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Whitehead Institute team resolves structure of master growth regulator
Whitehead Institute
October 10, 2019

Cambridge, MA — A team of Whitehead Institute scientists has for the first time revealed the molecular structure of a critical growth regulator bound to its partner proteins, creating a fine-grained view of how they interact to sense nutrient levels and control cell growth. Their findings, described in the October 10th online issue of Science, help answer longstanding questions about how the mTORC1 kinase, and its anchoring complex, Rag-Ragulator, work at a molecular level. Using cryo-electron microscopy, the researchers uncover key structures, including a large coiled region and a small, flexible claw. These discoveries help explain the biology of mTORC1 and also lay the foundation for a new generation of drugs that are more precisely tailored to its distinct molecular makeup.

“These interactions are fundamental to the biology of mTORC1, so we and other researchers have been trying to resolve them since the connection of mTORC1 to lysosomes was first discovered in my lab over 10 years ago,” says senior author David Sabatini, a Member of Whitehead Institute, a professor of biology at Massachusetts Institute of Technology, and investigator with the Howard Hughes Medical Institute (HHMI). “Now, we have a really deep look at how this important complex works, which opens up a panorama of new research.”

mTORC1 is a massive protein complex that enables cells to respond appropriately when food is either abundant or scarce, and has been implicated in a wide range of human diseases, including cancer, diabetes, and neurodegenerative disease. It operates within tiny compartments known as lysosomes — miniature recycling stations of the cell. In order to sense nutrient levels in the lysosome, and become active, mTORC1 must first dock at the lysosomal surface, where it meets up with its anchoring protein (called Rag-Ragulator).

However, this docking is an exquisitely complicated affair. It is regulated by a handful of proteins: an mTORC1 subunit (called Raptor) and the Rag GTPases, which bind Raptor as a non-identical pair and act like a control switch. This switch has four settings: one, which is used when nutrients are high, allows mTORC1 to dock at the lysosome and become active; the other three are used in times of hunger to push the complex away from the lysosomal surface and thereby deactivate it.

“Lacking a detailed structure, there were a lot of unanswered questions about how these proteins work together,” says first author Kacper Rogala, a postdoctoral fellow in Sabatini’s laboratory. “How does this switch machinery function at the molecular level? How does Raptor know when to bind the Rag GTPases and when not to? We knew we’d need a high-resolution view of the proteins’ structure in order to discover the answers.”

To achieve that view, Rogala turned to a method known as cryo-electron microscopy or cryo-EM. Instead of creating protein crystals, as in X-ray crystallography, cryo-EM relies on samples that are quickly frozen and then viewed with an electron microscope. But the challenge with mTORC1 and its partner proteins is that they are very dynamic, rapidly coming together and then falling apart, which greatly decreases the odds of capturing an intact complex.

To help turn the tables in their favor, Rogala and his colleagues engineered a variety of single-letter genetic mutations into the Rag GTPases. These mutations were first identified in the tumor DNA of lymphoma patients that exhibited stronger than usual mTORC1 activity. After testing several different mutation combinations, the Whitehead Institute team found the ideal one: two mutations in a single Rag GTPase, which caused the components to linger together in a bound state for slightly longer than usual.

This feat of molecular engineering allowed the researchers to resolve the structure of the Raptor-Rag-Ragulator complex at an extraordinary level of detail — roughly 3 Angstroms, which is about three times the length of a carbon-carbon bond. “At this level of resolution, we can visualize individual amino acids within the proteins and see exactly where their chemical groups are pointing,” says Rogala.

With a detailed protein structure in hand, Rogala and his colleagues were able to discern some key structural elements. One, which they describe for the first time, is a claw-like appendage that interacts with one of the Rag GTPases (known as RagC). The other is a large, coiled structure, shaped like a solenoid, that faces RagA.

“We think that, together, these two structures are acting as detectors for the Rag GTPases — so, is the switch in the right configuration for docking at the lysosome or not?” says Rogala.

Researchers at the MRC Laboratory of Molecular Biology in the UK also completed an analysis of these proteins’ structures using complementary experimental methods. Rogala and Sabatini collaborated with the group, whose study appears in the same issue of Science.

A deeper understanding of mTORC1 structure is vital not just for understanding how it interacts with its partners. A second, related protein complex (called mTORC2) shares some of the same protein components. Existing drugs against these proteins work non-specifically and often target both mTORC1 and mTORC2 signaling. That lack of specificity can be problematic from a therapeutic perspective — for example, causing unwanted, and often severe, side effects.

“This structure throws open a treasure trove of new biology for us, and that is incredibly exciting,” says Sabatini.

This work was supported by grants from the NIH (R01 CA103866, R01 CA129105, and R37 AI47389), Department of Defense (W81XWH-07-0448), and Lustgarten Foundation; fellowships from the Tuberous Sclerosis Association, the Koch Institute, NIH (F30 CA236179), and Charles A. King Trust; and a Saudi Aramco Ibn Khaldun Fellowship for Saudi Women. David M. Sabatini is an investigator of the Howard Hughes Medical Institute and an ACS Research Professor.

Papers cited:

Rogala K.B. et al. Structural basis for the docking of mTORC1 on the lysosomal surface. Science. DOI: 10.1126/science.aay0166

Madhanagopal et al. Architecture of human Rag GTPase heterodimers and their complex with mTORC1. Science. DOI: 10.1126/science.aax3939

The World Is Open To Me Now’: A Scientist With Dyslexia On How Learning To Read Changed Her Life
September 30, 2019

Catherine Drennan describes herself as insatiably curious, a trait she credits to her parents. Some of her first memories come from protest rallies and academic lectures that her mom attended while finishing her Ph.D. in anthropology.

She says her parents didn’t care much for babysitters. So she went wherever they went and became fascinated with the world around her.

“They were just always out there asking questions,” Drennan remembers. “I think I eventually took that on.”

Drennan says she was definitely on the “nerdy” side as a young kid. She remembers preferring the conversation at the adults’ table over what was happening at the kids’ table at family gatherings.

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“I could just listen or join in,” she says. “But I was fascinated to learn what people were talking about and how I could be a part of that.”

Drennan was excited when it came time to start school. But when she got to first grade, she hit a major stumbling block. Drennan couldn’t make sense of the reading exercises the class was doing.

“They put these pages in front of me or a little book in front of me and other people seemed to know what it said,” Drennan remembers. “I couldn’t figure out how they were doing that.”

She compares those pages full of words to a code that she couldn’t figure out how to crack. Drennan was eventually placed in the lowest reading level in her grade, a designation that felt extremely embarrassing.

“I was someone who was so in love with learning but learning was not in love with me,” she says.

Eventually, Drennan was diagnosed with dyslexia. At the time, in the 1970s, scientists and educators didn’t know a lot about the diagnosis and there was little in the way of advice for kids like her on how to find other ways to decode the written word.

Drennan’s mom hired after-school tutors to help guide and encourage her, but finding a method that clicked in her brain was still something Drennan had to figure out for herself.

Eventually, she found success by memorizing the shapes of words. It was slow going at first, but around the sixth grade Drennan remembers hitting a tipping point. Her vocabulary had grown large enough to allow her to effectively read.

“And when it started to click I was like, ‘The world is open to me now,'” she says.

Books went from a source of frustration to a source of joy. Drennan remembers relishing in her new found ability to talk with her peers about books they had read and dissecting the stories together.

“Being able to get at these stories and read them and experience them,” she says, “It was just incredible.”

By the time seventh grade rolled around, Drennan’s relationship with school changed dramatically. She suddenly found herself jumping from the remedial classes to the most rigorous. And going to college felt like more of a reality than a distant dream.

Drennan eventually went on to earn a Ph.D. from the University of Michigan in 1995. Today, she runs a chemistry lab at MIT exploring how proteins and enzymes in the human body interact with each other using computer generated models of their cellular structure.

In a way, Drennan says her dyslexia has been helpful in her research. Because she has become so skilled at recognizing shapes and interpreting what they mean, she’s able to notice details that other people in her lab often miss in those cellular pictures.

“People say we shouldn’t say ‘disabled’ we should say ‘differently abled’ and I totally believe that’s true for me,” she says.

Drennan explains she’s reached a stage in her life where she is comfortable in her own skin. She embraces her “geekiness” and looks at her dyslexia as an asset. She says her struggles learning to read have also helped her form better connections with the graduate students working in her lab.

“I know how to give them an environment where they can really show what they’re capable of doing,” she says.

Signaling factor seeking gene
Greta Friar | Whitehead Institute
September 25, 2019

Cambridge, MA — During embryonic development, stem cells begin to take on specific identities, becoming distinct cell types with specialized characteristics and functions, in order to form the diverse organs and systems in our bodies. Cells rely on two main classes of regulators to define and maintain their identities; the first of these are master transcription factors, keystone proteins in each cell’s regulatory network, which keep the DNA sequences associated with crucial cell identity genes accessible for transcription — the process by which DNA is “read” into RNA. The other main regulators are signaling factors, which transmit information from the environment to the nucleus through a chain of proteins like a game of cellular telephone. Signaling factors can prompt changes in gene transcription as the cells react to that information.

One long-standing conundrum of how cell identity is determined is that many species, including humans, use the same core signaling pathways, with the same signaling factors, in all of their cells, yet this uniform machinery can cue a diverse array of cell-type specific gene activity, like an identical line of code being entered in many computers and causing each to start running a completely different program. New research from Whitehead Institute Member Richard Young, who is also a professor of biology at the Massachusetts Institute of Technology, published online in Molecular Cell on September 25, sheds light on how the same signaling factor can lead to so many distinct responses — with the help of a mechanism called phase separation.

Co-senior author on the paper Jurian Schuijers, previously a postdoctoral researcher in Young’s lab and now a professor at the Center for Molecular Medicine at the University Medical Center Utrecht, was drawn to this puzzle after previously working in a signaling lab: “Two cells of different types that are right next to each other in the body can receive the exact same signal and have different reactions, and there was not a satisfying explanation for how that happens,” Schuijers says.

Young’s lab had previously found that signaling factors in pathways important for development tend to concentrate at super enhancers, clusters of DNA sequences that increase transcription of crucial cell identity genes. Because super enhancers are established at the genes important to identity in each cell, their activity is cell-type specific, so this co-localization provided a partial explanation of the puzzle, but it raised the question of how signaling factors are recruited to super enhancers. Young found the vague explanations that had been put forward, such as super enhancers being the most accessible DNA to signaling factors and their co-factors, unconvincing.

Young and his team suspected that an explanation for signaling factor recruitment might lie in their research on transcriptional condensates — droplets that form at super enhancers and concentrate transcriptional machinery there using phase separation, meaning the molecules separate out of their surroundings to form a distinct liquid compartment, like a drop of vinegar in a pool of oil. The proteins in condensates can do this because they contain intrinsically disordered regions (IDRs), stretches of amino acids that remain flexible, like wet spaghetti, and do not become fixed into a single shape the way most protein structures do. This property allows them to mesh together to form a condensate. The researchers reasoned that if signaling factors were joining transcriptional condensates, that could explain their concentration at super enhancers.

Young’s team confirmed that signaling factors in several of the most important pathways for embryonic development in mammals — WNT, TGF-β and JAK/STAT — contained IDRs. They further found that these factors were able to use their IDRs to form and join condensates, and that, in mouse cells, they appeared to join the condensates at super enhancers upon activation of their respective pathways.

The researchers then decided to focus on beta catenin, the signaling factor at the end of the Wnt signaling pathway, a pathway essential for development; it helps to coordinate things like body axis patterning and cell fate specification, proliferation and migration. When Wnt signaling goes awry in embryos, they fail to develop, and when it goes awry in adults it is implicated in diseases including cancer. The beta catenin protein has IDRs on both of its ends and a structured middle section, called the Armadillo repeat domain, where it binds to other transcription factors. Typically, beta catenin binds to transcription factors in the TCF/LEF family, which in turn bind to DNA—beta catenin cannot bind to DNA on its own — anchoring the signaling factor at the right site and prompting gene transcription. However, the researchers found that beta catenin could concentrate at super enhancers even when it could not bind to its usual partners, suggesting that transcriptional condensates were a sufficient recruitment mechanism. The researchers then created two abridged beta catenin molecules: one version that only contained the IDRs and one that only contained the Armadillo repeat domain. Both partial factors were able to concentrate at super enhancers, but neither was as effective as the combined whole.

“If you ask most people how these factors find their target locations in the genome, they would say it’s through their DNA binding domains,” says first author Alicia Zamudio, a graduate student in Young’s lab. “This research suggests that factors use both their structured DNA binding domains and their unstructured domains to find the right locations to bind in the genome and to activate target genes.”

One advantage for cells of using IDRs, versus DNA binding alone, might be reducing the time it takes for signaling factors to concentrate near the right genes, the researchers say. Speed is of the essence for some signaling pathways in order for cells to be able to respond quickly to environmental stimuli. Transcriptional condensates are larger in size and much fewer in number than DNA binding sites or DNA-binding co-factors, and so they shrink the space that a signaling factor entering the nucleus must search.

This research could provide new opportunities for drug discovery. Signaling pathways and super enhancers are both co-opted by oncogenes to drive the spread of cancer, so transcriptional condensates could be a promising target to disrupt both oncogenic signaling and oncogene transcription. Young also hopes that this research, which adds to his lab’s growing body of work on transcriptional condensates, will lead to a new appreciation of the disordered regions of proteins.

“For a long time, researchers have mostly ignored the intrinsically disordered regions of proteins — we literally cut them off when identifying the crystal structures — much in the same way that researchers used to study genes and ignore ‘junk DNA,’” Young says. “But, just as with junk DNA, we are discovering that the overlooked, less obviously functional regions of these molecules are very important after all.”

 

This work is supported by NIH grant GM123511 and NSF grant PHY1743900 (R.A.Y.), NIH grant GM117370 (D.J.T.), NSF Graduate Research Fellowship (A.V.Z.), NIH grant T32CA009172 (I.A.K.), and DFG Research Fellowship DE 3069/1-1 (T.M.D.).

 

Written by Greta Friar

***

Richard Young’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at the Massachusetts Institute of Technology.

***

Full citation:

“Mediator condensates localize signaling factors to key cell identity genes”

Molecular Cell, published online September 25, 2019. DOI: 10.1016/j.molcel.2019.08.016

Alicia V. Zamudio (1, 2), Alessandra Dall’Agnese (1), Jonathan E. Henninger (1), John C. Manteiga(1, 2), Lena K. Afeyan (1, 2), Nancy M. Hannett (1), Eliot L. Coffey (1, 2), Charles H. Li (1, 2), Ozgur Oksuz (1), Benjamin R. Sabari (1), Ann Boija (1), Isaac A. Klein (1,3), Susana W. Hawken (4), Jan-Hendrik Spille (5), Tim-Michael Decker (6), Ibrahim I. Cisse (5), Brian J. Abraham (1,7), Tong I. Lee (1), Dylan J. Taatjes (6), Jurian Schuijers (1,8,9), and Richard A. Young (1, 2, 9).

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

4. Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139 USA

5. Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 6. Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA

7. St. Jude Children’s Research Hospital, Memphis, TN, 038105, USA

8. Present address: Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.

9. Equal contribution

A soft spot for science and a passion for people lead to a career in consulting

Mary Lee PhD ’10 uses the analytic and interpersonal skills she learned at MIT to advise life science companies as a managing consultant.

Saima Sidik
September 24, 2019

In the early 2000’s, Mary Lee PhD ’10 was an undergraduate student at California State University in Los Angeles with a burgeoning interest in molecular biology. On a whim, she applied to the MIT Summer Research Program in Biology (MSRP-Bio) in the hopes of spending 10 weeks conducting research in the MIT Department of Biology. She soon found herself in professor Bob Sauer‘s lab, and her life changed forever. “MIT unlocked opportunities that I’m positive I wouldn’t have had otherwise,” she says. These opportunities included the chance to later return to MIT Biology as a graduate student, where she earned her PhD.

Now, almost two decades later, Lee says she relies heavily on the analytical skills she learned at MIT in her current role as a consultant. Her firm, Blue Matter, helps biotech and pharmaceutical companies bring new therapeutic medicines and tools to patients.

As an MSRP-Bio student, Lee began studying a molecule called transfer-messenger RNA (tmRNA) that ensures efficient protein production in bacteria. Her interest in molecular biology had already been kindled by researching environmental carcinogens as an undergraduate student at Cal State LA, and her time in the Sauer lab intensified her drive to understand how molecules form the subcellular machines that keep organisms alive.

“It was fascinating to me that I could understand portions of how the world works by looking at them on a micro-scale,” she says. “I had so much fun intellectually, but personally, too.”

After MSRP-Bio, Lee decided to pursue a PhD in biology, and with Sauer’s letter of recommendation combined with her previous research experience and good grades, she earned a spot in MIT Biology’s Graduate Program. In 2004, she returned to the Sauer lab and immersed herself in their research regarding a class of protein degrading enzymes called proteases. In particular, she focused on the protease ClpP, and her work uncovered the intricacies of ClpP’s association with the cofactors that regulate its activity to maintain cellular homeostasis.

The Sauer lab taught Lee how to build on scientific conclusions and sift through ideas to let the most valuable ones rise to the top. “Grad school taught me how to take a lot of evidence and data and information and do something useful with it,” Lee says. “I remember reading the scientific literature as a young grad student and trying to decide if I believed the authors, or if I disagreed with their conclusions.” This process of reading and critiquing taught Lee how to recognize the strengths of a lab’s work while also assessing their weaknesses.

At MIT, Lee met people with widely varying interests and mindsets. Some of this diversity came from within the biology department, where she was impressed by the creative and wide-ranging approaches that her classmates applied to their research. It also came from living in a graduate student dorm, and later acting as a graduate resident advisor in an undergraduate dorm. These experiences gave her an opportunity to meet people from a wide range of departments, from the sciences to architecture and urban planning.

As her graduate work progressed, Lee realized that some of her most enjoyable moments at MIT involved exchanging ideas with people whose expertise differed from hers. She wanted to put her gregarious nature to good use, and she decided that the best way to do that was to become a consultant.

“Life sciences consulting is an industry where you can tap into your love of science in a way that involves a lot of human interaction,” she says.

Today, Lee continues to use the analytical and interpersonal skills she gained as a member of the Sauer lab to guide her clients towards developing products that improve patients’ lives. If a client is in the early stage of drug development, they might come to her having discovered a compound that targets a particular class of enzymes, for example, and she helps them figure out which diseases it could treat. For medicines that are in the later stages of development, clients’ needs are more market-driven, and they need help finding the best way to educate patients and physicians about their products.

Lee says that one of the most fulfilling consulting projects she’s worked on involved a client who asked her to identify the needs of people with a rare eye disease. This condition is caused by a genetic mutation that patients carry from birth, but the mutation doesn’t manifest as a disease until early adulthood. The project made an impression on Lee because she got to talk with people who have this rare mutation and ask them questions like, “How has this disorder shaped your life?” and “How can the research and biotech communities better support your needs?” Finding ways for her clients to help real people keeps Lee motivated during the long hours she spends at the office.

Lee’s days still involve the blend of creativity and analytical thinking that fueled her work in the Sauer lab, but at a much faster pace. Instead of leading one project for five-and-a-half years, as she did in graduate school, she now oversees five to eight short-term projects at any given time — each involving four to five people.

Lee says she can maintain this busy lifestyle because, “working with people really energizes me.” Brainstorming with her coworkers keeps her motivated, as do her clients and the patients they serve.

Thinking back to her time as a bench scientist, Lee says, there are some days when she misses the “tactile” aspects of doing research. But the ever-changing nature of consulting engages her curiosity, and the interpersonal connections satisfy her gregarious side. The job is an ideal fit for her personality, but perhaps this career would never have come about were it not for the day — almost twenty years ago — that she decided to apply to MSRP-Bio.

“I really think MIT is so special,” she says. “It’s a community of people who believe that the world is a wonderful place, and that it can be even better, and that they can be part of that change.”

Photo courtesy of Blue Matter
Ruth Lehmann elected as director of Whitehead Institute

Lehmann, a world-renowned developmental and cell biology researcher, is the institute’s fifth director.

Lisa Girard | Whitehead Institute
September 19, 2019

The Whitehead Institute board of directors today announced the selection of Ruth Lehmann, a world-renowned developmental and cell biology researcher, as the institute’s fifth director. Lehmann will succeed current Director David Page on July 1, 2020.

Lehmann is now the Laura and Isaac Perlmutter Professor of Cell Biology and chair of the Department of Cell Biology at New York University (NYU), where she also directs the Skirball Institute of Biomolecular Medicine and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology. She is currently an investigator of the Howard Hughes Medical Institute. The Whitehead Institute appointment represents a homecoming: Lehmann was a Whitehead Institute member and a faculty member of MIT from 1988 to 1996, before beginning a distinguished 23-year career at NYU.

“Ruth Lehmann will continue a line of prestigious and highly accomplished scientist-leaders who have served as Whitehead Institute directors,” says Charles D. Ellis, chair of the Whitehead Institute board of directors. “She perfectly fits our vision for the next director: an eminent scientist and experienced leader, who is passionately committed to Whitehead Institute’s mission, and possesses a compelling vision for basic biomedical research in the coming decade.”

“I am delighted to return to Whitehead Institute and look forward to joining the illustrious faculty to recruit and mentor the next generation of Whitehead Institute faculty and fellows,” Lehmann says. “When I was recruited to Whitehead Institute in the late 1980s, David Baltimore took a huge risk in giving an inexperienced young scientist from Germany the chance to follow her passion for science with unending encouragement and minimal restraints. Now I am thrilled to have the opportunity to help shape the future of this wonderful institute that has been at the forefront of biomedical research for decades. I am pleased to become part of the succession of Whitehead Institute’s forward-thinking directors, David Baltimore, Gerald Fink, Susan Lindquist, and David Page. I look forward to working with faculty, fellows, trainees, and staff to build a future with ambitious goals that will allow us to reveal the unknown and connect the unexpected in a collaborative, diverse, and flexible environment.”

“Ruth Lehmann is an inspired choice to lead the institute into the future and I look forward to working with her in that capacity,” Page says. “Ruth is an internationally renowned and influential leader in the field of germ cell biology, and her outstanding contributions to the field are the product of her sustained brilliance, insatiable curiosity, uncompromising rigor and scholarship, and clarity of thought and expression. Across the course of the past three decades, no scientist anywhere in the world has made greater contributions to our understanding of germ cells and their remarkable biology. I’m especially pleased to gain a colleague with such an impressive track record of discovery and institutional leadership.”

The new director will have an impressive line of predecessors: Whitehead Institute’s founding director was Nobel laureate and former Caltech president David Baltimore; he was succeeded by internationally honored geneticist and science enterprise leader Gerald Fink, and then by National Medal of Science recipient Susan Lindquist, followed by the current director, leading human geneticist David Page, who became director in 2004.

“Ruth Lehmann is a brilliant choice as the next director of Whitehead Institute,” Baltimore says. “She is a world-class scientist and a seasoned leader. Most importantly, she understands the unique nature of Whitehead Institute and will maintain it as a key element of the biomedical complex that has grown up in Cambridge, Massachusetts.”

“Ruth Lehmann is an extraordinary scientist, who began her distinguished career here at Whitehead,” Fink says. “Her innovative work on germ cells, which give rise to eggs and sperm, has paved the path for the entire field. She is an inspiring leader who is an outspoken advocate for fundamental research. We are all delighted to welcome her back as our new director and scientific colleague.”

Lehmann has made seminal discoveries in the field of developmental and cell biology. Germ cells, the cells that give rise to the sperm and egg, carry a precious cargo of genetic information from the parent that they ultimately contribute to the embryo, transmitting the currency of heredity to a new generation. Work in Lehmann’s lab using Drosophila (fruit flies) has shed light on how these important cells “know” to become germ cells, and how they are able to make their way from where they originate to the gonad during early embryonic development. Her discoveries uncovering the mechanisms needed for proper specification and migration of germ cells have not only informed our understanding of processes essential for the perpetuation of life itself, but have also made important contributions to related fields including stem cell biology, lipid biology, and DNA repair.

“I’m so pleased to be welcoming Ruth back to the community,” MIT Provost Martin A. Schmidt says. “Her dedication to, and expertise in, basic research will underscore Whitehead Institute’s reputation as a leader in this arena.”

Susan Hockfield, MIT president emerita and professor of neuroscience, chaired the committee that recommended Lehmann to the Whitehead Institute board. “Our committee considered eminent candidates from across the globe,” Hockfield says, “and found in Ruth Lehmann a person uniquely qualified to guide this pioneering research institution forward.”

Lehmann earned an undergraduate degree and a PhD in biology from the University of Tubingen in Germany, in the laboratory of future Nobel laureate Christiane Nüsslein-Volhard. Between those programs, she conducted research at the University of Washington and earned a diploma degree — equivalent to a master’s degree — in biology from the University of Freiburg in Germany. She then conducted postdoctoral research at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. Then, Lehmann moved to Cambridge, Massachusetts, to become a Whitehead Institute member and MIT faculty member. In 1996, she accepted a professorship at NYU Langone School of Medicine and was subsequently named director of the Skirball Institute of Biomolecular Medicine and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU Stem Cell Biology Graduate Program director, and chair of the NYU Department of Cell Biology in 2014 (all roles that she continues to hold).

She has served as president of the Society for Developmental Biology, the Drosophila Board, and the Harvey Society; is currently editor-in-chief of the Annual Review of Cell and Developmental Biology; and will serve as president of the American Society for Cell Biology starting in 2021. Additionally, she has been a council member of the National Institute of Child Health and Human Development.

Among her many awards, Lehmann has received the Society for Developmental Biology’s Conklin Medal, the Porter Award from the American Society for Cell Biology, and the Lifetime Achievement Award from the German Society for Developmental Biology. She is an elected member of the National Academy of Sciences, a fellow of the American Academy of Arts and Sciences, and a member of the European Molecular Biology Organization.

Lehmann has also been a committed mentor, having fostered the education and professional development of scores of undergraduate and graduate students and postdoctoral researchers. Many of her mentees have gone on to become leaders in the biomedical industry or at academic institutions in the United States and around the world, including Johns Hopkins University, Princeton University, MIT, the University of Cambridge (UK), European Molecular Biology Laboratory (Heidelberg, Germany), and University of Toronto (Canada).

Study finds hub linking movement and motivation in the brain

Detailed observations in the lateral septum indicate region processes movement and reward information to help direct behavior.

David Orenstein | Picower Institute for Learning and Memory
September 19, 2019

Our everyday lives rely on planned movement through the environment to achieve goals. A new study by MIT neuroscientists at the Picower Institute for Learning and Memory at MIT identifies a well-connected brain region as a crucial link between circuits guiding goal-directed movement and motivated behavior.

Published Sept. 19 in Current Biology, the research shows that the lateral septum (LS), a region considered integral to modulating behavior and implicated in many psychiatric disorders, directly encodes information about the speed and acceleration of an animal as it navigates and learns how to obtain a reward in an environment.

“Completing a simple task, such as acquiring food for dinner, requires the participation and coordination of a large number of regions of the brain, and the weighing of a number of factors: for example, how much effort is it to get food from the fridge versus a restaurant,” says Hannah Wirtshafter PhD ’19, the study’s lead author. “We have discovered that the LS may be aiding you in making some of those decisions. That the LS represents place, movement, and motivational information may enable the LS to help you integrate or optimize performance across considerations of place, speed, and other environmental signals.”

Previous research has attributed important behavioral functions to the LS, such as modulating anxiety, aggression, and affect. It is also believed to be involved in addiction, psychosis, depression, and anxiety. Neuroscientists have traced its connections to the hippocampus, a crucial center for encoding spatial memories and associating them with context, and to the ventral tegmental area (VTA), a region that mediates goal-directed behaviors via the neurotransmitter dopamine. But until now, no one had shown that the LS directly tracks movement or communicated with the hippocampus, for instance by synchronizing to certain neural rhythms, about movement and the spatial context of reward.

“The hippocampus is one of the most studied regions of the brain due to its involvement in memory, spatial navigation, and a large number of illnesses such as Alzheimer’s disease,” says Wirtshafter, who recently earned her PhD working on the research as a graduate student in the lab of senior author Matthew Wilson, Sherman Fairchild Professor of Neurobiology. “Comparatively little is known about the lateral septum, even though it receives a large amount of information from the hippocampus and is connected to multiple areas involved in motivation and movement.”

Wilson says the study helps to illuminate the importance of the LS as a crossroads of movement and motivation information between regions such as the hippocampus and the VTA.

“The discovery that activity in the LS is controlled by movement points to a link between movement and dopaminergic control through the LS that that could be relevant to memory, cognition, and disease,” he says.

Tracking thoughts

Wirtshafter was able to directly observe the interactions between the LS and the hippocampus by simultaneously recording the electrical spiking activity of hundreds of neurons in each region in rats both as they sought a reward in a T-shaped maze, and as they became conditioned to associate light and sound cues with a reward in an open box environment.

In that data, she and Wilson observed a speed and acceleration spiking code in the dorsal area of the LS, and saw clear signs that an overlapping population of neurons were processing information based on signals from the hippocampus, including spiking activity locked to hippocampal brain rhythms, location-dependent firing in the T-maze, and cue and reward responses during the conditioning task. Those observations suggested to the researchers that the septum may serve as a point of convergence of information about movement and spatial context.

Wirtshafter’s measurements also showed that coordination of LS spiking with the hippocampal theta rhythm is selectively enhanced during choice behavior that relies on spatial working memory, suggesting that the LS may be a key relay of information about choice outcome during navigation.

Putting movement in context

Overall, the findings suggest that movement-related signaling in the LS, combined with the input that it receives from the hippocampus, may allow the LS to contribute to an animal’s awareness of its own position in space, as well as its ability to evaluate task-relevant changes in context arising from the animal’s movement, such as when it has reached a choice point, Wilson and Wirtshafter said.

This also suggests that the reported ability of the LS to modulate affect and behavior may result from its ability to evaluate how internal states change during movement, and the consequences and outcomes of these changes. For instance, the LS may contribute to directing movement toward or away from the location of a positive or negative stimulus.

The new study therefore offers new perspectives on the role of the lateral septum in directed behavior, the researchers added, and given the known associations of the LS with some disorders, it may also offer new implications for broader understanding of the mechanisms relating mood, motivation, and movement, and the neuropsychiatric basis of mental illnesses.

“Understanding how the LS functions in movement and motivation will aid us in understanding how the brain makes basic decisions, and how disruption in these processed might lead to different disorders,” Wirtshafter says.

A National Defense Science and Engineering Graduate Fellowship and the JPB Foundation funded the research.

Jazayeri and Sive awarded 2019 School of Science teaching prizes

Nominated by peers and students, professors in brain and cognitive sciences and biology are recognized for excellence in graduate and undergraduate education.

School of Science
September 18, 2019

The School of Science has announced that the recipients of the school’s 2019 Teaching Prizes for Graduate and Undergraduate Education are Mehrdad Jazayeri and Hazel Sive. Nominated by peers and students, the faculty members chosen to receive these prizes are selected to acknowledge their exemplary efforts in teaching graduate and undergraduate students.

Mehrdad Jazayeri, an associate professor in the Department of Brain and Cognitive Sciences and investigator at the McGovern Institute for Brain Research, is awarded the prize for graduate education for 9.014 (Quantitative Methods and Computational Models in Neuroscience). Earlier this year, he was recognized for excellence in graduate teaching by the Department of Brain and Cognitive Sciences and won a Graduate Student Council teaching award in 2016. In their nomination letters, peers and students alike remarked that he displays not only great knowledge, but extraordinary skill in teaching, most notably by ensuring everyone learns the material. Jazayeri does so by considering students’ diverse backgrounds and contextualizing subject material to relatable applications in various fields of science according to students’ interests. He also improves and adjusts the course content, pace, and intensity in response to student input via surveys administered throughout the semester.

Hazel Sive, a professor in the Department of Biology, member of the Whitehead Institute for Biomedical Research, and associate member of the Broad Institute of MIT and Harvard, is awarded the prize for undergraduate education. A MacVicar Faculty Fellow, she has been recognized with MIT’s highest undergraduate teaching award in the past, as well as the 2003 School of Science Teaching Prize for Graduate Education. Exemplified by her nominations, Sive’s laudable teaching career at MIT continues to receive praise from undergraduate students who take her classes. In recent post-course evaluations, students commended her exemplary and dedicated efforts to her field and to their education.

The School of Science welcomes nominations for the teaching prize in the spring semester of each academic year. Nominations can be submitted at the school’s website.