42-fold increase in risk. These infections included influenza, viral gastroenteritis, and severe urinary tract infections.

Similar effects have been described in mouse models of maternal inflammation, and in a 2016 Science paper, Choi and Huh found that a type of immune cells known as Th17 cells, and their effector molecule, called IL-17, are responsible for this effect in mice. IL-17 then interacts with receptors found on brain cells in the developing fetus, leading to irregularities that the researchers call “patches” in certain parts of the cortex.

In one of the new papers, the researchers set out to learn more about these patches and to determine if they were responsible for the behavioral abnormalities seen in those mice, which include repetitive behavior and impaired sociability.

The researchers found that the patches are most common in a part of the brain known as S1DZ. Part of the somatosensory cortex, this region is believed to be responsible for proprioception, or sensing where the body is in space. In these patches, populations of cells called interneurons, which express a protein called parvalbumin, are reduced. Interneurons are responsible for controlling the balance of excitation and inhibition in the brain, and the researchers found that the changes they found in the cortical patches were associated with overexcitement in S1DZ.

When the researchers restored normal levels of brain activity in this area, they were able to reverse the behavioral abnormalities. They were also able to induce the behaviors in otherwise normal mice by overstimulating neurons in S1DZ.

The researchers also discovered that S1DZ sends messages to two other brain regions: the temporal association area of the cortex and the striatum. When the researchers inhibited the neurons connected to the temporal association area, they were able to reverse the sociability deficits. When they inhibited the neurons connected to the striatum, they were able to halt the repetitive behaviors.

Microbial factors

In the second Nature paper, the researchers delved into some of the additional factors that influence whether or not a severe infection leads to autism. Not all mothers who experience severe infection end up having child with autism, and similarly not all the mice in the maternal inflammation model develop behavioral abnormalities.

“This suggests that inflammation during pregnancy is just one of the factors. It needs to work with additional factors to lead all the way to that outcome,” Choi says.

A key clue was that when immune systems in some of the pregnant mice were stimulated, they began producing IL-17 within a day. “Normally it takes three to five days, because IL-17 is produced by specialized immune cells and they require time to differentiate,” Huh says. “We thought that perhaps this cytokine is being produced not from differentiating immune cells, but rather from pre-existing immune cells.”

Previous studies in mice and humans have found populations of Th17 cells in the intestines of healthy individuals. These cells, which help to protect the host from harmful microbes, are thought to be produced after exposure to particular types of harmless bacteria that associate with the epithelium.

The researchers found that only the offspring of mice with one specific type of harmless bacteria, known as segmented filamentous bacteria, had behavioral abnormalities and cortical patches. When the researchers killed those bacteria with antibiotics, the mice produced normal offspring.

“This data strongly suggests that perhaps certain mothers who happen to carry these types of Th17 cell-inducing bacteria in their gut may be susceptible to this inflammation-induced condition,” Huh says.

Humans can also carry strains of gut bacteria known to drive production of Th17 cells, and the researchers plan to investigate whether the presence of these bacteria is associated with autism.

Sarah Gaffen, a professor of rheumatology and clinical immunology at the University of Pittsburgh, says the study clearly demonstrates the link between IL-17 and the neurological effects seen in the mice offspring. “It’s rare for things to fit into such a clear model, where you can identify a single molecule that does what you predicted,” says Gaffen, who was not involved in the study.

The research was funded by the Simons Foundation Autism Research Initiative, the Simons Center for the Social Brain at MIT, the Howard Hughes Medical Institute, Robert Buxton, the National Research Foundation of Korea, the Searle Scholars Program, a Pew Scholarship for Biomedical Sciences, the Kenneth Rainin Foundation, the National Institutes of Health, and the Hock E. Tan and K. Lisa Yang Center for Autism Research.

Robotic system monitors specific neurons

Anne Trafton |

Recording electrical signals from inside a neuron in the living brain can reveal a great deal of information about that neuron’s function and how it coordinates with other cells in the brain. However, performing this kind of recording is extremely difficult, so only a handful of neuroscience labs around the world do it.

To make this technique more widely available, MIT engineers have now devised a way to automate the process, using a computer algorithm that analyzes microscope images and guides a robotic arm to the target cell.

This technology could allow more scientists to study single neurons and learn how they interact with other cells to enable cognition, sensory perception, and other brain functions. Researchers could also use it to learn more about how neural circuits are affected by brain disorders.

“Knowing how neurons communicate is fundamental to basic and clinical neuroscience. Our hope is this technology will allow you to look at what’s happening inside a cell, in terms of neural computation, or in a disease state,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, and a member of MIT’s Media Lab and McGovern Institute for Brain Research.

Boyden is the senior author of the paper, which appears in the Aug. 30 issue of Neuron. The paper’s lead author is MIT graduate student Ho-Jun Suk.

Precision guidance

For more than 30 years, neuroscientists have been using a technique known as patch clamping to record the electrical activity of cells. This method, which involves bringing a tiny, hollow glass pipette in contact with the cell membrane of a neuron, then opening up a small pore in the membrane, usually takes a graduate student or postdoc several months to learn. Learning to perform this on neurons in the living mammalian brain is even more difficult.

There are two types of patch clamping: a “blind” (not image-guided) method, which is limited because researchers cannot see where the cells are and can only record from whatever cell the pipette encounters first, and an image-guided version that allows a specific cell to be targeted.

Five years ago, Boyden and colleagues at MIT and Georgia Tech, including co-author Craig Forest, devised a way to automate the blind version of patch clamping. They created a computer algorithm that could guide the pipette to a cell based on measurements of a property called electrical impedance — which reflects how difficult it is for electricity to flow out of the pipette. If there are no cells around, electricity flows and impedance is low. When the tip hits a cell, electricity can’t flow as well and impedance goes up.

Once the pipette detects a cell, it can stop moving instantly, preventing it from poking through the membrane. A vacuum pump then applies suction to form a seal with the cell’s membrane. Then, the electrode can break through the membrane to record the cell’s internal electrical activity.

The researchers achieved very high accuracy using this technique, but it still could not be used to target a specific cell. For most studies, neuroscientists have a particular cell type they would like to learn about, Boyden says.

“It might be a cell that is compromised in autism, or is altered in schizophrenia, or a cell that is active when a memory is stored. That’s the cell that you want to know about,” he says. “You don’t want to patch a thousand cells until you find the one that is interesting.”

To enable this kind of precise targeting, the researchers set out to automate image-guided patch clamping. This technique is difficult to perform manually because, although the scientist can see the target neuron and the pipette through a microscope, he or she must compensate for the fact that nearby cells will move as the pipette enters the brain.

“It’s almost like trying to hit a moving target inside the brain, which is a delicate tissue,” Suk says. “For machines it’s easier because they can keep track of where the cell is, they can automatically move the focus of the microscope, and they can automatically move the pipette.”

By combining several imaging processing techniques, the researchers came up with an algorithm that guides the pipette to within about 25 microns of the target cell. At that point, the system begins to rely on a combination of imagery and impedance, which is more accurate at detecting contact between the pipette and the target cell than either signal alone.

The researchers imaged the cells with two-photon microscopy, a commonly used technique that uses a pulsed laser to send infrared light into the brain, lighting up cells that have been engineered to express a fluorescent protein.

Using this automated approach, the researchers were able to successfully target and record from two types of cells — a class of interneurons, which relay messages between other neurons, and a set of excitatory neurons known as pyramidal cells. They achieved a success rate of about 20 percent, which is comparable to the performance of highly trained scientists performing the process manually.

Unraveling circuits

This technology paves the way for in-depth studies of the behavior of specific neurons, which could shed light on both their normal functions and how they go awry in diseases such as Alzheimer’s or schizophrenia. For example, the interneurons that the researchers studied in this paper have been previously linked with Alzheimer’s. In a recent study of mice, led by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, and conducted in collaboration with Boyden, it was reported that inducing a specific frequency of brain wave oscillation in interneurons in the hippocampus could help to clear amyloid plaques similar to those found in Alzheimer’s patients.

“You really would love to know what’s happening in those cells,” Boyden says. “Are they signaling to specific downstream cells, which then contribute to the therapeutic result? The brain is a circuit, and to understand how a circuit works, you have to be able to monitor the components of the circuit while they are in action.”

This technique could also enable studies of fundamental questions in neuroscience, such as how individual neurons interact with each other as the brain makes a decision or recalls a memory.

Bernardo Sabatini, a professor of neurobiology at Harvard Medical School, says he is interested in adapting this technique to use in his lab, where students spend a great deal of time recording electrical activity from neurons growing in a lab dish.

“It’s silly to have amazingly intelligent students doing tedious tasks that could be done by robots,” says Sabatini, who was not involved in this study. “I would be happy to have robots do more of the experimentation so we can focus on the design and interpretation of the experiments.”

To help other labs adopt the new technology, the researchers plan to put the details of their approach on their web site, autopatcher.org.

Other co-authors include Ingrid van Welie, Suhasa Kodandaramaiah, and Brian Allen. The research was funded by Jeremy and Joyce Wertheimer, the National Institutes of Health (including the NIH Single Cell Initiative and the NIH Director’s Pioneer Award), the HHMI-Simons Faculty Scholars Program, and the New York Stem Cell Foundation-Robertson Award.