From Dr. Concepcion: Lessons learned in the COVID-19 pandemic

March 15, 2021
Raoul S. Concepcion, MD

"I hope many readers have taken the opportunity to learn from the evolving science and gone back to review the basics of virology, immune response, and clinical trial development to gain a better understanding of this global pathogen," writes Raoul S. Concepcion, MD, FACS.

As we approach the 1-year mark of the COVID-19 pandemic lockdown, it is appropriate to reflect on what this historic year has taught us, perhaps not in ways we typically have read about repeatedly in many publications: how we are forced to adapt our workplaces, the role of telemedicine in patient care, and learning to handle the disruption of daily routines to meet the dynamic quarantine recommendations that remain in constant flux. Instead, I hope many readers have taken the opportunity to learn from the evolving science and gone back to review the basics of virology, immune response, and clinical trial development to gain a better understanding of this global pathogen.

Remembering our high school or college days in Biology 101, we know that a virus is probably the most efficient biological particle known: It hijacks the host cellular machinery to survive. It comes in 2 basic flavors, DNA and RNA. Coronaviruses (CoV) belong to a family of single-stranded RNA particles. This becomes crucial, given that replication takes place entirely in the cytoplasm, just like messenger RNA (mRNA), and the majority of RNA viruses do not enter the host cell’s nucleus and incorporate into the DNA. And because there tend to be more errors in translation of RNA to protein (or in this case, new virions), there is a higher mutation rate with RNA compared with DNA viruses. We are seeing that play out in real time with new infections because of mutated CoV-2 particles that are being sequenced. Our understanding of the viral replication cycle is a direct result of the technological advances made over the past 2 decades, many of which correspond to our ability to carry out next-generation sequencing (NGS) at both the genome and transcriptome.

Clinically, there has been a significant interest in trying to understand the immune response to this viral load. Why can certain individuals be infected but exhibit only minimal symptoms, whereas a recognized at-risk cohort can progress rapidly to full-blown respiratory failure, end up on a ventilator, and die? Much has been written about cytokine storm and how to mitigate to prevent pulmonary failure. My brief readings in attempts to better understand the immunopathology of this pathogen suggest that the virus and hijacked host cells can evade recognition, continue replication, and evade our body’s innate and adaptive immune response. This is very much akin to some of the immune-evading mechanisms that tumor cells develop, resulting in unregulated cell growth.

Finally, the rapid development and rollout of the SARS-CoV-2 vaccine has provided hope that we can soon possibly return to some sense of normalcy. What obviously has made this vaccine unique is that rather than depending on delivering an attenuated or killed viral strain to stimulate an immune response, using a modified mRNA-based sequence will prompt the host cells to mimic the viral protein expression and simulate the natural course of the infection with resultant neutralizing specific antibodies. This has the potential for possible long-term immunity, albeit not yet proven as the vaccine trials were not designed with that as the primary end point. There are many questions to be answered regarding immunity, long-term efficacy, safety in pregnancy, missed second dose, etc. But near-term results and the ability to prevent new symptomatic infections (the end point of the trials) have been promising.

The purpose of this missive is not to persuade the readers to become amateur virologists. Rather, by studying what is current, even though not exactly carcinogenesis, we can learn valuable lessons and translate that to our understanding of tumor growth and resistance. Many of the concepts and technologies being deployed to study SARS-CoV-2 are analogous to what we are using to learn about molecular drivers in cancer cell growth and regulation. We have discussed the ongoing educational needs for urologists to better grasp the fundamentals of genomics, sequencing, neoantigens, tumor mutation burden, promotors, hypermethylation, etc, as we drive toward this goal of precision medicine. What better way than to cross-train by studying the viral life cycle and enhancing our understanding of a disease that has and will
fundamentally change life as we know it?

Concepcion is director of the Comprehensive Prostate Center and clinical associate professor of urology at Vanderbilt University School of Medicine, Nashville, Tennessee. He is editor-in-chief of Urologists in Cancer Care™.