key: cord-0880426-od0y5ruh
authors: Coccia, Mario
title: Meta-analysis to explain unknown causes of the origins of SARS-COV-2
date: 2022-03-05
journal: Environ Res
DOI: 10.1016/j.envres.2022.113062
sha: bf13712bba1cb4d9a7236f97344d60950a8e620b
doc_id: 880426
cord_uid: od0y5ruh

New Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the Coronavirus Disease 2019 (COVID-19), an infectious illness that has generated a pandemic crisis worldwide. One of the fundamental questions in science and society is how SARS-CoV-2 has been originated to design best practices directed to prevent and/or to cope with future hazardous pathogens. The study confronts this question here developing a meta-analysis, which endeavors to explain and assess whenever possible, unknown sources of the SARS-CoV-2. Findings suggest that the natural spillover of novel viral agents that generate more than 5.90 M deaths in about two years (such as SARS-CoV-2 from February 2020 to March 2022) has a remote probability of occurrence (using an analogy with the probability of natural disasters), whereas science advances on hazardous viral agents and consequential lab accident have a (higher) probability of occurrence (about 13–20% like in manifold lab accidents). The findings of this meta-analysis suggest the vital role of improving the technical guidelines of biosafety at all levels in laboratories for scientific research and testing of hazardous pathogens to minimize biosecurity risks and pandemic threats in society.

Coronavirus 2 (SARS-CoV-2), which appeared in late 2019 at Wuhan (China) generating a pandemic crisis worldwide Anand et al., 2021; Coccia, 2020 Coccia, , 2021 Li et al., 2020) . One of the main questions in science and society is if the sources of SARS-CoV-2 are due to a natural event of spillover from wildlife or if it is associated with human activity of scientific research (Andersen et al., 2020; Boni et al., 2020; Frutos et al., 2021; Relman, 2020; Sachs et al., 2020; Wolfe et al., 2007) . Bloom et al. (2021) argue that information provided initially by Chinese scholars on SARS-CoV-2 does not clarify if this new viral agent is associated with a natural (zoonotic) spillover from bats (through an intermediate host) to humans or if it is due to a possible accident in laboratory. Frutos et al. (2022) discuss some factors of the natural origin of in Wuhan (China), such as the accident at Mojiang mine (China) in 2012 when six miners died with an unknown viral pneumonia (Rahalkar and Bahulikar, 2020) . In this context, Sirotkin and Sirotkin (2020) argue that the etiology of this novel coronavirus is hardly known because the intermediate host for completing a natural zoonotic jump is not clearly identified, and the application of research techniques of gain-of-function may be one of the possible sources of this new coronavirus (Latinne et al., 2020; Malaiyan et al., 2021; Riou and Althaus, 2020) . In fact, the molecular analyses of specimens raise further questions that suggest further investigations of the sources of SARS-CoV-2 (Sirotkin and Sirotkin, 2020) . Relman (2020) maintains that it is important to unravel the origins of SARS-CoV-2 to avoid next pandemics like COVID-19. Sirotkin and Sirotkin (2020) also point out that the origin of SARS-CoV-2 has important aspects for scientific research to develop effective drugs and apply appropriate treatments to cope with new airborne infectious diseases. Overall, then, COVID-19 is still circulating in 2022 with mutations of the SARS-CoV-2 but its origin is still an unknown problem (Casadevall et al., 2021) .

The present study confronts this problem here by developing a meta-analysis to clarify, whenever possible, likely sources of SARS-CoV-2 considering either the possibility of a natural spillover or a lab accident consequential to the activity of scientific research. This study is part of a large research project directed to explain factors determining transmission dynamics of COVID-19 and design effective policy responses and best practices to cope with and/or to prevent pandemic threats in society Coccia, 2020 Coccia, , 2020a J o u r n a l P r e -p r o o f 2021, 2021a,b,c,e,f; 2022, 2022a,c,d,e) .

COVID-19 is still circulating in 2022 with mutations of the initial coronavirus (SARS-CoV-2 ) 1 that is generating continuous infections and deaths in manifold countries (Johns Hopkins Center for System Science and Engineering, 2022). The method of inquiry here is based on multiple working hypotheses (MWHs) that might explain the origin of SARS-CoV-2, which is likely to result from several causes, not just one (Chamberlin 1897; Coccia and Benati, 2018; Coccia, 2018) . The method of MWHs considers and compares several factors to clarify the scientific problem under study, including the possibility that none of them are correct determinants and that some new explanations may emerge (Johnson 1990; Railsback, 2004) .

Firstly, the method of inquiry, based on MWHs, analyzes the sources of the SARS-CoV-2 comparing two events A and B.

− Event A. Natural (zoonotic) spillover of new coronavirus generating an airborne disease − Event B. Accident of laboratory consequential to scientific research for science advances in virology Secondly, the proposed events A and B are investigated by a meta-analysis for a comparative evaluation of their probability of occurrence in environment and human society. In particular:

Assuming the analogy between COVID-19 pandemic and a natural disaster, numbers of deaths of the first event A is assessed with estimates of the probability of occurrence used for big natural disasters that generate a lot of fatalities (USGS, 2022).

The second event B is analyzed by detecting research activity of virology on coronaviruses in publications until 2018 with a structured process of Boolean search of "bats and SARS-CoV" in the on-line database of Scopus (2022). The approach can detect documents published in international journals by research institutions in these specific topics to find out an accumulation of knowledge for possible science advances. After that, meta-analysis is based on some studies concerning accidents in laboratories of biology and chemistry to assess, per analogy, the probability of an accident of laboratory in the activities of scientific research of virology for science advances on novel coronaviruses.

• Finally, results of meta-analysis are used to compare the probability of events A and B and assess if event A is more probable or not than event B. The average probability of occurrence of a big natural disaster that generates in 2 years 1,000 fatalities is roughly 4.0%; mutatis mutandis, a natural disaster that generates over 2 years more than 5.75M deaths, like COVID-19, is infinitely small (i.e., probability of occurrence is a rare event). This basic meta-analysis leads to consider the natural event of spillover of new coronavirus with a remote probability of occurrence.

J o u r n a l P r e -p r o o f  Event B. Lab accident for science advances on novel coronaviruses Scientific development is due to a gradual growth of knowledge based on a sum of facts accumulated by scholars, institutions and other subjects (Haskins, 1965; Seidman, 1987) . Discoveries are driven by an accumulation of scientific research in areas of knowledge that is irreversible and can never go back (Coccia, 2022b; Science, 1965) . Manifold studies show that there have been several high-profile accidents in research laboratories of biology, chemistry and related disciplines worldwide (Ménard and Trant, 2020) . In fact, Hellman et al. (1986) , examining almost six hundred accidents between 1966 and 1984, found that 13% of accidents occurred in research labs and 2% in fabrication rooms. Van Noorden (2013), with a survey of about 2,500 scientists, reveals that 30% of interviewed reported having witnessed a severe lab injury. Another study in Canadian chemistry and biology labs reports that 15% of scholars surveyed had at least one injury (Ayi and Hon, 2018) . Simmons et al. (2018) found that accidents of laboratory represented 18.4% of the total incidents reported at the Iowa State University. Hence, results of these studies suggest that the sources of SARS-CoV-2 associated with a likely accident of lab and consequential diffusion in society seems to have a higher probability of occurrence. Moreover, Kou et al. (2021) argue that major accidents period (based on a platform of self-report safety stories occurring within the departments by researchers that were either directly involved with or witnessed a safety-related incident) reveals that the most frequently occurring hazards are: spill, fire, and equipment failures (Kou et al., 2021) . Ménard and Trant (2020, p. 18 ) maintain that factors determining accidents of laboratory can be due to: "risks associated with the materials or equipment being used, risks related to the skills, knowledge and choices of the research personnel doing the study, characteristics or qualities of the PI and the research lab in which the research is occurring and risk factors arising from the departmental or institutional level". 

Probability of occurrence of a natural event generating more than 5.75M deaths in two years Probability of an accident of laboratory  0 %  13-20 % Source: personal elaboration by author (2022).

The study here suggests that the natural spillover of new viral agents (e.g., SARS-CoV-2) that generate more than 5.75M deaths in about two years (event A) is a rare event (using the analogy with the probability of occurrence of other natural disasters in environment and society; cf., USGS, 2022), whereas an accident of lab associated with scientific research on coronaviruses (event B) seems to have a higher probability of occurrence. In particular, zoonotic spillover from bats, through an intermediate host, to humans, of new coronavirus generating almost six million of deaths over two years is a remote event because some scholars wrongly compare nature to an engineer that works with a conceived plan based on specific materials and equipment designed to achieve goals with its J o u r n a l P r e -p r o o f endeavors (Jacobs, 1977) . Relman (2020) argues that the explanation of the origin of SARS-CoV-2 plays a vital role in forecasting future pandemics. If the natural spillover is based on convincing evidence of the casual event of SARS CoV-2 passing directly from bat to human, or through an intermediate host, then efforts of prevention have to be directed to improve the management of the interactions between wildlife (and their ecosystems) and humans (cf., Latinne et al., 2020) . Daszak et al. (2020) argue that to prevent the next epidemic and pandemic similar to COVID-19, research and investment of nations should focus on:

1) surveillance among wildlife to identify the high-risk pathogens they carry 2) surveillance among people who have contact with wildlife to identify early spillover events

3) improvement of market biosecurity regarding the wildlife trade.

However, if new coronavirus is due to research for science advances and then "SARSCoV-2 escaped from a lab" (Relman, 2020) causing a pandemic crisis, critical aspects of prevention are the improvement of biosecurity in laboratory testing of hazardous pathogens. In fact, the event of likely accident of lab during the activity of research for science advance on coronaviruses leads to basic aspects of management of laboratories for improving the technical guidelines at all levels of biosafety in conducting scientific research and tests on hazardous pathogens similar to SARS-CoV-2 for minimizing the risk of future pandemic crisis. Hence, international institutions, to prevent a pandemic threat of new viral agents, have to support R&D investments and reinforce the surveillance and biosafety procedures in public and private institutes of virology that study viruses and new viruses to avoid an accidentally diffusion in surrounding environments with damages for population, vegetation and overall ecosystems (cf., Coccia, 2005; Mosleh et al., 2022; Roshani et al., 2021) . In this context, international collaboration among scientists is a basic aspect to address these risks and support decisions of policymakers to prevent accidents of lab and therefore threats for future pandemics that create huge socioeconomic issues worldwide (National Health Commission of The

People's Republic of China, 2020). Yuan et al. (2020) argue that in China, information of lab safety should be internally linked to the national intelligent syndromic surveillance system, which could help various levels of organizations to better coordinate and allocate resources for targeted investigations and interventions to improve the biosafety of labs and facilitate more comprehensive surveillance of risk for disease outbreak .

Moreover, prevention and preparedness of pandemic threats have also to be directed to design and implement strategic actions of improvements of the early warning systems in the international community using existing infrastructure to ensure rapid detection of suspected cases in humans based on reliable results of international laboratories that receive all data and clinical specimens needed for an accurate evaluation of an emergence of pandemic risk. These results can be used for applying timely containment operations al local and global level for reducing pandemic threats and consequential socioeconomic issues at national and global level (Coccia, 2018; Coccia, 2021d Coccia, 2022c Coccia, , 2022d .

The origins of new viral agents associated with future epidemics/pandemics pose, increasingly, fundamental questions for biosecurity and public health of nations and globally (Relman, 2020) . A future pandemic similar to COVID-19 is not a question of whether will happen, but when. Impact of next pandemic will be determined by how well-prepared countries are when it occurs at any time with little warning, and how countries timely respond. Any delay in detecting and sharing new virus samples; and in developing, producing, distributing, or administering a therapeutic or vaccine could result in significant additional morbidity and mortality, and deterioration of socioeconomic systems (Coccia, 2021c (Coccia, , 2022a Huang et al., 2021) . The findings of the study here suggest that natural spillover of new coronaviruses (e.g., SARS-CoV-2) that generate more than 5.75M deaths in about two years has a remote probability of occurrence (using an analogy with the probability of natural disasters), whereas the origins of hazardous viral agents associated with accident of lab during the process of science advances has a (higher) probability of occurrence (about 13 -20%, similarly to manifold lab accidents). For managers of research institutions, hazard assessments in experiments of virology and incident reporting methods allow a better understanding of the research safety. In fact, academic and public awareness of lab accidents create valuable learning processes in organizations and institutions to prevent similar mishaps from happening in the future (Kou et al., 2021) .

Although this study has provided interesting results, that are of course tentative, it has several limitations. First, a limitation of the study is the lack of data about scientific activity of laboratory testing for hazardous pathogens, also because of classified information for national security. Second, not all possible confounding factors that affect the J o u r n a l P r e -p r o o f origins of this new coronavirus are taken into consideration and in future these factors deserve to be analyzed for supporting results here. Third, the lack of data to find parents additional genome sequences of coronaviruses and measurements of SARS-CoV-2 evolution under a variety of defined conditions Kadam et al., 2021) . Future research should consider these aspects, new data and information when available, and to examine also other political and institutional factors associated with the origins of new viral agents (Coccia, 2018a) . Despite these limitations, results presented here suggest the critical aspect of the accumulation of scientific knowledge that is a main factor to support science advances in the field of virology but also the importance of best practices on biosecurity in laboratories to prevent accidents in dealing with hazardous pathogens (Wu et al., 2016; Zhang and Holmes, 2020) . There is need for much more detailed research in these topics and this study encourages further investigations that should be collaborative between scholars of different disciplines and nations to have access to relevant information and to clarify unknown sources of new viral agents to design appropriate policy responses to prevent a pandemic similar to COVID-19 both if the SARS-CoV-2 is due to a natural spillover from wildlife and if it is due to research for science advance and consequential accident of laboratory. In this context, science plays increasingly a significant role to explain sources of viral agents and cope with future pandemics but it is also basic is to invest in biosafety, in vaccine development, public health, etc., to create the bedrock for possible crisis management. Overall, then, different factors of the origins of SARS-CoV-2 are not only related to medicine but also to other social, technological, political and economic aspects, and their in-depth investigation plays a vital role to improve the preparedness of countries for pandemics similar to COVID-19 and/or control negative impact of pandemic crisis on public health, economy and society of countries (cf., Ardito et al., 2021; Coccia, 2005a Coccia, , 2015 Coccia, , 2017 Coccia, , 2019a Coccia, , 2021g, 2022b Coccia and Bellitto, 2018; Pagliaro and Coccia, 2021) .

The origins of the SARS-CoV-2 are still a question of hot discussion and debate in society. Scientific investigation has powerful tools, but it is not enough to clarify the problem under study here because available data and information can provide only probable, not certain results about the sources of current pandemic. To conclude, Relman (2020) provides farseeing words in this critical context for future science and society: "A deliberative process for investigating the origins of this pandemic must be representative of all relevant disciplines, expertise, and stakeholders; must achieve political neutrality, scientific balance, and access to all relevant information and samples;

J o u r n a l P r e -p r o o f and must operate with transparency and independent oversight.... A more complete understanding of the origins of COVID-19 clearly serves the interests of every person in every country on this planet. ... it will lead to more effective responses to this pandemic, as well as efforts to anticipate and prevent the next one. It will also advance our discussions about risky science".

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