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Revising the textbook on introns

Whitehead Institute researchers uncover a group of introns in yeast that possess surprising stability and function.

Nicole Davis | Whitehead Institute
January 16, 2019

A research team from Whitehead Institute has uncovered a surprising and previously unrecognized role for introns, the parts of genes that lack the instructions for making proteins and are typically cut away and rapidly destroyed. Through studies of baker’s yeast, the researchers identified a highly unusual group of introns that linger and accumulate, in their fully intact form, long after they have been freed from their neighboring sequences, which are called exons. Importantly, these persistent introns play a role in regulating yeast growth, particularly under stressful conditions.

The researchers, whose work appears online in the journal Nature, suggest that some introns also might accumulate and carry out functions in other organisms.

“This is the first time anyone has found a biological role for full-length, excised introns,” says senior author David Bartel, a member of the Whitehead Institute. “Our findings challenge the view of these introns as simply byproducts of gene expression, destined for rapid degradation.”

Imagine the DNA that makes up your genes as the raw footage of a movie. The exons are the scenes used in the final cut, whereas the introns are the outtakes — shots that are removed, or spliced out, and therefore not represented in the finished product.

Despite their second-class status, introns are known to play a variety of important roles. Yet these activities are primarily confined to the period prior to splicing — that is, before introns are separated from their nearby exons. After splicing, some introns can be whittled down and retained for other uses — part of a group of so-called “non-coding RNAs.” But by and large, introns have been thought to be relegated to the genome’s cutting room floor.

Bartel and his Whitehead Institute colleagues, including world-renowned yeast expert Gerald Fink, now add an astonishing new dimension to this view: Full-length introns — that is, those that have been cut out but remain otherwise intact — can persist and carry out useful biological functions. As reported in their Nature paper, the team discovered that these extraordinary introns are regulated by and function within the essential TORC1 growth signaling network, forming a previously unknown branch of this network that controls cell growth during periods of stress.

“Our initial reaction was: ‘This is really weird,’” recalls first author Jeffrey Morgan, a former graduate student in Bartel’s lab who is now a postdoc in Jared Rutter’s lab at the University of Utah. “We came across genes where the introns were much more abundant than the exons, which is the exact opposite of what you’d expect.”

The researchers identified a total of 34 of these unusually stable introns, representing 11 percent of all introns in the yeast, also known as Saccharomyces cerevisiae. Surprisingly, there are very few criteria that determine which introns will become stable introns. For example, the genetic sequences of the introns or the regions that surround them are of no significance. The only defining — and necessary — feature, the team found, is a structural one, and involves the precise shape the introns adopt as they are being excised from their neighboring exons. Excised introns typically form a lasso-shaped structure, known as a lariat. The length of the lasso’s handle appears to dictate whether an intron will be stabilized or not.

Remarkably, both yeast and introns have been studied for several decades. Yet until now, these unique introns went undetected. One reason, Bartel and his colleagues believe, is the conditions under which yeast are typically grown. Often, researchers study yeast that are growing very rapidly — so-called log-phase growth. That is because abnormalities are often easiest to detect when cells are multiplying quickly.

“Biologists have focused heavily on log-phase for very good reasons, but in the wild, yeast are very rarely in that condition, whether it’s because of limited nutrients or other stresses,” says Bartel, who is also professor of biology at MIT and a Howard Hughes Medical Institute investigator.

He and his colleagues decided to grow yeast under more stressful circumstances, and that is what ultimately led them to their discovery. Although their experiments were confined to yeast, the researchers believe it is possible other organisms may harbor this long-overlooked class of introns — and that similar approaches using less-often-studied conditions could help illuminate them.

“Right now, we can say it is happening in yeast, but we’d be surprised if this is the only organism in which it is happening,” Bartel says.

The research was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

School of Science honors postdocs and research staff with 2018 Infinite Kilometer Awards

Five winners are recognized for their outstanding contributions to colleagues, the school, and the Institute.

School of Science
December 25, 2018

The MIT School of Science has announced the 2018 winners of the Infinite Kilometer Award. The Infinite Kilometer Award was established in 2012 to highlight and reward the extraordinary work of the school’s postdocs and research staff.

Recipients of the award are exceptional contributors to their research programs. In many cases, they are also deeply committed to their local or global MIT community, and are frequently involved in mentoring and advising their junior colleagues, participating in the school’s educational programs, making contributions to the MIT Postdoctoral Association, or contributing to some other facet of the MIT community.

In addition to a monetary award, the honorees and their colleagues, friends, and family are invited to a celebratory reception in the spring semester.

The 2018 Infinite Kilometer winners are:

Matthew Golder, a National Institutes of Health Postdoctoral Fellow in the Department of Chemistry, nominated by Jeremiah Johnson, an associate professor of chemistry;

Robert Grant, manager of the crystallography lab in the Department of Biology, nominated by Michael Laub, a professor of biology;

Slawomir Gras, a research scientist on the LIGO project at the MIT Kavli Institute for Astrophysics and Space Research, nominated by Nergis Mavalvala, the Curtis and Kathleen Marble Professor of Astrophysics, and Matthew Evans, an associate professor of physics;

Yeong Shin Yim, a postdoc at the McGovern Institute for Brain Research, nominated by Gloria Choi, an assistant professor of brain and cognitive sciences; and

Yong Zhao, a postdoc in the Laboratory for Nuclear Science, nominated by Iain Stewart, a professor of physics.

The School of Science is also currently accepting nominations for its Infinite Mile Awards. All School of Science employees are eligible, and nominations are due by Feb. 15, 2019. The Infinite Mile Awards will be presented with the Infinite Kilometer Awards this spring.

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.

A tough case cracked
Greta Friar | Whitehead Institute
December 17, 2018

CAMBRIDGE, Mass. — For hundreds of millions of years, plants thrived in the Earth’s oceans, safe from harsh conditions found on land, such as drought and UV radiation. Then, roughly 450 million years ago, plants found a way to make the move to land: They evolved spores—small reproductive cells—and eventually pollen grains with tough, protective outer walls that could withstand the harsh conditions in the terrestrial environment until they could germinate and grow into a plant or fertilize an ovule. A key component of the walls is sporopollenin, a durable polymer — a large molecule made up of many small subunits — that is absent in algae but remains ubiquitous in all land plants to this day.

Understanding the molecular composition of polymers found in nature is a fundamental pursuit of biology, with a long history tracing back to the early days of elucidating DNA and protein structures. However, the very toughness that makes sporopollenin so important for all land plants also makes it tough for researchers to study. It is extremely inert, resistant to reacting with other chemicals, including the ones researchers typically use to determine the structures of other plant biopolymers, such as polysaccharides, lignin, and natural rubber. Consequently, scientists have struggled for decades to figure out exactly what the sporopollenin polymer is made of. Now, in an article published in the journal Nature Plants on December 17, Whitehead Institute Member Jing-Ke Weng and first author and Weng lab postdoc Fu-Shuang Li, together with collaborators Professor Mei Hong and graduate student Pyae Phyo from the Massachusetts Institute of Technology (MIT) Department of Chemistry, have used innovative chemical degradation methods and state-of-the-art nuclear magnetic resonance (NMR) spectroscopy to determine the chemical structure of sporopollenin.

“Plants could not have colonized the land if they had not developed a way to withstand harsh netbet online sports bettingenvironments,” says Weng, who is also an assistant professor of biology at MIT. “Sporopollenin helped make the terrestrial ecosystem as we know it possible.”

In addition to solving a longstanding puzzle in plant chemistry, identifying the structure of sporopollenin opens the door for its potential use in a host of other applications. Sporopollenin’s inertness is a desirable attribute to replicate in the development of, for example, medical implants such as stents, which prop open clogged arteries, to prevent negative interactions between the device and the body. It could also be a good model for durable paints and coatings, such as those used on boats, where its inertness would prevent reactions with compounds in the water and so protect the ship’s hull from environmental degradation.

Finding the shape and composition of sporopollenin was not a simple task. The first challenge was getting enough of the material to study, as pollen amounts that can be collected from most plants are minute. However, pollen from the pitch pine, Pinus rigida, is sold in bulk in China as a topping for rice cakes, so Weng used an unconventional sample collection method: He asked his parents in China to ship him copious quantities of pitch pine pollen.

A common approach to determine a complex plant polymer’s structure is to dissolve it in solutions with specific chemical compounds that will break it apart into smaller and smaller pieces from which the complete structure can be deduced. But since sporopollenin is inert and does not react with the researchers’ usual cadre of chemicals, figuring out how to break down the molecule was a key challenge.

In order to crack this problem — and make the sporopollenin dissolve more easily — Li used a specially designed grinder known as the high-energy ball mill to physically shear the tiny pollen coat into even finer pieces. Then he began testing different chemical mixtures to find ones that could break apart the sporopollenin polymer into more accessible fragments. The big breakthrough came when he tried a chemical degradation process called thioacidolysis, an acid catalyzed reaction with a pinch of a special sulfur-containing compound. This allowed Li to consistently break down 50% of the total sporopollenin polymer into small pieces, with the structure of each of these pieces resolved one by one.

To help complete the puzzle, the researchers collaborated with Mei Hong’s group in MIT’s Department of Chemistry and used magic-angle-spinning solid-state NMR spectroscopy, which can determine the chemical structures of insoluble compounds by having them interact with magnetic fields. This investigation narrowed the possible structures for sporopollenin. Combined with more chemical degradation tests to verify certain possibilities and eliminate others, it ultimately led to the complete structure.

With the structure of sporopollenin in hand, the researchers were then able to identify aspects of this unique polymer that make it such a good protective wall for spores and pollen.

A key finding was that sporopollenin molecules contain two types of cross-linkages, esters and acetals, that act like chemical clips, binding the chains of the molecule together. Other known plant polymers have only one main type of cross-link, and this unique characteristic likely provides the extreme chemical inertness of sporopollenin. Ester bonds are resistant to mildly acidic conditions, while acetals are resistant to basic conditions, meaning the molecule won’t break down in either type of environment in the wild or in the lab.

Other components of sporopollenin that the researchers found include multiple molecules known to provide UV protection, as well as fatty acids, which are water resistant and may protect spores and pollen from drought or other changes in water availability.

The researchers are now looking for differences in sporopollenin between species. Pine is not a flowering plant, but the majority of plants of interest to agriculture and medicine are, so Weng and Li are investigating how sporopollenin may have changed with the evolution of the flowering plants.

“Since I was a student, inspired by the magnificent discovery of the structure of DNA, I have been driven to discover the fundamental forms of things in nature,” Weng says. “It has been so rewarding to illuminate the structure of this crucial biopolymer in plants.”

This work was supported by the Pew Scholar Program in the Biomedical Sciences and the Searle Scholars Program, and the U.S. Department of Energy (# DE-SC0001090).

***

Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

***

Full citation:
“The molecular structure of plant sporopollenin”
Nature Plants, December 17, 2018, DOI: 10.1038/s41477-018-0330-7
Fu-Shuang Li (1), Pyae Phyo (2), Joseph Jacobowitz (1,3), Mei Hong (2), Jing-Ke Weng (1,3)
1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, United States.
2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Engineering “capture compounds” to probe cell growth

Researchers develop a method to investigate how bacteria respond to starvation and to identify which proteins bind to what they call the “magic spot” — ppGpp.

Raleigh McElvery | Department of Biology
December 17, 2018

In 1969, scientist Michael Cashel was analyzing the compounds produced by starved bacteria when he noticed two spots appearing on his chromatogram as if by magic. Today, we know one of these “magic spots,” as researchers call them, as guanosine tetraphosphate, or ppGpp for short. We also understand that it is a signaling molecule present in virtually all bacteria, helping tune cell growth and size based on nutrient availability.

And yet, despite decades of study, precisely how ppGpp regulates bacterial growth has remained rather mysterious. Delving further requires a more comprehensive list of the molecules that ppGpp binds to exert its effects.

Now, collaborators from MIT’s departments of Biology and Chemistry have developed a method to do just that, and used their new approach to pinpoint over 50 ppGpp targets in Escherichia coli — roughly half which had not been identified previously. Many of these targets are enzymes required to produce nucleotides, the building blocks of DNA and RNA. During times when the bacteria do not have enough nutrients to grow and divide normally, the researchers propose that ppGpp prevents these enzymes from creating new nucleotides from scratch, helping cells enter a dormant state.

“With small molecules or metabolites like ppGpp, it’s been difficult historically to determine which proteins they bind,” says Michael Laub, a professor of biology, a Howard Hughes Medical Institute investigator, and the senior author of the study. “This has been an intractable problem that’s held the field back for some time, but our new approach allows you to nail down the likely targets in a matter of weeks.”

Postdoc Boyuan Wang is the first author of the study, which appeares in Nature Chemical Biology on Dec. 17.

Since ppGpp was discovered nearly 50 years ago, it has been shown to suppress DNA replication, transcription, translation, and various metabolic pathways. It puts the brakes on cell growth and allows bacteria to persist in the face of starvation, stress, and antibiotics. Its influence over numerous regulatory processes has remained somewhat of a mystery, however — after all, it doesn’t just modulate a single pathway but coordinates multiple operations simultaneously to orchestrate a mass shutdown of the cell.

In order to discern which proteins ppGpp binds to effect such widespread change, the researchers built what they call “capture compounds” that contain ppGpp, allowing them to fish out its targets from bacterial extracts. These compounds included a photoreactive crosslinker that latched tightly onto the proteins of interest in the presence of light, and a biotin handle that helped the scientists pull out the proteins to identify them. Most importantly, they were joined to ppGpp in such a way that they wouldn’t interfere with its ability to bind to its targets. This method is more efficient and accurate compared to more traditional means of distinguishing ppGpp targets, which are far more arduous and lack sensitivity.

“Our approach solves these problems because you’re no longer required to do such labor-intensive protocols in order to identify ppGpp targets — and it works even in bacteria beyond E. coli,” says Wang. “Although ppGpp is common among many bacterial species, it seems to exert its effects through different mechanisms, which complicates things. Our capture compounds provide a way to unravel this diversity, and in short order.”

Although the 56 ppGpp targets Wang identified in his screen control a myriad of cellular processes, he homed in on the enzyme PurF — which initiates the biosynthesis of purine nucleotides bearing adenine and guanine bases, also known as A and G.

When bacteria are stressed netbet online sports bettingor starved, they enter a dormant state to survive. But simply curbing translation and transcription is not enough; nucleotides are still being generated and will build up if their synthesis is not put on pause. Cells can build nucleotides in one of two ways: either by salvaging existing materials or starting completely from scratch. PurF kicks off the first step in the latter process leading to the A and G nucleotides. However, when ppGpp binds to PurF, it causes the enzyme to change its shape, which prevents it from doing its job, thus reducing nucleotide production in the cell.

“This is the first time that an enzyme involved in that specific pathway or function has been identified as a ppGpp target,” Wang says. “If you limit the consumption of nucleotides but not their production, the nucleotide pool is going to explode, which isn’t good for the cell. So we’ve shown that ppGpp actually addresses this problem as well.”

In addition to PurF and other enzymes required for nucleotide production, the researchers noticed that ppGpp also binds to many GTPase enzymes involved in translation. This could indicate a failsafe mechanism slowing down translation by striking multiple, similar enzymes in an almost redundant manner in the face of starvation.

As Wang continues to refine his method, he aims to increase its specificity and ensure his capture compounds bind to the exact same proteins they would inside a live cell. He also hopes to screen for ppGpp binding proteins in other bacteria, including pathogens that rely on ppGpp to survive within their hosts and propagate conditions like tuberculosis.

“This is an exciting chemical approach to better understand the function of a long-studied conserved signaling molecule in bacteria,” says Jue Wang, professor of bacteriology at the University of Wisconsin at Madison, who was not involved with the study. “Their findings and techniques are highly relevant to many other bacteria, and will greatly improve knowledge of how bacteria use this critical signaling molecule to mediate everything from surviving in the human gut to causing disease.”

Adds Laub: “We are still discovering new nucleotide-based signaling molecules in bacteria even today, and every single one of them could eventually be derivatized in a similar way to identify their binding partners.”

This research was supported by a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and a grant from the National Institutes of Health.

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.

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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 netbet online sports bettingsite 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.

Friends of biology gather to recognize achievements
December 10, 2018

Members of the MIT biology community came together on Nov. 7, 2018, to celebrate the department’s myriad accomplishments at the inaugural Friends of Biology Reception at the Hyatt Regency Hotel along the Charles River. Current students, alumni, faculty, staff, parents, supporters, and industry representatives gathered to recognize the remarkable achievements of the Department of Biology, and to honor the many generous supporters who make it all possible. Guests had the opportunity to mingle with faculty and students, who discussed topics including the importance of basic science and research, and applications of this work in cancer, genetics, immunology, and microbiology.

Alan Grossman, Praecis Professor of Biology, and head of the Department of Biology, opened the program portion of the evening by thanking attendees for their crucial role in enabling innovative biology research at MIT. He highlighted recent progress and accomplishments by biology alumni, students, and faculty.

“It was wonderful to bring many of our friends and alumni together for this event and to be able to share with them some of the exciting work going on in our department,” Grossman said, reflecting on the Friends of Biology gathering. “I’m delighted that we were able to showcase talks by some of our graduate students. I think our core mission of excellence in research, teaching, and service resonated with everyone, and we are tremendously grateful to all those who support our mission.”

Five biology graduate students then spoke about their career paths and described the research taking place in each of their diverse laboratories.

Rebecca Silberman described the work of the Amon lab, which examines basic biological processes such as cell growth and division, and how errors in these processes lead to disease.

Conor McClune shared that in the Laub lab studies are revealing how cells process information and regulate their own behavior.

Steve Sando of the Horvitz lab noted their progress in using nematodes to learn more about fundamental human biology and the development of disease.

Jose Orozco discussed research from the Sabatini lab at the Whitehead Institute, which focuses on growth and metabolism regulation in mammals.

Frances Diehl, a student researcher in the Vander Heiden lab, concluded the evening by detailing her team’s efforts to better understand cell metabolism and its role in diseases like cancer.

Daniel E. Griffin, the development officer for the department and organizer of the event, said the reception had registrants from five countries and 13 states and received such a positive response that it will be held annually as a signature event.

Faculty members in attendance included Robert Horvitz, David H. Koch Professor of Biology; Robert Sauer, Salvador E. Luria Professor of Biology; Amy Keating, professor of biology and biological engineering; Rebecca Lamason, Robert A. Swanson Career Development Assistant Professor; and Gene-Wei Li, assistant professor of biology, as well as Michael Sipser, dean of the School of Science.

Professor of Biology Dennis Kim bids farewell to the department

Since his arrival in 2005, Kim has contributed to the MIT community through his exceptional research and commitment to undergraduate education and advising.

Raleigh McElvery
December 6, 2018

Dennis Kim, the Ivan R. Cottrell Professor of Immunology, is leaving the MIT Department of Biology at the end of this semester to serve as the Chief of the Division of Infectious Diseases at Boston Children’s Hospital.

Kim has been a member of the department for 13 years, serving as the Biology Undergraduate Officer for the past four years and Chair of the Committee on Prehealth Advising for the past six.

“Dennis has made remarkable contributions to our community, including outstanding research and as our Undergraduate Officer,” says Department Head Alan Grossman. “His teaching is exceptional, and his service to the department and MIT has been invaluable. He will be greatly missed.”

Kim became enthralled by basic science as an undergraduate at the University of California, Berkeley. There — in the cold and in the dark — he performed light- and temperature-sensitive experiments under Ken Sauer to understand the mechanism of water oxidation and oxygen evolution in plant photosynthesis. He traces his commitment to undergraduate education back to these formative experiences in the lab. Although he was already planning to attend graduate school, a run-in with a car on his motor scooter and a broken femur ignited an additional passion: human health.

As an MD-PhD student at Harvard Medical School, Kim had the opportunity to explore both avenues. There, under the mentorship of Chris Walsh, he studied enzymatic reaction mechanisms in bacterial cell wall synthesis, cultivating an interest in infectious disease that he pursued during his clinical training.

Later, as a postdoctoral fellow at Massachusetts General Hospital, Kim and his advisor Fred Ausubel, with help from Gary Ruvkun, worked to understand host-microbe interactions with a focus on innate immunity in a simple animal host, the roundworm Caenorhabditis elegans. Together, Kim and colleagues carried out a forward genetic analysis of host defense against pathogen infection in C. elegans, which eventually laid the foundation for his work as an independent investigator.

Kim arrived at the MIT Department of Biology in 2005, and since then has felt continually inspired and supported by the community. For all thirteen years, his lab has been located next door to Nobel Laureate H. Robert Horvitz, who also works in C. elegans.

“Dennis has been my nearest neighbor and closest colleague at MIT for many years,” Horvitz says. “He is a spectacular scientist whose curiosity and demand for rigor have led him to make striking discoveries repeatedly. Our labs have interacted daily, and Dennis has been a wonderful mentor to and role model for the members of my research group. Dennis netbet sports bettinghas been a great friend. I will miss his wisdom and his cheer.”

“It has been an incredible opportunity and privilege to work in the Department of Biology,” Kim says. “MIT Biology promotes freedom to pursue curiosity-driven research, with phenomenal students and fantastic colleagues. And I got to set up my ‘worm’ lab next door to Bob Horvitz’s lab. It’s hard to imagine how anyone could be more fortunate!”

Over the years — and “thanks to some really terrific graduate students” — Kim has discovered molecular pathways governing how C. elegans recognizes and responds to its microbial environment, with a more recent emphasis on understanding how bacterial metabolites can influence host animal behavior. Questions like these are particularly well-suited to C. elegans, given its simplicity, defined nervous system structure, and well-established genetics.

“A picture has started to emerge that reveals how immunity, stress, and physiology are integrated to promote survival of the host organism,” Kim says. “Our findings have implications for understanding how interactions with microbes can affect the physiology of more complex hosts as well.”

In addition to his achievements in the lab, Kim has been a passionate advocate for undergraduate education. He’s been the Department of Biology’s Undergraduate Officer for four years, working at the departmental and institutional levels to develop and implement initiatives related to campus life, educational programs, and the curriculum. He has also chaired the Committee on Prehealth Advising for the past six years and worked to help MIT undergraduates gain admission to competitive medical schools.

“I really enjoyed working in Professor Kim’s lab because he was accessible and always willing to answer questions,” says Sonika Reddy, a former undergraduate researcher in Kim’s lab and currently a student at New York Medical College. “His mentorship was an invaluable part of my education at MIT. He helped me navigate the biology major and decide which courses to take. He also helped me decide what I wanted to do in the future and was an amazing resource as I applied to medical school.”

“The students are really remarkable here at MIT,” Kim says. “Being the Undergraduate Officer and prehealth advisor has allowed me to engage with them on a regular basis and work to improve educational and advising programs based on their feedback. These roles have meant a lot to me over the years.”

During his time at MIT, Kim developed a new subject, 7.26/7.66 (Molecular Basis of Infectious Disease), which provides an overview of viruses, bacterial pathogenesis, and parasites to advanced undergraduates and graduate students, respectively.

Former student Eta Atolia, now an MD-PhD candidate at UCLA-Caltech, says this was one of her favorite classes as an undergraduate. “I already enjoyed the topic, but the elegant way Professor Kim told the story of bacteria, toxins, antibiotics, and drug resistance really made me appreciate the field,” she says. “He also mentored me during the MD-PhD application process. He was very approachable and always available to meet and provide feedback. He introduced me to microbiology, and is a major reason why I am pursuing an MD-PhD now.”

Kim also recently worked with the Biology Undergraduate Committee and colleagues in the Department of Chemistry to develop the new 5-7 (Chemistry and Biology) major.

“I am delighted that there are a number of students who are very enthusiastic about the major and are well-prepared to work at the exciting interface of these traditional disciplines,” he says.

Kim has served at the Institutional level, chairing the Committee on Curricula and serving on the Committee on Nominations, and maintained a part-time clinical instructor appointment at Harvard Medical School.

“When we interviewed Dennis, we were amazed by the versatility and breadth of his research interests,” says Chris Kaiser, the department head who initially hired Kim. “He moves effortlessly from genome wide approaches to incisive pointed tests of mechanism, with interests ranging from innate immunity to neurological sensing and avoidance of bad environments. While running a highly successful basic research lab at MIT, he maintained an enormously important clinical footing in infectious disease at Massachusetts General Hospital. He also developed or redesigned at least five undergraduate classes and energetically ran the Biology Undergraduate program. I will miss having him as an immediate colleague.”

Of his numerous pursuits, Kim has found working with the undergraduates and graduate students to be the most rewarding.

“I’ve really enjoyed watching the scientists and physicians of tomorrow grow and mature,” he says. “To me, being an undergraduate advisor and faculty member requires having an open door for students, and these mentor-mentee relationships have been incredibly gratifying.”

As Kim transitions to his new position as Chief of the Division of Infectious Diseases at Boston Children’s Hospital, it will take three people to fill his shoes as Undergraduate Officer and Prehealth Advisor. Adam Martin and Catherine Drennan have agreed to share the role of Undergraduate Officer, and Matthew Vander Heiden will co-chair the Committee on Prehealth Advising.

“Dennis has left a significant legacy at MIT as the Undergraduate Officer,” Martin says. “He worked with the Department of Chemistry to get the 5-7 major approved, and revised our lab curriculum to increase the flexibility in Course 7. Dennis is really committed to his trainees; I often see him talking with students and postdocs in his lab and he has trained some wonderful and creative students.”

What will Kim miss the most about MIT? That goes without saying: his students.

Decoding patterns and meaning in biological data

Senior Anna Sappington found her perfect balance of “innovative computer science and innovative biology” as a member of the team mapping every cell in the human body.

Raleigh McElvery
December 5, 2018

When Anna Sappington was six years old, her parents gave her a black and white composition notebook. Together, they began jotting down observations to identify the patterns in their wooded backyard near the Chesapeake Bay. How would the harsh winters or the early springs affect the blooming trees? How many bluebirds nested each season and how many eggs would they lay? When would the cicada population cycle peak? Her father, the environmental scientist, taught her to sift through data to uncover the trends. Her mother, the journalist, gave her the words to describe her findings.

But it wasn’t until Sappington competed in the Intel International Science and Engineering Fair her junior year of high school that she probed one tiny niche of the natural world more keenly than she ever had before: the physiology of the water flea. Specifically, she investigated the developmental changes that these minute creatures experienced after being exposed to the antimicrobial compound triclosan, present in many soaps and toothpastes. She was surprised to learn that it required only a low concentration of triclosan (0.5 ppm) to cause developmental defects.

She’d been familiar with the concept of DNA since middle school, but her fellow science fair finalists were delving beyond their observations and into the letters of the genetic code. This gave her a new impetus: to understand how triclosan worked at the level of the genome and epigenome to engender the physical deformities she observed under the microscope. She just needed the proper tools, so she made some calls.

Environmental geneticist and water flea aficionado John Colbourne took an interest, and invited her to his lab at University of Birmingham in the U.K. the following summer so she could learn basic lab techniques. Although her friends and classmates didn’t quite get why she needed to travel to an entirely different country to study an organism they’d never heard of, as she puts it, she had burning scientific questions that needed answers.

“That was the experience that really turned me on to genomics,” says Sappington, now a senior and 6-7 (Computer Science and Molecular Biology) major. “I was finally getting the tools to dig through large amounts of data, using code to find patterns and meaning. I wanted to keep asking ‘why?’ and ‘how?’ all the way down to the molecular level.”

The summer before her freshman year of college, Sappington asked these questions in humans for the time as an intern at the National Human Genome Research Institute (NHGRI). There, she helped create a computational pipeline to identify the genomic changes associated with heightened risk of cardiovascular disease.

She enrolled at MIT the following fall, because she wanted to be around people from every scientific subfield imaginable. When she arrived, the joint major in computer science and biology was still relatively new.

“While a few of the required classes did meld the two, many of them offered training in each separately,” she says. “That approach really appealed to me because I was hoping to develop both skill sets independently. I wanted netbet sports betting appto learn code and write algorithms that could be applied to any field, and I also loved understanding the biological mechanisms behind different diseases and viruses.”

Before she’d even officially declared her major, Sappington was already running experiments in Sangeeta Bhatia’s lab. There, at the Koch Institute, she studied the effects of HPV infection on gene expression in liver cells. Sappington’s main role was data analysis, striving to determine which genes were amplified in response to disease.Despite their obvious differences, Sappington found the two areas to be more similar than she had initially anticipated. In her Introduction to Algorithms class, she leveraged an arsenal of algorithms with certain outputs, conditions, and run times to decode her problem sets. In Organic Chemistry, she deployed a list of foundational reactions to solve synthesis questions on her exams. “In each case, you have to combine your understanding of these fundamental rules and come up with a creative solution to decipher an unknown,” she says.

One year later, Sappington moved to Aviv Regev’s lab at the Broad Institute. There, she learned computational techniques for decoding protein interaction networks. After a year, she began working on an international project called the Human Cell Atlas as a member of the Regev and the Sanes lab collaboration.

“The overarching mission is to create a reference map of all human cells,” Sappington explains. “We want to add a layer of functional understanding on top of what we know about the genome, to understand how different cell types differ and how they interact to impact disease. This kind of endeavor has never been undertaken on such a large scale before, so it’s incredibly exciting.”

Even within a single cell type — say, retinal cells — there are about six main cell categories, each of which splinter into as many as 40 subtypes with distinct molecular profiles and roles.

Beyond the biological challenges that go along with trying to distinguish all these cell types, there are numerous computational hurdles as well. Sappington enjoys these the most — grappling with how best to analyze the gene expression of a single cell separated from its tissue of origin.

“Since you’re only working with single cells rather than entire groups of cells from a tissue, the data that you get are much more sparse,” she says. “You have to sequence a lot of individual cells and build up lots of statistical power before you can be confident that a given cell is expressing specific genes. Coming up with models to determine what constitutes a cell type — and map cell types between time points or between species — are broad problems in computer science that we’re now applying to this very specific type of data.”

Although she’s been at the Broad since her sophomore year, Sappington has supplemented her MIT research experiences with summer studies elsewhere: another stint at the NHGRI and an Amgen Scholars fellowship in Japan. She’s especially excited because her first co-authored paper will soon be published. As she puts it, she’s finally found her ideal balance of “innovative computer science and innovative biology.”

But Sappington’s time at MIT has been defined by more than just lab work. She is the co-president of the Biology Undergraduate Student Association, which serves as a liaison between the Department of Biology and the wider community. She’s also a member of MedLinks, a volunteer at the Massachusetts General Hospital Department of Radiology, former managing director of TechX, and a performer for several campus dance troupes. In 2018, Sappington earned the prestigious Barry Goldwater Scholarship Award, alongside fellow 6-7 major Meena Chakraborty.

She was recently awarded the Marshall Scholarship, which will fund her master’s degrees in machine learning at University College London and oncology at the University of Cambridge beginning in the fall of 2019. After two years, she plans to start her MD-PhD. That way, she can become a practicing physician without having to give up her computer science research.

Her advice to prospective students: “When you get to MIT, just explore. Try different academic disciplines, different extracurriculars, and talk to as many people as you can. The campus is full of passionate individuals in every field imaginable, whether that’s computer science or political science.”

Posted 12.5.18