Julie Pryor, Author at MIT McGovern Institute

Can I rewire my brain?

by Halie Olson | September 6, 2019May 24, 2023

As part of our Ask the Brain series, Halie Olson, a graduate student in the labs of John Gabrieli and Rebecca Saxe, pens her answer to the question,”Can I rewire my brain?”

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Yes, kind of, sometimes – it all depends on what you mean by “rewiring” the brain.

Halie Olson, a graduate student in the Gabrieli and Saxe labs.

If you’re asking whether you can remove all memories of your ex from your head, then no. (That’s probably for the best – just watch Eternal Sunshine of the Spotless Mind.) However, if you’re asking whether you can teach a dog new tricks – that have a physical implementation in the brain – then yes.

To embrace the analogy that “rewiring” alludes to, let’s imagine you live in an old house with outlets in less-than-optimal locations. You really want your brand-new TV to be plugged in on the far side of the living room, but there is no outlet to be found. So you call up your electrician, she pops over, and moves some wires around in the living room wall to give you a new outlet. No sweat!

Local changes in neural connectivity happen throughout the lifespan. With over 100 billion neurons and 100 trillion connections – or synapses – between these neurons in the adult human brain, it is unsurprising that some pathways end up being more important than others. When we learn something new, the connections between relevant neurons communicating with each other are strengthened. To paraphrase Donald Hebb, one of the most influential psychologists of the twentieth century, “neurons that fire together, wire together” – by forming new synapses or more efficiently connecting the ones that are already there. This ability to rewire neural connections at a local level is a key feature of the brain, enabling us to tailor our neural infrastructure to our needs.

Plasticity in our brain allows us to learn, adjust, and thrive in our environments.

We can also see this plasticity in the brain at a larger scale. My favorite example of “rewiring” in the brain is when children learn to read. Our brains did not evolve to enable us to read – there is no built-in “reading region” that magically comes online when a child enters school. However, if you stick a proficient reader in an MRI scanner, you will see a region in the left lateral occipitotemporal sulcus (that is, the back bottom left of your cortex) that is particularly active when you read written text. Before children learn to read, this region – known as the visual word form area – is not exceptionally interested in words, but as children get acquainted with written language and start connecting letters with sounds, it becomes selective for familiar written language – no matter the font, CaPItaLIZation, or size.

Now, let’s say that you wake up in the middle of the night with a desire to move your oven and stovetop from the kitchen into your swanky new living room with the TV. You call up your electrician – she tells you this is impossible, and to stop calling her in the middle of the night.

Similarly, your brain comes with a particular infrastructure – a floorplan, let’s call it – that cannot be easily adjusted when you are an adult. Large lesions tend to have large consequences. For instance, an adult who suffers a serious stroke in their left hemisphere will likely struggle with language, a condition called aphasia. Young children’s brains, on the other hand, can sometimes rewire in profound ways. An entire half of the brain can be damaged early on with minimal functional consequences. So if you’re going for a remodel? Better do it really early.

Plasticity in our brain allows us to learn, adjust, and thrive in our environments. It also gives neuroscientists like me something to study – since clearly I would fail as an electrician.

Halie Olson earned her bachelor’s degree in neurobiology from Harvard College in 2017. She is currently a graduate student in MIT’s Department of Brain and Cognitive Sciences working with John Gabrieli and Rebecca Saxe. She studies how early life experiences and environments impact brain development, particularly in the context of reading and language, and what this means for children’s educational outcomes.

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Do you have a question for The Brain? Ask it here.

Call for Nominations: 2020 Scolnick Prize in Neuroscience

by Julie Pryor | August 13, 2019May 24, 2023

The McGovern Institute is now accepting nominations for the Scolnick Prize in Neuroscience, which recognizes an outstanding discovery or significant advance in any field of neuroscience, until December 15, 2019.

About the Scolnick Prize

The prize is named in honor of Edward M. Scolnick, who stepped down as president of Merck Research Laboratories in December 2002 after holding Merck’s top research post for 17 years. The prize, which is endowed through a gift from Merck to the McGovern Institute, consists of a $150,000 award, plus an inscribed gift. The recipient presents a public lecture at MIT, hosted by the McGovern Institute and followed by a dinner in Spring 2020.

Nomination Process

Candidates for the award must be nominated by individuals affiliated with universities, hospitals, medical schools, or research institutes, with a background in neuroscience. Self-nomination is not permitted. Each nomination should include a biosketch or CV of the nominee and a letter of nomination with a summary and analysis of the nominee’s major contributions to the field of neuroscience. Up to two representative reprints will be accepted. The winner, selected by a committee appointed by the director of the McGovern Institute, will be announced in January 2020.

More information about the Scolnick Prize, including details about the nomination process, selection committee, and past Scolnick Prize recipients, can be found on our website.

submit nomination

Finding the brain’s compass

by Sabbi Lall | August 12, 2019May 24, 2023

The world is constantly bombarding our senses with information, but the ways in which our brain extracts meaning from this information remains elusive. How do neurons transform raw visual input into a mental representation of an object – like a chair or a dog?

In work published today in Nature Neuroscience, MIT neuroscientists have identified a brain circuit in mice that distills “high-dimensional” complex information about the environment into a simple abstract object in the brain.

“There are no degree markings in the external world, our current head direction has to be extracted, computed, and estimated by the brain,” explains Ila Fiete, an associate member of the McGovern Institute and senior author of the paper. “The approaches we used allowed us to demonstrate the emergence of a low-dimensional concept, essentially an abstract compass in the brain.”

This abstract compass, according to the researchers, is a one-dimensional ring that represents the current direction of the head relative to the external world.

Schooling fish

Trying to show that a data cloud has a simple shape, like a ring, is a bit like watching a school of fish. By tracking one or two sardines, you might not see a pattern. But if you could map all of the sardines, and transform the noisy dataset into points representing the positions of the whole school of sardines over time, and where each fish is relative to its neighbors, a pattern would emerge. This model would reveal a ring shape, a simple shape formed by the activity of hundreds of individual fish.

Fiete, who is also an associate professor in MIT’s Department of Brain and Cognitive Sciences, used a similar approach, called topological modeling, to transform the activity of large populations of noisy neurons into a data cloud the shape of a ring.

Simple and persistent ring

Previous work in fly brains revealed a physical ellipsoid ring of neurons representing changes in the direction of the fly’s head, and researchers suspected that such a system might also exist in mammals.

In this new mouse study, Fiete and her colleagues measured hours of neural activity from scores of neurons in the anterodorsal thalamic nucleus (ADN) – a region believed to play a role in spatial navigation – as the animals moved freely around their environment. They mapped how the neurons in the ADN circuit fired as the animal’s head changed direction.

Together these data points formed a cloud in the shape of a simple and persistent ring.

“In the absence of this ring,” Fiete explains, “we would be lost in the world.”

“This tells us a lot about how neural networks are organized in the brain,” explains Edvard Moser, Director of the Kavli Institute of Systems Neuroscience in Norway, who was not involved in the study. “Past data have indirectly pointed towards such a ring-like organization but only now has it been possible, with the right cell numbers and methods, to demonstrate it convincingly,” says Moser.

Their method for characterizing the shape of the data cloud allowed Fiete and colleagues to determine which variable the circuit was devoted to representing, and to decode this variable over time, using only the neural responses.

“The animal’s doing really complicated stuff,” explains Fiete, “but this circuit is devoted to integrating the animal’s speed along a one-dimensional compass that encodes head direction,” explains Fiete. “Without a manifold approach, which captures the whole state space, you wouldn’t know that this circuit of thousands of neurons is encoding only this one aspect of the complex behavior, and not encoding any other variables at the same time.”

Even during sleep, when the circuit is not being bombarded with external information, this circuit robustly traces out the same one-dimensional ring, as if dreaming of past head direction trajectories.

Further analysis revealed that the ring acts an attractor. If neurons stray off trajectory, they are drawn back to it, quickly correcting the system. This attractor property of the ring means that the representation of head direction in abstract space is reliably stable over time, a key requirement if we are to understand and maintain a stable sense of where our head is relative to the world around us.

“In the absence of this ring,” Fiete explains, “we would be lost in the world.”

Shaping the future

Fiete’s work provides a first glimpse into how complex sensory information is distilled into a simple concept in the mind, and how that representation autonomously corrects errors, making it exquisitely stable.

But the implications of this study go beyond coding of head direction.

“Similar organization is probably present for other cognitive functions so the paper is likely to inspire numerous new studies,” says Moser.

Fiete sees these analyses and related studies carried out by colleagues at the Norwegian University of Science and Technology, Princeton University, the Weitzman Institute, and elsewhere as fundamental to the future of neural decoding studies.

With this approach, she explains, it is possible to extract abstract representations of the mind from the brain, potentially even thoughts and dreams.

“We’ve found that the brain deconstructs and represents complex things in the world with simple shapes,” explains Fiete. “Manifold-level analysis can help us to find those shapes, and they almost certainly exist beyond head direction circuits.”

Do thoughts have mass?

by Michal De-Medonsa | July 29, 2019May 24, 2023

As part of our Ask the Brain series, we received the question, “Do thoughts have mass?” The following is a guest blog post by Michal De-Medonsa, technical associate and manager of the Jazayeri lab, who tapped into her background in philosophy to answer this intriguing question.

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Portrat of Michal De-Medonsa — Jazayeri lab manager (and philosopher) Michal De-Medonsa.

To answer the question, “Do thoughts have mass?” we must, like any good philosopher, define something that already has a definition – “thoughts.”

Logically, we can assert that thoughts are either metaphysical or physical (beyond that, we run out of options). If our definition of thought is metaphysical, it is safe to say that metaphysical thoughts do not have mass since they are by definition not physical, and mass is a property of a physical things. However, if we define a thought as a physical thing, it becomes a little trickier to determine whether or not it has mass.

A physical definition of thoughts falls into (at least) two subgroups – physical processes and physical parts. Take driving a car, for example – a parts definition describes the doors, motor, etc. and has mass. A process definition of a car being driven, turning the wheel, moving from point A to point B, etc. does not have mass. The process of driving is a physical process that involves moving physical matter, but we wouldn’t say that the act of driving has mass. The car itself, however, is an example of physical matter, and as any cyclist in the city of Boston is well aware – cars have mass. It’s clear that if we define a thought as a process, it does not have mass, and if we define a thought as physical parts, it does have mass – so, which one is it? In order to resolve our issue, we have to be incredibly precise with our definition. Is a thought a process or parts? That is, is a thought more like driving or more like a car?

In order to resolve our issue, we have to be incredibly precise with our definition of the word thought.

Both physical definitions (process and parts) have merit. For a parts definition, we can look at what is required for a thought – neurons, electrical signals, and neurochemicals, etc. This type of definition becomes quite imprecise and limiting. It doesn’t seem too problematic to say that the neurons, neurochemicals, etc. are themselves the thought, but this style of definition starts to fall apart when we try to include all the parts involved (e.g. blood flow, connective tissue, outside stimuli). When we look at a face, the stimuli received by the visual cortex is part of the thought – is the face part of a thought? When we look at our phone, is the phone itself part of a thought? A parts definition either needs an arbitrary limit, or we end up having to include all possible parts involved in the thought, ending up with an incredibly convoluted and effectively useless definition.

A process definition is more versatile and precise, and it allows us to include all the physical parts in a more elegant way. We can now say that all the moving parts are included in the process without saying that they themselves are the thought. That is, we can say blood flow is included in the process without saying that blood flow itself is part of the thought. It doesn’t sound ridiculous to say that a phone is part of the thought process. If we subscribe to the parts definition, however, we’re forced to say that part of the mass of a thought comes from the mass of a phone. A process definition allows us to be precise without being convoluted, and allows us to include outside influences without committing to absurd definitions.

Typical of a philosophical endeavor, we’re left with more questions and no simple answer. However, we can walk away with three conclusions.

A process definition of “thought” allows for elegance and the involvement of factors outside the “vacuum” of our physical body, however, we lose out on some function by not describing a thought by its physical parts.
The colloquial definition of “thought” breaks down once we invite a philosopher over to break it down, but this is to be expected – when we try to break something down, sometimes, it will break down. What we should be aware of is that if we want to use the word in a rigorous scientific framework, we need a rigorous scientific definition.
Most importantly, it’s clear that we need to put a lot of work into defining exactly what we mean by “thought” – a job well suited to a scientifically-informed philosopher.

Michal De-Medonsa earned her bachelor’s degree in neuroscience and philosophy from Johns Hopkins University in 2012 and went on to receive her master’s degree in history and philosophy of science at the University of Pittsburgh in 2015. She joined the Jazayeri lab in 2018 as a lab manager/technician and spends most of her free time rock climbing, doing standup comedy, and woodworking at the MIT Hobby Shop.

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Do you have a question for The Brain? Ask it here.

New CRISPR platform expands RNA editing capabilities

by Sabbi Lall | July 11, 2019May 24, 2023

CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12 and targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain.

McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), described in the journal Science.

Zhang and his team, including first co-authors Omar Abudayyeh and Jonathan Gootenberg (both now McGovern Fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine — thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang’s team that changes adenine bases into inosine in RNA.

RESCUE significantly expands the landscape that CRISPR tools can target to include modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.

“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” says Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT. Zhang also has appointments in MIT’s departments of Brain and Cognitive Sciences and Biological Engineering.

Expanding the reach of RNA editing to new targets

The previously developed REPAIR platform used the RNA-targeting CRISPR/Cas13 to direct the active domain of an RNA editor, ADAR2, to specific RNA transcripts where it could convert the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion, and evolved it in the lab until it could change cytosine to uridine, or C to U.

RESCUE can be guided to any RNA of choice, then perform a C-to-U edit through the evolved ADAR2 component of the platform. The team took the new platform into human cells, showing that they could target natural RNAs in the cell as well as 24 clinically relevant mutations in synthetic RNAs. They then further optimized RESCUE to reduce off-target editing, while minimally disrupting on-target editing.

New targets in sight

Expanded targeting by RESCUE means that sites regulating activity and function of many proteins through post-translational modifications, such as phosphorylation, glycosylation, and methylation can now be more readily targeted for editing.

A major advantage of RNA editing is its reversibility, in contrast to changes made at the DNA level, which are permanent. Thus, RESCUE could be deployed transiently in situations where a modification may be desirable temporarily, but not permanently. To demonstrate this, the team showed that in human cells, RESCUE can target specific sites in the RNA encoding β-catenin, that are known to be phosphorylated on the protein product, leading to a temporary increase in β-catenin activation and cell growth. If such a change was made permanently, it could predispose cells to uncontrolled cell growth and cancer, but by using RESCUE, transient cell growth could potentially stimulate wound healing in response to acute injuries.

The researchers also targeted a pathogenic gene variant, APOE4. The APOE4 allele has consistently emerged as a genetic risk factor for the development of late-onset Alzheimer’s Disease. Isoform APOE4 differs from APOE2, which is not a risk factor, by just two differences (both C in APOE4 vs. U in APOE2). Zhang and colleagues introduced the risk-associated APOE4 RNA into cells, and showed that RESCUE can convert its signature C’s to an APOE2 sequence, essentially converting a risk to a non-risk variant.

To facilitate additional work that will push RESCUE toward the clinic as well as enable researchers to use RESCUE as a tool to better understand disease-causing mutations, the Zhang lab plans to share the RESCUE system broadly, as they have with previously developed CRISPR tools. The technology will be freely available for academic research through the non-profit plasmid repository Addgene. Additional information can be found on the Zhang lab’s webpage.

Support for the study was provided by The Phillips Family; J. and P. Poitras; the Poitras Center for Psychiatric Disorders Research; Hock E. Tan and K. Lisa Yang Center for Autism Research.; Robert Metcalfe; David Cheng; a NIH F30 NRSA 1F30-CA210382 to Omar Abudayyeh. F.Z. is a New York Stem Cell Foundation–Robertson Investigator. F.Z. is supported by NIH grants (1R01-HG009761, 1R01-222 MH110049, and 1DP1-HL141201); the Howard Hughes Medical Institute; the New York Stem Cell Foundation and G. Harold and Leila Mathers Foundations.

A chemical approach to imaging cells from the inside

by Karen Zusi | June 20, 2019June 8, 2023

Press Mentions

A new ‘DNA microscope’ peers deep inside living cells

STAT News

DNA Microscope Sees ‘Through the Eyes of the Cell’

The New York Times

A team of researchers at the McGovern Institute and Broad Institute of MIT and Harvard have developed a new technique for mapping cells. The approach, called DNA microscopy, shows how biomolecules such as DNA and RNA are organized in cells and tissues, revealing spatial and molecular information that is not easily accessible through other microscopy methods. DNA microscopy also does not require specialized equipment, enabling large numbers of samples to be processed simultaneously.

“DNA microscopy is an entirely new way of visualizing cells that captures both spatial and genetic information simultaneously from a single specimen,” says first author Joshua Weinstein, a postdoctoral associate at the Broad Institute. “It will allow us to see how genetically unique cells — those comprising the immune system, cancer, or the gut, for instance — interact with one another and give rise to complex multicellular life.”

The new technique is described in Cell. Aviv Regev, core institute member and director of the Klarman Cell Observatory at the Broad Institute and professor of biology at MIT, and Feng Zhang, core institute member of the Broad Institute, investigator at the McGovern Institute for Brain Research at MIT, and the James and Patricia Poitras Professor of Neuroscience at MIT, are co-authors. Regev and Zhang are also Howard Hughes Medical Institute Investigators.

The evolution of biological imaging

In recent decades, researchers have developed tools to collect molecular information from tissue samples, data that cannot be captured by either light or electron microscopes. However, attempts to couple this molecular information with spatial data — to see how it is naturally arranged in a sample — are often machinery-intensive, with limited scalability.

DNA microscopy takes a new approach to combining molecular information with spatial data, using DNA itself as a tool.

To visualize a tissue sample, researchers first add small synthetic DNA tags, which latch on to molecules of genetic material inside cells. The tags are then replicated, diffusing in “clouds” across cells and chemically reacting with each other, further combining and creating more unique DNA labels. The labeled biomolecules are collected, sequenced, and computationally decoded to reconstruct their relative positions and a physical image of the sample.

The interactions between these DNA tags enable researchers to calculate the locations of the different molecules — somewhat analogous to cell phone towers triangulating the locations of different cell phones in their vicinity. Because the process only requires standard lab tools, it is efficient and scalable.

In this study, the authors demonstrate the ability to molecularly map the locations of individual human cancer cells in a sample by tagging RNA molecules. DNA microscopy could be used to map any group of molecules that will interact with the synthetic DNA tags, including cellular genomes, RNA, or proteins with DNA-labeled antibodies, according to the team.

“DNA microscopy gives us microscopic information without a microscope-defined coordinate system,” says Weinstein. “We’ve used DNA in a way that’s mathematically similar to photons in light microscopy. This allows us to visualize biology as cells see it and not as the human eye does. We’re excited to use this tool in expanding our understanding of genetic and molecular complexity.”

Funding for this study was provided by the Simons Foundation, Klarman Cell Observatory, NIH (R01HG009276, 1R01- HG009761, 1R01- MH110049, and 1DP1-HL141201), New York Stem Cell Foundation, Simons Foundation, Paul G. Allen Family Foundation, Vallee Foundation, the Poitras Center for Affective Disorders Research at MIT, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, J. and P. Poitras, and R. Metcalfe.

The authors have applied for a patent on this technology.

McGovern Institute postcard collection

by Julie Pryor | June 12, 2019December 18, 2023

A collection of 13 postcards arranged in columns. — The McGovern Institute postcard collection, 2023.

The McGovern Institute may be best known for its scientific breakthroughs, but a captivating series of brain-themed postcards developed by McGovern researchers and staff now reveals the institute’s artistic side.

What began in 2017 with a series of brain anatomy postcards inspired by the U.S. Works Projects Administration’s iconic national parks posters, has grown into a collection of twelve different prints, each featuring a unique fusion of neuroscience and art.

More information about each series in the McGovern Institute postcard collection, including the color-your-own mindfulness postcards, can be found below.

Mindfulness Postcard Series, 2023

In winter 2023, the institute released its mindfulness postcard series, a collection of four different neuroscience-themed illustrations that can be colored in with pencils, markers, or paint. The postcard series was inspired by research conducted in John Gabrieli’s lab, which found that practicing mindfulness reduced children’s stress levels and negative emotions during the pandemic. These findings contribute to a growing body of evidence that practicing mindfulness — focusing awareness on the present, typically through meditation, but also through coloring — can change patterns of brain activity associated with emotions and mental health.

Download and color your own postcards.

Genes

The McGovern Institute is at the cutting edge of applications based on CRISPR, a genome editing tool pioneered by McGovern Investigator Feng Zhang. Hidden within this DNA-themed postcard is a clam, virus, bacteriophage, snail, and the word CRISPR. Click the links to learn how these hidden elements relate to genetic engineering research at the McGovern Institute.

The McGovern Institute’s “mindfulness” postcard series includes this DNA-themed illustration containing five hidden design elements related to McGovern research. Image: Joseph Laney

Neurons

McGovern researchers probe the nanoscale and cellular processes that are critical to brain function, including the complex computations conducted in neurons, to the synapses and neurotransmitters that facilitate messaging between cells. Find the mouse, worm, and microscope — three critical elements related to cellular and molecular neuroscience research at the McGovern Institute — in the postcard below.

The McGovern Institute’s “mindfulness” postcard series includes this neuron-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Human Brain

Cognitive neuroscientists at the McGovern Institute examine the brain processes that come together to inform our thoughts and understanding of the world. Find the musical note, speech bubbles, and human face in this postcard and click on the links to learn more about how these hidden elements relate to brain research at the McGovern Institute.

The McGovern Institute’s “mindfulness” postcard series includes this brain-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Artificial Intelligence

McGovern researchers develop machine learning systems that mimic human processing of visual and auditory cues and construct algorithms to help us understand the complex computations made by the brain. Find the speech bubbles, DNA, and cochlea (spiral) in this postcard and click on the links to learn more about how these hidden elements relate to computational neuroscience research at the McGovern Institute.

The McGovern Institute’s “mindfulness” postcard series includes this AI-themed illustration containing three hidden design elements related to McGovern research. Image: Joseph Laney

Neuron Postcard Series, 2019

In 2019, the McGovern Institute released a second series of postcards based on the anatomy of a neuron. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown beloSynapse

Synapse

Signals flow through the nervous system from one neuron to the next across synapses.

Synapses are exquisitely organized molecular machines that control the transmission of information.

McGovern researchers are studying how disruptions in synapse function can lead to brain disorders like autism.

Image: Joseph Laney

Axon

The axon is the long, thin neural cable that carries electrical impulses called action potentials from the soma to synaptic terminals at downstream neurons.

Researchers at the McGovern Institute are developing and using tracers that label axons to reveal the elaborate circuit architecture of the brain.

Image: Joseph Laney

Soma

The soma, or cell body, is the control center of the neuron, where the nucleus is located.

It connects the dendrites to the axon, which sends information to other neurons.

At the McGovern Institute, neuroscientists are targeting the soma with proteins that can activate single neurons and map connections in the brain.

Image: Joseph Laney

Dendrites

Long branching neuronal processes called dendrites receive synaptic inputs from thousands of other neurons and carry those signals to the cell body.

McGovern neuroscientists have discovered that human dendrites have different electrical properties from those of other species, which may contribute to the enhanced computing power of the human brain.

Image: Joseph Laney

Brain Anatomy Postcard Series, 2017

The original brain anatomy-themed postcard series, developed in 2017, was inspired by the U.S. Works Projects Administration’s iconic national parks posters created in the 1930s and 1940s. Each postcard includes text on the back side that describes McGovern research related to that specific part of the neuron. The descriptive text for each postcard is shown below.

Sylvian Fissure

Illustration of explorer in cave labeled with temporal and parietal letters — The Sylvian fissure is a prominent groove on the right side of the brain that separates the frontal and parietal lobes from the temporal lobe. McGovern researchers are studying a region near the right Sylvian fissure, called the rTPJ, which is involved in thinking about what another person is thinking.

Hippocampus

Basal Ganglia

The arcuate fasciculus is a bundle of axons in the brain that connects Broca’s area, involved in speech production, and Wernicke’s area, involved in understanding language. McGovern researchers have found a correlation between the size of this structure and the risk of dyslexia in children.

Order and Share

To order your own McGovern brain postcards, contact our colleagues at the MIT Museum, where proceeds will support current and future exhibitions at the growing museum.

Please share a photo of yourself in your own lab (or natural habitat) with one of our cards on social media. Tell us what you’re studying and don’t forget to tag us @mcgovernmit using the hashtag #McGovernPostcards.

New gene-editing system precisely inserts large DNA sequences into cellular DNA

by Karen Zusi, Broad Institute | June 11, 2019May 24, 2023

A team led by researchers from Broad Institute of MIT and Harvard, and the McGovern Institute for Brain Research at MIT, has characterized and engineered a new gene-editing system that can precisely and efficiently insert large DNA sequences into a genome. The system, harnessed from cyanobacteria and called CRISPR-associated transposase (CAST), allows efficient introduction of DNA while reducing the potential error-prone steps in the process — adding key capabilities to gene-editing technology and addressing a long-sought goal for precision gene editing.

Precise insertion of DNA has the potential to treat a large swath of genetic diseases by integrating new DNA into the genome while disabling the disease-related sequence. To accomplish this in cells, researchers have typically used CRISPR enzymes to cut the genome at the site of the deleterious sequence, and then relied on the cell’s own repair machinery to stitch the old and new DNA elements together. However, this approach has many limitations.

Using Escherichia coli bacteria, the researchers have now demonstrated that CAST can be programmed to efficiently insert new DNA at a designated site, with minimal editing errors and without relying on the cell’s own repair machinery. The system holds potential for much more efficient gene insertion compared to previous technologies, according to the team.

The researchers are working to apply this editing platform in eukaryotic organisms, including plant and animal cells, for precision research and therapeutic applications.

The team molecularly characterized and harnessed CAST from two cyanobacteria, Scytonema hofmanni and Anabaena cylindrica, and additionally revealed a new way that some CRISPR systems perform in nature: not to protect bacteria from viruses, but to facilitate the spread of transposon DNA.

The work, appearing in Science, was led by first author Jonathan Strecker, a postdoctoral fellow at the Broad Institute; graduate student Alim Ladha at MIT; and senior author Feng Zhang, a core institute member at the Broad Institute, investigator at the McGovern Institute for Brain Research at MIT, the James and Patricia Poitras Professor of Neuroscience at MIT, and an associate professor at MIT, with joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering. Collaborators include Eugene Koonin at the National Institutes of Health.

A New Role for a CRISPR-Associated System

“One of the long-sought-after applications for molecular biology is the ability to introduce new DNA into the genome precisely, efficiently, and safely,” explains Zhang. “We have worked on many bacterial proteins in the past to harness them for editing in human cells, and we’re excited to further develop CAST and open up these new capabilities for manipulating the genome.”

To expand the gene-editing toolbox, the team turned to transposons. Transposons (sometimes called “jumping genes”) are DNA sequences with associated proteins — transposases — that allow the DNA to be cut-and-pasted into other places.

Most transposons appear to jump randomly throughout the cellular genome and out to viruses or plasmids that may also be inhabiting a cell. However, some transposon subtypes in cyanobacteria have been computationally associated with CRISPR systems, suggesting that these transposons may naturally be guided towards more-specific genetic targets. This theorized function would be a new role for CRISPR systems; most known CRISPR elements are instead part of a bacterial immune system, in which Cas enzymes and their guide RNA will target and destroy viruses or plasmids.

In this paper, the research team identified the mechanisms at work and determined that some CRISPR-associated transposases have hijacked an enzyme called Cas12k and its guide to insert DNA at specific targets, rather than just cutting the target for defensive purposes.

“We dove deeply into this system in cyanobacteria, began taking CAST apart to understand all of its components, and discovered this novel biological function,” says Strecker, a postdoctoral fellow in Zhang’s lab at the Broad Institute. “CRISPR-based tools are often DNA-cutting tools, and they’re very efficient at disrupting genes. In contrast, CAST is naturally set up to integrate genes. To our knowledge, it’s the first system of this kind that has been characterized and manipulated.”

Harnessing CAST for Genome Editing

Once all the elements and molecular requirements of the CAST system were laid bare, the team focused on programming CAST to insert DNA at desired sites in E. coli.

“We reconstituted the system in E. coli and co-opted this mechanism in a way that was useful,” says Strecker. “We reprogrammed the system to introduce new DNA, up to 10 kilobase pairs long, into specific locations in the genome.”

The team envisions basic research, agricultural, or therapeutic applications based on this platform, such as introducing new genes to replace DNA that has mutated in a harmful way — for example, in sickle cell disease. Systems developed with CAST could potentially be used to integrate a healthy version of a gene into a cell’s genome, disabling or overriding the DNA causing problems.

Alternatively, rather than inserting DNA with the purpose of fixing a deleterious version of a gene, CAST may be used to augment healthy cells with elements that are therapeutically beneficial, according to the team. For example, in immunotherapy, a researcher may want to introduce a “chimeric antigen receptor” (CAR) into a specific spot in the genome of a T cell — enabling the T cell to recognize and destroy cancer cells.

“For any situation where people want to insert DNA, CAST could be a much more attractive approach,” says Zhang. “This just underscores how diverse nature can be and how many unexpected features we have yet to find.”

Support for this study was provided in part by the Human Frontier Science Program, New York Stem Cell Foundation, Mathers Foundation, NIH (1R01-HG009761, 1R01-MH110049, and 1DP1-HL141201), Howard Hughes Medical Institute, Poitras Center for Psychiatric Disorders Research, J. and P. Poitras, and Hock E. Tan and K. Lisa Yang Center for Autism Research.

J.S. and F.Z. are co-inventors on US provisional patent application no. 62/780,658 filed by the Broad Institute, relating to CRISPR-associated transposases.

Expression plasmids are available from Addgene.

Our brains appear uniquely tuned for musical pitch

by National Institutes of Health | June 11, 2019May 24, 2023

In the eternal search for understanding what makes us human, scientists found that our brains are more sensitive to pitch, the harmonic sounds we hear when listening to music, than our evolutionary relative the macaque monkey. The study, funded in part by the National Institutes of Health, highlights the promise of Sound Health, a joint project between the NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts, that aims to understand the role of music in health.

“We found that a certain region of our brains has a stronger preference for sounds with pitch than macaque monkey brains,” said Bevil Conway, Ph.D., investigator in the NIH’s Intramural Research Program and a senior author of the study published in Nature Neuroscience. “The results raise the possibility that these sounds, which are embedded in speech and music, may have shaped the basic organization of the human brain.”

The study started with a friendly bet between Dr. Conway and Sam Norman-Haignere, Ph.D., a post-doctoral fellow at Columbia University’s Zuckerman Institute for Mind, Brain, and Behavior and the first author of the paper.

At the time, both were working at the Massachusetts Institute of Technology (MIT). Dr. Conway’s team had been searching for differences between how human and monkey brains control vision only to discover that there are very few. Their brain mapping studies suggested that humans and monkeys see the world in very similar ways. But then, Dr. Conway heard about some studies on hearing being done by Dr. Norman-Haignere, who, at the time, was a post-doctoral fellow in the laboratory of Josh H. McDermott, Ph.D., associate professor at MIT.

“I told Bevil that we had a method for reliably identifying a region in the human brain that selectively responds to sounds with pitch,” said Dr. Norman-Haignere, That is when they got the idea to compare humans with monkeys. Based on his studies, Dr. Conway bet that they would see no differences.

To test this, the researchers played a series of harmonic sounds, or tones, to healthy volunteers and monkeys. Meanwhile, functional magnetic resonance imaging (fMRI) was used to monitor brain activity in response to the sounds. The researchers also monitored brain activity in response to sounds of toneless noises that were designed to match the frequency levels of each tone played.

At first glance, the scans looked similar and confirmed previous studies. Maps of the auditory cortex of human and monkey brains had similar hot spots of activity regardless of whether the sounds contained tones.

However, when the researchers looked more closely at the data, they found evidence suggesting the human brain was highly sensitive to tones. The human auditory cortex was much more responsive than the monkey cortex when they looked at the relative activity between tones and equivalent noisy sounds.

“We found that human and monkey brains had very similar responses to sounds in any given frequency range. It’s when we added tonal structure to the sounds that some of these same regions of the human brain became more responsive,” said Dr. Conway. “These results suggest the macaque monkey may experience music and other sounds differently. In contrast, the macaque’s experience of the visual world is probably very similar to our own. It makes one wonder what kind of sounds our evolutionary ancestors experienced.”

Further experiments supported these results. Slightly raising the volume of the tonal sounds had little effect on the tone sensitivity observed in the brains of two monkeys.

Finally, the researchers saw similar results when they used sounds that contained more natural harmonies for monkeys by playing recordings of macaque calls. Brain scans showed that the human auditory cortex was much more responsive than the monkey cortex when they compared relative activity between the calls and toneless, noisy versions of the calls.

“This finding suggests that speech and music may have fundamentally changed the way our brain processes pitch,” said Dr. Conway. “It may also help explain why it has been so hard for scientists to train monkeys to perform auditory tasks that humans find relatively effortless.”

Earlier this year, other scientists from around the U.S. applied for the first round of NIH Sound Health research grants. Some of these grants may eventually support scientists who plan to explore how music turns on the circuitry of the auditory cortex that make our brains sensitive to musical pitch.

This study was supported by the NINDS, NEI, NIMH, and NIA Intramural Research Programs and grants from the NIH (EY13455; EY023322; EB015896; RR021110), the National Science Foundation (Grant 1353571; CCF-1231216), the McDonnell Foundation, the Howard Hughes Medical Institute.

Can we think without language?

by Anna Ivanova | May 2, 2019May 24, 2023

As part of our Ask the Brain series, Anna Ivanova, a graduate student who studies how the brain processes language in the labs of Nancy Kanwisher and Evelina Fedorenko, answers the question, “Can we think without language?”

Graduate student Anna Ivanova studies language processing in the brain.

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Imagine a woman – let’s call her Sue. One day Sue gets a stroke that destroys large areas of brain tissue within her left hemisphere. As a result, she develops a condition known as global aphasia, meaning she can no longer produce or understand phrases and sentences. The question is: to what extent are Sue’s thinking abilities preserved?

Many writers and philosophers have drawn a strong connection between language and thought. Oscar Wilde called language “the parent, and not the child, of thought.” Ludwig Wittgenstein claimed that “the limits of my language mean the limits of my world.” And Bertrand Russell stated that the role of language is “to make possible thoughts which could not exist without it.” Given this view, Sue should have irreparable damage to her cognitive abilities when she loses access to language. Do neuroscientists agree? Not quite.

Neuroimaging evidence has revealed a specialized set of regions within the human brain that respond strongly and selectively to language.

This language system seems to be distinct from regions that are linked to our ability to plan, remember, reminisce on past and future, reason in social situations, experience empathy, make moral decisions, and construct one’s self-image. Thus, vast portions of our everyday cognitive experiences appear to be unrelated to language per se.

But what about Sue? Can she really think the way we do?

While we cannot directly measure what it’s like to think like a neurotypical adult, we can probe Sue’s cognitive abilities by asking her to perform a variety of different tasks. Turns out, patients with global aphasia can solve arithmetic problems, reason about intentions of others, and engage in complex causal reasoning tasks. They can tell whether a drawing depicts a real-life event and laugh when in doesn’t. Some of them play chess in their spare time. Some even engage in creative tasks – a composer Vissarion Shebalin continued to write music even after a stroke that left him severely aphasic.

Some readers might find these results surprising, given that their own thoughts seem to be tied to language so closely. If you find yourself in that category, I have a surprise for you – research has established that not everybody has inner speech experiences. A bilingual friend of mine sometimes gets asked if she thinks in English or Polish, but she doesn’t quite get the question (“how can you think in a language?”). Another friend of mine claims that he “thinks in landscapes,” a sentiment that conveys the pictorial nature of some people’s thoughts. Therefore, even inner speech does not appear to be necessary for thought.

Have we solved the mystery then? Can we claim that language and thought are completely independent and Bertrand Russell was wrong? Only to some extent. We have shown that damage to the language system within an adult human brain leaves most other cognitive functions intact. However, when it comes to the language-thought link across the entire lifespan, the picture is far less clear. While available evidence is scarce, it does indicate that some of the cognitive functions discussed above are, at least to some extent, acquired through language.

Perhaps the clearest case is numbers. There are certain tribes around the world whose languages do not have number words – some might only have words for one through five (Munduruku), and some won’t even have those (Pirahã). Speakers of Pirahã have been shown to make mistakes on one-to-one matching tasks (“get as many sticks as there are balls”), suggesting that language plays an important role in bootstrapping exact number manipulations.

Another way to examine the influence of language on cognition over time is by studying cases when language access is delayed. Deaf children born into hearing families often do not get exposure to sign languages for the first few months or even years of life; such language deprivation has been shown to impair their ability to engage in social interactions and reason about the intentions of others. Thus, while the language system may not be directly involved in the process of thinking, it is crucial for acquiring enough information to properly set up various cognitive domains.

Even after her stroke, our patient Sue will have access to a wide range of cognitive abilities. She will be able to think by drawing on neural systems underlying many non-linguistic skills, such as numerical cognition, planning, and social reasoning. It is worth bearing in mind, however, that at least some of those systems might have relied on language back when Sue was a child. While the static view of the human mind suggests that language and thought are largely disconnected, the dynamic view hints at a rich nature of language-thought interactions across development.

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