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MARLBOROUGH, Mass., May 11, 2021 /PRNewswire/ -- Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a biotechnology company developing the next generation of immuno-oncology therapeutics based on its proprietary self-delivering RNAi (INTASYL) therapeutic platform, today announced positive new in vivo data showing that PH-762 significantly enhanced the antitumor efficacy of HER2-targeted CAR-T cells (HER2CART) in solid tumors. Compared to untreated HER2CART cells, HER2CART cells treated with PH-762 showed a statistically significant and durable inhibition of tumor growth. These data, using a HER2-targeted CAR-T cell product against a HER2-expressing ovarian cancer xenograft model, provide proof-of-concept for the application of PD-1 checkpoint silencing with INTASYL in CAR-T cells prior to adoptive cell therapy to enhance the therapeutic efficacy of CAR-T cell therapy in solid tumors.

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"The in vivo data announced today further support advancing the development of PH-762 into the clinic as a viable approach to improve various forms of T cell based immunotherapy. These data are especially impressive considering that to date CAR T-cell therapy effectiveness in solid tumors has been disappointing and the use of additional genetic engineering to address these issues has proven challenging and costly. Indeed, in a recent clinical study it was shown that CRISPR-Cas9 mediated PD-1 disruption resulted in low efficiency, namely an editing efficiency of less than 6% and a median disruption of PD-1 expression of less than 50% in the edited T cells. This compares sharply with our results where we show that our INTASYL compound, PH-762, achieves PD-1 silencing efficiency of~90% in nearly 100% of the HER2CART cells used in this study," stated Dr. Simon Fricker, Phio's VP of Research. "In addition, these results are achieved by merely adding PH-762 to the HER2CART cell culture media, without the need for cell delivery vehicles or vectors, and without negative impact on cell growth/survival. In a prior presentation we also showed how PH-762 can improve the tumor cell killing activity of another adoptive cell therapy platform, namely tumor infiltrating lymphocytes. Taken together, you can start to see the full picture of the potential advancement that INTASYL could provide in adoptive cell therapy."

In this study the Company assessed the potential of PH-762, a PD-1 targeting INTASYL compound, to enhance the therapeutic efficacy of HER2CART cells in the treatment of a subcutaneous HER2-expressing SKOV3 model of human ovarian cancer in mice. On-target silencing of PD-1 in vitro was demonstrated in a dose associated manner in activated HER2CART cells, without significant impact on viability, and resulted in an enrichment of CD8+ and CD25+ cells. Analyses of PH-762-treated HER2CART cells isolated from tumors suggest that PH-762 enhances CAR-T function through multiple mechanisms including enhanced efficiency, degranulation, decreased suppressive potential, and promotion of memory/stem populations.

These data were presented today during the 24th Annual Meeting of the ASGCT in a poster titled "INTASYL PH-762 Self-Delivering RNAi Targeting PD-1 Enhances the Therapeutic Efficacy of Systemically Administered HER2-Targeted CAR-T Cells in a SKOV3 Model of Human Ovarian Adenocarcinoma in NCG Mice". An archived version of the poster presentation will be made available on the "Investors Events and Presentations" section of the Company's website (click here).

AboutPhio Pharmaceuticals Corp.

Phio Pharmaceuticals Corp. (Nasdaq: PHIO) is a biotechnology company developing the next generation of immuno-oncology therapeutics based on its self-delivering RNAi (INTASYL) therapeutic platform. The Company's efforts are focused on silencing tumor-induced suppression of the immune system through its proprietary INTASYL platform with utility in immune cells and the tumor micro-environment. Our goal is to develop powerful INTASYL therapeutic compounds that can weaponize immune effector cells to overcome tumor immune escape, thereby providing patients a powerful new treatment option that goes beyond current treatment modalities. For additional information, visit the Company's website, http://www.phiopharma.com.

Forward Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are neither historical facts nor assurances of future performance. These statements are based only on our current beliefs, expectations and assumptions regarding the impact to our business and operations by the recent coronavirus outbreak, results from our preclinical and clinical activities, the development of our product candidates, the ability to obtain future financing, the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results may differ materially from those indicated in the forward-looking statements as a result of a number of important factors, including, but not limited to, market and other conditions and those identified in our Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q under the caption "Risk Factors" and in other filings the Company periodically makes with the SEC. Readers are urged to review these risk factors and to not act in reliance on any forward-looking statements, as actual results may differ from those contemplated by our forward-looking statements. Phio does not undertake to update forward-looking statements to reflect a change in its views, events or circumstances that occur after the date of this release, except as required by law.

Contact Phio Pharmaceuticals Corp.[emailprotected]

Investor ContactAshley R. RobinsonLifeSci Advisors[emailprotected]

SOURCE Phio Pharmaceuticals Corp.

http://www.phiopharma.com

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Phio Pharmaceuticals Presents Positive In Vivo Data at ASGCT Showing PH-762 Significantly Enhanced Antitumor Efficacy of HER2-Targeted CAR-T Cells -...

Over the years, biomedical researchers have increasingly focused on developing efficient and reliable methods for precise and targeted changes to virtually any point of genome of any living cell. Recent advances in the genome engineering has triggered several biological researches and translational applications. Economical manipulation and modification of genomic sequences enable molecular biologists identify and characterize key genetic determinants to facilitate the investigation of various biological processes. Genome editing via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) is considered as an innovative technique in programmable and high-throughput functional genomics. CRISPR-Cas system consists of pattern of repetitive sequences in the DNA of certain bacteria, who used it as an adaptive immune system to find a protection mechanism against invading foreign DNA.

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In less than a decade, a host of novel targeted techniques and genomic engineering tools have been developed that facilitates precise and diverse genomic modifications in a variety of organisms and tissues. The recent tool having enormous potential in biomedical researches is the clustered regularly interspaced short palindromic repeats associated Cas9/sgRNA system, also called Cas9/sgRNA. Cas9 protein is an RNA guided endonuclease. Along with its variants it has generated considerable excitement versatile genomic engineering tool in the development of genetically edited (GE) crops. Primary areas research for this include examining gene function, understanding the regulatory signaling networks, and rewiring sgRNA for advance loss-of-function screening. This will help in combating biotic and abiotic stresses, thereby leading to the development of climate resilient crops and sustainable agriculture practices in the coming years.

Global CRISPR and CRISPR-Associated (Cas) Genes Market: Overview

In the past few years research and development of CRISPR or clustered regularly interspaced short palindromic repeats has allowed molecular biologists to designs solutions for repairing cells by genome editing. This method allows a change to a specific genome by the introduction of a new function or by correction of a mutation. The exceptional fidelity, simplicity of construction, and low cost has triggered a monumental demand for the several solutions offered by the global CRISPR and CRISPR-associated (Cas) genes market. The market is riding a wave of success as these factors have augmented the uptake of this method in several molecular biology laboratories.

The well-documented research report presents a fair case study of the global CRISPR and CRISPR-associated (Cas) genes market. The report includes a SWOT analysis and Porters five forces analysis, which help in understanding several facets of the global market in greater depth. Furthermore, analysts have used primary and secondary research methodologies, which ensure the authenticity of the facts. This information in the report has also been seconded by market experts with comments and recommendations about the subject matter. The comprehensive research report is aimed at guiding each of its readers to make well-informed business decisions.

CRISPR and CRISPR-Associated (Cas) Genes Market - Notable Developments

The global CRISPR and CRISPR-Associated (Cas) Genes Market is set to see a steady CAGR (Compound Annual Growth Rate) over the forecast period of 2017 to 2025. It is attributable to a number of factors. For instance, the genome editing principle is pervasive through verticals that work with biotechnology. This keeps the demand high. Secondly, there is an increasing level of awareness and adoption of advances technologies. This will thus, not only create untapped opportunities in the market but also pull the worth of the market by a considerable value.

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To understand whats impacting the growth in this market, it is important to be up-to-date with recent developments and key trends and drivers. Major ones are outlined below:

Global CRISPR and CRISPR-Associated (Cas) Genes Market: Trends and Drivers

The products available in the global CRISPR and CRISPR-associated (Cas) genes market are DNA-free Cas and vector-based Cas. The widening applications of these are expected offer several lucrative opportunities to the global market. Out of various applications, genome engineering is expected to be a key contributor to the soaring revenue of the overall market in the near future. This trend will be attributable to eh increasing uptake of genome editing method for the therapeutic development and germline modifications. The report indicates that advancements in plant genome engineering will result in positive impact on the global market.

Analysts predict that CRISPR could be the next biotechnology treatment that has the ability to gradually replace the present single-antibody drugs. Genome engineering is anticipated to pick up a phenomenal pace in the coming years as it is being developed to build an immune response for targeting cancer. The widening application of these methods in the field of oncology is likely to change the game for the global market in the coming years.

Global CRISPR and CRISPR-Associated (Cas) Genes Market: Regional Outlook

In terms of geography, the global market is segmented into North America, Asia Pacific, Latin America, the Middle East and Africa, and Europe. North America is estimated to lead the global CRISPR and CRISPR-associated (Cas) genes market as the U.S. has shown a keen interest in developing effective therapeutics. Asia Pacific is also expected to offer several growth opportunities to the overall market as the region is facing a challenge of mounting unmet medical needs.

Key Players Mentioned in the Report are:

The report has identified the following as the key operating players in the global CRISPR and CRISPR-associated (Cas) genes market: Thermo Fisher Scientific, Inc., Caribou Biosciences, Inc., CRISPR THERAPEUTICS, Addgene, Mirus Bio LLC, Merck KGaA, Editas Medicine, GE Healthcare Dharmacon Inc., Takara Bio USA, Horizon Discovery Group plc, and Intellia Therapeutics, Inc. Analysts predict that these companies will focus on making strategic collaborations to ahead of the competition present in the overall market.

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This study provides a particularized anatomy according to the L.E.A.P mechanism

The regional analysis offers market assays across:

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CRISPR and CRISPR-Associated (Cas) Genes Market | Know the trends that have the potential to bring expansive growth for the market - BioSpace

In the millions of articles, opinion pieces, and news stories written about Covid there is one topic that is more important than all the others. Its more important than masks, vaccines, or lockdown measures. The origin of the virus is critical because no matter how many people die from covid, or how many businesses are wiped out, its critical that IF the next virus can be stopped, it must be.

A science writer named Nicholas Wade has written the most thorough study on the origins of Covid to be released to the public. Wade has worked with Nature, Science, and the New York Times, but this article was released on the public platform Medium. In this article Wade goes through three possible scenarios and then draws the most likely conclusion. This is a long read, but it might be the mostimportant article yet written during this pandemic.

Here is the article from Medium. Click here to read it on Medium.

Origin of Covid Following the Clues

Nicholas Wade

Im a science writer and have worked on the staff of Nature, Science and, for many years, on the New York Times. [emailprotected]

The Covid-19 pandemic has disrupted lives the world over for more than a year. Its death toll will soon reach three million people. Yet the origin of pandemic remains uncertain: the political agendas of governments and scientists have generated thick clouds of obfuscation, which the mainstream press seems helpless to dispel.

In what follows I will sort through the available scientific facts, which hold many clues as to what happened, and provide readers with the evidence to make their own judgments. I will then try to assess the complex issue of blame, which starts with, but extends far beyond, the government of China.

By the end of this article, you may have learned a lot about the molecular biology of viruses. I will try to keep this process as painless as possible. But the science cannot be avoided because for now, and probably for a long time hence, it offers the only sure thread through the maze.

The virus that caused the pandemic is known officially as SARS-CoV-2, but can be called SARS2 for short. As many people know, there are two main theories about its origin. One is that it jumped naturally from wildlife to people. The other is that the virus was under study in a lab, from which it escaped. It matters a great deal which is the case if we hope to prevent a second such occurrence.

Ill describe the two theories, explain why each is plausible, and then ask which provides the better explanation of the available facts. Its important to note that so far there is no direct evidence for either theory. Each depends on a set of reasonable conjectures but so far lacks proof. So I have only clues, not conclusions, to offer. But those clues point in a specific direction. And having inferred that direction, Im going to delineate some of the strands in this tangled skein of disaster.

A Tale of Two Theories

After the pandemic first broke out in December 2019, Chinese authorities reported that many cases had occurred in the wet market a place selling wild animals for meat in Wuhan. This reminded experts of the SARS1 epidemic of 2002 in which a bat virus had spread first to civets, an animal sold in wet markets, and from civets to people. A similar bat virus caused a second epidemic, known as MERS, in 2012. This time the intermediary host animal was camels.

The decoding of the viruss genome showed it belonged to a viral family known as beta-coronaviruses, to which the SARS1 and MERS viruses also belong. The relationship supported the idea that, like them, it was a natural virus that had managed to jump from bats, via another animal host, to people. The wet market connection, the only other point of similarity with the SARS1 and MERS epidemics, was soon broken: Chinese researchers found earlier cases in Wuhan with no link to the wet market. But that seemed not to matter when so much further evidence in support of natural emergence was expected shortly.

Wuhan, however, is home of the Wuhan Institute of Virology, a leading world center for research on coronaviruses. So the possibility that the SARS2 virus had escaped from the lab could not be ruled out. Two reasonable scenarios of origin were on the table.

From early on, public and media perceptions were shaped in favor of the natural emergence scenario by strong statements from two scientific groups. These statements were not at first examined as critically as they should have been.

We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin, a group of virologists and others wrote in the Lancet on February 19, 2020, when it was really far too soon for anyone to be sure what had happened. Scientists overwhelmingly conclude that this coronavirus originated in wildlife, they said, with a stirring rallying call for readers to stand with Chinese colleagues on the frontline of fighting the disease.

Contrary to the letter writers assertion, the idea that the virus might have escaped from a lab invoked accident, not conspiracy. It surely needed to be explored, not rejected out of hand. A defining mark of good scientists is that they go to great pains to distinguish between what they know and what they dont know. By this criterion, the signatories of the Lancet letter were behaving as poor scientists: they were assuring the public of facts they could not know for sure were true.

It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the EcoHealth Alliance of New York. Dr. Daszaks organization funded coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Dr. Daszak would be potentially culpable. This acute conflict of interest was not declared to the Lancets readers. To the contrary, the letter concluded, We declare no competing interests.

Virologists like Dr. Daszak had much at stake in the assigning of blame for the pandemic. For 20 years, mostly beneath the publics attention, they had been playing a dangerous game. In their laboratories they routinely created viruses more dangerous than those that exist in nature. They argued they could do so safely, and that by getting ahead of nature they could predict and prevent natural spillovers, the cross-over of viruses from an animal host to people. If SARS2 had indeed escaped from such a laboratory experiment, a savage blowback could be expected, and the storm of public indignation would affect virologists everywhere, not just in China. It would shatter the scientific edifice top to bottom, an MIT Technology Review editor, Antonio Regalado, said in March 2020.

A second statement which had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus, the five virologists declared in the second paragraph of their letter.

Unfortunately this was another case of poor science, in the sense defined above. True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called no-see-um or seamless approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Dr. Andersen and his colleagues were assuring their readers of something they could not know.

The discussion part their letter begins, It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. But wait, didnt the lead say the virus had clearly not been manipulated? The authors degree of certainty seemed to slip several notches when it came to laying out their reasoning.

The reason for the slippage is clear once the technical language has been penetrated. The two reasons the authors give for supposing manipulation to be improbable are decidedly inconclusive.

First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.

If this argument seems hard to grasp, its because its so strained. The authors basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way. First they would calculate the strongest possible fit between the human ACE2 receptor and the spike protein with which the virus latches onto it. They would then design the spike protein accordingly (by selecting the right string of amino acid units that compose it). But since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it cant have been manipulated.

But this ignores the way that virologists do in fact get spike proteins to bind to chosen targets, which is not by calculation but by splicing in spike protein genes from other viruses or by serial passage. With serial passage, each time the viruss progeny are transferred to new cell cultures or animals, the more successful are selected until one emerges that makes a really tight bind to human cells. Natural selection has done all the heavy lifting. The Andersen papers speculation about designing a viral spike protein through calculation has no bearing on whether or not the virus was manipulated by one of the other two methods.

The authors second argument against manipulation is even more contrived. Although most living things use DNA as their hereditary material, a number of viruses use RNA, DNAs close chemical cousin. But RNA is difficult to manipulate, so researchers working on coronaviruses, which are RNA-based, will first convert the RNA genome to DNA. They manipulate the DNA version, whether by adding or altering genes, and then arrange for the manipulated DNA genome to be converted back into infectious RNA.

Only a certain number of these DNA backbones have been described in the scientific literature. Anyone manipulating the SARS2 virus would probably have used one of these known backbones, the Andersen group writes, and since SARS2 is not derived from any of them, therefore it was not manipulated. But the argument is conspicuously inconclusive. DNA backbones are quite easy to make, so its obviously possible that SARS2 was manipulated using an unpublished DNA backbone.

And thats it. These are the two arguments made by the Andersen group in support of their declaration that the SARS2 virus was clearly not manipulated. And this conclusion, grounded in nothing but two inconclusive speculations, convinced the worlds press that SARS2 could not have escaped from a lab. A technical critique of the Andersen letter takes it down in harsher words.

Science is supposedly a self-correcting community of experts who constantly check each others work. So why didnt other virologists point out that the Andersen groups argument was full of absurdly large holes? Perhaps because in todays universities speech can be very costly. Careers can be destroyed for stepping out of line. Any virologist who challenges the communitys declared view risks having his next grant application turned down by the panel of fellow virologists that advises the government grant distribution agency.

The Daszak and Andersen letters were really political, not scientific statements, yet were amazingly effective. Articles in the mainstream press repeatedly stated that a consensus of experts had ruled lab escape out of the question or extremely unlikely. Their authors relied for the most part on the Daszak and Andersen letters, failing to understand the yawning gaps in their arguments. Mainstream newspapers all have science journalists on their staff, as do the major networks, and these specialist reporters are supposed to be able to question scientists and check their assertions. But the Daszak and Andersen assertions went largely unchallenged.

Doubts about natural emergence

Natural emergence was the medias preferred theory until around February 2021 and the visit by a World Health Organization commission to China. The commissions composition and access were heavily controlled by the Chinese authorities. Its members, who included the ubiquitous Dr. Daszak, kept asserting before, during and after their visit that lab escape was extremely unlikely. But this was not quite the propaganda victory the Chinese authorities may have been hoping for. What became clear was that the Chinese had no evidence to offer the commission in support of the natural emergence theory.

This was surprising because both the SARS1 and MERS viruses had left copious traces in the environment. The intermediary host species of SARS1 was identified within four months of the epidemics outbreak, and the host of MERS within nine months. Yet some 15 months after the SARS2 pandemic began, and a presumably intensive search, Chinese researchers had failed to find either the original bat population, or the intermediate species to which SARS2 might have jumped, or any serological evidence that any Chinese population, including that of Wuhan, had ever been exposed to the virus prior to December 2019. Natural emergence remained a conjecture which, however plausible to begin with, had gained not a shred of supporting evidence in over a year.

And as long as that remains the case, its logical to pay serious attention to the alternative conjecture, that SARS2 escaped from a lab.

Why would anyone want to create a novel virus capable of causing a pandemic? Ever since virologists gained the tools for manipulating a viruss genes, they have argued they could get ahead of a potential pandemic by exploring how close a given animal virus might be to making the jump to humans. And that justified lab experiments in enhancing the ability of dangerous animal viruses to infect people, virologists asserted.

With this rationale, they have recreated the 1918 flu virus, shown how the almost extinct polio virus can be synthesized from its published DNA sequence, and introduced a smallpox gene into a related virus.

These enhancements of viral capabilities are known blandly as gain-of-function experiments. With coronaviruses, there was particular interest in the spike proteins, which jut out all around the spherical surface of the virus and pretty much determine which species of animal it will target. In 2000 Dutch researchers, for instance, earned the gratitude of rodents everywhere by genetically engineering the spike protein of a mouse coronavirus so that it would attack only cats.

Virologists started studying bat coronaviruses in earnest after these turned out to be the source of both the SARS1 and MERS epidemics. In particular, researchers wanted to understand what changes needed to occur in a bat viruss spike proteins before it could infect people.

Researchers at the Wuhan Institute of Virology, led by Chinas leading expert on bat viruses, Dr. Shi Zheng-li or Bat Lady, mounted frequent expeditions to the bat-infested caves of Yunnan in southern China and collected around a hundred different bat coronaviruses.

Dr. Shi then teamed up with Ralph S. Baric, an eminent coronavirus researcher at the University of North Carolina. Their work focused on enhancing the ability of bat viruses to attack humans so as to examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs [coronaviruses]. In pursuit of this aim, in November 2015 they created a novel virus by taking the backbone of the SARS1 virus and replacing its spike protein with one from a bat virus (known as SHC014-CoV). This manufactured virus was able to infect the cells of the human airway, at least when tested against a lab culture of such cells.

The SHC014-CoV/SARS1 virus is known as a chimera because its genome contains genetic material from two strains of virus. If the SARS2 virus were to have been cooked up in Dr. Shis lab, then its direct prototype would have been the SHC014-CoV/SARS1 chimera, the potential danger of which concerned many observers and prompted intense discussion.

If the virus escaped, nobody could predict the trajectory, said Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris.

Dr. Baric and Dr. Shi referred to the obvious risks in their paper but argued they should be weighed against the benefit of foreshadowing future spillovers. Scientific review panels, they wrote, may deem similar studies building chimeric viruses based on circulating strains too risky to pursue. Given various restrictions being placed on gain-of function (GOF) research, matters had arrived in their view at a crossroads of GOF research concerns; the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens. In developing policies moving forward, it is important to consider the value of the data generated by these studies and whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved.

That statement was made in 2015. From the hindsight of 2021, one can say that the value of gain-of-function studies in preventing the SARS2 epidemic was zero. The risk was catastrophic, if indeed the SARS2 virus was generated in a gain-of-function experiment.

Inside the Wuhan Institute of Virology

Dr. Baric had developed, and taught Dr. Shi, a general method for engineering bat coronaviruses to attack other species. The specific targets were human cells grown in cultures and humanized mice. These laboratory mice, a cheap and ethical stand-in for human subjects, are genetically engineered to carry the human version of a protein called ACE2 that studs the surface of cells that line the airways.

Dr. Shi returned to her lab at the Wuhan Institute of Virology and resumed the work she had started on genetically engineering coronaviruses to attack human cells.

How can we be so sure?

Because, by a strange twist in the story, her work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the U.S. National Institutes of Health (NIH). And grant proposals that funded her work, which are a matter of public record, specify exactly what she planned to do with the money.

The grants were assigned to the prime contractor, Dr. Daszak of the EcoHealth Alliance, who subcontracted them to Dr. Shi. Here are extracts from the grants for fiscal years 2018 and 2019. CoV stands for coronavirus and S protein refers to the viruss spike protein.

Test predictions of CoV inter-species transmission. Predictive models of host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice.

We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential.

What this means, in non-technical language, is that Dr. Shi set out to create novel coronaviruses with the highest possible infectivity for human cells. Her plan was to take genes that coded for spike proteins possessing a variety of measured affinities for human cells, ranging from high to low. She would insert these spike genes one by one into the backbone of a number of viral genomes (reverse genetics and infectious clone technology), creating a series of chimeric viruses. These chimeric viruses would then be tested for their ability to attack human cell cultures (in vitro) and humanized mice (in vivo). And this information would help predict the likelihood of spillover, the jump of a coronavirus from bats to people.

The methodical approach was designed to find the best combination of coronavirus backbone and spike protein for infecting human cells. The approach could have generated SARS2-like viruses, and indeed may have created the SARS2 virus itself with the right combination of virus backbone and spike protein.

It cannot yet be stated that Dr. Shi did or did not generate SARS2 in her lab because her records have been sealed, but it seems she was certainly on the right track to have done so. It is clear that the Wuhan Institute of Virology was systematically constructing novel chimeric coronaviruses and was assessing their ability to infect human cells and human-ACE2-expressing mice, says Richard H. Ebright, a molecular biologist at Rutgers University and leading expert on biosafety.

It is also clear, Dr. Ebright said, that, depending on the constant genomic contexts chosen for analysis, this work could have produced SARS-CoV-2 or a proximal progenitor of SARS-CoV-2. Genomic context refers to the particular viral backbone used as the testbed for the spike protein.

The lab escape scenario for the origin of the SARS2 virus, as should by now be evident, is not mere hand-waving in the direction of the Wuhan Institute of Virology. It is a detailed proposal, based on the specific project being funded there by the NIAID.

Even if the grant required the work plan described above, how can we be sure that the plan was in fact carried out? For that we can rely on the word of Dr. Daszak, who has been much protesting for the last 15 months that lab escape was a ludicrous conspiracy theory invented by China-bashers.

On 9 December 2019, before the outbreak of the pandemic became generally known, Dr. Daszak gave an interview in which he talked in glowing terms of how researchers at the Wuhan Institute of Virology had been reprogramming the spike protein and generating chimeric coronaviruses capable of infecting humanized mice.

And we have now found, you know, after 6 or 7 years of doing this, over 100 new sars-related coronaviruses, very close to SARS, Dr. Daszak says around minute 28 of the interview. Some of them get into human cells in the lab, some of them can cause SARS disease in humanized mice models and are untreatable with therapeutic monoclonals and you cant vaccinate against them with a vaccine. So, these are a clear and present danger.

Interviewer: You say these are diverse coronaviruses and you cant vaccinate against them, and no anti-virals so what do we do?

Daszak: Well I thinkcoronaviruses you can manipulate them in the lab pretty easily. Spike protein drives a lot of what happen with coronavirus, in zoonotic risk. So you can get the sequence, you can build the protein, and we work a lot with Ralph Baric at UNC to do this. Insert into the backbone of another virus and do some work in the lab. So you can get more predictive when you find a sequence. Youve got this diversity. Now the logical progression for vaccines is, if you are going to develop a vaccine for SARS, people are going to use pandemic SARS, but lets insert some of these other things and get a better vaccine. The insertions he referred to perhaps included an element called the furin cleavage site, discussed below, which greatly increases viral infectivity for human cells.

In disjointed style, Dr. Daszak is referring to the fact that once you have generated a novel coronavirus that can attack human cells, you can take the spike protein and make it the basis for a vaccine.

One can only imagine Dr. Daszaks reaction when he heard of the outbreak of the epidemic in Wuhan a few days later. He would have known better than anyone the Wuhan Institutes goal of making bat coronaviruses infectious to humans, as well as the weaknesses in the institutes defense against their own researchers becoming infected.

But instead of providing public health authorities with the plentiful information at his disposal, he immediately launched a public relations campaign to persuade the world that the epidemic couldnt possibly have been caused by one of the institutes souped-up viruses. The idea that this virus escaped from a lab is just pure baloney. Its simply not true, he declared in an April 2020 interview.

The Safety Arrangements at the Wuhan Institute of Virology

Dr. Daszak was possibly unaware of, or perhaps he knew all too well, the long history of viruses escaping from even the best run laboratories. The smallpox virus escaped three times from labs in England in the 1960s and 1970s, causing 80 cases and 3 deaths. Dangerous viruses have leaked out of labs almost every year since. Coming to more recent times, the SARS1 virus has proved a true escape artist, leaking from laboratories in Singapore, Taiwan, and no less than four times from the Chinese National Institute of Virology in Beijing.

One reason for SARS1 being so hard to handle is that there were no vaccines available to protect laboratory workers. As Dr. Daszak mentioned in his December 19 interview quoted above, the Wuhan researchers too had been unable to develop vaccines against the coronaviruses they had designed to infect human cells. They would have been as defenseless against the SARS2 virus, if it were generated in their lab, as their Beijing colleagues were against SARS1.

A second reason for the severe danger of novel coronaviruses has to do with the required levels of lab safety. There are four degrees of safety, designated BSL1 to BSL4, with BSL4 being the most restrictive and designed for deadly pathogens like the Ebola virus.

The Wuhan Institute of Virology had a new BSL4 lab, but its state of readiness considerably alarmed the State Department inspectors who visited it from the Beijing embassy in 2018. The new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory, the inspectors wrote in a cable of 19 January 2018.

The real problem, however, was not the unsafe state of the Wuhan BSL4 lab but the fact that virologists worldwide dont like working in BSL4 conditions. You have to wear a space suit, do operations in closed cabinets and accept that everything will take twice as long. So the rules assigning each kind of virus to a given safety level were laxer than some might think was prudent.

Before 2020, the rules followed by virologists in China and elsewhere required that experiments with the SARS1 and MERS viruses be conducted in BSL3 conditions. But all other bat coronaviruses could be studied in BSL2, the next level down. BSL2 requires taking fairly minimal safety precautions, such as wearing lab coats and gloves, not sucking up liquids in a pipette, and putting up biohazard warning signs. Yet a gain-of-function experiment conducted in BSL2 might produce an agent more infectious than either SARS1 or MERS. And if it did, then lab workers would stand a high chance of infection, especially if unvaccinated.

Much of Dr. Shis work on gain-of-function in coronaviruses was performed at the BSL2 safety level, as is stated in her publications and other documents. She has said in an interview with Science magazine that The coronavirus research in our laboratory is conducted in BSL-2 or BSL-3 laboratories.

It is clear that some or all of this work was being performed using a biosafety standard biosafety level 2, the biosafety level of a standard US dentists office that would pose an unacceptably high risk of infection of laboratory staff upon contact with a virus having the transmission properties of SARS-CoV-2, says Dr. Ebright.

It also is clear, he adds, that this work never should have been funded and never should have been performed.

This is a view he holds regardless of whether or not the SARS2 virus ever saw the inside of a lab.

Concern about safety conditions at the Wuhan lab was not, it seems, misplaced. According to a fact sheet issued by the State Department on January 15,2021, The U.S. government has reason to believe that several researchers inside the WIV became sick in autumn 2019, before the first identified case of the outbreak, with symptoms consistent with both COVID-19 and common seasonal illnesses.

David Asher, a fellow of the Hudson Institute and former consultant to the State Department, provided more detail about the incident at a seminar. Knowledge of the incident came from a mix of public information and some high end information collected by our intelligence community, he said. Three people working at a BSL3 lab at the institute fell sick within a week of each other with severe symptoms that required hospitalization. This was the first known cluster that were aware of, of victims of what we believe to be COVID-19. Influenza could not completely be ruled out but seemed unlikely in the circumstances, he said.

Comparing the Rival Scenarios of SARS2 Origin

The evidence above adds up to a serious case that the SARS2 virus could have been created in a lab, from which it then escaped. But the case, however substantial, falls short of proof. Proof would consist of evidence from the Wuhan Institute of Virology, or related labs in Wuhan, that SARS2 or a predecessor virus was under development there. For lack of access to such records, another approach is to take certain salient facts about the SARS2 virus and ask how well each is explained by the two rival scenarios of origin, those of natural emergence and lab escape. Here are four tests of the two hypotheses. A couple have some technical detail, but these are among the most persuasive for those who may care to follow the argument.

1) The place of origin.

Start with geography. The two closest known relatives of the SARS2 virus were collected from bats living in caves in Yunnan, a province of southern China. If the SARS2 virus had first infected people living around the Yunnan caves, that would strongly support the idea that the virus had spilled over to people naturally. But this isnt what happened. The pandemic broke out 1,500 kilometers away, in Wuhan.

Beta-coronaviruses, the family of bat viruses to which SARS2 belongs, infect the horseshoe bat Rhinolophus affinis, which ranges across southern China. The bats range is 50 kilometers, so its unlikely that any made it to Wuhan. In any case, the first cases of the Covid-19 pandemic probably occurred in September, when temperatures in Hubei province are already cold enough to send bats into hibernation.

What if the bat viruses infected some intermediate host first? You would need a longstanding population of bats in frequent proximity with an intermediate host, which in turn must often cross paths with people. All these exchanges of virus must take place somewhere outside Wuhan, a busy metropolis which so far as is known is not a natural habitat of Rhinolophusbat colonies. The infected person (or animal) carrying this highly transmissible virus must have traveled to Wuhan without infecting anyone else. No one in his or her family got sick. If the person jumped on a train to Wuhan, no fellow passengers fell ill.

Its a stretch, in other words, to get the pandemic to break out naturally outside Wuhan and then, without leaving any trace, to make its first appearance there.

For the lab escape scenario, a Wuhan origin for the virus is a no-brainer. Wuhan is home to Chinas leading center of coronavirus research where, as noted above, researchers were genetically engineering bat coronaviruses to attack human cells. They were doing so under the minimal safety conditions of a BSL2 lab. If a virus with the unexpected infectiousness of SARS2 had been generated there, its escape would be no surprise.

2) Natural history and evolution

The initial location of the pandemic is a small part of a larger problem, that of its natural history. Viruses dont just make one time jumps from one species to another. The coronavirus spike protein, adapted to attack bat cells, needs repeated jumps to another species, most of which fail, before it gains a lucky mutation. Mutation a change in one of its RNA units causes a different amino acid unit to be incorporated into its spike protein and makes the spike protein better able to attack the cells of some other species.

Through several more such mutation-driven adjustments, the virus adapts to its new host, say some animal with which bats are in frequent contact. The whole process then resumes as the virus moves from this intermediate host to people.

In the case of SARS1, researchers have documented the successive changes in its spike protein as the virus evolved step by step into a dangerous pathogen. After it had gotten from bats into civets, there were six further changes in its spike protein before it became a mild pathogen in people. After a further 14 changes, the virus was much better adapted to humans, and with a further 4 the epidemic took off.

But when you look for the fingerprints of a similar transition in SARS2, a strange surprise awaits. The virus has changed hardly at all, at least until recently. From its very first appearance, it was well adapted to human cells. Researchers led by Alina Chan of the Broad Institute compared SARS2 with late stage SARS1, which by then was well adapted to human cells, and found that the two viruses were similarly well adapted. By the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV, they wrote.

Even those who think lab origin unlikely agree that SARS2 genomes are remarkably uniform. Dr. Baric writes that early strains identified in Wuhan, China, showed limited genetic diversity, which suggests that the virus may have been introduced from a single source.

A single source would of course be compatible with lab escape, less so with the massive variation and selection which is evolutions hallmark way of doing business.

The uniform structure of SARS2 genomes gives no hint of any passage through an intermediate animal host, and no such host has been identified in nature.

Proponents of natural emergence suggest that SARS2 incubated in a yet-to-be found human population before gaining its special properties. Or that it jumped to a host animal outside China.

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On a mission to help agriculture come alive in the classroom and get the next generation excited about ag-based careers, organizations and federal agencies have created STEM-based curricula to educate students on the important relationship between agriculture and science.

On The Farm STEM, a program of the American Farm Bureau Foundation for Agriculture, with funding from the Beef Checkoff, aims to bring STEM learning into real life through beef-focused lessons for middle and high school students and various programs for educators.

Using a series of lesson plans called Storylines, educators let students take the lead in the classroom, combining science, education and agriculture, while implementing a three-dimensional approach that helps build an understanding of science over time. This approach is the foundation of the Next Generation Science Standards.

Middle school students study ecosystem dynamics and symbiosis, with a focus on the important role cattle play in the survival of prairie chickens. High school students study genetics and heredity in the context of how cattle can best serve human needs.

For most urban and suburban students, these classroom lessons and activities provide the first opportunity for them to experience agriculture and better understand how it relates to their lives and communities.

The On the Farm STEM initiative also offers real-world educational resources for educators such as farm tours, professional development webinars and an All About Beef App.

Two exciting programs offered in 2021 are the On the Farm STEM Immersive Experience which will be held in Nashville, Tennessee, and a three-part Professional Development Webinar Series with NexGenScience.

The foundation and the Beef Checkoff are not alone in their efforts to bring agriculture alive in the classroom. The Food and Drug Administration, in coordination with the Environmental Protection Agency and U.S. Department of Agriculture, created the Agricultural Biotechnology Education and Outreach Initiative to provide education and outreach to the public on agricultural biotechnology and food and animal feed ingredients derived from biotechnology.

This new initiative spurred the creation of FDAs Science and Our Food Supply, a STEM-based supplemental curriculum for middle and high school students focusing on food safety, nutrition and biotechnology.

This free and award-winning curriculum arms educators with challenging hands-on, minds-on activities that link food safety, nutrition and biotechnology to students everyday lives.

In February, the FDA released Science and Our Food Supply: Exploring Food Agriculture and Biotechnology, an online supplemental curriculum on genetically engineered plants and the science behind them.

The curriculum aims to help teachers instruct middle and high school students about traditional and modern agricultural methods, with a focus on genetic engineering and genome editing techniques that are used to produce foods commonly called GMOs.

These innovations have given farmers critical tools to increase efficiency and reduce their environmental impact, and this new program helps students understand how cutting-edge technology is changing modern farming by protecting crops and animals from disease and helping farmers use less water, fertilizer and pesticides.

And because learning never stops, another FDA program, Feed Your Mind, aims to help consumers of all ages better understand GMOs and their impact, both in agriculture and in our daily lives.

As STEM-based education becomes increasingly important to preparing students for the future, partners across the food and agriculture chain are working hard to ensure that students carry with them a deep understanding of how agriculture continues to shape our world.

Whats more, these curricula are providing the building blocks to train the next generation of agriculturalists and researchers who will be critical to helping farmers and ranchers meet their sustainability goals while providing the food, fiber and fuel for an ever-growing world.

Amber Downer is a communications assistant at the American Farm Bureau Federation.

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SUZHOU and SHANGHAI, China, May 10, 2021 /PRNewswire/--Gracell Biotechnologies Inc. (NASDAQ: GRCL) ("Gracell"), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, today announced the appointment of Dr. Jenny (Yajin) Ni as its Chief Technology Officer (CTO). In her role, Dr. Ni will be responsible for strategically leading CAR-T product development, Chemistry, Manufacturing, and Control (CMC), and supply chain management activities. Dr. Ni will lead the efforts to ensure the smooth technology transfer to Gracell's strategic collaborator, Lonza, for manufacturing of FasTCAR-enabled product candidates in the U.S.

Dr. Ni brings over 25 years of experience in process and product development for gene & cell therapies and vaccines to Gracell. Prior to joining Gracell, Dr. Ni served as Head of Process Development at both Pfizer and Allogene Therapeutics, where she served in senior leadership roles in technical development and operation functions, led allogeneic CAR-T product development, and advanced multiple first-in-human allogeneic CAR-T pipeline programs through preclinical to clinical development, including five IND approvals for hematological malignancy and solid tumor indications. Prior to that, Dr. Ni also served as Director of Tech Operations at VIRxSYS Inc., where she held roles of increasing responsibility across process and analytical development, technology transfer, as well as technical support for GMP manufacturing and QC testing. While at VIRxSYS, Dr. Ni was instrumental in bringing the first-ever lentiviral vector-modified autologous T cell product for HIV infection into clinical development. Dr. Ni holds a Ph.D. in Molecular Virology from Kyoto University in Japan and an M.D. in Internal Medicine from Kunming Medical University in China.

"We are delighted that Dr. Ni has joined Gracell as CTO," said Dr. William (Wei) Cao, Founder, Chairman and Chief Executive Officer of Gracell. "Manufacturing is often a critical bottleneck in developing and commercializing CAR-T therapies. With the establishment of an internal GMP-compliant manufacturing facility in Suzhou and a process development center in Shanghai, we are well-positioned to support our extensive pipeline. A key component of our manufacturing strategy is a fully-closed system that enables us to substantially reduce costs, improve productivity, and scale-up production of our autologous FasTCAR product candidates. With Dr. Ni's extensive knowledge and experience, I am confident that Gracell will further accelerate the expansion of its global manufacturing capability and enhance our leadership position within the cell and gene therapy field."

"Gracell has successfully built a GMP-compliant manufacturing facility and an R&D center in China, as well as started establishing a state-of-the-art cGMP process in the U.S. in collaboration with Lonza. Gracell's comprehensive manufacturing strategy serves as a great foundation for its preclinical and clinical development initiatives," said Dr. Jenny (Yajin) Ni. "As CTO, I am excited to lead our efforts to ensure the smooth transfer of our pioneering FasTCAR technology to Lonza, and continuously broaden our proprietary genetic engineering and cell manufacturing capabilities and advance the next generation of CAR-T cell therapies for the treatment of cancer."

About Gracell

Gracell Biotechnologies Inc.("Gracell") is a global clinical-stage biopharmaceutical company dedicated to discovering and developing breakthrough cell therapies. Leveraging its pioneering FasTCAR and TruUCAR technology platforms, Gracell is developing a rich clinical-stage pipeline of multiple autologous and allogeneic product candidates with the potential to overcome major industry challenges that persist with conventional CAR-T therapies, including lengthy manufacturing time, suboptimal production quality, high therapy cost and lack of effective CAR-T therapies for solid tumors. For more information on Gracell, please visit http://www.gracellbio.com. Follow @GracellBio on LinkedIn.

Cautionary Noted Regarding Forward-Looking Statements

Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to the expected trading commencement and closing date of the offering. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including factors discussed in the section entitled "Risk Factors" in Gracell's most recent annual report on Form 20-F as well as discussions of potential risks, uncertainties, and other important factors in Gracell's subsequent filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Gracell specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Readers should not rely upon the information on this page as current or accurate after its publication date.

Media contact Marvin Tang [emailprotected]

Investor contact Gracie Tong [emailprotected]

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Gracell Biotechnologies Appoints Seasoned Gene & Cell Therapy Executive Dr. Jenny (Yajin) Ni as Chief Technology Officer - PRNewswire