Lights, Camera, Splice!

In their paper “Ordered and Dynamic Assembly of Single Spliceosomes” appearing in Science this week, Brandeis postdoc Aaron Hoskins and co-workers use a combination of yeast genetic engineering, chemical biology, and multiwavelength fluorescence microscopy to work out the kinetic mechanism by which the spliceosome assembles on a model pre-messenger RNA prior to splice out an intron in the RNA. The work is a collaboration between Jefl Gelles’s lab in Biochemistry,  Melissa Moore’s lab at UMass Medical School, and  Virginia Cornish’s lab at Columbia.

Hoskins et al. use a single-molecule fluorescence approach that dubbed “CoSMoS” (Co-localization Single Molecule Spectroscopy), originally developed in the Gelles lab by Larry Friedman and Johnson Chung, that is a powerful method to study the assembly and function of the complex macromolecular machines that perform a wide variety of biological functions. In this movie, shown 150x faster than real time, the comings and goings of many U1 spliceosome components on a surface-tethered pre-mRNA are shown as the appearance and disappearances of white spots.  The white spots orginate from the fluorescence emission of specifically labeled U1 components upon excitation with a 532nm laser.

Pre-mRNAs are spliced in a complex cycle wherein the spliceosome assembles, is activated for catalysis, performs two transesterification reactions, and disassembles on every turnover.  Steps between the isolatable intermediates depicted in this cycle involve the coordinated association and dissociation of many spliceosome components.  A key finding by Hoskins et al. is that spliceosome assembly is reversible, and this is represented by the dashed arrows between the pre-mRNA, A, and B complexes.

The multi-wavelength, total internal reflection fluorescence (TIRF) microscope built by Larry Friedman and Johnson Chung in the Gelles laboratory uses lasers of different wavelengths to excite spectrally distinguishable fluorophores on various spliceosome components. Photo by Diane Katherine Hunt.

According to Hoskins, who will leave Brandeis to take up a faculty position in the Biochemistry Department at the University of Wisconsin, Madison

By far, the most challenging aspect of the project was determining two completely orthogonal methods for attaching fluorophores to endogenous spliceosomes in whole cell extract.  Since these experiments are quantitative, we needed to find methods that give a very high degree of fluorophore incoporation and specificity (in other words, 10% labeling would not cut it!).

The novel part, for me, is that for decades spliceosome kinetics have been “off-limits” to enzymologists due to the complexity of the system.  However, by developing the correct analytical tools, the spliceosome can be studied in detail usually reserved for enzymes orders of magnitude smaller.

Hoskins plans to continue these single molecule studies of the spliceosome in his new lab in Wisconsin and will be focusing on splice site selection and  coupling of nuclear RNA processing events.  He also aims to develop new methodologies for fluorescent labeling of ribonucleoproteins in vitro and in vivo.

Helfgott ’98 wins Adams Prize in mathematics

Harald Helfgott ’98 has been awarded the Adams Prize by the University of Cambridge (UK), one of its oldest and most prestigious prizes. The prize, awarded jointly to Helfgott and to Dr. Tom Sanders (University of Cambridge), honors young UK-based mathematicians  doing “first class international research in mathematical sciences”. Helfgott, currently a Reader at Univ. of Bristol and researcher at the CNRS/ENS (Paris), has been the recipient of additional prestigious prizes. In 2010 he was awarded the Whitehead Prize by the London Mathematical Society for his contributions to number theory and in 2008 he was awarded the Leverhulme Mathematics Prize for his work on number theory, diophantine geometry, and group theory.

Helfgott was a double major in Mathematics and Computer Science while at Brandeis, graduating summa cum laude with highest honors in both disciplines. Professors from both departments recall Harald as a top student, extremely well prepared, outspoken, and as one who truly loves to learn and  exchange ideas. He took full advantage of the opportunities for independent research in both departments, resulting in several conference papers and publications. In Computer Science, working with James Storer completed significant research projects on genetic algorithms for lossless image compression, Lempel-Ziv methods for two dimensional lossless compression, predictive coding, and maximal parsings. He formulated an approach to two dimensional coding that equaled one of the best methods in the literature at the time and had a number of computational advantages. According to Storer “He had an impact on nearly every research group in the Computer Science Department at that time.”

Regarding Helfgott’s work in the Math department, Ira Gessel remembers:

Although I never had him for a course, I did write a paper with him when he was an undergraduate here (the only paper I’ve ever written with an undergraduate).  Harald was involved in an undergraduate  research program with Jim Propp on tilings, and he had made some progress on solving some open problems on counting certain types of tilings. He was having trouble evaluating some determinants, and I helped him with that technical aspect of his work. But the main ideas of the paper were all Harald’s.

On graduation, Helfgott chose to focus on mathematics, doing his Ph.D. at Princeton and post-doctoral stints at Yale and at Concordia University before moving to his current position at Bristol. In addition to his current active research career, Helfgott also has been “strongly committed to the free sharing of information in all areas of intellectual activity“, giving lecture series to students and young researchers in the Third World, including lecture series in India, Cuba, Bolivia, and his native Peru.

According to Gessel:

It’s difficult to give a nontechnical account of most of Harald’s work, but here’s one of his results that’s not too hard to state.  He proved a difficult conjecture of Paul Erdős that if f(x) is a cubic polynomial with integer coefficients (satisfying some additional obvious necessary conditions that I’ll omit) then there are infinitely many primes p such that f(p) is not divisible by a square.

Mobile Applications and Game Development (JBS Summer 2011 Program)

Justice Brandeis Semester Programs for Summer 2011 are accepting applications – deadline is March 15, 2011. Among the programs is Mobile Applications and Game Development, run by Tim Hickey and Pito Salas, which is being offered for the second time this year. Last year’s student projects:

  • Cakewalk, a way to share routes and the information along them.
  • Social Market is a application which let you invest anytime and anywhere.
  • Definitious,  an online dictionary whose definitions are submitted and voted on by the online community.
  • Roommate Helper, an online resource for improving communication between roommates, in order to promote more harmonious living.

Separating proteins and manipulating live cells using magnetic nanoparticles

Brandeis grad students Yue Pan (Chemistry) and Marcus Long (Biochemistry), together with Professors Lizbeth Hedstrom and Bing Xu, have synthesized novel 6 nm diameter magnetic nanobeads (comparable in size to a globular protein) and used them to separate specific proteins from a cell lysate and manipulate live cells. This work has just appeared online in the journal Chemical Science.

Selectively binding glutathione-S-transferase fusion proteins using
glutathione-decorated iron oxide nanoparticles and down-stream applications

These small, magnetic beads have numerous advantages over larger traditional glutathione-modified beads, including rapid purification, and ultra low non-specific binding. Importantly, both the purified GST and the protein of interest (POI) preserve their innate properties. They also demonstrate that functionalized iron oxide nanoparticles can be used to manipulate live cells. This work  establishes design principles for decorating magnetic nanoparticles that will ultimately should lead to a general and comprehensive platform for studying biological interactions and biological systems using a magnetic force.

Undergraduate Biology Lab Students All Get Cataracts

After a series of renovations and modifications, the fall semester of introductory biology (Biol18b) is now an 11 week project-based lab course focused on Molecular and Structural Biology.  Students in the course now design their own mutant of γD crystallin (a human protein implicated in congenital and age-onset cataractogenesis) using site-directed mutagenesis, purify and express their protein, and then study its stability using fluorescence and AFM.

A new paper in CBE – Life Sciences Education by Brandeis undergraduates Dan Treacy, Rebecca Miller, Stefan Isaac, Danielle Saly, and Saumya Sankaran, together with grad student Susannah Gordon-Messer and Assistant Professor of Biology Melissa Kosinski-Collins,  discusses a two-year study focused on assessing both student perception of the course and analyzing the levels conceptual understanding and knowledge retention of participants.  This paper marks the second in a series of articles highlighting studies performed by life science undergraduates enrolled in an educational internship course (Ed92a) with Kosinski-Collins.

Biology research experiences at Brandeis (Summer 2011)

Thanks to new funding from the National Science Foundation, starting in Summer 2011 Brandeis will offer a new research experiences for undergraduates (REU) program in Cell and Molecular Visualization. This new grant, organized by principal investigator Susan Lovett, will provide funding for 10 undergraduates to spend 10 weeks at Brandeis in the summer doing independent research projects in close collaboration with faculty mentors. NSF REU programs place special emphasis on providing research opportunities for under-represented groups in science, and for students whose colleges cannot provide cutting-edge research facilities.

The new program will join Brandeis’s  existing MRSEC REU and other summer research activities in providing a lively atmosphere for young researchers. This competitive program will provide stipends of $5000 each plus housing and meal allowances. Participants must be US citizens or permanent residents, and should have completed their sophomore or junior year of study and be enrolled in an accredited undergraduate college or university. Further information including an application form is available on the Biology website.

Being given the opportunity to do research as an undergrad was amazing, fun, intellectual, and extremely useful; I’ve done it for two summers now.   At the beginning of my college career I was pre-med, but it only took a summer of research to help me realize that I actually want to do science over the course of my career […]

(see more quotes from undergraduates about summer research)

What we can learn about aging from worms

Coleen Murphy from the Dept of Molecular Biology at Princeton will tell us about “Slowing the Ticking Clock: What we can learn about aging and memory from C. elegans at the first Ruth Ann and Nathan Perlmutter Science Forum on Wednesday, March 9 at 4:00 pm in Gerstenzang 121. The focus of her research is on understanding the genes that regulate longevity, using C. elegans as a model system. Coleen performed her Ph.D. thesis research with Jim Spudich at Stanford where she studied myosin motors and then went on to  a post doctoral fellowship with Cynthia Kenyon at UCSF where she began studying aging. Since starting her own lab at Princeton, Coleen has been the recipient of numerous prestigious awards including a Pew Scholar Award, a Keck Distinguished Young Scholar Award, and an NIH Director’s Innovator Award. Her lab’s most recent work showed that TGF-β and insulin signaling regulates reproductive aging. In addition, her lab has also recently been looking into the connection between longevity mutants and memory in C. elegans

About the Forum: Ruth Ann Perlmutter has been a longtime friend of Brandeis University. In 1969, Nathan Perlmutter became vice president of development at Brandeis during the presidency of Morris Abrams. Perlmutter left Brandeis to become the National Director of the Anti Defamation League. Together the Perlmutters were leaders in the interfaith movement and civil rights debates for which activities Nathan received the Presidential Medal of Freedom shortly before his death in 1987. Mrs. Perlmutter earned her B.A. from the University of Denver and her masters degree in sociology from Wayne State University in Detroit. She is a sculptor and painter in her own right and currently lives in Prescott, Arizona.

Biology study abroad

The Biology Dept. and the Office of Study Abroad will hold a joint presentation about studying abroad as a Biology major at 3:30pm on Tuesday, March 8 in the Alumni Lounge in Usdan Student Center (event listing on facebook). Come and learn about the many study abroad programs available, how you can fit study abroad into your schedule, and the exciting places you can go!

There will be presentations from J. Scott Van Der Meid, the Director of Study Abroad, Dr. Dan Perlman, the Biology Department Study Abroad Liaison, and Dr. Joan Press, the Biology Undergraduate Advising Head. Students will also get the chance to ask talk to Biology majors who have studied abroad in the past, and learn how their experiences have enhanced their academic experience at Brandeis.

Hope to see you all there!

Biology UDRs

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