Author: mantulin

School of Science welcomes 10 professors

New faculty join the departments of Biology, Brain and Cognitive Sciences, Chemistry, Physics, Mathematics, and Earth, Atmospheric and Planetary Sciences.

School of Science
September 21, 2018

The MIT School of Science recently welcomed 10 new professors in the departments of Biology Brain and Cognitive Sciences, Chemistry, Physics, Mathematics, and Earth, Atmospheric and Planetary Sciences.

Tristan Collins conducts research at the intersection of geometric analysis, partial differential equations, and algebraic geometry. In joint work with Valentino Tosatti, Collins described the singularity formation of the Ricci flow on Kahler manifolds in terms of algebraic data. In recent work with Gabor Szekelyhidi, he gave a necessary and sufficient algebraic condition for existence of Ricci-flat metrics, which play an important role in string theory and mathematical physics. This result lead to the discovery of infinitely many new Einstein metrics on the 5-dimensional sphere. With Shing-Tung Yau and Adam Jacob, Collins is currently studying the relationship between categorical stability conditions and existence of solutions to differential equations arising from mirror symmetry.

Collins earned his BS in mathematics at the University of British Columbia in 2009, after which he completed his PhD in mathematics at Columbia University in 2014 under the direction of Duong H. Phong. Following a four-year appointment as a Benjamin Peirce Assistant Professor at Harvard University, Collins joins MIT as an assistant professor in the Department of Mathematics.

Julien de Wit develops and applies new techniques to study exoplanets, their atmospheres, and their interactions with their stars. While a graduate student in the Sara Seager group at MIT, he developed innovative analysis techniques to map exoplanet atmospheres, studied the radiative and tidal planet-star interactions in eccentric planetary systems, and constrained the atmospheric properties and mass of exoplanets solely from transmission spectroscopy. He plays a critical role in the TRAPPIST/SPECULOOS project, headed by Université of Liège, leading the atmospheric characterization of the newly discovered TRAPPIST-1 planets, for which he has already obtained significant results with the Hubble Space Telescope. De Wit’s efforts are now also focused on expanding the SPECULOOS network of telescopes in the northern hemisphere to continue the search for new potentially habitable TRAPPIST-1-like systems.

De Wit earned a BEng in physics and mechanics from the Université de Liège in Belgium in 2008, an MS in aeronautic engineering and an MRes in astrophysics, planetology, and space sciences from the Institut Supérieur de l’Aéronautique et de l’Espace at the Université de Toulouse, France in 2010; he returned to the Université de Liège for an MS in aerospace engineering, completed in 2011. After finishing his PhD in planetary sciences in 2014 and a postdoc at MIT, both under the direction of Sara Seager, he joins the MIT faculty in the Department of Earth, Atmospheric and Planetary Sciences as an assistant professor.

Ila Fiete uses computational and theoretical tools to better understand the dynamical mechanisms and coding strategies that underlie computation in the brain, with a focus on elucidating how plasticity and development shape networks to perform computation and why information is encoded the way that it is. Her recent focus is on error control in neural codes, rules for synaptic plasticity that enable neural circuit organization, and questions at the nexus of information and dynamics in neural systems, such as understand how coding and statistics fundamentally constrain dynamics and vice-versa.

After earning a BS in mathematics and physics at the University of Michigan, Fiete obtained her PhD in 2004 at Harvard University in the Department of Physics. While holding an appointment at the Kavli Institute for Theoretical Physics at the University of California, Santa Barbara from 2004 to 2006, she was also a visiting member of the Center for Theoretical Biophysics at the University of California at San Diego. Fiete subsequently spent two years at Caltech as a Broad Fellow in brain circuitry, and in 2008 joined the faculty of the University of Texas at Austin. She joins the MIT faculty in the Department of Brain and Cognitive Sciences as an associate professor with tenure.

Ankur Jain explores the biology of RNA aggregation. Several genetic neuromuscular disorders, such as myotonic dystrophy and amyotrophic lateral sclerosis, are caused by expansions of nucleotide repeats in their cognate disease genes. Such repeats cause the transcribed RNA to form pathogenic clumps or aggregates. Jain uses a variety of biophysical approaches to understand how the RNA aggregates form, and how they can be disrupted to restore normal cell function. Jain will also study the role of RNA-DNA interactions in chromatin organization, investigating whether the RNA transcribed from telomeres (the protective repetitive sequences that cap the ends of chromosomes) undergoes the phase separation that characterizes repeat expansion diseases.

Jain completed a bachelor’s of technology degree in biotechnology and biochemical engineering at the Indian Institute of Technology Kharagpur, India in 2007, followed by a PhD in biophysics and computational biology at the University of Illinois at Urbana-Champaign under the direction of Taekjip Ha in 2013. After a postdoc at the University of California at San Francisco, he joins the MIT faculty in the Department of Biology as an assistant professor with an appointment as a member of the Whitehead Institute for Biomedical Research.

Kiyoshi Masui works to understand fundamental physics and the evolution of the universe through observations of the large-scale structure — the distribution of matter on scales much larger than galaxies. He works principally with radio-wavelength surveys to develop new observational methods such as hydrogen intensity mapping and fast radio bursts. Masui has shown that such observations will ultimately permit precise measurements of properties of the early and late universe and enable sensitive searches for primordial gravitational waves. To this end, he is working with a new generation of rapid-survey digital radio telescopes that have no moving parts and rely on signal processing software running on large computer clusters to focus and steer, including work on the Canadian Hydrogen Intensity Mapping Experiment (CHIME).

Masui obtained a BSCE in engineering physics at Queen’s University, Canada in 2008 and a PhD in physics at the University of Toronto in 2013 under the direction of Ue-Li Pen. After postdoctoral appointments at the University of British Columbia as the Canadian Institute for Advanced Research Global Scholar and the Canadian Institute for Theoretical Astrophysics National Fellow, Masui joins the MIT faculty in the Department of Physics as an assistant professor.

Phiala Shanahan studies theoretical nuclear and particle physics, in particular the structure and interactions of hadrons and nuclei from the fundamental (quark and gluon) degrees of freedom encoded in the Standard Model of particle physics. Shanahan’s recent work has focused on the role of gluons, the force carriers of the strong interactions described by quantum chromodynamics (QCD), in hadron and nuclear structure by using analytic tools and high-performance supercomputing. She recently achieved the first calculation of the gluon structure of light nuclei, making predictions that will be testable in new experiments proposed at Jefferson National Accelerator Facility and at the planned Electron-Ion Collider. She has also undertaken extensive studies of the role of strange quarks in the proton and light nuclei that sharpen theory predictions for dark matter cross-sections in direct detection experiments. To overcome computational limitations in QCD calculations for hadrons and in particular for nuclei, Shanahan is pursuing a program to integrate modern machine learning techniques in computational nuclear physics studies.

Shanahan obtained her BS in 2012 and her PhD in 2015, both in physics, from the University of Adelaide. She completed postdoctoral work at MIT in 2017, then held a joint position as an assistant professor at the College of William and Mary and senior staff scientist at the Thomas Jefferson National Accelerator Facility until 2018. She returns to MIT in the Department of Physics as an assistant professor.

Nike Sun works in probability theory at the interface of statistical physics and computation. Her research focuses in particular on phase transitions in average-case (randomized) formulations of classical computational problems. Her joint work with Jian Ding and Allan Sly establishes the satisfiability threshold of random k-SAT for large k, and relatedly the independence ratio of random regular graphs of large degree. Both are long-standing open problems where heuristic methods of statistical physics yield detailed conjectures, but few rigorous techniques exist. More recently she has been investigating phase transitions of dense graph models.

Sun completed BA mathematics and MA statistics degrees at Harvard in 2009, and an MASt in mathematics at Cambridge in 2010. She received her PhD in statistics from Stanford University in 2014 under the supervision of Amir Dembo. She held a Schramm fellowship at Microsoft New England and MIT Mathematics in 2014-2015 and a Simons postdoctoral fellowship at the University of California at Berkeley in 2016, and joined the Berkeley Department of Statistics as an assistant professor in 2016. She returns to the MIT Department of Mathematics as an associate professor with tenure.

Alison Wendlandt focuses on the development of selective, catalytic reactions using the tools of organic and organometallic synthesis and physical organic chemistry. Mechanistic study plays a central role in the development of these new transformations. Her projects involve the design of new catalysts and catalytic transformations, identification of important applications for selective catalytic processes, and elucidation of new mechanistic principles to expand powerful existing catalytic reaction manifolds.

Wendlandt received a BS in chemistry and biological chemistry from the University of Chicago in 2007, an MS in chemistry from Yale University in 2009, and a PhD in chemistry from the University of Wisconsin at Madison in 2015 under the direction of Shannon S. Stahl. Following an NIH Ruth L. Krichstein Postdoctoral Fellowship at Harvard University, Wendlandt joins the MIT faculty in the Department of Chemistry as an assistant professor.

Chengyang Xu specializes in higher-dimensional algebraic geometry, an area that involves classifying algebraic varieties, primarily through the minimal model program (MMP). MMP was introduced by Fields Medalist S. Mori in the early 1980s to make advances in higher dimensional birational geometry. The MMP was further developed by Hacon and McKernan in the mid-2000s, so that the MMP could be applied to other questions. Collaborating with Hacon, Xu expanded the MMP to varieties of certain conditions, such as those of characteristic p, and, with Hacon and McKernan, proved a fundamental conjecture on the MMP, generating a great deal of follow-up activity. In collaboration with Chi Li, Xu proved a conjecture of Gang Tian concerning higher-dimensional Fano varieties, a significant achievement. In a series of papers with different collaborators, he successfully applied MMP to singularities.

Xu received his BS in 2002 and MS in 2004 in mathematics from Peking University, and completed his PhD at Princeton University under János Kollár in 2008. He came to MIT as a CLE Moore Instructor in 2008-2011, and was subsequently appointed assistant professor at the University of Utah. He returned to Peking University as a research fellow at the Beijing International Center of Mathematical Research in 2012, and was promoted to professor in 2013. Xu joins the MIT faculty as a full professor in the Department of Mathematics.

Zhiwei Yun’s research is at the crossroads between algebraic geometry, number theory, and representation theory. He studies geometric structures aiming at solving problems in representation theory and number theory, especially those in the Langlands program. While he was a CLE Moore Instructor at MIT, he started to develop the theory of rigid automorphic forms, and used it to answer an open question of J-P Serre on motives, which also led to a major result on the inverse Galois problem in number theory. More recently, in his joint work with Wei Zhang, they give geometric interpretation of higher derivatives of automorphic L- functions in terms of intersection numbers, which sheds new light on the geometric analogue of the Birch and Swinnerton-Dyer conjecture.

Yun earned his BS at Peking University in 2004, after which he completed his PhD at Princeton University in 2009 under the direction of Robert MacPherson. After appointments at the Institute for Advanced Study and as a CLE Moore Instructor at MIT, he held faculty appointments at Stanford and Yale. He returned to the MIT Department of Mathematics as a full professor in the spring of 2018.

Detangling DNA replication

Researchers identify an essential protein that helps enzymes relax overtwisted DNA so each strand can be copied during cell division.

Raleigh McElvery | Department of Biology
September 18, 2018

DNA is a lengthy molecule — approximately 1,000-fold longer than the cell in which it resides — so it can’t be jammed in haphazardly. Rather, it must be neatly organized so proteins involved in critical processes can access the information contained in its nucleotide bases. Think of the double helix like a pair of shoe laces twisted together, coiled upon themselves again and again to make the molecule even more compact.

However, when it comes time for cell division, this supercoiled nature makes it difficult for proteins involved in DNA replication to access the strands, separate them, and copy them so one DNA molecule can become two.

Replication begins at specific regions of the chromosome where specialized proteins separate the two strands, pulling apart the double helix as you would the two shoe laces. However, this local separation actually tangles the rest of the molecule further, and without intervention creates a buildup of tension, stalling replication. Enter the enzymes known as topoisomerases, which travel ahead of the strands as they are being peeled apart, snipping them, untwisting them, and then rejoining them to relieve the tension that arises from supercoiling.

These topoisomerases are generally thought to be sufficient to allow replication to proceed. However, a team of researchers from MIT and the Duke University School of Medicine suggests the enzymes may require guidance from additional proteins, which recognize the shape characteristic of overtwisted DNA.

“We’ve known for a long time that topoisomerases are necessary for replication, but it’s never been clear if they were sufficient on their own,” says Michael Laub, an MIT professor of biology, Howard Hughes Medical Institute Investigator, and senior author of the study. “This is the first paper to identify a protein in bacteria, or eukaryotes, that is required to localize topoisomerases ahead of replication forks and to help them do what they need to do there.”

Postdoc Monica Guo ’07 and former graduate student Diane Haakonsen PhD ’16 are co-first authors of the study, which appeared online in the journal Cell on Sept. 13.

Necessary but not sufficient

Although it’s well established that topoisomerases are crucial to DNA replication, it has now becoming clear that we know relatively little about the mechanisms regulating their activity, including where and when they act to relieve supercoiling.

These enzymes fall into two groups, type I and type II, depending on how many strands of DNA they cut. The researchers focused on type II topoisomerases found in a common species of freshwater bacteria, Caulobacter crescentus. Type II topoisomerases in bacteria are of particular interest because a number of antibiotics target them in order to prevent DNA replication, treating a wide variety of microbial infections, including tuberculosis. Without topoisomerases, the bacteria can’t grow. Since these bacterial enzymes are unique, poisons directed at them won’t harm human topoisomerases.

For a long time, type II topoisomerases were generally assumed adequate on their own to manage the overtwisted supercoils that arise during replication. Although researchers working in E. coli and other, higher organisms have pinpointed additional proteins that can activate or repress these enzymes, none of these proteins were required for replication.

Such findings hinted that there might be similar interactions taking place in other organisms. In order to understand the protein factors involved in compacting Caulobacter DNA — regulating topoisomerase activity specifically — the researchers screened their bacteria for proteins that bound tightly to supercoiled DNA. From there, they honed in on one protein, GapR, which they observed was essential for DNA replication. In bacteria missing GapR, the DNA became overtwisted, replication slowed, and the bacteria eventually died.

Surprisingly, the researchers found that GapR recognized the structure of overtwisted DNA rather than specific nucleotide sequences.

“The vast majority of DNA-binding proteins localize to specific locations of the genome by recognizing a specific set of bases,” Laub says. “But GapR basically pays no attention to the actual underlying sequence — just the shape of overtwisted DNA, which uniquely arises in front of replication forks and transcription machinery.”

The crystal structure of the protein bound to DNA, solved by Duke’s Maria Schumacher, revealed that GapR recognizes the backbone of DNA (rather than the bases), forming a snug clamp that encircles the overtwisted DNA. However, when the DNA is relaxed in its standard form, it no longer fits inside the clamp. This might signify that GapR sits on DNA only at positions where topoisomerase is needed.

An exciting milestone

Although GapR appears to be required for DNA replication, it’s still not clear precisely how this protein promotes topoisomerase function to relieve supercoiling.

“In the absence of any other proteins, GapR is able to help type II topoisomerases remove positive supercoils faster, but we still don’t quite know how,” Guo says. “One idea is that GapR interacts with topoisomerases, recognizing the overtwisted DNA and recruiting the topoisomerases. Another possibility is that GapR is essentially grabbing onto the DNA and limiting the movement of the positive supercoils, so topoisomerases can target and eliminate them more quickly.”

Anthony Maxwell, a professor of biological chemistry at the John Innes Centre who was not involved with the study, says the buildup of DNA supercoils is a key problem in both bacterial replication and transcription.

“Identifying GapR and its potential role in controlling supercoiling in vivo is an exciting milestone in understanding the control of DNA topology in bacteria,” he says. “Further work will be required to show how exactly these proteins cooperate to maintain bacterial genomic integrity.”

According to Guo, the study provides insight into a fundamental process — DNA replication — and the ways topoisomerases are regulated, which could extend to eukaryotes.

“This was the first demonstration that a topoisomerase activator is required for DNA replication,” she says. “Although there’s no GapR homolog in higher organisms, there could be similar proteins that recognize the shape of the DNA and aid or position topoisomerases.”

This could open up a new field of drug research, she says, targeting activators like GapR to increase the efficacy of existing topoisomerase poisons to treat conditions like respiratory and urinary tract infections. After all, many topoisomerase inhibitors have become less effective due to antibiotic resistance. But only time will tell; there is still much to learn in order to untangle the complex process of DNA replication, along with its many twists and turns.

The research was funded by NIH grants, the HHMI International Predoctoral Fellowship, and the Jane Coffin Childs Memorial Fellowship.

New perspectives at the bench

Three MIT postdocs earn competitive Howard Hughes Medical Institute fellowships that support diversity in the sciences.

David Orenstein | Erika Reinfeld | Lisa Girard | Picower Institute for Learning and Memory
September 12, 2018

In recognition of their exceptional potential to be leaders in the life sciences, three MIT postdocs at the Koch, Picower, and Whitehead institutes at MIT are among 15 young researchers to earn Hanna Gray Fellowships from the Howard Hughes Medical Institute (HHMI), the Chevy Chase, Maryland-based organization has announced.

The early-career awards are given to individuals around the U.S. who are from racial, gender, ethnic, and other groups underrepresented in the life sciences. The fellowships will support their work with up to $1.4 million in funding over eight years, enough to last well into a tenure track position after they complete their postdoctoral studies.

“This program will help us retain the most diverse talent in science,” HHMI President Erin O’Shea said in the announcement. “We feel it’s critically important in academia to have exceptional people from all walks of life, all cultures, and all backgrounds — people who can inspire the next generation of scientists.”

MIT’s three Hanna Gray Fellows are Matheus Victor, who works in the lab of Li-Huei Tsai in the Picower Institute for Learning and Memory; Quinton Smith, who works in Sangeeta Bhatia’s lab at the Koch Institute for Integrative Cancer Research; and Jarrett Smith, who works in the David Bartel Lab at the Whitehead Institute for Biomedical Research.

Jarrett Smith

Jarrett Smith was always interested in science, but no one in his family had ever received a PhD, making biology research feel like an unlikely career path for him. Nevertheless, he followed his passion, which led him to his PhD program at the Johns Hopkins University School of Medicine. Despite his strong academic performance, Smith began graduate school with doubts about his ability to become a scientist. His mentors were incredible teachers, he says, but their self-assuredness could be intimidating.

“They were absolutely my role models, but I didn’t think of them as having gone through what I was going through. In the first few years, I felt like I had a lot of catching up to do,” Smith says.

Now, as a postdoc in David Bartel’s lab at the Whitehead Institute, he studies how cells respond to stress. When a cell is exposed to environmental stressors such as heat, UV radiation, or viral infection, proteins and RNAs in the cell may clump together into dense aggregates called stress granules. The exact function of stress granules and their potential role in disease are unknown, so Smith is investigating changes in the cell linked to their formation. His findings could shed light on a potential role for stress granules in cancer, infection, and neurodegenerative disease.

“I’m grateful for the support that the fellowship will provide during the formative years of my career,” Smith says. “This kind of opportunity gives you the confidence to set ambitious research goals and find out what you can accomplish.”

Quinton Smith

Quinton Smith fell in love with regenerative medicine the summer after his sophomore year of college. Working on an epidemiological study at the University of New Mexico Cancer Research Facility in his hometown of Albuquerque, Smith found himself extracting DNA from hundreds of mouthwash samples in order to answer overarching questions about the biological and behavioral factors that contribute to cancer.

The experience left him with a strong appreciation for the complexities of human disease, and an even stronger desire to translate his knowledge into better interventions for patients. To this end, he completed his PhD at Johns Hopkins University, exploring a variety of engineering techniques to control and probe the differentiation of pluripotent stem cells. In 2017 he joined the laboratory of Sangeeta Bhatia, the John J. and Dorothy Wilson Professor at MIT’s Institute for Medical Engineering and Science and Electrical Engineering and Computer Science and director of the Marble Center for Cancer Nanomedicine.

By then, the lab had already demonstrated success developing implantable “mini-livers” able to engraft and respond to regenerative stimuli in mice with damaged livers. However, the design is incomplete and Smith wants to incorporate a biliary tree to guide hepato-secreted bile acids that aid in the breakdown of fats but pose as a potential toxin to these therapeutic grafts. He is working to build such a tree with an unexpected tool — microfluidic vessels, forged by biomaterial-encapsulated acupuncture needles that, once removed, can be used to create a network of biliary-lined tunnels through which bile can flow.

The ability to bolster cutting-edge research is but one benefit of Smith’s HHMI award. He and Bhatia praise the seeds the program plants within the academic environment, providing much-needed visibility that achievements in STEM are, and will continue to be, driven by scientists from all walks of life.

“I think this program is directing a shift in what a researcher looks like, offering a motivating exposure to the next generation of students who have the potential to impact science regardless of their background,” Smith says. “This is an incredible and humbling opportunity to explore my passion for the promise of regenerative medicine, and to have the resources to tinker and extend my creativity around translational research.”

Matheus Victor

As a graduate student at Washington University in St. Louis, Matheus Victor, a native of Recife, Brazil, who came to Florida at the age of 15, learned that in the U.S., Latino immigrants are rare among scientific researchers. But there he was, pursuing his dreams to become a neuroscientist. The realization inspired him to lead a Latin American student group at WashU and to conduct outreach activities including creating bilingual curricula for local students.

“I was so privileged to be in a top tier graduate program pursuing my interest,” he said. “How many people get to pursue an interest? We live in a world where you have to earn money and you have to feed your family.”

Now he’s a new postdoc at MIT’s Picower Institute for Learning and Memory in the lab of Institute director and Picower Professor Li-Huei Tsai, with a prestigious fellowship that will support him as he embarks on two investigations of the role of specific cell types in brain aging and cognitive decline.

In one, he plans to turn human induced pluripotent stem cells into microglia, an immune cell of the nervous system increasingly implicated in Alzheimer’s disease, and implant them in the brains of mice where the original microglia have been removed. With this chimera model Victor can test how microglia with different genetic variations act in a mammalian brain to see how those variations might contribute to disease pathology.

In the other, he is interested in studying how inhibitory interneurons change in the aging brain. The neurons are of particular interest because they are the source of a crucial brain rhythm that is notably reduced in Alzheimer’s disease. Understanding more about how they function and falter could help explain that important change.

Exploring cancer metabolism

Matthew Vander Heiden seeks new cancer treatments that exploit tumor cells’ abnormal metabolism.

Anne Trafton | MIT News Office
August 28, 2018

Nearly 100 years ago, the German chemist Otto Warburg discovered that cancer cells metabolize nutrients differently than most normal cells. His discovery launched the field of cancer metabolism research, but interest in this area waned; by the 1970s most cancer scientists had shifted their focus to the genetic mutations that drive cancer development.

In the past decade or so, interest in cancer metabolism has resurged, and the first drugs that target cancer cells’ abnormal metabolism were approved to treat leukemia in 2017.

“Cancer metabolism is a very sophisticated field at this point,” says Matthew Vander Heiden, an associate professor of biology at MIT. “We have a lot better understanding of what nutrients cancer cells use and what determines how those nutrients are used. This has led to different ways to think about drugs.”

Vander Heiden, who is also a member of MIT’s Koch Institute for Integrative Cancer Research, is one of the people responsible for the recent surge in cancer metabolism research. As a graduate student and postdoc, he published some of the first studies of how cancer cells alter their metabolism, and now his lab at MIT is devoted to the topic.

“All of the time that I was in grad school and working as a postdoc, I was never working in a lab that was dedicated to studying metabolism. So my vision, if someone gave me a job, was to set up a lab that could really be built in a way that would allow us to ask questions about metabolism,” he says.

Metabolism and cancer

Vander Heiden grew up in a small town in Wisconsin, and unlike most of his high school classmates, he headed out of state for college, to the University of Chicago. He was interested in science, so decided on a pre-med track. A work-study job in a plant biology lab led him to discover that he also enjoyed doing research.

“At that point I already had this idea I was going to go to medical school, but then the idea of MD/PhD came up, and I ended up going down that path,” Vander Heiden says.

While in the MD/PhD program at the University of Chicago Medical School, he worked in the lab of Craig Thompson, now president of Memorial Sloan Kettering Cancer Center. At that time, Thompson was studying the biochemical regulation of apoptosis, the programmed cell death pathway. For his PhD thesis, Vander Heiden investigated the function of a protein called Bcl-x, which is a regulator of apoptosis found in the membranes of mitochondria — cell organelles responsible for generating energy.

“That project really got me thinking about how the mitochondria work and how metabolism works,” Vander Heiden recalls. “At the time, I came to the realization that we don’t understand cell metabolism anywhere near as well as we thought we did, and someone should really study this.”

After finishing his degrees, he spent five years doing clinical training, then decided to pursue research in cancer metabolism.

“Altered metabolism has been known about in cancer for 100 years, but few people were studying it,” Vander Heiden says. “The challenge was finding a lab that would allow me to study metabolism and cancer, which in 2004-2005 was not such an obvious thing to do.”

He ended up going to Harvard Medical School to work with Lewis Cantley, who studies signaling pathways in cells and was receptive to the idea of exploring cancer metabolism. There, Vander Heiden began studying an enzyme called pyruvate kinase M2 (PKM2), which is involved in regulation of glycolysis, a biochemical process that cells use to break down sugar for energy.

In 2008, Vander Heiden, Cantley, and others at Harvard Medical School reported that when cells shift between normal and Warburg (cancer-associated) metabolism, they start using PKM2 instead of PKM1, the enzyme that adult cells normally use for glycolysis. Cantley and Craig Thompson have since founded a company, Agios Pharmaceuticals, that is developing potential drugs that target PKM2, as well as other molecules involved in cancer metabolism.

While at Harvard, Vander Heiden also worked on a paper that contributed to the eventual development of drugs that target cancer cells with a mutation in the IDH gene. These drugs, the first modern FDA-approved cancer drugs that target metabolism, shut off an alternative pathway used by cancer cells with the IDH mutation.

New drug targets

In 2010, Vander Heiden became one of the first new faculty members hired after the creation of MIT’s Koch Institute, where he set up a lab focused on metabolism, particularly cancer metabolism.

His research has yielded many insights into the abnormal metabolism of cancer cells. In one study, together with other MIT researchers, he found that tumor cells turn on an alternative pathway that allows them to build lipids from the amino acid glutamine instead of the glucose that healthy cells normally use. He also found that altering the behavior of PKM2 to make it act more like PKM1 could stop tumor cell growth.

Studies such as these can offer insights that may help researchers to develop drugs that starve tumor cells of the nutrients they need, offering a new way to fight cancer, Vander Heiden says.

“If one wants to develop drugs that target metabolism, one really needs to focus on the context in which it’s happening, which is the environment of the cell plus the genetics of the cell,” he says. “That is what defines the sensitivity to drugs.”

Tissue architecture affects chromosome segregation

Biologists discover that the environment surrounding a cell plays an integral role in its ability to accurately segregate its chromosomes.

Ashley Junger | Koch Institute
August 24, 2018

All growth and reproduction relies on a cell’s ability to replicate its chromosomes and produce accurate copies of itself. Every step of this process takes place within that cell.

Based on this observation, scientists have studied the replication and segregation of chromosomes as a phenomenon exclusively internal to the cell. They traditionally rely on warm nutritional cultures that promote growth but bear little resemblance to the cell’s external surroundings while in its natural environment.

New research by a group of MIT biologists reveals that this long-held assumption is incorrect. In a paper published this week, they describe how some types of cells rely on signals from surrounding tissue in order to maintain chromosome stability and segregate accurately.

Kristin Knouse, a fellow at the Whitehead Institute, is the lead author of the paper, which was published online in the journal Cell on Aug. 23. Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research, is the senior author.

“The main takeaway from this paper is that we must study cells in their native tissues to really understand their biology,” Amon says. “Results obtained from cell lines that have evolved to divide on plastic dishes do not paint the whole picture.”

When cells replicate, the newly duplicated chromosomes line up within the cell and cellular structures pull one copy to each side. The cell then divides down the middle, separating one copy of each chromosome into each new daughter cell.

At least, that’s how it’s supposed to work. In reality, there are sometimes errors in the process of separating chromosomes into daughter cells, known as chromosome mis-segregation. Some errors simply result in damage to the DNA. Other errors can result in the chromosomes being unevenly divided between daughter cells, a condition called aneuploidy.

These errors are almost always harmful to cell development and can be fatal. In developing embryos, aneuploidy can cause miscarriages or developmental disorders such as Down syndrome. In adults, chromosome instability is seen in a large number of cancers.

To study these errors, scientists have historically removed cells from their surrounding tissue and placed them into easily controlled plastic cultures.

“Chromosome segregation has been studied in a dish for decades,” Knouse says. “I think the assumption was … a cell would segregate chromosomes the same way in a dish as it would in a tissue because everything was happening inside the cell.”

However, in previous work, Knouse had found that reported rates for aneuploidy in cells grown in cultures was much higher than the rates she found in cells that had grown within their native tissue. This prompted her and her colleagues to investigate whether the surroundings of a cell influence the accuracy with which that cell divided.

To answer this question, they compared mis-segregation rates between five different cell types in native and non-native environments.

But not all cells’ native environments are the same. Some cells, like those that form skin, grow in a very structured context, where they always have neighbors and defined directions for growth. Other cells, however, like cells in the blood, have greater independence, with little interaction with the surrounding tissue.

In the new study, the researchers observed that cells that grew in structured environments in their native tissues divided accurately within those tissues. But once they were placed into a dish, the frequency of chromosome mis-segregation drastically increased. The cells that were less tied to structures in their tissue were not affected by the lack of architecture in culture dishes.

The researchers found that maintaining the architectural conditions of the cell’s native environment is essential for chromosome stability. Cells removed from the context of their tissue don’t always faithfully represent natural processes.

The researchers determined that architecture didn’t have an obvious effect on the expression of known genes involved in segregation. The disruption in tissue architecture likely causes mechanical changes that disrupt segregation, in a manner that is independent of mutations or gene expression changes.

“It was surprising to us that for something so intrinsic to the cell — something that’s happening entirely within the cell and so fundamental to the cell’s existence — where that cell is sitting actually matters quite a bit,” Knouse says.

Through the Cancer Genome Project, scientists learned that despite high rates of chromosome mis-segregation, many cancers lack any mutations to the cellular machinery that controls chromosome partitioning. This left scientists searching for the cause of the increase of these division errors. This study suggests that tissue architecture could be the culprit.

Cancer development often involves disruption of tissue architecture, whether during tumor growth or metastasis. This disruption of the extracellular environment could trigger chromosome segregation errors in the cells within the tumor.

“I think [this paper] really could be the explanation for why certain kinds of cancers become chromosomally unstable,” says Iain Cheeseman, a professor of biology at MIT and a member of the Whitehead Institute, who was not involved in the study.

The results point not only to a new understanding of the cellular mechanical triggers and effects of cancers, but also to a new understanding of how cell biology must be studied.

“Clearly a two-dimensional culture system does not faithfully recapitulate even the most fundamental processes, like chromosome segregation,” Knouse says. “As cell biologists we really must start recognizing that context matters.”

This work was supported by the National Institutes of Health, the Kathy and Curt Marble Cancer Research Fund, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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.

Study suggests glaucoma may be an autoimmune disease

Unexpected findings show that the body’s own immune system destroys retinal cells.

Anne Trafton | MIT News Office
August 11, 2018

Glaucoma, a disease that afflicts nearly 70 million people worldwide, is something of a mystery despite its prevalence. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness.

A new study from MIT and Massachusetts Eye and Ear has found that glaucoma may in fact be an autoimmune disorder. In a study of mice, the researchers showed that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore, these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body.

The discovery suggests that it could be possible to develop new treatments for glaucoma by blocking this autoimmune activity, the researchers say.

“This opens a new approach to prevent and treat glaucoma,” says Jianzhu Chen, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study, which appears in Nature Communications on Aug. 10.

Dong Feng Chen, an associate professor of ophthalmology at Harvard Medical School and the Schepens Eye Research Institute of Massachusetts Eye and Ear, is also a senior author of the study. The paper’s lead authors are Massachusetts Eye and Ear researchers Huihui Chen, Kin-Sang Cho, and T.H. Khanh Vu.

Genesis of glaucoma

One of the biggest risk factors for glaucoma is elevated pressure in the eye, which often occurs as people age and the ducts that allow fluid to drain from the eye become blocked. The disease often goes undetected at first; patients may not realize they have the disease until half of their retinal ganglion cells have been lost.

Most treatments focus on lowering pressure in the eye (also known as intraocular pressure). However, in many patients, the disease worsens even after intraocular pressure returns to normal. In studies in mice, Dong Feng Chen found the same effect.

“That led us to the thought that this pressure change must be triggering something progressive, and the first thing that came to mind is that it has to be an immune response,” she says.

To test that hypothesis, the researchers looked for immune cells in the retinas of these mice and found that indeed, T cells were there. This is unusual because T cells are normally blocked from entering the retina, by a tight layer of cells called the blood-retina barrier, to suppress inflammation of the eye. The researchers found that when intraocular pressure goes up, T cells are somehow able to get through this barrier and into the retina.

The Mass Eye and Ear team then enlisted Jianzhu Chen, an immunologist, to further investigate what role these T cells might be playing in glaucoma. The researchers generated high intraocular pressure in mice that lack T cells and found that while this pressure induced only a small amount of damage to the retina, the disease did not progress any further after eye pressure returned to normal.

Further studies revealed that the glaucoma-linked T cells target proteins called heat shock proteins, which help cells respond to stress or injury. Normally, T cells should not target proteins produced by the host, but the researchers suspected that these T cells had been previously exposed to bacterial heat shock proteins. Because heat shock proteins from different species are very similar, the resulting T cells can cross-react with mouse and human heat shock proteins.

To test this hypothesis, the team brought in James Fox, a professor in MIT’s Department of Biological Engineering and Division of Comparative Medicine, whose team maintains mice with no bacteria. The researchers found that when they tried to induce glaucoma in these germ-free mice, the mice did not develop the disease.

Human connection

The researchers then turned to human patients with glaucoma and found that these patients had five times the normal level of T cells specific to heat shock proteins, suggesting that the same phenomenon may also contribute to the disease in humans. The researchers’ studies thus far suggest that the effect is not specific to a particular strain of bacteria; rather, exposure to a combination of bacteria can generate T cells that target heat shock proteins.

One question the researchers plan to study further is whether other components of the immune system may be involved in the autoimmune process that gives rise to glaucoma. They are also investigating the possibility that this phenomenon may underlie other neurodegenerative disorders, and looking for ways to treat such disorders by blocking the autoimmune response.

“What we learn from the eye can be applied to the brain diseases, and may eventually help develop new methods of treatment and diagnosis,” Dong Feng Chen says.

The research was funded by the National Institutes of Health, the Lion’s Foundation, the Miriam and Sheldon Adelson Medical Research Foundation, the National Nature Science Foundation of China, the Ivan R. Cottrell Professorship and Research Fund, the Koch Institute Support (core) Grant from the National Cancer Institute, and the National Eye Institute Core Grant for Vision Research.

School of Science appoints eight faculty members to named professorships
School of Science
July 23, 2018

The School of Science announced that eight of its faculty members have been appointed to named professorships. These positions afford the faculty members additional support to pursue their research and develop their careers.

Eliezer Calo, assistant professor in the Department of Biology, has been named the Irwin W. and Helen Sizer Career Development Professor. He focuses on the coordination of RNA metabolism using a combination of genetic, biochemical, and functional genomic approaches. The core of Calo’s research program is to understand how ribosome biogenesis is controlled by specific RNA binding proteins, particularly RNA helicases of the “DEAD box” family, and how disregulation of ribosome biogenesis contributes to various diseases, including cancer. He proposes initially to characterize the functions of specific genes of interest, including the DDX21 RNA helicase and the TCOF1 factor involved in RNA Pol I transcription and rRNA processing, using biochemical, molecular and genome-wide approaches in mouse, Xenopus and Zebrafish models.

Steven Flavell, assistant professor in the Department of Brain and Cognitive Sciences, has been named the Lister Brothers Career Development Professor. He uses Caenorhabditis elegans to examine how neuromodulators coordinate activity in neural circuits to generate locomotion behaviors linked to the feeding or satiety states of an animal. His long-term goal is to understand how neural circuits generate sustained behavioral states, and how physiological and environmental information is integrated into these circuits. Gaining a mechanistic understanding of how these circuits function will be essential to decipher the neural bases of sleep and mood disorders.

Pablo Jarillo-Herrero, the Cecil and Ida Green Professor of Physics, explores quantum transport in novel condensed-matter systems such as graphene, transition metal dichalcogenides and topological insulators. In recent work, he has demonstrated the presence of a bandgap in graphene-based van der Waals heterostructures, novel quantum spin Hall and photothermoelectric effects in graphene, as well as light-emitting diodes, photodetectors and solar cells in the atomically thin tungsten diselenide system. He has also made advances in characterizing and manipulating the properties of other ultrathin materials such as ultrathin graphite and molybdenum disulphide, which lack graphene’s ultrarelativistic properties, but possess other unusual electronic properties.

Becky Lamason, assistant professor in the Department of Biology, has been named the Robert A. Swanson (1969) Career Development Professor of Life Sciences. She investigates how intracellular bacterial pathogens hijack host cell processes to promote infection. In particular, she studies how Rickettsia parkeri and Listeria monocytogenes move through tissues via a process called cell-to-cell spread. She utilizes cellular, molecular, genetic, biochemical, and biophysical approaches to elucidate the mechanisms of spread in order to reveal key aspects of pathogenesis and host cell biology.

Rebecca Saxe, the inaugural John W. Jarve (1978) Professor in Brain and Cognitive Sciences, is best known for her discovery of a brain region that is specialized for “theory of mind,” people’s ability to think about the thoughts, beliefs, plans, hopes and emotions of other people. Saxe continues to study this region and its role in social cognition, and is exploring the theory-of-mind system as a promising candidate for understanding the biological basis of autism. She also studies brain development in human babies, including her own.

Omer Yilmaz, assistant professor in the Department of Biology, has been named the Eisen and Chang Career Development Professor. He studies how the adult intestine is maintained by stem cells that require a cellular neighborhood, or niche, consisting in part of Paneth cells. Specifically, he investigates the molecular mechanisms of how intestinal stem cells and their Paneth cell niche respond to diverse diets to coordinate intestinal regeneration with organismal physiology and its impact on the formation and growth of intestinal cancers. By better understanding how intestinal stem cells adapt to diverse diets, he hopes to identify and develop new strategies that prevent and reduce the growth of cancers involving the intestinal tract that includes the small intestine, colon, and rectum.

Yufei Zhao, assistant professor in the Department of Mathematics, has been named the Class of 1956 Career Development Professor. He has made significant contributions in combinatorics with applications to computer science. Recently, Zhao and three undergraduates solved an open problem concerning the number of independent sets in an irregular graph, a conjecture first proposed in 2001. Understanding the number of independent sets — subsets of vertices where no two vertices are adjacent — is important to solving many other combinatorial problems. In other research accomplishments, Zhao co-authored a proof with Jacob Fox and David Conlon that contributed to a better understanding of the celebrated Green-Tao theorem that states prime numbers contain arbitrarily long arithmetic progressions. Their work improves our understanding of pseudorandom structures — non-random objects with random-like properties — and has other applications in mathematics and computer science.

Martin Zwierlein, the inaugural Thomas A. Frank (1977) Professor of Physics, studies ultracold gases of atoms and molecules. These gases host novel states of matter and serve as pristine model systems for other systems in nature, such as neutron stars or high-temperature superconductors. In contrast to bulk materials, in experiments with cold gases one can freely tune the interaction between atoms and make it as strong as quantum mechanics allows. This enabled the observation of a novel robust form of superfluidity: Scaled to the density of electrons in solids, superfluidity would in fact occur far above room temperature. Under a novel quantum gas microscope with single-atom resolution, the team recently studied charge and spin correlations and transport in a Fermi-Hubbard lattice gas. This system is believed to hold the key to high-temperature superconductivity in cuprate materials. Using ultracold molecules, Zwierlein’s group also demonstrated coherence times on the order of seconds, spurring hopes for the future use of such molecules in quantum information applications.

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.

Institute Archives spotlights pioneering women at MIT

Initiative is building collections highlighting the contributions of female faculty.

Brigham Fay | MIT Libraries
July 6, 2018

A new MIT Libraries initiative aims to highlight MIT’s women faculty by acquiring, preserving, and making accessible their personal archives. The Institute Archives and Special Collections (IASC) launched the project last year with the generous support of Barbara Ostrom ’78 and Shirley Sontheimer.

The first year of the project has focused on reaching out to faculty who are ending the active phase of their careers. Four faculty members added their personal collections, comprising 234 boxes and 50 gigabytes of material. They are:

  • Nancy Hopkins, the Amgen Inc. Professor of Biology Emerita, known for making zebrafish a widely used research tool and for bringing about an investigation that resulted in the landmark 1999 report on the status of women at MIT;
  • Mary Potter, professor emerita in the Department of Brain and Cognitive Sciences, former chair of the MIT faculty, and member of the Committee of Women Faculty in the School of Science, whose research and teaching focused on experimental methods to study human cognition;
  • Mary Rowe, adjunct professor at the MIT Sloan School of Management, special assistant to the president, and ombudsperson, a conflict resolution specialist whose work led to MIT having one of the nation’s first anti-harassment policies; and
  • Sheila Widnall ’60, SM ’61, ScD ’64, Institute Professor and professor of aeronautics and astronautics, the first woman to serve as secretary of the Air Force, and the first woman to lead an entire branch of the U.S. military.

A donation of the papers of Mildred Dresselhaus, late Institute Professor emerita of electrical engineering and computer science and physics, is also forthcoming. Dresselhaus, whose work paved the way for much of today’s carbon-based nanotechnology, was also known for promoting opportunities for women in science and engineering. Discussions with additional faculty are also underway.

“We are honored to be stewards of these personal archives that have been given to MIT,” says Liz Andrews, project archivist. “We’re committed to preserving and making accessible these unique materials so they can be shared with the world into the future.”

Acquisitions of MIT administrative records provide additional context to the personal archives and a broader view on issues of gender equity and the challenges faced by women in academia. In the next phase of the project, archivists will continue to manage donations, prepare collections for use, and enlarge this core group by reaching out to female faculty who were tenured in the 1960s, ’70s, and ’80s.

Ultimately, the collections will provide not only rich resources for researchers, journalists, teachers, and students, but also, as Sontheimer says, inspiration for generations of women to come. “I’m hoping the project will encourage more women to become engaged in science, technology, and engineering,” she says.