2021 ANNUAL REPORT BAR-ILAN INSTITUTE OF NANOTECHNOLOGY & ADVANCED MATERIALS
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TABLE OF CONTENTS A Note From our Director .......................................................... 4 Executive Summary ...................................................................... 6 Maintaining Israel’s Technological Superiority .................. 10 New Faculty ................................................................................... 14 RNA Editing—Genetic Engineering, Next Generation ...... 22 The Cryo-FIB-SEM ...................................................................... 26 It’s All about Communication ................................................. 30 Regulatory Governance and Advanced Sciences ............. 34 Bioconvergence ........................................................................... 38 A Decade of Research ............................................................... 48 Publications, Grants and Education ...................................... 52 Research Map .............................................................................. 60 Cover image: Scanning electron micrograph of hollow porous SiO 2 microparticles. [Prof. Shlomo Margel’s Lab] Articles by Ziv Adaki 3
A NOTE FROM OUR DIRECTOR 4
At BIU, and in BINA in particular, we have prominent material synthesis experts, some on the verge of retirement. By founding the new smart fabrication unit, we will maintain continuity while strengthening our capabilities in this field. Therefore, we have recruited the unit’s high-achieving leadership: With the help of the Ministry of Aliyah and Integration’s Center for Integration in Science, we have absorbed a new-immigrant wet chemical specialist from Ukraine who has chosen BINA as her new academic home in Israel; a postdoctoral Indian researcher who synthesizes organic materials; and a staff member who completed her PhD in BINA’s smart material laboratories and has gone on to specialize as a technical researcher in our microscopy unit. Together, we are now setting up the new unit to provide comprehensive smart material solutions to BIU’s and BINA’s faculty and to industry customers and partners. These will include medical solutions— primarily, drug delivery—and solutions for novel microelectronics, optoelectronics and next-generation communication devices, such as touch screens and long-distance antennas. This is only one example of how we are constantly attentive to the field, studying the needs and taking action to facilitate solutions. Inspired by Kohelet’s wise words—“Two are better than one […and] a threefold cord is not quickly broken” (Ecclesiastes 4:9–12)—BINA’s community is pledged to leading BIU’s scientific enterprise to groundbreaking and novel achievements. Best regards, Prof. Dror Fixler Director of the Bar-Ilan Institute of Nanotechnology and Advanced Materials Dear friends and colleagues, In Judaism, group learning or studying with partners (Hevruta) has always been fundamental. Our Sages designated 48 means by which one can acquire Torah (Pirkei Avot 6, 6). These include study, attentive listening, proper speech, paying attention to the Sages, critical give and take with friends and quality argumentation with disciples. They added that one should love one’s fellow creatures, share the burden of one’s colleague, and add to one’s knowledge by listening to others and oneself. Our Sages emphasized the importance of exposure to varied ideas and intensive interaction to maintain a productive learning process. The Bar-Ilan Institute of Nanotechnology and Advanced Materials (BINA) has a strategic role in incorporating these principles and leading the voyages of discovery of Bar-Ilan University (BIU), Israel and yes, even the world. Over the past year, we have thought long and hard over how best to harness our capacity. We have concluded that we must place BINA at the forefront of the university to navigate the stormy waters of our time. Looking carefully at our national and international vision and directions of research, we set sail on the bioconvergence flagship, implementing this innovation-accelerating approach across BIU (and not only across BINA). While doing so, and due to our many collaborations in the industry, we discovered a crucial need for design, research and development of smart and intelligent materials, metamaterials and 2D materials. Therefore, we decided to establish a new, targeted fabrication unit, which is also in line with the goals and interests of the Ministry of Economy and Industry and its subsidiary, the Israel Innovation authority. 5
EXECUTIVE SUMMARY Science is our compass, guiding us past the serious challenges facing humanity to a better future. In the past two years, we have had to overcome tall hurdles as the COVID-19 pandemic has questioned our very way of life. But we have prevailed, maintained our vitality and activities and even expanded our productive and innovative community of scientists. We set out on our way, aiming toward several milestones. First, we augmented the fixed annual budget from Bar-Ilan University (BIU) by increasing the revenue of our equipment center and obtaining grants from research and education programs. This strategy proved effective. It increased our exposure to Israeli industry and enhanced our ability to establish new connections with international consortia in order to submit joint grants. In 2020–2021 we emphasized equipment renewal: We purchased state-of-the-art machinery, including a Thermo Fisher Helios 5 UC DualBeam microscope, an Elionix ELS-BODEN 100 kV Electron Beam Lithography system, a High-resolution Laser Lithography system and an Ion Assist Sputter Deposition system. We have continued investing in our most important resource—the heart and engine of the institute— BINA’s unique team. We have increased the number of technical research and administrative personnel to 27 team members. We have absorbed Dr. Joseph E. Kantorovitsch, a new immigrant who is a world-class expert in the optical field and a highly experienced researcher with unique expertise in translating optical innovations into industrial applications. Having him on board has enabled us to expand our services to the design of optical components, which has increased the number of companies now working with us. BINA remains faithful to its commitment, under the Israeli National Initiative for Nanotechnology (INNI), to open the equipment center to industry and has become home to many startups. We mention, just for example, Zero EC SA, a German-Israeli-Swiss company that won the 2021 German Innovation Award for work carried out jointly with the BINA fabrication team. Today more than 150 companies receive services at BINA. BINA’s proactive policy of locating grant application opportunities is evident in our daily work. • With new recruit Ms. Anna Madar, we have broadened the services offered to BINA’s researchers and staff so as to include grantwriting assistance. • We are encouraging our professional team to initiate collaborations with the industry. • We are also applying for new types of grants. This year, for the first time, we submitted an application for the Teaming for Excellence European Union program that strives to support and build centers of excellence in Widening countries as role models to stimulate excellence, new investments and reforms of national research and innovation systems. Our Teaming submission’s leading group is the Czech Republic’s Advanced Technology and Research 6
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Institute (CATRIN)—Regional Centre of Advanced Technologies and Materials (RCPTM) of Palacký University Olomouc (UP); another partner is the Friedrich-Alexander University Erlangen Nürnberg (FAU). This year the entire university has been mobilized to purchase a piece of expensive equipment: an extremely advanced high-resolution transmission electron microscope (HR-TEM). We hope to report the purchase next year. Yet two essential needs remain unfunded: space for new equipment and personnel and the cost of additional faculty recruitment. Both pose a major challenge that we must tackle in the coming years. Human Resources BINA is uniquely creative in how it funds the salaries of technical research and administrative personnel employed by BIU. Ten employees are financed by the university’s overall budget, and an additional 17(!) are funded by BINA’s overall budget, based on grants and service income. Owing to the professionalism, initiative and creativity of our staff, BINA receives prestigious grant funding for its involvement in research programs such as Eurostars, MAGNET and Erasmus+. Taking part in these programs expands the scope of our collaborations with industrial companies and increases revenue from the services we provide them for research purposes. BINA’s continuous involvement in such programs allows us to hire more experts in various fields, which in turn generates additional opportunities for participation in new initiatives, thereby ensuring a steady flow of income. New Initiatives BINA signed a cooperation agreement with the Regional Centre of Advanced Technologies and Materials (RCPTM), and together we recently submitted a proposal to establish a sustainability (energy and agriculture) center of excellence at Palacký University Olomouc (UP), the Czech Republic, as part of the EU’s Teaming program mentioned above. BINA’s co-submitted proposal includes researchers from BIU’s Faculty of Law, Faculty of Life Sciences and Department of Geography. Rising to the bioconvergence global and national challenge, BINA has started taking steps to promote this new field at BIU. We have brought together for a joint workshop dozens of BIU’s and BINA’s leading life-science, electro-optic and bioengineering researchers and BlU’s big-data computer science experts—all of whom can contribute to bioconvergence-related research and programs. We have introduced the immense potential of bioconvergence research for advancing biology-based innovation and have formed five multidisciplinary task groups on topics relevant to bioconvergence, including synthetic biology and optogenetics. These groups, as well as the researchers who are already engaged in bioconvergence research projects, require new nano-bioconvergence research equipment. So we set out to locate funding and to purchase suitable machinery, such as a high resolution 3D printer (NanoScribe) and two bio-3D printers that we are purchasing with the Wolfson Foundation grant that BINA has received. Finally, yet importantly, although these years have been fraught with the challenges posed by the COVID-19 pandemic, we have held to our mission of fusing science with art. In May this year we celebrated the reopening to the public of the Joseph Fetter Museum of Nanotechnology with a new exhibition called New Languages. We are especially delighted to see the sparkling eyes of so many school visitors, who come from all over the country to the museum’s Boeing Nanovation Lab. Experiencing the exhibits’ playfulness and joy helps these youngsters feel confident that they can succeed in their science studies. Inspired by the growing interest in the interplay of science and creativity, in June this year we began the On Stage at BINA series with an exhibition of portraits by Dr. Yossi Abulafia, to be followed by shows of works by other BINA employees. 8
“In May this year we celebrated the reopening to the public of the Joseph Fetter Museum of Nanotechnology with a new exhibition called New Languages” 9
As the challenges facing humanity evolve, the need to enrich our knowledge and technology is becoming more pressing. Expediting scientific breakthroughs and innovation depends on the world’s ability to boost collaborations. “The experience and expertise we have gained from 15 years of breaking down silos and creating a common language between BINA’s diverse faculty members and technical research teams as well as with entrepreneurs of the industry through numerous joint projects are BINA’s added value in this national and global effort, now being translated into growth in international collaborations,” says Dr. Yosef Talyosef. BINA’s first international cooperation agreement was signed with the Beijing Institute of Nanoenergy and Nanosystems seven years ago. “Through seed grants, joint workshops and mutual visits, we encouraged BINA’s faculty to form contacts with their Chinese colleagues and set up initial research projects.” According to Dr. Talyosef, many of the small collaborations facilitated by this effort developed into substantial proposals that received funding from the Israel-China Joint Research Foundation (ISF-NSFC). “Following this success, we signed a five-year second agreement, just before the COVID-19 outbreak.” International connections provide researchers with the necessary opportunities to expand their research, participate in student exchange programs and gain access to diversified expertise and facilities. “We have built one such mutually beneficial partnership with the International Iberian Nanotechnology Laboratory (INL) in Portugal.” Like CERN in Switzerland, INL is an immense European Union research institute with extensive infrastructure. It enables both BINA’s researchers and industry customers to use its vast clean rooms or proceed from the initial development stages at BINA to small production-line processes at INL. Moreover, this fruitful cooperation has opened the way to BINA’s participation in significant projects whose focus is driven by policy makers and that involve many European entities. Stand Together as One —We’ll Make a Brighter Day In recent years, a global shift has moved bioconvergence, renewable energy and sustainability to the forefront of international efforts to secure humanity’s future. Massive investments are directed toward advancing science and innovation through trans-sectorial and comprehensive R&D consortia. “Aware of our capabilities, INL suggested that BINA join eight European partners in a bioconvergence proposal to develop integrated photonics.” Prof. Dror Fixler, BINA’s head and an expert in electrooptics and photonics, and his partners—physicists, engineers, physicians and production companies—aim to develop small, energy-efficient and highly reliable patient monitoring medical devices. The same multidisciplinary collaboration is essential in the struggle against global warming. BINA and BIU are exceptionally strong in the fields of energy and sustainability. To utilize this advantage, Prof. Fixler, Dr. Talyosef and Dr. Hamutal Engel, BINA’s projects unit manager, have assembled experts in these fields from every relevant faculty and have initiated cooperation with the Palacký University Olomouc (UP), the Czech Republic. “We have signed an agreement and submitted to the European Union a proposal for a $20 million joint project that will focus on developing energy solutions for agricultural needs. Our group intends to develop solar panels that can be positioned above fields. Although these panels use sunlight to provide solar energy, they do not block the light from reaching the crops, thus allowing them to grow.” Dr. Talyosef adds that the joint group will also take part in developing technology that converts CO2 emissions into clean energy. BINA’s physicists, who are experts in renewable energy solutions, together with BIU’s geography and earth science professors and its experts in law and regulation who have unique expertise in sustainability visited the Czech Republic recently to enhance work relations and locate more such promising partnerships. Maintaining Israel’s Technological Superiority 10
The Pandemic Did Not Stop Us Just prior to the COVID-19 outbreak, BINA’s international activity was at its peak. “In the first few weeks, everything seemed to have stopped, but we refused to give up. We kept in touch with our longtime partners and held on to nascent partnerships in Finland, the United Kingdom (UK) and the Far East. And now,” says Dr. Talyosef, “we are making a massive effort to realize these collaborations.” With exceptional foresight, BINA’s management has strategically included life science researchers in its faculty. “Today, we have a strong and large life science group, which is essential to bioconvergence research. To open up and expand their collaboration opportunities, we contacted the Nanoscience Center at the University of Jyväskylä in Finland, another of the few nano centers worldwide that incorporated life science research from the start.” Despite the original intention of linking BINA’s life science researchers with their peers at Jyväskylä, the first partnerships established were in the field of quantum physicists, Dr. Talyosef says, “but that only points out the vast potential of this cooperation.” Dr. Talyosef notes that BINA is now building its connections with the University of Exeter in the UK, a leading institute in quantum research and engineering that will also focus on bioconvergence research. “Upon leaving the EU, the UK became highly motivated to build its cooperation with Israel and allocated dozens of millions of pounds to establish the UK Science and Innovation Network (SIN), which includes Israel among more than 40 countries around the world.” BINA’s efforts are also directed toward its contacts with institutes in Asia, including the Hanyang University Institute of Nano Science and Technology, in the Republic of Korea, with which BINA has already signed an agreement that only now can be fully implemented. Flash Forward It appears that the world is slowly adjusting to a new COVID-19 routine, and BINA’s management hopes to sign agreements that were on the verge of being signed just prior to the pandemic’s outbreak. Dr. Talyosef says, “In January–February 2022 we will launch the collaboration with the University of Sydney Nano Institute (Sydney Nano), Australia, with two joint grants for energy and bioconvergence research.” As Dr. Talyosef elaborates, BINA also cooperates with Sydney Nano in the International Network for Sustainable Nanotechnology (N4SNano). N4SNano is a consortium of leading organizations in the field of nanotechnology, and consists of institutes, universities, nonprofit organizations and governmental agencies. The consortium’s founders include the Waterloo Institute for Nanotechnology (WIN) in Canada, MESA+ Institute for Nanotechnology in the Netherlands, Sydney Nano and the University of California Los Angeles (UCLA). “The purpose and focus of N4SNano is to promote scientific discoveries and nanotechnology advancements and applications as key mechanisms for sustainability—to bring positive and impactful solutions to society in line with the United Nations Sustainable Development Goals (UNSDG).” Later this year BINA hopes to host another delegation from Bangalore University, one of India’s highestranking universities. “Through our cooperation with Bangalore we aim to attract top students to conduct their doctoral studies and postdoctoral fellowships in BINA’s laboratories, upgrading our research teams while making those students into ambassadors of Israel’s scientific accomplishments.” International collaborations are high on BINA’s agenda and are a daily priority for Dr. Yosef Talyosef, BINA’s manager. The institute’s founders made the decision to establish BINA as a multidisciplinary institute—a strategy that has enabled it to keep growing and developing in line with global and national changes in trends and challenges. “Today, we have a strong and large life science group, which is essential to bioconvergence research” 11
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NEW FACULTY 14
large-scale integration of electronic and photonic circuits. Therefore, we are exploring ways to integrate these devices into large multidevice systems that will provide the optoelectronic community with the means for complex data operations.” On-chip nonlinear quantum devices, once successfully realized, are expected to provide the community with an outstanding platform for implementing optical quantum circuits, thereby increasing the practical applicability of quantum optics to address some of the unsolved fundamental problems that are still limiting the realization of quantum technology. “Joining BINA is an excellent opportunity to develop new connections and collaborations with the world’s greatest research groups and institutions,” states Dr. Desiatov, who also takes advantage of BINA’s stateof-the-art nanofabrication processes in his quest to develop these cutting-edge optical nanodevices. “Being a part of the BINA community will allow me to share my ideas with top nanoscience experts, learn from the broad nanotechnology community and expose my research and expertise to other scientists.” Dr. Boris Desiatov, an expert in nanophotonics, joined BINA in 2020. He completed his PhD in applied physics at the Hebrew University of Jerusalem and proceeded on to complete a four-year postdoctoral fellowship at the Harvard University School of Engineering and Applied Sciences as well as a one-year postdoctoral fellowship at MIT’s Research Laboratory of Electronics in Cambridge, Massachusetts. Upon his return to Israel from the United States, Dr. Destiatov joined BIU’s Alexander Kofkin Faculty of Engineering. Dr. Desiatov’s research focuses on developing novel optoelectronic nanotechnological on-chip devices for quantum applications. Such devices can emit, detect and process quantum states of light and may revolutionize our computation, communication and precision measurement capabilities. Quantum computers will be considerably more powerful and energy-efficient than our current computers; massive amounts of information will be accessible without bandwidth issues and sensors will be ultrasensitive to trace-amount toxins, viruses, or bacteria and detect them quickly and efficiently. “Specifically, we are using new optoelectronic materials combined with nanofabrication techniques to create novel devices with unique optical properties that are not available on other platforms. While the existing optical components are sufficient for proof-of-concept quantum experiments, scaling up these systems to tens, hundreds, or thousands of individually controllable quantum units requires very “Joining BINA is an excellent opportunity to develop new connections and collaborations with the world’s greatest research groups and institutions” Dr. Boris Desiatov 15
Prof. Gil Goobes, an expert in the design of biomaterials and advanced materials using solidstate NMR spectroscopy, joined BINA in 2021. He received his PhD from the Department of Chemical Physics at the Weizmann Institute of Science, where he developed pulse techniques in solid-state nuclear magnetic resonance (NMR) for various applications. From there, he went on to complete a postdoctoral study at the University of Washington in the United States, where he used NMR to study the structure of statherin-enamel binding. In 2008, Prof. Goobes returned to Israel and established his lab in BIU’s Department of Chemistry. “In my lab, we use advanced solid-state NMR with electron microscopy and X-ray diffraction techniques to advance the fundamental atomic understanding of how biogenic materials are formed, maintained and repaired in nature. We use our insights to construct biomimetic bone, coral and silica materials, which have significant implications for the development of implants and prosthetics, as well as for our ability to protect and preserve marine organisms,” says Prof. Goobes. He names a few examples of biomaterials with excellent mechanical properties: strong weightbearing bones, fracture-resistant skulls and seashells, and compression-resistant tooth enamel. “There are many hurdles to overcome in dealing with these and many other biomaterials before we will be able to replicate them in the lab in such a way that the artificial materials will perform like their natural counterpart,” he says. “I see great potential in BINA’s ability to elevate our recent work designing novel energy-related advanced materials for batteries and other future energy storage applications, as well.” In this research, Prof. Goobes focuses his efforts on providing unmatched atomic analysis of advanced materials for lithiumion and sodium-ion batteries. Many of the material elements investigated in his lab, such as the important coatings on electrodes, are nanometric in size and provide improvements of battery performance. “Using BINA’s advanced microscopy unit, we can gain a deeper understanding of the atomic structure of biogenic and synthetic materials. Based on this essential information, we can make great strides in the development of biocompatible and biodegradable materials and procedures to minimize waste and reduce carbon emissions—for a more sustainable future world.” “I see great potential in BINA’s ability to elevate our recent work designing novel energy-related advanced materials for batteries and other future energy storage applications, as well” Prof. Gil Goobes 16
The amazing developments in technology of the last few years have created countless opportunities and have enabled outcomes that were considered imaginary only a short while ago. To make BIU a hub in this crucial field, a strong network of scientists with varied areas of expertise is vital. In joining BINA, Prof. Levanon brings to the table a profound understanding of current genomic science and proficiency in this field. He believes that coupling that knowledge and expertise “with BINA’s translational strength and dedication to enhancing the interdisciplinary effort will make BIU a key player in this exciting future.” “For over 10 years my lab has been working on the development of genomic and algorithmic approaches to detection, quantification and analysis of RNA editing, which occurs naturally in the body” Prof. Erez Levanon, an expert in genomics and RNA editing, joined BINA in 2021. Previously, he completed his PhD in genomics at Tel Aviv University and traveled to the United States for a postdoctoral fellowship at Harvard Medical School. He returned to Israel and established his laboratory in BIU’s Mina and Everard Goodman Faculty of Life Sciences. In 1997– 2006 he also served as a senior scientist in genomics at Compuger LTD. “For over 10 years my lab has been working on the development of genomic and algorithmic approaches to detection, quantification and analysis of RNA editing, which occurs naturally in the body,” says Prof. Levanon. “This unique expertise has been translated into key contributions to the field. Recently, we started harnessing the knowledge of endogenous RNA editing to develop systems capable of RNA engineering.” Molecular interventions based on the understanding of the genome and manipulation of patients’ mRNA are transforming the landscape of therapeutics. As opposed to conventional drugs that target limited families of proteins, RNA-based technologies can be used to target any gene in the genome. This capability opens a new era in drug development because it enables not only blockade or downregulation of gene function but also alteration of gene function and sequence. Prof. Erez Levanon 17
paramagnetic resonance (EPR) spectroscopy. The power of EPR lies in its sensitivity to both atomic-level changes and nanoscale fluctuations. Using EPR, we can characterize the state of the matter (for example, redox state and ligand geometry) and determine the protein’s different functional states. This tool also provides us with information about the cell’s dynamics,” says Prof. Ruthstein. “The data collected in EPR experiments is complemented by various other biophysical and biochemical approaches and computational methods, including circular dichroism (CD), nuclear magnetic resonance (NMR), run-off transcription assays, ultracentrifuge experiments, cell microscopy experiments, 64Cu(II) cell experiments and molecular dynamic (MD) simulations that provide us a complete picture of the cellular copper cycle in eukaryotic and prokaryotic systems.” “In joining BINA’s unique environment of expertise, equipment and national and international engagements, I hope to expand my collaborations, particularly with microscopy experts, while implementing new and novel microscopic and spectroscopic tools in my lab and eventually move forward to in vivo research.” Prof. Sharon Ruthstein Prof. Sharon Ruthstein, an expert in biophysics, structural biology and magnetic resonance, joined BINA in 2021. She completed her PhD (with honors) in chemistry at the Weizmann Institute of Science and went on to complete a long-term postdoctoral fellowship at the University of Pittsburgh, Pennsylvania, in the United States through the European Molecular Biology Organization (EMBO). In 2011, Prof. Ruthstein returned to Israel and established her lab at BIU’s Department of Chemistry with funding provided by the European Research Council (ERC). Prof. Ruthstein’s research focuses on the cellular copper cycle. Copper has a key role in a wide range of physiologic processes such as antioxidant activities, iron metabolism and metabolism in general, tissue, muscle and bone building and more. Using novel equipment and techniques, Prof. Ruthstein expands the basic understanding of the cellular copper cycle in eukaryotic and prokaryotic systems, knowledge that is essential to the development of new biomarkers and therapeutic agents that depend on the copper cycle. Based on this knowledge, Prof. Ruthstein and her team have developed a 64Cu(II) radiotracer for diagnosing hypoxic cells for high-sensitivity tumor detection. In addition, they have designed peptides that can affect the metabolism of copper in eukaryotic and prokaryotic systems, laying the groundwork for the future design of antibiotics and therapies for neurological disorders and cancer. “My group utilizes various spectroscopic methods to resolve the cellular metal transfer mechanism in vitro and in a cell. The main biophysical tool we use is continuous wave (CW) and pulsed electron Using novel equipment and techniques, Prof. Ruthstein expands the basic understanding that is essential to the development of new biomarkers and therapeutic agents that depend on the copper cycle 18
Melanogaster , flies that serve as a model organism because they lack the immense complexity that exists in mammalian brains and are highly amenable to genetic manipulation. We analyze the effects of social opportunity or challenges on specific behavioral responses of the individual in social encounters, such as courtship display, aggressive behaviors, group dynamics and reward-related behaviors, and investigate their effect on reproductive physiology. We also identify mechanisms that encode the information gained from the interaction in the brain,” says Prof. Shohat-Ophir. Her fascinating work has bred many research collaborations both in Israel and around the world, including with BIU, Tel Aviv University, Haifa University, the Technion, HHMI, and both Brown and Stanford Universities. One such collaboration has led Prof. Shohat-Ophir to work with BINA’s Dr. Shahar Alon on the spatial localization of RNA molecules within specific brain circuits. Going forward, they plan to use BINA’s well-developed electron-microscopy infrastructure to identify motivation-encoding mechanisms within specific neurons. Her fascinating work has bred many research collaborations both in Israel and around the world, including with BIU, Tel Aviv University, Haifa University, the Technion, HHMI, and both Brown and Stanford Universities Neurobiologist Prof. Galit Shohat-Ophir joined BINA in 2020. She completed her PhD in cancer biology at the Weizmann Institute of Science and went on to complete postdoctoral fellowships at the University of California San Francisco (UCSF) and at the Howard Hughes Medical Institute (HHMI) Janelia Research Campus. Upon returning to Israel from the United States, Prof. Shohat-Ophir established her lab at BIU’s Mina and Everard Goodman Faculty of Life Sciences, where she studies the neurogenetics of social behavior. Living in a social environment requires members of the same species to engage in diverse interactions that are essential for their health, survival and reproduction. Effective social interaction requires the ability to recognize other group members and respond appropriately to different social encounters and contexts. The impairment of such functions is evident in several neuropsychiatric disorders such as autism spectrum disorders and schizophrenia. Similar responses to social stimuli are exhibited in very different animals, suggesting that the central systems that enable social interaction originated early in evolution and that similar basic building blocks and biological principles are involved in these processes. In her lab, Prof. Shohat-Ophir and her team explore the neuronal and molecular bases of the most fundamental social behaviors, how they are organized at the biological level and how genes and environment interact to influence behavior. “We study these basic questions in Drosophila Prof. Galit Shohat-Ophir 19
their AIRR-seq. We also developed VDJbase, a public database that includes genotype and haplotype inferences. Using these and other tools, we have so far studied immune responses in multiple sclerosis, celiac, Crohn’s disease, hepatitis C virus, COVID-19 and breast cancer. In healthy individuals (humans and mice), we study vaccine responses and aspects of the basic function of the adaptive immune system, its heredity and development, and its interactions with the microbiome.” BINA’s specialized equipment facilities will support Prof. Yaari to realize his future goals to develop nanotechnologies (e.g., lab on a chip) and design devices to identify immune repertoire patterns for personalized medicine, diagnostics and prognostics of diseases. Prof. Yaari’s research collaborations spread across all continents and include both leading universities and medical institutions in the United States, Canada, Australia, England, Germany, Norway and Israel. He says, “I trust BINA, with its broad and diverse partnerships, will help me continue to build new collaborations while strengthening the existing ones.” Prof. Gur Yaari, an expert in computational systems biology, joined BINA in 2021. He completed his PhD in multidisciplinary physics at the Hebrew University of Jerusalem and traveled to the United States to complete a postdoctoral fellowship at the Yale University School of Medicine. Prof. Yaari returned to Israel and established his laboratory in BIU’s Alexander Kofkin Faculty of Engineering. In 2018–2019, he also served as the scientific manager of the personalized medicine department at Rabin Medical Center. In his data science-driven lab, Prof. Yaari and his group combine experimental and computational expertise to address fundamental questions in biology, with particular emphasis on the adaptive immune system. Unlike innate immunity, adaptive immunity (also known as acquired immunity) develops throughout an organism’s life, in response to the specific pathogens to which it has been exposed. The adaptive immunity receptors—T-cell receptors, B-cell receptors and antibodies—are highly specific; each responds to a different threat. Hence, the adaptive immune response is different from one individual to another. “High-throughput sequencing of adaptive immune receptor repertoires (AIRR-seq) provides unprecedented insights into adaptive immunity. Although promising, the immense diversity of the receptor sequences makes the analysis of repertoire sequencing data distinct and extremely challenging,” says Prof. Yaari. “In my lab, we are continuously developing strategies to infer new receptor alleles, genotypes and haplotypes, methods to estimate affinity-dependent selection and machine-learning applications to classify clinical samples based on BINA’s specialized equipment facilities will support Prof. Yaari to realize his future goals to develop nano-technologies (e.g., lab on a chip) and design devices to identify immune repertoire patterns for personalized medicine, diagnostics and prognostics of diseases Prof. Gur Yaari 20
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Over a decade ago, CRISPR technology shook the world with its promise of bestowing on scientists previously unimaginable genetic engineering capabilities. Although it continues to improve, this technology is still not precise enough, it causes many off-target mutations, and every change it makes is forever stamped in the DNA. While CRISPR opened the door to a new era in medicine, it is RNA editing that is helping scientists bring genetic engineering to its full potential. RNA editing is a natural process through which the sequence of the genome can be changed after transcription—a process whereby a segment of the DNA is copied to the RNA. “Our genome is composed of four building blocks—nucleotides—represented by the letters A, G, T, and C. When RNA editing takes place, it means that one of the building blocks making up the DNA sequence in a specific place in the cell, typically the A nucleotide, is replaced in the RNA—some of the time, in some of the tissue—with a G nucleotide. Scientists have found that a family of enzymes called ADARs (adenosine deaminases acting on RNA) is implicated in almost all of the RNA editing occurrences in the human cell, over 99% of which involves the A nucleotide being replaced with G,” says Prof. Levanon, whose research group was the first to develop a scanning technology that enables the detection of RNA editing as it occurs and expose its magnitude in the human genome. Unlike CRISPR, which is based on an engineered bacterial protein that breaks the DNA, RNA editing chemically modifies the RNA without damaging or breaking the DNA, and because it is based on natural human enzymes, is also less likely to trigger an immune response. Thanks to advantages such as these, once scientists perfect their ability to manipulate the body’s natural system to make controlled changes to the RNA—the DNA’s production instructions—they will be able to develop safe and highly effective treatments for numerous genetic diseases as well as nongenetic ones. Prof. Erez Levanon, head of the Genomic Research Lab at BIU’s Mina and Evrard Goodman Faculty of Life Sciences, has returned to Israel after a postdoctoral fellowship at Harvard Medical School, Boston. He uses bioinformatics—computer and data sciences, mathematics, and information processing—to study the plasticity of the genome and build RNA-editing tools that can pave the way for effective and safe therapeutics. This past year, Prof. Levanon joined BINA, pairing his expertise in computational biology with that of BINA’s team of optics, nano-delivery, chemistry and engineering scientists. Together they hope to leverage cuttingedge science to benefit human health. RNA Editing— Genetic Engineering, Next Generation 23
Partner in the Evolution of Genetic Engineering Prof. Levanon and his collaborator, Prof. Shay BenAroya, developed a system that can design a synthetic DNA sequence that, when injected into a cell, triggers the ADAR system to do its job of editing the RNA. “Relying on the previous work of many researchers, we can already inject our system into the liver, heart and brain and trigger ADARs to modify specific genes,” says Prof. Levanon. He adds that although an RNA-editing-based drug is still a long way off, the efforts of scientists and industry around the world are already bearing fruit. Prof. Levanon’s lab, which focuses on the chemistry and protein engineering aspects of RNA editing, has partnered with ADARx Pharmaceuticals, one of three major American RNA-editing pharmaceutical companies to have been created thanks to the important advances in the technology over the past two years. In recent months, this new industry has already raised over $250 million, a sure sign of the confidence in the potential of RNA-editing therapies. Every scientific and technological advance in RNA editing depends on understanding the workings of the body’s own editing system—why it is needed, where it occurs in the genome, and how it adapts to different biological conditions. The evolutionary role of RNA editing is the regulation of our immune system. Because virus attacks are the greatest danger to the cells, the immune system constantly canvasses them to detect viruses and eliminate them. “But, it so happens, the typical structures of viruses are very similar to naturally occurring structures in our genome. So to prevent an immune attack against such a structure, the ADAR system switches one of the RNA nucleotides. This slight modification is enough to prevent the immune system from wrongly identifying the body’s own structure as a virus,” says Prof. Levanon. “A lowfunctioning ADAR system,” as he goes on to explain, “can cause autoimmune diseases, while one that is too high-functioning can weaken our immunity.” Mapping where in the genome RNA editing levels are too low and where they are too high will help researchers address the health consequences of each of these conditions. Furthermore, knowing where the ADAR system tends to naturally occur can help scientists learn how to deliver the RNA-editing technologies to any part of the human body. While working on his doctorate, Prof. Levanon started building a catalog showing each occurrence of RNA editing that he detected; he then completed the map of sites for the entire genome, here at BIU. This catalog and a tool to determine the global editing level of a sample, published in Nucleic Acid Research (2020) and Nature Methods (2019), have since been widely cited. Now, together with Prof. Eli Aizenberg, a theoretical physicist from Tel Aviv University, he is building a catalog comprising exclusively the RNA editing occurrences with the greatest clinical potential. “We saw differences in how this system works under different biological conditions and are studying them together with two research teams from Harvard University, Boston. We have already shown that inhibition of ADAR activity alerts the immune system and causes it to attack tumors more efficiently.” After this discovery was published in Nature (2019), many pharmaceutical companies began developing ADAR-inhibitor drugs, which has made it possible for a greater number of cancer patients to begin benefitting from immunotherapy. 24
Interdisciplinary Research— The Key for Future Advances Manipulating RNA sequences opens up a world of therapeutic opportunities that is not limited only to curing genetic diseases; it can be used to change host-microbiome interactions, diagnose illnesses and even alter organisms. Prof. Levanon emphasizes that fostering interdisciplinary knowledge is essential to the future of this technology. He says that joining BINA is exposing him to a wide array of technologies, including “advanced optic capabilities that can provide us with a higher sequencing resolution to perfecting our synthetic editing tool, miniature robotics that can help us overcome the delivery challenges still holding us back and more. Collaborating with BINA’s research teams will hopefully bring us closer to taking this promising technology from bench to bedside.” 25
Electron microscopes today have remarkably high spatial resolution. While SEM imaging provides us information about the morphology and composition of the surface’s sample at the nanoscale, TEM imaging resolution is higher; it goes up to the atomic level and reveals information about the sample’s atomic arrangement and its morphology and chemical composition. However, since they image only one surface at a time, both the SEM and the TEM can only give us limited information about the 3D characteristics of the sample. “This is where the new Cryo-FIB-SEM comes in,” says Dr. Yafit Fleger. “Having both an electron beam and an ion beam, the Cryo-FIB-SEM makes it possible to repeatedly slice and scan a sample in a technique called slice-and-view. Then, with the help of cuttingedge software, we merge the images into a 3D model.” Dr. Fleger and Dr. Maria Tkachev, who is in charge of the FIB-SEM, recently organized a seminar attended by scientists all around the country so that they and their colleagues could learn how to use the imaging software for processing and merging data into a 3D image. In the semiconductor industry, a process called failure analysis is used to diagnose how and why failures occur in a device. “When a semiconductor component malfunctions, it can set in motion a series of failures throughout the device. If we use the TEM and the SEM alone, we can only view and analyze one slice at a time, which means we may well miss significant information. For example, looking at a specific slice, we may miss overheating that is occurring somewhere else in the component, or we may detect traces of a leakage but not see where it’s coming from. But using the Cryo-FIB-SEM’s slice-and-view technique, we can cut and view a component stepby-step, slice-by-slice and merge the images to create a 3D digital model. This allows us to map out the entire component and trace the failure to its source.” The Cryo-FIB-SEM It’s a 3DMaterial World 26
BINA faculty members Prof. Zeev Zalevsky, Prof. Avinoam (Avi) Zadok and Prof. Adi Salomon, together with Dr. Yafit Fleger, head of BINA’s Charged Particle Microscopy (CPM) unit, won the Council for Higher Education’s Institutional Equipment Grant. This grant made possible the purchase of a Thermo Fisher Helios 5 UC DualBeam equipped with a cryogenic system from Leica, a state-of-the-art electron-ion microscope (CryoFIB-SEM) capable of producing 3D tomography of organic and inorganic molecules. The decade-old multidisciplinary team of PhDs from the life sciences, chemistry and physics making up the CPM unit have mastered the operation of seven powerful imaging and fabrication machines. The CPM unit is equipped with several scanning electron microscopes (SEMs), transmission electron microscopes (TEMs) and focused ion beams (FIBs) and provides analysis services to academia and industry in the fields of material science, electromagnetics, optic engineering and the life sciences, to name a few. Thanks to the unit’s diverse experience and expertise, the Cryo-FIB-SEM— which was installed just before the COVID-19 outbreak—is already operational, and it runs daily in order to keep up with the enormous demand for its unique slicing, fabricating, scanning and imaging capabilities. 27
Upgraded Capabilities, Deeper Insights Many scientists from BIU and elsewhere depend on the CPM team’s expertise using the Cryo-FIB-SEM; so do clients such as SolarEdge, Microtechmed, the defense industry, HIT and Ariel University. “We have carefully selected and trained a handful of BINA research students to operate this complex system,” says Dr. Fleger. “This gives them a rare opportunity to participate in advanced R&D and to gain specialized experience with today’s most powerful microscope.” “We make it even thinner, ending up with a sample 30-50nm thick. To put this into perspective, it’s like pulling a single sheet of paper out of a very thick book” Prof. Adi Salomon is one of the Cryo-FIB-SEM’s highvolume users. Her lab at BIU’s chemistry department focuses on plasmonic research, or matter-light interactions. Prof. Salomon fabricates nano layers of silver or gold and cuts carefully shaped and positioned grooves into their surface. When the layer is lit, these grooves restrict the electromagnetic field to a small area such that the returned optic signal is enhanced. Prof. Salomon and her team can then investigate the light deflection and reflection revealing the effect of different molecules or differences in molecular bonds on them. Awarded an Israel Science Foundation (ISF) grant, Prof. Salomon is studying the data that the Cryo-FIB-SEM yields to develop ultrasensitive and low-cost optical sensors for low-vision devices, toxin detectors and more. “A significant portion of our work entails the complex preparation of extremely thin samples called TEM lamellas. We use the Cryo-FIB-SEM’s ion beam to carve the sample, and then with a milling technique, we make it even thinner, ending up with a sample 30-50nm thick. To put this into perspective, it’s like pulling a single sheet of paper out of a very thick book,” says Dr. Fleger. The CPM team has produced such ultrathin samples of 2D materials for Prof. Doron Naveh, who prints the human-made 2D materials in his lab at BIU’s Alexander Kofkin Faculty of Engineering. “Testing these thin, high-quality lamellas with a high-resolution TEM revealed new data about the structure and characteristics of 2D materials.” Prof. Naveh’s research, published in Advanced Materials (2021), has contributed valuable knowledge to scientists who are working around the world to develop highly sensitive low-cost optic components and 2D-based devices, such as night vision equipment and more.” Another distinguishing feature of the Cryo-FIB-SEM is that it can work in the cryo mode imaging flashfrozen, or deep-frozen, biological samples (–150°C to –190°C). By using deep-frozen biological samples, we retain the natural state of the tissue and prevent it from collapsing under the electron beam, allowing us to capture the living moment. When the CPM unit makes this feature available as well, scientists here will be able to collect detailed 3D information about organic materials, which will let them probe deeper into the essence of natural matter. BINA as an R&D Accelerator BINA’s Surface Analysis, Nano Fabrication, and CPM units, together or separately, offer both established companies and startups in their initial stages essential added value: a one-stop shop combining advanced analysis equipment and an ensemble of experts with state-of-the-art knowledge. “We’re able to leverage our systems’ complementary capabilities to analyze different aspects of the same material. We then work as a team, comparing the images, extracting the important data and brainstorming together to come up with just the right solution,” says Dr. Fleger. “This intense collaborative work results in an accelerated R&D process.” 28
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Prof. Doron Aurbach was in the second year of his graduate studies in 1978 when, as a tour guide, he worked with a group from Ormat Technologies Inc., a prominent Israeli renewable energy company. “As a physical chemistry master’s student, I thought I knew something about thermodynamics, heat and energy and tried to start a conversation with Ormat’s excellent engineers, but discovered that we couldn’t understand each other. I felt extremely frustrated,” he says. So his next step was to enroll in the regular program in chemical engineering at the Technion—Israel Institute of Technology, in parallel to his theoretical and basic-research doctoral studies in organic chemistry at BIU. Thus he completed simultaneously a PhD at BIU and a degree in chemical engineering from the Technion, both with highest distinction. After closing this communication gap and completing a postdoctoral fellowship at Case Western Reserve University (CWRU) in Cleveland, Ohio, Prof. Aurbach returned to BIU, his alma mater, and in 1985 set up his electrochemical laboratory, basing it upon research and development collaborations with leading international and national energy companies. “Even then the industry understood that advances in technological energy solutions depend heavily on a profound knowledge of distinct scientific phenomena—how structure, morphology, surface chemistry, and various materials influence the electrochemical performance of, for example, electrodes. The energy companies needed our pioneering academic work, and through our collaborations we were, and still are, able to produce top-quality and impactful scientific work in this field.” Throughout the years, Prof. Aurbach has built numerous fruitful collaborations, from Japan in the east to the United States in the west, which provide him sufficient real-time funding to conduct the highest-level research projects. “In the last three years we have had a strategic collaboration with Nichia Corporation in Japan focusing on unique systems like lithium-sulfur and zinc-air batteries and optimization of storage systems for drones.” With the giant Chinese lithium-ion battery manufacturer Amperex Technology Limited (ATL), which produces billions of rechargeable batteries, Prof. Aurbach is striving to enlarge their voltage and energy density by at least 30%, while maintaining the number of charging cycles and their suitability for mobile equipment. “Success in this effort may be revolutionary,” he says. In Germany, Prof. Aurbach has a prominent collaboration with the chemical giant BASF. To establish this long-term collaboration with leading research groups in academia, BASF created a network of 10 leading research groups from Germany, Switzerland, Canada, the US, Japan and Israel (Prof. Aurbach’s group). “For 13 years, together we have developed new and advanced materials to improve It’s All about Communication “In the last three years we have had a strategic collaboration with Nichia Corporation in Japan focusing on unique systems like lithium-sulfur and zinc-air batteries and optimization of storage systems for drones” 30
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