Origins of Disease : On the Quest to End COVID-19 , the Most Critical Question Yet May Be How SARS- CoV-2 Causes Illness
By Ekaterina Pesheva
Since the beginning of the pandemic , once-esoteric scientific terms have become common parlance — spike protein , PCR , mRNA . Pathogenesis is not one of them . Yet , when it comes to understanding COVID-19 , this may well be the most important word that has yet to make its way into the mainstream lexicon .
Pathogenesis — or “ origin of disease ”— is the study of the processes that give rise to physiologic dysfunction and illness . In the case of COVID-19 , it is the study of virus-induced mischief — how SARS-CoV-2 interacts with various cells , tissues , and organs to cause COVID-19 .
As the world inches along on its journey through this ever-evolving pandemic , understanding the “ how ” of COVID-19 could be the most important question of all .
The question has motivated the research of Galit Alter and David Knipe over the last year . The two co-lead the pathogenesis research group of the Massachusetts Consortium on Pathogen Readiness ( MassCPR ), a multi-institutional , cross-disciplinary , international research effort established in March 2020 at Harvard Medical School to help combat the current pandemic and set the stage for fighting future ones .
Alter is a professor of medicine at HMS and an investigator at the Ragon Institute of MGH , MIT , and Harvard . Knipe is a professor of microbiology and molecular genetics in the Blavatnik Institute at HMS .
A year after the World Health Organization declared COVID-19 a global pandemic , Alter and Knipe discussed what they have learned about the disease-fueling interplay between the SARS- CoV-2 and its human host and their ongoing efforts to understand the shifting landscape of COVID-19 .
A triad of disease
The archetypal triad of infectious diseases involves a host , a pathogen , and the interaction between the two . To understand the mechanisms of infection , neither the human host nor the pathogen can be studied in isolation — a disease is invariably a function of the interplay between the two .
The pathogen — the structure and behavior of the virus and how it evolves over time under various pressures around it .
The host — the underlying individual factors — genetics , differences in immune response , overall health , age — determine how and why a virus might affect one person differently from another to cause a range of disease manifestations .
COVID-19 has demonstrated a stunning versatility in not only in the range of its severity — from asymptomatic to deadly — but also in range of organs and organ systems it can affect .
The interplay — the host and pathogen are engaged in an ongoing battle . The field where this battle unfolds is the immune system . The host immune response powerfully modifies how the virus behaves once inside the body , the magnitude of the infection , the severity of the disease , and the risk for organ damage and complications .
Yet , understanding COVID-19 , or any complex disease for that matter , is not a simple equation of summing up the individual parts . Each of the three variables carries multiple unknowns within itself . In a way , understanding the pathogenesis of COVID-19 is akin to solving a three-body problem , a notorious challenge in classical mechanics .
“ The study of pathogenesis is essentially puzzle-solving ,” Knipe says . “ It ’ s a systems approach to studying a disease , so one of the roles of our group is to put together the pieces of knowledge from areas of study to explain the system .”
Alter and Knipe emphasize that a comprehensive understanding of COVID-19 pathogenesis should go beyond how the virus behaves inside the human host . That classic view may be limiting . Alter points out that the host-pathogen interaction is but one link in a long chain of biologic events .
“ We are trying to ask every single question about this virus — how it infects , how it causes disease , how it affects the world around us but also how the virus survives in nature so that we can be prepared for the next coronavirus ,” Alter says . “ We are focused on everything that the pathogen can interact with , what allows it to survive and persist , and that ’ s a much bigger scope of inquiry .”
To be sure , that scope is staggering , but scientists have also generated immense knowledge about an entirely new human virus causing an entirely new human disease , and they have done so at a pace never before achieved in the history of science and medicine .
This growing knowledge has defined the contours of the disease and filled in many critical blanks . Here are some of the key insights gleaned by researchers from MassCPR ’ s pathogenesis working group .
The pathogen : survival of the wiliest
The structure of SARS-CoV-2 was elucidated early in the pandemic , and the virus ’ s genome was sequenced and published in early January 2020 — mere weeks after the first reports out of Wuhan , China .
The pathogen ’ s behavior has posed more of a challenge . One critical blind spot early in the pandemic was asymptomatic and