Category Archives: Post Human

Last week, Gilead Sciences said it would test its COVID-19 drug remdesivir against a related compound in its library called GS-441524 in animal trials, after facing scrutiny over the latter drug, which has been used for years to treat feline infectious peritonitis (FIP) despite not being licensed for that use.

Now, another California biotech, Anivive Lifesciences, is working on a COVID-19 antiviral drug thats inspired by cats, and it has new preclinical research findings to back up the project.

Scientists led by the University of Alberta reported that a drug developed to treat a coronavirus that can cause FIP inhibited the main protease of both SARS-CoV and SARS-CoV-2. That prevented the human coronaviruses from replicating in cell cultures, they reported in the journal Nature Communications.

Overcoming Scalability Challenges with Autologous Therapies

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Anivive originally licensed the drug, called GC376, from Kansas State University in 2018 and has been working since then to develop it as an antiviral to treat FIP, a progressive disease in cats thats often caused by a coronavirus and is fatal if left untreated. Last month, Anivive said it had started two preclinical studies to determine whether GC376 could also treat COVID-19.

RELATED: COVID-19: New animal data back up Gilead's remdesivir as other treatment candidates emerge

GC376 was designed to inhibit a protease called 3C, which promotes the replication of several coronaviruses that infect animals and people. They include feline coronavirus (FCoV), which usually causes mild symptoms in cats but can lead to FIP.

Two pilot studies of GC376 in pet cats infected with FIP showed that the drug was effective against the disease within two weeks and was well tolerated. Anivive is currently scaling up production of the drug for larger studies in cats.

For the new study, the University of Alberta team tested both GC376 and its parent drug, GC373, for their ability to inhibit the 3C protease. Both drugs blocked viral replication, they reported.

The authors acknowledged that vaccines against COVID-19 are advancing rapidly, but they suggested antiviral drugs are still necessary in the short term. SARS-CoV-2 is a virus with a significant mutation rate. Also, in some patients the virus has persisted longer than 2 months with some possibility of re-infection, they wrote in the study.

M. Joanne Lemieux, Ph.D., professor of structural biology at the University of Alberta, pointed out in an interview with Genetic Engineering & Biotechnology News that GC376 could be advanced rapidly into human trials, given its track record in veterinary medicine.

Because this drug has already been used to treat cats with coronavirus, and its effective with little to no toxicity, its already passed [preclinical] stages, and this allows us to move forward, Lemieux said.

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Cats point the way to potential COVID-19 remedies - FierceBiotech

Celyad Oncology is at the forefront of cutting-edge immunotherapy and is hopeful of providing a new way forward for patients with relapsed/refractory multiple myeloma. After receiving FDA approval on July 14th to begin Phase I trials, they plan to be in the clinic with their first patient the end of 2020.

The Belgian clinical-stage biotechnology company is focused on the discovery and development of chimeric antigen receptor T cell (CAR-T) therapies for cancer. Celyad Oncology is also developing CYAD-101, an investigational non-gene edited, allogeneic NKG2D-based CAR-T therapy for metastatic colorectal cancer.

The two primary types of cell therapy are autologous and allogeneic. Autologous CAR-T therapy uses the transplantation and genetic editing of a patients own immune cells in a single batch, while an allogeneic transplant uses immune cells from a donor manufactured in large batches. Celyad Oncology is only the fourth company to proceed to Phase I with an allogeneic CAR-T working against a target known as B-cell maturationantigen (BCMA), which is highly expressed in multiple myeloma patients.

The Phase I objectives for CYAD-211 are to establish the viability, effectiveness and further possibilities opened up by the shRNA-based technology. Along with analyzing the merits of targeting BCMA with a CAR-T, Celyad Oncology Chief Executive Officer Filippo Petti shared that the companys first priority is to prove the premise that ShRNA bears out for allogeneic CAR-T.

The first level is to get into the clinic and evaluate the question, is shRNA a novel, non-gene edited allogeneic approach to CAR-T? Where the majority of our peers in the space work on genome using the gene editing technology, if we can show that another non-gene editing technology like ShRNA works, it would just open up the whole field in terms of allogeneic CAR-T. It would demonstrate that we have an unencumbered asset and technology platform for us to create next-generation CAR-T candidates with, Petti said. Well know very quickly, within the first few patients, if we are seeing an absence of graft-versus-host disease, and if ShRNA carries its weight in terms of being an allogeneic technology.

He expects to have a sense of how competitive the data is in terms of both safety and clinical efficacy by end of year 2021.

Dr. Laurence Cooper, Chief Executive Officer (CEO) of Ziopharm Oncology, who is also a veteran innovator in pairing genetic engineering with immunotherapies, explained that Graft-versus-Host Disease (GvHD) is one of biggest challenges facing companies who take the allogeneic approach.

When you put in third party cells, those cells get really confused right off the bat because now theyre somewhere new, and all of a sudden they perceive the patient as the threat. This can result in Graft-versus-Host Disease, an autoimmune disease triggered by the native biology in the T cell through its T cell receptor, Cooper said. The engineering that youre talking about is to eliminate that threat. Some cut out the genetic material coding for the endogenous T cell receptor so that now a T cell can go into another person, and it cant perceive the threat anymore because its lost its antennae. Another way is to prevent expression of the T cell receptor. Now the T cell can do something useful if you put in a CAR, it can go off and targetBCMA.

Frdric F. Lehmann, Head of the Oncology Franchise at Celyad Oncology, explained how the shRNA-based therapy is engineered to reign in the cells new rampant disregard for threat, and lessen the chances of an autoimmune response.

One of the innovations for CYAD-211 is incorporating in the vector a short hairpin RNA (shRNA) targeting the CD3 subunit of the T cell Receptor (TCR). This effectively downregulates the surface expression of the TCR thereby inhibiting the signaling that would lead to Graft-versus-Host Disease, Lehmann said.

A notable drawback with the autologous approach to CAR-T therapy is that it is costly and time-consuming. Petti explained how CYAD-211 not only has the potential to improve efficacy, but also make the treatment process more scalable and therefore economically expedient.

When it comes to commercialization, because we use an all-in-one-vector approach, we benefit from less manipulations during manufacturing, allowing us to enrich for the engineered cells we want, which eventually could help during potential commercialization of a product thats streamlined, Petti said.

He added that the all-in-one vector approach increases efficiency because, as opposed to the case with the gene editing process, they are able to accomplish everything in a single step.

Long term, Cooper is excited about the possibility that, whether autologous or allogeneic, immunotherapy may one day replace bone marrow transplants, or even chemotherapy, but emphasized that it must be made accessible.

If these immunotherapies can be advanced really to replace chemotherapy, not to replace transplantation for liquid tumors, but to replace chemotherapy, which is a huge goal if you can get it to do that, you have to bring the costs down to make it available for the masses, inside first world economies as well as less privileged societies, Cooper said.

In 2013, the overall five-year survival rate for multiple myeloma stood at 49.6%. Relapsed/refractory patients for whom currently available treatments have failed, are the intended beneficiaries of much of the biotechnology work being done in this area. And impressive steps have recently been made.

GlaxoSmithKlines BLENREP (BelantamabMafodotin) is the first in its class to work against BCMA, while Janssen Biotechs (Johnson & Johnson) DARZALEX (Daratumumab) is the first human Anti-CD38 monoclonal antibody in the space. After their 2019 acquisition of Celgene Corp., Bristol-Myers Squibb gained Revlimid (Lenalidomide), a hematology drug approved for multiple myeloma, and Amgen and Takeda have popular proteasome inhibitors on the market.

With Celyad Oncology moving the needle forward once again, the future looks a little brighter for multiple myeloma patients.

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Celyad's High Hopes for a Path Forward in Cancer Immunotherapy with CYAD-211 - BioSpace

Efforts to use regenerative medicinewhich seeks to address ailments as diverse as birth defects, traumatic injury, aging, degenerative disease, and the disorganized growth of cancerwould be greatly aided by solving one fundamental puzzle: How do cellular collectives orchestrate the building of complex, three-dimensional structures?

While genomes predictably encode the proteins present in cells, a simple molecular parts list does not tell us enough about the anatomical layout or regenerative potential of the body that the cells will work to construct. Genomes are not a blueprint for anatomy, and genome editing is fundamentally limited by the fact that its very hard to infer which genes to tweak, and how, to achieve desired complex anatomical outcomes. Similarly, stem cells generate the building blocks of organs, but the ability to organize specific cell types into a working human hand or eye has been and will be beyond the grasp of direct manipulation for a very long time.

But researchers working in the fields of synthetic morphology and regenerative biophysics are beginning to understand the rules governing the plasticity of organ growth and repair. Rather than micromanaging tasks that are too complex to implement directly at the cellular or molecular level, what if we solved the mystery of how groups of cells cooperate to construct specific multicellular bodies during embryogenesis and regeneration? Perhaps then we could figure out how to motivate cell collectives to build whatever anatomical features we want.

New approaches now allow us to target the processes that implement anatomical decision-making without genetic engineering. In January, using such tools, crafted in my lab at Tufts Universitys Allen Discovery Center and by computer scientists in Josh Bongards lab at the University of Vermont, we were able to create novel living machines, artificial bodies with morphologies and behaviors completely different from the default anatomy of the frog species (Xenopus laevis) whose cells we used. These cells rebooted their multicellularity into a new form, without genomic changes. This represents an extremely exciting sandbox in which bioengineers can play, with the aim of decoding the logic of anatomical and behavioral control, as well as understanding the plasticity of cells and the relationship of genomes to anatomies.

Deciphering how an organism puts itself together is truly an interdisciplinary undertaking.

Deciphering how an organism puts itself together is truly an interdisciplinary undertaking. Resolving the whole picture will involve understanding not only the mechanisms by which cells operate, but also elucidating the computations that cells and groups of cells carry out to orchestrate tissue and organ construction on a whole-body scale. The next generation of advances in this area of research will emerge from the flow of ideas between computer scientists and biologists. Unlocking the full potential of regenerative medicine will require biology to take the journey computer science has already taken, from focusing on the hardwarethe proteins and biochemical pathways that carry out cellular operationsto the physiological software that enables networks of cells to acquire, store, and act on information about organ and indeed whole-body geometry.

In the computer world, this transition from rewiring hardware to reprogramming the information flow by changing the inputs gave rise to the information technology revolution. This shift of perspective could transform biology, allowing scientists to achieve the still-futuristic visions of regenerative medicine. An understanding of how independent, competent agents such as cells cooperate and compete toward robust outcomes, despite noise and changing environmental conditions, would also inform engineering. Swarm robotics, Internet of Things, and even the development of general artificial intelligence will all be enriched by the ability to read out and set the anatomical states toward which cell collectives build, because they share a fundamental underlying problem: how to control the emergent outcomes of systems composed of many interacting units or individuals.

Many types of embryos can regenerate entirely if cut in half, and some species are proficient regenerators as adults. Axolotls (Ambystoma mexicanum) regenerate their limbs, eyes, spinal cords, jaws, and portions of the brain throughout life. Planarian flatworms (class Turbellaria), meanwhile, can regrow absolutely any part of their body; when the animal is cut into pieces, each piece knows exactly whats missing and regenerates to be a perfect, tiny worm.

The remarkable thing is not simply that growth begins after wounding and that various cell types are generated, but that these bodies will grow and remodel until a correct anatomy is complete, and then they stop. How does the system identify the correct target morphology, orchestrate individual cell behaviors to get there, and determine when the job is done? How does it communicate this information to control underlying cell activities?

Several years ago, my lab found that Xenopus tadpoles with their facial organs experimentally mixed up into incorrect positions still have largely normal faces once theyve matured, as the organs move and remodel through unnatural paths. Last year, a colleague at Tufts came to a similar conclusion: the Xenopus genome does not encode a hardwired set of instructions for the movements of different organs during metamorphosis from tadpole to frog, but rather encodes molecular hardware that executes a kind of error minimization loop, comparing the current anatomy to the target frog morphology and working to progressively reduce the difference between them. Once a rough spatial specification of the layout is achieved, that triggers the cessation of further remodeling.

The deep puzzle of how competent agents such as cells work together to pursue goals such as building, remodeling, or repairing a complex organ to a predetermined spec is well illustrated by planaria. Despite having a mechanistic understanding of stem cell specification pathways and axial chemical gradients, scientists really dont know what determines the intricate shape and structure of the flatworms head. It is also unknown how planaria perfectly regenerate the same anatomy, even as their genomes have accrued mutations over eons of somatic inheritance. Because some species of planaria reproduce by fission and regeneration, any mutation that doesnt kill the neoblastthe adult stem cell that gives rise to cells that regenerate new tissueis propagated to the next generation. The worms incredibly messy genome shows evidence of this process, and cells in an individual planarian can have different numbers of chromosomes. Still, fragmented planaria regenerate their body shape with nearly 100 percent anatomical fidelity.

Permanent editingof the encoded target morphology without genomic editing reveals a new kind of epigenetics.

So how do cell groups encode the patterns they build, and how do they know to stop once a target anatomy is achieved? What would happen, for example, if neoblasts from a planarian species with a flat head were transplanted into a worm of a species with a round or triangular head that had the head amputated? Which shape would result from this heterogeneous mixture? To date, none of the high-resolution molecular genetic studies of planaria give any prediction for the results of this experiment, because so far they have all focused on the cellular hardware, not on the logic of the softwareimplemented by chemical, mechanical, and electrical signaling among cellsthat controls large-scale outcomes and enables remodeling to stop when a specific morphology has been achieved.

Understanding how cells and tissues make real-time anatomical decisions is central not only to achieving regenerative outcomes too complex for us to manage directly, but also to solving problems such as cancer. While the view of cancer as a genetic disorder still largely drives clinical approaches, recent literature supports a view of cancer as cells simply not being able to receive the physiological signals that maintain the normally tight controls of anatomical homeostasis. Cut off from these patterning cues, individual cells revert to their ancient unicellular lifestyle and treat the rest of the body as external environment, often to ruinous effect. If we understand the mechanisms that scale single-cell homeostatic setpoints into tissue- and organ-level anatomical goal states and the conditions under which the anatomical error reduction control loop breaks down, we may be able to provide stimuli to gain control of rogue cancer cells without either gene therapy or chemotherapy.

During morphogenesis, cells cooperate to reliably build anatomical structures. Many living systems remodel and regenerate tissues or organs despite considerable damagethat is, they progressively reduce deviations from specific target morphologies, and halt growth and remodeling when those morphologies are achieved. Evolution exploits three modalities to achieve such anatomical homeostasis: biochemical gradients, bioelectric circuits, and biophysical forces. These interact to enable the same large-scale form to arise despite significant perturbations.

N.R. FULLER, SAYO-ART, LLC

BIOCHEMICAL GRADIENTS

The best-known modality concerns diffusible intracellular and extracellular signaling molecules. Gene-regulatory circuits and gradients of biochemicals control cell proliferation, differentiation, and migration.

BIOELECTRIC CIRCUITS

The movement of ions across cell membranes, especially via voltage-gated ion channels and gap junctions, can establish bioelectric circuits that control large-scale resting potential patterns within and among groups of cells. These bioelectric patterns implement long-range coordination, feedback, and memory dynamics across cell fields. They underlie modular morphogenetic decision-making about organ shape and spatial layout by regulating the dynamic redistribution of morphogens and the expression of genes.

BIOMECHANICAL FORCES

Cytoskeletal, adhesion, and motor proteins inside and between cells generate physical forces that in turn control cell behavior. These forces result in large-scale strain fields, which enable cell sheets to move and deform as a coherent unit, and thus execute the folds and bends that shape complex organs.

The software of life, which exploits the laws of physics and computation, is enabled by chemical, mechanical, and electrical signaling across cellular networks. While the chemical and mechanical mechanisms of morphogenesis have long been appreciated by molecular and cell biologists, the role of electrical signaling has largely been overlooked. But the same reprogrammability of neural circuits in the brain that supports learning, memory, and behavioral plasticity applies to all cells, not just neurons. Indeed, bacterial colonies can communicate via ionic currents, with recent research revealing brain-like dynamics in which information is propagated across and stored in a kind of proto-body formed by bacterial biofilms. So it should really come as no surprise that bioelectric signaling is a highly tractable component of morphological outcomes in multicellular organisms.

A few years ago, we studied the electrical dynamics that normally set the size and borders of the nascent Xenopus brain, and built a computer model of this process to shed light on how a range of various brain defects arise from disruptions to this bioelectric signaling. Our model suggested that specific modifications with mRNA or small molecules could restore the endogenous bioelectric patterns back to their correct layout. By using our computational platform to select drugs to open existing ion channels in nascent neural tissue or even a remote body tissue, we were able to prevent and even reverse brain defects caused not only by chemical teratogenscompounds that disrupt embryonic developmentbut by mutations in key neurogenesis genes.

Similarly, we used optogenetics to stimulate electrical activity in various somatic cell types totrigger regeneration of an entire tadpole tailan appendage with spinal cord, muscle, and peripheral innervationand to normalize the behavior of cancer cells in tadpoles strongly expressing human oncogenes such as KRAS mutations. We used a similar approach to trigger posterior regions, such as the gut, to build an entire frog eye. In both the eye and tail cases, the information on how exactly to build these complex structures, and where all the cells should go, did not have to be specified by the experimenter; rather, they arose from the cells themselves. Such findings reveal how ion channel mutations result in numerous human developmental channelopathies, and provide a roadmap for how they may be treated by altering the bioelectric map that tells cells what to build.

We also recently found a striking example of such reprogrammable bioelectrical software in control of regeneration in planaria. In 2011, we discovered that an endogenous electric circuit establishes a pattern of depolarization and hyperpolarization in planarian fragments that regulate the orientation of the anterior-posterior axis to be rebuilt. Last year, we discovered that this circuit controls the gene expressionneeded to build a head or tail within six hours of amputation, and by using molecules that make cell membranes permeable to certain ions to depolarize or hyperpolarize cells, we induced fragments of such worms to give rise to a symmetrical two-headed form, despite their wildtype genomes. Even more shockingly, the worms continued to generate two-headed progeny in additional rounds of cutting with no further manipulation. In further experiments, we demonstrated that briefly reducing gap junction-mediated connectivity between adjacent cells in the bioelectric network that guides regeneration led worms to regenerate head and brain shapes appropriate to other worm species whose lineages split more than 100 million years ago.

My group has developed the use of voltage-sensitive dyes to visualize the bioelectric pattern memory that guides gene expression and cell behavior toward morphogenetic outcomes. Meanwhile, my Allen Center colleagues are using synthetic artificial electric tissues made of human cells and computer models of ion channel activity to understand how electrical dynamics across groups of non-neural cells can set up the voltage patterns that control downstream gene expression, distribution of morphogen molecules, and cell behaviors to orchestrate morphogenesis.

The emerging picture in this field is that anatomical software is highly modulara key property that computer scientists exploit as subroutines and that most likely contributes in large part to biological evolvability and evolutionary plasticity. A simple bioelectric state, whether produced endogenously during development or induced by an experimenter, triggers very complex redistributions of morphogens and gene expression cascades that are needed to build various anatomies. The information stored in the bodys bioelectric circuitscan be permanently rewritten once we understand the dynamics of the biophysical circuits that make the critical morphological decisions. This permanent editing of the encoded target morphology without genomic editing reveals a new kind of epigenetics, information that is stored in a medium other than DNA sequences and chromatin.

Recent work from our group and others has demonstrated that anatomical pattern memories can be rewritten by physiological stimuli and maintained indefinitely without genomic editing. For example, the bioelectric circuit that normally determines head number and location in regenerating planaria can be triggered by brief alterations of ion channel or gap junction activity to alter the animals body plan. Due to the circuits pattern memory, the animals remain in this altered state indefinitely without further stimulation, despite their wildtype genomes. In other words, the pattern to which the cells build after damage can be changed, leading to a target morphology distinct from the genetic default.

N.R. FULLER, SAYO-ART, LLC

First, we soaked a planarian in voltage-sensitive fluorescent dye to observe the bioelectrical pattern across the entire tissue. We then cut the animal to see how this pattern changes in each fragment as it begins to regenerate.

We then applied drugs or used RNA interference to target ion channels or gap junctions in individual cells and thus change the pattern of depolarization/hyperpolarization and cellular connectivity across the whole fragment.

As a result of the disruption of the bodys bioelectric circuits, the planarian regrows with two heads instead of one, or none at all.

When we re-cut the two-headed planarian in plain water, long after the initial drug has left the tissue, the new anatomy persists in subsequent rounds of regeneration.

Cells can clearly build structures that are different from their genomic-default anatomical outcomes. But are cells universal constructors? Could they make anything if only we knew how to motivate them to do it?

The most recent advances in the new field at the intersection of developmental biology and computer science are driven by synthetic living machines known as biobots. Built from multiple interacting cell populations, these engineered machines have applications in disease modeling and drug development, and as sensors that detect and respond to biological signals. We recently tested the plasticity of cells by evolving in silico designs with specific movement and behavior capabilities and used this information to sculpt self-organized growth of aggregated Xenopus skin and muscle cells. In a novel environmentin vitro, as opposed to inside a frog embryoswarms of genetically normal cells were able to reimagine their multicellular form. With minimal sculpting post self-assembly, these cells form Xenobots with structures, movements, and other behaviors quite different from what might be expected if one simply sequenced their genome and identified them as wildtype X. laevis.

These living creations are a powerful platform to assess and model the computations that these cell swarms use to determine what to build. Such insights will help us to understand evolvability of body forms, robustness, and the true relationship between genomes and anatomy, greatly potentiating the impact of genome editing tools and making genomics more predictive for large-scale phenotypes. Moreover, testing regimes of biochemical, biomechanical, and bioelectrical stimuli in these biobots will enable the discovery of optimal stimuli for use in regenerative therapies and bioengineered organ construction. Finally, learning to program highly competent individual builders (cells) toward group-level, goal-driven behaviors (complex anatomies) will significantly advance swarm robotics and help avoid catastrophes of unintended consequences during the inevitable deployment of large numbers of artificial agents with complex behaviors.

Understanding how cells and tissues make real-time anatomical decisions is central to achieving regenerative outcomes too complex for us to manage directly.

The emerging field ofsynthetic morphology emphasizes a conceptual point that has been embraced by computer scientists but thus far resisted by biologists: the hardware-software distinction. In the 1940s, to change a computers behavior, the operator had to literally move wires aroundin other words, she had to directly alter the hardware. The information technology revolution resulted from the realization that certain kinds of hardware are reprogrammable: drastic changes in function could be made at the software level, by changing inputs, not the hardware itself.

In molecular biomedicine, we are still focused largely on manipulating the cellular hardwarethe proteins that each cell can exploit. But evolution has ensured that cellular collectives use this versatile machinery to process information flexibly and implement a wide range of large-scale body shape outcomes. This is biologys software: the memory, plasticity, and reprogrammability of morphogenetic control networks.

The coming decades will be an extremely exciting time for multidisciplinary efforts in developmental physiology, robotics, and basal cognition to understand how individual cells merge together into a collective with global goals not belonging to any individual cell. This will drive the creation of new artificial intelligence platforms based not on copying brain architectures, but on the multiscale problem-solving capacities of cells and tissues. Conversely, the insights of cognitive neurobiology and computer science will give us a completely new window on the information processing and decision-making dynamics in cellular collectives that can very effectively be targeted for transformative regenerative therapies of complex organs.

Michael Levinis the director of the Allen Discovery Center at Tufts University and Associate Faculty at Harvard Universitys Wyss Institute. Email him atmichael.levin@tufts.edu. M.L. thanks Allen Center Deputy DirectorJoshua Finkelsteinfor suggestions on the drafts of this story.

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How Groups of Cells Cooperate to Build Organs and Organisms - The Scientist

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes

Tom Hanks and his wife, Rita Wilson, were among the earliest celebrities to catch the novel coronavirus. In an interview at the beginning of July, Hanks described how differently COVID-19 had affected each of them in March.

My wife lost her sense of taste and smell, she had severe nausea, she had a much higher fever than I did. I just had crippling body aches, he said. I was very fatigued all the time and I couldnt concentrate on anything for more than about 12 minutes.

Why does COVID-19 present such different symptoms or none at all in different people?

Preexisting conditions can only be part of the story. Hanks is over 60 and is a Type 2 diabetic, putting him in a high-risk group. Nevertheless, he survived his brush with the virus with no pneumonia and apparently without any long-lasting effects. Knowing what causes variation in different patients could help physicians tailor their treatments to individual patients an approach known as precision medicine.

In recent years, a gene-centric approach to precision medicine has been promoted as the future of medicine. It underlies the massive effort funded by the US National Institutes of Health to collect over a million DNA samples under the All of Us initiative that began in 2015.

But the imagined future did not include COVID-19. In the rush to find a COVID-19 vaccine and effective therapies, precision medicine has been insignificant. Why is this? And what are its potential contributions?

We are a physician geneticist and a philosopher of science who began a discussion about the promise and potential pitfalls of precision medicine before the arrival of COVID-19. If precision medicine is the future of medicine, then its application to pandemics generally, and COVID-19 in particular, may yet prove to be highly significant. But its role so far has been limited. Precision medicine must consider more than just genetics. It requires an integrative omic approach that must collect information from multiple sources beyond just genes and at scales ranging from molecules to society.

From genetics to microbes

Inherited diseases such as sickle cell anemia and Tay-Sachs disease follow a predictable pattern. But such direct genetic causes are perhaps the exception rather than the rule when it comes to health outcomes. Some heritable conditions for instance, psoriasis or the many forms of cancer depend on complex combinations of genes, environmental and social factors whose individual contributions to the disease are difficult to isolate. At best, the presence of certain genes constitutes a risk factor in a population but does not fully determine the outcome for an individual person carrying those genes.

The situation becomes yet more complicated for infectious diseases.

Viruses and bacteria have their own genomes that interact in complex ways with the cells in the people they infect. The genome of SARS-CoV-2 underlying COVID-19 has been extensively sequenced. Its mutations are identified and traced worldwide, helping epidemiologists understand the spread of the virus. However, the interactions between SARS-CoV-2 RNA and human DNA, and the effect on people of the viruss mutations, remain unknown.

The importance of multi-scale data

Tom Hanks and his wife caught the virus and recovered in a matter of weeks. Presumably each was infected over the course of a few minutes of exposure to another infected person, involving cellular mechanisms that operate on a timescale of milliseconds.

But the drama of their illness, and that of the many victims with far worse outcomes, is taking place in the context of a global pandemic that has already lasted months and may continue for years. People will need to adopt changes in their behavior for weeks or months at a time.

What should a precision medicine approach be in a pandemic? The gene-centric vision of precision medicine encourages people to expect individualised gene-targeted fixes. But, genes, behavior and social groups interact over multiple timescales.

To capture all the data needed for such an approach is beyond possibility in the current crisis. A nuanced approach to the COVID-19 pandemic will depend heavily on imprecise population level public health interventions: mask-wearing, social distancing and working from home. Nevertheless, there is an opportunity to begin gathering the kinds of data that would allow for a more comprehensive precision medicine approach one that is fully aware of the complex interactions between genomes and social behavior.

How to use precision medicine to understand COVID-19

With unlimited resources, a precision medicine approach would begin by analyzing the genomes of a large group of people already known to be exposed to SARS-CoV-2 yet asymptomatic, along with a similar-sized group with identified risk factors who are dying from the disease or are severely ill.

An early study of this kind by Precisionlife Ltd data mined genetic samples of 976 known COVID-19 cases. Of these, 68 high-risk genes were identified as risk factors for poor COVID-19 outcomes, with 17 of them deemed likely to be good targets for drug developments. But, as with all such statistical approaches, the full spectrum of causes underlying their association with the disease is not something the analysis provides. Other studies of this kind are appearing with increasing frequency, but there is no certainty in such fast-moving areas of science. Disentangling all the relevant factors is a process that will take months to years.

To date, precision medicine has proven better suited to inherited diseases and to diseases such as cancer, involving mutations acquired during a persons lifetime, than to infectious diseases. There are examples where susceptibility to infection can be caused by malfunction of unique genes such as the family of inherited immune disorders known as agammaglobulinemia, but these are few and far between.

Many physicians assume that most diseases involve multiple genes and are thus not amenable to a precision approach. In the absence of the kind of information needed for a multi-omic approach, there is a clear challenge and opportunity for precision medicine here: If it is to be the future of medicine, in order to complement and expand our existing knowledge and approaches, it needs to shift from its gene-centric origins toward a broader view that includes variables like proteins and metabolites. It must consider the relationships between genes and their physical manifestations on scales that range from days to decades, and from molecules to the global society.

Colin Allen, Distinguished Professor of History & Philosophy of Science, University of Pittsburgh and David Finegold, Professor, Department of Human Genetics, Pitt Public Health, University of Pittsburgh

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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How to use precision medicine to personalise COVID-19 treatment according to the patient's genes - Down To Earth Magazine

Before bacteria colonize a tissue in the human body, such as the intestine, they have to attach. Not only that, they have to achieve firm adhesion under hydrodynamic flow. New research reports a molecular mechanism behind an ultrastable protein complex responsible for resisting shear forces and adhering bacteria to cellulose fibers in the human gut. The results explain how gut microbes regulate cell adhesion strength at high shear stress through intricate molecular mechanisms including dual-binding modes, mechanical allostery, and catch bonds.

The researchers used single-molecule force spectroscopy (SMFS), single-molecule FRET (smFRET), and molecular dynamics (MD) simulations to uncover that two different binding modes allow bacteria to withstand the shear forces in the body. The findings are published in Nature Communications in the paper titled, High force catch bond mechanism of bacterial adhesion in the human gut.

Cellulose is a major building block of plant cell walls, consisting of molecules linked together into solid fibers. For humans, cellulose is indigestible, and the majority of gut bacteria lack the enzymes required to break down cellulose.

However, recently genetic material from the cellulose-degrading bacterium R. champanellensis was detected in human gut samples. Bacterial colonization of the intestine is essential for human physiology, and understanding how gut bacteria adhere to cellulose broadens our knowledge of the microbiome and its relationship to human health.

The bacterium under investigation uses an intricate network of scaffold proteins and enzymes on the outer cell wall, referred to as a cellulosome network, to attach to and degrade cellulose fibers. These cellulosome networks are held together by families of interacting proteins.

Of particular interest is the cohesin-dockerin interaction responsible for anchoring the cellulosome network to the cell wall. This interaction needs to withstand shear forces in the body to adhere to fiber. This vital feature motivated the researchers to investigate in more detail how the anchoring complex responds to mechanical forces.

By using a combination of single-molecule atomic force microscopy, single-molecule fluorescence, and molecular dynamics simulations, Michael Nash, PhD, assistant professor with joint appointments at the University of Basel, department of chemistry, and at ETH Zurich, department of biosystems science & engineering, along with collaborators from LMU Munich and Auburn University, studied how the complex resists external force.

Two binding modes allow bacteria to stick to surfaces under shear flow

They were able to show that the complex exhibits a rare behavior called dual binding mode, where the proteins form a complex in two distinct ways. The researchers found that the two binding modes have very different mechanical properties, with one breaking at low forces of around 200 piconewtons and the other exhibiting a much higher stability breaking only at 600 piconewtons of force.

Further analysis showed that the protein complex displays a behavior called a catch bond, meaning that the protein interaction becomes stronger as force is ramped up. The dynamics of this interaction are believed to allow the bacteria to adhere to cellulose under shear stress and release the complex in response to new substrates or to explore new environments.

We clearly observe the dual binding modes, but can only speculate on their biological significance. We think the bacteria might control the binding mode preference by modifying the proteins. This would allow switching from a low to high adhesion state depending on the environment, Nash explained.

By shedding light on this natural adhesion mechanism, these findings set the stage for the development of artificial molecular mechanisms that exhibit similar behavior but bind to disease targets. Such materials could have applications in bio-based medical superglues or shear-enhanced binding of therapeutic nanoparticles inside the body. For now, we are excited to return to the laboratory and see what sticks, said Nash.

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Bacterial Superglue Allows Adhesion to the Gut - Genetic Engineering & Biotechnology News

Jonathan Latham, Ph.D., and Allison Wilson, Ph.D., a virologist and a geneticist, respectively, have a plausible story to tell about the origin of SARS-CoV-2 the cause of COVID-19. It begins with a mystery disease that struck six Chinese miners in Yunnan province in 2012. These miners became ill while shoveling bat feces (guano) produced by Rhinolophus sinicus, a species of horseshoe bat, which was abundant in the mine.

The illness of the miners was later described in detail throughout a masters thesis entitled An Analysis of Six Severe Pneumonia Cases Related to Unknown Viruses, written in 2013 by Li Xu. The patients were remotely observed by Zhong Nan Shan, noting the following symptoms: dry cough, shortness of breath, fever, limb soreness (myalgia), headaches, and low blood oxygen.

Latham and Wilson arranged the translation of the neglected Chinese masters thesis that documented the symptoms and hospital treatment of these miners. Most importantly, the miners were diagnosed as having coronavirus infections, and second, their symptoms are now recognizable as those of classic COVID-19. This and other information in the thesis caused Wilson and Latham to rethink everything they thought they knew about the origins of the pandemic.

Latham and Wilson eventually published their theory on Independent Science News, a publication edited by Latham. This report details Latham and Wilsons search for the origins of the pandemic causing virus, focusing on the nearest genetic relative of SARS-CoV-2, a bat coronavirus called RaTG13. This virus was obtained during virus collecting trips during 2012 and 2013 to the same mine where, shortly before, six miners had developed an unknown illness.

In A Proposed Origin for SARS-CoV-2 and the COVID-19 Pandemic, the authors set out what they call the Mojiang Miners Passaging hypothesis. The theory proposes (1) that the miners acquired a coronavirus from the bats in the mine and (2) that this bat virus evolved extensively inside their bodies to become a highly human-adapted virus. This evolution occurred during a hospitalization period that, for some, lasted many months.

The translated thesis says blood and other samples were extracted from the miners and some of these were sent to the Wuhan Institute of Virology (WIV). Latham and Wilson suggest these samples contained highly human-adapted viruses and were used at the WIV for research. During this research, it is believed that the virus escaped, initiating the 2019 COVID-19 pandemic.

Latham holds a masters degree in crop genetics and a Ph.D. in virology. He was subsequently a postdoctoral research associate in the Department of Genetics at the University of Wisconsin, Madison. In addition to having published scientific papers in disciplines as diverse as plant ecology, plant virology, toxicology, genetics, and genetic engineering, Latham is the director of the Poison Papers project, which publicizes documents of the chemical industry and its regulators. Recently, I interviewed Latham to discuss his work on COVID-19.

***

Vigo: What makes this virus so hard to track down in origin?

Latham: There are a lot of complicated parts to this virus different from all its potential ancestors. For instance, it has various features that are very well adapted to people the spike protein bonds very well with the human receptor of the cell for instance. The virus as a whole is also well adapted to humans.

This is unlike the case with MERS and SARS, the previous pandemic coronaviruses. The early generation of people who were infected, the versions of the infections they got changed very quickly. Imagine if a virus comes from a bat or a pangolin, it has to come to adapt to people. The mutations outcompete older versions of the virus. This hasnt happened here, which implies that this has been in humans for a long time.

V: What would it take to prove your theory?

L: What we really want to see is for the World Health Organization (WHO) to go to the Wuhan Institute of Virology (WIV) to see what they were working on when they studied bat coronaviruses. This is the number one lab in the world for studying bat coronaviruses. A bat coronavirus that infects people could happen anywhere it could happen in America, in Italy, in Africa, and it just so happens that this laboratory where they store thousands of samples of coronavirus is also the precise geographic location of the outbreak of the pandemic.

V: Given that there are myriad theories floating about related to COVID-19s origin that are being dismissed by many as conspiracy theory, what makes your theory plausible?

L: Scientists are supposed to proceed based on evidence. The problem with the theories that claim that this virus was built from other viruses is that you have to have available all the different parts, and they arent really available. You have the spike protein, which this virus has, which is quite unique (many amino acids different from any relative).

The same applies to the other parts of this virus. The nearest relative to the SARS-CoV-2 is 4 percent different. So you dont have a basis for this argument the pieces dont even exist. So those people proposing an engineering theory cant identify the specific pieces from which SARS-CoV-2 is supposedly built.

Now for certain, the people from WIV have thousands of samples of bat viruses, but you have no evidence for those pieces existing. It is therefore quite difficult to propose a genetically engineered version of this virus.

V: So your theory doesnt follow this claim then?

L: Our theory is different. We organized the translation of a masters thesis which documents that in 2012 six miners got ill after shoveling bat feces. They were treated by the doctor who wrote the thesis and it states that they caught a novel coronavirus that gave them the same symptoms as COVID-19. Basically, those miners dont exist lost in China or deceased but the conclusion of the thesis is that the miners had coronavirus. The next important thing to understand is that the nearest known relative of SARS-CoV-2 was found in the same mine where the miners got sick.

What we do know is that they took samples from these miners and some of those samples were sent to the WIV in Wuhan and this is documented in the thesis. Our proposition is quite simple that the hospital sent samples to Wuhan from the miners and what evolved inside the miners was SARS-CoV-2.

What was really interesting to the researchers at the WIV in Wuhan were the samples from the miners. Our theory suggests that they didnt realize how infectious those samples would be because a radical evolution of the virus took place inside the miners. Normally, it is argued that to get TaTG13 to infect a human and become SARS-CoV-2 would take 20-50 years of evolution. But the miners were sick for many months inside the hospital and the virus was permanently incubating and evolving inside them.

If you get a normal coronavirus infection, you become sick for two weeks and the portion of time that you have high viral loads would be approximately one week. The miners had enough virus in them to kill them and it was adapting quickly because it was infecting a new species. Most coronaviruses dont infect the lungs they usually just infect the throat and never spread to the lungs. Unique to these miners, their lung infections offered a much larger space for evolution inside the miners bodies than would any normal coronavirus infection.

One of the puzzles of its origin is that the virus has a special mutation called a furin site (furins are protease enzymes). The furin site (a few amino acids in length) allows the proteins to be cut in half by the protease, which is made by the lung cells. Its evolution inside the lungs of the miners accounts for the origin of this furin site because this furin site greatly enhancing viral spread in the lungs and the body. If you dont have the furin site, then the disease is effectively limited to the throat only. With the furin site, however, you can have a viral infection move into the lungs and heart, as well as other organs.

V: So, what does this mean practically speaking, for the average reader who might not understand the implications of what you have just described?

L: Our theory is solid enough that we are going to put it up and see what people make of it. The WIV researchers say they have their high-security laboratory to prevent a virus leak, but we are saying that they created one. If you read their papers, you will see they have been collecting virus samples to make vaccines and diagnostic tools and treatments against viruses. They are claiming to be doing all this useful stuff to prevent pandemics and they managed to do the opposite.

V: Why is the scientific community not calling out this glaring oversight, then? Are they concerned about this getting the same reception as the theories that maintained that SARS-CoV-2 was engineered in a Chinese laboratory?

L: The people who are funding this research are claiming that contact with bats is potentially enough to set off a pandemic. I believe that is true, but they are actively putting themselves in harms way such that they went to the mine even after the miners died. You know, Richard Ebright tweeted recently that this method for preventing pandemics is like looking for a gas leak with a lighted match.

Their sampling methods of bats are one thing, but one step worse was the sampling of the miners and bringing the virus back to the WIV. It is standard practice when medical practitioners come into contact with potentially infected patients their doctors use PPE (personal protective equipment) and the virus dies out.

Thus, when a person falls ill you treat them, and either they die or the body gets rid of the infection. This process doesnt normally result in a pandemic. But they went around normal procedures to collect samples and brought the virus back into spaces of frequent human contact.

V: So, your theory is that this was an entirely human-created pandemic resulting from the mishandling of samples, down to incursion into places that scientists should have left alone knowing the high risks of transmission to humans. Are there other scientists who have expressed similar concerns for these methods, or is there an international oversight agency that might be able to take action to avoid any such instances of future pandemics created by human error?

L: Some people have expressed concern about these methods. Cambridge Working Group has complained about some of these methods, as has the Council for Responsible Genetics and the Sunshine Project that complained about these methods of collecting dangerous pathogens. Unfortunately, these groups are now defunct.

V: Are there no independent blocs of scientists or research alliances that have pushed back or which have demanded a more open debate about the origins of this virus, despite the Gates Foundation?

L: We want to point out that there is no scientific publication that claims there is a lab origin worth looking into. There are thousands of publications saying the virus has a zoonotic origin even though there is hardly any evidence for this. You can say that and it can be completely wrong, but nobody will call you out. Nobody has dared to write that it might just as well have come from a lab. No virologist has said this in a peer-reviewed paper.

The scientific community has made it very clear that they dont want to hear about a lab origin. You can see that in the coverage of the pandemic. There was a letter in Lancet calling the lab origin a conspiracy, and what you gather from that is that the bigwigs of virology who signed the letter have set up the dynamic that anyone who comes up with reasonable theories is necessarily a conspiracist.

Every scientist in the world knows what way the wind is blowing. We want to say that this is outrageous.

Julian Vigo is a freelance writer and journalist and the editor of Savage Minds. Her latest book is "Earthquake in Haiti: The Pornography of Poverty and the Politics of Development." You can follow her on Twitter @lubelluledotcom.

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Virologist Explains His Quest To Track Down The Origin Of COVID-19 - The Federalist

Dublin, Sept. 02, 2020 (GLOBE NEWSWIRE) -- The "Global Human Microbiome Immunology Therapeutics Market & Clinical Trial Insight 2025" clinical trials has been added to ResearchAndMarkets.com's offering.

The scale and scope of microbiome research activity has now become one of the fastest growing areas in biology. The relevance that it has shown for the welfare of the society and pharmaceutical industry has led to the development of a transdisciplinary environment that is however conducive to innovation with a mission to abolish the limitations in the pharmaceutical industry through excellence in microbiome research, awareness and outreach. Over the years now, gut microbiome is estimated to implicate success for the various immunotherapies.

Microbiome's role in immunology practices is to transform world-class treatment into the medicine of today and tomorrow. It is highly recognizable that the healthcare issues that mankind is facing today is now bigger than any one solution. The treatment of certain diseases requires multiple options for the treatment and ultimately prevention. Therefore, the amalgamation of two different treatment paradigms i.e. microbiome and immunology are apparently delivering some medical benefits that millions of patients were in need for long period of time. The ways in which microbiome is understood and manipulated to serve the immunological aspects has given great interest to all the researchers.

The essential and usual concept of immunology depicts targeting the immune system of the body to provoke an immune response with huge impact but then the unsuccessful implication of immunology therapies driven treatments led to an exploration of several other basic concepts that could play an important role in boosting the immune system when combined. Looking forward, the microbiome community in the gut represented beneficial patterns with respect to further research. The area of microbiome research and its combination with immunological aspect for the disease treatment has produced a real excitement in the area of medical research and specifically microbiome research.

All over the world, the amalgamation of the two has been well accepted and appreciated by the patients, physicians and the clinicians. Investigation of all the working sides of microbiome and how it plays an important role in boosting the manipulated immune cells have recently started in large numbers as the technology available in the medical field allows to capture it accurately. To facilitate the microbiome and immunology community in order to extract the best and trending opportunities that are stemmed into the microbiome research, the experts from both the relevant disciplines are analyzing it through clinical researches and surveys. Further, the area is getting supported by 86 different clinical trials getting conducted in different countries.

The Global Human Microbiome Immunology Therapeutics Market & Clinical Trial Insight 2025 report summarizes the view of the wider opportunities that are associated microbiome community for the advancement of the scientific information regarding immunology. The science that is related to microbiome has high interdisciplinary and various opportunities that somehow have remained hidden in the medical world. It is believed that the opportunities and all the desirable tangible benefits microbiome is capable of delivering when combined with immunology is large and needs coordinated and constructive approach. The call to the two different sectors i.e. microbiology and immunology is estimated to unlock the potential and promising benefits of microbiome. The approach leading to the extraction of advantages if properly embedded in the microbiome and immunology research, the future benefits will be huge

Report Highlights:

Key Topics Covered:

1. Overview of Microbiome1.1 Introduction to Microbiome1.2 History & Evolution of Microbiome

2. Role of Microbiome in Human Body

3. Microbiome: Various Forms3.1 Gut Microbiome3.2 Lung Microbiome3.3 Skin Microbiome3.4 Microbiome in Other Parts of the Body

4. Mechanism of Microbiome Activity4.1 Nature of Immune Response4.1.1 Immunosuppressive Activity4.1.2 Immunostimulatory Activity4.2 Messengers Involves in Microbiome Mechanism4.2.1 MAMPs/PAMPs4.2.2 Microbial Metabolites As Messengers4.2.3 Host Cytokines As Messengers4.2.4 Immune Cells As Messengers

5. Technological Requirement for Microbiota5.1 Technologies Used5.1.1 iChip5.1.2 Simulator of the Human Intestinal Microbial Ecosystem (SHIME)5.1.3 Gut-on-a-Chip System5.1.4 Colonic Stem Cell Construction5.2 Harnessing & Engineering the Microbiome5.2.1 Additive Approaches5.2.2 Subtractive Approaches

6. Need for Microbiome Immunology

7. Therapeutic Applications of Microbiome Immunology7.1 Microbiome Therapy7.2 Precision Medicine7.3 Drug discovery7.4 Biomarkers & Therapy Optimization

8. Human Microbiota in Infectious Diseases8.1 Infection with Clostridium Difficile8.2 Infection with Helicobacter Pylori8.3 Bacterial Vaginosis8.4 Infection with HIV

9. The Human Microbiota & Liver Diseases9.1 Non-Alcoholic Fatty Liver Disease (NAFLD)9.2 Alcoholic Liver Diseases (ALD)9.3 Liver Fibrosis & Cirrhosis

10. The Human Microbiota & Metabolic Disorders10.1 Obesity10.2 Type 2 Diabetes

11. The Human Microbiota & Other Diseases11.1 Microbiota & Allergic Diseases11.2 Microbiota & Psychiatric Diseases

12. Microbiome in Immuno Oncology12.1 Role of Microbiome in Immuno Oncology12.2 Microbiome Mechanism in Oncogenesis & Tumor Suppression

13. Microbiome Application by Cancer Types13.1 Gastric Cancer13.2 Colorectal Cancer13.3 Esophageal Cancer13.4 Hepatocellular Carcinoma13.5 Melanoma13.6 Solid Tumors

14. Industrial Approaches of Microbiome Therapy in Oncology14.1 Bacterial Approaches14.1.1 Fecal Microbiota Transplantation (FMT)14.1.2 Synthetic Bacteria14.1.3 Microbial Culture14.2 Microbiome as Vaccine14.3 Microbiome as Small Molecules14.4 Microbiome Therapy using Phage Virus

15. Global Human Microbiome Market Analysis15.1 Overview15.2 Human Microbiome Market Segmentation15.2.1 Regional Segmentation15.2.2 Disease Based Segmentation15.2.3 Segmentation by Application

16. Clinical Pipeline of Microbiome Based Therapy16.1 Microbiome Modulators in Clinical Trial16.2 Cancer Related Clinical Trials16.2.1 Preclinical & Discovery Phase16.2.2 Active Clinical Trials16.3 Clinical Trial Related To FMT16.3.1 Clinical Trial for Recurrent C. difficile16.3.2 Clinical Trial for Inflammatory Bowel Disease (IBD)16.3.3 Other FMT Related Clinical Trials

17. Global Microbiome Modulators Clinical Pipeline By Company, Indication & Phase17.1 Research17.2 Preclinical17.3 Clinical17.4 Phase-I17.5 Phase-I/II17.6 Phase-II17.7 Phase-II/III17.8 Phase-III

18. Marketed Microbiome Modulators Clinical Insight18.1 Sodium Oligomannurarate - Shanghai Green Valley Pharmaceutical18.2 Miya-BM

19. Global Microbiome Immunology Therapeutics Market Growth Drivers

20. Microbiome Technology - Investments, Acquisitions & Collaborations by Leading Microbiome Companies

21. Blockades in the Microbiome Immunology Market21.1 Stable Engraftment21.2 Development of Clinically Relevant Sensors21.3 Robustness and Evolutionary Stability of Genetic Circuits21.4 Regulation, Safety and Biocontainment

22. Global Microbiome Immunology Market Future Panorama

23. Competitive Landscape23.1 4D Pharma23.2 AbbVie23.3 AstraZeneca plc23.4 Biocodex23.5 Bristol Mayer Squibb23.6 Corebiome/Diversigen23.7 Elogi Bioscience23.8 Enterome23.9 Ferring Pharmaceuticals23.10 Finch Therapeutics23.11 Maat Pharma23.12 Merck23.13 Microbiome Therapeutics23.14 Novartis23.15 OpenBiome23.16 Pfizer23.17 Rebiotix23.18 Second Genome23.19 Seres Therapeutics23.20 Symberix23.21 Takeda Pharmaceuticals23.22 Vedanta Bioscience

For more information about this clinical trials report visit https://www.researchandmarkets.com/r/d6z6gb

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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Insights on the Human Microbiome Immunology Therapeutics Global Market to 2025 - Featuring Finch Therapeutics, MaaT Pharma & Merck Among Others -...

Roger Stone is an infamously execrable force in American politics. Perhaps his only saving grace is that he's not a hypocrite about it.

Stone is a proud "dirty trickster." The GOP kept him on a leash lest his amorality be too closely associated with the Republican brand. Part of his code is that the best defense against legitimate criticism is to shoot the messenger: "Admit nothing, deny everything, launch counterattack."

As a proud cynic, if not an outright sybaritic nihilist, Stone would probably find the very notion of legitimate criticism foolish. "Nothing is on the level," he says. What's right is whatever you can get away with. "It's better to be infamous than never famous at all." (These bits of wisdom are laid out in "Stone's Rules," which reads like Mao's Little Red Book of Trumpism.)

I suspect that one reason Stone has a cult following on the right and among many in the media a fan club that long predates his status as a Trump loyalist is his willingness to own his political amorality in unapologetic sound bite form, thus immunizing himself from conventional charges of hypocrisy. When you turn deceit and dishonor into guiding principles, the only way you can be a hypocrite is if you fail to go low enough.

But Stone's hypocrisy exemption isn't transferable. His defenders, and defenders of President Trump's Friday-night commutation of Stone's prison sentence for seven felony counts of perjury, obstruction of Congress and witness tampering, won't escape judgment for their two-faced behavior.

The three main commutation defenses, all offered with Stonian shamelessness, are: (1) The president has the power to do it; (2) it was warranted because Stone's conviction was part of the "Russia hoax"; and (3) other presidents used their pardon and commutation power corruptly, too.

The first defense is true as far as it goes, though its a straw man given that few dispute it.

Second, whatever you think of the Russia investigation, Stone is guilty of the crimes he was tried for. Indeed, if Stone believed Trump to be wholly innocent and that the Russia collusion claim was a hoax, why not fully cooperate with investigators to clear the air?

The third and most popular defense is the one that reeks of hypocrisy.

A common talking point is that Bill Clinton abused his pardon power, too. Clinton pardoned his own brother! He pardoned billionaire fugitive and Clinton fundraiser Marc Rich!

Roger Clinton's pardon was indeed unseemly. And liberals denounced it. Jimmy Carter was outraged by the Rich pardon. New York Sen. Chuck Schumer couldn't "think of a single justification for [it]." Massachusetts Rep. Barney Frank called it a "real betrayal" of Clinton's supporters. "It was contemptuous."

Liberals called the inexcusable inexcusable. Now, the majority of GOP senators seem not just willing but thrilled to excuse the inexcusable admitting nothing, denying everything and launching counterattacks. Indeed, Senate Judiciary Committee Chairman Lindsey Graham said he wants to grill special counsel Robert Mueller because Mueller penned an op-ed defending the Stone prosecution.

Congratulations, Roger Stone: You won. It's your party now.

Jonah Goldberg is editor-in-chief of The Dispatch and the host of The Remnant podcast.

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Jonah Goldberg: The Republican Party now belongs to Roger Stone - The Ledger

If only mobs were allowed to destroy federal property without consequence. Then there wouldnt have to be any dispute over federal agents defending a federal courthouse in Portland, Ore.; it could simply be overrun and burned to the ground with no unwelcome resistance from the government.

As it is, Portlands mayor, Ted Wheeler, who presides over a city that has become a watchword over the years for left-wing thuggery unchecked by municipal authorities, has roused himself to a state of high dudgeon over federal officers trying to counter ongoing assaults on a federal building.

He calls the feds a direct threat to our democracy and argues that they are engaging in unconstitutional arrests and inflaming protests that he had hoped would end within a matter of days.

Oregon Sen. Ron Wyden had this cool-headed take on the president and his acting secretary of Homeland Security: Now Trump and Chad Wolf are weaponizing the DHS as their own occupying army to provoke violence on the streets of my hometown, because they think it plays well with right-wing media.

If Portland was on the verge of calm prior to the arrival of the feds in force, it would have been the first time since the killing of George Floyd.

Protests have taken place every day since May 28. A few headlines form a timeline, from the local TV station Koin.com: For May 29: Massive Vigil in North Portland Leads to Declared Riot Downtown. For May 30: Curfew Imposed and Ignored. For June 30: Police Building Protest: Another Riot Was Declared by Police.

Although the federal courthouse has done nothing to provoke protesters and has been standing at the same spot since 1997, it has been a constant target. Protesters have smashed its glass doors, covered its exterior with graffiti and repeatedly attempted to light it on fire. This has been happening since at least early July.

True to form, protesters over the weekend took down fencing and lit a fire at the buildings entryway. As a statement by the Portland police put it, dozens of people with shields, helmets, gas masks, umbrellas, bats and hockey sticks approached the doors of the courthouse but surely it was just a misunderstanding that led the federal officers to believe they had to repulse them with tear gas.

This isnt hard: It is the people attacking federal property who bear moral responsibility for whats happening in Portland. In all the cities around the country where nihilistic mobs arent trying to burn down symbols of our justice system, theres no enhanced presence of federal officers.

The feds havent been wearing badges with their names and have been using unmarked cars for fear of retaliation against the officers involved and mob actions against vehicles.

Both are unquestionably legal tactics. According to DHS, the officers are wearing the insignia of their agencies and unique identifiers; they are arresting only people suspected of involvement of attacks against federal property; and they are identifying themselves to arrestees, although not to crowds.

Perhaps these officers should be more clearly identified, but there is no case whatsoever for calling them, as House Speaker Nancy Pelosi has, stormtroopers who are kidnapping protesters.

The arrest of a man named Mark Pettibone has gotten a lot of press attention. He says he did nothing wrong and was arrested by federal agents, who took him to the federal courthouse and read him his Miranda rights, before releasing him.

He wasnt detained indefinitely, or disappeared, or harmed in any way, but apparently arrested in error and then allowed to go on his way.

It would be one thing if municipal authorities in Portland could legitimately claim that they have things under control. They dont. The mobs have been clashing with the local cops for months.

This longstanding riot is a stark commentary on the misgovernance of Wheeler, who is far better at insulting federal law enforcement than he is at doing at his job.

Rich Lowry is author of The Case for Nationalism: How It Made Us Powerful, United and Free. Twitter: @RichLowry

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Nancy Pelosi and Democrats have it exactly wrong on feds vs. protesters in Portland - New York Post

WASHINGTON, July 20, 2020 /PRNewswire/ --Family Research Council's Cathy Ruse received the Ruth Institute's "Activist of the Year" awardfor exposing radical, anti-science sex ed and transgender mandates in public school systems, especially in Fairfax County, Virginia. The Ruth Institute seeks to inspire survivors of the sexual revolution. Cathy Ruse continues to trailblaze on this topic; she most recently authored FRC's publication, "Sex Education in Public Schools: Sexualization of Children and LGBT Indoctrination."

Cathy Ruse, FRC's Senior Fellow and Director of Human Dignity released the following statement:

"Wealthy international pressure groups are using sex ed in public schools to manipulate children. And leftist school boards like Fairfax County are willing accomplices. By their own admission, these groups view public schools in Northern Virginia as 'laboratories' for their experimental policies, like teaching children they can be born in the wrong body. Public schools should never experiment on children. Children are not lab rats. This scenario is playing out all across the country.

"Yes, we must protect our own children. But opting out is not enough. Because right down the street, at your local public school, there is a spiritual battle raging over the next generation and so often our side isn't even on the battlefield. It's time to get into the arena! Justice demands it, but wisdom too. Because the vast majority of our governors, teachers, sheriffs, doctors, and lawyers will come from our nation's public schools. We cannot let the sexual nihilists shape them in their own image," concluded Ruse.

To download a copy of Cathy Ruse's publication, "Sex Education in Public Schools: Sexualization of Children and LGBT Indoctrination," visit: https://www.frc.org/sexeducation.

To request an interview with Cathy Ruse, contact [emailprotected].

SOURCE Family Research Council

https://www.frc.org

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FRC's Cathy Ruse Receives 'Activist of the Year' Award - PRNewswire