“Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” Marie Curie
“Look for the silver lining
Whenever a cloud appears in the blue
Remember somewhere the sun is shining
And so the right thing to do is make it shine for you.”
- Jerome Kern
The silver lining in the COVID-19 pandemic is Science. While I find the speed and extent of devastation wrought by COVID-19 as staggering as anyone, I’m just as amazed by the breakneck pace of scientific discoveries about all aspects of the disease, ranging from studies of the fundamental nature of the culprit, SARS-CoV-2, to the epidemiology of the pandemic. This Germ Gem entry tells the story of exciting recent discoveries about how SARS-CoV-2 gets itself into cells of so many organs and of how these discoveries are fueling progress toward the “holy grail” of COVID-19 prevention—a vaccine.
Like all physician scientists, my perspective is rooted in the long track record of advancements in treatment and prevention that spring from clinical observations. In other words, moving from the bedside to the bench, that is, taking questions that arise in the care of patients to the research laboratory to find answers to these questions. While I’m no longer involved in this endeavor, I’ve witnessed with great admiration what active physician scientists and their research colleagues have accomplished in recent months. They’ve provided critical insights into the pathogenesis of SARS-CoV-2, that is, how this virus operates (causes disease) and how our bodies, in particular our immune system, defends us against it. These insights involve epithelial cells that line organs, such as, the respiratory and gastrointestinal tracts, and endothelial cells that line blood vessels throughout the body.
The bedside. At first, most of the clinical attention on COVID-19 was focused on the lungs. It immediately became clear that SARS-CoV-2 is a respiratory tract pathogen, a cause of life-threating pneumonia. This wasn’t surprising given that the other two coronavirus-mediated pandemics this century, SARS (severe acute respiratory syndrome) and MERS (Mideast respiratory syndrome), also raise havoc in the lungs.
But over the past two months it’s become increasingly clear that COVID-19 can involve many other organs: the heart, kidneys, nervous system, gastrointestinal tract and skin, as well as the coagulation and immune systems. In fact, COVID-19 might be considered a multisystem disease. As such, it is like other multisystem diseases, for example, the connective tissue diseases, systemic lupus erythematosus and rheumatoid arthritis, and the granulomatous disorder, sarcoidosis, which also involve multiple organs. But there’s a big difference. These other multisystem diseases are idiopathic, that is, their cause is unknown. The etiology of COVID-19, however, is established—SARS-CoV-2. As you would imagine, managing patients with damage to multiple organs, many of which are failing at the same time, is a huge challenge.
The bench. The explanation behind why COVID-19 is a multisystem disease was provided by researchers studying the structure of SARS-CoV-2, in particular the spike glycoprotein (S) on its surface, and its interaction with angiotensin converting enzyme 2 (ACE2) receptors on host cells. Like a key fitting into a lock, it is through this interaction that the virus gains entry into cells. (All viruses must hijack host cells to survive and multiply.) This breakthrough discovery was described in April in the journal Cell.
In another publication in April in Cell, researchers described ACE2 receptors for SARS-CoV-2 in lung pneumocytes that line the tiny air sacs (alveoli) where gas exchange occurs. And they found these same receptors in enterocytes (epithelial cells that line the gut) and in nasal goblet cells. (A loss of smell and taste is a common early symptom of COVID-19 as discussed in the May 6th Germ Gem blog.) Finally, they reported that expression of these receptors was increased when the cells were exposed to interferon, a cytokine that is produced by cells to ward off infection. And in May in the journal Lancet, expression of ACE2 receptors was reported in several organs, including the lung, heart, kidney, and intestine, as well as in endothelial cells that line blood vessels in these organs.
What does this knowledge of the pathogenesis of COVID-19 mean? Now we’re back to the silver lining of the pandemic. As you would likely surmise, scientific understanding of the “key” (the spike protein of SARS-CoV-2) and the “lock” (ACE2 receptors) opens many doors, not just for the virus to gain entry to cells. But this discovery also has opened minds of scientists searching for vaccines and medicines to help thwart the consequences of viral entry into cells.
My guess is that the word “unprecedented” will be one of the most overused word in the English language in the year 2020. Not only are we confronted with a virus that has an unprecedented mechanism of causing disease, but the scientific response to it (in academic centers, government laboratories, and pharmaceutical companies) is proceeding with unprecedented speed.
It is estimated that there at least 115 vaccine projects underway around the world. Many of these projects are aimed at the spike protein of SARS-CoV-2. The concept underlying this approach is that antibodies to the spike protein which develop following immunization will block viral entry into cells. Several candidate vaccines are already in early clinical trials for safety. And projections by some experts suggest a vaccine could be “on the market” early next year. Given all the hurdles that must be cleared to accomplish this goal, this would be an Unprecedented accomplishment (capital “U” intended).
Lightning speed also characterizes the search for an effective therapy. In the May 2020 issue of the journal Nature Communications, researchers described development of human monoclonal antibodies aimed at the S protein which neutralized viral entry into cultured cells. And drug makers are racing to produce monoclonal or polyclonal antibodies engineered to home in on pieces of the coronavirus. On a related note, clinical trials are already underway using blood plasma from recovered COVID-19 patients that contains antibodies to SARS-CoV-2 to treat COVID-19 patients. Preliminary results of this approach are very encouraging.
In addition to targeting the viral S protein, drugs that can shut the host cell door (ACE2 receptors) and thus keep the virus out are under development as potential therapeutic agents. (ACE inhibitors, like lisinopril, are already widely used for other purposes—to treat cardiovascular disease and hypertension.)
Studies of the pathogenesis of severe COVID-19 have revealed that a life-threatening consequence of viral entry into cells is the triggering of an overly exuberant response by cells of the immune system. While some cytokines have therapeutic potential, when they are released from T lymphocytes and macrophages in a dysregulated manner a cytokine release syndrome is unleashed (often referred to as a cytokine storm) resulting in severe tissue damage, and in some cases, death. One cytokine in particular, interleukin-6 (IL-6), plays a pivotal role in the cytokine release syndrome. And monoclonal antibodies (mAb) synthesized in the laboratory that neutralize IL-6 have shown great promise in treatment of COVID-19 patients. Several anti-IL-6 mAb products (tocilizmab, sultiximab, and sarilumab) are already in randomized clinical trials.
The silver lining is shining brighter. In April 2018, I participated in the “March for Science,” a demonstration that was spurred by a loss of trust in science by some Americans, at a time when science was becoming increasingly important in addressing climate change. I believe that this mistrust, as well as science denialism, are changing and that most Americans now realize development of a vaccine is crucial in stopping the COVID-19 pandemic. In the meantime, they can also see that we need drugs to treat patients suffering with this brutal disease.
I also think this is a time when all Americans can be thankful that their tax dollars going to support the National Institutes of Health (NIH), inarguably the greatest research institution in the world, are paying off. And we can be especially grateful for the leadership of Tony Fauci, “America’s Doctor,” a physician scientist who serves as director of the National Institute of Allergy and Infectious Diseases.
Finally, on a very exciting note, on May 11, 2020 in the journal Science, a strategic approach to a COVID-19 vaccine was announced. Recognizing the urgency and challenges of developing a vaccine, a collaboration spearheaded by the NIH was announced. This public-private partnership, designated ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines), involves the Food and Drug Administration, Centers for Disease Control and Prevention, the Departments of Defense and Veterans Affairs, the European Medicines Agency, and representatives from academia, philanthropic organizations, and more than 15 biopharmaceutical companies. In the war against SARS-CoV-2, this approach (fueled by science) should be welcomed by everyone.