Biological risks are more severe than has been widely appreciated. Recent discussions of mirror bacteria highlight an extreme scenario: a single organism that could infect and kill humans, plants, and animals, exhibits environmental persistence in soil or dust, and might be capable of spreading worldwide within several months. In the worst-case scenario, this could pose an existential risk to humanity, especially if the responses/countermeasures were inadequate.

Less severe pandemic pathogens could still cause hundreds of millions (or billions) of casualties if they were engineered to cause harm. Preventing such catastrophes should be a top priority for humanity. However, if prevention fails, it would also be prudent to have a backup plan.

One way of doing this would be to enumerate the types of pathogens that might be threatening (e.g. viruses, bacteria, fungi, etc), enumerate the subtypes (e.g. adenoviruses, coronaviruses, paramyxoviruses, etc), analyze the degree of risk posed by each subtype, and then develop specialized medical countermeasures in a prioritized way in advance of a threat.

This approach is a good way of tackling naturally occurring threats, but seems ultimately doomed against a determined adversary. It would be hard to feel confident that any list of threats was fully exhaustive—for example, mirror bacteria would have likely been left off of most lists like this. Second, even for threats on the list, surprising breakthroughs or concerted efforts could break assumptions around how effective a given medical countermeasure is. The public history of the Soviet bioweapons program^[1] gives ample examples: attempts to develop hybrids of smallpox and Ebola, engineering a strain of plague resistant to over 15 kinds of antibiotics, and modifying pathogens to intentionally trigger autoimmune reactions. There are simply too many ways that a creative adversary could cause catastrophic harm with a biological weapon, and we need fully generalized defenses that work in a future-proofed way.

Here we outline a hypothesis for ‘four pillars’ of biodefense that should work against even the most sophisticated engineered pathogens or ‘unknown unknowns’. These are:

Personal protective equipment (‘PPE’)
Pervasive physical barriers and layers of sterilization (‘biohardening’)
Pathogen-agnostic early-warning systems (‘detection’)
Rapid, reactive medical countermeasures (‘M

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