Research Area: Neurobiology

Real-time readouts of thinking in rats

New open-source system provides fast, accurate neural decoding and real-time readouts of where rats think they are.

David Orenstein | Picower Institute for Learning and Memory
December 19, 2018

The rat in a maze may be one of the most classic research motifs in brain science, but a new innovation described in Cell Reports by an international collaboration of scientists shows just how far such experiments are still pushing the cutting edge of technology and neuroscience alike.

In recent years, scientists have shown that by recording the electrical activity of groups of neurons in key areas of the brain they could read a rat’s thoughts of where it was, both after it actually ran the maze and also later when it would dream of running the maze in its sleep — a key process in consolidating its memory. In the new study, several of the scientists involved in pioneering such mind-reading methods now report they can read out those signals in real-time as the rat runs the maze, with a high degree of accuracy and the ability to account for the statistical relevance of the readings almost instantly after they are made.

The ability to so robustly track the rat’s spatial representations in real-time opens the door to a whole new class of experiments, the researchers said. They predict these experiments will produce new insights into learning, memory, navigation and cognition by allowing them to not only decode rat thinking as it happens, but also to instantaneously intervene and study the effects of those perturbations.

“The use of real-time decoding and closed-loop control of neural activity will fundamentally transform our studies of the brain,” says study co-author Matthew Wilson, the Sherman Fairchild Professor in Neurobiology at MIT’s Picower Institute for Learning and Memory.

The collaboration behind the new paper began in Wilson’s lab at MIT almost 10 years ago. At that time, corresponding authors Zhe (Sage) Chen, now an associate professor of psychiatry and neuroscience and physiology at New York University, and Fabian Kloosterman, now a principal investigator at Neuro-Electronics Research Flanders and a professor at KU Leuven in Belgium, were both postdocs at MIT.

After demonstrating how neural decoding can be used to read out what places are covertly replayed in the brain, the team began a series of technical innovations that progressively improved the field’s ability to accurately decode how the brain represents place both during navigation and in sleep or rest. They reached a first milestone in 2013 when the team published their novel decoding approach in a paper in the Journal of Neurophysiology. The new approach allows researchers to directly decipher hippocampal spatiotemporal patterns detected from tetrode recordings without the need for spike sorting, a computational process that is time-consuming and error prone.

In the new study, the team shows that by implementing their neural decoding software on a graphical processing unit (GPU) chip, the same kind of highly parallel processing hardware favored by video gamers, they were able to achieve unprecedented increases in decoding and analysis speed. In the study, the team shows that the GPU-based system was 20-50 times faster than ones using conventional multi-core CPU chips.

They also show that the system remains rapid and accurate even when handling more than 1,000 input channels. This is important because it extends the real-time decoding approach to new high-density brain recording devices, such as the Neuropixels probe co-developed by imec, HHMI and other institutions — think of a many electrodes recording from many hundreds of cells — that promise to measure cellular brain activity at larger scales and in more detail.

In addition, the new study reports the ability for the software to provide a rapid statistical assessment of whether a set of reactivated neural spatiotemporal activity patterns truly pertains to the task, or is perhaps unrelated.

“We are proposing an elegant solution using GPU computing to not only decode information on the fly but also to evaluate the significance of the information on the fly,” says Chen, whose graduate student, Sile Hu, is the new paper’s lead author.

Hu tested a wide range of neural recordings in brain areas such as the hippocampus, the thalamus and cortex in multiple rats as they ran a variety of mazes ranging from simple tracks to a wide-open space. In a video accompanying the paper, the system’s readout from 36 electrode channels in the hippocampus tracks the rat’s actual measured position in open space and provides real-time estimates of the decoded position from brain activity. Only occasionally and briefly do the trajectories diverge by much.

The software of the system is open source and available for fellow neuroscientists to download and use freely, Chen and Wilson say.

Prior experiments recording neural representations of place have helped to show that animals replay their spatial experiences during sleep and have allowed researchers to understand more about how animals rely on memory when making decisions about how to navigate — for instance to maximize the rewards they can find along the way. Traditionally, though, the brain readings have been analyzed offline (after the fact. More recently, scientists have begun to perform real-time analyses but these have been limited both in the detail of the content and also in the ability to understand whether the readings are statistically significant and therefore relevant.

In a recent major step forward, Kloosterman and two other co-authors of the new study, graduate students Davide Ciliberti and Frédéric Michon, published a paper in eLife on a real-time, closed-loop read-out of hippocampal memory replay as rats navigated a three-arm maze. That system used multi-core CPUs.

“The new GPU system will bring the field even closer to having a detailed, real-time and highly scalable read-out of the brain’s internal deliberations,” says Kloosterman, “That will be necessary to increase our understanding of how these replay events drive memory formation and behavior.”

By combining these capabilities with optogenetics — a technology that makes neurons controllable with flashes of light — the researchers could conduct what they call “closed-loop” studies in which they could use their instantaneous readout of spatial thinking to trigger experimental manipulations. For example, they could see what happens to navigational performance the day after they interfered with replay during sleep, or they could determine what temporarily disrupting communication between the cortex and hippocampus might do when a rat faces a key decision about which direction to go.

Hu is also affiliated with Zhejiang University in China. In addition to Hu, Wilson, Chen, Kloosterman, Ciliberti, and Michon, the paper’s other authors are Andres Grosmark of Columbia University, Daoyun Ji of Baylor College of Medicine, Hector Penagos of MIT’s Picower Institute, and György Buzsáki of NYU.

Funding for the study came from the U.S. National Institutes of Health, the National Science Foundation, MIT’s NSF-funded Center for Brains Minds and Machines, Research Foundation – Flanders (FWO), the National Science Foundation of China, and the Simons Foundation.

Biologists discover an unusual hallmark of aging in neurons

Snippets of RNA that accumulate in brain cells could interfere with normal function.

Anne Trafton | MIT News Office
November 27, 2018

As we age, neurons in our brains can become damaged by free radicals. MIT biologists have now discovered that this type of damage, known as oxidative stress, produces an unusual pileup of short snippets of RNA in some neurons.

This RNA buildup, which the researchers believe may be a marker of neurodegenerative diseases, can reduce protein production. The researchers observed this phenomenon in both mouse and human brains, especially in a part of the brain called the striatum — a site involved in diseases such as Parkinson’s and Huntington’s.

“The brain is very metabolically active, and over time, that causes oxidative damage, but it affects some neurons more than others,” says Christopher Burge, an MIT professor of biology. “This phenomenon appears to be a previously unrecognized consequence of oxidative stress, which impacts hundreds of genes and may influence translation and RNA regulation globally.”

Burge and Myriam Heiman, the Latham Family Career Development Associate Professor of Brain and Cognitive Sciences, are the senior authors of the paper, which appears in the Nov. 27 issue of Cell Reports. Peter Sudmant, a former MIT postdoc, is the lead author of the paper, and postdoc Hyeseung Lee and former postdoc Daniel Dominguez are also authors.

A mysterious finding

For this study, the researchers used a technique developed by Heiman that allows them to isolate and sequence messenger RNA from specific types of cells. Messenger RNA carries protein-building instructions to cell organelles called ribosomes, which read the mRNA and translate the instructions into proteins by stringing together amino acids in the correct sequence.

Heiman’s technique involves tagging ribosomes from a specific type of cells with green fluorescent protein, so that when a tissue sample is analyzed, researchers can use the fluorescent tag to isolate and sequence RNA from only those cells. This allows them to determine which proteins are being produced by different types of cells.

“This is particularly useful in the nervous system where you’ve got different types of neurons and glia closely intertwined together, if you want to isolate the mRNAs from one particular cell type,” Burge says.

In separate groups of mice, the researchers tagged ribosomes from either D1 or D2 spiny projection neurons, which make up 95 percent of the neurons found in the striatum. They labeled these cells in younger mice (6 weeks old) and 2-year-old mice, which are roughly equivalent to humans in their 70s or 80s.

The researchers had planned to look for gene expression differences between those two cell types, and to explore how they were affected by age. “These two types of neurons are implicated in several neurodegenerative diseases that are aging-related, so it is important to understand how normal aging changes their cellular and molecular properties,” says Heiman, who is a member of MIT’s Picower Institute for Learning and Memory and the Broad Institute of MIT and Harvard.

To the researchers’ surprise, a mysterious result emerged — in D1 neurons from aged mice (but not neurons from young mice or D2 neurons from aged mice), they found hundreds of genes that expressed only a short fragment of the original mRNA sequence. These snippets, known as 3’ untranslated regions (UTRs), were stuck to ribosomes, preventing the ribosomes from assembling normal proteins. “While these RNAs have been observed before, the magnitude and age-associated cell-type specificity was really unprecedented,” says Sudmant.

The 3’ UTR snippets appeared to originate from about 400 genes with a wide variety of functions. Meanwhile, many other genes were totally unaffected.

“There are some genes that are completely normal, even in aged D1 neurons. There’s a gene-specific aspect to this phenomenon that is quite interesting and mysterious,” Burge says.

The findings led the researchers to explore a possible role for oxidative stress in this 3’ UTR accumulation. Neurons burn a great deal of energy, which can produce free radicals as byproducts. Unlike many other cell types, neurons do not get replaced, so they are believed to be susceptible to accumulated damage from these radicals over time.

The MIT team found that the activation of oxidative stress response pathways was higher in D1 neurons compared to D2 neurons, suggesting that they are indeed undergoing more oxidative damage. The researchers propose a model for the production of isolated 3′ UTRs involving an enzyme called ABCE1, which normally separates ribosomes from mRNA after translation is finished. This enzyme contains iron-sulfur clusters that can be damaged by free radicals, making it less effective at removing ribosomes, which then get stuck on the mRNA. This leads to cleavage of the RNA by a mechanism that operates upstream of stalled ribosomes.

“Sending neural signals takes a lot of energy,” Burge says. “Over time, that causes oxidative damage, and in our model one of the proteins that eventually gets damaged is ABCE1, and that triggers the production of 3’ UTRs.”

RNA buildup

The researchers also found the same accumulation in most parts of the human brain, including the frontal cortex, which is very metabolically active. They did not see it in most other types of human tissue, with the exception of liver tissue, which is exposed to high levels of potentially toxic molecules.

In human brain tissue, the researchers found that the amount of 3’ UTRs gradually increased with age, which fits their proposed model of gradual damage by oxidative stress. The researchers’ findings and model suggest that the production of these 3′ UTRs involves the destruction of normal mRNAs, reducing the amount of protein produced from the affected genes.  This buildup of 3′ UTRs with ribosomes stuck to them can also block ribosomes from producing other proteins.

It remains to be seen exactly what effect this would have on those neurons, Burge says, but it is possible that this kind of cellular damage could combine with genetic and environmental factors to produce a general decline in cognitive ability or even neurodegenerative conditions such as Parkinson’s disease. In future studies, the researchers hope to further explore the causes and consequences of the accumulation of 3’ UTRs.

The research was funded by the National Institutes of Health and the JPB Foundation.

How returning to a prior context briefly heightens memory recall
Picower Institute
December 11, 2018

Whether it’s the pleasant experience of returning to one’s childhood home over the holidays or the unease of revisiting a site that proved unpleasant, we often find that when we return to a context where an episode first happened, specific and vivid memories can come flooding back. In a new study in Neuron, scientists in MIT’s Picower Institute for Learning and Memory report the discovery of a mechanism the brain may be employing to make that phenomenon occur.

“Suppose you are driving home in the evening and encounter a beautiful orange twilight in the sky, which reminds you of the great vacation you had a few summers ago at a Caribbean island,” said study senior author Susumu Tonegawa, Picower Professor of Neuroscience at MIT. “This initial recall could be a general recall of the vacation. But moments later, you may get reminded of details of some specific events or situations that took place during the vacation which you had not been thinking about.”

At the heart of that second stage of recall, where specific details are suddenly vividly available, is a change in the electrical excitability of “engram cells,” or the ensemble of neurons that together encode a memory through the specific pattern of their connection. In the new study Tonegawa’s lab, led by postdoc Michele Pignatelli and former member Tomas Ryan, now at Trinity College Dublin, showed that after mice formed a memory in a context, the engram cells encoding that memory in a brain region called the hippocampus would temporarily become much more electrically excitable if the mice were placed back in the same context again. So for instance, if they were given a little shock in a specific context one day, then the engram cells would be much more excitable for about an hour after they were put back in that same context the next day.

The specific change in the engram cells’ electrical properties has some direct implications for learning and behavior that hadn’t been appreciated before. Importantly, during that hour after returning to the initial context, because of the engrams’ elevated excitability, mice proved better able to learn from a shock in that context and better able to distinguish between that and distinct contexts even if they shared some similar cues. The increase in excitability therefore allowed them both to learn to avoid places where danger happened very recently and to continue to function normally in places that happen to have some irrelevant resemblance. And because the effect was short-lived, it didn’t oblige them to remain overly attuned for very long.

“The short-term reactivation increases the future recognition capability of specific cues,” Pignatelli and Tonegawa’s team wrote. “Engram cell excitability may be crucial for survival by facilitating rapid adaptive behavior without permanently altering the fundamental nature of the long-term engram.”

Tonegawa added that “while the survival interpretation may be an evolutionary origin of this multi-step episodic memory recall” it likely also applies to positive episodic memories, like the vacation sunset experience, just as much.

Only in Your Head
Greta Friar | Whitehead Institute
October 9, 2018

Cambridge, Mass. — Brain development is a delicately choreographed dance in which cell division and differentiation into mature cell types must be performed in the right balance for normal growth. In order to better understand factors affecting brain development, Whitehead Institute researchers investigated a genetic mutation that leads to a brain-specific developmental disorder in spite of the gene’s prevalent expression in other cell types.

Kinetochore null protein 1 (KNL1) acts throughout the body during cell division to help ensure the accurate segregation of chromosomes into each daughter cell. A mutation in the KNL1 gene caused by a single change in its DNA sequence leads to microcephaly, a condition in which the brain fails to properly develop, causing babies to be born with small heads, often accompanied by intellectual disabilities and other health problems. In an article published online October 9 in the journal Cell Reports, Whitehead Institute Founding Member Rudolf Jaenisch and colleagues investigated how this KNL1 mutation can lead to microcephaly without affecting other cell types, providing important insights into the underlying basis of microcephaly and the role that KNL1 normally plays in brain development.

“The key question we were interested in was why, if the gene is ubiquitously expressed, is there a brain-specific phenotype,” says Jaenisch, who is also a professor of biology at the Massachusetts Institute of Technology.

Jaenisch lab graduate student Attya Omer Javed, a co-first author on the paper along with past lab members Yun Li and Julien Muffat, used CRISPR-Cas9 to recreate the mutation—a point mutation, or one-letter change in the DNA sequence of the KNL1 gene—in several different cell types derived from human stem cells in the lab. Of the three cell types tested, they found that only the neural progenitor cells, early stage cells that become brain cells, appeared to be affected.

As the brain develops, each neural progenitor can either keep dividing to increase the overall number of cells in the brain, or it can mature into a differentiated brain cell, at which point it is no longer able to divide. For a healthy brain to develop, there needs to be a careful balance between these two processes of proliferation and differentiation. If the progenitors take too long to differentiate, the developing brain won’t have the specific cells it needs to assemble. But if all of the cells differentiate too quickly, before they can divide, there will be a shortage of cells and the brain will be too small.

“Neural progenitors are going through many cell cycles, dividing quickly during brain development. Even a small defect could accumulate to have a huge impact,” Omer Javed says.

The researchers discovered that neural progenitors with the KNL1 mutation differentiated prematurely at the cost of proliferation, resulting in the small brain size that characterizes microcephaly. The brain cells with the mutation also were at a greater risk of cell death, disruption of the cell cycle, ending up with the wrong number of chromosomes, and malfunctions during attempted cell division.

KNL1’s role is in the kinetochore, an assembly of proteins that operate during mitosis to attach chromosomes to the machinery that will pull them apart into the daughter cells. This is why the KNL1 mutation negatively affects cell division. Co-author and Whitehead Member Iain Cheesemanhelped identify KNL1’s role in the kinetochore as a postdoctoral researcher years ago, and his expertise provided an opportunity for collaboration between his lab and Jaenisch’s.

“I have always found it interesting that inherited mutations to the kinetochore seem to lead to microcephaly,” Cheeseman says. “Investigating KNL1 together was an exciting chance to combine our labs’ diverse scientific knowledge.”

In order for the researchers to study the cells in an environment that more closely mimicked a human brain, they used a 3D cell culture technique to grow organoids made up of neural progenitors. Omer Javed found that the neural progenitors were extremely sensitive, as the organoids with the mutation expressed the microcephaly phenotype after as little as two weeks of growth.

Omer Javed then looked for differences between neural progenitors and the other cell types that would explain the brain-specific effects of the mutation. Even with the mutation, the KNL1 gene appeared able to make a functioning protein, explaining its lack of effect on the other cell types. So Omer Javed turned her attention to factors involved in regulating gene expression. For many of our genes to be expressed, first sections called introns must be removed, or spliced out, in order for the correct DNA sequence to then be read into RNA and then translated into a functional protein.

Omer Javed found that the KNL1 mutation created a site for splicing inhibitors to bind and silence the KNL1 gene by preventing it from being read into RNA. She also found a disparity in the level of a protein involved in this process between the cell types: the inhibitory splicing protein hnRNPA1 was much more prevalent in neural progenitors than elsewhere. When hnRNPA1 came across the site caused by the mutation, it prevented the gene from being expressed. The high quantity of hnRNPA1 in neural progenitors appears to be the main factor mediating the brain-specific effects of the mutation.

The work complements and extends previous investigations by the researchers into how neural progenitor proliferation may have contributed to the evolution of large human brains, as well as studies investigating why neural progenitors are so vulnerable to the Zika virus, which has been associated with microcephaly. Given their work suggesting that KNL1 could be a regulator of brain size, Omer Javed hopes that future research will reveal its role in the evolution of the human brain.

 

This research was supported by Boehringer Ingelheim Fonds, the Simons Foundation, the International Rett Syndrome Foundation, Brain & Behavior Research Foundation, the European Leukodystrophy Association, the National Institutes of Health (NIH grants HD 045022, R37-CA084198 and 1U19AI131135-01). Jaenisch is a cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics.

 

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Rudolf Jaenisch’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.
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Full citation:
“Microcephaly modeling of kinetochore mutation reveals a brain-specific phenotype”
Cell Reports, online October 9, 2018
Attya Omer (1,2,8), Yun Li (2,3,4,8), Julien Muffat (2,4,5,8), Kuan-Chung Su (2), Malkiel A. Cohen (2), Tenzin Lungjangwa (2), Patrick Aubourg (1,6), Iain M. Cheeseman (2,7), and Rudolf Jaenisch (2,7).
1. Université Paris-Saclay, ED 569, 5 Rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France
2.  Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA
3. Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M4G 0A4, Canada
4. Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
5. Program in Neurosciences and Mental Health, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada
6. INSERM U1169, CHU Bicêtre Paris Sud, Le Kremlin-Bicêtre, France.
7. Department of Biology, MIT, 31 Ames Street, Cambridge, MA 02139, USA
8. These authors contributed equally
Antidepressant restores youthful flexibility to aging inhibitory neurons

Neural plasticity and arbor growth decline with age, study in mice shows.

David Orenstein | Picower Institute for Learning and Memory
August 20, 2018

A new study provides fresh evidence that the decline in the capacity of brain cells to change (called “plasticity”), rather than a decline in total cell number, may underlie some of the sensory and cognitive declines associated with normal brain aging. Scientists at MIT’s Picower Institute for Learning and memory show that inhibitory interneurons in the visual cortex of mice remain just as abundant during aging, but their arbors become simplified and they become much less structurally dynamic and flexible.

In their experiments published online in the Journal of Neuroscience they also show that they could restore a significant degree of lost plasticity to the cells by treating mice with the commonly used antidepressant medication fluoxetine, also known as Prozac.

“Despite common belief, loss of neurons due to cell death is quite limited during normal aging and unlikely to account for age-related functional impairments,” write the scientists, including lead author Ronen Eavri, a postdoc at the Picower Institute, and corresponding author Elly Nedivi, a professor of biology and brain and cognitive sciences. “Rather it seems that structural alterations in neuronal morphology and synaptic connections are features most consistently correlated with brain age, and may be considered as the potential physical basis for the age-related decline.”

Nedivi and co-author Mark Bear, the Picower Professor of Neuroscience, are affiliated with MIT’s Aging Brain Initiative, a multidisciplinary effort to understand how aging affects the brain and sometimes makes the brain vulnerable to disease and decline.

In the study the researchers focused on the aging of inhibitory interneurons which is less well-understood than that of excitatory neurons, but potentially more crucial to plasticity. Plasticity, in turn, is key to enabling learning and memory and in maintaining sensory acuity. In this study, while they focused on the visual cortex, the plasticity they measured is believed to be important elsewhere in the brain as well.

The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months. (Mice are mature by 3 months and live for about 2 years, and 18-month-old mice are already considered quite old.) In previous work, Nedivi’s lab has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But in the new paper, the team shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months.

But the study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.

Retraction and inflexibility with age

Instead the changes the team observed were in the growth and performance of the interneurons. For example, under the two-photon microscope the team tracked the growth of dendrites, which are the tree-like structures on which a neuron receives input from other neurons. At 3 months of age mice showed a balance of growth and retraction, consistent with dynamic remodeling. But between 3 and 18 months they saw that dendrites progressively simplified, exhibiting fewer branches, suggesting that new growth was rare while retraction was common.

In addition, they saw a precipitous drop in an index of dynamism. At 3 months virtually all interneurons were above a crucial index value of 0.35, but by 6 months only half were, by 9 months barely any were, and by 18 months none were.

Bear’s lab tested a specific form of plasticity that underlies visual recognition memory in the visual cortex, where neurons respond more potently to stimuli they were exposed to previously. Their measurements showed that in 3-month-old mice “stimulus-selective response potentiation” (SRP) was indeed robust, but its decline went hand in hand with the decline in structural plasticity, so that it was was significantly lessened by 6 months and barely evident by 9 months.

Fountain of fluoxetine

While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. In prior work Nedivi’s lab had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.

To test this, they put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in 6-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.

The researchers also saw similar effects on SRP. Here, too, the effects ran parallel to the structural plasticity decline. Treating mice for just three months did not restore SRP, but treating mice for six months did so significantly.

“Here we show that fluoxetine can also ameliorate the age-related decline in structural and functional plasticity of visual cortex neurons,” the researchers write. The study, they noted, adds to prior research in humans showing a potential cognitive benefit for the drug.

“Our finding that fluoxetine treatment in aging mice can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration,” they continued.

In addition to Eavri, Nedivi and Bear, the paper’s other authors are Jason Shepherd, Christina Welsh, and Genevieve Flanders.

The National Institutes of Health, the American Federation for Aging Research, the Ellison Medical Fondation, and the Machiah Foundation supported the research.

Altering Neuronal Activity at Will

Graduate student Nicole Aponte Santiago uses fruit flies to probe the relationship between the many nerve cells passing signals from the brain to the muscles.

Raleigh McElvery
August 16, 2018

As fifth year graduate student Nicole Aponte Santiago puts it, she has the power to alter nerve cell activity in fruit flies at will. She’ll also tell you point-blank that flies are her favorite model organism, although that wasn’t always the case. They have many well-cited advantages — they procreate often, have short lifespans, and many of their genes overlap with humans while being easy to manipulate. But Aponte suggests an additional reason for her change of heart. She suspects “looking them straight in the eye” so frequently ultimately convinced her, using their physical features to deduce their genetic makeup, and from there investigate the relationship between the many nerve cells (neurons) passing signals from the brain to the muscles.

Aponte credits her initial interest in science to her father, a dentist who used to take her for long walks on the beaches of Puerto Rico where she grew up. Together the two would examine the minute details of the coastal world around them, discussing various phenomena. Where does sand come from? How do the tides form? What types of shelled critters reside at the sea’s edge?

She first set foot on MIT’s campus in January of 2011 while a sophomore at the University of Puerto Rico, Río Piedras, attending the weeklong Quantitative Methods Workshop to learn various quantitative tools and programming languages. In June of that same year she returned, this time for 10 weeks as an MIT Summer Research Program (MSRP) student. Aponte joined Hazel Sive’s lab at the Whitehead Institute for Biomedical Research, gathering preliminary data for a paper that was eventually published in Fluids and Barriers of the CNS.

“I was introduced to basic science through both programs,” Aponte says. “Discovery-based research lays the foundation for translational research later on, and it allows you to address questions that no one has answered before. If you’re lucky enough to witness those discoveries, for a few moments you’re the only person in the world with that knowledge, and I find that prospect incredibly exciting.”

As a first-year graduate student in 2013, she tested out several different labs and ultimately chose Troy Littleton’s lab located in the Picower Institute for Learning and Memory. She was drawn to the friendly and collaborative atmosphere, as well as the breadth of potential projects — from those related to the central nervous system and Huntington’s disease to the connections between nerve cells.

Aponte investigates how nerve cells interface with one another and neighboring muscles, focusing on the tiny gap between neurons and muscles, known as neuromuscular junctions. Multiple neurons can form connections with the same neuron or muscle cell, but which connections remain depends on competition between the nerve cells and how often those connections are used. New ones are constantly being shaped as we learn new things and acquire new experiences, while less frequently used connections get trimmed away. Aponte wants to understand how neurons that talk to the same muscle cell interact with each other, determining which lines of communication will be strengthened and which will be pruned away.

When Aponte first began in the Littleton lab five years ago, she screened scores of unique drivers — segments of DNA that “drive” gene expression in specific cells during a specific time in development. She hoped to find drivers that could trigger the expression of a green fluorescent protein (GFP) at the neuromuscular junction, and ultimately identified two different drivers which caused GFP expression in two separate neurons targeting the same muscle near the back of the fly. These drivers would allow her to control the expression of not just GFP, but also other genes that she connected to the drivers, including genes that can increase or decrease the activity of the neurons, or even kill them.

“It’s really from there that my entire project was born,” Aponte recalls.

Each morning, she heads to the fly room to collect virgin flies and determine which ones to breed in order to generate progeny with her desired genetic makeup. She can infer something about the flies’ chromosomes based on their physical characteristics, which allow her to keep track of their genes and create offspring with the GFP marker in her neurons of interest. As is true for most things these days, there’s an app for that. As we chat, she takes out her phone and begins to scroll through images that illustrate which genetic markers engender which physical characteristics. The Tubby mutation makes the flies rather fat, whereas Bar makes their eyes noticeably skinnier.

“In the same way that I can express GFP in just one of the two motor neurons to distinguish between them and monitor their shape,” she says, “I can also express genes that increase or decrease activity of one of the neurons, or even kill one of the neurons. In this way, I create an input imbalance by increasing or decreasing the activity in either neuron to see how that affects the activity of its partner neuron.”

In the afternoons, sometimes she uses molecular fluorophores to highlight the changes in structure of these neurons. She also assesses the activity in the muscles by poking them with electrodes and observing what happens when the muscle receives more or less input from one of the motor neurons. Additionally, she explores what happens to surrounding muscles when these inputs are modified

Recently, she’s stumbled upon a rather baffling phenomenon. When she kills one of the two neurons (let’s call it “Neuron A”) the other one, Neuron B, remains relatively unchanged. Yet, when she kills Neuron B, Neuron A shrinks. This suggests Neuron B may be sending a “permissive” signal to Neuron A, telling it to contact the muscle. She is monitoring the neuromuscular junction over time to determine if Neuron A will ever reach the muscle, and if the muscle will change over time in response.

“This has never been seen before, so right now I’m trying to identify the smaller neuron to see if it is functional,” she says. “I’m going to look at it during different stages of development to see if it starts and stops communicating with the muscle at some point.”

This endeavor will constitute her main focus over the next few months. After she graduates, Aponte intends to pursue an academic postdoc studying flies, despite developing an allergy to her subjects over the past year. (She’s since acquired a face mask that keeps dust and fly particles away.) “I’m just excited to see where the research will take me,” she says. Now that’s dedication.

Photo credit: Raleigh McElvery
What separates the strong from weak among connections in the brain

MIT study finds synapses develop strength with calcium, maturation.

David Orenstein | Picower Institute for Learning and Memory
July 10, 2018

To work at all, the nervous system needs its cells, or neurons, to connect and converse in a language of electrical impulses and chemical neurotransmitters. For the brain to be able to learn and adapt, it needs the connections, called synapses, to be able to strengthen or weaken. A new study by neuroscientists at MIT’s Picower Institute for Learning and Memory helps to explain why strong synapses are stronger, and how they get that way.

By pinpointing the properties of synaptic strength and how they develop, the study could help scientists better understand how synapses might be made weaker or stronger. Deficiencies in synaptic development and change, or plasticity, have a role in many brain diseases such as autism or intellectual disability, says senior author Troy Littleton, the Menicon Professor of Neuroscience in MIT’s Department of Biology.

“The importance of our study is figuring out what are the molecular features of really strong synapses versus their weaker neighbors and how can we think about ways to convert really weak synapses to stronger ones,” Littleton says.

In the study, published in eLife, Littleton’s team used innovative imaging techniques in the model organism of the fruitfly Drosophila to focus on “active zones,” which are fundamental components of synapses. The scientists identified specific characteristics associated with a strong connection on both sides of the synapse.

The team, led by postdoc Yulia Akbergenova and graduate student Karen Cunningham, also studied how strong synapses and active zones grow, showing that those that have the longest to mature during a few critical days of development become the strongest.

Sources of strength

The team’s study began with a survey of active zones at a junction where a motor neuron links up a muscle. About 300 active zones were present at the neuromuscular junction, which gave the team a rich diversity of synapses to examine.

Typically, neuroscientists study neural connectivity by measuring the electrical currents in the postsynaptic neuron after activation of the presynaptic one, but such measures represent an accumulation of transmission from many active zones. In the new study, the team was able to directly visualize the activity of individual active zones with unprecedented resolution using “optical quantal imaging.”

“We optimized a genetically encoded calcium sensor to position it near active zones,” Akbergenova says. “This allows us to directly visualize activity at individual release sites. Now we can resolve synaptic transmission at the level of each individual release site.”

Across many flies, the team consistently found that only about 10 percent of the active zones at the junction were strong, as measured by a high likelihood that they would release the neurostransmitter glutamate when the presynaptic neuron was stimulated. About 70 percent of the active zones were much weaker, barely ever releasing glutamate given the same stimulation. Another 20 percent were inactive. The strongest active zones had release probabilities as much as 50 times greater than weak ones.

“The initial observation was that the synapse made by the exact same neuron are not of the same strength,” Littleton says. “So then the question became, what is it about an individual synapse that determines if it is strong or weak?”

The team ran several tests. In one experiment, for instance, they showed that it’s not their supply of synaptic vesicles, the containers that hold their cache of glutamate. When they stimulated the presynaptic neurons over and over, the strong ones retained their comparatively higher likelihood of release, even as their synaptic vesicle supply was intermixed with those from nearby active zones.

The presynaptic tests that showed a difference had to do with measuring the rate of calcium influx into the active zone and the number of channels through which that calcium reaches the active zone. Calcium ions stimulate the vesicles to fuse to the membrane of the presynaptic cell, allowing neurotransmitters to be released.

At strong synapses, active zones had a significantly greater influx of calcium ions through a notably higher abundance of calcium ion channels than weak synapse active zones did.

Stronger active zones also had more of a protein called Bruchpilot that helps to cluster calcium channels at synapses.

Meanwhile, on the postsynaptic side, when the scientists measured the presence and distribution of glutamate receptor subtypes they found a dramatic difference at strong synapses. In the typical weak synapse, GluRIIA and GluRIIB containing receptors were pretty much mixed together. But in strong synapses, the A subtype, which is more sensitive, crowded into the center while B was pushed out to the periphery, as if to maximize the receiving cell’s ability to pick up that robust signal.

Might through maturity

With evidence of what makes strong synapses strong, the scientists then sought to determine how they get that way and why there aren’t more of them. To do that, they studied each active zone from the beginning of development to several days afterward.

“This is the first time people have been able to follow a single active zone over many days of development from the time it is born in the early larvae through its maturation as the animal grows,” Littleton says.

They did this “intravital imaging” by briefly anesthetizing the larvae every day to check for changes in the active zones. Using engineered GluRIIA and GluRIIB receptor proteins that glow different colors they could tell when a strong synapse had formed by the characteristic concentration of A and marginalization of B.

One phenomenon they noticed was that active zone formation accelerated with each passing day of development. This turned out to be important because their main finding was that synapse strength was related to active zone age. As synapses matured over several days, they accumulated more calcium channels and BRP, meaning that they became stronger with maturity, but only a few had the chance to do it for several days.

The researchers also wanted to know whether activity affected the rate of maturation, as would be expected in a nervous system that must be responsive to an animal’s experience. By tinkering with different genes that modulate the degree of neuronal firing, they found that active zones indeed matured faster with more activity and slower when activity was reduced.

“These results provide a high resolution molecular and developmental understanding of several major factors underlying the extreme heterogeneity in release strength that exists across a population of active zones,” Cunningham says. “Since the cohort of proteins that make up the presynaptic active zone in flies is largely conserved in mammalian synapses, these results will provide valuable insight into how active zone release heterogeneity might arise in more complex neural systems.”

In addition to Littleton, Akbergenova, and Cunningham, the paper’s other authors are MIT postdoc Shirley Weiss-Sharabi and former MIT postdoc Yao Zhang.

The National Institutes of Health supported the research.

Stem cell-derived zika model suggests mechanisms underlying microcephaly
Nicole Giese Rura | Whitehead Institute
June 21, 2018

Cambridge, MA  – Scientists turn to model organisms, like mice and yeast, to investigate the biology underlying emerging diseases. But for the Zika virus, the lack of a good model hampered this type of research. Now, a team of researchers in the laboratory of Whitehead Institute Founding Member Rudolf Jaenisch has devised a way to model Zika and other neural diseases in a dish. Their work is described this week in the journal PNAS.

The Zika virus was identified in 1947 in Uganda, but a 2013 epidemic in French Guinea first brought it to the public’s attention. As the disease spread throughout the Americas and the Caribbean in 2014, abnormalities, such as microcephaly in newborns, were increasingly reported when mothers were infected during their first trimester. Scientists’ efforts to better understand the virus and its mechanisms quickly hit a snag: mice, which are often used to model disease pathology, are not vulnerable to the Zika virus unless their innate immune defenses are knocked out. Additionally, neural diseases, such as those that cause microcephaly, affect cells that reside deep in the brain, and they cannot be easily accessed for observation and manipulation.

In order to circumvent these challenges and to model Zika in the lab, the researchers turned to induced pluripotent stem cells (iPSCs)–adult cells that have been pushed back to a embryonic stem cell-like state. iPSCs can in turn be nudged to mature into almost any cell type in the body. In previous work, Julien Muffat and Yun Li, former postdoctoral researchers in the Jaenisch lab, were the first to use iPSCs to create microglia, the specialized immune cells that maintain the brain and spinal cord and care for them after injury.

In the current work, Muffat and Li teamed up with Attya Omer, also a graduate student in the Jaenisch lab, and Lee Gehrke’s lab at MIT to study the effect of the Zika virus on iPSC-derived versions of three neural cell types critical during human fetal brain development: microglia, neural progenitors, and astrocytes. Whether the Zika virus can infect these cells and how well the cells can clear the virus could provide insight into why the virus can cause birth defects like microcephaly. Using their model, the team determined that after being infected with a strain derived from the initial Ugandan Zika virus, microglia can survive and can continue to harbor the virus. This is important because in a developing embryo, microglia move from the yolk sac to the developing brain very early in gestation. The study shows that, like their in vivo counterparts, iPSC-derived microglia could invade the immature neural tissue of a brain organoid, and pre-infected microglia could transfer the virus to the organoids. According to Muffat, this suggests that if microglial precursors are infected before their journey, they could shuttle the Zika virus to the developing brain and infect the neural progenitors residing there.

Neural progenitor cells, which during gestation produce the neurons and glia that constitute the majority of the human brain, are particularly vulnerable to the Zika virus and die when infected. To better understand why these cells are so susceptible, the team compared how the Zika virus and the closely related dengue virus affect the neural progenitor cells. Dengue, which does not cause birth defects like microcephaly, triggers a strong cellular immune response, called interferon, in the neural progenitors, which enables the progenitor cells to efficiently fight and clear the dengue virus. In sharp contrast, when exposed to the Zika virus, neural progenitors mount little if any interferon immune defense. Pretreating the neural progenitor cells with interferon before exposure to the Zika virus impedes the virus’s progression and proliferation, and reduces cell death. These results suggest that therapeutically altering interferon levels could prevent some of the more dire effects of Zika infection on the neural progenitor cells.

According to the team, using iPSC-derived cells has great potential for modeling Zika virus as well as many other diseases that affect the central nervous system.

This work was supported by the European Leukodystrophy Association, the Brain & Behavior Research Foundation, the Simons Foundation (SFARI 204106), the International Rett Syndrome Foundation, Howard Hughes Medical Institute, the National Institutes of Health (NIH grants HD 045022, R37-CA084198, AI100190), the ELA Foundation, the Emerald Foundation, and Biogen. Jaenisch is a cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics.

Written by Nicole Giese Rura
***
Rudolf Jaenisch’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.
 ***
Full citation:
“Human Induced Pluripotent Stem Cell-derived Glial Cells and Neural Progenitors Display Divergent Responses to Zika and Dengue Infections”
PNAS, online June 18, 2018.
Julien Muffat (1,8), Yun Li (1,8), Attya Omer (1,8), Ann Durbin (3,4,5), Irene Bosch (3,4,5), Grisilda Bakiasi (6), Edward Richards (7), Aaron Meyer (7), Lee Gehrke (3,4,5), Rudolf Jaenisch (1,2).
1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA
3. IMES, Massachusetts Institute of Technology, Cambridge MA 02139, USA
4. Department of Microbiology and Immunobiology, Harvard Medical School, Boston 02115, USA
5. Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA
6. Bryn Mawr College, Bryn Mawr, PA
7. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
8. These authors contributed equally
Study: Fragile X syndrome neurons can be restored

Whitehead Institute researchers are using a modified CRISPR/Cas9-guided activation strategy to investigate the most frequent cause of intellectual disability in males.

Nicole Giese Rura | Whitehead Institute
February 15, 2018

Fragile X syndrome is the most frequent cause of intellectual disability in males, affecting one out of every 3,600 boys born. The syndrome can also cause autistic traits, such as social and communication deficits, as well as attention problems and hyperactivity. Currently, there is no cure for this disorder.

Fragile X syndrome is caused by mutations in the FMR1 gene on the X chromosome, which prevent the gene’s expression. This absence of the FMR1-encoded protein during brain development has been shown to cause the overexcitability in neurons associated with the syndrome. Now, for the first time, researchers at Whitehead Institute have restored activity to the fragile X syndrome gene in affected neurons using a modified CRISPR/Cas9 system they developed that removes the methylation — the molecular tags that keep the mutant gene shut off — suggesting that this method may prove to be a useful paradigm for targeting diseases caused by abnormal methylation.

Research by the lab of Whitehead Institute for Biomedical Research Founding Member Rudolf Jaenisch, which is described online this week in the journal Cell, is the first direct evidence that removing the methylation from a specific segment within the FMR1 locus can reactivate the gene and rescue fragile X syndrome neurons.

The FMR1 gene sequence includes a series of three nucleotide (CGG) repeats, and the length of these repeats determines whether or not a person will develop fragile X syndrome: A normal version of the gene contains anywhere from 5 to 55 CGG repeats, versions with 56 to 200 repeats are considered to be at a higher risk of generating some of the syndrome’s symptoms, and those versions with more than 200 repeats will produce fragile X syndrome.

Until now, the mechanism linking the excessive repeats in FMR1 to fragile X syndrome was not well-understood. But Shawn Liu, a postdoc in Jaenisch’s lab and first author of the Cell study, and others thought that the methylation blanketing those nucleotide repeats might play an important role in shutting down the gene’s expression.

In order to test this hypothesis, Liu removed the methylation tags from the FMR1 repeats using a CRISPR/Cas9-based technique he recently developed with Hao Wu, a postdoc in the Jaenisch lab. This technique can either add or delete methylation tags from specific stretches of DNA. Removal of the tags revived the FMR1 gene’s expression to the level of the normal gene.

“These results are quite surprising — this work produced almost a full restoration of wild type expression levels of the FMR1 gene,” says Jaenisch, whose primary affiliation is with Whitehead Institute, where his laboratory is located and his research is conducted. He is also a professor of biology at MIT. “Often when scientists test therapeutic interventions, they only achieve partial restoration, so these results are substantial,” he says.

The reactivated FMR1 gene rescues neurons derived from fragile X syndrome induced pluripotent stem (iPS) cells, reversing the abnormal electrical activity associated with the syndrome. When rescued neurons were engrafted into the brains of mice, the FMR1 gene remained active in the neurons for at least three months, suggesting that the corrected methylation may be sustainable in the animal.

“We showed that this disorder is reversible at the neuron level,” says Liu. “When we removed methylation of CGG repeats in the neurons derived from fragile X syndrome iPS cells, we achieved full activation of FMR1.”

The CRISPR/Cas-9-based technique may also prove useful for other diseases caused by abnormal methylation including facioscapulohumeral muscular dystrophy and imprinting diseases.

“This work validates the approach of targeting the methylation on genes, and it will be a paradigm for scientists to follow this approach for other diseases,” says Jaenisch.

This work was supported by the National Institutes of Health, the Damon Runyon Cancer Foundation, the Rett Syndrome Research Trust, the Brain and Behavior Research Foundation, and the Helen Hay Whitney Foundation. Jaenisch is co-founder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics.

Reading and writing DNA

Department of Biology kicks off IAP seminar series with a lecture by synthetic-biology visionary George Church.

Raleigh McElvery | Department of Biology
January 31, 2018

Thanks to the invention of genome sequencing technology more than three decades ago, we can now read the genetic blueprint of virtually any organism. After the ability to read came the ability to edit — adding, subtracting, and eventually altering DNA wherever we saw fit. And yet, for George Church, a professor at Harvard Medical School, associate member of the Broad Institute, and founding core faculty and lead for synthetic biology at the Wyss Institute — who co-pioneered direct genome sequencing in 1984 — the ultimate goal is not just to read and edit, but also to write.

What if you could engineer a cell resistant to all viruses, even the ones it hadn’t yet encountered? What if you could grow your own liver in a pig to replace the faulty one you were born with? What if you could grow an entire brain in a dish? In his lecture on Jan. 24 — which opened the Department of Biology’s Independent Activities Period (IAP) seminar series, Biology at Transformative Frontiers — Church promised all this and more.

“We began by dividing the Biology IAP events into two tracks: one related to careers in academia and another equivalent track for industry,” says Jing-Ke Weng, assistant professor and IAP faculty coordinator for the department. “But then it became clear that George Church, Patrick Brown, and other speakers we hoped to invite blurred the boundaries between those two tracks. The Biology at Transformative Frontiers seminar series became about the interface of these trajectories, and how transferring technologies from lab bench to market is altering society as we know it.”

The seminar series is a staple in the Department of Biology’s IAP program, but during the past several years it has been oriented more toward quantitative biology. Weng recalls these talks as being relegated to the academic sphere, and wanted to show students that the lines between academia, industry, and scientific communication are actually quite porous.

“We chose George Church to kick off the series because he’s been in synthetic biology for a long time, and continues to have a successful academic career even while starting so many companies,” says Weng.

Church’s genomic sequencing methods inspired the Human Genome Project in 1984 and resulted in the first commercial genome sequence (the bacterium Helicobacter pylori) 10 years later. He also serves as the director of the Personal Genome Project, the “Wikipedia” of open-access human genomic data. Beyond these ventures, he’s known for his work on barcoding, DNA assembly from chips, genome editing, and stem cell engineering.

He’s also the same George Church who converted the book he co-authored with Ed Regis, “Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves,” into a four-letter code based on the four DNA nucleotides (A, T, C, and G), subsisted on nutrient broth from a lab vendor for an entire year, and dreams of eventually resurrecting woolly mammoths. He’s being featured in an upcoming Netflix Original documentary, so when he arrived at the Stata Center to give his lecture last week he was trailed by a camera crew.

According to Church, the transformative technologies that initially allowed us to read and edit DNA have grown exponentially in recent years with the invention of molecular multiplexing and CRISPR-Cas9 (think Moore’s Law but even more exaggerated). But there’s always room for improvement.

“There’s been a little obsession with CRISPR-Cas9s and other CRISPRs,” said Church. “Everybody is saying how great it is, but it’s important to say what’s wrong with it as well, because that tells us where we’re going next and how to improve on it.”

He outlined several of his own collaborations, including those aimed at devising more precise methods of genome editing, one resulting in 321 changes to the Escherichia coli genome — the largest change in any genome yet — rendering the bacterium resistant to all viruses, even those it had not yet come into contact with. The next step? Making similarly widespread changes in plants, animals, and eventually perhaps even human tissue. In fact, Church and his team have set their sights on combatting the global transplantation crisis with humanlike organs grown in animals.

“Since the dawn of transplantation as a medical practice, we’ve had to use either identical twins or rare matches that are very compatible immunologically, because we couldn’t engineer the donor or the recipient,” said Church.

Since it’s clearly unethical to engineer human donors, Church reasoned, why not engineer animals with compatible organs instead? Pigs, to be exact, since most of their organs are comparable in size and function to our own.

“This is an old dream; I didn’t originate it,” said Church. “It started about 20 years ago, and the pioneers of this field worked on it for a while, but dropped it largely because the number of changes to the genome were daunting, and there was a concern that the viruses all pigs make — retroviruses — would be released and infect the immunocompromised organ recipient.”

Church and his team successfully disrupted 62 of these retroviruses in pig cells back in 2015, and in 2017 they used these cells to generate living, healthy pigs. Today, the pigs are thriving and rearing piglets of their own. Church is also considering the prospect of growing augmented organs in pigs for human transplantation, perhaps designing pathogen-, cancer-, and age-resistant organs suitable for cryopreservation.

“Hopefully we’ll be doing nonhuman primate trials within a couple of years, and then almost immediately after that human trials,” he said.

Another possibility, rather than cultivating organs in animals for transplant, is to generate them in a dish. A subset of Church’s team is working on growing from scratch what is arguably the most complicated organ of all, the brain.

This requires differentiating multiple types of cells in the same dish so they can interact with each other to form the complex systems of communication characteristic of the human brain.

Early attempts at fashioning brain organoids often lacked capillaries to distribute oxygen and nutrients (roughly one capillary for each of the 86 billion neurons in the human brain). However, thanks to their new human transcription factor library, Church and colleagues have begun to generate the cell types necessary to create such capillaries, plus the scaffolding needed to promote the three-dimensional organization of these and additional brain structures. Church and his team have not only successfully integrated the structures with one another, but have also created an algorithm that spits out the list of molecular ingredients required to generate each cell type.

Church noted these de novo organoids are extremely useful in determining which genetic variants are responsible for certain diseases. For instance, you could sequence a patient’s genome and then create an entire organoid with the mutation in question to test whether it was the root cause of the condition.

“I’m still stunned by the breadth of projects and approaches that he’s running simultaneously,” says Emma Kowal, a second-year graduate student, member of Weng’s planning committee, and a former researcher in Church’s lab. “The seminar series is called Biology at Transformative Frontiers, and George is very much a visionary, so we thought it would be a great way to start things off.”

The four-part series also features Melissa Moore, chief scientific officer of the Moderna Therapeutics mRNA Research Platform, Jay Bradner, president of the Novartis Institutes for BioMedical Research, and Patrick Brown, CEO and founder of Impossible Foods.