Aug 25, 2020

COVID-19: A Misdirected Search for the Cure

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Upshot

  • Severe Acute respiratory Syndrome (SARS) viruses are not exactly new. In fact, SARS-CoV-2 is the seventh coronavirus to infect humans (SARS-CoV, SARS-CoV-2, MERS-CoV, HKU1, NC63, OC43, and 229E).
  • While scientists are still unsure of the exact origins of the virus, genomic analysis suggests that it came from a pangolin, given the similarities in the most heavily mutated regions of the genes that encode for the viral proteins, and that those regions are under “purifying selection forces” suggesting natural evolution of the virus.
  • Invasion of the virus causes cell death and sets off a cascade of inflammation focused in the lungs and upper respiratory tract that very quickly leads to lung .This hyperinflammation is mediated by small signaling molecules called “cytokines”, which play a role in directing other immune cells to sources of infection.
  • Hyperactive cytokines produce a destructive inflammatory effect in the lungs termed the “cytokine storm”. The cytokine storm is responsible for destroying the lung tissue and irritating the vascular system, decreasing the transport of oxygen in the lungs causing them to fail.
  • There are currently no effective therapies on the market (the FDA has approved remdesivir and convalescent plasma, but neither have demonstrated substantial improvement in patient survival and are dubious at best).
  • An effective therapy for COVID-19 would inhibit the inflammatory and hypercoagulation symptoms in the lungs, allowing patients to live long enough to develop adaptive immunity against the virus.

What does not bend, breaks

The outbreak of SARS-CoV-2, the virus that leads to COVID-19 disease, has inspired mass hysteria on an unprecedented level (maybe on par with the Black Plague?). Never in the modern era has a pathogen captured the attention of the global populace, inspired so many armchair epidemiologists, and politicized human health and well-being. The COVID epidemic has cast a spotlight on the ill-preparedness of the WHO and national centers of disease control to deal with pandemic of this magnitude and has also illuminated the ineffectiveness of a bipartisan, fragmented government and the fragility of the global economy. The life sciences industry is rapidly evolving as attention is turned towards developing novel anti-virals while regulation is being aggressively scrutinized as governments push for new COVID therapies and vaccines to enter the market ASAP

While the negative impacts of COVID-19 on our healthcare system and the global economy cannot be overstated, many biotech companies have seized upon the critical unmet need to develop robust and effective diagnostics, vaccines, and therapeutics for SARS-CoV-2 infection. With great calamity comes great disruption, followed by rapid consolidation as the wheat separates from the chaff. The ability to seize upon this once-in-a-lifetime opportunity and pivot within the dynamic landscape of drug development is a strong sign that a biotech company’s research and development program is innovative, has broad applications, and is not limited to a niche disease area. This agility also highlights the excellence of the management team’s grasp of corporate strategy, R&D, and project management.

But first, a bit of science

Severe Acute respiratory Syndrome (SARS) viruses are not exactly new. In fact, SARS-CoV-2 is the seventh coronavirus to infect humans (SARS-CoV, SARS-CoV-2, MERS-CoV, HKU1, NC63, OC43, and 229E). But for some reason this one hit differently. The high rate of infection and severe respiratory symptoms of the disease, combined with media-driven panic, thrust the world into a state of emergency. Luckily, scientists have a good understanding of how the virus works and progresses to the associated disease “COVID-19”. 

It all starts with viral invasion of the cell. Viruses have co-evolved with humans to locate “doorways” into cells, which they can pass through concealed before wreaking havoc. For SARS-CoV-2 this doorway is the “ACE2 receptor” which functions as a bridge between the exterior of a cell (where the virus floats around) and the interior (where the molecular machinery is located). The ACE2 receptor is highly concentrated in the lungs, which is why COVID-19 is primarily an upper respiratory disease that kills lung function and oxygen transport. Binding of the virus to the ACE2 receptor on human cells sets off a cascade of molecular signaling that results in internalization of the viral particle into the intracellular space (if high-school biology didn’t fail you, you probably remember this as the “cytoplasm”).

It is this unique binding and internalization mechanism that allows scientists to study the evolution of the disease by comparing it to other SARS viruses. Computational analyses of the binding interaction between the virus and the host human cell has revealed that SARS-CoV-2 is actually more inefficient at entering cells than previous strains, casting doubt on the notion that the virus was engineered in a Wuhan lab (why would a scientist create a subpar virus, after all?). This idea of natural evolution of the virus is further supported by evidence that the virus evolved in the presence of an immune system (based upon certain “polybasic” chemical modifications to the exterior of the virus), indicating that it was not engineered ex vivo in a lab. While scientists are still unsure of the exact origins of the virus, genomic analysis suggests that it came from a pangolin, given the similarities in the most heavily mutated regions of the genes that encode for the viral proteins, and that those regions are under “purifying selection forces” suggesting natural evolution of the virus. 

Understanding how SARS-CoV-2 enters the human cell and replicates is critical to developing effective treatments. There are ways to block the binding of the virus to the ACE-2 receptor, prevent the virus from internalization after binding, and prevent replication after internalization. These ideas have been seemingly lost by the scientific community as the pressure to develop a vaccine consumes everyone’s attention. It is unlikely that a single vaccine alone will be the solution to treating COVID-19. 

The search for an effective treatment

Infection with SARS-CoV-2 follows the classic pathway of viral invasion beginning with the internalization of the virus into the human host cells, a Trojan Horse approach that has been optimized over evolutionary timescales. The CoV-2 virus hijacks the human cell’s replicative machinery and turns it into a virus-producing factory, with the end goal of using the cell until exhaustion and pumping out carbon copies of the virus until the cell eventually dies. Cell death and recognition of the virus by the body’s immune system sets off a cascade of inflammation focused in the lungs and upper respiratory tract that very quickly leads to lung failure (at which point the patient is put on a ventilator) and death in the elderly and other compromised patients (i.e. patients with comorbid obesity, diabetes, asthma, COPD, pneumonia, tuberculosis, etc.). This hyperinflammation is mediated by small signaling molecules called “cytokines,” which play a role in directing other immune cells to sources of infection. Hyperactive cytokines produce a destructive inflammatory effect in the lungs termed the “cytokine storm”. The cytokine storm is responsible for destroying the lung tissue and irritating the vascular system, decreasing the transport of oxygen in the lungs causing them to fail. Clinicians have also noted the formation of life-threatening blood clots throughout the body. An effective therapy for COVID-19 would inhibit the inflammatory and hypercoagulation symptoms in the lungs, allowing patients to live long enough to develop adaptive immunity against the virus. 

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