Student Research Results in Recent JIB Paper

Images from research paper from Pochapsky and Lovett labsBy Thomas Pochapsky, Professor of Chemistry & Biochemistry

We don’t usually consider PineSol, Vick’s VapoRub and Lemon Pledge as food, but it is a good thing that some bacteria can.  The active components of those products are terpenes, small organic molecules that are produced by evergreens to repel insects, promote wound healing and prevent infection.  The bacteria that can use terpenes as food are a critical part of the forest ecosystem:  Without them, the soil would rapidly become saturated with toxic terpenes.  Members of the Pochapsky and Lovett laboratories in Chemistry and Biology are curious about what enzymes are involved in terpene metabolism.  In particular, why would one bacterial strain feast on a particular terpene (camphor, for example) while ignoring others?

The first step in terpene breakdown by bacteria is often the addition of an oxygen atom at a particular place in the terpene molecule, providing a “handle” for subsequent enzymes in the breakdown pathway.  The enzymes that catalyze these oxygenation reactions are called cytochromes P450.  P450 enzymes perform important reactions in humans, including steroid hormone biosynthesis and drug metabolism and activation.  Human P450s are targets for cancer chemotherapy and treatment of fungal infections.  A specific inhibitor of P450 is a component of the AIDS “cocktail” treatment, slowing the breakdown of the other cocktail components so the drugs do not have to be taken as often.

Despite the importance and wide scope of the P450 enzyme family, we don’t know much about how a particular P450 goes about choosing a molecule to work on (the substrate) or where it will put the oxygen (the product).  This is what the Brandeis labs are interested in finding out.  What particular sequence of amino acids gives rise to the substrate/product combination of a given P450? Answers to this question will aid in drug design and bio-engineering projects.

The project employs multiple scientific techniques in order to get at the answers to these questions, including bacterial genome sequencing, messenger RNA transcription, enzyme isolation, activity assays, mass spectrometry and enzyme structure determination.  As complicated as it sounds, though, the project lends itself nicely to undergraduate research:  Three of the authors on this paper are undergraduates, Phillix Esquea ‘18, Hannah Lloyd ’20 and Yihao Zhuang ’18.  Phillix was a Brandeis Science Posse recruit, and is now working with a Wall Street investment bank in NYC.  Yihao is enrolled in graduate school at the University of Michigan School of Pharmacy, and Hannah Lloyd is still at Brandeis, continuing her work on the project.  Even high school students got in on the act:  Teddy Pochapsky and Jeffrey Matthews are both seniors at Malden Catholic High School, and collected soil samples used for isolation of terpene-eating bacterial strains.  (One of the newly isolated bacterial strains is named in their honor, Pseudomonas strain TPJM).

“A new approach to understanding structure-function relationships in cytochromes P450 by targeting terpene metabolism in the wild.” Nathan R.Wong, Xinyue Liu, Hannah Lloyd, Allison M. Colthart, Alexander E. Ferrazzoli, Deani L. Cooper, Yihao Zhuang, Phillix Esquea, Jeffrey Futcher, Theodore M. Pochapsky, Jeffrey M. Matthews, Thomas C. Pochapsky.  Journal of Inorganic Biochemistry. Volume 188, November 2018, Pages 96-101.  https://doi.org/10.1016/j.jinorgbio.2018.08.006.

HMS Professor Stephen Harrison to Receive 48th Rosenstiel Award

Prof. Stephen C. Harrison will receive the 48th Rosenstiel Award for Distinguished Work in Basic Medical Research on March 25, 2019. He is being honored for his studies of protein structure using X-ray crystallography.  His work has ranged from the landmark elucidation of the structure of viruses, to understanding the recognition of DNA sequences by transcription factors, to the regulation of protein kinases implicated in cancer. The event will take place from 4:00 to 5:00 PM on Monday, March 25 in Gerstenzang 123.

Harrison is the Giovanni Armenise-Harvard Professor of Basic Medical Sciences and Director of the Center for Molecular and Cellular Dynamics at the Harvard Medical School.  He is also Head of the Laboratory of Molecular Medicine at Boston Children’s Hospital and an Investigator of the Howard Hughes Medical Institute.   He has been elected a member of the US National Academy of Sciences, the American Academy of Arts and Sciences,  the American Philosophical Society; he is a foreign member of the Royal Society and the European Molecular Biology Organization.

Dr. Harrison’s initial studies of virus structure provided an understanding of how viruses invade cells and how virus particles are assembled.  He has extended his work to reveal the structures of many viruses, including influenza, HIV, ebola and dengue.  Knowledge of these structures is guiding the development of new vaccines against these viruses.  Moreover, the methodology that he and his colleagues developed to visualize virus structure has made it possible to learn about the molecular architecture of other very large assemblies of proteins.

Harrison’s lab has also revealed the ways that proteins recognize specific DNA sequences to regulate gene expression.  More recently his lab has been exploring the complex structure of the many proteins that are assembled in the kinetochore, which anchors the centromeres of chromosomes to microtubules, to permit their proper segregation in mitosis.

“Steve Harrison has done much more than giving us astonishing pictures of proteins at the atomic level; he has used this structural information to show us how these proteins perform their precise functions,” said James E. Haber, Director of the Rosenstiel Center for Basic Medical Sciences.

The Rosenstiel Award has had a distinguished record of identifying and honoring pioneering scientists who subsequently have been honored with the Lasker and Nobel Prizes. Awards are given to scientists for recent discoveries of particular originality and importance to basic medical research.

View full list of awardees.

 

 

Ivanovic Receives 2017 NIH Director’s New Innovator Award

photo: Mike Lovett

Assistant Professor of Biochemistry Tijana Ivanovic has received a 2017 NIH Director’s New Innovator Award. This award is part of the NIH’s High-Risk, High-Reward Research program, designed to fund early career investigators who propose innovative and potentially transformative projects. Ivanovic will receive $1,500,000 in direct costs over five years to spearhead a research program aimed at comprehensively characterizing molecular changes in the viral cell-entry protein hemagglutinin (HA) that define pandemic influenza viruses. With the generated insights, Ivanovic hopes to ultimately be in a position to predict the pandemic potential of influenza viruses circulating in nature.

HA densely covers the influenza virion surface, where it allows the virus to both recognize and penetrate (fuse with) the cells of its host. HA is also a key target of neutralizing antibodies that protect us from influenza infection. An influenza pandemic is characterized by the adaptation of a new HA subtype to cell entry into human cells (of what was originally an avian virus). Without the pre-existing immunity to protect us, the virus quickly spreads around the globe. During pandemic adaptation, both HA functions in target-cell recognition and membrane fusion undergo key molecular changes. Ivanovic will use a custom-built Total Internal Reflection Fluorescence Microscope (TIRFM) to visualize, in real time, individual virus particles as they engage and fuse with target cell membranes. This system will allow her to obtain large-scale quantitative information about distinct HA functions at an unprecedented level of detail. She will compare avian viruses with their evolutionary offspring that infected humans, including past pandemic strains. She hopes to develop models for predicting which viruses will lead to a major flu outbreak.

Ivanovic obtained a PhD in virology from Harvard University and carried out postdoctoral research with Stephen Harrison in molecular biophysics. She integrates these diverse backgrounds in her laboratory, where members are trained across these two and other synergistic areas (such as laser microscope optics, and analytical and computational modeling). The funds from the New Innovator award have created new opportunities for hiring, and the lab is actively recruiting postdocs, PhD students (from the Biochemistry and Biophysics, Molecular and Cell Biology, and Physics graduate programs) and undergraduate researchers to undertake this ambitious program.

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.

Research Funding For Undergrads: MRSEC Summer Materials Undergraduate Research Fellowships

The Division of Science wishes to announce that, in 2017, we will offer seven MRSEC Summer  Materials Undergraduate Research Fellowships (SMURF) for Brandeis students doing undergraduate research, sponsored by the Brandeis Materials Research Science and Engineering Center.

The fellowship winners will receive $5,000 stipends (housing support is not included) to engage in an intensive and rewarding research and development program that consists of full-time research in a MRSEC lab, weekly activities (~1-2 hours/week) organized by the MRSEC Director of Education, and participation in SciFest VII on Aug 3, 2017.

The due date for applications is February 27, 2017, at 6:00 PM EST.

To apply, the application form is online and part of the Unified Application: https://goo.gl/9LcSpG (Brandeis login required).


Eligibility

Students are eligible if they will be rising Brandeis sophomores, juniors, or seniors in Summer 2017 (classes of ’18, ’19, and ’20). No prior lab experience is required. A commitment from a Brandeis MRSEC member to serve as your mentor in Summer 2017 is required though. The MRSEC faculty list is: http://www.brandeis.edu/mrsec/people/index.html

Conflicting Commitments
SMURF recipients are expected to be available to do full time laboratory research between May 30 – August 4, 2017. During that period, SMURF students are not allowed to take summer courses, work another job or participate in extensive volunteer/shadowing experiences in which they commit to being out of the lab for a significant amount of time during the summer. Additionally, students should not be paid for doing lab research during this period from other funding sources.

Application Resources
Interested students should apply online (Brandeis login required). Questions that are not answered in the online FAQ may be addressed to Steven Karel <divsci at brandeis.edu>.

The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

benefits-midage

They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

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