Dynamic, Sophisticated, and Environmentally Sensitive: How mRNA Formulates Its Instructions to Ribosomes
Technion researchers have discovered a new mechanism in the control of protein synthesis by ribosomes: an enzyme that edits mRNA and regulates its activity according to the organism’s needs. Their recent article describes similar gene editing processes to those used by Pfizer and Moderna in developing the new mRNA vaccines
In the diagram: Left: The vaccines. mRNA vaccines are based on the introduction of synthetic mRNA into cells to serve as a mold for building the viral protein that activates the immune system. Shortly after the mRNA molecules have penetrated the cell they begin to initiate production of the immunological proteins the cell needs. mRNA contains a number of chemical modifications that enhance its activity in the cell. Right: The natural mechanism. The study published in Nucleic Acids Research demonstrates how similar chemical modifications occurring naturally in mRNA serve as links to control elements. These links affect ribosome activity, thus enabling protein production in quantities that are more accurate and are aligned with the organism’s needs.
Technion researchers have discovered an unknown mechanism that controls protein synthesis in the cell. The mechanism uses chemical modifications on mRNA to influence the rate of protein production by the ribosome, the cellular protein machine. The researchers, Professor Yoav Arava and doctoral student Ofri Levi of the Faculty of Biology, published news of the discovery in Nucleic Acids Research.
Gene expression control is responsible for translating the genetic code (written in DNA) into proteins that are adapted for their purpose in the specific tissue, taking changing environmental conditions into account. “If DNA is the cookbook,” said Ofri Levi, “then the chef is the ribosome – the cellular protein machine. The main mediator in the process is the mRNA molecule, which carries the recipe from the DNA to the ribosome. The right interaction between mRNA and the ribosome is vital to the normalcy and quality of the proteins.”
Prof. Yoav Arava
For some years, it has been known that mRNA does not carry the instructions from DNA in their original form, but undergoes numerous modifications on the way. These chemical changes recently made headlines in the context of the COVID-19 vaccines; the Pfizer and Moderna vaccines are based on the introduction of synthetic mRNA into the body to create immunological proteins inside our cells. However, since the cell treats mRNA as a foreign body, it tends to attack it, and the rapid mRNA breakdown does not leave it with enough time to manufacture the essential proteins.
To overcome this challenge, the two companies integrated modifications that mimic natural changes that occur in the body into their mRNA molecules. These modifications indeed enable the synthetic molecule to survive and to work long enough to create the protein from the virus.
According to Prof. Arava, “The connection between mRNA and the production of proteins is a process that has occupied us for some years, and we are focusing on the effect of mRNA on building the proteins and on their stability. We are trying to understand the ‘conversation’ in which mRNA tells the ribosome what to manufacture for the cell. We are conducting the basic research on Saccharomyces cerevisiae, a budding yeast that we know as baking or brewing yeast, and we have a solid basis to assume that what happens in the yeast is highly relevant to what happens in the human body.”
In a previous article published in PLoS Biologyin July 2019, Mr. Levi and Prof. Arava presented a new role for certain enzymes prevalent in all kingdoms of life. The researchers discovered that these enzymes serve as significant control elements in protein production – a role that was unknown before the article was published. To perform this function, these enzymes bind to the mRNA and regulate the quantity of mRNA molecules available to the ribosome.
In the present study, Mr. Levi and Prof. Arava thoroughly explored the question as to how those enzymes identify mRNA among the medley of cellular components. They discovered that the answer lies in a unique chemical modification occurring in mRNA. This modification, known as pseudouridine, is created in various locations on mRNA; control elements identify the change and time ribosome activity accordingly.
To prove the importance of this modification, the researchers developed a method based on CRISPR/Cas9, which enabled them to “surgically” remove the psuedouridine without causing any other damage to the cells. Indeed, in the absence of psuedouridine, control of protein production was lost. According to Mr. Levi, “Like many scientists in the world, we too owe a huge thank you to Professor Emmanuelle Charpentier and Professor Jennifer Doudna for the dramatic breakthrough they achieved in the development of the CRISPR/Cas9 technology.”
Profs. Charpentier and Doudna were awarded the Technion Harvey Prize on November 3, 2019, and one year later, on December 10, 2020, they received the Nobel Prize in Chemistry for the development of the revolutionary technology for editing, repairing, and rewriting DNA. Thanks to this technology, Mr. Levi said, “we have been able to make progress in our research with unprecedented speed and accuracy.”
The Technion researchers estimate this is an evolutionarily conserved mechanism that exists across the animal kingdom. Since the mechanism is sensitive to environmental changes, it provides mRNA molecules with instructions tailored to environmental conditions, thus directing the ribosomes to optimal protein production.
As mentioned, one of the most important tasks faced by Pfizer and Moderna was to improve the activity of artificial mRNA in the human body, so they introduced a modification to the “immunological” mRNA that is very similar to pseudouridine. “We don’t yet know if the control elements we discovered are also able to detect the modification in synthetic mRNA,” said Prof. Arava. “If they are, this may open up further possibilities to improve mRNA activity and produce larger quantities of proteins.”
Beyond the present research and its implications, said Prof. Arava, “our discovery illustrates the importance of basic research in the development of sophisticated medical treatments and innovative vaccines. The public and the media are mainly hungry for publications about developments and applied science, but without a strong, broad infrastructure of basic science – in directions in which the applied horizon is not always clear – we would not witness such dramatic breakthroughs in diagnosis, treatment, and vaccines, as well as in areas of life outside the world of medicine.”
The research was funded by the Israel Science Foundation (ISF). Ofri Levi is the winner of the Jacobs Scholarship for Outstanding Students.
Click herefor the complete article in Nucleic Acids Research.
Revolutionary Neu-ChiP project will see scientists use human brain stem cells on microchips to push the boundaries of artificial intelligence (AI)
Scientists have started work on a project that will see human brain stem cells used to power artificial intelligence (AI) devices and bring about a revolution in computing.
The Neu-ChiP project, an international collaboration led by researchers at Aston University, has been awarded €3.5m (£3.06m) to show how neurons – the brain’s information processors – can be harnessed to supercharge computers’ ability to learn while dramatically cutting energy use.
SEM image of a primary rat neuronal culture grown on the 3D CMOS-MEA. Neurons are located on top and at the base of the structured electrodes CREDIT: 3Brain AG
The research team is now embarking on a three-year study to demonstrate how human brain stem cells grown on a microchip can be taught to solve problems from data, laying the foundations for a “paradigm shift” in machine learning technology.
The use of AI is becoming ever more prevalent in areas as diverse as healthcare, finance, autonomous vehicles, and speech recognition, right through to recommending films through on-demand services like Netflix. The ‘big four’ tech companies – Apple, Google, Amazon, and Facebook – and many others are investing heavily in machine learning to tailor their products and better understand their customers.
But current electronic approaches to machine learning have limits, requiring ever-growing computing power and high energy demands. The recent trend towards ‘neuromorphic computing’, which aims to mimic human neural activity electronically, is hampered by the inherent limitations of conventional electronics.
In contrast, human brain cells effortlessly combine these functions and have extremely low power demands, requiring only a small volume of a nutrient-rich solution to operate.
In the Neu-ChiP project, the team will layer networks of stem cells resembling the human cortex onto microchips. They will then stimulate the cells by firing changing patterns of light beams at them. Sophisticated 3D computer modeling will allow them to observe any changes the cells undergo, to see how adaptable they are. This imitates the ‘plasticity’ of the human brain, which can rapidly adapt to new information.
The project, funded by the European Commission’s Future and Emerging Technologies (FET) program and involving partner institutions in the UK, France, Spain, Switzerland, and Israel, is also expected to produce new knowledge about the functioning of the brain which could be used to develop novel stem cell-based treatments.
Professor David Saad, Professor of Mathematics at Aston University, said: “Our aim is to harness the unrivaled computing power of the human brain to dramatically increase the ability of computers to help us solve complex problems. We believe this project has the potential to break through current limitations of processing power and energy consumption to bring about a paradigm shift in machine learning technology.”
Dr. Rhein Parri, Reader in Pharmacology at Aston University, said: “We are very excited to have won support from the European Commission for this ambitious project. Our international team will combine their expertise and work together to develop technology that we expect to provide great future benefits for science and society.”
Dr. Eric Hill, Senior Lecturer in Stem cell Biology at Aston University, said: “Our ability to turn human stem cells into brain cells has revolutionized the study of the human brain. This exciting interdisciplinary project will bring international scientists from diverse backgrounds together to develop new technologies that will provide huge insight into the development of human neuronal networks”.
The project involves academic partners from Loughborough University (UK), the University of Barcelona (Spain), Centre National de la Recherche Scientifique (CNRS, France), Technion Israel Institute of Technology (Israel), and the company 3Brain AG (Switzerland).
Drs Jordi Soriano, Associate Professor in Physics, and Daniel Tornero, Tenure Track Professor in Biology, both at the University of Barcelona, said: “Our ability to engineer neuronal circuits in a dish and train them to conduct data analysis will provide new insights on how the brain computes information and finds solutions. The developed technology may even help to design unique and exciting human-machine interfaces.”
Professor Rémi Monasson, Director of Research at the Centre National de la Recherche Scientifique (CNRS), said: “In Neu-ChiP, we will not only model a system made of many extraordinarily complex components – human neural cells – but we will try to go far beyond. Our aim is to drive the neural system to a state in which it will be able to carry out nontrivial computations.”
Drs Shahar Kvatinsky, Associate Professor of Electrical Engineering, and Daniel Ramez, Assistant Professor of Biomedical Engineering, both at Technion Israel, said: “We are seeking to build neuromorphic circuits and combine emerging electronic devices with biological neurons and this project is a major step towards this target. In the context of synthetic biology, it is impressive to see how computation in living cells is evolving from digital through analog and moving towards a neuromorphic computing paradigm.”
Dr. Alessandro Maccione, co-founder and Chief Scientific Officer of 3Brain AG, said: “The Neu-ChiP project has the ambitious plan to overcome current machine learning approaches through the study of complex human-brain-based circuits. We are proud to put our technology at the service of this pioneering and exciting challenge.”
Dr. Paul Roach, Senior Lecturer in Biomaterials and Interface Science at Loughborough University, said: “This work really brings together an exciting interdisciplinary team of researchers to build on our individual strengths and interests. The focus of this project is on revolutionizing the way we analyze information using specifically designed complex living neuronal circuits.”
Technion researchers have developed an innovative technology for the automated monitoring of stress in agricultural crops. Early detection of water and heat stress is crucial for agricultural growers since the reduction in moisture is reflected in limited stomatal conductance, resulting in dwindled growth and eventually to the plant’s premature death. The development was led by the people of GIP, the Geometric Image Processing Laboratory, in the Henry and Marilyn Taub Faculty of Computer Science.
Fig. 1 – Artificial images of tobacco plants (right) and two Arabidopsis species (middle, left). The top row presents the artificial images, and the bottom row – the leaf masks. By creating a large quantity of artificial (synthetic) leaf images deep neural networks can be trained, thus providing for better leaf separation in real photographs.
Israel, which was renowned in the first decades of its existence as a modern agricultural power, transitioned over the years into the Startup Nation. In recent years, it turns out that the connection between the two – hi-tech and agriculture, agritech, for short – is likely to give the food world a significant boost. This is the backdrop for the establishment of the Phenomics Consortium, sponsored by the Israel Innovation Authority, in the framework of which the present research was conducted. The Consortium was created with the goal of furthering scientific and technological innovation through collaboration between academic research institutes and industrial companies.
The Technion researchers – research assistant Alon Zvirin, head of the GIP lab Professor Ron Kimmel, and chief engineer Yaron Honen – have developed smart technology for the monitoring and prediction of crop stress and leaf segmentation. In the context of the former, Zvirin explains: “The detection of drought stress enables the plant to be saved, allows for the identification of diseases and the prediction of crop yield quantities, all of which are crucial information for the grower.” Through the use of color photographs, thermal imaging and deep learning, the researchers were able to predict stress and new leaf development with great success; in a test of the technology on banana seedlings, an impressive prediction level of over 90% accuracy was achieved. In the context of the latter – leaf segmentation – the researchers achieved unprecedented results in the identification of Arabidopsis and tobacco leaves by applying deep learning. To train the system on a large quantity of samples, the research team developed a vast database containing artificial leaf images, and then also tested the technology on other crops – avocado, bananas, cucumbers and maize.
According to Zvirin, “We included young researchers who were just starting out in the technology development process. They brought excellent ideas and did a great job. Two of them are also listed as lead authors of the articles: Dmitri Kuznichov, who will shortly be completing his master’s degree under the supervision of Prof. Irad Yavneh and Prof. Ron Kimmel, and Sagi Levanon – a graduate of the Psagot Excellence Program, who has started studying for his second degree in the Faculty.” The article on stress detection was published at the European Conference on Computer Vision, ECCV, and the paper on segmentation was published at the Conference on Computer Vision and Pattern Recognition, CVPR.
The Phenomics Consortium
The name “Phenomics” is derived from the word “phenotype”, i.e. the observable physical properties of an organism, which possess agricultural, agronomic, or biological significance. In our case, this refers to the diagnosis of the plant’s condition on the basis of its observable characteristics – color, shape, and size. High throughput automated phenotyping today accounts for the bottleneck in the improvement of agricultural crops, and hence the importance of the present achievement. The Technion’s partners in the Consortium are agro-tech and biotech companies Rahan Meristem, Hazera Seeds, and Evogene; tech companies Elbit Systems, Opgal Optronics Industries, and Sensilize; and the following academic and research institutes: Ben-Gurion University, Tel Aviv University, the University of Haifa, the Hebrew University of Jerusalem and the Volcani Center.
A study by three Technion researchers has revealed that simply spending time in nature isn’t enough: to be happy, we need to get really close to it, to touch it and smell it. And surprise: there’s no need to turn off your phone
During the first COVID-19-related lockdown, everyone baked sourdough bread. In the second lockdown, the trend was home gardening, and social media was flooded with a plethora of photos of pot plants and close-ups of colorful succulents. According to researchers, the change in trend can be explained by the fact that the second lockdown found Israelis in lower spirits that even carbs would find it hard to lift. The forced stay that kept entire families indoors turned even the brightest, most beautiful homes into traps that created a sense of being closed in, and their residents tried to mitigate its impacts with a little greenery on which they could feast their eyes and spirits.
Professor Assaf Shwartz
Numerous research studies have supported this intuitive choice, demonstrating the importance of nature and green spaces to people’s emotional and physical wellbeing, but a new study has shown that “feasting one’s eyes on greenery” is merely the tip of the iceberg. In order to benefit emotional wellbeing, humans must get close up and physically touch natural elements. In a research study published in Conservation Biology, Technion researchers found that interaction with nature alone is not enough. In order for tangible benefits to be derived, they found it is important that planners design green spaces that positive and close interaction with nature. The effect of interaction of this kind occurs in two stages, In the first, “cues of close psychological distance,” such as smelling and touching natural elements, increase the state of nature relatedness. This state in turn intensifies the pleasure derived by participants.
The researchers, Professor Assaf Shwartz and Dr. Agathe Colléony of the Faculty of Architecture and Town Planning, and Dr. Liat Levontin of the William Davidson Faculty of Industrial Engineering and Management, explain that closeness to nature improves wellbeing more than passive exposure or simply looking at the green landscape. Based on a survey of 1,023 visitors at Ramat Hanadiv Nature Park, they found that the closer the interaction with nature (for example, interaction that included touching natural elements or smelling flowers), the more the positive affect of visitors was enhanced following the visit to the nature reserve, compared to other visitors who experienced nature from a greater distance (for example, by simply taking a walk).
Dr. Liat Levontin
“Our research has shown that people who have an emotional affinity for nature are generally happier and derive greater benefit from visits to green spaces or nature reserves,” explained Prof. Shwartz.
Following these findings, the researchers conducted an experiment among 303 Technion students. All participants spent half an hour outdoors on campus, with each assigned one of nine different cues-to-experience to perform while walking. These included smelling flowers, taking photographs of nature, touching natural elements, or turning off their phones. The findings showed that participants assigned cues of close psychological distance from nature (smelling and touching natural elements) indeed felt closer to nature and felt better after the walk than the control group (with no cues). Contrary to the prevailing opinion that it is important to experience nature undisturbed, participants who were asked to turn off their phones during the walk interacted less with nature, and reported both an increase in their negative feelings and a decrease in positive feelings after the walk was recorded. According to Dr. Levontin, “Turning off the phone may possibly cause people to think about it more and lead to FOMO (Fear of Missing Out) and does not enable significant interaction with nature.”
“People today are increasingly alienated from nature, and this has negative implications on their health and wellbeing and on the importance they attribute to the world of nature,” said Prof. Shwartz. “It’s important to plan green spaces that enable significant interactions with nature to improve our affinity to nature and emotional wellbeing.”
Dr. Agathe Colléony
“I think we all felt it in the recent lockdowns,” added Dr. Levontin. “But it’s possible that as a result of our growing alienation from nature, planning green spaces is not enough to create a significant nature experience and contribute to quality of life. So thought must be given to how to encourage people to go outdoors and enhance their nature experience.”
“This is precisely where our research comes in,” Prof. Shwartz explained. “In the experiment, we demonstrated that with the help of minor cues, which we called “cues-to-experience,” people can be brought closer to nature. We also found that it is possible to enhance the nature experience among visitors, as well as its positive effect after the visit. Even smartphones can be used to create meaningful nature experiences for all of us in parks, gardens, and nature reserves. At the same time, it is important to make sure to also protect biodiversity and not to encourage interaction that is liable to be harmful to nature, such as picking flowers. Landscape architects and environmental planners need to think about solutions that will encourage the creation of interactions with nature, whose negative impact on biodiversity is minimal and positive impact is strong.”
The paper in Conservation Biology can be accessed here
Three young scientists from leading research institutions in Israel will each be awarded US$ 100,000 for their groundbreaking scientific research
The Blavatnik Family Foundation, the New York Academy of Sciences, and the Israel Academy of Sciences and Humanities announced today the Laureates of the 2021 Blavatnik Awards for Young Scientists in Israel.
This year’s Laureates, who will each receive US$100,000, are:
Professor Ido Kaminer (Physical Sciences & Engineering)—Technion – Israel Institute of Technology
Professor Rafal Klajn (Chemistry)—Weizmann Institute of Science
Professor Yossi Yovel (Life Sciences)—Tel Aviv University
The Blavatnik Awards recognize outstanding, innovative scientists at the early stages of their careers for both their extraordinary achievements and their promise for future discoveries. The prizes are awarded to researchers aged 42 and younger for groundbreaking work in the disciplines of Life Sciences, Chemistry, and Physical Sciences & Engineering. The Blavatnik Awards in Israel sit alongside their international counterparts, the Blavatnik National Awards and Blavatnik Regional Awards in the United States, and the Blavatnik Awards in the United Kingdom.
The 2021 Blavatnik Awards for Young Scientists in Israel will be conferred, as pandemic restrictions allow, at a ceremony held at the Israel Museum in Jerusalem on August 1, 2021. The Laureates will join a cadre of young scientists from across Israel who have been honored by the Blavatnik Awards in Israel since their launch in 2017. In addition, the Laureates will become part of the international Blavatnik Science Scholars community, which, by the close of 2021, will total 350 young scientists from around the world. Each summer the Laureates are invited to attend the annual Blavatnik Science Symposium in New York City at the New York Academy of Sciences, where past and present Blavatnik Awards honorees from around the world come together to share new ideas and forge collaborations for novel, cross-disciplinary research.
Professor Ido Kaminer (Physical Sciences & Engineering)—Technion – Israel Institute of Technology
“The passing year has demonstrated just how important groundbreaking science is,” said Len Blavatnik, Founder and Chairman of Access Industries and Head of the Blavatnik Family Foundation. “It’s imperative to encourage young scientists to venture broadly in their respective fields and to push the boundaries of scientific discovery. The achievements by these three outstanding Israeli scientists are a testament to their brilliance, perseverance, and imagination—characteristics held by many young Israeli researchers who will continue to make remarkable contributions to science for generations to come.”
Nicholas B. Dirks, President and CEO of the New York Academy of Sciences,said that “The 2021 Blavatnik Awards in Israel Laureates are an impressive group of scientific pioneers. On behalf of the New York Academy of Sciences, we are proud of the contributions that these young scientists in Israel are making to the global scientific community, improving lives for the better through their research. We congratulate them on their achievements and look forward to seeing what their future holds.”
Professor Nili Cohen, President of the Israel Academy of Sciences and Humanities, said: “In the midst of a challenging year, we are extremely proud that our young scientists are venturing forward to new heights, and advancing scientific innovation and breakthrough. Together with the Blavatnik Family Foundation and the New York Academy of Sciences, we are delighted to honor these exceptional Israeli scientists with this prestigious Award.”
During the nomination period for the 2021 Blavatnik Awards for Young Scientists in Israel, 37 nominations were received from seven universities across the country. Members of the Awards’ Scientific Advisory Council, which includes Nobel Laureates, Professors Aaron Ciechanover, and David Gross, along with Chairman of the Israel Space Agency and Chairman of the National Council for R&D for the Ministry of Science and Technology of Israel, Professor Isaac Ben-Israel, were also invited to submit nominations. Three distinguished juries composed of leading scientists representing the three disciplinary categories and lead by Israel Academy members selected the 2021 Laureates.
About the Laureates
PHYSICAL SCIENCES & ENGINEERING:
Prof. Ido Kaminer, Assistant Professor, The Viterbi Faculty of Electrical Engineering, Technion – Israel Institute of Technology
The work of Ido Kaminer, PhD, Head of the Robert and Ruth Magid Electron Beam Quantum Dynamics Laboratory, has influenced fundamental physics research with real-world applications by transforming our understanding of the quantum nature of light-matter interactions. New technologies developed in his laboratory open up the possibility of compact and tunable X-ray apparatuses for applications such as medical imaging and security scanning. He has also uncovered new aspects of the Cherenkov Effect—a burst of light seen when high-speed particles travel through gas, liquid, or solid—that was first discovered in 1934. The Cherenkov Effect was thought to be fully understood, but Professor Kaminer discovered hidden quantum features not previously identified by classical physics. This discovery led him to develop novel high energy particle detectors for particle accelerators such as the one at CERN.
Prof. Kaminer is affiliated with the Helen Diller Quantum Center and the Russell Berrie Nanotechnology Institute
CHEMISTRY:
Prof. Rafal Klajn, Associate Professor and Head of the Helen and Martin Kimmel Center for Molecular Design, Weizmann Institute of Science
Most man-made materials are intrinsically static, and thus not capable of undergoing change in response to external signals. The ability to react to external stimuli, such as light, heat, and touch, is fundamental to the existence and functioning of living organisms. Organic chemist, Rafal Klajn, PhD, has developed dynamic nanomaterials that are engineered to possess some of these “life-like” characteristics. For example, he has created cube-shaped, magnetic nanoparticles that are capable of self-assembling into complex double-helical materials in the presence of a magnetic field. These and other dynamic nanomaterials have potential applications in such diverse fields as water purification, energy storage, and catalysis.
LIFE SCIENCES:
Prof. Yossi Yovel, Associate Professor of Zoology, Tel Aviv University, Israel Young Academy member
Yossi Yovel, PhD, is working to bridge the gap between two of the most influential fields in biology—ecology, the study of animals in their environment, and neuroscience, the study of how the brain controls actions. He has helped to establish the new field of neuroecology, the study of how the brain controls behavior in a rapidly changing natural environment; this combination is crucial to our understanding of biological processes in the natural world. Professor Yovel uses bats to study behavioral responses. He is a leading expert on the use of bats in scientific research and studies their use of echolocation to perceive and navigate through the world as a model for how the brain integrates sensory information to guide behavior. He has developed novel miniaturized GPS and other devices that monitor the behavior of freely moving bats in the wild. This work provides broader insight into group behaviors, integration of sensory information in the brain, and real-time decision making. Yovel also applies his understanding of bat echolocation in a range of robots. Yovel has made his technology freely available; it is used in fieldwork internationally and has the potential to aid in engineering acoustic control of autonomous vehicles.
About the Blavatnik Awards for Young Scientists
The Blavatnik Awards for Young Scientists, established by the Blavatnik Family Foundation in the United States in 2007 and independently administered by the New York Academy of Sciences, began by identifying outstanding regional scientific talent in New York, New Jersey, and Connecticut. The Blavatnik National Awards were first awarded in 2014, and in 2017 the Awards were expanded to honor faculty-rank scientists in the United Kingdom and in Israel. By the close of 2021, the Blavatnik Awards will have awarded prizes totaling US$11.9 million. Of all the Award recipients, 61 percent are immigrants to the country in which they were recognized and hail from 47 countries across six continents. For updates about the Blavatnik Awards for Young Scientists, please visit www.blavatnikawards.org or follow us on Twitter and Facebook @BlavatnikAwards.
The European Union has awarded another grant to the research group of Professor Amit Meller of the Technion Faculty of Biomedical Engineering for their OpiPore project. The aim of OpiPore is to advance novel technology for analyzing single molecules, including detecting the presence of SARS-CoV-2 RNA molecules. To do this, the researchers are developing a new method to produce solid-state Nanopores (ssNPs)– diagnostic devices based on nanopores – en mass.
The European Union has awarded a supplemental grant to Technion Professor Amit Meller’s research group to accelerate a novel technology for laser-based drilling of nano-apertures in thin film. The planned device will serve to analyze single molecules for the purpose of quick diagnosis of COVID-19 as well as other diseases
The ssNPs are a novel type of biosensors, capable of analyzing single molecules. Such analysis has immense medical and research value, since it can replace common diagnosis methods based on analysis of bulk solution. Such methods suffer from multiple disadvantages, including high costs, cumbersome lab equipment and insufficient accuracy.
Professor Amit Meller
To explain the leap provided by the ssNP devices, the researchers used the example of Coronavirus SARS-CoV-2. Existing Coronavirus tests are based on RT-qPCR technology, which requires a complicated process of collecting a sample from the patient using a swab, “opening” the virus to extract its genetic material, extracting the RNA, and reverse-transcription of the RNA to DNA. But that is not the end. For the existing equipment to detect the presence of viruses in the sample, a massive amplification (PCR) is performed, doubling the amount of DNA over and over until a sufficient amount is reached. Not only is the process long and expensive, but the amplification stage can sometimes cause significant errors in detecting the presence of the virus, i.e., in determining whether a patient is positive or negative for COVID-19.
The diagnostic process developed in Meller’s lab completely obviates the amplification stage, allowing direct counting and quantifying samples of the virus’ RNA, as well as normal human RNA molecules simultaneously. In this fashion, precious time can be saved, and mistakes may be avoided. The new method is based on drawing individual biological molecules, such as DNA and RNA, by means of an electric field, into a nanopore containing an electrical sensor. The output undergoes an analysis which allows direct and immediate identification and quantification of the molecules.
Dr. Yana Rozevsky
The technology was originally developed to detect tumor-associated RNA biomarkers that make it possible to diagnose cancer in its early stages. A short while after the COVID-19 epidemic, Prof. Meller’s group started working on adjusting this technology to address the urgent need for fast and precise Coronavirus tests. Proof of concept results showed the efficiency of this method in detecting the presence of SARS-CoV-2 even when the sample contained only trace amounts of the virus. This method, named “RT-qNP”, was recently published in ACS Nano. RT-qNP development was led by a post-doctoral fellow, Dr. Yana Rozevsky, in Prof. Meller’s lab, in collaboration with colleagues in Charité hospital in Berlin. The work has been supported by Prof. Meller’s ERC grant awarded by the European Union.
As previously mentioned, this month the group was awarded a supplemental “Proof of Concept” ERC grant. This grant is focused on the production of the device itself, since large-scale drilling the nano-apertures is an immense technological challenge that currently delays the widespread implementation of ssNP devices. Through long and in-depth work, Prof. Meller’s research group has developed a unique technology for drilling the nano-apertures using a focused beam of blue laser. This technology will now be further developed, to bring it to clinical use as soon as possible.
While both grants were awarded at a time when the world is dealing with the Coronavirus pandemic, the aforementioned technologies are relevant to the diagnosis of many other diseases – not only viral and microbial, but also multiple types of cancer, as preliminary studies in the Technion laboratories have already demonstrated. The Coronavirus research is performed in close collaboration with the bio-bank unit of the Rambam Medical Center.
Technion scientists are deciphering a mechanism that integrates all the stages of the mRNA lifecycle into a unified system
Figure: The mRNA coordinator Rpb4/7 receives and transmits messages between the components of the gene expression process through small molecules, thus revealing a molecular language with a rich and varied vocabulary. Illustration by Dr. Tehilah Meged-Book
Researchers from the Rappaport Faculty of Medicine at the Technion have uncovered a mechanism that coordinates the multi-stage process of gene expression: i.e., translating the information stored in the DNA into proteins. The study, published in Cell Reports, was led by molecular microbiology principal investigator Professor Mordechai Choder and Dr. Stephen Richard, with Dr. Tamar Ziv and Keren Bendalak of the Smoler Proteomics Center at the Technion.
The DNA can be thought of as the cell’s “recipe book,” written using four “letters” – the nucleotide molecules. Every cell in our body contains DNA with the same nucleotide sequence (with some exceptions). However, the tissues of our body – muscle, bone, skin, etc. are quite different from each other in how they are formed and how they function.
How is possible that all tissues’ cells contain the same DNA sequence but cells in different tissues express different sets of genes and function differently?
Professor Mordechai Choder
The answer lies in the regulation of gene expression – a wide range of mechanisms that, together, regulate which recipes out of the DNA-book will be “cooked,”i.e., which genes would be expressed in each particular cell, in what amounts, and when. Although this recipe book is the same in all cells, the recipes cooked from it may be quite different.
The mechanisms that regulate gene expression may be broken into four major stages, revolving around the production, transfer, translation, and decay of messenger RNA (mRNA) molecules – each encodes a unique protein:
mRNA Synthesis and Maturation: the DNA is a large molecule (almost 2 meters long). In the process called “transcription”, a gene encoding one protein (one recipe of the cookbook), is copied out into mRNA molecule, the nucleotide sequence of which is dictated by the DNA nucleotide sequence; this molecule carries the instructions for building the protein.
mRNA Transport from the cell nucleus into the cytoplasm, an intra-cell environment outside the nucleus, where proteins are produced. The nucleus can be thought of as a “safe” where the precious recipe book is kept. Recipes are copied out of it as necessary, but the book itself is never taken out of the safe.
mRNA Translation: this stage is carried out by the ribosome – the “protein factory.” The ribosome reads the mRNA instruction (a single recipe) and produces a protein. Proteins are composed of amino acids, the sequence of which is dictated by the mRNA nucleotide sequence; the amino acids sequence determines the protein nature and functionality. Proteins perform many functions in our body and are responsible, in part, for what we are.
mRNA Decay: like most molecules in our body, mRNAs are turned over. Their degradation is carried out by factors that, as Choder’s group reported in 2013 (in Cell), also participate in transcription. Thus, mRNA synthesis and decay processes are linked.
Dr. Stephen Richard
“Every stage is regulated by a sophisticated mechanism, consists of many dozens of dedicated factors that execute the process and ensure its precision,” said Professor Choder. “I was interested in understanding the mechanism that integrates all these stages into a unified system, trying to obtain a bird’s eye view. I have hypothesized that, for proper expression, all stages must be coordinated. It is for this reason that I have focused for the last 15 years on “zooming out” our point of view from the discrete processes – transcription, translation, etc. to the whole system.”
This continued research, performed on the baker’s yeast S. cerevisiae, has yielded some dramatic discoveries, among them the discovery of mRNA coordinators, published in 2010 in Cell. The coordinators bind to the mRNA during transcription and accompany it throughout its life; a life that involves all the above-mentioned stages.
“To use a musical analogy, the coordinator is like a conductor of an orchestra, responsible for the coordination between the various instruments, that is to say – the different stages,” continued Professor Choder. “It evolved because a ‘false note’ in the orchestra, i.e., discoordination among the stages, can have fateful consequences to the organism.”
In the current article, the researchers went a step further and examined the means by which the stages’ components and the coordinators communicate. They found that they use a “language,” the “letters” of which are small molecules (such as phosphoryl, methyl, and acetyl) and the “words” are combinations thereof. These molecules bind to the coordinator, while it is attached to the mRNA, forming an mRNA/coordinator/small molecule complex. The coordinators, in turn, spread the “rumour” among the stages.
The language contains many different words, each representing a certain combination of letters and the positions within the coordinator (which position within its amino acid sequence) that they bind. Every “word” delivers information and commands to the various stages and affects their functionality. As for what kinds of information the stages need to deliver, they range from the simple (e.g., “all is well, you may proceed”) to the more complicated (e.g., “slow down, something’s missing” or “send the mRNA to degradation – the problem is irreparable” etc.). This mechanism allows the transfer of information between stages, thus reducing errors along the way. According to Prof. Choder, it would be interesting to see if other molecular systems use similar coordinators and a similar language (or a dialect).
The study was done with the generous support of the Israeli Science Foundation (ISF).
While Israel undergoes a mass vaccination program, the ongoing window of risk is being closed at Technion through an innovative system of rapid testing for COVID-19.
The Technion announced the extensive testing operation as a fundamental protective measure for dormitory residents. The “NaorCov19” test being used in Haifa was developed in April 2020 by Professor Naama Geva-Zatorsky of the Ruth and Bruce Rappaport Faculty of Medicine.
“To protect the health of campus visitors and residents, to lead as normal a lifestyle as possible, and to return to routine life during the pandemic, it is necessary to break the chain of infection rapidly, through effective monitoring and diagnosis,” said Technion President, Professor Uri Sivan. “Living alongside COVID-19 is an enormous challenge for all the population, and I hope and believe the rapid implementation of the novel technologies developed by Technion researchers will assist us in arresting the spread of the virus, and that it will serve as a model for other places across the country.”
The technology has been commercialized by the Technion for further development by Rapid Diagnostic Systems ltd., which is developing the molecular diagnostic platform under the name “Naor.” (www.naordia.com). The technology had been field-tested and developed in collaboration with multiple institutions and researchers including MAFAT (the R&D arm of the Israeli Ministry of Defence) and the Rambam Health Care Campus.
The NaorCov19 test rapidly detects the SARS-CoV-2 virus and is based on a saliva sample and a short isothermal process that can be done on-premises. The process takes less than an hour if done on-site, and dozens or even hundreds of samples can be processed simultaneously. Technion students and staff leave saliva samples at stations around campus and use their phones to record it. They are then electronically notified about the results within a few hours of the sample collection. The Technion community members are encouraged to be tested at least once a week, in order to reduce the risk of campus infection.
Thanks to its simplicity, the NaorCov19 is suitable for rapid testing on campuses and schools, at workplaces, airports and even onboard airplanes. It is also scheduled for self-testing at home.
The on-campus Naor tests are being performed as part of a study that has received the approval of the local institutional review board (IRB).
At the start of the 2020-21 academic year, the Technion administration announced the “Creating an Open and Safe Campus” initiative, which offers multi-layered protection of campus visitors.
The First Layer is strict adherence to the “purple badge” rules: wearing a mask, hygiene, and social distancing.
The Second Layer involves the monitoring of the campus sewage system using novel technology developed at Technion by Professor Eran Friedler of the Department of Environmental and Water Engineering. Sewage testing supports the monitoring of a large population, effectively and rapidly locating cases without the need to reach each individual. It has already effectively disrupted potential chains of coronavirus infection.
The soon to be implemented Third Layer is the Technion-developed “NaorCov19” test. This individual, rapid, and non-invasive system will help track and diagnose cases on campus.
The Fourth Layer involves regular PCR tests for those who have relevant symptoms or who test positive on the “NaorCov19” test. Since the “NaorCov19” test is still waiting for the approval of Israel’s Ministry of Health, persons who test positive go on to take a regular PCR test for confirmation.
The “Creating an Open and Safe Campus” project is led by Executive Vice President for Research Professor Koby Rubinstein, Professor Avigdor Gal of the Faculty of Industrial Engineering & Management and Professor Danny Raz of the Henry and Marilyn Taub Faculty of Computer Science.
The President of the Technion – Israel Institute of Technology, Professor Uri Sivan announced today that the Technion will award an honorary doctorate to Pfizer CEO and Chairman Dr. Albert Bourla, for his extraordinary achievement in leading the record time development of the novel vaccine against SARS-CoV-2, the virus that causes COVID-19. The vaccine, which is helping to end the coronavirus crisis, is expected to serve as a model for the development of a wide range of future mRNA-based treatments.
Dr. Albert Bourla (Credit: Pfizer)
“As Chairman of the Board of Pfizer Inc., Dr. Bourla headed the trailblazing effort to develop a vaccine against the coronavirus,” explained Technion President Sivan. “In his 27 years with Pfizer, Dr. Bourla promoted multiple areas within the company, among them technological innovation. The development of the COVID-19 vaccine is an extraordinary biotechnological achievement that exemplifies the importance of science and multidisciplinary research. The vaccine, and similar ones, will bring healing to all of humanity and will rescue the world from the crisis that began at the end of 2019, with the epidemic outbreak. Dr. Bourla’s family history, as a son of Holocaust survivors from Thessaloniki, is a symbol of the remarkable vitality of the Jewish people, their liveliness, and their renewal capacity in the wake of the Holocaust.”
“I am moved by the news and honored to receive a degree from such an important and historical institution as the Technion,” Dr. Bourla said to President Sivan during a phone conversation informing him of being awarded the degree. “In my youth, I considered studying at the Technion; this is an emotional closure for me.”
Dr. Albert Bourla was born in Thessaloniki in 1961 to a Jewish family, part of which perished in the Holocaust. His family, who arrived in Greece from Spain following the Alhambra Decree, dealt in jewelry and diamonds, and their business spread across many countries. The Thessaloniki Jewish community, once the largest in Greece, had a population of approximately 80,000 in the 1930s. Approximately two-thirds of them perished in the Holocaust.
Dr. Bourla completed all of his academic degrees at the Aristotle University of Thessaloniki and holds a Ph.D. in veterinary medicine and reproductive biotechnology. In 1993 he joined Pfizer, one of the world’s leading biopharmaceutical companies, where he went on to hold a series of positions. He oversaw antibody development and served as Group President of Pfizer’s Global Vaccines, Oncology, and Consumer Healthcare business. In 2018 he was appointed Chief Operating Officer, and in 2020 he became the company’s Chief Executive Officer.
In recent years Dr. Bourla has led Pfizer in strengthening ties with technology companies and in adopting technologies such as artificial intelligence. At the beginning of 2020, following the global outbreak of the COVID-19 epidemic, he harnessed most of the company’s resources to develop a vaccine, meeting challenging schedules. Throughout the process, Dr. Bourla promised there would be no compromise with regard to the safety of the vaccine, and approval was obtained after an extensive study that included more than 40,000 subjects.
The honorary doctorate will be conferred on Dr. Bourla during the next annual Technion Board of Governors meeting in November 2021.
In the midst of the Coronavirus pandemic, a rapid and extensive testing operation developed at Technion benefits all residents of Technion City
While Israel undergoes a mass vaccination program, the ongoing window of risk is being closed at Technion through an innovative system of rapid testing for COVID-19.
The Technion announced the extensive testing operation as a fundamental protective measure for dormitory residents. The “NaorCov19” test being used in Haifa was developed in April 2020 by Professor Naama Geva-Zatorsky of the Ruth and Bruce Rappaport Faculty of Medicine.
“To protect the health of campus visitors and residents, to lead as normal a lifestyle as possible, and to return to routine life during the pandemic, it is necessary to break the chain of infection rapidly, through effective monitoring and diagnosis,” said Technion President, Professor Uri Sivan. “Living alongside COVID-19 is an enormous challenge for all the population, and I hope and believe the rapid implementation of the novel technologies developed by Technion researchers will assist us in arresting the spread of the virus, and that it will serve as a model for other places across the country.”
The technology has been commercialized by the Technion for further development by Rapid Diagnostic Systems ltd., which is developing the molecular diagnostic platform under the name “Naor.” (www.naordia.com). The technology had been field tested and developed in collaboration with multiple institutions and researchers including MAFAT (the R&D arm of the Israeli Ministry of Defence) and the Rambam Health Care Campus.
The NaorCov19 test rapidly detects the SARS-CoV-2 virus and is based on a saliva sample and a short isothermal process that can be done on-premises. The process takes less than an hour if done on site, and dozens or even hundreds of samples can be processed simultaneously. Technion students and staff leave saliva samples at stations around campus and use their phones to record it. They are then electronically notified about the results within a few hours of the sample collection. The Technion community members are encouraged to be tested at least once a week, in order to reduce the risk of campus infection.
Thanks to its simplicity, the NaorCov19 is suitable for rapid testing on campuses and schools, at workplaces, airports and even onboard airplanes. It is also scheduled for self-testing at home.
The on-campus Naor tests are being performed as part of a study that has received the approval of the local institutional review board (IRB).
At the start of the 2020-21 academic year, the Technion administration announced the “Creating an Open and Safe Campus” initiative, which offers multi-layered protection of campus visitors.
The First Layer is strict adherence to the “purple badge” rules: wearing a mask, hygiene, and social distancing.
The Second Layer involves the monitoring of the campus sewage system using novel technology developed at Technion by Professor Eran Friedler of the Department of Environmental and Water Engineering. Sewage testing supports the monitoring of a large population, effectively and rapidly locating cases without the need to reach each individual. It has already effectively disrupted potential chains of coronavirus infection.
The soon to be implemented Third Layer is the Technion-developed “NaorCov19” test. This individual, rapid, and non-invasive system will help track and diagnose cases on campus.
The Fourth Layer involves regular PCR tests for those who have relevant symptoms or who test positive on the “NaorCov19” test. Since the “NaorCov19” test is still waiting for the approval of Israel’s Ministry of Health, persons who test positive go on to take a regular PCR test for confirmation.
The “Creating an Open and Safe Campus” project is led by Executive Vice President for Research Professor Koby Rubinstein, Professor Avigdor Gal of the Faculty of Industrial Engineering & Management and Professor Danny Raz of the Henry and Marilyn Taub Faculty of Computer Science.
Researchers at Technion – Israel Institute of Technology and the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, in collaboration with scientists in Israel and Spain, have discovered remarkable molecular properties of an antimicrobial peptide from the skin of the Australian toadlet. The discovery could inspire the development of novel synthetic drugs to combat bacterial infections.
The peptide uperin 3.5 is secreted by the Australian toadlet’s skin in a “dormant” form, in which the peptide self-assembles into a stable amyloid fibril in the so-called cross-β form. When exposed to bacteria, it rapidly changes into cross-α fibrils that affect the bacterial membrane, thereby killing the bacteria. The pictures were taken using a transmission electron microscope (TEM) in the Electron Microscopy Centers in the Technion Department of Materials Science and Engineering and in the Department of Chemical Engineering. The cross-α atomic structure was determined by data collected at the ESRF synchrotron.
An antibacterial peptide that turns on and off
Professor Meytal Landau
The researchers solved the 3D molecular structure of an antibacterial peptide named uperin 3.5, which is secreted on the skin of the Australian toadlet (Uperoleia mjobergii) as part of its immune system. They found that the peptide self-assembles into a unique fibrous structure, which via a sophisticated structural adaptation mechanism can change its form in the presence of bacteria to protect the toadlet from infections. This provides unique atomic-level evidence explaining a regulation mechanism of an antimicrobial peptide.
The antibacterial fibrils on the toadlet’s skin have a structure that is reminiscent of amyloid fibrils, which are a hallmark of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Although amyloid fibrils have been considered pathogenic for decades, it has recently been discovered that certain amyloid fibrils can benefit the organisms that produce them, from humans to microbes. For example, certain bacteria produce such fibrils to fight human immune cells.
Dr. Einav Tayeb-Fligelman
The findings suggest that the antibacterial peptide secreted on the toadlet’s skin self-assembles into a “dormant” configuration in the form of highly stable amyloid fibrils, which scientists describe as a cross-β conformation. These fibrils serve as a reservoir of potential attacker molecules that can be activated when bacteria are present. Once the peptide encounters the bacterial membrane, it changes its molecular configuration to a less compact cross-α form and transforms into a deadly weapon. “This is a sophisticated protective mechanism of the toadlet, induced bytheattacking bacteria themselves,” says structural biologist Prof. Meytal Landau, the lead author of this study. “This is a unique example of an evolutionary design of switchable supramolecular structures to control activity.”
Potential for future medical applications
Antimicrobial peptides are found in all kingdoms of life and thus are hypothesized to be commonly used as weapons in nature, occasionally effective in killing not only bacteria but also cancer cells. Moreover, the unique amyloid-like properties of the toadlet’s antibacterial peptide, discovered in this study, shed light on the potential physiological properties of amyloid fibrils associated with neurodegenerative and systemic disorders.
Dr. Nir Salinas
The researchers hope that their discovery will lead to medical and technological applications, e.g. development of synthetic antimicrobial peptides that would be activated only in the presence of bacteria. Synthetic peptides of this kind could also serve as a stable coating for medical devices or implants, or even in industrial equipment that requires sterile conditions.
The study is a result of a collaboration between scientists at EMBL Hamburg and Technion, and groups in Israel and Spain. It is an example of EMBL’s approach to life science research in its next scientific Programme Molecules to Ecosystems. EMBL will integrate interdisciplinary approaches to understand the molecular basis of life in the context of environmental changes, and to provide translational potential to support advances in human and planetary health.
