Sprout Grant Winners 2011

Entrepreneurship is alive and well at Brandeis.

Last week, fourteen teams of Brandeis scientists presented their research to a panel of industry experts to compete for funding from the Brandeis University Virtual Incubator Sprout Grant Program.  The Virtual Incubator seeks to nurture and support entrepreneurial scientists at Brandeis by providing education, mentoring, networking and seed grants to help move their discoveries from the laboratory to the market.

Judges were impressed by the team presentations. The teams ranged from biologists who have projects that could be ready for licensing as early as next year, to computer science / IT entrepreneurship students with a web application that already has 1200 users.

“We were overwhelmed by the phenomenal proposals we received” says Irene Abrams, Associate Provost for Innovation.  “The response was incredible – with only a few weeks notice, 23 teams applied for Sprout Grants and 14 presented their proposals to the panel of judges.  I was impressed by the level of creativity among the applicants, and by the hard work the teams put into the presentations.  We only had $50,000, so we had to turn down many excellent applications, which we would have funded if we had more money.”

The 2011 winning projects are:

  • Generation Of A Rapid And Efficient Protein Knockout System, Lead Scientist:  Erin Jonasson (with Satoshi Yoshida)
  • Identification Of Molecules For Stabilizing DJ-1, A Protein Involved In Parkinson And Alzheimer Diseases. Lead Scientist: Joey Salisbury (with Brian Williams, Ala Nassar, Jeff Agar and Greg Petsko)
  • Targeting Oncogenic Ras For Protein Degradation, A Novel Approach To Therapy. Lead Scientist: Rory Coffey (with Marcus Long, Ruibao Ren, and Liz Hedstrom)
  • Identifying Pharmacological Chaperones that Promote Survival in Mouse Models of ALS, Lead Scientist: Jared Auclair (with Joey Salisbury, Dagmar Ringe, Greg Petsko, and Jeff Agar)
  • A Novel, Low Cost, Highly Sensitive Form Of Suppression PCR, Lead Scientist: Ken Sugino (with Sean O’Toole and Sacha Nelson)
  • Zen.Do, Team: Bill DeRusha, Joshua Silverman, Jason Urton (Computer Science)

see also: Brandeis NOW

Physics students present research at 20th Annual Berko Symposium on May 16

On Monday, May 16, the Physics Department will hold the Twentieth Annual Student Research Symposium in Memory of Professor Stephan Berko in Abelson 131. The symposium will end with talks by the two Berko Prize winning students, undergraduate Netta Engelhardt and graduate student Tim Sanchez. The whole department then gathers for a lunch of cold cuts, cookies and conversation. “It’s a great way to close out the academic year,” said Professor of Astrophysics and Department Chair John Wardle. “We come together to celebrate our students’ research and hear what the different research groups are doing.”

The undergraduate speakers will describe their senior thesis honors research. This is the final step in gaining an honors degree in physics, and most of them will also be co-authors on a paper published in a mainline science journal. The graduate student speakers are in the middle of their PhD research, and will disucss their progress and their goals.

The prize winners are nominated and chosen by the faculty for making particularly noteworthy progress in their research. Graduate student winner Sanchez’ talk is titled “Reconstructing cilia beating from the ground up.” He works in Professor Zvonimir Dogic’s lab studying soft condensed matter. Undergraduate winner Engelhardt’s talk is titled “A New Approach to Solving the Hermitian Yang-Mills Equations”. She works with Professors Matt Headrick and Bong Lian (Math) on problems in theoretical physics and string theory. The schedule for Monday morning and abstracts of all the talks can be found on the Physics Department website.

Sanchez’ research very much represents the growing interdisciplinary nature of science at Brandeis. Here, a physicist’s approach is used to study a biological organism. Professor Zvonimir Dogic says of his work “He has made a whole series of important discoveries that are going to have a measurable impact on a number of diverse fields ranging from cell biology, biophysics, soft matter physics and non-equilibrium statistical mechanics.  His discoveries have fundamentally transformed the direction of my laboratory and probably of many other laboratories as well.”

Engelhardt’s research is much more abstract and mathematical, and concerns fundamental problems in string theory, not usually an area tackled by undergraduates. Professor Headrick says “Netta really, really wants to be a theoretical physicist, preferably a string theorist. She has a passion for mathematics, physics, and the connections between them.” He adds that she is utterly fearless in tackling hard problems. Netta has been awarded an NSF Graduate Research Fellowship based on her undergraduate work here.  Next year she will enter graduate school at UC Santa Barbara and will likely work with eminent string theorist Gary Horowitz, who has already supervised the PhD research of two other Brandeis physics alumni, Matthew Roberts ’05, and Benson Way ’08.

This Student Research Symposium is now in its 20th year. The “First Annual…..” (two words which are always unwise to put next to each other) was initiated in 1992 by Wardle to honor Professor Stephan Berko, who had died suddenly the previous year. Family, friends and colleagues contributed to a fund to support and celebrate student research in his memory. This provides the prize money which Netta and Tim will share.

Stephan Berko was a brilliant and volatile experimental physicist who was one of the founding members of the physics department. He was born in Romania in 1924 and was a survivor of both the Auschwitz and Dachau concentration camps. He came to the United States under a Hillel Foundation scholarship and obtained his PhD at the University of Virginia. He came to Brandeis in 1961 to establish a program in experimental physics and worked tirelessly to build up the department. Together with Professors Karl Canter (dec. 2006) and Alan Mills (now at UC Riverside) he established Brandeis as a world center for research into positrons (the anti-matter mirror image of ordinary electrons). In a series of brilliant experiments they achieved many “firsts,” culminating in election to the National Academy of Sciences for Steve, and, it has been rumored, in a Nobel Prize nomination for the three of them. Steve was as passionate about teaching as he was about research, and when he died, it seemed most appropriate to honor his memory by celebrating the research of our graduate and undergraduate students. During the coffee break on Monday, we will show a movie of Steve lecturing on “cold fusion,” a headline-grabbing but phony claim for producing cheap energy from 1989.

Mapping hydrogens in chymotrypsin structures with neutron diffraction

In a new paper “Time-of-flight neutron diffraction study of bovine γ-chymotrypsin at the Protein Crystallography Station” published in this month’s edition of the journal Acta Cryst F, Biochemistry grad student Louis Lazar and co-workers from the Petsko-Ringe lab report progress on their project to determine exact hydrogen positions in proteins using neutron diffraction.

Neutron diffraction was chosen, as opposed to X-ray diffraction, because one can visualize hydrogen species directly using neutrons, while it is extremely difficult and in most cases impossible to do so using X-ray diffraction. They chose the protein γ-chymotrypsin in order to determine hydrogen positions, as it fills the necessary requirements to be suitable for a neutron diffraction experiment. These requirements include a very large crystal size (> 1 mm3), moderately sized unit cell axes (no dimension greater than 100 Å), and it must be very stable as well as well-characterized. γ-chymotrypsin is the stereotypical serine protease, cleaving C-terminal to aliphatic and aromatic residues and containing a catalytic triad of serine, histidine, and aspartate. This information on hydrogen placement can then be applied to improve computational methods in which said placement is paramount, such as molecular modeling and rational drug design.

The paper details the collection of neutron data at pD (pH*) 7.1, with the help of the scientists at the Los Alamos National Laboratory. In particular, from the initial maps, they note that the catalytic histidine is doubly protonated, while the serine and aspartate making up the catalytic triad do not show density for the presence of deuterium. In order to complete the study of γ-chymotrypsin, data at a variety of pH values must be collected; data at pD (pH*) 5.6 has already been collected (Acta Cryst F65, 317-320), and data at pD (pH*) 9.0 will be collected in the future.

see also: full text of article (Brandeis users)

A molecular function of Zillion Different Screens protein explained

In a recent paper in Journal of Cell Biology entitled “Spatial regulation of Cdc55-PP2A by Zds1/Zds2 controls mitotic entry and mitotic exit in budding yeast“, Brandeis postdoctoral fellow Valentina Rossio and Assistant Professor of Biology Satoshi Yoshida reveal a molecular function of a mysterious protein Zds1.

The Zds1 protein in yeast  was identified some years ago in “a zillion different screens” for cell cycle mutants, stress response mutants, RNA metabolism mutants, etc., but the molecular function of the protein remained a mystery for more than 15 years. Rossio revealed that Zds1’s key target is a protein phosphatase 2A (PP2A) complex. She showed that Zds1 controls nucleocytoplasmic distribution of PP2A complex, and that this regulation is critical for cells to know when to enter and to exit from mitosis (picture below; cells lacking Zds proteins adopt an abnormal shape because of problems in mitosis). Rossio thinks all the other complicated phenotypes associated with ZDS1 can also be explained by PP2A regulation and is currently studying mechanistic details about the Zds1-PP2A interaction.

See also the accompanying commentary “Proteins keep Cdc55 in its place

The Story Behind the Paper: How calmodulin became efficient

by John Lisman

Story behind: Nat Neurosci. 2011 Mar;14(3):301-4. Calmodulin as a direct detector of Ca2+ signals. Faas GC, Raghavachari S, Lisman JE, Mody I.

Long-term potentiation, a model for memory, is triggered by the activation of the calmodulin-dependent protein, CaMKII in dendritic spines. Sri Raghavachari, my former postdoc, and I were interested in how exactly CaMKII gets activated during LTP. It seemed that it should be straightforward to account for this in a computational model. Our confidence was based on the fact that a lot of groundwork had been done—the elevation of Ca2+ that triggered this process had been measured by Ryohei Yasuda and the interactions of Ca2+, calmodulin and CaMKII had all been determined in test tube experiments. But when Sri put this all together in a standard biochemical model, the simulations indicated that there would be virtually no CaMKII activation. Clearly something was wrong because Ryohei Yasuda had shown that under the same conditions in which he measured Ca2+ elevation in spines, he could also measure strong CaMKII activation.

During the summer I work at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts and Sri came down to visit. We spent hours trying to figure out what was wrong with the simulations. Sri had carefully checked the simulations and determined that the program could accurately account for other data. Thus, the problem was not a bug in the program, but rather in an assumption we had put into the program. Every day, we awoke, convinced we had found the erroneous assumption; by nightfall we had rejected that idea.

One of the great things about working at MBL is the number of other neuroscientists there and the collegial atmosphere. We went to talk to Bill Ross, an expert in the measurement of Ca2+ in neurons. It had long been known that when Ca2+ enters neurons, very little of it stays free because most gets bound to “buffer” molecules. These are like the pH buffers all biochemists use; it’s just that Ca2+ buffers bind Ca2+ instead of protons. Bill asked us a lot about the particular Ca2+ buffers that were in spines—what was known about their molecular identity and their Ca2+ binding properties. Moreover, he wanted to know what assumptions about the buffers we had built into our simulations.

The answer to this was simple: we had followed the “standard” dogma based on the work of the Nobel Prize winner, Ernst Neher. He had determined that neurons contained a “fast buffer” that very rapidly binds the entering Ca2+. He had not been able to determine what type of molecule this was. Every model of Ca2+ dynamics that had since been developed had incorporated this fast buffer into the scheme and we had followed this convention. Thus, when Ca2+ entered the cytoplasm, 95% got bound to the fast buffer; only the remaining 5% was free and could activate calmodulin.

Perhaps there was something wrong with this assumption, but to evaluate this issue we had to learn about how Ca2+ buffers work, something we knew little about. Fortunately, Isabelle Llano was working as instructor in the MBL Neurobiology course. Because of her expertise in the small proteins that buffer Ca2+ in neurons, we went to chat with her. We learned a lot from her, but she also pointed us to Guido Faas, who was working with Istvan Mody at UCLA and measuring the kinetics of how Ca2+ binds to protein buffers. Previous work had measured the equilibrium properties of Ca2+ binding to proteins—the binding rate was then inferred by calculation. In contrast, Guido was using advanced methods to rapidly jump the Ca2+ concentration and then actually measure how fast Ca2+ would bind.

As we learned more about Ca2+ buffers from Guido and read the literature more carefully about calmodulin, we finally came up with a radical but intellectually satisfying new model—-perhaps the fast buffer that Neher had measured was none other than calmodulin itself. This would certainly radically change our computer simulations—-instead of calmodulin responding to only the 5% of Ca2+ that remained free after the bulk of Ca2+ was soaked up the unknown “fast buffer”, calmodulin would be activated by all the Ca2+ ions that entered, making the process of calmodulin activation and CaMKII activation much more efficient.

But for this to be true, calmodulin would have to bind to Ca2+ fast, faster than to the other major Ca2+ binding proteins in neurons (e.g. calbindin). When we talked to Guido about this possibility, he was excited to test it. His previous work had dealt only with calbindin, but he could now extend the work to calmodulin. Indeed, he could reconstitute the buffering in spines, putting both calmodulin and calbindin into his cuvettes. When the results came in, they were stunning; calmodulin has extraordinarily fast Ca2+ binding kinetics, much faster than that of calbindin.

With the new binding parameters provided by Guido, Sri reformulated his computer model. He took out the unknown fast buffer and replaced it with only calmodulin (which is at surprisingly high concentration) and calbindin. The simulations now showed that enough calmodulin was activated to account for the measured activation of CaMKII, our holy grail.

The new view we propose makes sense: Calmodulin is the transducer that couples Ca2+ entry to enzyme activation. It would make sense for calmodulin to be as efficient a detector of Ca2+ as possible and thus to directly intercept the entered Ca2+. Our results indicate that this is the case. Ca2+ triggered reactions are implicated in hundreds of forms of biological signaling. We therefore believe that this new view of Ca2+ signaling will have broad applicability.

Yeast genetics and familial ALS

In a recent paper in PLoS Biology, “A Yeast Model of FUS/TLS-Dependent Cytotoxicity“, Brandeis postdoc Shulin Ju and coworkers applied yeast genetics to examine the function of the human protein FUS/TLS. The gene for FUS/TLS is mutated in 5-10$ of cases of Familial ALS. The yeast model expressing the mutant protein recapitulates many important features of the pathology.

A particular feature of interest is that  FUS/TLS form cytoplasmic inclusions of this protein which is normally localized to the nucleus. Over-expression of a number of yeast proteins rescues the cells from the toxic effect without removing the inclusions. The results are suggested to implicate RNA processing or RNA quality control in the mechanism of toxicity, which I find really interesting in light of the talk Susan Lindquist (an author on this paper) gave at Brandeis about yeast prions and regulatory proteins earlier this month.

Other authors on the paper include Brandeis professors Dagmar Ringe and Gregory Petsko, and Brandeis alumni Dan Tardiff (PhD, Mol. Cell. Biol.,  ’07), currently a postdoc in the Lindquist lab at the Whitehead Institute,  and Daryl Bosco (PhD, Bioorganic Chem, ’03), currently on the faculty at U. Mass. Medical School.

For more information, please see the paper itself or the longer article about the research on Brandeis NOW.

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