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May 20th, 2020

Weizmann Scientists Demonstrate Self-Synthesis & Self-Assembly of 30S Subunit of Ribosome

As the cell's protein factory, the ribosome is the only natural machine that manufactures its own parts. That is why understanding how the machine itself is made, could unlock the door to everything from understanding how life develops to designing new methods of drug production. An intensive, long research effort at the Weizmann Institute of Science in Israel has now demonstrated the self-synthesis and assembly of the small subunit of a ribosome-the 30S subunit--on a surface of a chip. Professor Roy Bar-Ziv, PhD, and Staff Scientist Dr. Shirley Shulman Daube, PhD, of the Institute's Chemical and Biological Physics Department have been working on this project for around seven years. One of the main challenges to such a project is the sheer number of different molecules the cell must produce to make the subunit: The core is a long strand of RNA, and 20 different proteins must be attached to the strand. These get organized by the weak chemical forces between the protein molecules and the RNA--repelling at some points and attracting at others--and the whole structure thus relies on the proper manufacture and organization of each component. Add to that another six proteins that are not part of the structure, but act as chaperones to assist in the assembly. That makes at total of a least 27 different genes--one to encode the RNA and each protein component or chaperone--that must work together to make the subunit. Together with postdoctoral fellow Michael Levy, PhD, who led the current study, and research student Reuven Falkovich, the team produced the subunits on tailored chips that Dr. Bar-Ziv has developed in his lab. Ultimately, they succeeded in mimicking the natural process of synthesizing the parts and assembling them into the ribosome subunits.

AstraZeneca Receives Over $1 Billion in US BARDA Investment to Support Development & Production of Oxford mRNA Vaccine (AZD1222); First Agreements to Supply 400 Million Doses, with Total Capacity of 1 Billion Doses Through 2020 and into 2021

OnMay 21, 2020, AstraZeneca announcedthat it is advancing its ongoing response to address the unprecedented challenges of COVID-19, collaborating with a number of countries and multilateral organizations to make the University of Oxford’s potential vaccine (an adenovirus vector carrying mRNA coding for the virus Spike protein; the vaccine was first called ChAdOx1 nCoV-19, and is now known as AZD1222) widely accessible around the world in an equitable manner. The Company has concluded the first agreements for at least 400 million doses and has secured total manufacturing capacity for one billion doses so far and will begin first deliveries in September 2020. AstraZeneca aims to conclude further agreements supported by several parallel supply chains, which will expand capacity further over the next months to ensure the delivery of a globally accessible vaccine. AstraZeneca today received support of more than $1 billion from the US Biomedical Advanced Research and Development Authority (BARDA) for the development, production, and delivery of the vaccine, starting in the fall. The development program includes a Phase III clinical trial with 30,000 participants and a pediatric trial. In addition, AstraZeneca is engaging with international organizations such as the Coalition for Epidemic Preparedness Innovations (CEPI), Gavi the Vaccine Alliance, and the World Health Organization (WHO), for the fair allocation and distribution of the potential vaccine around the world. AstraZeneca is also in discussions with governments around the world to increase access. Furthermore, AstraZeneca is in discussions with the Serum Institute of India and other potential partners to increase production and distribution.

Researchers May Have Uncovered Achilles Heel of Viruses; Many Inhibit Host STING Protein to Thwart Immune Response; Efforts to Block This Inhibition & Activate STING May Aid Efforts to Fight Variety of Viral Infections, Including Herpes & Coronaviruses

Viruses have an exceptional ability to circumvent the body's immune system and cause diseases. The majority of people recover from a viral infection such as influenza, although the current COVID-19 pandemic demonstrates how dangerous viruses can be when there is no effective vaccine or treatment. Professor and virologist Søren Riis Paludan, PhD, from the Department of Biomedicine at Aarhus University, Denmark, has been leading a research partnership amongst Aarhus University, the University of Oxford, and the University of Gothenburg, which has brought us one step closer to understanding the tactics used by viruses when they attack the immune system. Dr. Paludan heads a laboratory that carries out research into the immune system's ability to fight diseases caused by the herpes virus, influenza viruses, and, most recently, SARS-CoV-2, a coronavirus. In the new study, which has just been published online on May 8, 2020 in the scientific journal Journal of Experimental Medicine, the researchers have investigated how the herpes simplex virus circumvents the immune system in order to cause infections of the brain. This is a rare infection, but one which has a high mortality rate among those who are affected. The open-access JEM article is titled “HSV1 VP1-2 Deubiquitinates STING to Block Type I Interferon Expression and Promote Brain Infection.” "In the study, we found that the herpes simplex virus is capable of inhibiting a protein in the cells, known as STING (image)(stimulator of interfereon genes) (https://en.wikipedia.org/wiki/Stimulator_of_interferon_genes), which is activated when there is a threat.

New Device Quickly Detects Lithium Ions in Blood of Bipolar Disorder Patients; Advance Should be Boon for Bipolar Patients Taking Lithium

Lithium carbonate is used for treating bipolar disorder, a mental health condition that causes extreme mood swings. But using this drug requires caution because the therapeutic concentration range of lithium ions in blood is narrow and close to the toxic range. Japan’s Pharmaceuticals and Medical Devices Agency warns doctors to regularly examine lithium ion concentration levels in the blood of patients given the drug. However, existing examination methods require a large amount of blood, special operations, and large, expensive devices. These methods can be performed only by certain testing laboratories. The present study led by Takeshi Komatsu, a doctoral student at Hokkaido University’s Graduate School of Chemical Sciences and Engineering, and Professor Manabu Tokeshi, PhD, of the University’s Faculty of Engineering was conducted to address this problem by developing a user-friendly, low-cost method. The study was published online on April 14, 2020 in ACS Sensors. The open-access article is titled “Paper-Based Device for the Facile Colorimetric Determination of Lithium Ions in Human Whole Blood.”The researchers succeeded in making a colorimetric paper-based device that allows point-of-care testing in one step. The device consists of two paper-based elements linked to each other: a blood cell separation unit and a colorimetric detection unit. High-purity cotton blotting paper and a blood cell separation membrane, which are both available on the market, are used as a substrate for each unit, respectively. Hydrophobic ink was coated on the device to allow easy liquid handling.

May 20th

DNA Vaccines Protect Against SARS-CoV-2 in Rhesus Macaques, Science-Published Study Reports; Companion Study Suggests Initial Infection with SARS-Cov-2 Protects Against Re-Infection Following Repeat Exposure to the Virus

With nearly 5 million confirmed cases globally and more than 300,000 deaths from COVID-19, much remains unknown about SARS-CoV-2, the virus that causes the disease. Two critical questions are whether vaccines will prevent infection with COVID-19 and whether individuals who have recovered from COVID-19 are protected against re-exposure to the virus. Now, a pair of new studies, led by researchers at Beth Israel Deaconess Medical Center (BIDMC), suggests the answer to these questions is yes, at least in animal models. Results of these studies were published on May 20, 2020 in Science. The titles of the two open-access articles are “DNA Vaccine Protection Against SARS-CoV-2 in Rhesus Macaques,” and “SARS-CoV-2 Infection Protects Against Rechallenge in Rhesus Macaques.” “The global COVID-19 pandemic has made the development of a vaccine a top biomedical priority, but very little is currently known about protective immunity to the SARS-CoV-2 virus,” said senior author Dan H. Barouch (photo), MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC. “In these two studies, we demonstrate in rhesus macaques that prototype vaccines protected against SARS-CoV-2 infection and that SARS-CoV-2 infection protected against re-exposure.” In the first study, the team found that six candidate DNA vaccines--each formulation using a different variant of the key viral protein--induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques. Dr. Barouch and colleagues, who began working toward a COVID-19 vaccine in mid-January when Chinese scientists released the SARS-CoV-2 genome, developed a series of candidate DNA vaccines expressing variants of the spike protein, the part used by the virus to invade human cells and a key target for protective antibodies.

INOVIO's COVID-19 DNA Vaccine INO-4800 Demonstrates Robust Neutralizing Antibody and T Cell Immune Responses in Preclinical Models; Article Published in Nature Communications

On May 20, 2020, INOVIO (NASDAQ:INO) announced the publication of the preclinical study data for IN0-4800, its COVID-19 DNA vaccine, demonstrating robust neutralizing antibody and T cell immune responses against coronavirus SARS-CoV-2. The open-access study was published in the peer-reviewed journal Nature Communications and is titled, "Immunogenicity of a DNA Vaccine Candidate for COVID-19" and authored by INOVIO scientists and collaborators from The Wistar Institute, the University of Texas, Public Health England, Fudan University, and Advaccine. Kate Broderick (photo), PhD, INOVIO's Senior Vice President of R&D and the Team Lead for COVID-19 vaccine development, said, "These positive preclinical results from our COVID-19 DNA vaccine (INO-4800) not only highlight the potency of our DNA medicines platform, but also build on our previously reported positive Phase 1/2a data from our vaccine against the coronavirus that causes MERS, which demonstrated near-100% seroconversion and neutralization from a similarly designed vaccine INO-4700. The potent neutralizing antibody and T cell immune responses generated in multiple animal models are supportive of our currently on-going INO-4800 clinical trials." INO-4800 targets the major surface antigen Spike protein of SARS-CoV-2 virus, which causes COVID-19 disease. The studies demonstrated that vaccination with INO-4800 generated robust binding and neutralizing antibodies, as well as T cell responses in mice and guinea pigs.

Eavesdropping Crickets Drop from Sky to Evade Capture by Bats

Researchers have uncovered the highly efficient strategy used by a group of crickets to distinguish the calls of predatory bats from the incessant noises of the nocturnal jungle. The research, led by scientists at the University of Bristol (UK) and the University of Graz (Austria), and published online on May 18, 2020 in Philosophical Transactions of the Royal Society B, revealed that the crickets eavesdrop on the vocalizations of bats to help them escape their grasp when hunted. The open-access article is titled “Decision Making in the Face of a Deadly Predator: High-Amplitude Behavioural Thresholds Can Be Adaptive for Rainforest Crickets Under High Background Noise Levels.” Sword-tailed crickets (photo) of Barro Colorado Island, Panama, are quite unlike many of their nocturnal, flying-insect neighbors. Instead of employing a variety of responses to bat calls of varying amplitudes, these crickets simply stop in mid-air, effectively dive-bombing out of harm's way. The higher the bat call amplitude, the longer the crickets cease flight and farther they fall. Biologists from Bristol's School of Biological Sciences and Graz's Institute of Zoology discovered why these crickets evolved significantly higher response thresholds than other eared insects. Within the plethora of jungle sounds, it is important to distinguish possible threats. This is complicated by the cacophony of katydid (bush-cricket) calls, which are acoustically similar to bat calls and form 98 per cent of high-frequency background noise in a nocturnal rainforest. Consequently, sword-tailed crickets need to employ a reliable method to distinguish between calls of predatory bats and harmless katydids. Responding only to ultrasonic calls above a high-amplitude threshold is their solution to this evolutionary challenge.

Researchers Reveal Origins of Quarternary Hemoglobin Complex by Resurrecting Ancient Proteins; Surprisingly, Complexity Can Evolve Quickly on Evolutionary Scale

Most biological processes are carried out by complexes of multiple proteins that work together to carry out some function. How these complicated structures could have evolved is one of modern biology's great puzzles, because the proteins generally stick together using elaborate molecular interfaces, and the intermediate forms through which they came into being have been lost without a trace. Now, an international team of researchers led by University of Chicago Professor Joseph Thornton, PhD, and graduate student Arvind Pillai has revealed that complexity can evolve through surprisingly simple mechanisms. The group identified the evolutionary "missing link" through which hemoglobin--the essential four-part protein complex that transports oxygen in the blood of virtually all vertebrate animals--evolved from simple precursors. And they found that it took just two mutations more than 400 million years ago to trigger the emergence of modern hemoglobin's structure and function. The study, titled "Origin of Complexity in Haemoglobin Evolution," was published online in Nature on May 20, 2020. The research team also includes scientists at Texas A&M University, the University of Nebraska-Lincoln, and Oxford University (UK). Each hemoglobin molecule is a four-part protein complex made up of two copies each of two different proteins, but the proteins to which they are most closely related do not form complexes at all. The team's strategy, pioneered in Dr. Thornton's lab over the last two decades, was a kind of molecular time travel: use statistical and biochemical methods to reconstruct and experimentally characterize ancient proteins before, during, and after the evolution of the earliest forms of hemoglobin.

Antibody (S309) from 2003 SARS Survivor Neutralizes SARS-CoV-1 and SARS-CoV-2 by Blocking Attachment of Viral Spike Protein to Human Host Cell Receptor

An antibody first identified in a blood sample from a patient who recovered from Severe Acute Respiratory Syndrome (SARS) in 2003 inhibits related coronaviruses, including SARS-CoV-2, the cause of COVID-19, according to a new report in Nature. The antibody, called S309, is now on a fast-track development and testing path at Vir Biotechnology (https://www.vir.bio/) in the next step toward possible clinical trials. Laboratory research findings on the S309 antibody were reported online on May 18, 2020, in Nature. The article is titled: "Cross-Neutralization of SARS-CoV-2 by a Human Monoclonal SARS-CoV Antibody” (https://www.nature.com/articles/s41586-020-2349-y). The senior authors on the paper are David Veesler, PhD, Assistant Professor of Biochemistry at the University of Washington School of Medicine, and Davide Corti, PhD, Chief Scientific Officer, Humabs Biomed SA, a subsidiary of Vir Biotechnology. The lead authors are Dora Pinto and Martina Beltramello of Humabs, as well as Young-Jun Park and Lexi Walls, research scientists in the Veesler lab, which for several years has been studying the structure and function of the infection mechanisms of a variety of coronaviruses. "We still need to show that this antibody is protective in living systems, which has not yet been done," Dr. Veesler said. "Right now, there are no approved tools or licensed therapeutics proven to fight against the coronavirus that causes COVID-19," he added. If the S309 antibody is shown to work against the novel coronavirus in people, it could become part of the pandemic armamentarium. Dr. Veesler said that his lab is not the only one seeking neutralizing antibodies for COVID 19 treatment.

Using 3D-Printed Synthetic Human Lymph Nodes, Prellis Biologics Generates 300 Human Antibodies That Bind SARS-CoV-2 Virus; Company Pursuing Development of Treatment and Preventative Therapy for COVID-19 Infection

On May 19, 2020, Prellis Biologics, Inc., announced that it has generated 300 human IgG antibodies that bind to either the S1 or S2 spike protein of the SARS-CoV-2-Wuhan strain of the novel coronavirus. Using the Prellis Externalized Human Immune System™ technology, the team produced 960 synthetic human lymph nodes that were challenged with a SARS-CoV-2 vaccine-like cocktail, leading to virus-specific antibody generation. “Three hundred virus-specific IgG antibodies is a tremendous number to have at this stage. Our pipeline for class-switched antibodies has produced an order of magnitude larger pool than the typical antibody development program,” said Erin Stephens, PhD, Director of Tissue Engineering at Prellis. Prellis Biologics first built bioactive synthetic human lymph nodes in 2017, demonstrating their potential by producing human antibodies against the Zika virus. Notably, the process does not require an infected donor, extensive screening, or generation of antibodies in animals, dramatically reducing the time to produce a targeted library of candidate antibodies to less than one month. Prellis Bio recently closed a $4.3 million investment round led by Future Ventures, Khosla Ventures, and IndieBio to support the development of human anti-SARS-CoV-2 antibodies. “We funded the formation of an army of synthetic human lymph nodes to identify antibody therapies for SARS-CoV-2 and potentially all new pandemic diseases, both viral and bacterial,” said Steve Jurvetson, co-founder of Future Ventures. “It’s like having a surrogate human immune system from hundreds of people without needing to sample from infected patients, offering a rapid response procedure for any pathogen.”