by Suren Grigorian
Following the recent outbreak of the novel coronavirus resulting in an increasing number of infected people, we are entering a new era filled with fearful projections of the future. A large majority of that fear appears to originate from fear of the unknown, specifically from the fact that among the individuals representing the statistical majority of the public, a small quantity possess actual knowledge of the scientific mechanisms responsible for the dissemination of the virus or what may remain attempted to halt the aforementioned spread. The fact that the mechanisms of the virus, to the general public, remain an opaque novelty is particularly dangerous, as ignorance fosters misinformation and misconceptions; thus, this article shall attempt to elucidate the fundamental principles behind the outbreak in a manner which, the author hopes, shall relieve a small quantity of the anxiety associated with this event, an event which has effected great change upon the lives of us and our relatives.
For an individual to understand the fundamentals of the outbreak, it first remains necessary to understand the virus itself. The virus, currently designated as the Severe Acute Respiratory Disease Coronavirus 2 or SARS-CoV-2 via scientists, primarily remains classified as a member of the family Coronaviridae; generally named for their appearance, similar to a crown beneath an electron microscope. Coronaviruses remain associated with numerous mild illnesses affecting the upper respiratory tract, including the common cold, a small fraction of which remains attributed to them. However, 3 viruses within this family, with the inclusion of SARS-CoV-2, remain attributed to severe respiratory diseases. The origins of the current virus remain slightly obscure, though the development of the virus allows for the delineation of its development. According to current scientific research, the genetic composition of the virus resembles the genetic composition of coronaviruses prevalent among bat species; however, additional evidence links the proteins upon the surface of the virus (discussed in additional detail further onwards) to pangolins, with the former remaining a particularly plausible explanation. Though the origins of the virus do not remain certain, a recent scientific statement within The Lancet regarding the danger of virus conspiracy theories cites papers analysing its genetic composition. One such paper concludes that the coronavirus possesses an approximate 88% similarity to 2 bat coronaviruses, providing general evidence that the virus remains of natural origin.
With a generalised scientific outline of the taxonomy and epidemiological history of the virus established, one can proceed to the biological components of the virus within its generality. To establish the fundamental biology of the virus, one must begin with its typology. The novel coronavirus remains classified as a positive-sense single-stranded RNA virus; the virus itself possesses an approximate width of 90 nanometres, while 4 varying proteins remain contained within the virus, in addition to the previously referenced genetic material. The virion primarily remains distinguished as a mammalian virus due to its external phospholipid membrane; such a membrane, primarily constructed from the external plasma membrane of the cells which the virus infects, assists within entry. The genetic material of the virus primarily contains approximately 29,900 nucleotides, a miniscule quantity in comparison to the gene sizes known to us today, but massive for the large majority of RNA viruses. The internal components of the genetic material of the virus determine the process of infection. 20,000 RNA bases, 20 kilobases within the virus, remain devoted to replicase genes, responsible for the construction of polyproteins, which remain divided into non-structural proteins. An additional 10 kilobases remain devoted to essential and accessory proteins, including the spike, envelope, nucleocapsid and membrane proteins. However, the large majority of scientific discussion concerns the membrane of the virus; here, the key to entry within a cell remains located.
ACE2, scientifically known as Angiotensin I Converting Enzyme 2, remains established as a protein receptor upon the surface of human cells responsible for regulation of cardiovascular and renal metabolism. However, it serves as a binding protein receptor to the spike proteins of SARS-CoV-2, forming a primary and crucial component of the entry of the virus into a healthy cell. An additional factor responsible for assisting the entry of the virus into the archetypal cell remains the serine protease TMPRSS2, responsible for assisting within S protein priming. The function of this remains the splicing of the aforementioned spike protein, producing a fusion peptide and allowing finalisation of entry. The surface of the virus additionally possesses such receptors as hemagglutinin esterase; however, this does not remain particularly applicable to the mechanisms via which the virus remains responsible for infecting human cells.
However, an essential component of the general effect of the virus upon the human body remains the entry of a singular virus within a singular human cell. This occurs via a detailed biological process responsible for general infection. Firstly, the spike protein receptors upon the surface of the virus attach to the ACE2 receptors upon the surface of the human cell (As previously referenced, the serine protease TMPRSS2 splices the spike protein, producing a fusion peptide and allowing entry). Following this, a series of processes occur which allow for the replication of the simplified genetic material of the cell via the utilisation of replicase enzymes which exist within the cell itself; a set of pp1a and pp1b polyproteins remain produced, primarily responsible for the formation of a replicase-transcriptase complex, which manufactures replicated RNA segments. As viral proteins remain manufactured and assemble concomitantly to the proteins comprising the viral body, exocytosis occurs, releasing additional viruses into the interstitial fluid of the body and producing the incipient entrance instances of a viral infection within the body. The spike proteins which mediate these processes within viruses (including the virus responsible for the SARS outbreak within the early 2000s) and those within the coronavirus remain generally similar.
Though individual mechanisms of infection remain a component of the damage produced via the virus, its general effects upon the body and its methodology of attack remain an additional component. Analysis of this requires a general understanding of the immune system. A singular component of the mechanism utilised via the coronavirus to conduct a total bodily infection remains the offensive upon the human lungs. Following infection, virions enter the alveoli of the lungs, the primary centre for respiration and the general absorption of oxygen from atmospheric substances. With the virus inflicting severe damage upon the cells of the alveoli, leukocytes within the blood attempt to halt the damage, with the immune system producing an excessive reaction known as a cytokine storm. Within the worst instances, the walls of the alveoli collapse, producing acute respiratory distress syndrome. Acute respiratory distress syndrome remains defined as a respiratory disorder within which fluid from capillaries within the alveoli begins to leak, producing decreased quantities of oxygen within the blood stream and a condition known as hypoxemia. Following this, severe organ damage occurs, with potential sepsis resulting from immune system activity and producing a possibility of death. The final stage within the dissemination of the virus remains its spread to additional individuals. This primarily occurs via a system of release which necessitates the utilisation of masks; according to the Centers for Disease Control and Prevention, the virus primarily remains released via infectious droplets of saliva or mucus, producing infections within additional individuals.
However, to produce a general understanding of the methodologies necessary for the development of an epidemic and an eventual pandemic, one must understand the mathematics of epidemiological dissemination; in particular, the development of the coronavirus remains reliant upon exponential growth. In particular, the general model utilised via epidemiologists remains the SIR model, additionally known as the susceptible, infected and recovered model, with the addition of exposed individuals. Utilisation of this model requires the application of Rₒ, the quantity of individuals which may remain infected as a fraction of the quantity who contact an infected individual. Following the progression of an epidemic, epidemiologists adjust this in association with variations within the progression of the pandemic, though the Rₒ of the virus remains 3. The mathematics of the development of the pandemic ultimately remain dependent upon this; the development of the epidemic, however, progresses beyond simple transmission models.
One could primarily characterise the development of the pandemic within an SIR model via a formula within which the change within the quantity of cases per day, perhaps represented as ΔC, remains equivalent to the quantity of individuals exposed each day, multiplied via the quantity of existing cases, multiplied via the probability of contracting the virus provided an instance of contact. When one utilises such a model, it remains effortless to note that at a particular point within the outbreak, all individuals within the population will remain infected and the virus will remain incapable of disseminating further. The question remains if the outbreak remains capable of infecting all individuals within the population, a definitively avoidable outcome; if this occurs, one could expect to observe exponential growth within an outbreak, decaying following a period of time. However, epidemics tend to follow, with the occurrence of restrictions, logistic growth, a mathematical methodology of growth whereby a function continues within a stage of exponential
growth for a period of time, following which, at the inflection point, the derivative of the function begins to decrease, within a bell curve pattern. Following this, the development of the epidemic remains drastically reduced, culminating within a flatline, where the quantity of additional cases remains particularly small. In fact, if one plots the derivative of the resulting function, known as the sigmoid function, the derivative intersects the Y-axis at precisely 50% of the value at which the sigmoid intersects; this indicates that the inflection point for the sigmoid function and thus, the point at which the dissemination of the disease begins to halt, occurs at the point within which the derivative attains its largest value.
Though this aspect of the outbreak possesses relevance, a particularly primary aspect remains the history of the outbreak; within weeks of its development, the entirety of the developed world screeched to a halt, industrially, commercially and governmentally. How did this occur? Beginning with the outbreak itself, one could analyse the development of the outbreak from its inception; on November 17, 2019, according to Chinese officials and the South China Morning Post, an individual, 55 years of age, became the first recorded case worldwide of the virus. During the previous year, approximately 266 individuals placed within medical surveillance remained registered; however, the extent of the outbreak became clear to Chinese Communist Party officials upon December 31, when government officials within the province of Hubei announced that several dozen individuals remained within treatment for a novel infectious virus, as of yet unknown to the scientific community. Upon January 11, the Chinese government reported the first death from the novel disease, a man of 61 years who purchased materials from the wet market where the virus remains suspected to have begun; the death occurred upon January 9, when the man, admitted to a medical facility for treatment, failed to recover and died of heart failure. Following this, the first confirmed cases were reported within external nations, as within the following days, Thailand, South Korea and Japan reported cases; upon January 21, the first case within the United States was reported, with a man of 30 years developing symptoms following his return from Wuhan.
Upon January 23, Chinese government officials ordered the immediate placement of the city of Wuhan and the province of Hubei within lockdown, prior to the Chinese Lunar New Year. At this point, approximately 570 individuals remained infected, with approximately 17 dead. The remainder of the nation experienced increased lockdown measures, with Lunar New Year celebrations cancelled. Upon February 2, 3 days following the WHO declaration regarding the coronavirus as an emergency of international concern, China reported approximately 14,380 cases. As the nation of China remained placed within severe lockdown, precautions began within additional nations; several governments imposed testing upon all entering flights and their passengers. Several days prior, human-to-human transmission remained conclusively located, massively increasing the urgency of global preparations. Upon February 9, approximately 37,198 cases remained recorded, with noted Chinese whistleblower Dr. Li Wenliang dying of the disease upon February 7.
On February 14, France became the first nation within Europe to report a death resulting from the novel virus, with Italy reporting 3 deaths upon February 23 and local government officials halting the Venice Carnival, an event which, were it to continue upon its charted schedule, could produce hundreds or perhaps thousands of additional infections. From February 24 to March 1, a wave of incipient cases occurred, with nations such as the Netherlands, Greece, Georgia, Denmark and numerous contemporaries reporting initial cases. With cases exiting the quarantined and docked Diamond Princess cruise ship, upon February 27, the United States government began to consider the implementation of the Defense Production Act, which would grant President Trump the ability to control national production facilities within emergency situations. The first death within the United States occurred upon February 29, with President Trump disrupting travel from Europe upon March 11 and declaring a national emergency upon March 13. Gathering within groups of 50 or greater was promptly chastised via the Centers for Disease Control and Prevention and upon March 15, the New York school system, the largest within the United States, closed. Though the European Union, facing increasing infections, restricted non-essential travel into the bloc, 2 days following the announcement, upon March 19, China reported 0 local infections, with 14 resulting from external travel and approximately 80,967 infections total; the first nation to experience an immediate halt to the continuation of the virus, China reported positive results primarily due to their brutal quarantine measures.
Upon March 30, an influx of state isolation directives remained issued within the United States, with approximately 265 million Americans placed within isolation. Earlier, upon March 13, the Los Angeles Unified School District, the second largest within the United States, announced a 2-week closure, extended first to May 1 and, following the initial announcement, to the terminal end of the school year. As the outbreak continued, numerous additional events began to contribute to its dissemination, with cases surging within Russia, deaths increasing within Iran and Italy and the United States assuming the mantle of the nation with the largest recorded quantity of coronavirus cases upon the planet. `Russia now possesses approximately 300,000 cases, an issue compounded via the manipulation of statistics due to bureaucratic machinations. And thus, our story returns to today.
With this immense quantity of suffering and death, as well as economic difficulties for millions of Americans and global citizens, one would naturally wonder: does there remain a cure? Scientists, researchers and pharmaceutical specialists across the world are labouring to locate a cure; so far, 7 promising treatments remain within clinical trials, according to The Economist. A promising option, one which I am sure our readers have observed within televised media, remains remdesivir, a treatment originally developed via Gilead Sciences, a prominent American pharmaceutical corporation. As a nucleoside analogue, a treatment which mirrors the chemical structure of genetic material, the efficacy of remdesivir primarily remains attributed to its ability to prevent genetic replication. In addition to 2 trials within Asia developed via Gilead Sciences, the chemical remains authorised for emergency clinical utilisation within the United States, with supplies allocated to hospitals within multiple states. However, though promising, it does not halt the effects of the virus totally, with several researchers insisting it possesses a minor effect and a previously cited Chinese study within this article additionally supplementing this view.
If not remdesivir, then what? Trials of the clinical cocktail Lopinavir-Ritonavir, commercially known as Kaletra, remain within progress or completed. However, as within the case of a study published within the New England Journal of Medicine, they do not necessarily deliver promising results, with an additional study published within The Lancet indicating that triple antiviral therapy performed superiorly to Kaletra. Perhaps favipiravir, known as Avigan, then; this appears to remain the case, as the Russian government, in association with domestic pharmaceutical groups, indicated that a trial of the treatment remains near completion, displaying greater than 80% efficacy. Tocilizumab, known as Actemra commercially, remains an additional option; approved for utilisation within China and sparingly utilised within Italy, it prevents inflammatory responses such as the referenced cytokine storm within its standard application as an arthritis drug.
As for vaccines, numerous varying methodologies exist for the development of vaccines to combat the virus. These include live vaccines, viral vector vaccines, nucleic acid vaccines, protein-based vaccines and additional types. Within a live vaccine, a weakened or destroyed version of the virus, with spike proteins intact, remains introduced within the body, allowing for immediate recognition via the immune system and the development of immunity. The American biotechnology corporation Codagenix, within collaboration with the Serum Institute of India, currently remains within the process of developing a deactivated live vaccine. Viral vector vaccines, additionally known as recombinant vector vaccines, utilise the process of genetic modification to introduce relevant spike protein genome sections within the genomes of varying viruses, such as adenoviruses, an approach pursued via Johnson & Johnson and CanSino, the latter of which possesses a Phase II vaccine. Nucleic acid vaccines, a novel and untested development within the field, primarily remain reliant upon recent advances within genetic engineering, whereby the coronavirus spike peptide gene, in addition to a quantity of DNA, remains subjected to electroporation, developing membrane pores to increase acceptance and allowing for the production of spike proteins, triggering an immune response. This remains within Phase I trials under the guidance of Beijing Advaccine Biotechnology Inovio Pharmaceuticals as a DNA vaccine and an RNA vaccine under Moderna and CureVac, the latter of which aims to “print” such components. Protein-based vaccines primarily insert large quantities of independent antigens, triggering an individual immune response; this remains pursued via Clover Pharmaceuticals, Novovax, the notable Sanofi Pasteur and the United States military, among others. With such entities as Oxford University, the US government and Chinese state apparatus developing vaccines, there remains a slight quantity of hope. However, solutions remain within the distant intervals of several months onward.
In conclusion, the author hopes that this analysis of the individual components of the worldwide coronavirus outbreak shall provide a sufficient quantity of comfort to those who are subjected to the jarring reality we face today. Hopefully, this virus shall be eradicated, but for now, our thoughts and hopes remain both with the relatives of those lost to the outbreak and to the researchers attempting to develop a cure.
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