REU Students Arrive for 2016 Summer Research

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Amber Jones and Susan Okrah

Alongside the more than 100 Brandeis science undergrads doing research this summer, there are 19 students who are participating in our Research Experiences for Undergraduates (REU) programs. Some students are from Brandeis, but most call universities in Kansas, Virginia, Pennsylvania, New Jersey their academic homes. Eight students are from Hampton University as part of the Partnership for Research and Education in Materials (PREM) initiative between Hampton and Brandeis. The two universities are focused on fostering interest in research science in under-represented groups of undergraduates.

The two independent REU programs were each created 6 years ago with funding from the National Science Foundation (NSF) with a goal of providing a 10-week period of intensive lab research experience to rising sophomores and juniors interested in scientific careers. Professor Susan Lovett is the director of the Cell and Molecular Visualization REU and Dr. Anique Olivier-Mason is the director of the Material Research Science and Engineering Center (MRSEC) REU.

The online application process required each student to submit a transcript, two letters of recommendation and write two essays describing their research experience (if any) and their academic and research goals. This year, 8 students are participating in the MRSEC site; 11 students are working in the Biology-based Cell and Molecular Visualization REU.

Amber Jones, who is going to be a junior at Hampton University this fall, is working in the Avi Rodal lab where she is researching how proteins can be taken on and off of cell membranes. From here, she is hoping to target specific proteins that will ultimately aid in disease research.

Amber has worked in a lab before, but believes nothing could have prepared her for her experience at Brandeis. Her REU lab work has been very involved, but she wasn’t expecting the ups and downs that are a part of lab research. The graduate students and other lab members have been supportive. She has been told “it’s okay; it’s science!”

Returning REU student, Alex Cuadros is working in the Liz Hedstrom lab, says he can go to Cell and Molecular Visualization REU coordinators Cara Pina and Laura Laranjo for assistance. They “have more experience in the lab and they tell me that things don’t always work for them. They say that ‘it’s just part of the science’.”

Nicholas Martinez, who is working in Timothy Street’s lab said, “The biggest challenge I have encountered this summer with my research is being able to do cope with disappointment. Since I am working on a defined timetable and my time here at Brandeis is limited, I want to make as much progress as possible with my research.”

Susan Okrah is working in the Seth Fraden lab this summer. She believes this experience is different from a Chemistry class at Hampton University where you are given an experiment and the results are known. In the REU program, students are given a project that is a subset of their lab’s research. Unlike school, the outcome of their research is unknown. Susan said, “We are given a direction and told to see if it works.”

Alex said that in class he has learned how to do experiments, but at Brandeis he is “doing something that has not been done before so there’s no right method.” It’s also helpful to be able to ask advice about how to approach his research and “Then you go back and you figure out how to do it. You are forced to think independently.”

During the academic year, Alex works in a Biochemistry lab at UMass Amherst. He landed the job last fall as a direct result of his 2015 REU research. How did he get the job in a very competitive environment on the large UMass campus? He presented the poster that he prepared for SciFest 2015.

The most valuable lesson learned this summer? “Resilience” said Amber. Learning to cope with the changing tides of research is important. As Susan said, “people don’t really understand what goes into research until they’re here.”

Part of the REU program involves attending journal clubs and lab meetings, but the most valuable experience of this program is simply being in a lab. Both Amber and Susan agree that anyone thinking about a career in research should go through an intensive research experience such as this. Jones noted, “I wasn’t really expecting to get this type of understanding. I really appreciate that now that I’m here.”

Both Nicholas and Alex ultimately would like to attend graduate school. For Nicholas, “being able to participate in the Cell and Molecular Visualization REU program at Brandeis has been a great opportunity for me to diversify my knowledge and skill set in scientific research prior to applying for graduate school next year. This It has been a great way for me to gain experience in a new area of research that I am interested in and to become part of a different scientific community.”

The REU students are hard at work wrapping up their research and preparing their posters for the SciFest 2016 poster session that is scheduled for Thursday, August 4.

Celebrating Chris Miller at Christravaganza Millerpalooza

Since its founding at Brandeis in 1976, Chris Miller’s lab has been home to 25 graduate students and 35 postdocs. Many of them, together with friends and colleagues from around the world, came together on July 8 and 9 for a two day symposium celebrating Chris’ 70th birthday.

For four decades Miller has used electrophysiological methods to study single ion channels. Ion channels are proteins that open and close, selectively allowing specific ions to cross cell membranes, for example to drive muscle contraction or nerve cell signaling. The selective transport of ions across membranes is a fundamental feature of cells.

Miller began studying channels selective for potassium ions, and then in 1978 discovered a chloride selective channel, from Torpedo, the first member of the important CLC chloride channels whose malfunction is implicated in a variety of diseases. (Its name comes from the electric ray Torpedo californica from which the channel was first isolated.) Chris discovered the unusual “double barreled” architecture of the CLC family of ion channels. The lab continues to work on related proteins, including Cl/H+ exchange-transporters.

Miller’s lab has followed clues in recent years to find additional novel channels to study, including bacterial proteins involved in acid resistance and most recently channels that are selective for fluoride. Chris has been a Howard Hughes Medical Institute investigator since 1989 and in 2007 he was elected to the US National Academy of Sciences.

Rod MacKinnon ’78 was Chris’ very first student while he was an undergraduate at Brandeis. After medical school, Rod came back to Chris’ lab as a postdoc, and together they investigated the mechanism of calcium activated potassium ion channels. Later, at Rockefeller University, Rod used high resolution x-ray diffraction to determine the complete molecular structure of the proteins that form the channel. For this he was awarded the Nobel Prize for Chemistry in 2003. The structure confirmed a cartoon picture of how the potassium channel works that Chris, with postdoctoral fellows MacKinnon and Jaques Neyton, had developed ten years earlier.

Chris’ wife, Brandeis Professor of Russian and Comparative Literature Robin Feuer Miller, and their three daughters were in attendance. Lulu Miller (who is also co-host of the NPR program Invisibilia) introduced her father for the final talk of the symposium.

The editors thank Dan Oprian for help with this article. The photographs were taken by Heratch Ekmekjian.

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.

Sprout Award Winners Announced

The recipients of the 6th annual Sprout Awards have been announced. There will be eight teams from labs in the Biology, Biochemistry, and Chemistry departments sharing the $100,000 in funding in FY 2017. The Sprout program’s grant pool was doubled this year in order to expand the support for the promising innovation and research that is happening here at Brandeis University.  The Sprout program, created 6 years with the intent to encourage entrepreneurial activity, is sponsored by the Office of the Provost and the Hassenfeld Family Innovation Center. It is administered by the university’s Office of Technology Licensing

(read more at Brandeis Now).

 

Using computer simulations to model bacterial microcompartment assembly

Bacterial microcompartments are protein shells found in bacteria that surround enzymes and other chemicals required for certain biological reactions.  For example, the carboxysome is a type of microcompartment that enables bacteria to convert the products of photosynthesis into sugars (thus taking carbon out of the atmosphere).  During the formation of a microcompartment, the outer protein shell assembles around hundreds of enzymes and chemicals required for the reaction.  Because the intermediates in this assembly process are small and short-lived, it is hard to study in detail using experiments. It is therefore useful to develop computational models that can help explain how proteins collect the necessary cargo, and then assemble into an ordered shell with the cargo on the inside.  The videos in this post show some examples of computer simulations of a model for bacterial microcompartment assembly, with each video corresponding to a different set of parameters that control the strengths of interactions among the proteins and cargo.

The study is described in the research article “Many-molecule encapsulation by an icosahedral shell” by Jason Perlmutter, Farzaneh Mohajerani, and Michael Hagan in eLife (eLife 2016;10.7554/eLife.14078).

Video 1: Multistep assembly of a microcompartment encapsulating hundreds of molecules (I) video1
Video 2: Multistep assembly of a microcompartment encapsulating hundreds of molecules (II)  video2
Video 3: Assembly of a microcompartment and encapsulation of hundreds of diffuse cargo molecules  video3

Jeffery Kelly to receive the 2016 Jacob and Louise Gabbay Award

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Jeffery W. Kelly

Jeffery W. Kelly, the Lita Annenberg Hazen Professor of Chemistry, and Chairman of the Department of Molecular and Experimental Medicine at the Scripps Research Institute, has been selected to receive the 2016 Jacob and Louise Gabbay Award in Biotechnology and Medicine “in recognition of his profound and paradigm-shifting contributions to our understanding of protein folding mechanisms and protein misfolding diseases”.

The award, administered by the Rosenstiel Center at Brandeis, consists of a $15,000 cash prize and a medallion. Dr. Kelly will deliver the award lecture on “The Chemistry and Biology of Adapting Proteostasis for Disease Intervention” in the Shapiro Campus Center Theater at 4:00PM, on Thursday, September 29, 2016.

The Kelly Group focuses their research on understanding the principles of protein folding and comprehending the basis for misfolding diseases. They strive to develop novel therapeutic strategies using chemistry, biophysical and cell biology approaches.

 

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.”

 

Trapping individual cell types in the mouse brain

Lines labeling cortical subplate, mesencephalic, and diencephalic cell types

Lines labeling cortical subplate, mesencephalic, and diencephalic cell types (see Fig. 7 in Shima et al.)

The complexity of the human brain depends upon the many thousands of individual types of nerve cells it contains. Even the much simpler mouse brain probably contains 10,000 or more different neuronal cell types. Brandeis scientists Yasu Shima, Sacha Nelson and colleagues report in the journal eLife on a new approach for genetically identifying and manipulating these cell types.

Cells in the brain have different functions and therefore express different genes. Important instructions for which genes to express, in which cell types, lie not only in the genes themselves, but in small pieces of DNA called enhancers found in the large spaces between genes. The Brandeis group has found a way to highjack these instructions to express other artificial genes in particular cell types in the mouse brain. Some of these artificially expressed genes (also called transgenes) simply make the cells fluorescent so they can be seen under the microscope. Other transgenes are master regulators that can be used to turn on or off any other gene of interest. This will allow scientists to activate or deactivate the cells to see how they alter behavior, or to study the function of specific genes by altering them only in some cell types without altering them everywhere in the body. In addition to developing the approach, the Brandeis group created a resource of over 150 strains of mice in which different brain cell types can be studied.

website: enhancertrap.bio.brandeis.edu

Shima Y, Sugino K, Hempel C, Shima M, Taneja P, Bullis JB, Mehta S, Lois C, Nelson SB. A mammalian enhancer trap resource for discovering and manipulating neuronal cell types. eLife. 2016;5.

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