The NIBN Is Currently in Its Fourth Year Since Its Establishment

July 2013 3

Dear Friends:

he NIBN is currently in its fourth year since its establishment Tin 2009 as an autonomous research institute. With NIBN’s mission of promoting applicative scientific projects with the intent for translation towards eventual commercialization, NIBN’s team continues to make significant inroads and navigate NIBN’s roadmap towards this goal. Several strides have been taken towards bridging the gap between basic and applied research, with the aim to raise interest among investors and big Pharmaceutical companies. The experienced NIBN team with Yuval Kupitz (MBA), responsible for business development and Lewis Neville (PhD), recently recruited as Deputy Director with expertise in drug development, aim to guide NIBN members towards an applicative avenue, creating novel projects whilst redirecting and focusing on others. NIBN’s financial support for performing research in the scientists’ laboratories or via outsourcing, together with appropriate business development opportunities, represent a unique approach present only in the NIBN.

The International Scientific Advisory Board (SAB) continues to mentor and provide valuable consulting advice in helping to implement creative changes in the NIBN members’ research activities with respect to advancing the applied commercial aspects in parallel with basic research efforts. With the spirit of cooperation and entrepreneurship, we are now reaching a “critical mass” for significant industrial collaborations. This confirms that NIBN is becoming a renowned and highly respected center of scientific excellence.

I would like to welcome the new NIBN SAB members, Prof. Nathan Nelson, Tel-Aviv University, Recipient of Israel Prize for Life Sciences, (2012), Director of the Daniella Rich Institute for Structural Biology and former President of the Israel Society for Biochemistry and Molecular Biology and Prof. Hermona Soreq, Hebrew University, former President of the Israeli Society of Biochemistry and Molecular Biology (2000), Dean of the Faculty of Natural Sciences of the Hebrew University (2005), and recipient of Israeli Ministry of Health prize (2000). Three dimensional cyst The recruitment of Nathan and Hermona to our revered SAB formation of MDCK cells consisting of Profs. Raymond Dwek, Philip Needleman, Sir Aaron grown in collagen matrix Klug, Aaron Ciechanover and Richard Ulevitch, will contribute (Dr. Natalie Elia)

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a highly valuable, local outlook in terms of scientific excellence.

As part of the NIBN development, the new NIBN building is in its advanced stage (see page 9). It is axiomatic that to realize the full potential of the NIBN, the scientists and the service units cannot be limited by space constraints and must be closely located. Thus, moving NIBN members’ laboratories, currently in six different buildings, to the new Professor Raymond Dwek building by July 2014, will be a major advantage for NIBN’s recognized in the U.K. New Years entire development, infra-structure and business model. Honors List (2013) As in previous NIBN newsletters, in this issue we highlight three newly recruited NIBN members. We introduce you to rofessor Raymond Dwek, a member Dr. Natalie Elia (Department of Life Sciences), Dr. Dan Levy of the NIBN’s Scientific Advisory P (Department of Microbiology, Immunology and Genetics) and Board, Director of the Glycobiology Dr. Eyal Arbely (Department of Chemistry). We also introduce Institute, Emeritus Professor of you to Dr. Lewis Neville, Deputy Director, NIBN. Glycobiology and Emeritus Fellow of Exeter College, University of Oxford, Commitment towards the development of the NIBN is not received the prestigious award of CBE only reflected in the recruitment of new members, but also (Commander of the Most Excellent in establishing new centers for scientific excellence. An Order of the British Empire) for services example of such commitment is underscored following the to UK-Israel scientific collaborations. recent inauguration of The Aaron Klug Integrated Centre for Prof. Dwek serves as a Special Advisor Biomolecular structure and function (AKIC-BSF; see page 3). on Biotechnology to the President of Ben-Gurion University of the Negev NIBN members and the International Scientific Advisory Board, and played an instrumental role in congratulate Prof. Raymond Dwek on being awarded a CBE in helping to establish the NIBN and to recognition of services to UK-Israel scientific collaboration, Dr. monitor its scientific level. Prof. Dwek is Esti Yeger-Lotem on being awarded the Toronto Prize as well also co-chair of the BIRAX initiative on as a number of PhD students on receipt of awards. Additionally, Regenerative Medicine, together with many congratulations to Profs. Amir Sagi and Ohad Birk for BGU President Prof. Rivka Carmi and “crossing the boundaries” following their recent visits to the UK Ambassador, HE Mr. Mathew Myanmar and Qatar, respectively. Gould. Finally, I would like to take this opportunity to thank the SAB members for their commitment and immense support. Also, many thanks to NIBN Executive Committee members, BGU President, Prof. Rivka Carmi, Vice-President and Dean for R&D, Prof. Moti Herskowitz and the Director-General, Mr. David Bareket, for their help and guidance in advancing the NIBN towards reaching its goal.

I wish everyone much success.

Prof. Varda Shoshan-Barmatz NIBN Director

2 The Aaron Klug Integrated Centre for Biomolecular Structure and Function (AKIC-BSF)

he NIBN and Ben- link between Britain and Israel. It is a particular pleasure TGurion University have to be here for three reasons. First, the opening of the recently established the centre ties together two of my favourite universities, AKIC-BSF, named after BGU (Gould received an honorary doctorate from BGU Professor Sir Aaron Klug, in December 2011) and Cambridge University and winner of the Nobel Prize specifically Peterhouse, which is Prof. Klug’s college in Chemistry in 1982. and where I studied. Second, it is a celebration of the Prof. Klug was awarded the Nobel for his development relationship between Britain and Israel in science. of crystallographic electron microscopy and structural Both are scientific superpowers with complementary elucidation of biologically important nucleic acid-protein strengths. Third, because it pays tribute to Prof. Klug. complexes. Prof. Aaron Klug has been centrally involved He is universally known as kind, fair and decent. He is in the establishment of the NIBN and has remained a world class scientist without the ego to match. He continuously involved in its growth and development, has shown us what science can achieve and should be having served as Acting Executive Director for two years. doing to unlock Nature’s secrets to provide pathways to healing.” The AKIC-BSF is a National Centre of Excellence for structural studies and will serve as a focal point The scope and mission of the AKIC-BSF was for scientists throughout Israel and from around the presented by Dr. Natalie Elia (NIBN and Department world. The centre focuses on integrative approaches of Life Sciences, BGU). Prof. Klug’s background and of structural biology aiming to unveil the mechanistic achievements were lucidly presented by Prof. Ueli Aebi basis of physiological processes from atomic to cellular (a member of the centre’s steering committee), which levels. included many anecdotal stories that arose during Prof. Klug’s distinguished career. The AKIC-BSF will create a unique environment to facilitate state-of-the-art research in structural biology The scientific session included an outstanding lecture and it is our goal that the AKIC-BSF will mature and by Prof. Ian Wilson (The Scripps Research Institute) develop into a unique and internationally-recognized entitled “An integrative approach to structure-based centre. vaccine design for HIV and Influenza virus ” and a video lecture by Prof. Klug on Engineered zinc finger protein. The centre maintains state-of-the-art equipment, which will be further strengthened with acquisition of additional equipment to comply with its commitment to scientific excellence.

The Steering Committee of AKIC-BSF includes Prof. Ueli Aebi, Prof. Sir Alan Fersht FRS, Nobel laureate Prof. Roger D. Kornberg, Prof. Jennifer Lippincott-Schwartz and Prof. Ian Wilson FRS, FRSE.

The dedication ceremony of the AKIC-BSF took place on April 11th, 2013, in the presence of HE Mr. Matthew Gould MBE (UK ambassador to Israel), Profs. Raymond Dwek, Ian Wilson and Ueli Aebi, members of the Klug family and scientists from BGU and other academic institutions in Israel. The dedication ceremony was organized by the NIBN and was moderated by Prof. Varda Shoshan-Barmatz, NIBN Director.

The ceremony was opened by Prof. Raymond Dwek (University of Oxford) who introduced Mr. Matthew Opening of the Aaron Klug Integrated Centre for Gould. Mr. Gould gave a very warm introductory Biomolecular Structure and Function with an invited panel address to the participants. Gould explained why he consisting (Left to right) of Prof. Moti Herskowitz (VP and Dean for R&D, BGU), Prof. Raymond Dwek (University of was delighted to be at this dedication. He commented Oxford), HE Matthew Gould (British Ambassador to Israel), that “any ambassador would be delighted to pay tribute Prof. Ian Wilson (The Scripps Research Institute) and Prof. to Prof. Klug and to be at an event that sets in stone the Ueli Aebi (University of Basel).

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Genetically encoded non-canonical amino acids: Adding new chemistries to ribosomally synthesized proteins

he ribosomal translation Tmachinery has evolved to decode 64 triple-nucleotide codons, each encoding either one of the canonical 20 amino acids (with the rare exceptions of selenocysteine and pyrrolysine), or the termination of translation. Although evolved to near perfection, this cellular apparatus is far from exploiting its full potential. This is evident by recent advances in the field of genetic code expansion that allow the genetic encoding and incorporation of non-canonical amino acids during ribosomal protein synthesis in bacteria, yeast, mammalian cells, Caenorhabditis elegans and Drosophila. The addition of new chemical groups (via the incorporation of new amino acids) enables the design of tailor-made Figure 1: Genetic code expansion. A tRNA synthetase evolved recombinant proteins with novel chemical properties to recognize a non-canonical amino acid, amino-acylates a and the study of biological processes that are difficult specific tRNA with the AUC anti-codon. The non-canonical amino acid is incorporated during ribosomal translation, in or impossible to address by more classical methods. response to genetically encoded Amber stop codon UAG. The expressed protein will have a non-canonical amino acid Site-specific incorporation of non-canonical amino at a single and pre-defined position. acids during mRNA translation has been made possible by exploiting the natural redundancy of the genetic code and the hyper-promiscuous character of the methods for directed evolution using large libraries of aminoacyl-binding site, the EF-Tu and the ribosome. synthetases with altered active site. Four different tRNA In this approach, the amber stop codon (UAG) is re- synthetase/tRNA pairs are currently used for genetic assigned to specify the new amino acid and is placed code expansion, but the Methanococcus jannaschii at a user-defined position (Figure 1). The in-frame Tyrosyl-tRNA synthetase (MjTyrRS)–tRNACUA pair and amber stop codon is then recognized during mRNA the pyrrolysyl-tRNA synthetase (PylRS)–tRNACUA pair translation by an orthogonal amber suppressor tRNA, from Methanosarcina species are the most commonly aminoacylated with the new (i.e., non-canonical) amino used pairs. While the MjTyrRS–tRNACUA pair is naturally acid. To ensure site specific incorporation of the non- orthogonal to the synthetases and tRNAs in E. coli but canonical amino acid, this amber suppressor tRNA must not to those in eukaryotic cells, the PylRS–tRNACUA not be recognized by endogenous tRNA synthetases pair is orthogonal to those in E. coli, yeast, mammalian and at the same time, it should be recognized by an cells, Caenorhabditis elegans and drosophila. Together, orthogonal tRNA synthetase that can aminoacylate it these couples have been evolved to incorporate with only the non-canonical amino acid. To maintain dozens of non-canonical amino acids with diverse full orthogonality, the tRNA synthetase should not physicochemical and biological properties. The recognize and aminoacylate any endogenous tRNAs. new chemistries, added to ribosomally synthesized Last, the non-canonical amino acid must be efficiently proteins by genetically encoded non-canonical amino transported to the cytoplasm, be metabolically stable acids, allow a variety of chemical manipulations and and recognized by the orthogonal tRNA synthetase measurements that cannot be done with natural amino only. acids (Figure 2).

The orthogonal amber suppressor tRNA and its Non-canonical amino acids may carry chemical cognate tRNA synthetase are generated in two handles that can be used for site-specific chemical steps. First, a tRNA synthetase/tRNA couple from an manipulation (3 and 4, Figure 2) or bioorthogonal evolutionary divergent organism is expressed in the chemistry (5 and 6, Figure 2). For example, the host of interest (e.g., E. coli). Second, the specificity bioorthogonal inverse-electron-demand Diels-Alder of the tRNA synthetase is altered so it will recognize reaction, between strained alkynes and tetzrazines, the non-canonical amino acid and not one of the that takes place at exceptionally high rate within natural amino acids. This is usually done by applying the cellular environment (Figure 3a). By coupling the

4 tetrazine molecule to a fluorescent for ribosomal synthesis of proteins organic dye, proteins can be site- with novel chemical properties. specifically labeled with a small Specifically, we are interested in organic fluorophore with superior studying the role of p53 lysine photophysical properties (compared acetylation in the induction of to fluorescent proteins). Expression apoptosis. Here, we apply methods of proteins with a genetically for genetic code expansion to better encoded photo-caged residue in live understand the structural effects of mammalian cells provides us with lysine acetylation on DNA binding unparalleled spatiotemporal control (in vitro) and transactivation (in of signaling pathways and enzymatic live cells). Other projects involve activities (Figure 3b and 3c). For the application of methods for example, photo-caged tyrosine photo control of cellular processes (2, Figure 2) residue cannot be to study the kinetics of signal- phosphorylated, since the hydroxyl transduction processes within group is protected. Photolysis of the JAK-STAT pathway. To further the O-nitro protecting group using enhance the chemical diversity of (non-invasive) light, exposes the ribosomally synthesized proteins we ‘native’ hydroxyl group, allows its are developing new methodologies phosphorylation and consequently for posttranslational enzymatic the activation/deactivation of the modifications of protein backbone protein under study (Figure 3b). and amino acid side chains.

Of special interest to the work As a faculty member of the in my laboratory, is the ability Figure 2: Non-canonical amino Department of Chemistry and the to genetically encode the site- acids added to the genetic codes National Institute for Biotechnology specific incorporation of post- of prokaryotes and/or eukaryotes. in the Negev, my goal is to develop Acetylated lysine (1); Photo-caged translationally modified residues tyrosine (2); δ-thiol-L-lysine, methodologies for the synthesis such as acetylated lysine (1, Figure for traceless and site specific of biologically active compounds 2). Lysine acetylation is now ubiquitination of recombinant that are based on ribosomally believed to be involved in a variety proteins (3); p-benzoylphenylalanine synthesized proteins and translate of fundamental cellular processes, for photocrosslinking (4); lysine knowledge gained from this derivatives with alkyne and azide with a correlation between the level groups for Cu2+ catalyzed click research to the biotechnology of acetylation and metabolism and chemistry (5, 6). arena. the development of cancer. A key requirement for elucidating the mechanism underlying acetylation- induced cellular responses, is to study a homogenous population of the acetylated protein, which in most cases, is impossible to obtain with conventional methods, such as in vitro enzymatic labelling, chemical synthesis, or native chemical ligation. More importantly, the application of these methods to measurements in live cells is limited. An elegant solution to this problem is to genetically encode the incorporation of acetylated lysine. Using this approach, site- specifically acetylated proteins can be expressed in bacteria and mammalian cells, and allow direct measurement of acetylation induced processes based on gain Figure 3: Examples for the use of non-canonical amino acids. (a) Bicyclononyne of function (acetylation) and not loss used in bioorthogonal labeling with tetrazine-fluorescent organic dye of function (e.g., lysine to arginine conjugate. The non-fluorescent tetrazine-conjugated fluorophore has a strong mutation). enhancement in fluorescence upon binding to bicyclononyne and hence, low background fluorescence. (b, c) Photo-deprotection of photo-caged tyrosine (b) and photocaged lysine (c). The photo-labile protecting groups can be cleaved off The work in my laboratory is aimed within the complex chemical environment of the cell, using non-invasive short at developing and applying methods pulse of light.

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Cell biology in the new era of microscopy

ells are the smallest bounded by membranes, both intra- and extra-cellular Cautonomous units of communication are mediated by a series of membrane life capable of executing fission and fusion events that result in the budding of numerous cellular processes cargo-containing vesicles that deliver the information at a given time. How these from one cellular component to another. These complex processes are energetically demanding processes of membrane orchestrated in the cellular remodeling are mediated by several different protein milieu have fascinated cell families that carry the unique ability to physically bend biologist for many decades. biological membranes. The ESCRT machinery is a multi- Over these years, many of protein complex that has come to be recognized as the molecular players that the driving force for membrane constriction and participate in executing the fission in a variety of cellular processes including different cellular functions the multivesicular (MVB) pathway for degradation of have been identified and transmembrane proteins and cell division. Notably, characterized in great detail both inside and outside several retroviruses, including HIV-1, hijack the cells. These studies have emphasized the dynamic ESCRT machinery for budding out of host cells to nature of protein complexes in cells and stressed infect neighboring cells. By combining a variety of the need to characterize these protein complexes high resolution imaging tools and by developing new in their native environment and under physiological molecular tools to acutely interfere with the function conditions. Direct visualization of the structure and of the ESCRT machinery as they execute their cellular dynamics of protein complexes in cells is therefore function, we aim to decipher the underlying mechanism expected to contribute extremely valuable information for ESCRT mediated membrane remodeling in living on their mechanistic role in driving cellular processes. cells. This was however, technically challenging for many During my post-doctoral training at the National years due to the small dimensions and fast dynamics Institutes of Health (NIH), I identified a role for the ESCRT of protein complexes relative to the spatiotemporal machinery in cell division. These studies highlighted the resolution of microscopes. Thanks to recent advances advantages of using cell division as a model cellular in fluorescence light microscopy techniques, this has process to study ESCRT-driven membrane constriction now become possible. The development of Confocal and fission in a physiologically relevant system. The spinning disk microscopy and digital imaging provides relatively large dimensions of the structure (>1 µm the high imaging speed, sensitivity and dynamic range compared to ~100 nm of a viral bud) and the relatively needed to measure protein dynamics in cells at real slow progression of the process (~ 2 hours compared time. In addition, Super resolution microscopy, provides to ~20 minutes in HIV viral budding) offers an ideal exquisite spatial resolution (less than 100nm) allowing system to study mechanistic aspects of the ESCRT characterization of the structural organization contractile machinery in cells using the newly available of multiprotein complexes in their native, cellular imaging tools. Moreover, the abundance of molecular environment. players already identified in cell division offer a unique In our laboratory, we are utilizing the new developments opportunity to study how ESCRT function is regulated in light microscopy to decipher the underlying at the cellular level and to characterize the dynamic mechanisms of cellular processes. By combining interplay between the ESCRT membrane bending the temporal information obtained by spinning disk machine and other fundamental cellular machineries microscopy with the detailed structural information obtained by Super resolution imaging, we can generate spatiotemporal maps of protein complexes in a given cellular process. Constituting such maps will facilitate mechanistic understanding of different cellular machineries. Of special interest to us are processes that mediate cellular communication. To ensure proper function, cells routinely maintain both extracellular communication with their outside environment and intracellular communication between different organelles and inside the cell. As all cells and most cellular organelles are Figure 1: Cellular membrane fission processes mediated by the ESCRT complex.

6 including microtubules, actin, phospholipids and membrane trafficking.

On April 2012, I joined the NIBN and the department of Life Sciences at Ben-Gurion University of the Negev. During my PhD at the Hebrew University of Jerusalem, I studied the dynamic interactions of peripheral proteins with the membrane using biochemical approaches. Realizing that these processes should be studied at the single cell level, I continued with post-doctoral training in the laboratory of Dr. Jennifer Lippinicott-Schwartz, an internationally-renowned leader in cellular imaging and super resolution microscopy. During my postdoctoral training, I acquired expertise in cellular imaging in general and in super resolution imaging in particular through practical trainings and extensive experience. My current laboratory is equipped with two state-of-the-art imaging systems. The first system is the 3i Marianas confocal spinning disk system that is optimized for live cell imaging and protein dynamics measurements. The second is the Elyra super resolution imaging system by Zeiss. This system uses a technique called Structured Illumination Microscopy (SIM) and is capable of three-dimensional (3D) multi-color imaging at 100 nm lateral and 350 nm axial resolution in any biological sample that is up to 10 micron thick. As such, SIM is one of the most suitable techniques for mapping the spatial organization of protein complexes in their native environment at nanometer scale. By utilizing these new state-of-the-art tools and by developing new tools for cellular imaging and genetic manipulation, we will continue to study cellular mechanisms at the single cell level with superb spatiotemporal resolution. Our ultimate goal is to obtain mechanistic understanding of fundamental cellular processes in order to better Figure 2: Mammalian cells are connected by a thin microtubule understand the fascinatingly complex, yet superbly and membrane based bridge at the end of cell division. Top orchestrated machine called the cell. panel, cells expressing tubulin-GFP imaged live using a spinning disk confocal microscope. Bottom panel, the bridge connecting two diving cells as seen by electron microscopy.

Figure 3: Localization of the ESCRT-I component, TSG101, at the bridge of dividing cells as imaged by spinning disk microscopy (top) or by SIM (bottom). The comparison demonstrates the remarkable increase in resolution achieved by SIM.

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How lysine methylation modulates epigenetics programs in human health pigenetics is the study chemical moieties from the histone proteins. Reversible Eof heritable changes covalent post-translational modifications (PTMs), such in gene expression or as phosphorylation, acetylation, and methylation, are cellular phenotype, caused critical modulators of these epigenetics programs. by mechanisms other than While phosphorylation is the most extensively studied changes in the underlying PTM, lysine methylation is emerging as a key player DNA sequence; hence the in regulating these processes. The methylation of name epi-(Greek: επί- histones was originally identified in the 1960’s. over, above, outer) genetics. However, it was not until 2000 when the first histone In this context, every cell lysine methyltransferase family was discovered, that in our body contains the highlighted the importance of this chemical mark. The same genetic information. methylation of lysine residues is performed by protein However, sharing the lysine (K) methyltransferases (PKMTs), which add exact DNA sequence is not mono-, di- or tri-methyl marks to the lysine. The degree sufficient to modulate the extraordinary different of methylation is enzyme specific and can lead to a properties of diverse cell types, tissues and of course distinct biological outcomes by recruiting specialized it is not enough for the maintenance of the body in regulatory factors, known as “readers”, that recognize different physiological and pathological scenarios. specific modifications. Lysine methylation regulates For example, stem cells in our body can differentiate diverse cellular signaling pathways that influence to form a variety of cell types with distinct function, survival, growth, and proliferation, and disruption of whereas brain and heart cells, are fixed in solid these pathways is thought to fundamentally impact the tissues and do not divide. Different biological signaling development and progression of many differentiation pathways should be turned on in response to diverse processes, leading to disease. physiological consequences while other target genes The large number of enzymes devoted to placing should be turned off. How do these differences in cell methyl groups on lysine residues argues for the types arise without alterations in the DNA sequence? presence of numerous protein substrates in addition How do stem cells know how to differentiate into to the few that have already been characterized. And muscle cells and not bone cells? What are the molecular indeed, over the past decade, many studies have shed mechanisms that regulate the fine tuning of switching light on mechanisms that couple the methylation of “on” and\or switching “off” a define target gene. histone and non-histone proteins to the regulation of The DNA in our body is packed and condensed by various epigenetics cellular programs with fundamental proteins (histones) into a highly dynamic structure impact on diseases pathology (Figure 1). termed chromatin. Epigenetic regulation is partly In October, 2012, I joined the NIBN and the maintained by the modulation of chromatin structure Department of Microbiology, Immunology and and is achieved by addition and removal of distinct Genetics at Ben-Gurion University of the Negev. I performed my undergraduate studies at the Hebrew University, majoring in agriculture, plant genetics and biotechnology. For my MSc. studies I moved to Tel-Aviv University and was exposed to the world of mRNA splicing. To pursue my interest in mammalian systems with specific focus on signaling pathways in physiology and regulation of disease, I moved to the Weizmann Institute and studied oncogenic signaling pathways through tyrosine phosphorylation. For my postdoctoral work, I moved to Stanford University to work with Prof. Or Gozani, a worldwide leading expert in the epigenetic research field. During my postdoctoral training, I continued to study transcription factor regulation by PTM but shifted my research to focus on lysine methylation, chromatin biology and the regulation of gene expression and epigenetics programs. I described a methylation signaling cascade, which is initiated by site-specific methylation of the NF-κB subunit RelA by the PKMT SETD6 and leads to stabilization of the H3K9 PKMT GLP at chromatin Figure 1: Involvement of methylation of histone and non- and repression of cell proliferation and inﬂammatory histone proteins in the regulation of diverse biological gene expression programs. In collaboration with Dr. processes and the development of diseases Xiaodong Cheng (Emory University), we solved the

8 To achieve this goal, I also developed a unique proteomic methodology to identify new substrates for different PKMTs using a ProtoArray-based proteomic platform (Figure 2). We demonstrated that more than 9500 unique substrates can be screened in a single experiment in a reproducible and efficient manner using two independent detection methods. In future work, we will utilize the ProtoArray system to develop additional applications to study the enzymatic activity, substrate specificity and physiological roles of other PKMTs. The overall goal of our research is based on the hypothesis that dynamic methylation of histone and non-histone proteins plays an important role in the Figure 2: ProtoArray system. A. ProtoArrays containing regulation cellular signal transduction pathways with ~9500 human proteins printed in duplicates on a glass slide. fundamental effect on human health. In our research B. Differential methylation signal (green boxes) from arrays we combine biochemical, molecular, cellu¬lar, genomic incubated without (left) or with a PKMT (right). and cutting edge proteomic experimental approaches crystal structure of SETD6 in complex with RelA peptide to identify novel lysine methylation events on histone in the presence of the methyl donor S-adenosyl-l- and non-histone proteins with the aim of understanding methionine (SAM) and provided structural evidence of how these marks are generated and under which that supports the model of the methylation signaling specific physiological conditions; to investigate how cascade detailed above. This work represents a these marks are sensed by other cellular factors; to new paradigm of how integrated crosstalk between elucidate the molecular mechanisms that transduce modifications on transcription factors and histones these signals; how these methylation events affect governs gene expression. This work also proposes an gene expression programs; what the clinical relevance intriguing and perhaps generalizable model by which of these events are; and how this knowledge can be pre-existing methylation of a transcription factor translated into therapeutic applications in the future. stabilized at its target promoters aids in the rapid I believe that the excellent scientific environment and and dynamic modulation of specific gene expression the fruitful collaborations among the NIBN research programs by establishing transcriptional memory at groups will allow us to combine both basic and marked genes. applicative research to gain a global understanding of A powerful approach to decipher the biochemical the connection between the different aspects of lysine and physiological significance of a methylated protein methylation biology and the modulation of cellular is to employ unbiased proteomic screening platforms. epigenetics programs.

Status of the new NIBN building

Construction of NIBN’s state-of-the-art building is in its advanced stage and will be ready for occupancy by NIBN members during 2014. Having all NIBN’s efforts under “one-roof” will help to create a dynamic and synergistic scientific environment which will help facilitate NIBN’s mission, especially research development programs and ultimate commercial opportunities. NIBN building will be named after Mr. Edgar de Picciotto and called “The Edgar de Picciotto and Family National Institute for Biotechnology in the Negev”.

9 NIBN | Newsletter CONFERENCES

Mini-Symposium: Synthetic Life Symposium - A Concept in “From Gene Pure and Applied Biology Historical Origins, Targeting Philosophical Questions, Current Developments to Genetic and Ethical Issues Diseases”

A one day mini- The NIBN together symposium was with the Jacques Loeb held in honor Centre for the History of the Nobel and Philosophy of the Prize Laureate Life Sciences at BGU, for Medicine or headed by Prof. Ute Physiology, Prof. Deichmann, organized Mario R. Capecchi, following bestowment the Minerva-Gentner of an honorary doctoral degree from BGU. Symposium on Synthetic Prof. Capecchi, Professor of Human Genetics Life. A respected at the University of Utah School of Medicine, grant was obtained received the 2007 Nobel Prize for medicine from the Minerva- or physiology based on his innovative work Gentner Foundation. in gene targeting of mouse embryo-derived The international stem cells. The conference was organized symposium addressed by NIBN and the Genetics Society of Israel the topic of synthetic and included a plenary lecture given by life from the perspectives of basic and applied Prof. Capecchi entitled: “Gene targeting into science. It explored the historical origins of synthetic the 21st Century: Mouse Models of Human life research, which included a reflection on the Diseases from Cancer to Neuropsychiatric meaning of the term life in different contexts and also Disorders”. Other speakers included Profs’ O. discussed ethical issues. Participants from the USA, Birk (BGU), L. Gepstein (Technion), K. Avraham France, Germany as well as Israel attended. (TAU) and M. Metzstein (Univ. of Utah).

Dr. Lewis F. Neville, Deputy Director, NIBN

NIBN is pleased to announce the recruitment of Dr. Lewis F. Neville as Deputy Director of NIBN. Lewis has a wealth of experience in the biopharmaceutical industry having served at Senior Scientist positions (1996-2009) at different Israeli and US-based companies. In 2009, Lewis established his own biopharmaceutical company via the Office of the Chief Scientist (Incubator Program), serving as its CEO/CSO until 2012. The company focused on the development of fully human monoclonal antibody-based therapeutics targeting hospital-associated bacterial infections. Lewis graduated in Biochemistry and Pharmacology from the University of Leeds, UK in 1985 and completed his PhD at the University of Southampton, UK in 1988 on the pre-synaptic control of excitatory amino acid release from the CNS. Following postdoctoral periods at the Hebrew University of Jerusalem (with Prof. Hermona Soreq) and SmithKline Beecham (now GSK), King of Prussia, PA (with Dr. Giora Z. Feuerstein), Lewis was recruited to the Department of Surgery at Thomas Jefferson University, Philadelphia as Research Assistant Professor. During this period, he applied a number of novel molecular biological techniques (eg. differential display, subtractive hybridization) to unveil pro-inflammatory genes involved in the development of sepsis-associated, acute microvascular lung injury. Additionally, he worked on the development of a synthetic blood substitute with the US Navy. During his academic period, Lewis successfully forged research collaborations with GSK and received NIH, US Navy and American Heart Association funding. In 1996, Lewis and his family made aliyah to Israel and settled in Rehovot. Lewis has published more than 40 peer-reviewed articles and holds a number of patents.

10 New scientists at the NIBN Sciences Beba Idelson award, a Levi Eshkol fellowship from the Israeli Ministry of Science and Technology and NIBN is pleased to announce the recruitment of the a Shimona Geresh award for excellence in research. following individuals. • Dr. Eyal Arbely joined the NIBN in August 2012 and Emad Muhammad, a PhD student in the laboratory of is affiliated to the Department of Chemistry. Prof. Ruti Parvari (NIBN and the Department of Virology • Dr. Natalie Elia joined the NIBN in April 2012 and is and Developmental Genetics), received a studentship affiliated to the Department of Life Sciences. from the Arab community for scientific excellence. • Dr. Dan Levy joined the NIBN in October 2012 and is affiliated to the Department of Microbiology, Tal Pecht, a PhD student in the laboratory of Prof. Immunology and Genetics. Assaf Rudich (NIBN and the Department of Clinical Biochemistry and Pharmacology) was awarded a Academic promotions received by NIBN members Negev Fellowship for scientific excellence.

• Dr. Amir Aharoni was promoted to Associate Professor Visits and meetings at the NIBN and tenure at the Department of Life Sciences. during 2012-2013 • Dr. Alon Monsonego was promoted to Associate Professor at the Department of Microbiology, Of central importance for the mission of the NIBN, is to Immunology and Genetics BGU. constantly promote all its sponsored research activities • Dr. Ariel Kushmaro was promoted to Associate with the intent to create investment opportunities Professor and tenure at the Department of via external funding organizations (eg. VC’s, private Biotechnology Engineering. foundations) as well as to forge collaborative • Prof. Ruti Parvari was promoted to full Professor research efforts or potential licensing deals with at the Department of Virology and Developmental major pharmaceutical companies. To that end, many Genetics, BGU. meetings and visits are arranged by NIBN’s team who present the overall strategy of the NIBN and highlight Faculty Prize those Principal Investigators and their specific projects that might be of particular relevance to the visiting Dr. Esti Yeger-Lotem (NIBN and the Department organizations. The following lists some of the visitors of Clinical Biochemistry and Pharmacology) was to the NIBN during 2012 and the first half of 2013: awarded The Toronto Award for excellence in research • Dr. Yair Adereth, GE Global Research, Israel Technology sponsored by the University Associates Foundation in Center, Biotech Research – a subsidiary of the GE giant. Toronto, Canada. • Ms. Yudi Hwang Barashi, Senior Manager of the Studentship Awards GlobalTech Korea office in Israel, visited the NIBN accompanied by a large Korean delegation of Natalie Zeytuni, a PhD student in the laboratory of Dr. representatives from various Korean companies. Raz Zarivach (NIBN and the Department of Life Sciences), • Mr. Kobi Barkai, Global Vector Control Manager & was awarded the Rector prize for achievements during Senior Product Manager Innovative Sector, Makhteshim- the previous academic year. Additionally, Natalie was Agan, Israel. awarded a UNESCO-L’Oreal Fellowship (2014) in recognition of her outstanding scientific achievements • Jacques Baudier, Scientific and Academic Advisor , during her PhD. The L’Oréal-UNESCO For Women in French Embassy, Israel. Science Awards is given each year to five outstanding • Dr. Michel Bodkier, Founder and CEO of VEDICI. women scientists – one per continent – for the contributions of their research, the strength of their • Dr. Bernarda Castillo, Executive Director; Andres commitments and their impact on society. Guerrero, Research Coordinator; and Desiree Guerrero, Innovation Institute in Biotechnology & Industry, Neri Amera, a PhD student in the laboratory of Prof. Dominican Republic. Michael Meijler (NIBN and the Department of Chemistry), • A large delegation of scientists from Cincinnati was invited to participate in the 63rd Lindau Nobel Children’s Hospital Medical Center, USA, visited the Laureate Meeting (Lindau, Germany). NIBN with the mission of exploring potential research collaborations with NIBN scientists. Danya Ben-Hail, a PhD student in the laboratory of Prof. Varda Shoshan-Barmatz (NIBN and the Department of • Dana Cohen, CEO; Dr. Ouriel Faktor, Chief Scientific Life Sciences), was awarded a Prof. Nechamia Levtzion Officer, BioMarCare Technologies – a cancer diagnostic studentship. company. • Dr. Nissim Darvish, Senior Managing Director, Erez Karina Golberg, a PhD student in the laboratory of Chimovits and Anat Naschitz, Managing Directors, Prof. Ariel Kushmaro (NIBN and the Department of OrbiMed (Herzilya) – a leading healthcare-dedicated Biotechnology Engineering) received a Na’amat Life venture capital.

11 NIBN | Newsletter

• Prof. Mario Feldman, Department of Biological Sciences, University of Alberta, Edmonton. • Prof. Ernest Frenkel, the Department of Biological Engineering at MIT. • Tal Fuhrer, VP Business & Corporate Development; Sharon NEWS Orenstein, Manager, Strategic Planning & Business Development, Neopharm Group – the leading marketer and distributer of prescription medications in Israel. • Dr. Ari Gargir, Sr. Manager R&D; Galia Feldman, Researcher; Roni Lamir, Project Manager, Life Technologies – NIBN Members in the News a global leader of a life science products and services from instruments to everyday lab essentials. Dr. Raz Zarivach, an EMBO Young Investigator award recipient was • Dr. Michael R Hayden, President of Global R & D and Chief recently interviewed on the EMBO web Scientific Officer and Mr. Ram Waisbourd, Chief of the R & D site. For broadcast, see www.embo.org/ Office, both from Teva Pharmaceutical Industries Ltd. funding-awards/instillation-grants. • Dr. Shmulik Hess, CEO, Valin Technologies – a Prof. Ohad Birk, featured on Al Jazeera biopharmaceutical company developing BioSimilars/ English’s television channel in a BioBetters protein therapeutics. discussion entitled: “Cousin marriages: • Prof. Roger Kornberg (Nobel Prize Laureate, Chemistry tradition versus taboo”. 2006), Stanford School of Medicine, USA. For broadcast see, http://www.youtube. com/watch?v=Cd5lgBgFBXs. Prof. Birk • A large delegation from L’Oreal, France visited the NIBN to also participated in a Doha Debate explore collaboration in different projects. in Qatar, where he spoke for the • Dr. Zvi Marom, Founder & CEO, BATM Ltd. – a developer and motion: “This House believes marriage a producer of telecom systems and of medical laboratory between close family members should diagnostic systems. be discouraged.” A Gulf report called him “the most compelling speaker” of • Prof. Xuetao Pei, Director of Beijing Institute of Transfusion the evening. The debate was chaired Medicine and AMMS Stem Cell & Regenerative Medicine by the award-winning, former BBC Research Center. correspondent and interviewer Tim • Zvi Rubinstein (RIP), CEO; Prof. Eliora Ron; Prof. Gideon Sebastian. Gross, Migal Galilee Technology Center - an applied research institute working in the fields of biotechnology, environmental Prof. Amir Sagi was invited to present sciences and agriculture. a seminar at Myanmar University entitled “The Crustacean Androgenic • Benjamin NG Kam Yiu, AVIC, China - Chinese biotech Gland, Sex Differentiation, Insulin entrepreneur and Biotechnology”. Prof. Sagi also • Dr. Andrew L. Salzman, Chairman, Radikal Therapeutics, participated in a signing ceremony USA – a start-up biopharmaceutical company developing in Can Tho, Vietnam marking the nitric oxide donors. realization of an agreement between the Israeli Tiran Group and Green • Prof. Low Teck Seng, Mr. George Loh, National Research Advances, a Vietnamese company. The Foundation Singapore. agreement is to advance aquaculture • Regine Shevach, Managing Director; Dr. Arie Zauberman, in Vietnam using BGU’s cutting-edge R&D Director; Simone Botti, Head Israel Bioincubator Fund; biotechnological tool to switch prawn Dr. Moshe Smolarsky, Scientific Advisor; Merck-Serono, gender resulting in faster-growing male Yavne - a subsidiary of the Swiss based international populations of the species, greater yield Pharmaceutical company. and higher farmer income. • Prof. Offie Soldin, Director, PregnaTox, USA – A spin out company based at the Georgetown University Medical Center • Sir Mark Walport, Former Director, Wellcome Trust, UK – a biomedical research fund, and currently Chief Scientific Officer to the UK government.

NIBN, Ben-Gurion University of the Negev | Beer-Sheva 84105, Israel Tel: 972-8-6477193 | Fax: 972-8-6472983 | www.bgu.ac.il/nibn | [email protected] 12