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Our own worst bioenemy
by Wendy Orent
Los Angeles Times
AUG. 13, 2008 12 AM PT

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‘Whatever you can say about the Soviet bioweapons scientists,” a Bush administration official once told me, “they never killed anyone.”

We can’t say the same about our bioweapons scientists. Someone, most likely Bruce Ivins, at the U.S. Army Medical Research Institute of Infectious Diseases at Ft. Detrick, Md., turned powdered anthrax spores into a deadly weapon. It’s ironic that the Soviet scientists were making offensive weapons. Our people, since 1969, have worked strictly to defend us.

One of those defenders killed five people, sickened 17 others and plunged the nation into hysteria for weeks in the fall of 2001. After a seven-year investigation by the FBI, the source of the deadly anthrax strain has been identified -- our own biodefense program at Ft. Detrick. That is the real legacy of the FBI investigation.

Since the anthrax-laced letters were mailed in September and October of 2001, U.S. biodefense has blown up out of all proportion to any rational assessment of the bioweapons threat. Earlier this year, an article in the journal Biosecurity and Bioterrorism, analyzing government biodefense spending from 2001 to 2008, stated that $49.66 billion has been allocated for civilian biodefense. According to microbiologist and longtime biodefense critic Richard Ebright of Rutgers University, actual spending is even higher, amounting to $57 billion.

In 2005, he and 757 other microbiologists sent a stinging open letter to Elias Zerhouni, director of the National Institutes of Health, protesting the government’s preoccupation with “priority pathogens” -- germs such as anthrax that could be used in a bioweapons attack. But Zerhouni and Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, would have none of it. In a letter published in the journal Science, they disagreed: “The United States has experienced an anthrax attack, and security experts repeatedly express concern that future attacks with biological weapons are likely, if not inevitable.”

But we didn’t actually experience an anthrax attack. The whole incident amounted to a snake eating its own tail. No ingenious biowarrior from Al Qaeda sent the lethal envelopes through the U.S. postal system. An American scientist did. The FBI and its genetic analyses leave no doubt: Though 16 laboratories had access to the “Ames strain” of anthrax used in the letters, only the samples that came from Ivins’ laboratory at Ft. Detrick matched the genetic fingerprint of the attack strain.

In the sorry aftermath of the anthrax investigation, it’s clear that the National Institutes of Health and the Centers for Disease Control and Prevention have to rethink the priority-pathogens list, which includes anthrax, smallpox, plague, tularemia, Ebola and other germs that rarely, if ever, threaten American lives. It’s the “non-defense-related” germs that are killing us. Randall Wolcott of the Southwest Regional Wound Care Center points out that 500,000 Americans a year die of biofilm infections -- such as diabetic ulcers -- that are almost impossible to treat by conventional means. That’s almost twice as many as die of cancer.

According to the CDC, infections caused by methicillin-sensitive Staphylococcus aureus, or MRSA, kill 19,000 people a year. Still, staph itself isn’t considered a priority pathogen, despite the emergence of highly resistant and increasingly virulent strains. Only one of 40 staph toxins is on the priority list.

There’s another problem created by the priority-pathogens list. The ballooning of the biodefense program, according to Ebright, means that about 14,000 individuals are now considered qualified to work with priority pathogens.

It hasn’t always been easy to find qualified people for this research. In the days when the FBI was pursuing former “person of interest” -- and now exonerated -- Steven J. Hatfill, one senior government scientist said of Hatfill’s background, “You take what you can get -- not many people with his abilities show up very often.” So where do 14,000 suddenly qualified biodefense experts come from? And how can they be vetted? As biodefense expert Leonard Cole, author of “The Anthrax Letters,” told me: “There are 15,000 to 16,000 people now working in labs on select agents -- that’s many more possibilities of another bizarre individual doing illicit work.”

The lesson of the anthrax letters isn’t that we’re in danger of a bioweapons attack from terrorists. It’s that U.S. biodefense itself has become a threat: We have met the enemy -- and it is us.

The next administration should pull the plug on the biodefense excesses of the Bush administration and put most of the thousands of microbiologists to work on the germs we really need to worry about.

Wendy Orent is the author of “Plague: The Mysterious Past and Terrifying Future of the World’s Most Dangerous Disease.”

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Part 1 of 2

Synthetic Viral Genomics: Risks and Benefits for Science and Society
by Ralph S. Baric
University of North Carolina at Chapel Hill
2007

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Cite as: Baric RS. 2006. Synthetic Viral Genomics. In: Working Papers for Synthetic Genomics: Risks and Benefits for Science and Society, pp. 35-81. Garfinkel MS, Endy D, Epstein GL, Friedman RM, editors. 2007.

I. Introduction

A. Viruses and Biological Warfare


Viral disease outbreaks have long inspired fear in human populations. Highly pathogenic infectious disease has shaped world history, primarily by impacting the outcome of wars and other global conflicts and precipitating human movement. Historic accounts have documented the catastrophic consequences and human suffering associated with widespread viral outbreaks like smallpox virus, yellow fever virus, measles virus, human immunodeficiency virus (HIV), the severe acute respiratory syndrome coronavirus (SARS-CoV), the 1918 influenza virus and others (51). News accounts and film have reinforced the serious threat posed by the emergence of new viral diseases as well as the catastrophic consequences of intentional release of highly pathogenic viruses in human populations. As illustrated by the SARS epidemic and the continuing evolution of the H5N1 avian influenza, global and national infectious disease outbreaks can overwhelm disaster medical response networks and medical facilities, disrupt global economies, and paralyze health and medical services by targeting health care workers and medical staff (21). This review focuses on viruses of humans, animals and plants that are viewed as potential weapons of mass disruption to human populations, critical plant and animal food sources, and national economies; and will consider whether and how the availability of synthetic genomics technologies will change this landscape.

Biological warfare (BW) agents are microorganisms or toxins that are intended to kill, injure or incapacitate the enemy, elicit fear and devastate national economies. Because small amounts of microorganisms might cause high numbers of casualties, they are classified as weapons of mass destruction. A number of naturally occurring viruses have potential uses as BW agents, although the availability of these agents is oftentimes limited. This report discusses the potential use of recombinant and synthetic DNAs to resurrect recombinant BW viruses de novo and the potential for altering the pathogenic properties of viruses for nefarious purposes. Examples of weaponized viruses include Variola major (Smallpox), Venezuelan equine encephalitis virus (VEE), and the filoviruses Marburg and Ebola viruses, with the classic example being the use of smallpox virus-contaminated blankets against indigenous North American Indian populations (76). It is now clear that many viruses possess properties consistent with applications in biological warfare and bioterrorism.

B. Properties of Select BW Agents

Traditionally, biological warfare concerns have focused on a relatively limited, select group of naturally occurring pathogens viewed as having a set of desirable characteristics: 1) highly pathogenic, 2) readily available, 3) easily produced, 4) weaponizable, 5) stable, 6) infectious at a low dose, 7) easily transmissible, and 8) inspiring of fear (32). Viruses of concern include pathogens that replicate and produce serious morbidity and mortality in humans to pathogens that target farm animals and plants of economic importance. Historically, weaponization of agents has been constrained by availability, the biological characteristics specified within the genome of these organisms, the ability to replicate and produce large quantities of the material, and by the lack of appropriate associated technologies. Culture (growth) and containment conditions for most of the virus agents of concern have been solved and are readily available in the literature. Natural hosts and reservoirs of many viral agents have been identified, providing a means of readily acquiring these pathogens in nature, although this is not always the case. Most recently, full length genome sequences have been solved for many important human, animal and plant pathogens, providing a genetic template for understanding the molecular mechanisms of pathogenesis and replication. Structural studies have identified contact points between the virus and the host receptors needed for docking and entry, providing the means to humanize animal pathogens (42). With the advent of synthetic biology, recombinant DNA technology, reverse genetic approaches (i.e. the development of molecular clones of infectious genomes) and the identification of virulence alleles, not only are new avenues available for obtaining these pathogens, but more ominously, tools exist for simultaneously modifying the genomes for increased virulence, immunogenicity, transmissibility, host range and pathogenesis (22, 59). Moreover, these approaches can be used to molecularly resurrect extinct human and animal pathogens, like the 1918 human influenza virus (81).

National biodefense strategies are focused on threats posed by this small group of plant, animal and human pathogens that occur in nature. However, counterterrorism think-tanks anticipate that these particular threats will ameliorate over the next decade because of medical countermeasures (e.g., drugs, vaccines, diagnostics), coupled with a limited set of pathogens that include all of the biological warfare characteristics. More important, the anticipated long-term threat in biological warfare is in recognizing and designing countermeasures to protect against genetically modified and designer pathogens, made possible by newly emerging technologies in recombinant DNA, synthetic biology, reverse genetics and directed evolution (59). How will synthetic genomics effect future biological weapons development? What are the risks and benefits of these new technologies and how serious a threat do they pose for human health and the global economy? This paper builds upon earlier work and seeks to review the methodologies in isolating recombinant viruses in vitro and the application of these methods globally to biological warfare and biodefense (27).

II. Virus Classification and Reverse Genetic Approaches

A. Overview of Virus Classification and Reverse Genetics


From the genome, all viruses must generate a positive strand mRNA that is translated into proteins essential for genome replication and the assembly and formation of progeny virions. Depending upon the nature of the genome, all viruses can be clustered into seven fundamentally different groups, which utilize different strategies to synthesize mRNA from the input genome, a scheme called the Baltimore Classification (Figure 1).1 Because virus infectivity is dependent upon the ability to transcribe mRNAs, reverse genetic strategies are designed to insure expression of critical viral mRNAs that encode essential replicase proteins needed to “boot” (initiate) genome infectivity and initiate genome replication.

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Figure 1. Baltimore Classification Scheme

Group I viruses include the double-stranded DNA (dsDNA) viruses, like the Herpes viruses and Poxviruses which replicate in the nucleus or cytoplasm, respectively. The dsDNA viruses use cellular and/or virally-encoded transcriptase components to mediate expression of viral mRNAs. Poxviruses for instance require one or more viral proteins to initiate mRNA transcription and boot infectivity of the viral genome. Hence, smallpox virus genomes are not infectious unless the appropriate suite of viral proteins is provided in trans (in addition to the genome itself). In contrast, the Herpes virus genome is infectious in the absence of any viral proteins as cellular transcriptase machinery induces expression of early mRNAs and proteins that regulate expression of other viral genes and replication. Using vaccinia (poxvirus) as a model, an approach to successfully initiate/jump start and boot the infectivity of poxviruses has been developed, providing a template strategy for the family (11, 24). Herpes virus genomes are infectious in the absence of additional viral factors. Group II viruses encode single stranded DNA genomes which must be used as templates for the synthesis of a dsDNA before transcription and translation of mRNAs can occur within cells. At this time, group II BW agents have not been identified.

The Group III viruses contain double stranded RNA viruses, like reoviruses. Reovirus genomes consist of complementary positive and negative strands of RNA that are bound by hydrogen bonding, wrapped within a multistructured icosahedral core that is essential for virus transcription. The virion structure contains the necessary proteins required for initiating mRNA synthesis. Unlike many of the single-stranded RNA viruses, the dsRNA virus genomes are not infectious in isolation and the components necessary for booting genome infectivity remain unresolved.

Group IV viruses contain a single-stranded positive polarity RNA genome and include the flaviviruses, alphaviruses, picornaviruses (including poliovirus), coronaviruses (including the SARS virus), caliciviruses and others. Upon entry into cells, positive strand RNA genomes are immediately recognized by host translational machinery and the genome is translated into a suite of viral proteins, including the replicase proteins and RNA-dependent RNA polymerase which is necessary for initiating the viral replication cycle. Consequently, genome infectivity usually does require viral proteins or transcripts provided in trans to boot genome infectivity, although some exceptions have been reported (13). Group V viruses contain a single-stranded negative polarity RNA genome and include filoviruses (Ebola/Marburg), myxoviruses (influenza), and paramyxoviruses (Hendra). Group V genomes come in two different flavors, segmented (e.g., myxoviruses) or nonsegmented (e.g., paramyxoviruses and filoviruses). In either case, the genome is not infectious because it is complementary in sequence (anti-sense); it is the opposite of the positive strand that specifies amino acids and thus cannot be translated directly into any of the critical viral structural or replicase proteins needed for producing infectious virions. Negative strand RNA genomes are encapsidated into a complex ribonucleoprotein structure (RNP) usually composed of several virally encoded replicase proteins (e.g., polymerase complex proteins, support proteins, trans-acting proteins) that are incorporated into the virion during assembly. Together, these compose a functional replication complex. Upon entry, these RNP complexes immediately transcribe the genome negative strand RNA into mRNA that can be translated into the viral proteins. Consequently, genome infectivity requires the presence of full length RNA and a set of virally encoded replicase proteins that function as a transcriptional complex to express mRNAs. If mRNAs encoding the transcripton complex are provided in trans, group V genomes become infectious and virus will be successfully recovered.

Group VI viruses, retroviruses (including HIV) and lentiviruses, encode single stranded positive polarity RNA genomes, but virions encode a reverse transcriptase enzyme to convert the mRNA genome into a complementary DNA (cDNA) which serves as template for dsDNA synthesis. Following the synthesis of dsDNA, group VI viruses use cellular transcriptional and translational machinery to express viral transcripts encoding structural and nonstructural proteins. At this time, the group VI viruses do not include any BW agents.

B. Infectious Genomes, Molecular Clones and Reverse Genetics

The basic concepts central to understanding virus reverse genetics and molecular clones are summarized in Figures 1 and 2. The central idea is that the virion is an extracellular vehicle that transfers the viral genome (e.g., RNA or DNA genomes) between susceptible cells and protects the nucleic acid genome from degradation in the environment (Figure 2, Part A). Following entry, the viral genome is programmed to initiate a series of events that result in the production of a replicase complex that transcribes mRNA and replicates the genome. As discussed in the previous section, nucleic acid structure and organization determines the pathway of events needed to express mRNA and initiate virus gene expression and infection. Not all viruses, however, require virion attachment and entry to mediate a productive infection. In these cases, viral genomes can be isolated from virions and transfected directly into susceptible host’s cells. If the genome is infectious, viral RNAs and proteins will be expressed allowing for the production and release of progeny virions (Figure 2, Part B). Classic examples of viruses with “infectious genomes” include the herpes viruses, polioviruses, alphaviruses, polyomaviruses, and flaviviruses which are classified among the Group I, II or IV viruses. However, not all viral genomes are infectious upon delivery into cells. Viruses with Group III or V genomes have never been demonstrated to be infectious upon genome delivery into susceptible cells. Some Group I (poxviruses) and group IV virus genomes (e.g., norovirus, a causative agent of non-bacterial gastroenteritis, or “cruise ship disease” and the coronavirus infectious bronchitis virus) are not infectious upon delivery into susceptible cells (13). In these instances, genome infectivity requires the presence of specific cofactors to initiate viral replication. These cofactors typically represent one or more proteins that encode essential replicase proteins or encapsidate the genome into an RNP structure necessary for initiating transcription of mRNA from the genome. In this example, infectious bronchitis virus genome infectivity requires the nucleocapsid protein in trans while the components needed to boot norovirus genome infectivity remain unknown (13).

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Figure 2. Virus Reverse Genetic Strategies

In the late 1970’s, a simple observation altered the course of virology research globally. Using a small dsDNA virus genome as a model (the Group I polyomavirus SV40) researchers cloned the viral genome into a bacterial plasmid and propagated the viral genome in bacteria. Upon isolation of the plasmid DNA from bacteria, restriction enzymes were used to excise the dsDNA viral genome, re-ligate the genome in vitro into a circular dsDNA and rescue virus following transfection of the genome into susceptible cells (Figure 2, Part C)(28). (Many advances in biotechnology have been, and continue to be, dependent upon this restrict-isolate-ligate technique, or variations of it.) Shortly thereafter, full length cDNAs of positive strand RNA genomes were isolated following reverse transcription, the cDNAs cloned and propagated in bacterial plasmids, and following introduction of full length DNA into eukaryotic cells, recombinant viruses were rescued from the transfected cultures, although very inefficiently. The major problems with this approach were the difficulty in generating the appropriate termini, accurate genome sequence, problems in nuclear transport of the full length RNA genome, and splicing of the viral genomic RNA. To rectify the efficiency problems, bacteriophage promoters (T7, SP6, T3) were introduced upstream of the cloned viral cDNAs, allowing in vitro transcription of full length RNA copies of the viral genome using the appropriate phage RNA polymerase, nucleotide triphosphates, and other constituents (Figure 2, Part D). The full length RNAs, near exact replicas of the viral genome, were highly infectious upon transfection of susceptible host cells (Figure 2, Part E)(2, 65, 66). The ability to clone full length copies of viral genomes allowed for ease of manipulation of the genome and the introduction of specific mutations. Recovered viruses contained the introduced mutations that were encoded within the full length cDNA clones, providing a ready means of performing detailed genetic analyses of virus replication and pathogenesis.

As noted earlier not all viral genomes are infectious, complicating the development of full length cDNAs and the recovery of recombinant viruses. Isolated dsRNA genomes from Group V negative sense RNA viruses are not infectious because the genome sequence cannot be translated directly into a functional replicase complex needed to transcribe the incoming genomic RNA. As Group V virions contain a replicase protein complex essential for transcription, genome infectivity requires that cells be co-transfected with plasmids that express the genomic RNA and plasmids expressing transcripts that encode the replicase protein complex are needed for genome infectivity (Figure 3a). For most group V viruses, both genome negative and positive sense RNA infectivity can be booted using this approach with most investigators expressing full length plus (coding) strands from the initial transcript. The plus strands are transcribed to full length negative strands, which are used to express the appropriate set of mRNA encoding the full component of positive and negative strand RNAs. Using this approach Schnell et al. successfully recovered the first recombinant negative stranded RNA virus, rabies virus, from a cloned cDNA, ushering in an era of Group V virus reverse genetics (68, 82). These findings were rapidly extended to other linear negative stranded RNAs like paramyxoviruses and then to segmented negative strand RNA viruses like influenza and other myxoviruses, and then select bunyaviruses and arenaviruses (20). Reverse genetic strategies for group V viruses with segmented genomes are most complex as multiple plasmids expressing copies of each genome segment must be simultaneously delivered to a cell along with the support plasmids encoding the transcriptase complex.

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Figure 3a. Category V (Linear negative sensed RNA genome) Reverse Genetic Approach

Most of the RNA viruses have relatively small genomes (under approximately 20,000 bases or base-pairs). Viruses with extremely large genomes (over 100,000 base-pairs, e.g., herpes viruses, poxviruses, or ~20,000-30,000 base pairs, e.g., coronaviruses, filoviruses) have presented additional obstacles in the development of stable molecular clones. Generation of infectious clones for viruses encoding large RNA or DNA genomes is complicated by the need for sequence accuracy (e.g., incorrect sequences usually contain lethal mutations), the lack of suitable cloning vectors that stably maintain large DNA inserts, large genome size, and that the genomes oftentimes encode regions that are toxic or unstable in bacteria. In poxviruses for example, the ~200 kilobase pair (kbp) genome has covalently closed hairpin ends (structures formed by the DNA itself) that are required for genome replication and virion encoded products are also essential for booting genome infectivity (24).

Herpes virus genomes are ~150 kbp in size. One solution was to stably clone large viral genomes as bacterial artificial chromosome (BAC) vectors. BAC vectors are based on the replication of F factor in E.coli, which is tightly controlled and allows stable maintenance of large, complex DNA fragments up to 600 kbp and both herpesvirus and poxvirus genomes can be stably maintained in BAC vectors (17, 24). For Herpes viruses, BAC shuttle vector sequences encoding a marker are inserted by homologous recombination into the genome. Circular viral DNA, which is generated during the Herpes virus replication cycle, is purified from infected cells (so-called Hirt prep) and introduced in bacterial cells, which essentially generates a large plasmid containing the Herpes virus genome (49). As herpesvirus genomes are infectious, the BAC DNA sequences are rapidly lost after delivery to a suitable host cell, along with some surrounding viral sequences, because they are dispensable for viral DNA replication (71). Using the Cre/lox system (another basic tool of molecular biology), a self-recombining full length pseudorabies virus BAC was developed where the full length genome is automatically removed from the BAC sequences by the expression of Cre recombinase after transfection, reducing the potential for random deletions of viral sequences (72) (Figure 3b). Recombinant Herpes virus genomes that have been successfully cloned include mouse cytomegalovirus, herpes simplex virus 1, human cytomegalovirus, pseudorabies virus, and Kaposi’s Sarcoma virus (11, 24, 49).

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Figure 3b. Bac Vector Based Recombinant Clones for Herpesviruses (HV).

Poxvirus genome structure and replication modes make the development of an infectious poxvirus molecular clone an order of magnitude more difficult than generation of the Herpes virus molecular clone. Poxvirus genomes replicate in the cytoplasm and require several viral proteins to mediate mRNA transcription and a unique DNA-dependent RNA polymerase that are normally contained within the virion to initiate virus infection.

Consequently, purified poxvirus DNA is not infectious. In addition, the linear dsDNA genome has closed hairpins at each end of the genome that are essential for DNA replication. How were these problems solved? As described with Herpes viruses, a mini BAC encoding a marker called green fluorescent protein (GFP) was recombined into the thymidine kinase gene encoded in the vaccinia genome (a model for smallpox). Recombinant viruses harboring the BAC cassette were identified by GFP expression. However, transformation of Vaccinia BAC vectors into E.coli required conversion of the linear genome with covalently closed ends into a closed circular DNA. To accomplish this, Domi and Moss blocked late viral gene expression knowing that this favored additional recombination events that allowed head to tail concatamers of full length genome from which monomeric recombinant genome in a covalently closed circle would result, a favored genome orientation for insertion into E.coli. Transfection of VAC-BAC DNA into mammalian cells, previously infected with a helper fowl pox virus whose replication is defective in mammalian cells, allowed recovery of recombinant vaccinia virus (23, 24).

Although BACs are remarkably stable, both poxviruses and herpesvirus genomes contain repetitive sequence elements and other sequences that might be unstable with passage as no biological selective pressure exists to maintain virus genome sequence fidelity in E. coli. Because the large genome size makes it impractical to sequence the entire genome, in vivo pathogenesis studies have been used to demonstrate equivalent levels of pathogenicity and virulence between wildtype and recombinant herpes viruses, further supporting the hypothesis that BAC recombinant genomes are highly stable in E.coli (12). The availability of large dsDNA genomes in BACs provides two major opportunities for future research, the construction of expression vectors for treatment of human diseases and the mutagenesis of the viral genome for understanding gene function, virus replication and pathogenesis.

A second solution to large genome instability was developed using coronaviruses as models. Seven contiguous cDNA clones that spanned the 31.5 kilobase (kb) coronavirus genome (e.g., mouse hepatitis virus [MHV] or SARS-CoV) were amplified, isolated and ligated into standard polymerase chain reaction (PCR) cloning vectors (PCR is one technique used to amplify sequences that are rare and/or not available in large quantities, to provide enough material for subsequent experiments). The ends of the cDNAs were engineered with unique junctions, generated by class IIS restriction endonucleases like BglI or Esp3I. These enzymes leave asymmetric ends, which are designed to seamlessly reproduce the exact virus sequence, allow directional assembly of adjacent cDNA subclones, and direct the production of an intact full length cDNA construct of ~31.5 Kb in length. With enzymes like Esp3I, interconnecting restriction site junctions can be located at the ends of each cDNA and systematically removed during the assembly of the complete full-length cDNA product (Figure 4a). The availability of a contiguous set of DNAs containing unique interconnecting junctions provides for the systematic assembly of large DNA molecules greater than 1,000,000 base pairs by in vitro ligation (85). In the case of coronaviruses (Figure 4b), full length cDNAs are assembled that contain a T7 transcription site at the 5’ end of the genome. RNA transcripts driven from the full length cDNA were infectious upon delivery into susceptible cells (85, 87). Alternatively, coronavirus genomes can be stably cloned into BAC vectors. T7 or eukaryotic promoters encoded upstream of the viral sequences allow for the synthesis of full length RNA genome sequences, which are infectious upon introduction into cells (1).

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Figure 4a. Systematic Whole Genome Assembly Techniques

Seamless assembly (also called No See’m Sites (85)) cascades have been used to assemble full length cDNAs of the coronaviruses mouse hepatitis virus, transmissible gastroenteritis virus, infectious bronchitis virus and the SARS-CoV (85,86,87). Because certain type IIS restriction endonucleases (e.g., Esp3I, AarI, Sap1) recognize asymmetric binding sites and leave asymmetric ends, these enzymes can be used to create the unique interconnecting junctions, which can be subsequently removed from the final assembly product allowing for the seamless reconstruction of an exact sequence (Figure 4b). This approach avoids the introduction of nucleotide changes that are normally associated with building a full-length cDNA product of a viral genome. These non-palindrome restriction sites will also provide other novel recombinant DNA applications. For example, by PCR it will be possible to insert Esp3I or a related non-palindromic restriction site at any given nucleotide in a viral genome and use the variable domain for simple and rapid site-specific mutagenesis. By orientating the restriction sites as “No See’m”, the sites are removed during reassembly, leaving only the desired mutation in the final DNA product. The dual properties of strand specificity and a variable end overhang that can be tailored to match any sequence allow for Esp3I sites to be engineered as “universal connectors” that can be joined with any other four nucleotide restriction site overhangs (e.g. EcoRI, PstX1, BamH1). Alternatively, “No See’m” sites can be used to insert foreign genes into viral, eukaryotic, or microbial genome or vector, simultaneously removing all evidence of the restriction sites that were used in the recombinant DNA manipulation.

Finally, these restriction sites allow for the rapid assembly of small synthetically produced cDNAs into progressively larger cDNAs. For example, enzymes like AarI recognize a 7 nucleotide recognition sequence and leave a four nucleotide asymmetric end (usually). In a random DNA sequence, this site occurs every 8,000 base pairs or so. Using a recursive assembly cascade 2~256 different 8Kb cDNAs can be assembled into extremely large >1,000,000 bp DNAs designed in BACs for stable maintenance in bacteria (85-87).

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Figure 4b. Systematic Assembly of Coronavirus Genomes.

At this time, well developed molecular clones have been constructed with representative viruses in most of the known virus families; specifically, the Groups I-IV genomes, thus providing a systematic approach for generating molecular clones of many Categories I, III, and IV BW agents. In addition, recent advances in synthetic biology provides promise for reconstructing microbial genomes de novo (15), as has been elegantly demonstrated with the recovery of recombinant poliovirus and ΦX174 viruses (14, 73) from synthetically derived genomes. In these instances, accurate sequences were available for de novo synthesis, as functional molecular clones had existed for both viruses for many years. Consequently, the combination of proof of principle, available templates for genome construction and sequence information make it likely that any virus genome could be synthetically reconstructed from sequence databases, assuming that the sequence is correct (18, 36).

C. Review of Controlled Viruses

The United States Department of Health and Human Services (HHS), the Centers for Disease Control and Prevention (CDC), and the United States Department of Agriculture (USDA) have identified bacteria, viruses, toxins, rickettsia, and fungi that pose a potential threat to public health or welfare. Some of these organisms are considered Select Agents and High Consequence Livestock Pathogens and all research laboratories with access to these agents must submits names and fingerprints of all individuals listed as working with Select Agents to the Department of Justice. Every person who enters a laboratory containing registered Select Agents must have FBI security clearance or be accompanied and monitored by such a cleared person. This includes visitors and employees performing routine cleaning, maintenance, and repairs. The CDC oversees and regulates all laboratories that possess or use select agents and the transfer of select agents and toxins that may be used to threaten the overall public health and safety as published in the Federal Register on March 18, 2005 (42 C.F.R. Part 73, 7 C.F.R. Part 331, and 9 C.F.R. Part 121) (Appendix 1). In addition, the Department of Commerce regulates the transport of many pathogenic agents deemed important for maintaining the public health or that could impact the economic vitality of the US. Many, but not all, overlap with the Select Agent List and the USDA High Consequence Livestock Pathogens. Finally, the National Institutes of Health has assembled a list of high priority agents for biodefense research, and provides special funding for basic science, vaccines and therapeutics. Select agents are typically grouped among category A agents that pose the most serious perceived risk to national security while category B agents include many important food and waterborne agents that are easy to disseminate. The category C agents are emerging pathogens of special concern or pathogens that could be engineered for mass dissemination.

All work with microbes that might be harmful to workers or to the environment is conducted according to a variety of regulations directed to the general area of “biosafety and containment”. What is important here is that biosafety and containment are accomplished through a suite of institutional and worker actions and these activities are referred to by the level of containment achieved. “Biosafety Level 1” (BSL-1) is the least stringent containment; BSL-4 the most stringent (used for the deadliest pathogens for which there are no treatments).

Priority viruses will be discussed according to the Baltimore Classification Scheme. The key columns in these tables are the last three, Nature, Laboratory, and Synthetic. A “yes” in Nature indicates that the virus can be found in nature (thus, all viruses on the list except smallpox, 1918 H1N1 and 1957 H2N2 influenza, and the 2002-2003 strain of SARS CoV). A “yes” under Laboratory means that the virus can be found in some kind of lab, be it a research laboratory, a reference laboratory (e.g., the American Type Culture Collection), a commercial laboratory, etc. This is virtually all viruses on the list (smallpox is closely guarded, and the recently resurrected 1918 influenza virus, at least for now, is in a limited number of known laboratories). Synthetic captures two characteristics. First, is it possible to synthetically construct a virus of a specific family? These are indicated in bold, and takes into account both whether a synthetic DNA construct can supply the appropriate nucleic acid, and if enough is known about the other aspects of booting the system that it is imaginable that a synthetic approach would be taken. Second, for the individual viruses on the list, the range of possibility takes into account both whether it is possible to construct, and whether this would be an attractive possibility compared to finding it in nature, or trying to steal it from a laboratory (in the case of a bioterrorist). So for example, even though foot-and-mouth disease virus is easy to find in nature and highly contagious, it is also easy enough to synthesize that bioterrorists hoping to hide their tracks may prefer the synthetic route.

The Group I agents include the dsDNA viruses contained among the Herpes viruses, Poxviruses and Asfarviruses (Figure 5). Herpes viruses contain linear dsDNA genomes of about 150,000 base pairs and include Herpes B virus (primate) and Malignant catarrhal fever viruses (swine), both of which are readily available in nature and for which culture conditions have been detailed in the literature. Herpes virus genomes are infectious; full length molecular clones and recombinant viruses have been described for several human and animal herpes viruses (72). Although molecular clones for Herpes B virus and Malignant catarrhal fever virus have not been described, a significant body of literature provides a theoretical template and guide for the development of similar constructs with a high probability of success.

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Figure 5. Category I Restricted Agents.

Poxvirus genomes range in size from 150,000 to 196,000 base pairs in length and the genomes are not infectious upon introduction into susceptible cells. However, poxvirus genome infectivity can be booted by coinfection with an avian poxvirus that has an abortive infection in mammalian cell lines, but provides essential proteins for transcribing the poxvirus genome. A molecular clone has been described for vaccinia virus, providing a theoretical template for guiding similar technology with other members in the family (23, 24). Poxviruses like Variola major and Variola minor (smallpox) and monkey pox viruses are select agents. Although most poxviruses can be readily found in nature and/or are maintained in laboratory settings, Variola major and minor are notable exceptions that are thought extinct in the wild. These two viruses are maintained in high security facilities in the US and Russia and it is very unlikely that these agents can be recovered from natural settings.

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Figure 6. Category III Priority Viruses.

Group III priority agents include the reoviruses African horse sickness and exotic bluetongue strains, which primarily infect domesticated animals (Figure 6). Reovirus genomes contain ten segments of double stranded RNA and these genomes are not infectious in isolation. Reproducible schemes to boot reovirus genome infectivity have recently been developed by the Dermody laboratory. Although these viruses are available in nature and in laboratory settings, the inability to initiate genome infectivity had hampered the successful development of reverse genetic approaches and molecular clones. Consequently, the use of natural or laboratory acquired strains represented the most likely approach to acquiring these agents for bioterrorism purposes, although the reovirus reverse genetic system should be an appropriate template for developing molecular clones to other reoviruses.

Group IV viruses contain single stranded positive polarity RNA genomes and include agents in the calicivirus, potyvirus, picornavirus, alphavirus, flavivirus and coronavirus families (Figure 7). These viruses have dramatically different virion structures, genome organizations, and transmission modes between hosts; they target different tissues, display different virulence and pathogenic determinants and use different replication strategies upon entry into susceptible cells. Common features, however, include an infectious positive sense RNA genome and relatively straightforward and well developed approaches for obtaining full length cDNA clones from which recombinant viruses can be easily isolated in culture. In most cases these viruses replicate efficiently in culture, and animal models of disease exist, allowing for easy cultivation, maintenance, and testing in a laboratory setting. A general rule of thumb is that the BSL2 positive single stranded RNA (e.g., human noroviruses) pathogens are more readily accessible than the BSL3 pathogens (e.g., SARS-CoV, VEE, etc.) in laboratory settings. BSL4 pathogens are the least accessible. Poliovirus, which is targeted for eradication, is not included among any of the high priority pathogen lists but has been synthetically reconstructed by the Wimmer laboratory. Wild poliovirus is eradicated from the North and South American continents and Europe, but is still prevalent in Africa and parts of Asia. The virus has been present in many laboratories throughout the world, although current efforts are aimed at limiting the availability of wildtype stocks to a few locations in the US. Should eradication efforts prove successful, poliovirus should almost certainly be listed as a high priority agent. In the future, poliovirus might represent a likely candidate for synthetic reconstruction efforts because whole genome sequence is available, genome size is small and could be purchased for about $10,000 US dollars, and synthetic polioviruses have been reconstructed in the laboratory. This possibility, however, may be several decades away and is also dependent upon an end to global vaccination efforts.

The Group IV viruses are also very abundant in nature and many are present in laboratories. The main exception is the human 2002-3 SARS-CoV epidemic strain that is likely extinct in the wild, but is present in many laboratories throughout the world. Globally, most SARS-CoV isolates were late phase epidemic strains because many early and zoonotic (animal) isolates were never successfully cultured and not distributed outside of China (19, 41). Molecular clones have been described for prototype animal caliciviruses, picoronaviruses, potyviruses, alphaviruses, flaviviruses and coronaviruses, including many, but not all of the agents of interest in Figure 7. At this time, molecular clones for human noroviruses have not been successfully developed.

Group V viruses contain a single stranded negative polarity RNA genome and include members of the bunyavirus, arenavirus, filovirus, paramyxovirus, rhabdovirus, and influenza virus families (Figure 8, below). As with the group IV viruses, these viruses differ dramatically in virion structure, genome organization, transmission modes, human disease severity, virulence and pathogenesis. In general, negative stranded RNA genomes are either nonsegmented and linear (e.g., paramyxovirus, filoviruses, rhabdovirus) or segmented and linear (e.g., bunyavirus, arenavirus, myxoviruses). These viruses are readily found in nature either in human and animal hosts or vectors; all of which have been well described in the literature. Most are easily cultured in laboratory settings. Again, laboratory availability diminishes with increased BSL ratings, so that BSL3 (e.g., 1918 influenza, Rift Valley Fever) and BSL4 (e.g., Ebola, Marburg, Lassa Fever, etc.) are the least available. The exceptions include the 1918 Spanish influenza virus and H2N2 (1957 pandemic) Asian influenza viruses which are likely extinct in the wild. The 1918 Spanish influenza was resurrected from a molecular clone and is only available in a few laboratories worldwide, but the H2N2 strain is more prevalent in laboratory settings (81). Both viruses are likely capable of producing pandemic disease, as the Spanish Flu H1N1 and Asian H2N2 strains have not circulated in human populations for over 90 and 50 years, respectively. Reverse genetics systems for prototypic members of each virus family have been reported in the literature although success is more rare with arenaviruses and bunyaviruses. In contrast, well documented reverse genetic systems have been described for paramyxoviruses, rhabdoviruses, myxoviruses, and filoviruses providing clear templates for reconstruction of synthetic viruses.

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Figure 7. Category IV Priority Viruses.  

Although many Category I-V agents are available in laboratory settings, serial passage of virus in cell culture oftentimes selects for “culture adapted” variants that display altered or reduced pathogenicity in the original host. In fact, serial passage in cell culture or alternative animal model has been used to attenuate virus pathogenesis and was used as a method to develop live attenuated poliovirus and measles virus vaccines. Consequently, laboratory strains may not reproduce wildtype virus pathogenicity and virulence when reintroduced into the natural host and may not represent the preferred source of starting material for bioterrorism applications.

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III. Barriers to Synthesizing and Resurrecting Viruses by Synthetic Biology and Reverse Genetics

Genetic engineering of viruses requires the development of infectious clones from which recombinant viruses can be isolated. Two basic strategies exist to develop and molecularly clone a viral genome: classic recombinant DNA approaches or synthetic biology. Although the basic methodology is different, the outcome is the same, a full length DNA copy of the viral genome is constructed which is infectious upon delivery to a permissive host cell. Classic recombinant DNA approaches require the availability of viral nucleic acid, which is normally isolated from infected tissues or cells and used as template for cloning and sequence analysis. For RNA viruses, the approach includes using reverse transcriptase and polymerase chain reaction to clone overlapping pieces of the viral genome and then whole genome assembly and sequence validation before successful recovery of recombinant viruses (10). Virus genome availability is an important issue and until recently, a major bottleneck in constructing a molecular clone to any BW virus. Most, though not all, viral BW agents are not readily available except in high containment BSL3 and BSL4 laboratories throughout the world. The few sites and lack of funding support historically limited access to a small number of researchers, although increased support for BW research has greatly increased the distribution and availability of these agents throughout the world (31). Most viruses are also available in zoonotic reservoirs although successful isolation may require an outbreak or knowledgeable individuals carrying out systematic sampling of hosts in endemic areas. Then, containment facilities for replicating virus are necessary. Some exceptions to this general availability of controlled viruses include early 20th century influenza viruses like the 1918 H1N1 (Spanish flu), the 1957 H2N2 (Asian Flu), smallpox viruses (extinct 1977) and perhaps the 2002-2003 epidemic SARS-CoV strains, all of which are likely extinct in the wild given the lack of recent human disease. With the molecular resurrection of the 1918 H1N1 strain using recombinant DNA techniques (81), these viruses only exist in select laboratories distributed throughout the world.

Two general approaches exist for synthetic reconstruction of microbial genomes from published sequence databases: de novo DNA synthesis and polymerase cycling assembly (PCA). Roughly 50 commercial suppliers worldwide provide synthetic DNAs using either approach, mostly in the range of <5.0Kb, although at this time only a few companies can assemble DNAs >30Kb. For example, Blue Heron’s GeneMaker™ is a proprietary, high-throughput gene synthesis platform with a ~3-4 week turnaround time and is reported to be able to synthesize any gene, DNA sequence, mutation or variant-including SNPs, insertions, deletions and domain-swaps with perfect accuracy regardless of sequence or size (http://www.blueheronbio.com/). Most commercial suppliers, however, use polymerase cycling assembly (PCA), a variation on PCR. Using published sequence, sequential ~42 nucleotide oligomers are synthesized and oriented in both the top and bottom strand, as pioneered for ΦX174 (73) (Figure 9). Top and bottom strand oligomers overlap by ~22 bp. The PCA approach involves: 1) phosphorylation of high purity 42-mers (oligonucleotide strands of DNA) in the top and bottom strand, respectively, 2) annealing of the primers under high stringency conditions and ligation with the Taq ligase at 55oC, 3) assembly by polymerase cycling assembly (PCA) using the HF polymerase mixture from Clontech (N-terminal deletion mutant of Taq DNA polymerase lacking 5’-exonuclease activity and Deep VentR polymerase [NEB] with 3’ exonuclease proofreading activity), 4) PCR amplification and cloning of full length amplicons (Figure 9). The key issue is to use HPLC to maximize oligomer purity and to minimize the numbers of prematurely truncated oligmers used in assemblages. As PCR is an error prone process, the PCA approach is also error prone and it requires sequence verification to ensure accurate sequence. PCA is also limited to DNAs of 5-10 Kb in length which is well within the genome sizes of many viral genomes, although improvements in PCR technologies could extend this limitation. Both approaches, coupled with systematic genome assembly techniques shown in Figure 4, will allow assembly of extremely large viral genomes, including poxviruses and herpes viruses.

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Figure 9. PCA Technique. Synthetic Reconstruction of Exotic SARS-CoV Spike Glycoproteins.

Consequently, knowledgeable experts can theoretically reconstruct full length synthetic genomes for any of the high priority virus pathogens, although technical concerns may limit the robustness of these approaches. It is conceivable that a bioterrorist could order genome portions from various synthesis facilities distributed in different countries throughout the world and then assemble an infectious genome without ever having access to the virus. To our knowledge, no international regulatory group reviews the body of synthetic DNAs ordered globally to determine if a highly pathogenic recombinant virus genome is being constructed.

What, then, are the technical barriers to the reconstruction of viral genomes? Three major issues are generally recognized: sequence accuracy, genome size and stability, and expertise. They are discussed in this order below.

Sequence databases record submissions from research facilities throughout the world. However, they have limited ability to review the accuracy of the sequence submission. Consequently, these databases are littered with mistakes ranging from 1 in 500 to 1 in 10,000 base pairs. In general, large sequencing centers are more accurate than independent research laboratories (18, 36). Accurate sequence is absolutely essential for rescuing recombinant viruses that are fully pathogenic (7, 10, 30, 85, 86) as even a single nucleotide change can result in viable virus that are completely attenuated in vivo (74). Sequence accuracy represents a significant barrier to the synthetic reconstruction of these highly pathogenic viruses. RNA viruses exist in heterogeneous “swarms” of “microspecies,” thus requiring the identification of a “master sequence;” i.e., the predominant sequence identified after sequencing the genome numerous times. Consequently, full length sequence information may have been reported, but the published sequence may actually not be infectious. Problems with sequence accuracy are proportional to genome size, as reported sequence for large viral genomes will more likely include a higher number of mutations than small genomes. In many instances, sequence errors will reside at the ends of viral genomes because the ends are oftentimes more difficult to clone and sequence.

Using state of the art facilities, the smallpox genome from a Bangladesh 1975 strain was sequenced (47). However, an error rate of 1:10,000 would result in about 19-20 mistakes and 10-14 amino acid changes in the recombinant genome. Should these mistakes occur within essential viral proteins or occur in virulence alleles, recovery of highly pathogenic recombinant viruses might be impossible. More recently, another genome sequence of Variola major (India 1967) has been reported in the literature (Bangladesh 75, and India 67; Accession # X69198 and L22579). These full length genomes differ in size by 525 base pairs, contain ~1500 other allelic changes scattered throughout the genomes, and also differ in size and sequence with the Variola minor genome (Figure 5). Although roughly 99.1% identical, which of these reported sequences are correct? Will pathogenic virus be recovered from a putative molecular clone of either, both or neither? If neither is infectious, which changes are responsible for the lethal phenotype? In the absence of documentation of the infectivity of a reported sequence, it becomes difficult to accurately predict the correct sequence that will allow for the recovery of infectious virus. At best, a combination of bioinformatics, evolutionary genetic and phylogenetic comparisons among family members may identify likely codon and nucleotide inconsistencies, simultaneously suggesting the appropriate nucleotide/codon at a given position. In the case of poxviruses, only two full length sequences of Variola major have been reported, hampering such sequence comparisons. Ultimately this approach only allows informed guesses that may not result in the production of recombinant virus. Obviously, reported full length genomic sequences that have been demonstrated to generate infectious viral progeny provide an exact sequence design for synthetic resurrection of a recombinant virus, greatly increasing the probability of success. In the absence of this data, multiple full length submissions are needed to enhance the probability of success.

Another problem hampering the development of synthetic DNA genomes for genetic manipulation are genome size and sequence stability in microbial vectors. Many viral full-length cDNAs, including coronavirus genomes and certain flavivirus genomes like yellow fever virus are unstable in microbial vectors (10). Low copy BAC vectors and stable cloning plasmids oftentimes reduce the scope of this problem although instability has been reported with large inserts following passage (1, 85). Plasmid instability might be caused by sequence toxicity associated with the expression of viral gene products in microbial cells or the primary sequence might simply be unstable in microbial vectors, especially sequences that are A:T rich. To circumvent this problem, plasmid vectors have been developed that contain poly-cloning regions flanked by several transcriptional and translational stops to attenuate potential expression of toxic products (86). The development of wide host range, low copy vectors that can be used in Gram positive or lactic acid bacteria may also allow amplification of sequences that are unstable in E. coli hosts. Alternatively, theta-replicating plasmids that are structurally more stable and that accommodate larger inserts than plasmids that replicate by rolling circle models may alleviate these concerns in the future (3, 35, 58). Poxvirus vectors also provide an alternative approach for stably incorporating large viral genome inserts, although long-term stability of these vectors is unknown (1, 77).

The technical skill needed to develop full length infectious cDNAs of viruses is not simple and requires a great deal of expertise and support: technically trained staff, the availability of state of the art research facilities, and funding. Theoretically, the ability to purchase a full length DNA of many viral biodefense pathogens is now possible, especially for those virus genomes that are less than 10 kb in length. In addition, defined infectious sequences are documented and methods have been reported in the literature. Infectious genomes of many Class IV viruses could be purchased and the need for trained staff becomes minimized. Today, a picornavirus or flavivirus genome could be purchased for as little as $15,000, a coronavirus genome for less than $40,000. It is much more difficult to reconstruct large viral genomes, meaning that trained staff and state of the art facilities become very essential to the process.

However, it is conceivable that technical advances over the next decade may even render large viral genomes commercially available for use by legitimate researchers, but perhaps also by bioterrorists.

IV. Risk and Benefits of Synthetic Organisms

A. Benefits to Society


The benefits of recombinant DNA have been heavily reviewed in the literature and include the development of safe and effective virus platform technologies for vaccine design and gene therapy, the production of large quantities of drugs and other human and animal medicines, and agricultural and other products key to robust national economies. Genetic engineering of bacteria and plants may allow for the production of large quantities of clean burning fuels, produce complex drugs, design highly stable biomolecules with new functions, and develop organisms that rapidly degrade complex pollutants (52, 56, 64, 78). Comparative genomics also provides numerous insights into the biology of disease-causing agents and is allowing for the development of new diagnostic approaches, new drugs and vaccines (27). Synthetic biology enhances all of the opportunities provided by recombinant DNA research. The main advantages of synthetic genomics over classic recombinant DNA approaches are speed and a mutagenesis capacity that allow for whole genome design in a cost effective manner (6). How will synthetic biology protect the overall public health?

A major advantage is in the development of rapid response networks to prevent the spread of new emerging diseases. Platform technologies allow for rapid detection and sequencing of new emerging pathogens. The SARS-CoV was rapidly identified as a new coronavirus by gene discovery arrays and whole genome sequencing techniques within a month after spread outside of China (37, 46, 83, 84). Similar advances were also made in the identification of highly pathogenic avian H5N1 influenza strains, hendra virus and in other outbreaks. Sequence information allowed for immediate synthesis of SARS and H5N1 structural genes for vaccines and diagnosis and the rapid development of candidate vaccines and diagnostic tools within a few months of discovery. Classic recombinant DNA approaches requires template nucleic acid from infected cells and tissues (limited supply), followed by more tedious cloning and sequence analysis in independent labs throughout the world. As access to viral nucleic acids historically limited response efforts to only a few groups globally, research productivity was stifled. Synthetic biology results in a true paradigm shift in virus vaccine, therapeutic and diagnostic discovery, resulting in the near simultaneously engagement of multiple laboratories as genome sequence becomes available (Figure 10).

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Figure 10. Synthetic DNA Rapid Response Applications.

Genome sequence provides for rapid incorporation of synthetic genes into platform technologies that allow for rapid diagnosis and epidemiologic characterization of the incidence, prevalence and distribution of new pathogens in human and animal hosts. Synthetic genes can be immediately incorporated into recombinant virus or bacterial vaccine platforms and tested in animal models and/or humans. Synthetic genes and proteins become essentially immediately available for structural studies, for high throughput identification of small molecule inhibitors and for the rational design of drugs. Synthetic full length molecular clones become available for genetic analysis of virus pathogenicity and replication, construction of heterotypic strains for vaccine and drug testing, rapid development of recombinant viruses containing indicator genes for high-throughput screens and for the development of live attenuated viruses as vaccines or seed stocks for killed vaccines.

Thus, the availability of synthetic genes and genomes provides for rapid development of candidate drugs and vaccines, although significant bureaucratic hurdles must be overcome to allow for rapid use in vulnerable human populations. We note that highly pathogenic respiratory viruses can be rapidly distributed worldwide, providing only limited opportunities and time for the prevention of global pandemics and the preservation of the overall public health.

B. Risks to Society

1. Bioterrorism


The historical record clearly shows that many nations have had biological weapons programs (of varying degrees of development) throughout the 20th century including many European nations, the USSR and the United States, Japan and Iraq. From relatively unscientific programs early in the 20th century, progressively more sophisticated scientific programs developed during WWI and the Cold War. There is little doubt that the genomics revolution could stimulate a new generation of potential program development (27, 76). It is also well established that the biological revolution, coupled with advances in biotechnology could be used to enhance the offensive biological properties of viruses simply by altering resistance to antiviral agents (e.g., herpes viruses, poxviruses, influenza), modifying antigenic properties (e.g, T cell epitopes or neutralizing epitopes), modifying tissue tropism, pathogenesis and transmissibility, “humanizing” zoonotic viruses, and creating designer super pathogens (27, 59). These bioweapons could be targeted to humans, domesticated animals or crops, causing a devastating impact on human civilization. Moreover, applications of these approaches are certainly not limited to the list of pathogens recorded throughout this report—well developed engineering tools have been developed for only a few BW agents, making them relatively poor substrates for biodesign. A clever bioterrorist might start with a relatively benign, easily obtainable virus (BSL2) and obtain an existing molecular clone by simply requesting it from the scientists who work with these agents. Then, using the expanding database of genomic sequences and identified virulence genes, the benign viral genome could be modified into more lethal combinations for nefarious use.

As recombinant DNA approaches, infectious DNA clones and the general methods needed to bioengineer RNA and DNA viruses have been available since the 1980-1990’s, what new capabilities does synthetic biology bring to a biowarrior’s arsenal? Clearly, recombinant viral genomes and bioweapon design can be accomplished using either or a combination of both approaches, suggesting that synthetic biology will have little impact on the overall capabilities of bioweapons research. However, synthetic biology provides several attractive advantages as compared with standard recombinant DNA approaches; specifically 1) speed, 2) mutagenic superiority, 3) ease of genome construction and 4) low cost. The main paradigm shift may be that the approach is less technically demanding and more design-based, requiring only limited technical expertise because the genome can be synthesized and purchased from commercial vendors, government sponsored facilities, or from rogue basement operations (e.g., bioterrorist sponsored or private entrepreneur). Main technical support might include a competent research technician and minimal equipment to isolate recombinant pathogens from the recombinant DNAs.

Standard recombinant DNA techniques are hands-on, laborious and slow, requiring multiple rounds of mutagenesis and sequence validation of the final product. At the end of this effort, there is no guarantee that the designer or synthetic genome will function as intended (see other sections), dictating the need for high throughput strategies. Synthetic genomes can be devised fairly rapidly using a variety of bioinformatics tools and purchased fairly cheaply ($1.10/base at current rates), allowing for rapid production of numerous candidate bioweapons that can be simultaneously released (e.g., survival of the fittest approach) or lab tested and then the best candidate used for nefarious purposes. The latter approach assumes that an organization has funded the development of a secure facility, has provided trained personnel and is willing to test the agents and/or passage them in humans, as animal models may be unreliable predictors of human pathogenesis. Assuming the technology continues to advance and spread globally, synthetic biology will allow for rapid synthesis of large designer genomes (e.g., ~30 Kb genome in less than a couple of weeks); larger genomes become technically more demanding. It seems likely that a standard approach could be designed for recovering each synthetic virus, further minimizing the need for highly trained personnel.

Will synthetic or recombinant bioweapons be developed for BW use? If the main purpose is to kill and inspire fear in human populations, natural source pathogens likely provide a more reliable source of starting material. Stealing the BW agent from a laboratory or obtaining the pathogen from natural outbreak conditions is still easier than the synthetic reconstruction of a pathogenic virus. These conditions, however, change as 1st and 2nd generation candidate vaccines and drugs are developed against this select list of pathogens, limiting future attempts to newly emerged viruses. If notoriety, fear and directing foreign government policies are principle objectives, then the release and subsequent discovery of a synthetically derived virus bioweapon will certainly garner tremendous media coverage, inspire fear and terrorize human populations and direct severe pressure on government officials to respond in predicted ways.

2. Prospects for Designer Super Pathogens

Advances in genomics may provide new approaches for mixing and matching genetic traits encoded from different viral pathogens, as over 1532 genome length sequences are available in Genbank. A large number of recombinant viruses have been assembled using reverse genetic approaches including chimeric flaviviruses, chimeric enteroviruses and coronaviruses, HIV, lentiviruses and others usually for the purposes of generating vaccines or dissecting basic questions about, e.g., viral metabolism (29, 34, 39, 40, 50). Importantly, recombinant viruses are actively being designed with programmed pathogenic traits as a means of controlling certain insect and animal pests, providing both theoretical and practical strategies for conducting effective biowarfare (53, 69). More importantly, the identification of numerous virus virulence genes that target the innate immune response (e.g., interferons, tumor necrosis factors, interleukins, complement, chemokines, etc.), apoptosis (programmed cell death) and other host signaling pathways provides a gene repository that can be used to potentially manage virus virulence (5, 8, 9, 26, 70). Poxviruses and Herpes viruses, for example, encode a suite of immune evasion genes and pro-apoptotic genes (48, 54). More recently, virus encoded microRNAs were identified in Epstein Barr Virus (EBV) and other herpes viruses, which function to silence specific cellular mRNAs or repress translation of host genes that function in cell proliferation, apoptosis, transcription regulators and components of signal transduction pathways (62). Although the function of many viral micro-RNAs are unknown, it is likely that they regulate protein coding gene expression in animals and influence pathogenesis (61). Moreover, microRNAs could also be designed and targeted to downregulate specific human signaling pathways.

The identification of virulence alleles is traditionally a first step to attenuating virus virulence. However, highly virulent murine pox virus (ectromelia) were recovered after the host IL-4 gene was incorporated into the genome. IL-4 expression altered the host Th1/Th2 immune response leading to severe immunosuppression of cellular immune responses, high viremias, and increased pathogenesis following infection. The recombinant virus was lethal in both control and in immunized or therapeutically treated mice (33, 67). More troubling was the belated recognition that this outcome could have been predicted based on our understanding of pox molecular virology and pathogenesis, suggesting that increased virulence can be rationally modeled into existing pathogens (55) and subsequent extension of these findings to other, but not all animal poxviruses (75). Many key questions remain unanswered regarding the ability to translate results with inbred mouse strains and murine poxviruses to outcome responses in outbred human populations infected with recombinant human poxviruses. Today, these outcomes cannot be predicted. Is it possible to enhance virulence by recombinant DNA approaches in other virus families and animal models? The influenza NS1 gene (an interferon antagonist gene) also enhances the replication efficiency of avian Newcastle disease virus in human cells (57), although the in vivo pathogenesis of these isolates has not been evaluated.

More recently the SARS-CoV ORF6, but not the ORF3a group specific antigens (specific proteins of the virus) were shown to enhance mouse hepatitis virus virulence in inbred mice strains. The mechanism by which the SARS-CoV ORF6 product enhances MHV virulence is not known at this time (60). Finally, viral gene discovery and sequence recovery using DNA microarrays will greatly increase the electronic availability of sequences from many novel human, animal and insect viruses (83, 84). This revolution in pathogen detection, coupled with rapid genome sequencing, provides a rich parts list for designing novel features into the genome of viruses.

Another approach might be to “humanize” zoonotic viruses by inserting mutations into virus attachment proteins or constructing chimeric proteins that regulate virus species specificity (viral attachment proteins bind receptors, mediating virus docking and entry into cells). For example, the mouse hepatitis virus (MHV) attachment protein, the S glycoprotein, typically targets murine cells and is highly species specific. Recombinant viruses contain chimeric S glycoproteins that are composed of the ecto-domain of a feline coronaviruses fused with the c-terminal domain of MHV S glycoproteins targets feline, not murine cells for infection. The pathogenicity of these chimeric coronaviruses is unknown (39). As information regarding the structure and interactions between virus attachment proteins and their receptors accumulate, data will provide detailed predictions regarding easy approaches to humanize zoonotic strains by retargeting the attachment proteins to recognize human, not the animal receptors (43-45). Conversely, it is not clear whether species retargeting mutations will result in viruses that produce clinical disease in the human host.

Synthetic DNAs and systematic assembly approaches also provide unparalleled power for building genomes of any given sequence, simultaneously providing novel capabilities for nefarious use. For example, genome sequences represent fingerprints that allow geographic mapping of the likely origin of a given virus. Recombinant viruses generated from classic recombinant DNA techniques will carry the signature of the parental virus used in the process as well as novel restriction sites that were engineered into the genome during the cloning process. In contrast, synthetic viral genomes can be designed to be identical with exact virus strains circulating in any given location from any year. This powerful technique provides the bioterrorist with a “scapegoat” option; leaving a sequence signature that misdirects efforts at tracking the true originators of the crime. Even better, the approach could be used to build mistrust and/or precipitate open warfare between nations. A simple example might involve the use of the picornavirus foot and mouth disease virus, which is not present on the North American continent, yet is endemic in Africa, Asia, the Middle East and South America. North American herds are not vaccinated against this pathogen, the virus is highly contagious, and the disease is subject to international quarantine. Geographically distinct FMDV strains contain unique sequence signatures allowing ready determination of origin. A North American outbreak of an infectious “synthetic” FMDV virus containing signature sequences reminiscent of strains found in select Middle East or Asian nations that are viewed as terrorist states by the US government would inflame worsening tensions and could provide a ready excuse for military retaliation. Project costs would likely be less than $50K, including synthesis, recovery and distribution. Another possibility may be to optimize replication efficiency by optimizing for human codon use, especially useful in “humanizing” zoonotic viruses although to our knowledge codon optimization has never been linked to increased replication or pathogenesis. In both examples, standard recombinant DNA approaches would be difficult and tedious, while synthetically derived genomes could be readily manufactured within weeks.

Virus pathogenesis is a complex phenotype governed by multiple genes and is heavily influenced by the host genetic background. Virus genes influence virus-receptor interaction, tissue tropism, virus-host interactions within cells, spread throughout the host, virion stability and transmission between hosts. Colonization of hosts is influenced by ecologic factors including herd immunity, cross immunity and host susceptibility alleles. In general, the rules governing virulence shifts are hard to predict because of the lack of research and ethical concerns that have historically limited this type of research. In fact, the research itself promotes an emerging conundrum as to the limits of biodefense research: the need to know to protect the overall public health versus the development of models to elucidate the fundamental principles of pathogen design (4). Synthetic biology and recombinant DNA approaches provide numerous opportunities to construct designer pathogens encoding a repertoire of virulence genes from other pathogens, while simultaneously providing a rapid response network for preventing the emergence and spread of new human and animal diseases. The state of knowledge prevents accurate predictions regarding the pathogenic potential of designer viruses; most likely, replication and pathogenesis would be attenuated. As a principle goal of bioterrorism is to inspire fear, highly pathogenic outcomes may not be necessary as large scale panic would likely result after the release of designer pathogens in US cities. Given the reported findings and the large repertoire of host, viral and microbial virulence genes identified in the literature, the most robust defense against the development of designer viral pathogens for malicious use is basic research into the mechanisms by which viral pathogenesis might be manipulated and applied counter measures that ameliorate these pathogenic mechanisms. This justification, however, blurs the distinction between fundamental academic research and bio-weapon development.

3. Ancient Pathogen Resurrection

Paleomicrobiology is an emerging field dedicated to identifying and characterizing ancient microorganisms in fossilized remains (25). Mega-genomic high throughput large scale sequencing of DNA isolated from mammoths preserved in the permafrost not only identified over 13 million base pairs of mammoth DNA sequence, but also identified novel bacterial and 278 viral sequences that could be assigned to dsDNA viruses, retroviruses and ssRNA viruses (63). Although DNA genomes can survive for almost 20,000 years (25), RNA virus fossil records do not exist beyond a ~90-100 year window, making it difficult to understand the evolution of virulence, molecular evolution, and the function of modern day viral genes. Among RNA viruses, the current record is the molecular resurrection of the highly pathogenic 1918 influenza virus, which required almost 10 years of intensive effort using standard recombinant DNA approaches from many laboratories (81). Obviously, synthetic reconstruction of ancient viral genomes may provide a rapid alternative as sequence database grow more robust over the next few decades. How pathogenic are these ancient pathogens? Will vaccines and anti-virals protect humans from ancient virus diseases?

Moreover, alternative approaches also exist to regenerate ancient viral sequences. Ancestral gene resurrection using bioinformatics approaches offers a powerful approach to experimentally test hypotheses about the function of genes from the deep evolutionary past (79). Using phylogenetic methods (38), ancestral sequences can be inferred but the approach suffers from the lack of empirical data to refute or corroborate the robustness of the method. More recently, the sequence of ancestral genes was accurately predicted as evidenced by the synthetic reconstruction of a functional ancestral steroid receptor, Archosaur visual pigment and other genes (15, 16, 79, 80). To our knowledge, phylogenic reconstruction of ancient virus sequences has not been tested empirically but it may be possible to construct replacement viruses encoding ancient structural genes from inferred sequence. Such viruses would have unpredictable pathogenicity, but would likely be highly resistant to vaccines and therapeutics targeted to modern day strains.

4. Summary

Chemical synthesis of viral genomes will become less tedious over the coming years. Costs will likely decrease as synthesis capabilities increase. Moreover, the technology to synthesize DNA and reconstruct whole viral genomes is spreading across the globe with dozens of commercial outfits providing synthetic DNAs for research purposes. DNA synthesizers can be purchased through on-line sites such as eBay. It is likely that engineering design improvements will allow for simple construction of larger genomes. The technology to synthetically reconstruct genomes is fairly straightforward and will be used, if not by the United States, then by other Nations throughout the world. It is also likely that synthetic genes and synthetic life forms will be constructed for improving the human condition and they will be released into the environment. As with most technology, synthetic biology contains risks and benefits ranging from a network to protect the public health from new emerging diseases to the development of designer pathogens. Synthetic genome technology will certainly allow for greater access to rare viral pathogens and allow for the opportunity to attempt rationale design of super pathogens. It is likely that the threat grows over time, as technology and information provide for more rational genome design. The most robust defense against the development of designer viral pathogens for malicious use may be basic research into the mechanisms by which viral pathogenesis might be manipulated so that applied counter- measures can be developed.

Addendum (November 2007): Since the writing of this initial report, recent studies have demonstrated the availability of a reverse genetic systems for reovirus, a group III dsRNA virus (Kobayashi T, Antar AA, Boehme KW, Danthi P, Eby EA, Guglielmi KM, Holm GH, Johnson EM, Maginnis MS, Naik S, Skelton WB, Wetzel JD, Wilson GJ, Chappell JD, Dermody TS. A plasmid-based reverse genetics system for animal double-stranded RNA viruses. Cell Host Microbe. 2007 Apr 19;1(2):147-57) and for additional group V single stranded negative polarity RNA viruses like Rift Valley Fever Virus (Ikegami T, Won S, Peters CJ, Makino S. Rescue of infectious rift valley fever virus entirely from cDNA, analysis of virus lacking the NS gene, and expression of a foreign gene. J Virol. 2006 Mar;80(6):2933-40.)

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Appendix 1. EHS/CDC Select Agent List (Viruses)

1. African horse sickness virus 1
2. African swine fever virus 1
3. Akabane virus 1
4. Avian influenza virus (highly pathogenic) 1
5. Blue tongue virus (exotic) 1
6. Camel pox virus 1
7. Cercopithecine herpes virus (Herpes B virus) 3
8. Classical swine fever virus 1
9. Crimean-Congo haemorrhagic fever virus 3
10. Eastern equine encephalitis virus 2
11. Ebola viruses 3
12. Foot and mouth disease virus 1
13. Goat pox virus1
14. Japanese encephalitis virus 1
15. Lassa fever virus 3
16. Lumpy skin disease virus 1
17. Malignant catarrhal fever 1
18. Marburg virus 3
19. Menangle virus 1
20. Monkey pox virus 1
21. Newcastle disease virus (exotic) 1
22. Nipah and Hendra complex viruses 2
23. Peste des petits ruminants 1
24. Plum pox potyvirus4
25. Rift Valley fever virus 2
26. Rinderpest virus 1
27. Sheep pox 1
28. South American haemorrhagic fever viruses (Junin, Machupo, Sabia, Flexal, Guanarito) 3
29. Swine vesicular disease virus 1
30. Tick-borne encephalitis complex (flavi) viruses (Central European Tick-borne encephalitis, Far Eastern Tick-borne encephalitis, Russian Spring and Summer encephalitis, Kyasanur Forest disease, Omsk Hemorrhagic Fever) 3
31. Variola major virus (Smallpox virus) and Variola minor (Alastrim) 3
32. Venezuelan equine encephalitis virus 2
33. Vesicular stomatitis virus (exotic) 1
34. Reconstructed replication competent forms of the 1918 pandemic influenza virus containing any portion of the coding regions of all eight gene segments (Reconstructed 1918 Influenza virus)

Prions

1. Bovine spongiform encephalopathy agent (USDA High Consequence Livestock Pathogens or Toxin)

_______________

Notes:

1USDA High Consequence Livestock Pathogens or Toxin

2USDA/HSS Overlap Agent

3HHS Select Infectious Agent

4APHIS Plant Pathogens (Animal and Plant Health Inspection Service, a division of USDA)

*** 

Appendix II. US Department of Commerce-Pathogen and Zoonotic virus list a. Viruses:

a.1. Chikungunya virus;
a.2. Congo-Crimean haemorrhagic fever virus;
a.3. Dengue fever virus;
a.4. Eastern equine encephalitis virus;
a.5. Ebola virus;
a.6. Hantaan virus;
a.7. Japanese encephalitis virus;
a.8. Junin virus;
a.9. Lassa fever virus
a.10. Lymphocytic choriomeningitis virus;
a.11. Machupo virus;
a.12. Marburg virus;
a.13. Monkey pox virus;
a.14. Rift Valley fever virus;
a.15. Tick-borne encephalitis virus (Russian Spring-Summer encephalitis virus);
a.16. Variola virus;
a.17. Venezuelan equine encephalitis virus;
a.18. Western equine encephalitis virus;
a.19. White pox; or
a.20. Yellow fever virus.

***

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_______________

Notes:

1 Named for the virologist David Baltimore, who proposed the system.

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Tue Feb 09, 2021 12:49 am
by admin
Covid: South Africa halts AstraZeneca vaccine rollout over new variant
by bbc.com
February 8, 2021

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South Africa has put its rollout of the Oxford-AstraZeneca vaccine on hold after a study showed "disappointing" results against its new Covid variant.

Scientists say the variant accounts for 90% of new Covid cases in South Africa.

The trial, involving some 2,000 people, found that the vaccine offered "minimal protection" against mild and moderate cases.

But experts are hopeful that the vaccine will still be effective at preventing severe cases.

South Africa has recorded almost 1.5 million coronavirus cases and more than 46,000 deaths since the pandemic began - a higher toll than any other country on the continent.

The country has received one million doses of the Oxford-AstraZeneca jab and was preparing to start vaccinating people.

On Monday, the World Health Organization (WHO) warned against jumping to conclusions about the efficacy of Covid vaccines.

Dr Katherine O'Brien, the WHO's director of immunisation, said it was very plausible that the Oxford-AstraZeneca vaccine would still have a meaningful impact on the South African variant, especially when it came to preventing hospitalisations and death.

"Comparing from one piece of evidence to the next really can't be done without a sort of level playing field," she said, referring to the evaluation of different trials in different populations and age groups.

Dr O'Brien stressed that the WHO's expert panel held "a very positive view" of proceeding with the use of the vaccine, including in areas where variants were circulating, but that more data and information would be needed as the pandemic continued.

South Africa's Health Minister Zweli Mkhize said his government would wait for further advice on how best to proceed with the AstraZeneca vaccine in light of the findings.

In the meantime, he said, the government would offer vaccines produced by Johnson & Johnson and Pfizer in the coming weeks.

What does it mean for serious cases?

The trial was carried out by researchers at the University of the Witwatersrand in South Africa and the UK's Oxford University, but has not yet been peer reviewed.

The trial's chief investigator, Prof Shabir Madhi, said it showed that "unfortunately, the AstraZeneca vaccine does not work against mild and moderate illness".

Prof Madhi said the study had not been able to investigate the vaccine's efficacy in preventing more serious infections, as participants had an average age of 31 and so did not represent the demographic most at risk of severe symptoms from the virus.

The vaccine's similarity to one produced by Johnson & Johnson, which was found in a recent study to be highly effective at preventing severe disease in South Africa, suggested it would still prevent serious illness, according to Prof Madhi.

"There's still some hope that the AstraZeneca vaccine might well perform as well as the Johnson & Johnson vaccine in a different age group demographic that I address of severe disease," he told the BBC.

Other experts were also hopeful that the vaccine remained effective at combating more serious cases.

"What we're seeing from other vaccine developers is that they have a reduction in efficacy against some of the variant viruses and what that is looking like is that we may not be reducing the total number of cases, but there's still protection in that case against deaths, hospitalisations and severe disease," Prof Sarah Gilbert, Oxford's lead vaccine developer, told the Andrew Marr Show on Sunday.

She said developers were likely to have a modified version of the injection against the South Africa variant, also known as 501.V2 or B.1.351, later this year.

Ministers in the UK have sought to reassure the public over the effectiveness of the Oxford-AstraZeneca vaccine. Vaccines Minister Nadhim Zahawi said the injection appeared to work well against dominant variants in the UK, while Health Minister Edward Argar said there was "no evidence" the vaccine was not effective at preventing severe illness.

Image
How some of the Covid-19 vaccines compare. Source: UK government, Reuters

We should be careful about rushing to judgement
Analysis by Nick Triggle, health correspondent

Viruses mutate - so what is happening is not surprising.

The mutations seen in South Africa change the part of the virus that the vaccines target. It means all the vaccines that have been produced so far are likely to be affected in some way.

Trials for Novavax and Janssen vaccines that were carried out in South Africa showed less effectiveness against this variant. Both are currently before the UK regulator.

Therefore the news about Oxford-AstraZeneca does not come out of the blue.

The fact it now only has "minimal" effect according to reports is concerning - the other vaccines showed effectiveness in the region of 60% against the South African variant.

But we should be careful about rushing to judgement. The study was small so there is only limited confidence in the findings.

What is more, there is still hope the vaccine will prevent serious illness and hospitalisation.

What this once again illustrates is the pandemic is not going to end with one Big Bang. Vaccines are likely to have to change to keep pace with the virus.

Progress will be incremental. But vaccines are still the way out of this.

What do we know about the variant?

The South Africa variant carries a mutation that appears to make it more contagious or easy to spread.

However, there is no evidence that it causes more serious illness for the vast majority of people who become infected. As with the original version, the risk is highest for people who are elderly or have significant underlying health conditions.

At least 20 other countries including Austria, Norway and Japan, have found cases of the variant.

Health officials say all is not lost
Analysis by Pumza Fihlani, southern Africa reporter

Many South Africans have reacted with shock and disappointment at news that the 1.5 million doses of the Oxford/AstraZeneca vaccines will not be as effective as experts had hoped against the new variant first discovered here in November.

While there are now more questions than ready answers, the message from health officials is that all is not lost. They believe the vaccine may still be effective in preventing severe illness and go some way in reducing the number of people who need to be admitted into hospital for treatment.

This is important in a country where some 80% of the population cannot afford private health care and rely on state hospitals - which are currently overstretched - for health care.

So what's the plan now? South Africa's health minister has said they will take a steer from local scientists on how to repurpose the vaccine to get the most out of it.

It has been suggested that the vaccine may be useful if given to the older population and to people with co-morbidities.

In terms of managing people's concerns, the government and scientists may need to go the extra mile in reassuring citizens that there is still a plan in place and lives can and will be saved.

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Fri Mar 19, 2021 10:42 am
by admin
How For-Profit Health Care Worsened the Pandemic: Hundreds of Thousands of Deaths and Millions of Infections Would Likely Have Been Prevented Under Medicare for All
by Public Citizen
March 16, 2021
https://www.citizen.org/article/unprepa ... 6f6806d861

WASHINGTON, D.C. – A new white paper by Public Citizen lays out how the for-profit health care system left the U.S. vulnerable and unprepared for the COVID-19 pandemic, and how a single-payer, government-run health care system in which all Americans were covered would have helped the U.S. response to the crisis and prevented thousands of deaths.

“The pandemic has shown how wide the gaps in our health care system remain and how easy it is for families to fall through them. Too many Americans were already suffering unnecessarily prior to the pandemic and COVID-19 just exacerbated the challenges people face,” said Eagan Kemp, Public Citizen’s health care policy advocate. “We already spend far more than any comparably wealthy country on health care while achieving far less and were left wholly unprepared for the COVID-19 pandemic.”

The U.S. remains the only one of the 25 wealthiest countries to not provide universal health care, and the health care system’s focus on profits and not health has cost Americans their lives. Despite having less than 5% of the world’s population, the U.S. has had 25% of the world’s confirmed cases and 20% of the deaths. Public Citizen’s new report demonstrates how:

• Before the pandemic, approximately 87 million Americans were uninsured or underinsured. About one-third of COVID-19 deaths and 40% of infections were tied to a lack of insurance;
• About half of Americans receive their health care through their employer. With more than 22 million Americans losing their job during the pandemic, millions have lost their health insurance;
• Racial health disparities, including access to care, have led to disproportionate deaths in communities of color;
• We have the highest rate of unmet need of any comparably wealthy country, with one-third of Americans reporting that they or a family member has avoided going to the doctor when sick or injured in the past year due to cost;
• Americans are significantly more likely to die of chronic respiratory disease, cardiovascular disease, diabetes or cancer than people in comparably wealthy countries with universal health care systems; and
• A lack of essential funding led to insufficient hospital capacity. The U.S. had only around half the hospital beds per capita of peer nations and far fewer than countries like Japan or Germany.

Thousands of deaths would have been avoided if Medicare for All had been in place prior to the COVID-19 crisis, highlighting the need to enact policy before the next pandemic hits. Under such a system:

• Hospitals, particularly rural hospitals, would receive the funds they need to stay open via yearly budgets instead of relying on admission rates and elective procedures;
• Providers would better be able to coordinate patient care;
• No American would have to skip a doctor visit because of cost or a lack of insurance; and
• People of color would no longer face disproportionately high rates of uninsurance, reducing an important contributor to racial disparities in access to health care.

“We need to be prepared for the next pandemic, and we can’t be under the current for-profit system. The time has come for a health care system that guarantees health care for everyone in the U.S.,” said Kemp. “The time has come for Medicare for All.”

***

Unprepared for COVID-19: How the Pandemic Makes the Case for Medicare for All
by Eagan Kemp
March 16, 2021

Introduction

The COVID-19 crisis should be a sobering wake up call for the American health care system. Despite having less than 5% of the world’s population, the U.S. has had 25% of the world’s confirmed cases and 20% of the deaths.[1] Of the 25 wealthiest countries in the world, the United States remains the only one that does not provide universal health care.[2] Many factors hindered the U.S. response – including failed federal leadership and willful disinformation from a variety of sources – but the reality is that our for-profit health care system put the U.S. at a dangerous disadvantage and hindered rapid response at every turn. It has also meant millions of Americans have contracted COVID-19 unnecessarily and hundreds of thousands of deaths could have been prevented.[3]

Further, the global pandemic has highlighted huge gaps in the foundation of the U.S. health care system. While a full accounting is beyond the scope of this report, six areas particularly highlight just how much our health care system has failed to prepare for and respond to the COVID-19 crisis. Our health care system has been failing Americans for decades and its weaknesses were particularly susceptible to the challenges posed by the COVID-19 pandemic. This report explores the system’s focus on generating profit and revenue for wealthy corporations instead of health and wellbeing for the American people in a number of ways: 1) private insurers profiting by limiting access to care; 2) millions losing their insurance when they lost their jobs during the pandemic; 3) hospitals focusing on profit and revenue over patient wellbeing; 4) many nursing homes failing to meet patients’ needs; 5) our public health preparedness system lacking adequate funding; and 6) the massive health disparities experienced across the U.S., including the particularly devastating effects on communities of color. All of these issues, and many more, would have been significantly improved if a single-payer Medicare for All system had been in place prior to the COVID-19 crisis, highlighting the need to enact Medicare for All before the next pandemic hits.[4]

For-Profit Health Care Left the U.S. Unprepared for COVID-19

The cardinal sin of our health care system is that it puts profits over people and corporations over communities. While examples abound, insurers, hospitals and nursing homes highlight how the motive to generate profit and revenue in our health care system distorts incentives and has hurt Americans in numerous ways before and during the COVID-19 crisis.

Private Insurance System Hindered Access to Care

At the start of the COVID-19 pandemic, approximately 87 million Americans were uninsured or underinsured.[5] While this placed the health of millions of Americans at risk in normal times, the risks are even higher during a pandemic. A recent study found that one-third of COVID-19 deaths and around 40% of infections were linked to a lack of health insurance.[6] For every 10% increase in a county’s uninsured rate, the researchers found a 70% increase in COVID-19 infections and nearly a 50% increase in deaths from COVID-19.[7]

The COVID-19 pandemic showed just how greedy private insurers are, as they were reporting record profits because they were paying out far less in claims due to millions of Americans delaying care.[8] This disparity highlights just how little value insurers are bringing to the health care system despite how much they cost consumers and the health care system in general.[9] And insurers continue to focus on their profits, even as Americans continue to struggle to get the care they need. For example, the Centers for Medicare and Medicaid Services (CMS) had to recently step in to stop insurers from denying claims for COVID-19 testing, as well as to increase compliance with COVID-19 relief legislation that required that plans cover such tests without cost sharing.[10]

Employer-Sponsored Insurance Failed at the Worst Possible Time

Another absurdity of our system, where more than half of all Americans depend on insurance provided through their job, was also laid bare by COVID-19 pandemic. Americans are always at risk of losing coverage through job loss, especially during an economic downturn and catastrophically so during a downturn caused by a global pandemic. Around 22 million Americans lost their job due to COVID-19, meaning millions also lost their insurance during a global pandemic.[11] While Congress recently passed legislation that would help address the huge loss of health insurance coverage, the scope of the reforms are limited and so Americans will continue to struggle without a comprehensive solution like Medicare for All.

Compounding the overall uninsured and underinsured rates is that many industries deemed to be essential have among the highest uninsured rates for their employees. A recent Public Citizen analysis found high rates of uninsured workers across several industries deemed essential.[12] Prior to the pandemic, more than half of all agricultural workers were uninsured, while around one in four workers across construction, home care, and restaurant workers lacked insurance. [Figure 1]

Image
Figure 1 – Uninsured Rate by Employment Category for Frontline Industries

Figure note: Data are based on a number of academic and governmental sources.[13]

Even before COVID-19, paying for health insurance coverage for their workforces was a huge burden for employers, hurting their competitiveness. If an employer does not provide insurance to its employees, it may struggle to attract and retain top-level talent. And if an employer does choose to provide health insurance, the rising annual costs may mean fewer wage increases, less generous plans, cuts to other benefits or perhaps even challenges to their ability to stay in business.

Small businesses – which have been hit the hardest under COVID-19 – were already facing the biggest challenges providing health insurance. Because of their size and the lack of economies of scale, small businesses often struggle to afford insurance for their employees. They face a significant disadvantage when negotiating with insurers and end up paying higher prices than larger companies. Employers with fewer than 10 employees face premiums nearly 20% higher, for the same benefits, than those paid by large businesses, and employers with 10 to 25 employees can expect to pay around 10% more.[14]

Under Medicare for All, everyone would have consistent coverage regardless of their employment status or employer. And because Americans would have their choice of providers, instead of facing the narrow networks their employers choose for them, they would face fewer challenges getting care, especially during a pandemic where some hospitals and providers are overwhelmed by demand.[15]

Hospitals Focused on Profit and Revenue Were Unable to Respond To COVID-19 While Safety Net Hospitals Faced Closure

Our current system creates incentives for hospitals to maximize profit and revenue, for example, by building expensive new hospital wings or buying unneeded equipment and then pressuring providers to refer patients for care to utilize those expensive investments, instead of furnishing the most sensible and necessary care. This has led to some particularly pernicious practices, including hospitals finding that debt collection can be more profitable than providing care and that hospitals can forgo charging a patient’s insurer and instead target patients’ accident settlements to increase hospital revenue, leading to patients facing huge bills and being hounded by debt collectors if they fail to pay them.[16] For example, the New York Times reported that a single hospital system in New York sued more than 2,500 patients even during the COVID-19 pandemic, a time when many families found their budgets stretched to the breaking point.[17] At the same time, hospitals continue to fight against any accountability as they game the system through charging exorbitant prices while slowing down any efforts at transparency regarding the prices they charge for care.[18]

Even before the pandemic, private equity companies were already consolidating hospital systems (many of which were then moving profitable specialties to other facilities) and contracting with certain provider types and taking them all out of insurance networks to allow charging exorbitant prices directly to patients through surprise bills.[19] This focus on profit and revenue meant that many hospitals were already in a precarious financial position – especially hospitals in rural and urban areas where it can be less profitable to provide care – and hospital closures left many communities with limited access to care even prior to the pandemic.[20]

In addition, many hospitals use just-in-time supply chains that can be brittle, especially during a surge in demand resulting from a pandemic, which led to shortages of key medicines, materials, and personal protective equipment (PPE).[21] These shortages place providers at risk, leading to reports of hospitals hoarding PPE and accusations that hospitals muzzled providers who spoke out about unsafe conditions due to a lack of access to PPE.[22]

Medicare for All would use comprehensive budgets negotiated between the government and health care institutions (such as hospitals and nursing homes) rather than the current approach of institutions making investments based on increasing profits or revenue. Known as global budgets, this approach would allow better control of overall spending while ensuring everyone can access needed services. These global budgets would allow hospitals on which communities depend to stay open by ensuring consistent funding year to year as well as providing emergency funding to be able to better respond to pandemics or natural disasters.

Nursing Homes Were Overwhelmed and Understaffed With Deadly Consequences for Patients

Historical under funding of long-term care – the majority of long-term care are funded by Medicaid at minimal rates – left many nursing homes unprepared for a pandemic and already struggling to contain infectious diseases.[23] And with seniors at among the highest risk for COVID-19 complications and deaths, it is no wonder that COVID-19 tore through nursing homes and other institutional settings. As the U.S. continues to lack a comprehensive and coherent approach to guaranteeing access to needed long-term services and supports, as described below, it falls to family members, state programs, and, overwhelmingly, Medicaid to bear the burden of funding long-term care, something it was never intended to do when it was passed.

The current system pushes people into nursing homes instead of home and community-based services (HCBS), despite such services being less expensive and often more desirable to patients than nursing home care. Such settings can be crowded and more likely to lead to the spread of infectious disease.[24] This is because state Medicaid programs are required to cover nursing home care, while HCBS is optional for states to provide. As such, the availability of home and community-based services varies widely by state. Several states have expanded access to home and community-based services coverage through requesting waivers of certain federal Medicaid requirements.[25]

Further, because many of the workers are paid poorly, they may work at multiple facilities or also contract with a home health agency. The intimate nature of this life-sustaining work limits the ability for social distancing, placing both workers and their patients at risk. In addition, the bias in funding toward institutional long-term care may have contributed to the spread of COVID-19 because seniors were often unable to social distance in nursing homes or other similar settings. Even before the COVID-19 crisis, the focus on profits in nursing homes was leading to increased deaths, according to a recent study that found that private-equity owned nursing homes had higher mortality rates than others.[26]

Around 70% of people over 65 will require at least some long-term care in their lifetimes.[27] Given our changing demographics—by 2030 all baby boomers will be 65 or older and by 2035 Americans age 65 and older will outnumber the number of children under 18 for the first time in U.S. history—we must ensure that we are providing access to needed long-term care in the most humane and efficient way possible, with the potential to also help limit the spread of future pandemics.[28] By including comprehensive long-term care coverage without cost-sharing and focusing on home and community based care, Medicare for All would meet both of these goals and begin the crucial transition from the institutional bias of our current long-term care system to a system that serves patients in the setting and community of their choice.

Underfunded Public Health System Struggled to Meet Demand for Testing, Contact Tracing, and Medical Supplies

Even though the U.S. spends far more than any comparably wealthy country on health care, public health spending, including prevention, preparedness, and adequate PPE and others supplies, has declined in recent decades.[29] At the same time as corporations funnel health spending into more profitable areas, as highlighted in the above sections, a smaller and smaller proportion of health spending has gone to public health.[30] As a result, many states’ public health infrastructure has struggled to meet the needs of the communities they serve on any given day, whether that be to address chronic health diseases blooming from early childhood or to provide affordable and appropriate care to its low-income population. These failures became particularly acute during the COVID-19 crisis and meant that the U.S. failed to even be able to keep up with other comparably wealthy countries when it came to things like testing and contact tracing.[31]

COVID-19 has been the largest public health emergency this country has faced in a century. However, our public health system has historically shown its importance through helping address emergencies, including the September 11th terrorist attacks, outbreaks of other contagious diseases, and extreme flu seasons. Yet the system continues to lack the resources required in times of need. Despite being a pillar of federal preparedness planning, funding for public health has fluctuated in recent years in response to congressional and presidential priorities as well as public health emergencies. [Figure 2]

Image
Figure 2 – Funding for Various Public Health Programs, 2000-2019

In analyzing two decades of Department of Health and Human Services (HHS) funding, Public Citizen found that the public health infrastructure lacks a strong foundation as funds are unstable and have fluctuated over time, with cuts taking place under both recent Democratic and Republican administrations.[32] For example, the Affordable Care Act (ACA) initially created the Prevention and Public Health Fund (PPHF) in 2010, and included a promise to dedicate $15 billion to improve the public health system.[33] However, two years later, former President Barack Obama cut $6.25 billion from the PPHF to pay for other policies followed by additional cuts. However, in response to the 2015 Zika outbreak, former President Obama pushed Congress to pass some additional public health funding.[34]

The funding increase tied to fighting Zika was consistent with the responses to other recent health care crises. Since 2000, national emergencies correlated with a dramatic infusion of money into the public health infrastructure. The Sept. 11, 2001, and anthrax terror attacks caused a spike in funding which was followed by another steep increase in response to the 2003 SARS outbreak. Similarly, the devastation from Hurricane Katrina sharply increased funding from 2005 to 2007 which then dramatically declined until it was raised in response to the 2009 H1N1 virus, but then was subsequently cut the following year. And, as discussed earlier, the implementation of the ACA caused huge spikes in funding for its first year, which then decreased until the 2015 global Zika scare.

While funding for public health continues to rise and fall, public health emergencies continue to get more expensive. Last year was the tenth consecutive year America endured eight or more disastrous events in a year that had damages exceeding $1 billion dollars. In 2020 alone, the nation experienced the beginning of COVID-19, hurricanes, storms, floods, fires, extreme temperatures, widespread outbreaks of Hepatitis A, thousands of opioid overdose deaths, spikes in lung diseases associated with vaping and mass casualty shootings.[35]

At the state level, public health infrastructure is largely funded by the federal government in the form of contracts and grants as well as by state allocations or designated taxes. However, during an economic downturn it can be difficult for states to rapidly approve additional funds, as they are generally unable to take on debt. Even with infusions of cash from the federal government in response to specific crises, local officials can struggle to cover all state and municipal costs. As a result, one study found that between 2010 and 2019 only 6 states experienced an increase in the number of public health staff, while many states remained stagnant and others experienced as much as a 30% drop in total staff.[36]

The significant shortfall in public health spending in recent decades is a contributing factor to the challenges we are experiencing with the current COVID-19 emergency, including an overstretched health care workforce, a lack of proper protective equipment, and failures by the Trump Administration and several states, all contributing to unnecessary suffering and death.[37]

The variance in public health expenditures per capita is drastically different across states, limiting communities’ access to health care services and producing serious health disparities throughout the nation. For example, in 2020 Mississippi and Pennsylvania spent $60 and $61 per person, respectively on non-hospital health care, Hawaii and Massachusetts spent $205 and $144, respectively.[38] Further, the majority of each states’ increase in spending has failed to keep up with the rate of health care inflation, meaning states are expected to address increasingly expensive emergencies without adequate resources.

In addition, the fragmented nature of the U.S. health care system makes it harder for any one agency or group to track how rapidly diseases, including the coronavirus, spread. Countries that had more unified systems were better able to roll out testing, track the spread of the disease via a central information hub, and intervene appropriately. The U.S., on the other hand, had to negotiate with numerous private insurers, issue regulations or orders for multiple public insurance programs, and figure out how handle testing and treatment for the uninsured. Other countries also did not need to rely on private companies voluntarily reducing their profit margins to provide affordable care in a time of crisis.[39]

By rolling out tests more quickly and ramping up to address the COVID-19 crisis without requiring coordination of as many stakeholders, countries like Taiwan and New Zealand were able to react quickly and begin testing widely.[40] In addition, many wealthy countries with universal health care systems were simply better prepared than the U.S. to treat patients with serious COVID-19 symptoms. For example, while the average Organization for Economic Co-operation and Development (OECD) country has 5.4 hospital beds per 1,000 people, the U.S. only has around half of that capacity at 2.8 beds per 1,000 people.[41] By comparison, some countries, such as Japan and Germany, have much higher capacity, with 13.1 and 8.1 per 1,000, respectively. The lack of adequate resources led to heartbreaking situations where doctors and nurses in the U.S. had to choose who would receive treatment and who would be left to die.[42]

Under Medicare for All, public health spending and preparedness would be fully funded, meaning a healthier population, which would help keep health care costs lower over time, and adequate resources to respond to crises, which would ensure we never again experience the chaotic and inept response that we saw in reaction to COVID-19. And because the government would be better able to track diseases, through consistent reporting requirements, and roll out testing or treatments through centralized purchasing and distribution, the country’s health care system would be nimbler and more coherent.

Finally, Medicare for All would be better able to disburse funds in emergency situations and to purchase necessary supplies, such as PPE or testing materials, and machinery, such as ventilators or respirators, during a crisis and get them where they need to go in a timely manner. Unlike our current health care system, Medicare for All would include specific funding for dealing with pandemics or other health emergencies that could be distributed quickly without requiring additional legislation. The United States must never again be left unprepared for mass health crises like COVID-19.

Existing Disparities Increased Deaths in Many Communities

After explaining how the health care system puts profit over patients and leads to underfunding of public health, it is no wonder that the U.S. entered into the COVID-19 pandemic with some of the starkest health disparities of any comparably wealthy country.[43] Even before the pandemic, Americans faced the highest rates of unmet need of any comparably wealthy country. In 2019, a third of Americans reported that they or a family member had avoided going to the doctor when sick or injured during the previous year due to cost.[44]

Our broken health care system, insufficient environmental protections and widening income and wealthy inequality, among other factors, COVID-19 further exacerbated those already poor health outcomes. Among the most concerning statistics, given the potential for COVID-19 to strike patients with respiratory illness particularly hard, the U.S. has much higher rates of asthma hospitalizations – nearly 90 hospitalizations per 100,000 people. This is double the average of comparable countries, around 42 hospitalizations per 100,000.[45] Further, Americans already are significantly more likely to die of chronic respiratory disease, cardiovascular disease, diabetes or cancer than people in comparably wealthy countries with universal health care systems.[46] Of the 246 million individuals in the country that are over the age of 18, 41.4 million of them are at high risk for a more serious illness if they contract COVID-19 due to an underlying medical condition.[47]

As COVID-19 spread around the nation, the CDC highlighted two communities that were most at risk for significant illness or death, those 65 and older and those with serious chronic diseases.[48] The chronic conditions that are of highest risk are asthma and lung disease, heart disease, unmanaged diabetes, severe obesity, and a weakened immune system due to HIV or cancer. While the nation suffers from high rates of each of these conditions, there is a growing health gap across race and ethnicity. For example, Hispanic and non-Hispanic Black adults had a 47% and 46.8%, respectively, higher prevalence of obesity than non-Hispanic White adults[49]. If looking at rates of diabetes, African Americans have a 77% higher chance of being diagnosed than whites, while Hispanics have a 66% higher chance.[50]

Further, racial and ethnic disparities resulting from institutional racism, including historical underfunding of care for communities of color, ongoing wealth and income gaps, and suppression of voting and political power to address these inequalities, have led to higher rates of morbidity and mortality for Black and Brown Americans. In addition, historical forces that led to disproportionate representation in lower-waged, frontline jobs and increased the risk of overcrowding in workplaces and homes in many parts of the country meant more people of color in these communities had a higher likelihood of contracting the coronavirus.[51]

People of color make up the majority of essential workers, especially in the food industry and agriculture where they represent more than 50% and 75% of the industries, respectively.[52] Essential positions require employees to come to work every day, increasing an individual’s risk to be exposed the COVID-19. Many essential workers had to fend for themselves in finding personal protective equipment, had little or no sick leave, and many were reluctant to get tested or report symptoms or a positive COVID-19 test for fear of losing their job.[53]

Further, the lack of coverage and basic worker protections for millions of nonimmigrant guestworkers and undocumented workers before and during the COVID-19 pandemic has meant that workers least able to protect themselves are, unsurprisingly, among the most likely to have contracted the coronavirus. Limited coverage options for guestworkers and the undocumented meant particular risk for certain communities and many essential industries that are dependent on employing non-citizens. And with the refusal of the Occupational Safety and Health Administration (OSHA) to deliver more than a slap on the wrist to corporations, even for violations that led to the death of workers, it is no wonder so many communities experienced outbreaks with slaughterhouses, agricultural facilities, or factory settings as their epicenter.[54]

While Medicare for All wouldn’t instantly undo damage done by centuries of institutional racism and decades of for-profit health care, it could begin the process of addressing substantial racial and ethnic disparities. It would mean the end of private insurance exacerbating these disparities, both on the economic side and especially for health outcomes. Importantly, Medicare for All could affirmatively remediate substantial problems – not just by ensuring care for all, but providing a positive counterbalance to the negative health impacts of institutional racism and growing inequality. And through funding Medicare for All through progressive taxes, including a wealth tax, Medicare for All could also serve to help begin the process of narrowing economic inequality.

Conclusion

Under Medicare for All, our health care system would focus on health and wellbeing instead of generating profit and revenue for wealthy insurers. Hospitals, including many rural hospitals, currently at risk of closure would have the funds they need to serve their communities. Patients could get the long-term care they need in the setting of their choice. The U.S. would finally be able to ensure sufficient funding for public health, including future pandemics. And the nation could finally begin addressing massive health disparities in a comprehensive way.

As the pandemic has shown, everyone depends on the health care system throughout their lives. Whether we face a public health emergency like a global pandemic or simply need to meet routine medical needs, Medicare for All would ensure necessary treatments are available to everyone regardless of their ability to pay.

There would be no out-of-pocket costs or sudden loss of coverage, for example, due to unemployment, to get in the way of Americans receiving the care they need. Small businesses would not be further stressed by providing health care for their employees. In addition, under Medicare for All, Americans would have the freedom to choose a doctor or hospital to receive care wherever is most convenient during a crisis, instead of facing the additional burden of finding providers within narrow private insurance networks which may get overwhelmed during a pandemic.

Footnotes

[1]As of March 11, 2021, the global number of cases was 118,328,593 and the number of U.S. cases was 29,191,168 (24.7%). The total number of deaths was 2,624,833 and the total number of U.S. deaths was 530,013 (20.2%).

Center for Systems Science and Engineering at Johns Hopkins University, COVID-19 Dashboard (2021), https://bit.ly/3euGjhz

[2]Judith Rodin and David de Ferranti, Universal Health Coverage: The Third Global Health Transition?, 380 The Lancet 861-862, 861 (2012).

[3]Steffie Woolhandler, David U. Himmelstein, Sameer Ahmed, et al., 397 Public Policy and Health in the Trump Era, 705, 708-714 (2021).

[4]Medicare for All would improve traditional Medicare and expand it to everyone in the U.S. with no out-of-pocket costs or premiums. Care would be provided in the setting and by the provider of each person’s choice as there would no longer be narrow insurer networks to deal with. It would also mean that everyone would have coverage throughout their lifetime, regardless of their employment status.

[5]The Commonwealth Fund, Health Insurance Coverage Eight Years After the ACA, 5 (2019), https://bit.ly/3rFsrVJ.

[6]Stan Dorn and Rebecca Gordon, Families USA, The Catastrophic Cost of Uninsurance: COVID-19 Cases and Deaths Closely Tied to America’s Health Coverage Gaps, 1, (2021), https://bit.ly/38vUKOQ.

[7]M. McLaughlin, F. Khan, and S. Pugh, et al., County-Level Predictors of COVID-19 Cases and Deaths in the United States: What Happened, and Where Do We Go from Here? Clinical Infectious Diseases 1729, 1736 (2020).

[8]Reed Abelson, Major U.S. Health Insurers Report Big Profits, Benefiting From the Pandemic, The New York Times (August 5, 2020), https://nyti.ms/3bC26C5.

[9]Steffie Woolhandler and David U. Himmelstein, Single-Payer Reform: The Only Way to Fulfill the President’s Pledge of More Coverage, Better Benefits, and Lower Costs, 166 Annals of Internal Medicine 587-588, 588 (2017).

[10]Nick Paul Taylor, CMS Moves to Stop COVID-19 Testing Denials, Cost Sharing in Private Plans, MedTech Dive (March 1, 2021), https://bit.ly/3t352Oe.

[11]Jonathan Ponciano, It Could Take 4 Years to Recover The 22 Million Jobs Lost During Covid-19 Pandemic, Moody’s Warns, Forbes (November 30, 2020), https://bit.ly/3rGvY5U.

[12]Public Citizen, Holes in the Safety Net, 1 (October 2020), https://bit.ly/3rF6s16.

[13]Id.

[14]Claire Martin, In the Health Law, an Open Door for Entrepreneurs, The New York Times (November 23, 2013), https://nyti.ms/2O463R5.

[15]Many hospitals were overwhelmed by surges in COVID-19, creating challenges for patients who needed care from seeking care at their normal facility. This meant facing out-of-network charges and even surprise bills when pursuing care.

Mike Baker and Sheri Fink, At the Top of the Covid-19 Curve, How Do Hospitals Decide Who Gets Treatment?, The New York Times (March 31, 2020), https://nyti.ms/3bGx4ZZ.

[16]John Tozzi, A Hospital Giant Discovers That Collecting Debt Pays Better Than Curing Ills, Bloomberg (December 18, 2017), https://bloom.bg/30Bj0uA.

Sarah Kliff and Jessica Silver-Greenberg, How Rich Hospitals Profit From Patients in Car Crashes, The New York Times (February 1, 2021), https://nyti.ms/3rJuLLi.

[17]Brian M. Rosenthal, One Hospital System Sued 2,500 Patients After Pandemic Hit, The New York Times (January 5, 2021), https://nyti.ms/3l8Dcx5.

[18]David Lazarus, Medicare Says a Procedure is Worth $5,869. This Hospital Imposed a 1,200% Markup, Los Angeles Times (January 26, 2021), https://lat.ms/3tgatcN.

Alexandra Ellerbeck, Hospitals Drag Feet on New Regulations to Disclose Costs of Medicare Services, The Washington Post (January 25, 2021), https://wapo.st/3t9R1hJ.

[19]Joseph D. Bruchs, Suhas Gondi, and Zirui Song, Changes in Hospital Income, Use, and Quality Associated with Private Equity Acquisition, 180 JAMA Internal Medicine 1428, 1429-1432 (2020).

[20]U.S. Government Accountability Office, Rural Hospital Closures: Affected Residents Had Reduced Access to Health Care Services (2021), https://bit.ly/30C8iUp.

[21]Lizzie O’Leary, The Modern Supply Chain is Snapping, The Atlantic (March 19, 2020) https://bit.ly/2OfReBn.

[22]Alicia Gallegos, Hospitals Muzzle Doctors and Nurses on PPE, COVID-19 Cases, Medscape (March 25, 2020) https://wb.md/3tc1TeZ.

[23]U.S. Government Accountability Office, Infection Control Deficiencies Were Widespread and Persistent in Nursing Homes Prior to COVID-19 Pandemic (May 2020), https://bit.ly/3eEPRqF.

[24]Id.

[25]Erica L. Reaves and Marybeth Musumeci, Kaiser Family Foundation, Medicaid and Long-Term Services and Supports: A Primer (December 2015), https://bit.ly/2CAzEPY.

[26]Atul Gupta, Sabrina T. Howell, Constantine Yannelis, and Abhinav Gupta, National Bureau of Economic Research, Does Private Equity Investment in Healthcare Benefit Patients? Evidence From Nursing Homes (February 2021), https://bit.ly/30O1h2U.

[27]Emily Gurnon, The Staggering Prices of Long-Term Care 2017, Forbes (September 26, 2017), https://bit.ly/2W5hFZp.

[28]Press Release, U.S. Census Bureau, Older People Projected to Outnumber Children for First Time in U.S. History (Sep. 6, 2018), https://bit.ly/2p8zoQY.

[29]David U. Himmelstein and Steffie Woolhandler, Public Health’s Falling Share of US Health Spending, 106 American Journal of Public Health 56, 56-57 (2016).

[30]Rabah Kamal and Julie Hudman, Peterson-KFF Health System Tracker, What Do We Know About Spending Related to Public Health in the U.S. and Comparable Countries?, at 2 (September 2020), https://bit.ly/3lg1IN6.

[31]Eric C. Schneider, Failing the Test — The Tragic Data Gap Undermining the U.S. Pandemic Response, 383 The New England Journal of Medicine 299, 299-231 (2020).

[32]We analyzed two decades of funding the Department of Health and Human Services (HHS) to identify spending levels across the Health Resources and Services Administration (HRSA), the Centers for Disease Control and Prevention (CDC), and General Department Management. These entities can be further broken down by the programs that directly impact public health. Our analysis grouped programs into the following categories; infectious disease, the Public Health Preparedness and Response Fund, hospital preparedness and the Public Health Social Services Emergency Fund, rural health, healthcare workforce, and health centers. One limitation of the data for tracking the rate of for each of these programs from 2000 to 2019 was that programs’ names or the structure of the programs were altered in some years, requiring us to classify them manually.

[33]Funding: PPHF, Centers for Disease Control and Prevention (viewed on March 11, 2021), https://bit.ly/3qBuzMJ.

[34]James W. Begun, and Jan K. Malcolm. Leading Public Health: A Competency Framework. (Springer Publishing Company, 2014).

[35]Colorado School of Public Health, The National Health Security Preparedness Index: 2020 Release 2 (2020), https://bit.ly/2Q0XBJ9.

[36]Lauren Weber, Laura Ungar, Michelle R. Smith, et al., Hollowed-Out Public Health System Faces More Cuts Amid Virus, Kaiser Health News (July 1, 2020), https://bit.ly/3lkcj9J.

[37]Amanda Holpuch, US could have averted 40% of Covid deaths, says panel examining Trump’s policies, The Guardian (February 11, 2021) https://bit.ly/38GLMOB.

[38]Public Health Impact: Public Health Funding, America’s Health Ranking (viewed on March 15, 2021), https://bit.ly/3qOxH8b.

[39]Public Citizen, Health Insurers’ Offers of Free COVID-19 Care Are Less Generous Than They Appear (May 2020), https://bit.ly/3cu24vs.

[40]Jennifer Summers, Hao-Yuan Cheng, and Hsien-Ho Lin, et al., Potential Lessons From the Taiwan and New Zealand Health Responses to the COVID-19 Pandemic, 4 The Lancet Regional Health Western Pacific 1, 1-3 (2020)

[41]Dylan Scott, Coronavirus is Exposing All of the Weaknesses in the US Health System, Vox (March 16, 2020), https://bit.ly/3eICcyO.

[42]Mike Baker and Sheri Fink, At the Top of the Covid-19 Curve, How Do Hospitals Decide Who Gets Treatment?, The New York Times (March 31, 2020), https://nyti.ms/2OzCWeP.

[43]Ezekiel J. Emanuel, Emily Gudbranson, and Jessica Van Parys, et al., Comparing Health Outcomes of Privileged US Citizens With Those of Average Residents of Other Developed Countries, 181 JAMA Internal Medicine 339, 339-342 (202).

[44]Lydia Saad, More Americans Delaying Medical Treatment Due to Cost, Gallup (December 9, 2019), https://bit.ly/3tnOvVm.

[45]Irene Papanicolas, Liana R. Woskie, and Ashish K. Hja, Health Care Spending in the United States and Other High-Income Countries, 319 JAMA 1024, 1032 (2018).

[46]World Health Organization, World Health Statistics 2018: Monitoring Health for the SDGs, Sustainable Development Goals 31 (2018), https://bit.ly/3rP0smo.

[47]Wyatt Koma, Tricia Neuman and Gary Claxton, et al., Kaiser Family Foundation, How Many Adults Are at Risk of Serious Illness If Infected with Coronavirus? Updated Data 1 (April 2020), https://bit.ly/30MwqUA.

[48]National Association of Chronic Disease Directors, Chronic Disease and COVID-19: What You Need to Know 1 (2020), https://bit.ly/2Q6riZo.

[49]Racial and Ethnic Approaches to Community Health (REACH), Centers for Disease Control and Prevention (viewed on March 15, 2021), https://bit.ly/38ZNRpl.

[50]Kenneth E. Thorpe, Kathy Ko Chin, and Yanira Cruz, et al., The United States Can Reduce Socioeconomic Disparities By Focusing On Chronic Diseases, Health Affairs Blog (August 17, 2017), https://bit.ly/3tmV0HL.

[51]Hye Jin Rho, Hayley Brown and Shawn Fremstad, Center for Economic And Policy Research, A Basic Demographic Profile of Workers in Frontline Industries 3 (April 2020), https://bit.ly/3cDdltg.

Labor Force Statistics from the Current Population Survey, U.S. Bureau of Labor Statistics (viewed on March 15, 2021), https://bit.ly/2OrJg8l.

[52]Celine McNicholas and Margaret Poydock, Who are Essential Workers? A Comprehensive Look at Their Wages, Demographics, and Unionization Rates, EPI Working Economics Blog (May 19, 2020), https://bit.ly/3cBHfya.

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[53]Daniel Schneider and Kristen Harknett, The Shift Project, Essential and Vulnerable: Service-Sector Workers and Paid Sick Leave https://bit.ly/2Npbwb4.

[54]Irina Ivanova, U.S. Workplace Safety Enforcer Failed During COVID-19, Watchdog Says, CBS News (March 2, 2021), https://cbsn.ws/3qQULmy.

Kimberly Kindy, More than 200 Meat Plant Workers in the U.S. Have Died of Covid-19. Federal Regulators Just Issued Two Modest fines., The Washington Post (September 13, 2020), https://wapo.st/3vuU2uQ.

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Sun Mar 28, 2021 3:28 am
by admin
Trump brags to Fox host Laura Ingraham that he did opposite of what top expert advised amid pandemic: "I didn't really listen to [Dr. Anthony Fauci] too much, because I was doing the opposite of what he was saying"
by Bob Brigham
March 26, 2021 8:30AM (UTC)

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Over 30 million Americans have contracted coronavirus, with over 546,000 fatalities, but former President Donald Trump took to Fox News on Thursday to brag about refusing to follow the medical advice of Dr. Anthony, Fauci, the country's top infectious disease expert.

Trump made his comments during a telephone interview with Fox News personality Laura Ingraham.

"If you saw him throw out the first pitch in Washington, right? He is a better pitcher than he is as what he does," Trump taunted.

"But if you really look, I didn't really listen to him too much, because I was doing the opposite of what he was saying," Trump admitted.

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Sun Mar 28, 2021 3:49 am
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Lancet Study Finds 40 Percent of U.S. COVID-19 Deaths Could Have Been Avoided
by Elliot Hannon
slate.com
Feb. 11, 20218:23 AM

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The British medical journal the Lancet, on Wednesday, published a damning assessment of Donald Trump’s presidency and its impact on Americans’ health, concluding that 40 percent of the nearly 500,000 COVID-19 deaths in the U.S. over the past year were avoidable. The journal came to the conclusion by comparing the U.S. health outcomes on the coronavirus—the country leads the world in COVID deaths and confirmed cases with more than 27 million—with the weighted average of other G-7 nations. So it’s not a wildly abstract conclusion to draw: the U.S. could have saved hundreds of thousands of lives if it had just performed similarly to its economic peers.

The report assailed Trump for his response to the pandemic, but emphasized that the disastrous response to the virus’s spread was the result of years of destructive public policy decisions on health that extended well beyond the Trump years. From the Lancet:

Many of the cases and deaths were avoidable. Instead of galvanizing the U.S. populace to fight the pandemic, President Trump publicly dismissed its threat (despite privately acknowledging it), discouraged action as infection spread, and eschewed international cooperation. His refusal to develop a national strategy worsened shortages of personal protective equipment and diagnostic tests. President Trump politicized mask-wearing and school reopenings and convened indoor events attended by thousands, where masks were discouraged and physical distancing was impossible.


The result, the Lancet notes, is more than 450,000 deaths where “about 40 percent of which could have been averted had the U.S. death rate mirrored the weighted average of the other G7 nations.” But the trajectory of the U.S. falling behind G-7 nations in life expectancy is nothing new, and the gap has grown over the past decade even before the coronavirus exacerbated existing deficiencies in the U.S. health system. The number of excess deaths in the U.S. when compared to similar countries in the G-7 already stood at more than 450,000 in 2018 alone—a number that has been climbing for decades. Most of those unnecessary deaths in the U.S. are in people under the age 65, such that, “if U.S. death rates were equivalent to those of other G7 nations, two of five deaths before age 65 years would have been averted,” the Lancet notes. “To put this number in context, the number of missing Americans each year is more than the total number of COVID-19 deaths in the USA in all of 2020.”

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Sun Mar 28, 2021 3:55 am
by admin
Autopsy of a pandemic: 6 doctors at the center of the US Covid-19 response
by CNN
Published March 26, 2021 7:54 am


Dr. Birx drops bombshell about US Covid-19 deaths
Mar 29, 2021
Dr. Deborah Birx, the coronavirus task force coordinator until former President Donald Trump, revealed in an interview with CNN's Dr. Sanjay Gupta that the number of coronavirus deaths could have been "decreased substantially" if cities and states across the country had aggressively applied the lessons of the first surge toward mitigation last spring, potentially preventing the surges that followed.
"I look at it this way. The first time we have an excuse," Birx said. "There were about a hundred thousand deaths that came from that original surge. All of the rest of them, in my mind, could have been mitigated or decreased substantially."


This past January, just a few days after the inauguration of President Joe Biden, six of the doctors responsible for the previous administration’s Covid-19 response agreed to sit down — in strict confidence — and talk with me about the events of the past year.

Over the period of a few weeks, in Houston, Washington, DC, and Baltimore, our team secured nondescript, large hotel ballrooms with plenty of space and ventilation to allow these extraordinary one-on-one conversations to take place with Dr. Deborah Birx, Dr. Anthony Fauci, Dr. Brett Giroir, Dr. Stephen Hahn, Dr. Robert Kadlec and Dr. Robert Redfield.

Given our shared medical backgrounds, I explained to each of the doctors that I was going to frame the discussions in a way that would be tough, but familiar: as an autopsy.

We were going to meticulously dissect and discuss how the United States became home to the worst Covid-19 outbreak on the planet.

There is no question an autopsy or post mortem is painful and gruesome to witness. And, it does nothing for the deceased patient on the table — in this case, the nearly 550,000 Americans who have died from Covid-19. And, yet we do it because there are often important lessons to learn; lessons that can still be applied during this ongoing pandemic and for future pandemics, which all of the doctors agree is inevitable. Autopsies are particularly important if the death was thought to have been preventable.

And here again, the doctors were in agreement — while Covid-19 is a serious disease, the vast majority of deaths in the United States could’ve been avoided.

Most of the doctors I interviewed are household names nowadays, but you have probably only previously heard them in soundbites or seen them briefly at the lectern in the White House briefing room. All but one of the doctors are private citizens now, unbridled and unrestrained by the watchful eyes of the White House, and they had a lot to say. Our cathartic and frank discussions lasted hours on end, covered a wide range of topics and were at times horrifying in what they revealed.

The first cut

When I met up with Dr. Robert Redfield on a snowy February day in Baltimore, his mood was both reflective and determined. A trained virologist, Redfield was tapped by President Donald Trump back in 2018 to lead the CDC after a long career in public health. Before the pandemic, the new director had been largely focused on two other epidemics: opioids and HIV/AIDS. Alongside his colleagues Fauci and Birx, Redfield has been best known for decades for his work as one of the world’s leading AIDS researchers.

As with his term as CDC director, Redfield’s earlier career had not been without controversy. In the ’80s and ’90s, as one of the Army’s top AIDS researchers, he was accused of overselling the effectiveness of a possible AIDS vaccine, though Redfield stood by his work. During the Covid-19 pandemic, critics argued Redfield failed to protect the credibility of the massive scientific agency he was tasked to lead and was outmaneuvered by an executive branch found to be meddling in science-based CDC guidance involving school closings and religious gatherings. Redfield dismissed those concerns, however. When I asked him if he felt prepared for the job, he told me, “I think I trained my whole life for this.”

When we sat down to talk, just days after his successor, Dr. Rochelle Walensky, had taken the helm at the CDC, Redfield wanted to start at the beginning: China.

While every doctor harbored deep suspicions about the information initially coming from China, Redfield was the most vocal about it. He believes the current pandemic began in Wuhan as a localized outbreak in September or October of 2019 — much earlier than the official timeline — and then spread to every province in China over the next couple of months. The United States wasn’t formally notified of the “mysterious cluster of pneumonia patients” until December 31, 2019. Those were critical weeks and months that countries around the world could’ve been preparing.

“So they had about a 30 day head start,” Kadlec affirmed days before I sat down with Redfield.

Kadlec was the HHS assistant secretary for preparedness and response, known as the ASPR. “They were already buying things on the market well in advance of what we were,” he told me. “Even things that were made here in the United States, we found that the domestic supplies were drying up because of foreign purchases.”

And while the rest of the world was told the only initial Covid-19 cases in China had originated from a wet market in Wuhan, Redfield is confident the evidence suggests that was simply not the case. According to Redfield, even his counterpart at the China CDC, Dr. George Gao, was initially left in the dark about the magnitude of the problem until early January. He described a private phone call he had with Gao in early January 2020, when Gao became distraught and started crying after finding “a lot of cases” among individuals who had not been to the wet market. Gao, Redfield says, “came to the conclusion that the cat was out of the bag.”

The initial mortality rates in China were somewhere between “5-10%,” Redfield told me. “I’d probably be cryin’ too,” he added.

One of the most significant things “that affected our success in this pandemic was not being allowed into China” earlier, he told me. Fauci echoed a similar sentiment when I asked him about it.

“I think it would have been a significant difference,” Fauci said. “I think if we had sent our people into Wuhan and been able to talk to the Chinese scientists in a conversation that might have lasted an hour, you could have gotten so much information right from the get go. They would have told us, don’t believe what you’re reading. This is spread asymptomatically. It spreads highly efficiently and it’s killing people.”

Neither President Trump’s calls to President Xi Jinping nor Secretary Alex Azar’s pleas to China’s minister of health could get them in, according to Redfield.

The question laid bare from our autopsy was, why?

The earliest symptoms

If US investigators had been allowed into China, there is something else they may have discovered: the origins of the virus. Where and how this outbreak began is not simply an exercise of curiosity, or an attempt to assign blame. It is a necessity for scientists and public health experts around the world to try and stop future pandemics.

So far, the official word has been that this pandemic started when the novel coronavirus was introduced through an intermediary species or jumped directly from a bat to a human, something that Redfield, the former head of the CDC, believes doesn’t make “biological sense.”

Reminding me that his career has been spent as a virologist, he told me “I do not believe this somehow came from a bat to a human. And at that moment in time, the virus came to the human, became one of the most infectious viruses that we know in humanity for human to human transmission … Normally, when a pathogen goes from a zoonot to human, it takes a while for it to figure out how to become more and more efficient.”

Without assigning intentionality, Redfield told me he believes the origin of the pandemic is a lab in China that was already studying the virus, exposing it to human cell cultures.

“Most of us in a lab, when trying to grow a virus, we try to help make it grow better, and better, and better, and better, and better, and better so we can do experiments and figure out about it. That’s the way I put it together.”

It is a controversial, politically charged theory — one the World Health Organization calls “extremely unlikely,” and there has been no clear evidence to support this “lab leak” theory.

Yet, more than a year after the outbreak, a team of WHO scientists inside Wuhan has still been unable to determine the definitive origin of the virus. At this point, it is not clear they ever will.

In response to the Biden administration’s call for more transparency from China about data from the earliest days of the outbreak, China released a statement out of its Washington embassy alleging that the United States is now “pointing fingers at other countries.” Meanwhile, Chinese officials and state media have been increasingly promoting an unsubstantiated, so-called “multiple-origin” theory, suggesting the pandemic may have started in various locations around the world, even a US military lab.

Final cause of death

Over nearly 20 hours of interviews, I asked each doctor the question that ends every autopsy. What do they believe was the final cause of death? What led to the preventable deaths of so many Americans?

From the role of leadership and the cost of unpreparedness to the obligations of citizens to care for one another, Redfield and the Covid doctors shared their painful lessons from the worst public health crisis of our lifetimes.

Their answers offer an illuminating and frightening glimpse into what exactly happened over the past year, and also a plan for how to handle the next one.

“As bad as this was,” Kadlec told me, “it could be worse. And there will be another pandemic, guaranteed.”

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Fri Apr 02, 2021 9:23 pm
by admin
W.H.O. Inquiry on the Pandemic’s Origin: What We Know: Did Covid-19 come from animal markets? It’s unclear. Did it emerge from a lab? Also unclear. Here’s what a new W.H.O. report says — including questions that the agency’s own chief raised about the findings.
by Javier C. Hernández
New York Times
March 30, 2021

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Image
Members of the World Health Organization team that investigated the coronavirus’s origins gathered in Wuhan, China, last month. Credit...Aly Song/Reuters

More than a year after the coronavirus pandemic began, the World Health Organization released a report on Tuesday laying out theories on how the virus first spread to humans — but it is already raising more questions than answers, including from the health body’s own leader.

The report, drafted by a 34-member team of Chinese scientists and international experts who led a mission to Wuhan, China, examines a series of politically contentious questions, including whether the virus might have accidentally emerged from a Chinese laboratory.

Some members of the expert team have raised concerns about China’s refusal to share raw data about early Covid-19 cases. In an unusual move, Dr. Tedros Adhanom Ghebreyesus, the W.H.O.’s director-general, acknowledged those concerns while speaking about the report on Tuesday. He said he hoped future studies would include “more timely and comprehensive data sharing.”

Here’s what we know about the report.

The experts dismissed a lab leak theory.

For months, scientists, politicians and others outside China have promoted the theory that the virus might have emerged after a laboratory accident in China. While many experts doubt this theory, they have urged the W.H.O. team to rigorously investigate the possibility.

The report dismisses the lab leak theory outright, calling it “extremely unlikely.” The experts largely base their conclusion on conversations with scientists in Wuhan.

But Dr. Tedros, the W.H.O. chief, took the unexpected step of publicly raising doubts, saying that the theory required further investigation and that he was ready to deploy more experts to do so.

“I do not believe that this assessment was extensive enough,” he said on Tuesday at a briefing for member states on the report, according to prepared remarks released to the news media. “Further data and studies will be needed to reach more robust conclusions.”

The experts had said that officials at the Wuhan Institute of Virology, which houses a state-of-the-art laboratory known for its research on bat coronaviruses, assured them that they were not handling any viruses that appeared to be closely related to the coronavirus that caused the recent pandemic, according to meeting notes included in the report. They also said that staff members had been trained in security protocols.

The report noted that a separate laboratory run by the Wuhan Center for Disease Control and Prevention had moved in late 2019 to a new location near the Huanan Seafood Wholesale Market in Wuhan, where many early cases of Covid-19 emerged. The expert team said that there appeared to be no connection, writing that the lab had not reported any “disruptions or incidents caused by the move” and had not been doing research on coronaviruses.

Some critics have suggested that the team seemed to take the Chinese official position at face value and did not adequately investigate lab officials’ assertions.

Raina MacIntyre, who heads the biosecurity program at the Kirby Institute of the University of New South Wales in Sydney, Australia, said the report seemed to dismiss the idea of a lab leak “without strong evidence.”

“A lab accident is certainly a possibility,” she said.

The role of animal markets is still unclear.

The expert team concluded that the coronavirus probably emerged in bats before spreading to humans through an intermediate animal. But the team said there was not enough evidence to identify the species or to pinpoint where the spillover of the virus from animals first occurred.

Early in the pandemic, Chinese officials floated theories suggesting that the coronavirus outbreak might have started at the Huanan market. More than a year later, the role of animal markets in the story of the pandemic is still unclear, according to the report.

The expert team found that many early cases had no clear connection to Huanan market, which sold sika deer, badgers, bamboo rats, live crocodiles and other animals, according to vendor records cited in the report.

Among those initial confirmed cases, about 28 percent had links to the Huanan market and 23 percent were tied to other markets in Wuhan, while 45 percent had no history of market exposure, according to the report.

“No firm conclusion therefore about the role of the Huanan market in the origin of the outbreak, or how the infection was introduced into the market, can currently be drawn,” the report says.

It says that further studies of farms and wild animals in China are needed, and that more clues about the markets’ role may emerge.

The inquiry’s success will depend on China.

The expert team offers a long list of recommendations for additional research: more testing of wildlife and livestock in China and Southeast Asia, more studies on the earliest cases of Covid-19 and more tracing of pathways from farms to markets in Wuhan.

But it is unclear whether China, which has repeatedly hindered the W.H.O. inquiry, will cooperate. Chinese officials have sought to redirect attention elsewhere, suggesting that the virus could have emerged in the United States or other countries.

Experts say the delays in the inquiry have hurt the ability to prevent other pandemics.

“This delay has obviously compromised the ability of the investigation to reconstruct the origins of Covid-19 and identify ways of reducing the risk of such events happening again in the future,” said Michael Baker, a professor of public health at the University of Otago in New Zealand.

Javier C. Hernández is a China correspondent. He has covered the rise of the authoritarian state under Xi Jinping, the spread of social causes like the #MeToo movement and the plight of China’s most vulnerable citizens, including migrant workers and pollution victims. @HernandezJavier

Re: U.S. government gave $3.7 million grant to Wuhan lab at

PostPosted: Fri Apr 02, 2021 9:40 pm
by admin
Some Scientists Question W.H.O. Inquiry Into the Coronavirus Pandemic’s Origins: Those who still suspect the outbreak in China may have been caused by a lab leak or accident are pressing for an independent investigation.
by James Gorman
New York Times
March 4, 2021

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A small group of scientists and others who believe the novel coronavirus that spawned the pandemic could have originated from a lab leak or accident is calling for an inquiry independent of the World Health Organization’s team of independent experts sent to China last month.

While many scientists involved in researching the origins of the virus continue to assert that the SARS-CoV-2 pandemic almost certainly began in a leap from bats to an intermediate animal to humans, other theories persist and have gained new visibility with the W.H.O.-led team of experts’ visit to China. Officials with the W.H.O. have said in recent interviews that it was “extremely unlikely” but not impossible that the spread of the virus was linked to some lab accident.

The open letter, first reported in The Wall Street Journal and the French publication Le Monde, lists what the signers see as flaws in the joint W.H.O.-China inquiry, and state that it could not adequately address the possibility that the virus leaked from a lab. The letter further posits the type of investigation that would be adequate, including full access to records within China.

The W.H.O. mission, as with everything involving China and the coronavirus, has been political from the start as the international team’s members acknowledged.

Richard Ebright, a molecular biologist at Rutgers University and one of the scientists who signed the letter, said it grew out of a series of online discussions among scientists, policy experts and others who came to be known informally as the Paris group. Many of those who signed the letter were based in France and Dr. Ebright, who has been outspoken about the need to investigate a possible laboratory leak, said such discussion had been less vigorous in the United States.

He said that no one in the group thought that the virus had been intentionally created as a weapon, but they were all convinced that an origin in a lab through research or by accidental infection was as likely as a spillover occurring in nature from animals to humans.

Dr. Ebright said the letter was released because the Paris group expected to see an interim report from the W.H.O. on Thursday. The letter, he added, “was communicated to high levels of the W. H.O. on Tuesday.”

Asked to respond to the letter, Tarik Jasarevic, a spokesman for the W.H.O., replied in an email that the team of experts that had gone to China “is working on its full report as well as an accompanying summary report, which we understand will be issued simultaneously in a couple of weeks.”

The open letter noted that the W.H.O.’s study was a joint effort by a team of outside experts, selected by the global health organization, who worked along with Chinese scientists, and that the team’s report must be agreed on by all. The letter emphasized that the team was denied access to some records and did not investigate laboratories in China.

Findings by the team, the letter stated, “while potentially useful to a limited extent, represent neither the official position of the W.H.O. nor the result of an unrestricted, independent investigation.”

Without naming him, the letter criticized Peter Daszak, an expert in animal diseases and their connection to human health, who is the head of EcoHealth Alliance. The letter linked to articles about Dr. Daszak and said he had previously stated his conviction that a natural origin of the virus was most likely.

Dr. Daszak said the letter’s push to investigate a lab origin for the virus was a position “supported by political agendas.”

“I strongly urge the global community to wait for the publication of the report from the W. H.O. mission,” he added.

Filippa Lentzos, a senior lecturer in science and international security, at King’s College London, and one of the signers of the letter, said, “I think in order to get a credible investigation, it has to be more of a global effort in the sense that it should be taken to the U.N. General Assembly where all the nations of the world are represented and can vote on whether or not to give a mandate to the U.N. secretary general, to carry out this kind of investigation.”

Dr. David A. Relman, a professor of medicine and microbiology at Stanford University and a member of the intelligence community studies board at the National Academies of Science, Engineering and Medicine, an advisory body to the federal government, said he was “quite supportive” of the open letter.

“I completely agree, based on what we know so far, that the W.H.O. investigation appears to be biased, skewed, and insufficient,” he said in an email. “Most importantly, without full transparency and access to the primary data and records, we cannot understand the basis for any of the comments issued so far on behalf of the investigation or by W.H.O.”


At the same time, scientists working on coronaviruses continue to unearth and report evidence to support the natural evolution and spillover of the virus from animals.

Robert F. Garry, a virologist at Tulane University Medical Center, recently posted on the website Virological a report that is not yet peer-reviewed that described new evidence that aspects of the virus that seemed unusual at first had been found in new viruses in Japan, Thailand and Cambodia. He and his co-authors concluded, “These observations are consistent with the natural origin of SARS-CoV-2 and strongly inconsistent with a laboratory origin.”

He said that he was familiar with some of the views of the letter signers expressed in previous media appearances or on social media, involving speculation about ways the virus could have come from laboratory work, and that none of those views appeared in the letter.

Dr. Garry said the possible scenarios described in the letter were that “the Wuhan Institute of Biology either had SARS-CoV-2 or something very close to it before the outbreak. And for whatever reason, some grand conspiracy, they just didn’t want to tell anybody about it.”

He said he continued to believe that a lab origin was “next to impossible.” He said, “We need to look in animals.”

That seems to strike at the heart of the concerns of the Paris group, which is the nature of future research. Dr. Ebright said that everyone in the group was concerned about both wildlife surveillance and laboratory research into viruses as potentially increasing, not lessening the likelihood of future pandemics.

If either collecting samples in the wild or work with those samples in labs were implicated in the origin of the pandemic, he said, the need would be urgent “to assess whether benefits outweigh risks and if not to restrict those activities.”


James Gorman is a science writer at large and the host and writer of the video series “ScienceTake.” He joined The Times in 1993 and is the author of several books, including “How to Build a Dinosaur,” written with the paleontologist Jack Horner.