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A new model aims to predict genetic changes that have unintended consequences in trees that researchers genetically modify.

It could pave the way for more efficient research in the fields of both genetic modification and forestry.

Researchers want to genetically modify trees for a variety of applications, from biofuels to paper production. They also want to steer clear of modifications to one gene that result in unexpected changes to other genes.

The research at issue focuses on lignin, a complex material found in trees that helps to give trees their structure. It is, in effect, what makes wood feel like wood.

Whether you want to use wood as a biofuel source or to create pulp and paper products, there is a desire to modify the chemical structure of lignin by manipulating lignin-specific genes, resulting in lignin that is easier to break down, says corresponding author Cranos Williams, an associate professor of electrical and computer engineering at North Carolina State University. However, you dont want to make changes to a trees genome that compromise its ability to grow or thrive.

The researchers focused on a tree called Populus trichocarpa, which is a widely used model organismmeaning that scientists who study genetics and tree biology spend a lot of time studying P. trichocarpa.

Previous research generated models that predict how independent changes to the expression of lignin genes impacted lignin characteristics, says Megan Matthews, first author of the paper, a former PhD student at NC State, and a current postdoctoral researcher at the University of Illinois.

These models, however, do not account for cross-regulatory influences between the genes. So, when we modify a targeted gene, the existing models do not accurately predict the changes we see in how non-targeted genes are being expressed. Not capturing these changes in expression of non-targeted genes hinders our ability to develop accurate gene-modification strategies, increasing the possibility of unintended outcomes in lignin and wood traits.

To address this challenge, we developed a model that was able to predict the direct and indirect changes across all of the lignin genes, capturing the effects of multiple types of regulation. This allows us to predict how the expression of the non-targeted genes is impacted, as well as the expression of the targeted genes, Matthews says.

Another of the key merits of this work, versus other models of gene regulation, is that previous models only looked at how the RNA is impacted when genes are modified, Matthews says. Those models assume the proteins will be impacted in the same way, but thats not always the case. Our model is able to capture some of the changes to proteins that arent seen in the RNA, or vice versa.

This model could be incorporated into larger, multi-scale models, providing a computational tool for exploring new approaches to genetically modifying tree species to improve lignin traits for use in a variety of industry sectors.

In other words, by changing one gene, researchers can accidentally mess things up with other genes, creating trees that arent what they want. The new model can help researchers figure out how to avoid that.

The paper appears in the journal PLOS Computational Biology. Support for the work came from the National Science Foundation and a National Physical Science Consortium Graduate Fellowship.

Source: NC State

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Model warns of genetic modification gone awry in trees - Futurity: Research News

Researchers are interested in genetically modifying trees for a variety of applications, from biofuels to paper production. They also want to steer clear of modifications with unintended consequences. These consequences can arise when intended modifications to one gene results in unexpected changes to other genes. A new model aims to predict these changes, helping to avoid unintended consequences, and hopefully paving the way for more efficient research in the fields of genetic modification and forestry.

The research at issue focuses on lignin, a complex material found in trees that helps to give trees their structure. It is, in effect, what makes wood feel like wood.

Whether you want to use wood as a biofuel source or to create pulp and paper products, there is a desire to modify the chemical structure of lignin by manipulating lignin-specific genes, resulting in lignin that is easier to break down, says Cranos Williams, corresponding author of a paper on the work and an associate professor of electrical and computer engineering at NCState. However, you dont want to make changes to a trees genome that compromise its ability to grow or thrive.

The researchers focused on a tree called Populus trichocarpa, which is a widely used model organism meaning that scientists who study genetics and tree biology spend a lot of time studying P. trichocarpa.

Previous research generated models that predict how independent changes to the expression of lignin genes impacted lignin characteristics, says Megan Matthews, first author of the paper, a former Ph.D. student at NCState and a current postdoc at the University of Illinois. These models, however, do not account for cross-regulatory influences between the genes. So, when we modify a targeted gene, the existing models do not accurately predict the changes we see in how non-targeted genes are being expressed. Not capturing these changes in expression of non-targeted genes hinders our ability to develop accurate gene-modification strategies, increasing the possibility of unintended outcomes in lignin and wood traits.

To address this challenge, we developed a model that was able to predict the direct and indirect changes across all of the lignin genes, capturing the effects of multiple types of regulation. This allows us to predict how the expression of the non-targeted genes is impacted, as well as the expression of the targeted genes, Matthews says.

Another of the key merits of this work, versus other models of gene regulation, is that previous models only looked at how the RNA is impacted when genes are modified, Matthews says. Those models assume the proteins will be impacted in the same way, but thats not always the case. Our model is able to capture some of the changes to proteins that arent seen in the RNA, or vice versa.

This model could be incorporated into larger, multi-scale models, providing a computational tool for exploring new approaches to genetically modifying tree species to improve lignin traits for use in a variety of industry sectors.

In other words, by changing one gene, researchers can accidentally mess things up with other genes, creating trees that arent what they want. The new model can help researchers figure out how to avoid that.

The paper, Modeling cross-regulatory influences on monolignol transcripts and proteins under single and combinatorial gene knockdowns in Populus trichocarpa, is published in the journal PLOS Computational Biology. The paper was co-authored by Ronald Sederoff, a professor emeritus of forestry and environmental resources at NCState; Jack Wang, an assistant professor of forestry and environmental resources at NCState; and Vincent Chiang, a Jordan Family Distinguished Professor Emeritus and Alumni Outstanding Research Professor with the Forest Biotechnology Group at NCState.

This work was supported by the National Science Foundation Grant DBI-0922391 to Chiang and by a National Physical Science Consortium Graduate Fellowship to Matthews.

-shipman-

Note to Editors: The study abstract follows.

Modeling cross-regulatory influences on monolignol transcripts and proteins under single and combinatorial gene knockdowns in Populus trichocarpa

Authors: Megan L. Matthews, Ronald Sederoff and Cranos M. Williams, North Carolina State University; Jack P. Wang and Vincent L. Chiang, Northeast Forestry University, Harbin, China, and North Carolina State University

Published: April 10, PLOS Computational Biology

Abstract: Accurate manipulation of metabolites in monolignol biosynthesis is a key step for controlling lignin content, structure, and other wood properties important to the bioenergy and biomaterial industries. A crucial component of this strategy is predicting how single and combinatorial knockdowns of monolignol specific gene transcripts influence the abundance of monolignol proteins, which are the driving mechanisms of monolignol biosynthesis. Computational models have been developed to estimate protein abundances from transcript perturbations of monolignol specific genes. The accuracy of these models, however, is hindered by their inability to capture indirect regulatory influences on other pathway genes. Here, we examine the manifestation of these indirect influences on transgenic transcript and protein abundances, identifying putative indirect regulatory influences that occur when one or more specific monolignol pathway genes are perturbed. We created a computational model using sparse maximum likelihood to estimate the resulting monolignol transcript and protein abundances in transgenicPopulus trichocarpabased on targeted knockdowns of specific monolignol genes. Using in-silicosimulations of this model and root mean square error, we showed that our model more accurately estimated transcript and protein abundances, in comparison to previous models, when individual and families of monolignol genes were perturbed. We leveraged insight from the inferred network structure obtained from our model to identify potential genes, including PtrHCT, PtrCAD, and Ptr4CL, involved in post-transcriptional and/or post-translational regulation. Our model provides a useful computational tool for exploring the cascaded impact of single and combinatorial modifications of monolignol specific genes on lignin and other wood properties.

Continue reading here:
Better Predicting the Unpredictable Byproducts of Genetic Modification - NC State News

University Relations

Sarah DuRant and Jeffrey Lewis, assistant professors of biology, were awarded major early career awards by the National Science Foundation.

FAYETTEVILLE, Ark. Two researchers Sarah DuRant and Jeffrey Lewis from the Department of Biological Sciences in the J. William Fulbright College of Arts and Sciences recently received Faculty Early Career Development Awards from the National Science Foundation. DuRant, an assistant professor, received $1.5 million, while Lewis, also an assistant professor, received $1.2 million.

Known as CAREER awards, they are the NSF's most prestigious award for early-career faculty who have the potential to serve as academic role models in research and education and to lead advances in the mission of their department or organization. The awards are for five years and include teaching and public-outreach components.

Working with domestic canaries, DuRant plans to study the effects of disease on avian parental care behaviors and subsequent offspring responses to disease, including likelihood of disease transmission.

"In the world of the disease, a lot of focus is on how mothers, when they are exposed to a pathogen, develop antibodies to the pathogen and can pass them along to the offspring," she said. "One of the things I am interested in how behavior is shaping the immune phenotype of the offspring."

A pathogen can affect reproductive traits in parents such as incubation behaviors, DuRant explained, which in turn shape how an offspring responds to pathogens. "Ultimately what can happen is that how any individual responds to the pathogen can start to shape pathogen growth, transmission and virulence."

Lewis is studying how organisms with different genetic makeups respond differently to environmental stress. Using brewer's yeast, he will try to unlock the reasons why some strains are more sensitive to high levels of stresses such as ethanol than others.

"In pretty much every organism, if you expose them to mild stress there are a bunch of stress-protective proteins that get turned on," he said. "The thought has long been that this response is for adapting to that initial stress. But the genes getting turned on by stress seemed largely dispensable for stress survival. The big question was why is the cell turning these genes on if they are not required to protect cell from insult that provoked the response?"

It turns out that the function of the proteins is, in part, to protect the cell against future severe stress, "analogous to vaccinating the cell," he said.

Yeast cells are easy to grow and manipulate with genetic engineering, he added, making them a good test subject for identifying the genes necessary for acquiring resistance to severe stress. "We can grow billions of them really easily and do high-throughput genetics really easily."

A side benefit is that the research could lead to improved yeast strains for brewing beer. "Some strains do better withstanding brewing stresses than others. We will have students analyze and incorporate genomic data and gain experience with that."

Both DuRant and Lewis are in the first year of the five-year CAREER funding cycle.

See the article here:
University of Arkansas Biologists Receive NSF CAREER Awards - University of Arkansas Newswire

One of the major limitations of the first-generation rDNA-based GM methods is the randomness of DNA insertions into plant genomes, just as the earlier mutagenesis methods introduced mutations randomly. The newer methods increase the specificity and precision with which genetic changes can be made. Known under the general rubric of sequence-specific nuclease (SSN) technology or gene/genome-editing, this approach uses proteins or protein-nucleic acid complexes that bind to and cut specific DNA sequences.1 SSNs include transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), and meganucleases.2

[This is part three of a four-part series on the progress of agricultural biotechnology. Read part one and part two.]

The DNA cuts made by SSNs are repaired by cellular processes that often either change one to several base pairs or introduce deletions and/or insertions (aka indels) at the target site. Another recently added technology capable of editing gene sequences is termed oligonucleotide-directed mutagenesis (ODM) and uses short nucleic acid sequences to target mutations to selected sites.3

The hottest and the coolest

What is rapidly emerging as the most powerful of the SSN technologies is known by the uninformative acronym CRISPR/Cas, which contracts the unwieldy designation clustered regularly interspaced short palindromic repeats (CRISPR)CRISPR-associated protein (Cas9). Its based on a bacterial defense system against invading viruses and promises extraordinary versatility in the kinds of genome changes that it can make.1,4

The CRISPR/Cas editing molecular machine is comprised of an enzyme (Cas9 and other variants) that binds an RNA molecule (called the guide RNA or gRNA) whose sequence guides the complex to the matching genomic sequence, allowing the Cas9 enzyme to introduce a double-strand break within the matching sequence. The CRISPR/Cas system can be used to edit gene sequences, to introduce a gene or genes at a pre-identified site in the genome, and to edit multiple genes simultaneously, none of which could be done with rDNA methods.1,5

Many of the genetic changes created using either SSN or ODM are indistinguishable at the molecular level from those that occur in nature or are produced by mutation breeding. Since both spontaneous mutants and chemical- and radiation-induced mutants have been used in crop improvement without regulation, there is no scientific rationale for regulating mutants produced by the newer methods. In hopes of creating a distinction that will permit exemption of gene-edited crops from regulation, the newer methods are increasingly referred to as new plant breeding techniques (NPBTs or just NBTs).

Quick successes for NBTs?

Prime targets of gene editing are cellular proteins that are involved in pathogenesis.6 Virus reproduction requires the recruitment of cellular proteins for replication, transcription and translation. There can be sufficient redundancy in the requisite protein infrastructure so that partial or complete virus resistance can be achieved by disrupting genes that code for proteins required for viral replication without damaging crop productivity.

For example, work with mutants of the model plant Arabidopsis identified translation initiation factor eIF4E as required for potyvirus translation. CRISPR/Cas-induced point mutations and deletions have recently been reported to enhance viral resistance not only in Arabidopsis, but in cucumber and cassava, as well.7

The many ways that plants and their bacterial and fungal pathogens interact offer opportunities to use gene editing to enhance plant disease resistance and reduce agricultures dependence on chemical control agents.6 The two main strategies are to inactivate genes whose products render the host plant sensitive to pathogen invasion and to enhance the ability of the host plant to resist invasion by providing functional resistance factors they lack.

An example of the former is provided by the mildew resistance resulting from the inactivation of all three homeoalleles of the mildew resistance locus (MLO) of hexaploid wheat.8 The efficiency of targeting both multiple alleles and multiple loci has taken a further jump with the development of multiplexed gene editing using vectors carrying several gRNA sequences capable of being processed by cellular enzymes to release all of them. This allows the gRNAs to edit multiple genes simultaneously.9

The second approach is to capitalize on the formidable arsenal of resistance genes residing in plant genomes.10 Fungal resistance genes have long been a major target of breeders efforts and have proved frustratingly short-lived, as pathogens rapidly evolve to evade recognition.11 While desirable resistance genes missing from domesticated crops still reside in wild relatives, extracting them by conventional breeding methods can be time-consuming or impossible.

European academic researchers created transgenic potatoes resistant to the late blight (Phytophthora infestans) that caused the Irish potato famine by inserting resistance (R) genes cloned from wild potato species into commercial potato varieties.12 A blight-resistant variety, called the Innate Generation 2 potato, is being commercialized by J.R. Simplot company in the U.S. and Canada and is already being marketed in the U.S. as the White Russet Idaho potato.13 Transgenic disease-resistance traits have been introduced in other crops, but have yet to be commercialized.14

Plant genomes contain hundreds to thousands of potential R genes, but it is not yet possible to determine whether a given one will confer resistance to a particular pathogen. Methods are currently being developed to accelerate the identification and cloning of active ones.14 Once identified, CRISPR/Cas can be used to introduce cassettes carrying multiple R genes, making it possible to create more durable resistance than can be achieved by introducing a single R gene through conventional breeding14. Finally, direct editing of resident inactive R genes using a ribonucleoprotein (RNP) strategy that avoids creating a transgenic plant may prove useful, although no such products appear to be in the pipeline to commercialization at present.15,16

Multiplexed editing has proved particularly useful for editing genes in polyploid species. For example, Cas9/sgRNA-mediated knockouts of the six fatty acid desaturase 2 (FAD2) genes of allohexaploid Camelina sativa was reported to markedly improve the fatty acid composition of Camelina oil.17 Using a different approach, Yield10 Biosciences is moving toward commercialization of a high-oil Camelina developed by editing a negative regulator of acetyl-CoA carboxylase.18

As of this writing, the only gene-edited product that has been commercialized is a soybean oil with no trans-fat, trademarked Calyno, developed by Calyxt.19 Gene-edited crops that have been approved but not commercialized or are still in the regulatory pipeline include miniature tomatoes, high-fiber wheat, high-yield tomatoes, improved quality alfalfa, non-browning potatoes and mushrooms, as well as high starch-content and drought-resistant corn, most being developed by small biotech companies.19

Getting beyond the low-hanging fruit

It is becoming increasingly clear that yield increases in our major crops by traditional breeding approaches are not keeping pace with demand.20 The gap is likely to widen as climate warming moves global temperatures farther from those prevailing when our crops were domesticated.

Overexpression of stress-related transcription factors has been reported to increase yields under water-stress conditions, but such increases are generally not maintained under optimal conditions.21 Monsantos drought-tolerant (Genuity DroughtGard) corn hybrids are based on the introduction of bacterial chaperone genes.22 Fortunately, research into drought stress tolerance in wheat and other grains continues apace, although no drought-tolerant varieties have yet reached farmers.23

Real progress on crop yield is slow. What stands in the way is that we have so limited an understanding of how plants work at the molecular level. At every level of analysis, organisms are redundant networks of interconnected proteins that adjust their manifold physical and enzymatic interactions in response to internal signals and external stimuli, then send messages to the information storage facilities (DNA) to regulate their own production and destruction rates.

As well, many genes are present in families of between two and hundreds or thousands of similar members, making it difficult to determine either the function or the contribution of any given member to a complex trait such as stress tolerance or yield. That said, gene family functions are identifiable and some, such as transcription factor genes, encode proteins that influence multiple other genes, making them among the likeliest candidates for manipulation. Indeed, studies on the genetics of domestication often point to changes in transcription factor genes.24

But while there have been reports that constitutive overexpression of single transcription factor gene can increase grain yield in both wheat and maize, none appear to have been commercialized yet.25 The challenge of developing a yield-improved variety by simply overexpressing transcription factor genes is illustrated by a recent report from Corteva.26 It describes a tour-de-force involving generation and testing of countless transgenic plants to identify a single transcription factor gene, ZMM28, that reproducibly increased yield when incorporated into 48 different hybrids and tested over a 4-year period in 58 locations.26

Getting there by a different route

Might gene-editing facilitate the task of generating and identifying yield-enhancing genetic variation? While the CRISPR/Cas toolkit is growing at dizzying speed, its utility in crop improvement has so far been limited to the simple traits controlled by individual genes, albeit including multiple alleles.1,27

Crop domestication and plant breeding have vastly narrowed genetic diversity because the very process of selecting plants with enhanced traits imposes a bottleneck, assuring that only a fraction of the ancestral populations genetic diversity is represented in a new elite variety. This, in turn, limits what can be done by mutagenizing existing elite varieties, a process that is also burdened with the necessity to eliminate deleterious mutations through back-crossing.

But to widen the genetic base and to modify genes that contribute to quantitative traits, it is still first necessary to identify the genes that contribute to agronomically important traits. Identifying such genes is currently a slow and tedious process of conventional and molecular mapping.28 A recent report describes a method for combining pedigree analysis with targeted CRISPR/Cas-mediated knockouts that promises to markedly accelerate the identification of the individual contributing genes in the chromosomal regions that are associated with quantitative traits, technically known as quantitative trait loci (QTLs).29

Even as the QTL knowledge gap narrows, gRNA multiplexing is extending the power of SSNs to understanding and modifying complex traits in crop plants. For example, using multiplexed gRNAs, Cas nuclease was simultaneously targeted to three genes known to be negative regulators of grain weight in rice.30 The triple mutants were reported to exhibit increases in the neighborhood of 25% in each of the three grain weight traits: length, width and thousand grain weight.

In another study, 8 different genes affecting rice agronomic traits were targeted with a single multiplexed gRNA construct and all showed high mutation efficiencies in the first generation.31 Conversely, it has been reported that editing the same QTLs gives different outcomes in different elite varieties, improving yield in some but not other.32

Mutations affecting the expression of regulatory genes, such as transcription factors genes, account for a substantial fraction of the causative genetic changes during crop domestication.33 Multiplexed gRNAs constructs targeting cis-regulatory elements (CREs) have been used to generate large numbers of allelic variants of genes affecting fruit size in tomato, mimicking some of the mutations accumulated during domestication and breeding of contemporary tomato varieties.34

Knowledge of domestication genes can also be used to accelerate domestication of wild plants that retain traits of value, such as salt tolerance, as reported for tomato.35 This opens the possibility of rapidly domesticating wild species better adapted to the harsher climate conditions of the future.

While the above-described advances have been based on the CRISPR/Cas-mediated deletions, approaches to more precise sequence editing are developing as well. While Cas-generated cuts in the DNA are most commonly repaired by the non-homologous end joining pathway (NHEJ), the less frequent homology-directed repair pathway (HDR) has been shown to edit sequences at useful frequencies using Cas-gRNA ribonucleoprotein complexes.15,36

As well, mutant Cas9 proteins lacking nuclease activity have been fused with base-editing enzymes such as cytidine and adenosine deaminases to direct gene editing without DNA cleavage.37,38 This approach can change single base pairs precisely in both coding and non-coding regions, as well alter mRNA precursor processing sites.38 Finally, the sequence targeting properties of the CRISPR-Cas system can be used to deliver other types of hybrid proteins to target sequences to regulate gene expression and DNA methylation.27

In sum, the many variations on gene editing now developing hold the promise of revolutionizing crop breeding, prompting several colleagues to whimsically title a recent review of CRISPR/Cas-based methodology: Plant breeding at the speed of light.39 And indeed, the new methods make it possible to replace chemicals with biological mechanisms in protecting plants from pests and disease, as well as increase their resilience to stress.

That said, extraordinary progress in increasing grain yields has already been accomplished by what are now considered to be traditional breeding methods and increased fertilizer use. Further improvements continue, but will likely be harder won than the many-fold increases in corn, wheat and rice yields of the last century and its Green Revolution. But there is a persistent disconnect between what can be done to accelerate plant breeding using the new gene-editing toolkit and what is actually being done by both the public and private sectors to get varieties improved by these methods out to farmers.

1Zhang Y et al. (2019). The emerging and uncultivated potential of CRISPR technology in plant science. Nature Plants 5:778-94.

2Podevin N et al. (2013). Site-directed nucleases: a paradigm shift in predictable, knowledge-based plant breeding. Trends Biotechnol 31:375-83.

3Sauer NJ et al. (2016). Oligonucleotidedirected mutagenesis for precision gene editing. Plant Biotechnol J 14:496-502.

4Zhang D et al. (2016). Targeted gene manipulation in plants using the CRISPR/Cas technology. J Genet Genomics 43:251-62.

5Cong L et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science 339:819-23.

6Borrelli VM et al. (2018). The enhancement of plant disease resistance using CRISPR/Cas9 technology. Frontiers Plant Sci 9:Article 1245.

7Chandrasekaran J et al. (2016). Development of broad virus resistance in nontransgenic cucumber using CRISPR/Cas9 technology. Molec Plant Pathol 17:1140-53; Pyott DE et al. (2016). Engineering of CRISPR/Cas9mediated potyvirus resistance in transgenefree Arabidopsis plants. Molec Plant Pathol 17:1276-88; Gomez MA et al. (2019). Simultaneous CRISPR/Cas9mediated editing of cassava eIF 4E isoforms nCBP1 and nCBP2 reduces cassava brown streak disease symptom severity and incidence. Plant Biotechnol J 17:421-34.

8Wang Y et al. (2014). Simultaneous editing of three homoeoalleles in hexaploid bread wheat confers heritable resistance to powdery mildew. Nature Biotechnol 32:947.

9Xie K et al. (2015). Boosting CRISPR/Cas9 multiplex editing capability with the endogenous tRNA-processing system. Proc Natl Acad Sci 112:3570-5; Wang W et al. (2018). Transgenerational CRISPR-Cas9 activity facilitates multiplex gene editing in allopolyploid wheat. The CRISPR J 1:65-74.

10Petit-Houdenot Y and Fudal I (2017). Complex interactions between fungal avirulence genes and their corresponding plant resistance genes and consequences for disease resistance management. Frontiers Plant Sci 8:1072.

11Bebber DP and Gurr S (2015). Crop-destroying fungal and oomycete pathogens challenge food security. Fungal Genet Biol 74:62-4; van Esse HP et al. (2020). Genetic modification to improve disease resistance in crops. New Phytol 225:70-86.

12Jones JD et al. (2014). Elevating crop disease resistance with cloned genes. Phil Trans Royal Soc B: Biol Sci 369:20130087; Haesaert G et al. (2015). Transformation of the potato variety Desiree with single or multiple resistance genes increases resistance to late blight under field conditions. Crop Protection 77:163-75.

13Halsall M. Innate outlook. Spudsmart, 24 April 2019 https://spudsmart.com/innate-outlook/

14Dong OX and Ronald PC (2019). Genetic engineering for disease resistance in plants: recent progress and future perspectives. Plant Physiol 180:26-38.

15Svitashev S et al. (2016). Genome editing in maize directed by CRISPRCas9 ribonucleoprotein complexes. Nature Communications 7:1-7.

16Mao Y et al. (2019). Gene editing in plants: progress and challenges. Nat Sci Rev 6:421-37.

17Morineau C et al. (2017). Selective gene dosage by CRISPRCas9 genome editing in hexaploid Camelina sativa. Plant Biotechnol J 15:729-39; Jiang WZ et al. (2017). Significant enhancement of fatty acid composition in seeds of the allohexaploid, Camelina sativa, using CRISPR/Cas9 gene editing. Plant Biotechnol J 15:648-57.

18Yield10 Bioscience (Jan 16, 2020 ). Yield10 Bioscience submits Am I Regulated? letter to USDA-APHIS BRS for CRISPR genome-edited C3007 in Camelina to pave the way for U.S. field tests. https://www.globenewswire.com/news-release/2020/01/16/1971418/0/en/Yield10-Bioscience-Submits-Am-I-Regulated-Letter-to-USDA-APHIS-BRS-for-CRISPR-Genome-Edited-C3007-in-Camelina-to-Pave-the-Way-for-U-S-Field-Tests.html

19Genetic Literacy Project (2020). Global Gene Editing Regulation Tracker. https://crispr-gene-editing-regs-tracker.geneticliteracyproject.org/united-states-crops-food/

20Ray DK et al. (2013). Yield trends are insufficient to double global crop production by 2050. PloS One 8:e66428.

21Rice EA et al. (2014). Expression of a truncated ATHB17 protein in maize increases ear weight at silking. PLoS One 9:e94238; Araus JL et al. (2019). Transgenic solutions to increase yield and stability in wheat: shining hope or flash in the pan? J Experimental Bot 70:1419-24.

22Castiglioni P et al. (2008). Bacterial RNA chaperones confer abiotic stress tolerance in plants and improved grain yield in maize under water-limited conditions. Plant Physiol 147:446-55.

23Mwadzingeni L et al. (2016). Breeding wheat for drought tolerance: Progress and technologies. J Integrative Agricult 15:935-43; Sallam A et al. (2019). Drought stress tolerance in wheat and barley: Advances in physiology, breeding and genetics research. Internat J Mol Sci 20:3137.

24Swinnen G et al. (2016). Lessons from domestication: targeting cis-regulatory elements for crop improvement. Trends Plant Sci 21:506-15.

25Nelson DE et al. (2007). Plant nuclear factor Y (NF-Y) B subunits confer drought tolerance and lead to improved corn yields on water-limited acres. Proc Natl Acad Sci 104:16450-5; Qu B et al. (2015). A wheat CCAAT box-binding transcription factor increases the grain yield of wheat with less fertilizer input. Plant Physiol 167:411-23; Yadav D et al. (2015). Constitutive overexpression of the TaNF-YB4 gene in transgenic wheat significantly improves grain yield. J Experiment Bot 66:6635-50.

26Wu J et al. (2019). Overexpression of zmm28 increases maize grain yield in the field. Proc Natl Acad Sci 116:23850-8.

27Chen K et al. (2019). CRISPR/Cas genome editing and precision plant breeding in agriculture. Annu Rev Plant Biol 70:667-97.

28Cavanagh C et al. (2008). From mutations to MAGIC: resources for gene discovery, validation and delivery in crop plants. Curr Opin Plant Biol 11:215-21.

29Huang J et al. (2018). Identifying a large number of high-yield genes in rice by pedigree analysis, whole-genome sequencing, and CRISPR-Cas9 gene knockout. Proc Natl Acad Sci 115:E7559-E67.

30Xu R et al. (2016). Rapid improvement of grain weight via highly efficient CRISPR/Cas9-mediated multiplex genome editing in rice. J Genet Genom 43:529.

31Shen L et al. (2017). Rapid generation of genetic diversity by multiplex CRISPR/Cas9 genome editing in rice. China Sci Life Sci 60:506-15.

32Shen L et al. (2018). QTL editing confers opposing yield performance in different rice varieties. J Integrative Plant Biol 60:89-93; Zhou J et al. (2019). Multiplex QTL editing of grain-related genes improves yield in elite rice varieties. Plant Cell Rep 38:475-85.

33Meyer RS and Purugganan MD (2013). Evolution of crop species: genetics of domestication and diversification. Nature Rev Genet 14:840-52.

34Rodrguez-Leal D et al. (2017). Engineering quantitative trait variation for crop improvement by genome editing. Cell 171:470-80. e8.

35Li T et al. (2018). Domestication of wild tomato is accelerated by genome editing. Nature Biotechnol 36:1160-3; Zsgn A et al. (2018). De novo domestication of wild tomato using genome editing. Nature Biotechnol 36:1211-6.

36Puchta H et al. (1996). Two different but related mechanisms are used in plants for the repair of genomic double-strand breaks by homologous recombination. Proc Natl Acad Sci 93:5055-60; Zhang Y et al. (2016). Efficient and transgene-free genome editing in wheat through transient expression of CRISPR/Cas9 DNA or RNA. Nature Communications 7:1-8.

37Komor AC et al. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533:420-4; Hua K et al. (2019). Expanding the base editing scope in rice by using Cas9 variants. Plant Biotechnol J 17:499-504.

38Kang B-C et al. (2018). Precision genome engineering through adenine base editing in plants. Nature Plants 4:427-31.

39Wolter F et al. (2019). Plant breeding at the speed of light: the power of CRISPR/Cas to generate directed genetic diversity at multiple sites. BMC Plant Biol 19:176.

Nina V. Fedoroff is an Emeritus Evan Pugh Professor at Penn State University

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Next-generation gene-editing technology: Path to a second Green Revolution? - Genetic Literacy Project

BEIJING, April 15, 2020 /PRNewswire/ -- According to the latest news from Science and Technology Daily (April 14th), two COVID-19 inactivated vaccines were just approved for a phase I & II combined clinical trial by the National Medical Products Administration (NMPA) of China, making them the first batch in this category. The two vaccines were developed respectively by Wuhan Institute of Biological Products Co., Ltd of Sinopharm and Sinovac Research & Development Co., Ltd together with research institutes.

This is another piece of good news since the team of Chen Wei, academician at China Academy of Engineering and researcher at Academy of Military Medical Sciences, managed to get clinical trial approval for the recombinant COVID-19 vaccine they developed on March 17th.

"We are taking the lead in developing COVID-19 vaccines in a global perspective," said with pride by Wang Junzhi, academician at China Academy of Engineering. Then he proposed four factors for this achievement: early start, accurate direction, being science-based and collaboration from all parts.

Vaccine is not a distant solution for a current emergency, but rather the most powerful weapon to defeat COVID-19.

China made the decision to accelerate the pace based on rational judgement and organization with the premise of safety assurance. As early on January 21st, the Ministry of Science and Technology (MOST) announced the establishment of an expert group of joint epidemic prevention and control against COVID-19. The expert group was led by Zhong Nanshan, academician at China Academy of Engineering, and consisted of 14 experts. On 22nd, the first eight emergency programs of Scientific Response to COVID-19 were initiated swiftly.

The expert group had decided on five directions for vaccine development: inactivated vaccines, genetic engineering subunit vaccines, adenovirus vector vaccines, nucleic acid vaccines, and vaccines using attenuated influenza virus as vectors. All five directions were to be followed at the same time. Eight teams of advantage in vaccine development were singled out to collaborate on this mission with a detailed plan of work nodes accurate to the day.

Thanks to Chen Wei's accurate judgement and accumulation of knowledge and experience in vaccine development, her team was the first to reach breakthrough achievements. In early February, she suggested that COVID-19 remains a coronavirus despite its possible variation. Therefore, mutual target antigen, pathogenesis and receptor could be identified quickly with the help of bioinfomatics and big data mining once the variation appears. And the vaccine development can be improved swiftly accordingly.

Since the start of the program, Chen Wei's team has conducted research on recombinant COVID-19 vaccine (adenovirus vector vaccine) based on the successful experience in Ebola vaccine development with great speed. On March 17th, the team's recombinant COVID-19 vaccine was approved for clinical trial, which took place one month in advance than expected. By April 2nd, all 108 subjects of phase I clinical trial in Wuhan had been inoculated. On 9th, phase II clinical trial, which has a larger scale and introduces placebo control groups, started recruitment for volunteers.

Meanwhile, all other directions have also made progress.

Lei Chaozi, head of Department of Science and Technology of the Ministry of Education, introduced the current achievements: research on the safety and validity of experimental animal for attenuated influenza vector vaccine is ongoing and pre clinical trial research for vaccine candidates and application for clinical trial are expected by the end of April; animal experiments on mice and rabbits regarding recombinant protein vaccine are being conducted and the technology of large-scale production of vaccine with high quality and purity has been mastered; nucleic acid vaccine development is a new technology being explored by the whole world, but no such vaccine has entered the market yet.

At the same time, Wang Junzhi specifically emphasized the safety issue of the vaccine: "On the one hand, Chinese scientists seek to make full use of time with great effort. On the other hand, they conduct research under scientific laws and ensure the safety and validity of the vaccine. All research and development activities are in accordance with corresponding regulations and technological requirements."

View original content:http://www.prnewswire.com/news-releases/three-chinese-vaccines-against-covid-19-are-on-the-way-301041665.html

SOURCE Science and Technology Daily

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Three Chinese Vaccines against COVID-19 are on the Way - BioSpace

Researchers are interested in genetically modifying trees for a variety of applications, from biofuels to paper production. They also want to steer clear of modifications with unintended consequences. These consequences can arise when intended modifications to one gene results in unexpected changes to other genes. A new model aims to predict these changes, helping to avoid unintended consequences, and hopefully paving the way for more efficient research in the fields of genetic modification and forestry.

The research at issue focuses on lignin, a complex material found in trees that helps to give trees their structure. It is, in effect, what makes wood feel like wood.

Whether you want to use wood as a biofuel source or to create pulp and paper products, there is a desire to modify the chemical structure of lignin by manipulating lignin-specific genes, resulting in lignin that is easier to break down, says Cranos Williams, corresponding author of a paper on the work and an associate professor of electrical and computer engineering at NC State. However, you dont want to make changes to a trees genome that compromise its ability to grow or thrive.

The researchers focused on a tree called Populus trichocarpa, which is a widely used model organism meaning that scientists who study genetics and tree biology spend a lot of time studying P. trichocarpa.

Previous research generated models that predict how independent changes to the expression of lignin genes impacted lignin characteristics, says Megan Matthews, first author of the paper, a former Ph.D. student at NC State and a current postdoc at the University of Illinois. These models, however, do not account for cross-regulatory influences between the genes. So, when we modify a targeted gene, the existing models do not accurately predict the changes we see in how non-targeted genes are being expressed. Not capturing these changes in expression of non-targeted genes hinders our ability to develop accurate gene-modification strategies, increasing the possibility of unintended outcomes in lignin and wood traits.

To address this challenge, we developed a model that was able to predict the direct and indirect changes across all of the lignin genes, capturing the effects of multiple types of regulation. This allows us to predict how the expression of the non-targeted genes is impacted, as well as the expression of the targeted genes, Matthews says.

Another of the key merits of this work, versus other models of gene regulation, is that previous models only looked at how the RNA is impacted when genes are modified, Matthews says. Those models assume the proteins will be impacted in the same way, but thats not always the case. Our model is able to capture some of the changes to proteins that arent seen in the RNA, or vice versa.

This model could be incorporated into larger, multi-scale models, providing a computational tool for exploring new approaches to genetically modifying tree species to improve lignin traits for use in a variety of industry sectors.

In other words, by changing one gene, researchers can accidentally mess things up with other genes, creating trees that arent what they want. The new model can help researchers figure out how to avoid that.

The paper, Modeling cross-regulatory influences on monolignol transcripts and proteins under single and combinatorial gene knockdowns in Populus trichocarpa, is published in the journal PLOS Computational Biology. The paper was co-authored by Ronald Sederoff, a professor emeritus of forestry and environmental resources at NC State; Jack Wang, an assistant professor of forestry and environmental resources at NC State; and Vincent Chiang, a Jordan Family Distinguished Professor Emeritus and Alumni Outstanding Research Professor with the Forest Biotechnology Group at NC State.

This work was supported by the National Science Foundation Grant DBI-0922391 to Chiang and by a National Physical Science Consortium Graduate Fellowship to Matthews.

Link:
Study: Better Predicting the Unpredictable Byproducts of Genetic Modification - Tdnews

Documentary "Human Nature" examines how gene editing can help - and hurt - humanity.

If youre familiar with the Replicates from Blade Runner, the velociraptors from Jurassic Park or the genetic engineering so chillingly laid out in Aldous Huxleys novel Brave New World, youll be fascinated by how much science fiction has become science fact in Adam Bolts Human Nature. And its all due to CRISPR (pronounced crisper), a gene-altering technology that not only could facilitate designer babies, but possibly play a central role in putting the clamps on another acronym, COVID-19.

That timeliness is obviously on the side of Human Nature, a snazzy-looking documentary using sparkling graphics and top geneticists, journalists and one very adorable sickle-cell anemic to spell out a complicated subject in compelling, easy-to-grasp terms. But that same timeliness also works against it, given how now is not an advantageous moment for the films commercial aspects amid a landscape of shuttered theaters and a frightened populace whod like to avoid anything to do with medicine and science as sources of entertainment.

Yet, that double-edged sword fits snuggly in the wheelhouse of CRISPR (short for clustered regularly interspaced short palindromic repeats), a microorganism able to locate and repair defective DNA, as well as fend off invading viruses like COVID-19 by acting as a defense shield mimicking the offenders own DNA. But like the Internet, a revolutionary breakthrough for which CRISPR is often compared, theres a serious downside involving the morality of whether humans should have the right to, as the film calls it, play God. Namely, should parents be allowed to treat an embryo the same way theyd approach ordering a pizza? Well have the regular with blue eyes, blonde hair and an IQ of Einstein. Oh, and could you throw in some immense athletic ability, too?

Clearly, CRISPR has the potential to put us at the mercy of the type of mad scientists weve become accustomed to in just about every Bond film ever made. One geneticist, whose very name, Jennifer Doudna, includes DNA, admits having had a nightmare in which she comes face-to-face with Adolf Hitler! Are we willing to toy with the very real prospect of creating a master race?

Thats just one of the troubling questions Bolt confronts you with while weighing the pros and cons of a new frontier brimming in possibilities and danger. Personally, I come down on the side of CRISPRs benefits, particularly after meeting David Sanchez, a teen with sickle cell thats spent about half of his young life in hospitals receiving precious blood transfusions. Hes smart, personable and amazingly brave, so much so, you cant help but be all in when CRISPR offers him a chance at a more normal life. Yet, hes just as quick to recall to how hes learned to embrace -- even appreciate -- his illness because its made him a better, more resourceful kid, insights he would not have acquired had CRISPR been available when he was in utero. See? Hes torn, too.

Do we embrace a discovery wielding the promise of curing and preventing cancers and birth defects, or shun it for its ability to rob us of our unique individuality? Its a compelling argument I frankly wish Bolt had expanded more upon in his movies all-too-brief 90 minutes. But whats here is more than enough to spark a multitude of kitchen-table conversations about where we should set the limits on science, and more importantly, who should be making those decisions.

Given the disarray COVID-19 has put the world in, now probably isnt the time for us to evaluate, especially when CRISPR could well determine our fate by ridding our planet of a crippling plague. But what about after? Will, as Trump is fond to say, the cure be worse than the disease? Its a question for which Human Nature holds no answers, only utopian and despotic possibilities well be forced to uneasily choose between when and if the time comes.

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Movie review: Doc Human Nature strikes a nerve in the age of coronavirus - The Patriot Ledger

Alain Mrieux, founder of BioMrieux.

Latest update: April 1, 2020, at 4:47 pm ET.

Businesses around the world are shifting into overdrive to help battle the coronavirus, providing everything from rubber gloves and ventilators to diagnostic tools and, hopefully soon, vaccines. While the pandemic continues to wreak havoc, large corporations and small businesses are developing creative solutions to halt the spread of the virus.

Just as automakers famously shifted to make tanks and planes during World War II, todays global giants LVMH, Ford and GE to name a few are retooling their production lines to help make everything from hand sanitizers to respirators. On the medical front, there are more than three dozen COVID-19 vaccines under development, a smart move considering that two out of every three vaccines for infectious diseases fail, according to a study by the Massachusetts Institute of Technology.

Forbes will continue to update this list of private companies and how they are stepping up to fight the COVID-19 pandemic:

Testing:

Abbott Laboratories: Abbott Park, Illinois healthcare firm obtained emergency FDA authorization for its 5-minute coronavirus testing kit on March 27, with plans to start manufacturing 50,000 kits a day.

Alphabet: Through its healthcare arm Verily, Googles parent company launched a website where users can find nearby testing sites in four California counties.

Jeff Bezos.

Amazon: Jeff Bezos retail behemoth invested $20 million in the Amazon Web Services Diagnostic Initiative, which aims to speed up delivery of COVID-19 tests to the market.

BioMrieux: French biotech company, founded by billionaire Alain Mrieux,received emergency FDA approval for its subsidiarys new testing kit, which cuts testing times for the virus down to 45 minutes.

Carbon: California-based 3D printing unicorn backed by Russian tech investor Yuri Milner will soon be distributing testing swabs and face shields to hospitals in the Bay Area.

Cepheid: Sunnyvale, California molecular diagnostics company gained emergency FDA authorization for its new 45-minute COVID-19 testing kit.

Copan Diagnostics: Family-owned company located at the heart of Italys hard-hit Lombardy region makes diagnostic swabs for testing, airlifting 500,000 swabs to the U.S.

DiaSorin: Italian biotech company owned by billionaire Gustavo Denegri obtained emergency authorization from the FDA for its new 60-minute testing kit for COVID-19.

Mammoth Biosciences: South San Francisco-based biotech startup, founded by three 30 Under 30 alums, prototyped a rapid test by using the gene-editing tool Crispr to detect the disease.

Mesa Biotech: San Diego biotech business obtained FDA approval for its new 30-minute testing kit for COVID-19.

Puritan Medical Products: Maine-based diagnostic maker, one of the worlds largest makers of diagnostic swabs along with Italys Copan Diagnostics, is reportedly increasing production to make one million COVID-19 testing swabs a week.

Treatments:

AbbVie: North Chicago-based, publicly traded pharma firm is collaborating with authorities in the EU, the U.S. and China on experimental use of its HIV drug lopinavir/ritonavir to treat COVID-19.

AIM Immunotech: Florida-based pharmaceutical company announced on March 9 it would begin experimental testing of its chronic fatigue syndrome drug rintatolimod as a treatment for COVID-19 in Japan, at the National Institute of Infectious Diseases and the University of Tokyo.

Algernon Pharmaceuticals: Vancouver-based pharmaceutical firm is requesting FDA approval to begin trials of its chronic cough medication ifenprodil as a treatment for COVID-19.

AlloVir: Houston-based cell and gene therapy company is collaborating with Baylor College of Medicine to discover and develop T-cell therapies to fight COVID-19.

Apeiron Biologics: Vienna-based biotech firm started small-scale trials of its immunotherapy treatment on COVID-19 in China in February.

Ascletis: Hangzhou, China pharmaceutical company announced results of clinical trials of its antiviral drug danoprevir on COVID-19 patients in China; the small-scale study found that danoprevir combined with ritonavir is safe and well tolerated in all patients.

Bioxytran: Boston-based biotech outfit is developing a viral inhibitor to treat COVID-19.

Celltrion: South Korean healthcare firm is developing an antiviral treatment for COVID-19 as well as rapid self-testing kits that would provide results within fifteen to twenty minutes.

Cocrystal Pharma: Bothell, Washington pharma outfit is developing antivirals to treat COVID-19 using patents it recently acquired from the Kansas State University Research Foundation.

CytoDyn: Vancouver, Washington biotech firm announced preliminary results from three days of testing its antiviral drug leronlimab on COVID-19 patients in New York; the company stated in a press release that test results from the first four patients suggests immunological benefit within three days following treatment with leronlimab.

Eli Lilly: Indianapolis pharma company is partnering with Vancouver-based biotech outfit AbCellera to develop antibody-based treatments for COVID-19.

Emergent BioSolutions: Maryland drugmaker is developing treatments derived from the antibodies found in the blood of people who tested positive for the disease.

EUSA Pharma: British pharmaceutical firm initiated trials of its siltuximab antibody treatment on COVID-19 patients at the Papa Giovanni XXIII hospital in Bergamo, Italy; the company released initial data on April 1 showing that one third of patients experienced clinical improvement with reduced need for oxygen support and a further 43% saw their disease stabilise.

Fujifilm Toyama Chemical: Tokyo-based conglomerates flu drug favipiravir has shown promising results in early clinical trials on COVID-19 patients in China, and the company is investing $83 million in its biological manufacturing capabilities.

Gilead: The Californian biotech giant initiated clinical trials in March for its antiviral drug remdesivir on patients in the U.S.

Harbour BioMed: Cambridge, Massachusetts biomedical firm announced a collaboration with New Yorks Mount Sinai Health System to develop new human antibodies to treat COVID-19.

I-Mab Biopharma: Shanghai-based biopharma outfit announced it would begin clinical trials of its TJM2 antibody treatment on COVID-19 patients in the United States, with plans to expand to other countries affected by the pandemic.

ImmunoPrecise: Canadian life sciences company is teaming up with New York-based AI startup EVQLV Inc on researching antibody-based therapies and a vaccine for COVID-19.

Innovation Pharmaceuticals: Wakefield, Massachusetts biopharma firm is researching the use of its drug brilacidin part of a category of investigational new drugs called defensin mimetics, which could have antimicrobial effects as both a treatment and a vaccine for COVID-19, in separate efforts with a major U.S. university and with the Department of Health and Human Services.

ISR Immune System Regulation: Swedish immunotherapy firms subsidiary, ISR HBV, is conducting toxicological studies to determine whether its Immunolid ISR50 treatment could be used against COVID-19.

Kamada: Israeli pharmaceutical company is working on an antibody-based treatment for COVID-19 using the blood plasma of patients who recovered from the disease.

Mateon Therapeutics: Californian biopharma firm is testing a number of antiviral drugs as potential treatments for COVID-19 and is preparing to submit an application to the FDA in order to begin clinical trials on patients.

Merck KGaA: Darmstadt, Germany-based pharma multinational donated a supply of its multiple sclerosis drug interferon beta-1a to the French National Institute of Health and Medical Research in Paris for clinical trials on COVID-19 patients. The companys North American life sciences arm, MilliporeSigma, is supplying several vaccine efforts with reagents and other essential raw products for vaccine development.

Mesoblast: Australian medical firm is working with authorities in the U.S., Australia, China and Europe to evaluate the use of its remestemcel-L drug to treat COVID-19.

Mylan: Pennsylvania-based pharmaceutical firm restarted production of hydroxychloroquine, a drug used to fight lupus, malaria and arthritis, at its West Virginia factory; the drug is being tested as a treatment for COVID-19 in human trials in New York.

Pluristem Therapeutics: Haifa, Israel-based medical company is developing a cell-based therapy to treat COVID-19, announcing on March 30 it had dosed three Israeli patients under a compassionate use program, with plans to enroll more.

Leonard Schleifer.

Regeneron Pharmaceuticals: Westchester, New York biotech outfit, run by billionaires Leonard Schleifer and George Yancopoulos, is conducting clinical trials of its rheumatoid arthritis drug sarilumab, developed with French firm Sanofi, on patients in New York.

Roche: Swiss pharma titan, part-owned by billionaire Maja Oeri, is testing its arthritis drug tocilizumab to treat patients in China and received FDA approval to begin U.S. trials.

Roivant Sciences: Swiss pharma company is working with U.S. authorities to begin trials of its antibody treatment, gimsilumab, on COVID-19 patients.

Takeda: Japanese medical firm is working on hyperimmune therapy using blood plasma from previously infected patients.

Vir Biotechnology: The San Francisco-based firm is collaborating with Biogen and Chinese medical firm WuXi Biologics to manufacture antibodies that could treat the virus.

Vaccines:

AJ Vaccines: Danish vaccine developer is working on a COVID-19 vaccine that could hit the market in 2021.

Altimmune: The company is developing a novel intranasal vaccine for the coronavirus, making it one of three firms based in Gaithersburg, Maryland along with Emergent Biosolutions and Novavax thats working on treatments and vaccines for COVID-19.

Arcturus Therapeutics: San Diego-based vaccine maker is developing a COVID-19 vaccine with researchers at the Duke-National University of Singapore medical school in Singapore.

Biocad: Russian drug developer is researching a COVID-19 vaccine, with animal trials scheduled for late April.

Thomas and Andreas Struengmann.

BioNTech: German biotech firm backed by billionaire twins Thomas and Andreas Struengmann is working to develop a coronavirus vaccine in partnership with Pfizer and Fosun Pharma, chaired by billionaire Guo Guangchang.

CanSino Biologics: Tianjin, China-based pharma company isstarting clinical trials for its COVID-19 vaccine, using the vaccine technology deployed to develop the Ebola vaccine.

Codagenix: Melville, New York biotech firm is teaming up with the Serum Institute of India to develop a live-attenuated COVID-19 vaccine, which uses a live but weakened form of the virus.

Dietmar Hopp.

CureVac: German firm, funded by billionaire Dietmar Hopp and the Bill and Melinda Gates Foundation, received $87 million from the European Commission to scale up development of its coronavirus vaccine.

Dyadic: Jupiter, Florida company is collaborating with the Israel Institute for Biological Research on both treatment and a vaccine against COVID-19, using the firms gene expression platform.

Dynavax: Emeryville, California vaccine maker is working with the Coalition for Epidemic Preparedness Innovations (CEPI) and the University of Queensland to develop a COVID-19 vaccine.

EpiVax: Providence-based immunology firm is working with the University of Georgia and Miramar, Florida biotech outfit Generex on separate COVID-19 vaccine efforts.

ExpreS2ion: Danish biotech company received a grant of nearly $1 million from the European Union to develop a vaccine for COVID-19.

GeoVax: Atlanta-based medical company is collaborating with Wuhan-based BioVax to jointly produce a COVID-19 vaccine.

GlaxoSmithKline: British pharma titan is partnering with CEPI and Chengdu, China-based Clover Pharmaceuticals to use its pandemic vaccine adjuvant platform which boosts the immune response in patients receiving a shot to speed up development of COVID-19 vaccines.

Greffex: Houston-based genetic engineering firm is preparing to begin animal trials for its COVID-19 vaccine.

Heat Biologics: North Carolina biopharma company is developing a COVID-19 vaccine with the University of Miami.

iBio: Newark, Delaware biotech upstart is collaborating with Beijing-based CC-Pharming on the rapid development of a COVID-19 vaccine.

Inovio: Plymouth Meeting, Pennsylvania biotech business received $11.9 million in funding from the Department of Defense to rapidly produce a DNA vaccine for COVID-19 with drugmaker Ology Bioservices.

Johnson & Johnson: The companys pharma unit, Janssen, will start manufacturing its vaccine developed with the Department of Health and Human Services this month, with human trials set to begin by September and a public rollout hoped for early 2021. The company and the federal government are investing more than $1 billion in the vaccine effort.

Medicago: Quebec City-based biotech company received more than $7 million from the Canadian and Quebec governments to fund development of its COVID-19 vaccine.

Moderna: Massachusetts biotech company was the first tobegin human trials of its vaccine on March 16 in Seattle and could deploy it to health workers for emergency use by the fall.

Novavax: Maryland-based vaccine maker received $4 million in funding from CEPI to accelerate development of its vaccine candidates, with clinical trials expected in the late spring.

Sanofi: French medical firm is working with the federal government and Massachusetts-based Translate Bio to expedite its coronavirus vaccine, using technology previously used to develop one for SARS.

Sorrento Therapeutics: San Diego-based biotech firm is teaming up with Cambridge, MA gene therapy company SmartPharm Therapeutics to develop a gene-encoded COVID-19 vaccine; its also working with Chinese drugmaker Mabpharm on a fusion protein treatment for the disease.

Takis Biotech: Italian startup with just 25 employees is developing a vaccine with Stony Brook-based Applied DNA Sciences, with plans to begin human trials before the end of the year.

Themis Bioscience: Austrian biotech firm is part of a group, with the Institut Pasteur and the University of Pittsburgh, which received $4.9 million in initial funding from CEPI to build a COVID-19 vaccine modeled on the vaccine for measles.

Tonix Pharmaceuticals: New York-based pharma outfit is researching a potential COVID-19 vaccine based on the virus that causes horsepox.

Vaxart: San Francisco vaccine manufacturer Vaxart is working with Emergent Biosolutions to develop and manufacture an oral vaccine that can be taken as a tablet.

Vaxil: Israeli biotech startup began preclinical trials for its COVID-19 vaccine candidate.

Zydus Cadila: Indian pharma company announced it would fast-track development of a COVID-19 vaccine in February.

Protective Equipment And Sanitizer:

Anheuser-Busch InBev: The worlds largest beer company is making more than one million bottles of hand sanitizer from surplus alcohol at its breweries around the world.

Giorgio Armani.

Armani: Billionaire Giorgio Armanis luxury fashion brand converted all production at its Italian factories to manufacture single-use medical overalls on March 26.

Bacardi: The Bermuda-based spirits giant converted production at nine production facilities in Mexico, France, England, Italy, Scotland, Puerto Rico and the continental U.S. to make hand sanitizer.

BrewDog: Independent beermaker is making hand sanitizer at its distillery in Scotland.

Bulgari: The Italian luxury jeweler is manufacturing hand sanitizer with its fragrances partner, ICR, with plans to make hundreds of thousands of bottles by May.

Sandro Veronesi.

Calzedonia Group: Italian retail clothing group, owned by billionaire Sandro Veronesi, converted production at several plants in Italy and Croatia to manufacture masks and medical gowns, with initial production of 10,000 masks a day.

Cantabria Labs: Spanish health products and cosmetics firm converted production at one of its factories to make hand sanitizer.

Consomed: Tunisian mask and medical equipment maker put all of its workers, more than 70% of which are reportedly women, on quarantine inside the companys Kairouan factory to maximize production of protective gear.

Decathlon: Sporting goods empire founded by French billionaire Michel Leclercq partnered with Isinnova, a small engineering and design firm based in Italy, to convert snorkeling masks into respirators.

Diageo: The maker of Johnnie Walker whisky and Smirnoff vodka donated two million liters of ethyl alcohol, a byproduct of the distillation process, to hand sanitizer manufacturers.

Fanatics: Billionaire Michael Rubins online sportswear retailer converted its baseball jersey factory in Pennsylvania to make masks and gowns for medical workers.

Fiat Chrysler Automobiles: The multinational automaker announced on March 23 it would begin installing capacity to produce masks, which will be initially distributed in the U.S., Canada and Mexico.

Fippi: Italian diapers producer worked with the Lombardy region and the Polytechnic University of Milan to convert its factory to make up to 900,000 masks a day, which will go to frontline health workers facing a devastating outbreak in the region.

Go here to read the rest:
Coronavirus Business Tracker: How The Private Sector Is Fighting The COVID-19 Pandemic - Forbes

The quarter was brutal to say the least for most asset classes amid the coronavirus (COVID-19) pandemic. The S&P 500 Index was down about 20% for the quarter.

Amid the market mayhem, some health care stocks defied the downturn, thanks to announcements concerning development of drug/vaccine/diagnostic tests for new coronavirus.

Focusing on biotechs (leaving out diagnostics stocks), here the top five winners and losers for the quarter.

Benzinga is covering every angle of how the coronavirus affects the financial world.For daily updates,sign up for our coronavirus newsletter.

Genprex Inc (NASDAQ: GNPX): (+656.25%)

After ending 2019 in penny stock territory, shares of this gene therapy company began to gain ground after the company announced Fast Track Designation for its immunogene therapy in combination with AstraZeneca's(NYSE: AZN) Tagrisso for treating lung cancer. The momentum accelerated after it signed an exclusive agreement to license a diabetes gene therapy from the University of Pittsburgh.

After topping $7 in late February, the stock came off the highs amid the COVID-19 sell-off and managed to end the quarter with huge gains.

Vaxart Inc (NASDAQ: VXRT): (+405.71%)

Vaxart is a COVID-19 play and much of the quarter's gains were achieved on the back of the experimental oral vaccine candidate it's developing in partnership with Emergent Biosolutions Inc (NYSE: EBS).

Ibio Inc (NYSE: IBIO): (+324%)

Ibio, which develops human therapeutic proteins using advanced genetic engineering, joined the fray for a COVID-19 vaccine, which explains the surge in the stock.

Novavax, Inc. (NASDAQ: NVAX) (+241.2%)

Novavax was the beneficiary of dual catalysts: a COVID-19 vaccine in development and positive late-stage readout for its flu vaccine.

Trillium Therapeutics Inc (NASDAQ: TRIL): (+192.23%)

Thisimmuno-oncology company did not have much developments to justify its gain for the quarter.

Following a jump of about 63% in a single session in late February, the company issued a statement thatsaid "it is not aware of any material, undisclosed information related to the company that would account for the recent increase in the market price and level of trading volume of its common shares."

Related Link: Attention Biotech Investors: Mark Your Calendar For These April PDUFA Dates

Milestone Pharmaceuticals Inc (NASDAQ: MIST): (-88.51%)

This cardiovascular-diseases-focused biopharma was cruising along fine until COVID-19 sell-off started in March. The real punch came from an adverse clinical readout.

Novan Inc (NASDAQ: NOVN): (-84.97%)

Novan, which leverages on nitric oxide's naturally occurring anti-microbial and immunomodulatory mechanisms of action to treat various diseases, fell steeply at the start of the year. The trigger was a late-stage readout of its SB206 in molluscum contagiosum, which showed that the pipeline asset did not achieve statistically significant results for the primary endpoint.

The stock did not recover from this onslaught.

Acasti Pharma Inc (NASDAQ: ACST): (-84.49%)

Acasti also succumbed to a negative clinical readout for its lead prescription drug candidate CaPre, which did not achieve statistical significance for the primary endpoint of a late-stage study that evaluated it for treating elevated levels of triglycerides.

The company is now seeking FDA guidance for unblinding data from another Phase 3 study, and therefore expects a delay in reporting of topline results until the third quarter.

Salarius Pharmaceuticals Inc (NASDAQ: SLRX): (-81.98%)

This oncology-focused biotech gradually declined through the quarter, with some steep sell-off materializing amid its presentation at the BIO CEO & Investor conference in mid-February.

Amarin Corporation plc (NASDAQ: AMRN): (-81.34%)

Amarin shares, which ran up ahead and after the late-December FDA verdict on its application seeking label expansion for its fish oil pill, pulled back in January. The weakness intensified through the market meltdown. A negative court ruling sent the stock reeling this week.

2020 Benzinga.com. Benzinga does not provide investment advice. All rights reserved.

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10 Biotech Winners And Losers In Q1 - Benzinga

How prepared do you think we were for this moment of social distancing and for this global moment of hunkering down amidst uncertainty?In terms of social distancing, weve been social distancing; weve been virtualizing our lives since at least the advent of the telegraph in the 19th century. We have this idea of distance even now, where were communicating from away and communicating to others. But we also, as humans, have this deep need for physical connectivity. We are not virtual beings. And so, emotionally, were not ready for it. All of these structures for physical connectivity are gone, at least temporarily. Were almost in this Battlestar Galactica remake moment where were having to reconceptualize space and community. Its not that we will become un-physical beings, but were gonna have to figure out different ways of virtually sharing emotion and connectivity, at least until this danger passes.

Thats why organizations like PEN that are so focused on values are so critical, because these are the conversations that we have to have. Were going to have this incredible technology, but its up for grabs whether these technologies will be used to help or harm us.

You wrote at CNN.com about the human need for intimate physical connectivity. Can technology be a substitute for that? It seems like probably not.It cant be a substitute, but it can be a complement. And again, in our best possible world, I, for one, would love to live in some kind of hippie commune with real people there, and I also live, like many people, this global life where my friends and contacts are distributed around the world. I think we need to find that balance. But at times like this, our lives are becoming and feeling more virtual. And yes, theres a loss, and I think many of us are mourning that loss. But this is the world that we have now, and we have to make the most of it. Theres a lot of simple things that people can do. Make a list of all the people who you love and care about in your life, all the people who you think may be feeling isolated or alone, and just create a schedule of reaching out to them. My girlfriend and I are doing a virtual tea party with friends on Sunday where were gonna make tea, theyre gonna make tea, were gonna connect on FaceTime. We have to think of how we might do things differently. But its also not the case that when this crisis ends, society is just going to snap back to where it was, and were going to say, Wow, that was a crazy experience. Theres something happening now that is going to last beyond this.

What are some things that could be irrevocably different about our culture and the way we work and live, as a result of this moment?Were for sure not going fully back on virtualization. Were going to do things differently. Our sense of space is going to be different. A lot of people who are now working from home arent going to go back to physical offices because once companies figure out how they can work in this way, itll just be cheaper to have people stay at home. Were certainly going to change the way we think about global public health. If you asked a regular person, Wouldnt it make sense to have a super empowered World Health Organization with a global surveillance system that whenever any trip wire was hit, youd have an emergency response team that would fly to wherever that was and they would set up a command center and do what needed to be done? They would say, Yeah, dont we have that? And the answer is we dont. Because we have starved organizations like the WHO, because we have states that are demanding a level of control that doesnt make sense in our world of global challenges. One of the things that Im working on very, very actively now is imagining a third leg of the global political stool in addition to states and international institutions, and that is the democratic expression of the needs of our common humanity. It seems like its this big, crazy idea. But in these negotiations, no one is saying, Hey, climate change affects all of us; destroying our oceans affects all of us; global pandemics affect all of us. Who is standing up to help humanity? And thats what I think we need now.

I feel like Im at war from the battlestation of my office here on 81st Street in New York, so Im pretty focused on reading what I need to read now.

In Hacking Darwin, you wrote about genetics, you wrote about changing our genetic identity, perhaps to yield cures for diseases. Are you more or less optimistic about the potential for genetic science and cures than you were before?Im extremely optimistic. We are facing an enormous challenge today, but we now have almost godlike capacities to read, write, and hack the code of life. And those tools, Im firmly convinced, are going to save us, and were going to figure out treatments and were gonna have a vaccine not just for this, but for all kinds of challenges in the future. But these technologies dont come with a built-in value system. All technologies are value-neutral. Its up to us to determine what are the values that will guide the application of our most powerful technologies, and thats the issue. Thats why organizations like PEN that are so focused on values are so critical, because these are the conversations that we have to have. Were going to have this incredible technology, but its up for grabs whether these technologies will be used to help or harm us.

Finally, what are you reading, watching, or listening to right now?I would advise people at times of crisis like this to read poetry and literature. Im trying to do a little bit of that, but Im just all in and obsessed. Just last night I finished this incredible book, Spillover, by the amazing journalist David Quammen. And thats about zoonotic viruses like this, and our experiences in the past. Im now reading Betrayal of Trust by Laurie Garrett, which is about the destruction of our public health infrastructure. So when this is done, Im just going to beand I myself am a novelistback to reading the novels that I love so much. Maybe Ill read Proust and start thinking about Maman and her madeleine. But for now, I feel like Im at war from the battlestation of my office here on 81st Street in New York, so Im pretty focused on reading what I need to read now.

Wed like to know what books youre reading and how youre staying connected in the literary community. Click here to leave a voicemail for us. Your message could end up on a future episode of this podcast!

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The PEN Pod: Reimagining the Future with Jamie Metzl - PEN America

In the field of prevention, the work of Mexican molecular medicine researcher Laura Palomares stands out. And today, her team is developing a vaccine against SARS-CoV-2, based on the work they have been doing in recent years against dengue and zika.

I am convinced that the only way that we are going to be able to respond to this type of pandemic in a timely manner is going to be using platforms. I am referring to a vaccine, for which we already have the entire production, development, stability train, etc. , said the chemical engineer from the Instituto Tecnolgico y de Estudios Superiores de Monterrey (ITESM), that holds a masters in Biotechnology, and a doctorate in science from UNAM.

Many times we think that the laboratory is going to discover a vaccine to cure the patient, and it is not like that. This type of vaccine requires a lot of time and a lot of effort in developing the processes for production and characterization, before reaching the final patient, Laura Palomares added.

With this idea in mind, the also researcher at the Institute of Biotechnology (IBt) of UNAM has promoted the development of one of these technological and methodological platforms focused on the aforementioned Zika and Dengue viruses, conditions particularly significant for Mexico due to their high numbers of contagion, every year in different parts of the country.

The result has been a vaccine created with recombinant DNA technology, which Palomares calls a chimera.

Lets put it in simple words, for people to understand: If we take away from the platform the zika and dengue viruses, and we put the coronavirus there, that way we can get a vaccine against SARS-Cov-2, says the member of the University Commission for Attention of the Coronavirus Emergency.

What took us two years in genetic engineering, adding on and taking off proteins, understanding how these capsids were going to be assembled, characterizing them, etc., all that we had already done. So now, we are replacing that with SARS-CoV-2, and that is precisely why we have advanced so much right now , Palomares continued.

The approach to the development of vaccines through platforms has also been the route taken by two vaccines against Covid-19 in the world that are currently under clinical evaluation: that of the North American company Moderna and that of the Chinese company CanSino Biologics, stated the expert.

The coronavirus vaccine is in the testing phase in animal models, a process in which the Zika and dengue vaccine has already been evaluated. If everything progresses positively, Palomares estimates that the first human tests could be carried out in three years.

In the case of the SARS-CoV-2 vaccine that she and her team are currently developing, they plan to collaborate wth the Mexican company Liomont, which has a manufacturing plant that would allow the production of this vaccine, this way Mexico does not have to depend on transnational companies.

So this pandemic is obviously terrible for us, because it is affecting the health of a large part of the population, but also a great opportunity to raise awareness, the researcher concluded.

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Mexico is already testing its own Covid-19 vaccine - The Yucatan Times

Pharma and biopharma companies dont want to work on their relationships. These companies want their relationships to work for them. Fair enough. Still, when it comes to relationships with contract manufacturing and drug development organizations (CDMOs), pharma and biopharma companies cant avoid intimacy. These relationships are rewarding to the extent pharma and biopharma companies are clear about their needs and the kinds of associations consistent with those needs.

Typically, the most pressing need is keeping costs down. But other needs are important, too. These include expertise with specialized technologies, challenging drugs, and complex formulations. Identifying needs will help pharma and biopharma companies decide whether their CDMOs should help with discrete activities or provide complete, end-to-end services. Pharma and biopharma companies may also want their CDMOs to help with business strategy and regulatory compliance.

Besides identifying potentially compatible CDMO partners, pharma and biopharma companies need to build CDMO relationships characterized by mutual trust. Here again, clear communication is essential. It can help both parties in a CDMO relationship resolve misunderstandings and overcome unanticipated challenges together. For a fuller discussion of the ways CDMO relationships can benefit from clear communication, see the rest of this article, which presents various pointers and perspectives from CDMO experts.

Thierry Cournez is head of end-to-end solutions at MilliporeSigma, which offers a comprehensive portfolio of high-quality products and services, including testing services, for biopharmaceutical development. According to Cournez, most emerging biotech companies that have very early data and need to take their molecule to commercialization dont have all the expertise in-house that they need to navigate the entire process. One major trend is complete services, as opposed to la carte offerings.

MilliporeSigmas Plug & Play Upstream Development Service eliminates the need to work with multiple vendors for upstream development, relieving bottlenecks and reducing time to clinic. The service covers cell line development from DNA transfection to cell banking. Process development activities, which run in parallel, start when the company receives material from the first clones.

Cournez says that two services that will continue to be important in pharmaceutical development are process development and analytical services. A robust process is critical for manufacturing success, he explains, and analytical services are the foundation that supports the entire life cycle of biologics.

A trend toward all-in-one CDMO services has also been observed by Richard Shook, director of drug product technical services and business integration at Cambrex. Any time a client has to go to multiple vendors, it creates a lot of seams and communication problems, he points out. A lot of dots are not connected. Critical items can be lost, especially internal knowledge. When a client works with a single vendor, he stresses, the partners create a knowledge base that can be carried forward with the project. Cambrex provides drug substance, drug product, and analytical services across the entire drug lifecycle.

Fujifilm Diosynth Biotechnologies (FDB) is a division of Fujifilm that focuses on biopharmaceutical contract manufacturing, especially drug substances for biologics. That includes cell culture and fermentation, development and manufacturing, and advanced therapies like gene therapy. Fujifilms director of strategic business development, Daniel DeVido, PhD, says there is growing interest in gene therapy products and gene modified cell therapies.

In the area of viral vectors, new products on the market such as Luxturna (from Spark Therapeutics) and Zolgensma (from Novartis) have moved that sector of the industry forward. Newly approved chimeric antigen receptor (CAR) T-cell therapies, such as Kymriah (from Novartis) and Yescarta (from Kite Pharma) are also injecting energy into the field. And monoclonal antibodies have been going strong for the last 10 to 15 years, with approximately 80 therapies approved and on the market.

The industry is well funded right now, DeVido points out. A lot of companies are pushing candidates forward.

That increased demand for cell culture services brings new technical challenges. Everybodys looking for increased titers, DeVido emphasizes. For gene therapy, yields and titers are much less than they are for cell culture, so everybodys looking for the next thing that will get gene therapy to produce on the scale that monoclonal antibodies are on now.

Lonza offers a range of CDMO services. Karen Fallen, the companys head of mammalian and microbial development and manufacturing, says that Lonza works with companies from several different segments, including small and virtual companies that have limited in-house resources and capabilities. A lot of them are really focusing on the science, she notes. Theyre looking for preclinical and clinical services.

In Lonzas view, some of the trends among the smaller companies are due to larger Series A financings. In past years, Series A deals would have been $10 or $15 million, but now they are running higher, up to $70 or $80 million. They have different ambitions now, Fallen points out. They want and are able to take the molecule further along the supply chain, even to launch. They want to stay with Lonza longer before they partner up with large pharma and/or out-license these molecules. She adds that Lonzas customers also have more complex molecules in their pipelines.

Lonzas other big segment consists of large pharma companies. They have assets, and they have experience, she says. What theyre looking for now is newer technologies, with newer modalitiesbioconjugation, highly potent small molecules, or cell and gene therapies, for example.

Almac Group provides an extensive range of contract development and manufacturing services across the drug development life cycle. The increased interest in pediatric formulations is driving a demand for mini-tablets, especially those in stick-pack dosage form. The rapidly expanding oncology space, by its nature, creates a need for CDMOs that have extensive capabilities in processing highly potent active pharmaceutical ingredients at the small-to-medium scale.

Were seeing an industry trend toward higher value, lower volume products, says Jonas Mortensen, vice president of business development at Almac. Our clients are asking us to take on commercial supply of their product, often at, or close to, the same scale we had previously provided for their clinical studies.

To meet these new needs, Almac has installed multiple stick-pack machines across its sites in the United Kingdom and the United States. Almac is also finalizing the qualification of a dedicated suite of eight processing rooms and equipment solely designed for, and dedicated to, processing of highly potent active pharmaceutical ingredients.

Mortensen anticipates that some near-term trends in CDMO services will include supply chain risk mitigation, end-to-end services, and GMP floor space. CDMOs, he points out, are increasingly being asked to demonstrate their ability to support multisite supply strategies through global facilities or act as a secondary site of manufacture.

Communication is a common theme when it comes to recommendations for working with a CDMO. MilliporeSigmas Cournez says that biotech companies should choose a CDMO that has the most experienced people in-house. Doing so can help biotech companies avoid having to deal with multiple vendors. He also recommends having a dedicated project manager who can provide transparent communication with the vendor and connect with subject matter experts in case of unexpected changes.

Good communication also contributes to transparency in a project. Project transparency is really important, insists Cambrex Shook. That can be limited due to the competitive landscape of the project.

If problems arise during project execution, ownership and communication is really important. If its not there, losses occur and there are timeline setbacks. This could impact the scope, and once you get off scope, [it takes] money and resources to get back on track.

An illustration of the importance of communication comes from Catalent, a company that offers a range of CDMO services, including its recently introduced GPEx Boost technology for cell line development. Michael Riley, vice president and general manager of biologics at Catalent, says that in a program the company is currently working on, a customer was on a highly accelerated path to a product filing for a fast-track product. Catalent was working with regulatory authorities to characterize the companys manufacturing process and move toward validation of that process. To do that, Riley explains, we had to have very robust conversations between multiple functions within our organization and their organization from a quality and development standpoint.

Trust can be a delicate issue in relations between a CDMO and a customer. To illustrate this point FDBs DeVido describes a face-to-face discussion that the company had with one of its customers. This discussion, which took place in FDBs office in Cambridge, MA, resolved some contractual disagreements. We were able to sit around the table and go through the legal issues, DeVido recalls. We cleared up a lot very quickly.

When you sit down face to face and have good discussions, he says, everyones a little more comfortable. Even though people may feel theyre not completely safeguarded from a one-in-a-million occurrence, they may feel comfortable the two parties are going to work together through whatever the issue is.

DeVido said that once youve selected a CDMO, its important to be transparent and trust the company. Youve done your due diligence, he proposes. Now trust your selection and the system theyre operating in.

Benefits of working with an experienced vendor can go beyond development and manufacturing. Cournez says that in one instance, an emerging biotech customer had the opportunity to engage in licensing discussions with a large pharmaceutical company. Because the emerging biotech was small, we hosted the large pharma company at one of our sites and ran the due diligence, which was a great success, he relates. This former emerging biotech now funds many different programs because of the success of their first molecule.

Some vendors warn that business strategies can backfire. Focusing too much on price and speed to market can be risky when researching or working with CDMO/CMO partners, according to Cournez. The service provider must simplify the process and reduce touchpoints throughout the process.

Mortensen says that due to the significant investment required in resource and training, many smaller biopharma companies often do not have a regulatory affairs department of their own. Therefore, its critical for sponsors to recognize the consultative benefit CDMOs bring to the table as an extension of their company to help fill in any regulatory knowledge gaps. This timely advice, integrated with early- and late-stage development, can enable a sponsor to adequately prepare, ensuring little or no delay when bringing its products to market.

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Making the Most of a CDMO Relationship - Genetic Engineering & Biotechnology News

Science writer, New Yorker contributor and author of the book Denialism Michael Specter joins Felix Salmon on the Slate Money podcast to break down the ongoing coronavirus crisis.

Specter explains how the virus spreads, potential food and medicine shortages it could cause and the possibility of developing immunity to infection. While the pandemic has shocked most of the world, Specter argues the only thing that should surprise anyone is the inept response of policy makers to the outbreak, particularly in the United States.

Specter also challenges some common misconceptions surrounding biotechnology, including the idea that GMOs are unnatural. Concerns about monoculture, the practice of growing a single crop like corn, on the other hand, are valid, Specter says. But that issue has nothing to do with genetic engineering. Its a problem that could be solved by a change in government policies: ending subsidies to corn and soybean growers. However, there are trade offs involved, and eliminating monoculture farms isnt the simple decision it seems.

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Podcast: Science writer Michael Specter on what you should know about the coronavirus, food security and GMOs - Genetic Literacy Project

Genetic engineering will allow the production of tomatoes and kiwis that are more tolerant to saline lands and will require less water. The initiative will also develop biostimulants directly applicable to plants to make them more tolerant to stress caused by drought and salinity .

Agriculture has been one of the activities hardest hit by climate change. Figures in this regard indicate that around 40% of the worlds land area corresponds to land affected by drought, a value that could increase to 50% between now and 2025.

One of the initial focuses of the project is to generate new varieties of tomatoes and kiwis using the CRISPR / Cas9 genetic engineering technique. In the case of tomato, the characteristics of Poncho Negro, a Chilean variety originating in the Azapa Valley that has high resistance to salinity and the effect of heavy metals, will be studied.

Components to improve tomato 7742 (seminis), the most widely produced and marketed variety in Chile, will also be investigated. Regarding kiwis, the aim will be to increase tolerance to salinity and drought of varieties used as rootstocks, to improve the productivity of Hayward commercial kiwi plants; the third most exported in Chile.

[Editors note: This article was published in Spanish and has been translated and edited for clarity.]

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Bengaluru/New Delhi: As the coronavirus outbreak continues to spread across the world, the cyberspace has been abuzz with claims that the Covid-19 strain in India is a less virulent mutation than the one travelling abroad. BJP leader and Rajya Sabha MP Subramanian Swamy and gastroenterologist D. Nageshwar Reddy are among those who have made such claims.

While Swamy quoted an American friend in a tweet last week to say the Covid-19 strain in India can be defeated more effectively by our bodys natural defense mechanism than the strains abroad, Reddy in an interview floated similar claims without quoting any research.

Some users responded to Swamys tweet posting a link to a study that they claimed supported his notion. But this study, which is yet to be peer reviewed, has faults of its own, including use of limited data.

A number of experts in the field have termed such assertions baseless. Dr Gagandeep Kang, executive director at the Translational Health Science & Technology Institute in Faridabad, called Reddys comments appalling & misleading.

As such claims circulate online, ThePrint highlights the science of virus mutation and whether you should be worried.

Also read:WHO says coronavirus outbreak in Europe could be approaching peak

The overarching problem is the use of the term Indian SARS-CoV-2 strain that is in itself misleading.

A strain is a sub-type of a virus, characterised by different cell surface proteins, eliciting a different immune response from other strains. A mutation, however, is very minor genetic errors in genome sequences made during replication that doesnt fundamentally change the nature or behaviour of the virus.

So far, only two isolates from India have been genetically sequenced. Both are from coronavirus patients in Kerala who had arrived from Chinas Wuhan in late January. The strains are nearly identical to the ones sequenced in Wuhan and cannot be identified as a separate Indian strain.

Anu Raghunathan, a scientist at the Council of Scientific and Industrial Researchs (CSIR) National Chemical Laboratory in Pune, told ThePrint that the researchers of the aforementioned study used computational biology to analyse the genomic data from different strains around the world.

Theinitial attempt of the team from the International Centre for Genetic Engineering and Biology, New Delhi, at analysing the virus strain is not sufficient to conclude that all Indian strains would have only one unique mutation, said Raghunathan.

The mutations themselves are composed of changes in base pairs.

The novel coronaviruss genome is made up of 30,000 base pairs, while a human genome contains over 3 million. The small numbers make it easy for scientists to track changes and new lineages as they evolve.

To understand what these mutations mean for India, the country will have to sequence a much larger set of the viral isolates from the patients here.

Rakesh K. Mishra, director of CSIRs Centre for Cellular and Molecular Biology in Hyderabad, told ThePrint that his institute has the capacity to run the genome sequencing of the isolates from at least 500 people within a couple of weeks. This can help scientists decide the correct course of action for treating the disease.

For example, if a virus mutates too fast, vaccines being developed now will potentially become useless, and pharmaceuticals will have to constantly keep up with the mutations by developing new vaccines all the time, a financially unviable prospect.

Also read:China now wants people to shop, eat out while rest of the world locks down

Regularly switching up the genetic code is an essential part of how a virus evolves. Some viruses, such as the coronaviruses that cause flu, change their genetic code extremely rapidly. This is the main reason why its so difficult to find a vaccine for coronaviruses. They evolve quickly, making vaccines defunct.

The flu vaccine, now available and recommended especially for older people, needs to be taken annually for this reason. By the time the next season comes along, the vaccine is no longer effective on the circulating form of the virus.

Coronaviruses are ribonucleic acid (RNA) viruses, containing just RNA strands (single or double) as its genetic material. They have about 26,000 to 32,000 bases or RNA letters in their length.

RNA viruses mutate continuously. Such a mutation is what made SARS-CoV-2s jump from animals to humans possible.

The virus multiplies inside living organisms cells by creating copies for the RNA. However, the process it uses to make these copies is not perfect, and often introduces tiny errors in the sequence of letters much like a game of Chinese whispers.

The errors that do not help the survival of the virus eventually get eliminated, while other mutations get embedded. It is these mistakes that help scientists track how the virus travelled around different geographic locations.

For example, by genetically sequencing over 2,000 isolates of samples from different countries, scientists tracked how the novel coronavirusspread to different countries, and how the virus evolved and geographically mutated in different areas.

The word mutations often conjures images of humans with superpowers thanks to Hollywood movies but it doesnt mean the virus acquires superpowers. The genetic changes are normal in the evolution of the virus. In some cases, the changes are extremely rapid because the replication is not rigorous or thorough.

The only problem with mutations is the problem of development of vaccines, which would require constant upgrade.

Also read:Why asymptomatic coronavirus carriers arent as contagious but still a big danger

The novel coronavirus, unlike its cousins, mutates slowly. It seems to have a proofreading mechanism in place that reduces the error rate and slows down the speed of mutation. But the mutations are completely random.

One mutation that supports the virus replication and transmission from human to human or any other host sustains whereas the virus that cannot infect many eventually dies out, explained Shweta Chelluboina, clinical virologist at the Interactive Research School for Health Affairs in Pune.

These are random events and such a phenomenon has caused the outbreak in the first place.The newcoronavirushad mutated successfully enoughthat it jumped from animal tohuman, allowingit to infect manywith still no containment in sight, said Chelluboina.

There were reports earlier about how the novel coronavirus has mutated into two strains so far the original S-type which originated in Wuhan, and the subsequent L-type that evolved from the S-type and is more prevalent in countries like the US. Scientists at the Peking Universitys School of Life Sciences and the Institut Pasteur of Shanghai announced these findings.

The L-type is the more aggressive one, and spreads rapidly but is no more or less virulent than the S-type. The researchers urged everyone to take preventive measures because the mutation indicates that more could be coming.

But these arent really two strains as such. A strain is a genetic variant characterised by different forms of surface proteins. But the L-type and the S-type are not quite different enough to call them strains just yet. They are just mutations, referred to as types, according to the study.

To explain the lower population of S-type, the authors of the study suggested that human-adopted measures of curbing contact contained the S-type to the Wuhan region, and allowed the L-type to spread elsewhere uncontained. While the S-type emerged around the time the virus jumped from animals to humans, the L-type emerged soon after that within humans, the team suggested.

Experts think there is also a definite sampling bias for the L-type, which was just sampled more, and uniformly, resulting in higher representation. The mutations were discovered in a preliminary study, as cautioned by the authors as well, and was performed on a limited population of 103 samples.

The study is not peer-reviewed yet, and as most Covid-related studies are under the open community, is a pre-print for now. It was uploaded on 4 March.

These findings strongly support an urgent need for further immediate, comprehensive studies that combine genomic data, epidemiological data, and chart records of the clinical symptoms of patients with coronavirus disease 2019 (Covid-19), said the study.

The science is evolving rapidly, as more and more genome data is collected from around the world.

Newer research data gathered from genetic sequences uploaded to open source website NextStrain.org indicate that anywhere from eight to 18 different sequences of the coronavirus are making their way around the globe, according to researchers who have genetically sequenced over 1,400 isolates from around the world. These are extremely tiny differences within the viruses in their nucleotide sequences, and none of the sequenced groups seem to be growing any more or less lethal than others.

Most importantly, none of them are new strains despite their coverage as such in the mediaand subsequent clarifications by Nextstrain, who have the data for 2,243 SARS-CoV-2 genomes, of which 1,150 have minor mutations.

On Nextstrain, nearly every virus reveals a slightly different genome. But there are very few mutations and none are strong or vital enough to affect the way the virus spreads, attacks, or lives. The sequences are all named by location where they were first sequenced.

It is very common that during an outbreak, especially during a global pandemic, the genome sequence of earlier isolates from one particular geographical location will differ from that of the later isolates collected elsewhere, said Sreejith Rajasekharan, virologist and post doc at the International Center for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy, over an email.

This is what is observed in the current pandemic as well. The first sequence collected from positive patients in Rome, Italy was from a Chinese tourist. This and the one collected after, from an Italian citizen returning from China resemble those that were isolated in China, said Rajasekharan.

However, the ones isolated later in Lombardia and Friuli Venezia Giulia regions (in Italy) match the European clad and not the one from China.

The mutations in the virus are like moving targets, which cant be hit because they keep changing their genetic sequence.

Genome sequencing on a large scale can tell us whether viral isolates are different in different countries from what we saw from China. So this will help us decide whether the treatments being contemplated in those places will be applicable for our strains or not, Rakesh Mishra said.

It will also help decide if the different strains vary so much that developing vaccines may not be viable, Mishra said.

Some behaviours are unique in different strains like how we know that aged people are at high risk but we saw in India young people have also died, said Chelluboina. Some variations in the virus cause the virus to behave in a certain way.

The sequencing will provide a fundamental understanding of how to address the problem without it, the treatments are based on what is known of other viruses which may or may not work for the novel coronavirus, and also likely take up a long time.

That is why it is important to understand the sequence of the virus in local infections to know which countries have a similar virus, so that we can attempt to better predict the outcome, added Chelluboina.

However, Rajasekharan added, The general public needs not be concerned in this regard as the genome of SARS-CoV-2 is quite stable, and therefore the rate of mutation is low.

The novel coronavirus will continue to mutate and pose a challenge to researchers developing a vaccine. Nonetheless, the idea of viruses mutating is not something that needs to worry people in terms of their health when it comes to Covid-19.

Also read:Seasonal flu far more common than coronavirus, but its vaccine is not popular in India

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How the novel coronavirus is mutating, and if you should be concerned - ThePrint

A virus spreads by replicating itself each time it replicates, it could change a little. Mapping the genome of each changed form of the virus, therefore, helps track where it came from and how. The Translational Bioinformatics Group at the International Centre for Genetic Engineering & Biotechnology in New Delhi studied the genomes of the virus from five locations Wuhan, India , Nepal, Italy and the US to identify what is unique to the novel coronavirus and what difference geographical location makes. A country-specific mutation would explain the severity of illness, the extent and timing of exposure to symptomatic carriers and, consequently, hold the clue to a containment strategy. For instance, the study found the presence of unique mutations identified in the genome from Italy are responsible for the sudden upsurge in the number of affected cases and deaths, combined with other factors a speculation which may be verified with more evidence. Any strategy to counter the virus, then, would have to factor this in.Mutations help viruses survive in hosts and influence its virulence (how it attaches, infects and multiplies in a host). The mutations could be favourable or detrimental to the viruses, depending on the type of mutation. If a mutation results in a more virulent virus, its transmission is enhanced, Dr Dinesh Gupta, group leader of the study which published its preliminary findings in a preprint paper, told TOI.

Mutations help viruses survive in hosts and influence its virulence (how it attaches, infects and multiplies in a host). The mutations could be favourable or detrimental to the viruses, depending on the type of mutation

So what did they find? In the samples the group studied, the sequence from Nepal showed no variation at all. And the maximum mutations were seen in the Indian sequence, six. Mutations bring about variations in viral genomes as the virus evolves to survive in its host. A mutation may be good or bad. Very fast mutations produce viruses which are not able to survive. The viruses that do survive, adapt and transmit are the ones that are sequenced and analysed, Dr Gupta said.

Of the six mutations in Indian genome, only one was unique to India

Mutations in Indian genome

Spike surface glycoprotein (unique to India): A virus protein which helps a virus attach itself to a host cell and enter it

ORF1ab: Polyprotein which is cleaved to form 16 smaller proteins, each known as non-structural protein (Nsp)

Nsp2: Believed to hamper signalling process in host cell

Nsp3: Protein which breaks down other proteins

Helicase or Nsp12, unwinds DNA molecules

ORF8 protein: Helps virus in human adaptation

For specific conclusions, however, Dr Gupta said, a wider base of study would be needed. The current data of just two sequences from Indian samples is too small to make a definitive statement, and requires more sequences to be analysed. He also clarified that one finding of the preliminary report that the microRNA hsa-miR-27b (small RNA molecules that can influence the expression of virus proteins) was found to have a target only in the Indian genome in the first study could not be replicated. We didn't find any target for the miRNA hsa-miR-27b in the second sequence, whereas the miRNA was predicted to uniquely target the spike glycoprotein in the first sequence, he said.

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India What we know about the genome of the virus in India A mutation unique to - Times of India

What is a vaccine?

According to the World Health Organization (WHO) a vaccine is understood to be any preparation intended to generate immunity against a disease by stimulating the production of antibodies. This may be, for example, a suspension of killed or attenuated microorganisms, or products or derivatives of microorganisms. Most vaccines are given by an injection, but some are given orally (by mouth) or sprayed into the nose.

In a previous article we had talked about the immune system, which is like the bodys defense army. One is born with a capacity to respond to what the body recognizes as foreign, as a threat (such as a virus, a bacterium, a fungus, or a parasite). That primary responsiveness is quick, but it is not specific and, therefore, sometimes not enough, the threat manages to get past that barrier. We call that first, fast and nonspecific immunity innate immunity.

The body has another way of defending itself, specially designed for each type of threat. Lets say that the body has, from birth, a group of cells ready to design and produce specific weapons for each pathogen. This second army works on what we call acquired immunity.

Since there is a wide variety of pathogens, [1] these cells do not produce these specific weapons until the pathogen enters the body, they recognize it, and they can design exactly the weapon that will harm it. This response is more specific, but it takes longer to start working.

One of the most powerful weapons in this army are the antibodies (also known as immunoglobulins). Antibodies are molecules (glycoproteins) that synthesize cells of the immune system (lymphocytes), these antibodies are synthesized with the exact composition that allows it to specifically (very specifically) bind to a part of the pathogen.

Antibodies have two main functions: they mark these pathogens to be attacked and eliminated by other cells of the immune system, or they bind to a specific part of the pathogen that blocks its ability to enter and harm cells in the body.

Antibodies are generated against specific substances of the pathogens; these substances are called antigens. They are that part of the pathogen that, by interacting with the cells of the immune system, provokes the immune response, which is why identifying them is an important part in the production of vaccines.

Once this army that participates in acquired immunity, designs this production line against a specific pathogen, it already leaves it there programmed (immunological memory), so if this pathogen attacks us again all these specific weapons are ready, the response is faster, if you get sick it is usually much less serious, and many times you do not get sick because the immune system of your body fought the threat and eliminated it before it could harm you and cause symptoms.

Thats what a vaccine does, getting in contact with the pathogen (or parts of it), in a safe (non-disease-causing) way, but enough to trigger your immune response and leave all your weapons ready so if that pathogen attacks you naturally, your response is quick, specific and protective.

What types of vaccine are there?

There are different types of vaccines. Some of them contain the complete infectious agent (live attenuated vaccines and inactivated or dead vaccines). In live attenuated vaccines, an attenuated or weakened form of the disease-causing pathogen (such as chickenpox or smallpox vaccines) is used. So that it elicits a very strong immune response, most of these vaccines need a single dose to immunize you for life. However, when using an attenuated form of the pathogen it should be used with caution in people with weakened immune systems, and it has specificities for its preservation (they should always be kept cold).

Inactivated vaccines use the inactivated version of the pathogen (for example, against polio or rabies). They use a harmless version of the pathogen, but usually do not provide an immunity as strong as live vaccines, which is why multiple doses are often required.

On the other hand, vaccines with toxoids (against diphtheria and tetanus, for example) are those that use the toxins (toxic substances) released by the pathogen when they are the cause of the disease. It generates immunity against this harmful toxin, not against the pathogen itself.

There is another group of vaccines with greater biotechnological complexity: conjugate and recombinant vaccines. These employ fragments of the pathogens molecular structure, which elicit a protective immune response, which is the goal of all vaccines.

They are very safe vaccines, that can be used in anyone and offer a very strong immune response directed at key parts of the pathogen. Conjugates combine these parts of the infectious agent (virus or bacteria) with other molecules that increase their immunogenic capacity (for example, vaccines against some meningococci and pneumococci), while recombinants (such as vaccines against hepatitis B, human papilloma virus or herpes zoster) involves introducing into any vectorit is usually a virus or bacterium that does not cause diseaseregions of the pathogen that we know to be immunogenic; that is, they have the capacity to activate the immune system.

Among the novel techniques being used for the production of vaccines are DNA vaccines, nanoparticle vaccines, among others.

Those involving genetic engineering, the so-called DNA vaccines, have had a major boost with technological development that has succeeded in sequencing (knowing the genetic information) of many pathogens very quickly. The sequence of the current coronavirus, for example, was obtained in just days. Researchers use an organisms genome (its genetic information) to extract the genes that are most likely to match known antigens that could be used in a vaccine.

Once identified, those genes can be combined and inserted into a different, rapidly multiplying organism, such as yeast, to produce experimental antigens, which are then studied to determine their ability to elicit a protective immune response. This method is known as reverse vaccination; no licensed vaccine has yet been released, but several experimental vaccines are already being studied, some of which are in the later stages of clinical trial (for example, a group B meningococcal vaccine). [2] Several of the vaccine candidates against COVID-19 follow this method.

What process does a vaccine candidate have to follow until it is approved for use in humans?

The creation of a vaccine is a long and complex process that often takes 10 to 15 years, and involves the combined participation of governments, and public and private organizations.

The World Health Organization establishes a protocol that many governments and regulatory institutions in the world follow, although each of them has specific regulations.

Ensuring that vaccines are safe, effective and of quality is a crucial element in their development and distribution. It begins with the first phases of the vaccine, generally in the laboratory, where its components are subjected to tests to determine aspects such as purity and potency. The clinical trials consisting of three phases are then commenced.

The license, or authorization for use in humans is the fundamental step in the process. The official entity that grants the authorization, the national regulatory body is the arbitrator that decides whether the established standards have been met to guarantee the quality of the vaccine.

What are the steps that have to be followed?

Exploration stage

This stage involves basic laboratory research, and often lasts 2 to 4 years.

Preclinical stage

Preclinical studies use tissue culture or cell culture systems and animal testing to assess the safety of the candidate vaccine and its ability to elicit an immune response.

Researchers can tailor the candidate vaccine during the preclinical phase to try to make it more effective. They can also perform exposure studies on animals, which means animals are vaccinated and then they try to infect them with the target pathogen; these types of studies are never performed on humans.

Many candidate vaccines do not go beyond this stage, as they cannot elicit the desired immune response. Often the preclinical stages last 1 to 2 years.

To continue the studies, after completing this phase, an application must have been approved by a competent agency.

Human clinical studies

Phase I

This first attempt to evaluate the candidate vaccine in humans involves a small group of adults, generally between 20 to 80. If the vaccine is aimed at children, the researchers will first test it in adults, and will gradually reduce the age of the test subjects until they reach the target. The goals of phase I trials are to assess the safety of the candidate vaccine and to determine the type and extent of the immune response that the vaccine elicits.

Phase II

A larger group of several hundred people participates in phase II testing. Some of the people may belong to groups at risk of contracting the disease; the trials are randomized and well controlled, and include a placebo group. The goals of phase II trials are to study the candidate vaccine for its safety, immunogenicity, proposed doses, vaccination schedule, and method of application.

Phase III

Candidate vaccines that are successful in phase II advance to larger trials, involving thousands to tens of thousands of persons. Phase III trials are randomized and double-blind, and involve the experimental vaccine that is tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance). One of phase IIIs goals is to evaluate the safety of the vaccine in a large group of persons. Some unusual side effects may not be apparent in smaller groups of people who were part of the previous phases.

During these phases, the efficacy of the vaccine to protect against the disease is assessed. Tests are done that have to do with the production of antibodies and the immune response of the persons who receive the vaccine. After a phase III trial is successful, accredited agencies will inspect the product, the factories and research results, until approval is issued.

After approved for large-scale use, the vaccines continue to be monitored.

Structure of the SARS-Cov-2 coronavirus

SARS-COV-2 is an enveloped, RNA-positive virus. The key to enter the cell is found in the so-called spike proteins (S), which cover the virus envelope.

SARS-CoV-2 coronavirus vaccines and treatments

The process to start a vaccine can take many years, however, we are told that probably in just over a year we can have a vaccine against this new virus. A response that, if possible, would be of a speed never seen before against a new disease.

This is mainly due to advances in the biotechnology sector. First of all, just one week after China reported the first cases of severe pneumonia of unknown origin to the WHO, the causative agentthe new SARS-CoV-2 coronaviruswas identified. A few days later its genome was already available. In just under three months, more than 970 scientific articles are available in the PubMed database.

Knowing the biology of the virus facilitates the design of therapeutic (antiviral) and preventive (vaccines) strategies. The similarity of genetic information with another coronavirus that has been studied for years, SARS-Cov, which caused the epidemic of acute respiratory syndrome (SARS) in 2002, has led to rapid progress in the pre-clinical phases.

In just these three months there are already several therapeutic proposals and vaccine candidates against the new coronavirus. Science has never advanced so far in such a short time to combat an epidemic. Many of the proposals come from research groups that have spent years working against other viruses, especially against SARS and MERS. This accumulated knowledge has now made it possible to go at a speed never seen before.

Antiviral therapies

Some already available antiviral drugs have been tested to see if they can be effective in fighting COVID-19. Chloroquine, which has been used for years against malaria, is being studied by a group of researchers, as it could reduce the viral load by blocking the virus from entering cells. Some anti-inflammatories, such as barcitinib and mesmosate from camostat (Japan), are being used in some protocols because they could block the entry of the virus into lung cells.

One of the most promising antivirals against SARS-CoV-2 is remdesivir, an inhibitor that prevents the virus from multiplying within the cell. It has already been used against SARS and MERS and has been successfully tested in the latest Ebola epidemics, and against other viruses with the RNA genome. It is, therefore, a broad-spectrum antiviral. At least twelve phase II clinical trials are already underway in China and the U.S., and another has started in phase III with 1,000 patients in Asia.

In the United States, in New York, the FDA has approved the use of plasma from sick patients who have recovered. This involves obtaining blood from donors who have recovered from COVID-19, and isolating the plasma (where the antibodies are located), to transfuse it to sick people. It is not a new treatment; it was used in the Spanish Flu pandemic in 1918. According to the journal Nature, this effort in the United States is following preliminary studies carried out in China. The convalescent plasma approach has also had modest success during previous outbreaks of severe acute respiratory syndrome (SARS) and Ebola. It could be an emergency response in which more effective treatments appear.

There are at least 27 clinical trials with different combinations of antiviral treatments such as Interferon Alfa-2B, ribavirin, methylprednisolone, and azvudine. At the moment they are experimental treatments, but they are a hope for the most serious and severe cases.

COVID-19 vaccines for the future

The main hope for controlling the disease is based on achieving effective vaccines. The WHO, until March 20, had a list of 41 candidates, but based on press reports from various countries, we know that more are being worked on.

An article published on March 23 by The Conversation summarizes some of the most promising projects.

In clinical trial phase

According to the publication, one of the most advanced is the Chinese proposal, a recombinant adenovirus vector-based vaccine with the SARS-CoV-2 S gene, which has already been tested in monkeys and is known to produce immunity. A phase I clinical trial will be started with 108 healthy volunteers, between 18 and 60 years old, in which three different doses will be tested.

Other proposals are being promoted by CEPI (Coalition for Epidemic Preparedness Innovations), an international association in which public, private, civil and philanthropic organizations collaborate to develop vaccines against epidemics. It is currently funding eight SARS-CoV-2 vaccine projects that include recombinant, protein, and nucleic acid vaccines.

mRNA-1273 vaccine (Moderna, Seattle)

It is a vaccine made up of a small fragment of messenger RNA with the instructions to synthesize part of the protein S of the SARS-Co-V. The idea is that, once introduced into our cells, it is these cells that make this protein, which would act as an antigen and stimulate the production of antibodies. It is already in the clinical phase and it has begun to be tested in healthy volunteers.

Preclinical phases

Recombinant measles virus vaccine (Pasteur Institute, Themis Bioscience and University of Pittsburg)

It is a vaccine built on a live attenuated measles virus, which is used as a vehicle and contains a gene that encodes a protein of the SARS-CoV-2 virus. It is in the preclinical phase.

Recombinant Influenza Virus Vaccine (University of Hong Kong)

It is also a live vaccine that uses an attenuated influenza virus as a vector, which has had the virulence gene NS1 removed, and is therefore not virulent. A SARS-CoV-2 virus gene is added to this vector virus. This proposal has some advantages: it could be combined with any strain of seasonal influenza virus and thus serve as a flu vaccine, it can be quickly manufactured in the same production systems that already exist for influenza vaccines, and they could be used as intranasal vaccines via spray. It is in the preclinical phase.

Recombinant protein vaccine obtained by nanoparticle technology (Novavax)

This company already has vaccines against other respiratory infections such as adult flu (Nano-Flu) and respiratory syncytial virus (RSV-F) in clinical phase III and has manufactured vaccines against SARS and MERS. Its technology is based on producing recombinant proteins that are assembled into nanoparticles and administered with its own adjuvant, Matrix-M. This compound is a well-tolerated immunogen capable of stimulating a powerful and long-lasting nonspecific immune response. The advantage is that in this way the number of necessary doses would be reduced (thus avoiding revaccination). It is in the preclinical phase.

Recombinant vaccine using as a vector the Oxford chimpanzee adenovirus, ChAdOx1 (Jenner Institute, Oxford University)

This attenuated vector is capable of carrying another gene that encodes a viral antigen. Models for MERS, influenza, chikungunya and other pathogens such as malaria and tuberculosis have been tested in volunteers. This vaccine can be manufactured on a large scale in bird embryo cell lines. The recombinant adenovirus carries the glycoprotein S gene of the SARS-CoV-2. It is in the preclinical phase.

Recombinant Protein Vaccine (University of Queensland)

It consists of creating chimeric molecules capable of maintaining the original three-dimensional structure of the viral antigen. It uses the technique called molecular clamp, which allows vaccines to be produced using the virus genome in record time. It is in the preclinical phase.

Messenger RNA Vaccine (CureVac)

This is a proposal similar to that developed by the modern biotechnology company, with recombinant messenger RNA molecules that are easily recognized by the cellular machinery and produce large amounts of antigen. They are packaged in lipid nanoparticles or other vectors. In preclinical phase.

DNA INO-4800 vaccine (Inovio Pharmaceuticals)

It is a platform that manufactures synthetic vaccines with DNA of the S gene from the surface of the virus. They had already developed a prototype against MERS (the INO-4700 vaccine) that is in phase II. They recently published the phase I results with this INO-4700 vaccine and found that it was well-tolerated and produced a good immune response (high antibody levels and a good T-cell response, maintained for at least 60 weeks after vaccination). In preclinical phase.

Cuba

According to the director of biomedical research of the CIGB, Gerardo Guilln, the Center for Genetic Engineering and Biotechnology (CIGB) of Cuba has a vaccine design that could be used against the new coronavirus.

According to the Cuban scientist, this vaccine is in the methodological and design phase. However, according to his statements, there is an advanced path since a platform that the institution has already developed is being used, where it works with virus-like particles with great capacity to stimulate the immune system.

Another platform that is very attractive and promising being developed by the center is by immunization through the nose. Cuba has experience in this regard, since it has a registered vaccine that uses this nasal spray.

The Cuban vaccine candidate is being developed with the Cuba-China joint research and development center, located in Hunan province. It is not known when clinical trials could begin.

Cuba is also carrying out research in therapeutic drugs. The results so far published by China in the treatment of COVID 19, with the Cuban Interferon Alfa 2B, showed positive results.

***

All proposals for specific treatments and vaccines for COVID-19 are in the experimental phase. But technological advances and the accumulation of research results in the fields of antiviral therapies and vaccines against other viruses, and specifically against other coronaviruses, make many experts affirm that there is a high probability of success. Although we want and need faster responses, science cannot be asked to have a vaccine in less than a year, in reality that would already be a record time.

The international scientific communitys actions, in terms of sharing scientific results, collaboration and training, is the backbone of this battle, and my greatest hope.

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Why can't we have a COVID-19 vaccine right now? - OnCubaNews

Wow.

Thats the word Candace Johnson, the president and chief executive officer of Roswell Park Comprehensive Cancer Center, uses early in Cubas Cancer Hope. It airs as part of the PBS series Nova at 9 p.m. Wednesday.

She added the words, in Cuba, jeez, referring to the small communist countrys work on a vaccine for the treatment for certain forms of cancer.

But the word can also be applied to the positive national publicity Roswell Park is receiving in the program.

"Wow," indeed.

It certainly could use some good publicity after Roswell Park fired a top executive over the weekend for things she wrote on her Facebook page that bashed President Trump's response to the Covid-19 outbreak.

The Nova documentary plays like a promotion for Roswell Parks partnership with Cuba in search of a treatment. Roswell Park is especially highlighted in the second half of the hourlong program.

Several Roswell Park doctors, including Dr. Kelvin Lee, Dr. Kunle Odunsi, Dr. Mary Reid, Dr. Grace K. Dy and Dr. Joseph Tario, appear. The program centers around how Roswell became involved with scientists in a small Communist country where American citizens go to receive treatment illegally because of a United States trade embargo that complicates the relationship between the countries.

Dr. Kelvin Lee (Photo courtesy of Roswell Park)

I think everyone here thought that Cuba was stuck in I Love Lucy days, the 1950s, old cars, there cant possibly be good science going on, Lee says early in the program.

The beautifully filmed hour also may appeal to supporters of Democratic presidential candidate Bernie Sanders, who was criticized for old comments about Fidel Castros regime in Cuba expanding education and health care.

Cubas Cancer Hope acknowledges Castro's dictatorial sins that led to half its doctors leaving the country early in his reign. But it also credits the dictator for emphasizing science and giving Cubans something not available to all Americans free health care.

Lee and other doctors give a basic understanding of immunotherapy, genetic engineering, checkpoints and what Cuban scientists have discovered in the treatment of cancer that has resulted in some Americans going there to extend their lives.

"Cubas Cancer Hope humanizes the story by following some people who have been given the treatment and lived beyond expectations.

The question of how Roswell Park was chosen as a partner is raised, but not as thoroughly as I hoped. Odunsi explained that he was told Roswell Park was approached because it was one of the few institutions where discoveries in Cuba could be taken to the next level.

The relationship began in 2011 when Cuban doctors made a presentation at Roswell Park before a standing room audience.

Scientists, were a little crazy, Johnson explained. We all want to hear something really interesting. It sparked curiosity of how it came to be ... Wow, in Cuba. Jeez.

The bigger question is whether all the challenges of bringing the potential life-extending drug to Buffalo and across the United States will ever be conquered.

If it does, wow will be an understatement.

Dr. Candace Johnson (Photo courtesy of Roswell Park)

In a telephone interview, Johnson made aspects of the development of the partnership between Roswell Park and the Cuba doctors sound even more dramatic than portrayed in the documentary.

She noted that the April 2015 trade mission led by Gov. Andrew Cuomo that resulted in Roswell Park signing an agreement with Cubas Center for Molecular Immunology to set up a clinical trial for a lung cancer vaccine CimaVax was done under unusual circumstances.

At the time that (Cuomo) did that, that was pretty bold because no one had really gone there, she said. I was asked to go with Kelvin Lee and they had to charter a plane that left from JFK (Airport in New York City). The CEO of JetBlue was on the plane. They had to carry their own mechanics because there were no mechanics in Havana, there was no way to pay them. There was no way to pay rent. They refueled and left and refueled at Fort Lauderdale.

It was precedent-setting to say the least, she added. And then for us to come out of that trip with an agreement with the CIM to be able to work with, test and work toward doing a clinical trial was really exciting. When we first came back from Cuba from that trade mission, the world was abuzz because at that time really no one was going to Cuba.

I think for the whole world it was, 'what's going on here? I mean we did interviews from that very first trip from places all around the world. I guess the thing that I'm most proud of is that it wasn't just a flash in the pan where we got in the spotlight at the Havana airport with the governor. But we actually did something and we worked hard to be able to use this vaccine approach in a clinical trial that is ongoing.

Johnson hasnt seen the documentary, but she views it as a really intriguing story that gave Cuban doctors the respect they have sought and deserved.

When we first started talking about Cuba and this has changed the Cuban scientists and this vaccine, the arrogance that you would hear from people, she recalled. Why are they smarter than we are? They are just a third world country. How could they possibly be doing anything that's maybe better than we have? So I think it's a combination of sort of a little guy doing well that also makes this story pretty interesting.

She had a more thorough answer to why the Cuban scientists chose to partner with Roswell instead of cancer centers that are bigger, more famous or have more money.

I think the one thing that really contributed to that is Dr. Lee is a very engaging guy, she said. Youve got to look Cubans in the eye. They have to know you to trust you. And I think part of the reason we were successful is we developed a trust between our two institutions even though the politics between our two countries is very tense and sometimes controversial."

If the vaccine eventually passes the clinical trials, Johnson expects the Food and Drug Administration would approve its use in the U.S. so patients would no longer need to go to Cuba.

I know everything that we do with Cuba can be a challenge because of the relationship between our two countries, Johnson said. Were very hopeful. It seems to me it would be very difficult from the FDA's perspective, if this drug has a role, that it wouldn't be available in this country.

email: apergament@buffnews.com

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Column: Roswell Park's alliance with Cuba gets the 'wow' treatment from PBS' 'Nova' - Buffalo News

Research by a University of Southern Denmark team has found that the cannabis compound cannabidiol (CBD) may act as a helper compound to boost the effectiveness of antibiotics against drug-resistant Gram-positive bacteria. A study headed by Janne Kudsk Klitgaard, PhD, associate professor, clinical microbiology, found that combining CBD with the antibiotic bacitracin (BAC) had a more powerful effect against bacteria including Staphylococcus aureus, than BAC alone. Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic-resistant Gram-positive bacteria, the researchers stated in their published paper in Scientific Reports, titled, Cannabidiol is an effective helper compound in combination with bacitracin to kill Gram-positive bacteria.

Since the discovery of penicillin by Sir Alexander Fleming in 1928, antibiotics have saved millions of lives from fatal infections worldwide, the authors wrote. However, over time, bacteria have developed mechanisms to escape the effects of one or more antibioticsmultidrug resistance (MDR)leading to an increasing global health threat. With fewer antibiotics available to treat MDR bacterial infections, the possibility of entering a pre-antibiotic era is looming ahead, the team stated.

Among alternative strategies that are being explored to help address antibiotic resistance, helper compounds, also known as antibiotic potentiators or resistant breakers, are gaining attention. Such helper compounds are non-antibiotic compounds that act as adjuvants for antibiotics, operating synergistically through mechanisms including efflux pump inhibition, enzyme inhibition, or changing membrane permeability, which can contribute to improving antibiotic efficacy.

Given that overuse of antibiotics is the main cause of antibiotic resistance, the combination of an antibiotic with a helper compound could reduce the amount of antibiotic needed to achieve bacterial growth inhibition or killing than if the antibiotic was used alone. This strategy may, therefore, decrease the likelihood of resistance development, and investigations to identify efficient helper compounds are thus important, the investigators suggested.

CBD, from the cannabis plant Cannabis sativa, acts as an antagonist of both the cannabinoid type 1 and 2 (CB1 and CB2) receptors, and has been shown to have anti-sedative, anti-psychotic, and anxiolytic effects, the team noted. The compound has also been linked with a variety of effects, including inhibiting cancer cell growth, neuroprotection in neurodegenerative diseases such as Parkinsons disease, and post-ischemia, and anti-inflammatory effects, as in type 1 diabetes.

CBD has also been observed to inhibit bacterial growth, but the use of cannabidiol as an antibiotic adjuvant hasnt yet been investigated, the team continued. Not much is known regarding antimicrobial effects of cannabinoids and even less on the mechanism of action the use of cannabidiol as an antibiotic adjuvant has not been studied so far.

For their reported study, the researchers evaluated whether CBD could act as a potential helper compound to increase the effectiveness of the antibiotic bacitracin, which is a mixture of cyclic peptides that interfere with the bacterial cell wall and interrupt biosynthesis of peptidoglycan, leading to cell lysis. The team first validated the antimicrobial effect of cannabidiol against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus (MRSA), and also against Enterococcus faecalis, Listeria monocytogenes, and methicillin-resistant Staphylococcus epidermidis (MRSE). They then tested the effects of combining CBD and BAC against different Gram-positive bacteria, providing initial indication that CBD could potentiate the antimicrobial effects of the antibiotic.

Further tests with the combination of CBD and BAC against S. aureus showed that dual treatment caused morphological changes in the bacterial cells that affected cell division, so that the bacteria could no longer divide normally. the combination of CBD and BAC affects the cell envelope causing irregular cell division visualized by multiple septa formations and irregular cell membrane. These effects werent seen with either treatment on its own; CBD and BAC alone caused no morphological changes, they wrote.

The combined treatment was also found to decrease autolysis in S. aureus, while CBD was shown to cause depolarization of the cytoplasmic membrane. Gene expression analysis confirmed that treatment using CBD in combination with BAC resulted in reduced expression of key cell division and autolysis genes in the bacteria. The combination of BAC and CBD was, however, and as expected, not effective in Gram-negative bacteria. As a mixture of cyclic peptides that interrupt cell wall synthesis in Gram-positive bacteria, the antibiotic is probably unable to cross the outer membrane in Gram-negative bacteria, the researchers pointed out.

In this study, we found that the antibacterial effects of BAC against S. aureus as well as other Gram-positive bacteria can be enhanced by cannabidiol originating from the cannabis plant, the scientists concluded. They acknowledged that further work will be needed to understand the mechanisms of action of combined CBD and BAC treatment on Gram-positive bacteria. Changes observed in morphology were not caused by compositional changes in the cell wall muropeptide composition. Membrane potential changes for the combination of CBD and BAC compared to either CBD or BAC treatment alone did not reveal the mechanism of action for the combination of CBD and BAC, they wrote. Future studies are therefore focused on the cell division and cell envelope to identify the mechanism of action.

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Cannabis Compound CBD Acts as Helper to Boost Antibiotic Effectiveness - Genetic Engineering & Biotechnology News

As conspiracy theories started spreading like wildfire on the Internet, several misguided rumours about the connection between 5G and coronavirus surfaced online. COVID-19, is believed to have originated from a wet market in Wuhan, China, in November. Coincidentally, China also turned on some of its 5G networks in November.

Rumours gained steam when Keri Hilson, popular American singer, with 4.2 million followers on Twitter, sent out tweets last week about the alleged connection between 5G and COVID-19, writing, "People have been trying to warn us about 5G for YEARS. Petitions, organizations, studies... what we're going through is the affects [sic] of radiation. 5G launched in CHINA. Nov 1, 2019. People dropped dead."

Several conspiracy theorists also alleged that the viral videos of people dropping on the ground and fainting in China, were a result of 5G radio waves messing with the oxygen levels in blood of the general public.

Soon, a UK based fact checking website, FullFact, debunked the claims and argued that there is no evidence that 5G is harmful to peoples health.

Read more:
A Bioweapon Or Effects Of 5G? 7 Conspiracy Theories Around Coronavirus That Will Shock You - The Biggest Humanitarian Crisis - Economic Times