Amy Lee Named 2017 Searle Scholar

Figure from Amy Lee

Assistant Professor of Biology Amy Si-Ying Lee was named a 2017 Searle Scholar, receiving $300,000 in flexible funding to support her work over the next three years. Lee’s research is focused on discovering how gene regulation occurs through novel mechanisms of mRNA translation. Specifically, her lab studies how non-canonical translation pathways shape cell growth and differentiation, and why defects in mRNA translation lead to developmental disorders and cancer.

Lee, who came to Brandeis in Summer 2016, has a PhD form Harvard and did her postdoc at UC Berkeley. She has also been awarded a 2017 Sloan Research Fellowship and in January won the Charles H. Hood Foundation Child Health Research Award. Lee’s lab is up and running and recruiting postdocs and PhD students (through the Molecular & Cell Biology and Biochemistry & Biophysics graduate programs). In Fall 2017, Lee will teach BIOL 105, Molecular Biology.

Amy Lee Joins Biology Faculty

On August 1, Amy Lee joined the Biology department as an Assistant Professor. Previously, Amy was an American Cancer Society Postdoctoral Scholar in Jamie Cate’s lab at University of California, Berkeley. She received her Ph.D. in Virology from Harvard University in Sean Whelan’s lab and her Bachelors of Science in Biology from Massachusetts Institute of Technology.

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eIF3d structure, see Figure 2 at http://rdcu.be/jzDD

Amy’s research focuses on understanding how gene regulation shapes cell growth and differentiation, and how dysregulation leads to human diseases like carcinogenesis and neurodegeneration. She is interested in discovering new mechanisms of mRNA translation initiation and novel functions of RNA-binding proteins and eukaryotic translation factors. Her research combines genome-wide and computational approaches together with molecular genetics, cell biology, biochemistry, and structural biology techniques.

Amy recently published a paper in Nature together with the Jamie Cate, Jennifer Doudna, and Philip Kranzusch describing the discovery of a new translation pathway that controls the production of proteins critical to regulating the growth and proliferation of cells. Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. One key insight more than 40 years ago was that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

Amy and her colleagues discovered that for a certain specialized subset of mRNAs – most of which have been linked somehow to cancer – initiation is triggered by a different protein, called eIF3d. The finding was a surprise because the protein is part of an assembly of 13 proteins called eIF3 -eukaryotic initiation factor 3 – that has been known and studied for nearly 50 years, and no one suspected its undercover role in the cell. This may be because eIF3’s ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3d that then latches onto the end-cap of mRNA to trigger the translation process. Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the cap-binding pocket. eIF3d thus presents a promising new drug target in cancer, as a drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016.

 

Inside the Marder Lab

Marder Office MobileProfessor Eve Marder’s office door is unmistakable. Tucked between the certificates, accolades, official photos, and award plaques that plaster her lab’s walls, her office door is decorated with a collage of fading photos of students and yellowing cartoons of lobsters and crabs. Inside the office, the shelves are crammed with neuroscience books and stacks of primary and review articles published by her lab throughout her career. But among all of the awards and publications there’s something else that draws your eye. Hanging just above her computer is a homemade mobile built by a former student. Dangling from the mobile are photos of lab members and important scientific figures, faces and images gently pirouetting and circling around one another just above Marder’s head.

Now Marder has another award to add to her vast collection. In June 2016, she was announced as a winner of the Kavli Prize in Neuroscience. Marder shares the Prize with Carla Shatz, of Stanford University, and Michael Merzenich, of the University of California, San FMarder Office Doorrancisco. The award was given to these scientists “for the discovery of mechanisms that allow experience and neural activity to remodel brain function.” The Prize includes a gold medal ceremony and a one-million-dollar award (to be split among the winners), which will be conferred by His Majesty King Harald V of Norway in Oslo in September 2016. First awarded in 2008, the Kavli Prize was established to recognize scientific achievement and to honor creative scientists in the fields of Neuroscience, Astrophysics, and Nanoscience.

The illustrations of lobsters and crabs on Marder’s office door pay homage to the creatures that her lab has used as research subjects to shed light on the fundamental rules that govern how nervous systems function. Her life’s work has been studying a group of neurons called the stomatogastric ganglion (STG). These neurons control rhythmic chewing and filtering of food through the stomachs of crustaceans like crabs and lobsters. The STG is a relatively small (~30 neurons) circuit of cells. It can be dissected out from the animal and placed in a dish, where it can continue to function for up to weeks at a time. In the dish, the neurons will continue to produce electrical rhythms as if the stomach were still chewing and filtering. These electrical rhythms can be studied using a technique called electrophysiology where changes in cell voltage are measured and recorded. The STG contains well-studied central pattern generators (CPGs), circuits that produce rhythmic patterns without sensory feedback. In fact, insight gained from studying the general principles involved in STG activity has given neuroscientists a better understanding of CPGs involved in human behaviors including walking, sleeping, and breathing.

pyloric rhythm

From The Cancer borealis STG guide (Rutgers University)

Because the STG is robust and relatively simple, it makes an excellent model to study how neural circuits work. Gina Turrigiano, a colleague at Brandeis, has written that the ideas Marder and her lab developed from studying this system have “catalyzed paradigm shifts in fields as diverse as neural circuit function, computational neuroscience, and neuronal homeostasis…Her ideas have proved to be highly generalizable, and have fundamentally changed the way neuroscientists think about these problems.”

Neuroscientists used to think that the brain was wired like an electronic circuit board. In other words, neurons were wired together via simple connections that could only be “on” or “off.” When all the connections were turned on, the circuit produced a single behavior. Understanding the brain was thought to be as simple as determining how each neuron was physically connected to all others. While working as a graduate student at the University of California San Diego, Marder made a discovery that questioned this dogma. She found that neurons in the STG release acetylcholine in addition to the already known neurotransmitter, glutamate. This result, published in 1974, suggested that neuronal connections could be turned on in more than one way. Her discovery was instrumental in shifting how neuroscientists think about nervous systems. It could no longer be assumed that a simple connection diagram was sufficient.

Further work uncovered many different neuromodulators (neurotransmitters and peptides hormones) that could modulate or alter the neurons’ rhythms of the STG. Dr. Marder found that release of these neuromodulators could shift the activity of the neural circuit without changing any physical connections. This shift can happen very quickly and be long lasting. In addition, neuromodulation can also induce certain neurons to synchronize with different circuits switching their activity to coordinate with one circuit (like the ‘chewing’ circuit) and then to another (like the ‘filtering’ circuit). Both of these findings opened new questions for the entire field of neuroscience. A neural circuit with the same physical connections could have many different output activities so that even simple neural circuits could accomplish a surprising variety of tasks.

Partial Summary of Neuromodulation of the STG, see Marder (2012) Neuron 76:1–11.

Much of the Marder lab’s work in recent years has grown from this initial work in neuromodulation. With so much flexibility of activity, it became important to explore how these systems are able to maintain stability. Although a neuron can live over 100 years, the components of that neuron, including proteins that make up ion channels, constantly change on a timescale of seconds to weeks. Marder worked in collaboration with Larry Abbott and his lab to study how neurons maintain appropriate activity despite such rapid turnover. This work resulted in theoretical models suggesting that neurons have an intrinsic “set-point.” An individual neuron mediates changes in ion channels to produce a specific desirable activity output. This work informed our understanding of how neurons and nervous systems are able to be both plastic, but also to remain functional in a constantly changing environment. It has given rise to work investigating how synapses are able to respond to changing activity or “synaptic scaling” and research into how neurons determine their “set-point” at a molecular level.

Many of the numerous primary and review papers stacked in Marder’s office have been co-authored by some of her almost 80 graduate students and post-docs. These papers have been the work of both experimentalists, who gather data from real neurons, and theorists, who use computers to make hypothetical models of neurons. The collaborative working environment lends strength to the work completed in the Marder lab and forces students and post-docs to explain their work to peers with very different skill sets. It also gives lab members an opportunity to use both theory and experiments to cooperatively build stronger models and to design better experiments. As one example of this, Marder and Abbott together developed the dynamic clamp tool. Using this tool, real biological neurons are connected to model neurons generated within computer programs. This system, now used by scientists all over the world, makes well-controlled manipulations while still probing a dynamically complex biological system.

Wandering through the Marder lab on any given day, it is always buzzing with students and postdocs at computers, doing dissections, or popping into Marder’s office for a quick chat and some chocolate. Currently, the Marder lab is investigating variability in neural circuits. Scientists often view variability as a result of experimental error and attempt to minimize it through averaging over multiple trials. Marder’s approach has revealed that variability is a natural part of how neurons and circuits are constructed and can reveal very important information about how these systems work. Both experimental and theoretical work from the Marder lab has shown that neurons with widely varying characteristics can exhibit nearly identical activity patterns. Thus rather than finding the average properties of a neuron, it is crucial to understand how functionality is maintained in the presence of this variability.

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Dye fill of STG neuron by Marder lab members

One way the Marder lab currently studies this variability is using temperature change, a physiologically relevant stimulus for crabs who live in varying depths of water throughout the year. Understanding more about how different neuromodulators affect the activity rhythm continues to be an ongoing project since approximately 50 neuromodulators have been discovered in the STG. Other lab members are interested in observing variability in the morphology of different cell types. STG neurons visually have a cell body with a single axon that branches many times so that the cells look less like a traditional ‘neuron’ image but rather a cell body connected to something that looks like a tangled ball of hair. Other work in the lab is interested in investigating where different ion channels are located on this highly branched and complex structure.

To those scientists who have met Dr. Marder she is a source of inspiration and advice. She clearly enjoys engaging with younger scientists especially graduate students and postdocs and many of them have experienced her mentorship throughout their careers. Barbara Beltz of Wellesley College wrote of Marder “It has been clear to me for a long time that although I had PhD and postdoctoral advisors who were supportive and kind, it was Eve who was the most influential mentor in my career.” Marder provides supportive encouragement always paired with frank honesty sometimes in the form of tough love. Ted Brookings, a former Marder lab post-doc says that Marder takes mentorship very seriously and her greatest pride as an advisor is not in selecting the most brilliant people but instead seeing the evidence of how much they have grown during their time in the lab. Many female scientists in particular see her as a trail-blazer and those who have been to her office find the life-sized cutout of Xena Warrior Princess to be appropriate decor.

Working at her undergraduate alma mater, Brandeis University since 1978, Marder helped to build one of the first undergraduate neuroscience programs in the country and a highly regarded neuroscience PhD program. Even as a senior professor, Marder often teaches the Principles of Neuroscience course taken by upper-level undergraduates and required for incoming graduate students. She is unique among the faculty for teaching the course using the blackboard rather than Powerpoint and begins each year with a new bucket of large colorful sidewalk chalk. According to a former Marder lab graduate student, Marder’s teaching permeates everything she does, whether she’s in front of the classroom, having a personal sit down in her office or giving a grand seminar.

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Celebration party after Kavli Prize 2016 announcement. Photo by Steven Karel.

Marder received hundreds of congratulatory emails from colleagues and former students and post-docs after the announcement of the Kavli Prize. The extensive body of research from Marder and her students, using the STG, has revealed fundamental properties that apply to all nervous systems. One of her colleagues at Brandeis University, Leslie Griffith has written “Her work has provided a platform for much of our current cellular understanding of circuit function and stability and the mechanisms by which circuits negotiate the flexibility/stability trade-off.” The homemade mobile rotating above her head in her office appears to capture the essence of how Marder views her work and her lab – old and new people constantly in motion orbiting groundbreaking discoveries in neuroscience.

Drawing by Ben Marder

Drawing by Ben Marder

 

 

About the Author

Maria Genco is a PhD candidate in the Neuroscience Program working in the Griffith Lab at Brandeis University.

Marder, Shatz, and Merzenich share 2016 Kavli Prize in Neuroscience

Eve MarderBreaking news: The 2016 Kavli Prize in Neuroscience is awarded to Eve Marder (Brandeis), Carla Shatz (Stanford), and Michael M. Merzenich (UCSF), “for the discovery of mechanisms that allow experience and neural activity to remodel brain function.”

 

Simons Foundation funds Brandeis Math, Physics collaborations

In 2014, the Simons Foundation, one of the world’s largest and most prominent basic science philanthropies, launched an unprecedented program to fund multi-year, international research collaborations in mathematics and theoretical physics. These are $10M grants over four years, renewable, that aim to drive progress on fundamental scientific questions of major importance in mathematics, theoretical physics, and theoretical computer science. There were 82 proposals in this first round. In September 2015, two were funded. Both involve Brandeis.

Matthew Headrick (Physics) is deputy director of the Simons Collaboration It from Qubit, which involves 16 faculty members at 15 institutions in six countries. This project is trying from multiple angles to bring together physics and quantum information theory, and show how some fundamental physical phenomena (spacetime, black holes etc.) emerge from the very nature of quantum information. Fundamental physics and quantum information theory remain distinct disciplines and communities, separated by significant barriers to communication and collaboration. “It from Qubit” is a large-scale effort by some of the leading researchers in both communities to foster communication, education and collaboration between them, thereby advancing both fields and ultimately solving some of the deepest problems in physics. The overarching scientific questions motivating the Collaboration include:

  • Does spacetime emerge from entanglement?
  • Do black holes have interiors?
  • Does the universe exist outside our horizon?
  • What is the information-theoretic structure of quantum field theories?
  • Can quantum computers simulate all physical phenomena?
  • How does quantum information flow in time?

Bong Lian (Mathematics) is a member of the Simons Collaboration on Homological Mirror Symmetry, which involves nine investigators from eight different institutions in three countries. Mirror Symmetry, first discovered by theoretical physicists in late ‘80s, is a relationship between two very different-looking physical models of Nature, a remarkable equivalence or “duality” between different versions of a particular species of multidimensional space or shape (Calabi-Yau manifolds) that seemed to give rise to the same physics. People have been trying to give a precise and general mathematical description of this mirroring ever since, and in the process have generated a long list of very surprising and far-reaching mathematical predictions and conjectures. The so-called “Homological Mirror Symmetry Conjecture” (HMS) may be thought of as a culmination of these efforts, and Lian was a member of the group (including S.-T. Yau) that gave a proof of a precursor to HMS in a series of papers in the late ‘90s.

Lian and his Simons collaborators are determined to prove HMS in full generality and explore its applications. One consequence of HMS says that if one starts from a “complex manifold” (a type of even-dimensioned space that geometers have been studying since Riemann described the first examples in 1845), then all its internal geometric structures can in fact be described using a certain partner space, called a “symplectic manifold”. The latter type of space was a mathematical edifice invented to understand classical physics in the mid-1900s. This connection goes both ways: any internal geometric structure of the symplectic partner also has an equally compelling description using the original complex partner. No one had even remotely expected such a connection, especially given that the discoveries of the two types of spaces — complex and symplectic — were separated by more than 100 years and were invented for very different reasons. If proven true, HMS will give us ways to answer questions about the internal geometric structure of a complex manifold by studying its symplectic partner, and vice versa.

Proving HMS will also help resolve many very difficult problems in enumerative geometry that for more than a century were thought to be intractable. Enumerative geometry is an ancient (and until recently moribund) branch of geometry in which people count the number of geometric objects of a particular type that can be contained inside a space. Mirror symmetry and HMS have turned enumerative geometry into a new way to characterize and relate shapes and spaces.

Sekuler elected to Society of Experimental Psychologists

Robert Sekuler photoLouis and Frances Salvage Professor of Psychology and Professor of Neuroscience Robert Sekuler has been elected a fellow of the Society of Experimental Psychologists.  The society, founded by Edward Titchener in 1904, elects 6 new members annually from among the leading experimentalists in North America. Sekuler and his lab continue to research issues involved with visual perception, visual and auditory memory, and the cognitive process, often using video games in the research process.

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