Thought-Provoking Hypotheses About the Novel Coronavirus
Richard Feynman described the scientific method in three steps: First you guess how nature might work, then you make predictions based on your hypothesis, then you test these predictions against experiment, experience, or observation. I’d like to present a few different highly speculative hypotheses about the novel coronavirus. Some these are optimistic or “Positive” while others are pessimistic or “Negative”. They are offered as fodder for prospective lines of research. Each hypothesis is ranked with ratings of Plausibility, Potential Importance, and Testability, explained below.
- Reasonable, even likely
- Could go either way
- Very unlikely
Potential Importance: Suppose the idea is correct, how much would that change thinking about the pandemic?
- A lot
- Not much
Testability: How easy or hard would experiments be to address predictions of the hypothesis?
- Difficult but doable
- Very hard to impossible
And now, the hypotheses:
Positive: A virtuous cycle follows from social distancing and isolation measures leading to low-inoculation infections that still promote immunity. A new kind of herd immunity might emerge with a lower fraction of disease. The fraction of infections that lead to serious disease, including mortality, may not be a fixed number as most modeling now assumes. The underlying biological mechanism might be akin to Variolation. Infections that result consequent to social distancing not only arise more slowly but also offer more protection at a cost of fewer symptoms. A plausible implication is less harm in low population density areas. Conversely, high-inoculation infections could be the reason that health care workers are at special risk. An implication is the need for "Precision Public Health" in understanding the microbial environment of assisted care homes, cruise ships, aircraft carriers, and expeditions. Plausibility 2; Potential Importance 1, Testability 2-3
Negative: Suppose antibody response in some cases makes things worse because some antibodies that bind to the virus facilitate uptake and productive infection. Such mechanisms are known for other viruses, including related coronaviruses in vitro but not documented specifically for the novel coronavirus. Plausibility 2, Potential Importance 1 Testability 2
Positive: Other currently available vaccines may protect more generally than the specific target they are aimed at, such as BCG, and other childhood vaccines. Maybe it is the adjuvant which is a benign stimulator of immunity. This would be great good luck and perhaps contribute to the reason why some countries have been relatively spared so far. Plausibility 3, Potential Importance 1, Testability 2-3
Negative: Phenotypic mutation of the virus could render a vaccine difficult or even dangerous. Depending on virus strain, which antibody selection itself might drive, the same antibody might in some cases be beneficial and in other cases detrimental to the patient. This has not been documented nor shown for COVID-19. Why worry till it happens? With so many people infected, a lot of variants likely exist and more will be generated. Plausibility 2, Potential Importance 2, Testability 3 (Deliberate Gain Of Function experiments by engineering would be foolish and dangerous.)
Positive: The virus might mutate into less virulent but immunologically active forms that are equally contagious. In this scenario the virus naturally evolves into its own vaccine and spreads spontaneously. Plausibility 3, Potential Importance 1, Testability 3 (On the other hand, excellent science underlies the possibility of deliberately making live vaccines that efficiently spread.)
Both Positive and Negative: Suppose simultaneous or prior infections with other agents modify the reaction to the Covid-19 virus. Effects could run the gamut from protection to potentiation for more severe outcomes. There are many unknowns regarding the heterogeneity of outcomes regarding infection. Co-infection scenarios are among the lessor considered. Polymicrobial – including polyviral – infections are appreciated to play a bigger role than previously thought and a strictly Koch’s postulate view of infectious disease – one pathogen, one disease – is not always the way things work. Plausibility 1, Potential Importance 1-2, Testability 3
Both Positive and Negative: Super-spreaders might be key. Some aspects relate to the circumstances of travel and events. Others might be biology of individuals and/or timing within the course of disease. Now poorly characterized, super-spreaders need to be better studied, their leverage modeled so that trade-offs between individual rights and public health could become better based on reliable data. Plausibility 1, Potential Importance 1, Testability 2
Negative: Animals of industrial agriculture could become reservoirs of virus and the emergence of new viruses. They already harbor some and may well be the origin of others. Harold zu Hausen (Nobel prize for work on HPV as causitive agent of cervical cancer) has a research program looking into the possibility that the carcinogenic association of meat is consequent to viruses in these animals. Plausibility 1, Potential Importance 1, Testability 2
Very Negative: Suppose humans become infected with enough different viruses to supplant the zoonotic generation of new human pathogens. The example of HIV is important, in showing that recombination is frequent when humans are infected by multiple strains. Recombination is the mechanism whereby viruses make great leaps over the evolutionary landscape. Most microbial diseases have been relatively stable targets once in humans but this is not inevitable. If enough recombination-capable viruses become endemic in humans, co-infection will bring them into the same cells and recombination will ensue. In this scenario, humans become the source as well as the sink of new diseases. Plausibility 2, Potential Importance 1 (because it could change our species’ evolutionary landscape), Testability 2-3