Wildlife Infectious Disease Biology Is Important

The steel-man case for wildlife virology, from a lab origin theorist and biosafety proponent

One of the most insightful intuition-building things I learned from my PhD advisor was about the discrete logistic map, a model of population dynamics where every year (or more general discrete time interval) a population grows or shrinks based on how far away it is from the carrying capacity.

The equation is a well-known and shockingly simple path to chaos, mathematically speaking. When the time lag and intensity of feedback is very fine-tined (i.e. rapid, incremental moves towards carrying capacity), the population converges nicely to its carrying capacity. When the combined time lag and intensity of population feedback gets too large, the population begins to whipsaw erratically above and below the carrying capacity.

Bifurcation diagram of the discrete logistic map showing how the possible end states, X, can change as the intensity of feedback R increases. Around R=3, the system oscillates between two states. At R=3.5, another period-doubling bifurcation occurs and there are four states at equilibrium. Eventually, the system fluctuates chaotically in infinitely many states, revealing intuition that greater feedback intensity leads to more chaotic, unstable dynamics.

The intuition from the model is simple: smaller, more frequent feedback leads to more stable dynamics. Larger, less-frequent feedback throws the world into chaos. This intuition applies to populations as well as discrete pendulums, including the political pendula by which popular outrage leads to policy feedback on various topics.

Prior to the COVID-19 pandemic, wildlife virology was de mode, DARPA PREEMPT teams like the one I was on were attempting to preempt pandemics by studying pathogens circulating in animals. Then, wildlife virology was an epidemiological analog to securing national defense by fighting wars abroad so we didn’t have to fight wars at home.

Then, SARS-CoV-2 emerged in Wuhan, at the doorstep of the Wuhan Institute of Virology, bearing signs of synthetic biological tinkering proposed in the DEFUSE grant submitted to the DARPA PREEMPT program. The pendulum now swings against the wishes of wildlife virologists due to widespread public belief in a lab origin, several key branches of the US intelligence community assessing a lab origin is more likely, and findings that academic virologists used their expertise to mislead the public by calling a lab origin “implausible” in papers ghost-written by the lab’s funders all while privately acknowledging a lab origin was “so friggin likely”.

In this chasm separating wildlife virologists from outraged political coalitions, I’m the lone scientist straddling the gap. I’m the only DARPA PREEMPT awardee to publicly state a lab origin is most likely and corresponding author on the most important paper documenting evidence of a synthetic origin. I’ve written a lot about the disappointing behavior of many virologists who abandoned objectivity, and my consternation for many who normalized risky research that likely caused the COVID-19 pandemic. I advised the NIH Office of the Director on the dangerous Gain of Function Executive Order aiming to improve bioscience risk management and avoid any unauthorized research enhancing pathogens in ways that could cause significant societal consequences.

As a lab origin theorist and biosafety proponent, I am alone as one of the only such lab origin scientist to have a significant background in wildlife virology. I published on bioattribution and the taxonomic patterns of zoonotic viruses before COVID, was a fellow guest editor on a Proceedings of the Royal Society journal special edition on pathogen spillover in 2019. One of my co-authors on the “taxonomic patterns” paper was listed on the DEFUSE grant. According to a new report by Paul D. Thacker, another co-author is now reportedly under an FBI investigation for transporting monkeypox samples from Congo without the appropriate paperwork.

When I say I burned bridges in my career by publishing objective findings pointing to a lab origin with methods used by my colleagues, that’s an understatement. I have no regrets in my objectivity nor any problems with the analyses I’ve produced, but as I see the ship of wildlife virology sinking I feel an obligation to make a steel-man case for why good people and good scientists may still see value in wildlife virology work.

All new pathogens come from animals

Every pathogen comes from somewhere, and that “somewhere” is another species. Even pathogens now endemic in humans such as measles or smallpox likely originated from hooved mammals and spread to humans during the agricultural revolution. Rinderpest, a pathogen that plagued cows and caused famines across Africa, was a close relative of measles. Horsepox, chickenpox, monkeypox, and other-animal-pox viruses are relatives of smallpox. The hantavirus outbreak on a cruise ship today likely started from a hantavirus-infected rodent. Ebolavirus likely comes from bats as its relatives Lloviu and Marburg viruses are also found in bats. Nipahvirus, Hendravirus and other Henipaviruses are found in flying foxes, so every time some idiot drinks date palm sap in Bangladesh and has a 50-75% chance of death from their Nipah virus infection, the virus likely to kill them and anyone they infect came from a bat.

The only viruses endemic to humans and NOT found in other primates are, thankfully for its reflection on the moral choices of our ancestors, STDs like Herpesviruses and Pappilomaviruses (see my ‘taxonomic patterns’ paper - this was a strangely reassuring finding!). HIV is a strange exception of an STD likely originating through blood transfer (I hope) from wildlife trade exposing some human’s blood to the blood of a primate containing the primate-infecting Simian Immunodeficiency Virus.

There are a few pathogens that plague humans as curses of our primate ancestry. All the rest come from humanity’s many interactions with non-human animals.

One approach to saving human lives in light of limited health science funds is to focus only on the pathogens infecting humans. Another approach, and the original intention of the DARPA PREEMPT program, was to research and develop ways to add defensible space between humans and infected animals, possibly by immunizing animals against the infections likely to cause outbreaks in humans. The ethics of what we can do with animals are more relaxed than the ethics of what we can mandate humans do. Some pathogens could plausibly (in an unlikely but not impossible event) end modern human civilization and prevention of spillover for these pathogens - Nipah, Hendra SARS, MERS, avian influenza, and more - could plausibly buy humanity more time since spillover events are one step prior to the human-human transmission chain where contact tracing is required to stop a pandemic, the stakes are much higher, and our ability to create defensible immunological space not established as many people don’t want to take mandatory vaccines.

Prevention of pathogen spillover has worked before. We eradicated rinderpest through a successful animal vaccination campaign. Most people aren’t aware that we regularly tamp down outbreaks of avian influenza in poultry (and recently dairy) farms and mad cow disease in dairy farms. We hold back the tide of brucellosis through hunting permit allocations for elk outside Yellowstone National park aimed at limiting elk-cow overlap as elk are intermediaries in the bison—>elk—>cow transmission chain that threatens livestock. We test ungulates for chronic wasting disease, a prion disease like mad cow disease, and inform hunters on the importance of monitoring the behavior of their prey, testing their meat, and cooking wild game thoroughly to prevent a much-feared, completely untreatable, potentially civilization-ending prion pandemic.

Epidemiological studies of animals - a field called “epizootiology” like epidemiology for the zoo - can plausibly reduce the risk of pandemics in humans. Like any other field of science, most studies are relatively early in their technological readiness, so unlike the motivational introductions of grants it’s not like every study is single-handedly holding back the tide of infectious diseases and eradicating mankind’s greatest threats. A lot of work is relatively mundane yet difficult fact-finding in the field to learn how transmission happens, which animals are susceptible, what immunity exists in the population, and more. From that foundational knowledge, we’re better able to assess the feasibility of proposed wildlife interventions.

Wildlife samples can be handled safely

A common critique of wildlife virology among lab origin theorists and biosafety advocates is that wildlife virologists are pulling dangerous viruses from remote areas of the world and bringing them back to big cities where they are more likely to cause a pandemic in dense human populations than they would if they infected some backcountry animal trafficker.

This is a fair critique, yet there are also fair counterarguments and fair solutions that mitigate this risk.

For a counterargument, the risk of any given wildlife epizootiological effort must be weighed against baseline risks from spillovers that occur - people who catch bats that may contain Nipahvirus, for example, wear PPE and adamantly refuse to touch date palm sap, the primary path to human infections and onward transmission chains that occur every single year. The risks of my colleague Vincent Munster studying monkeypox from clinical samples in his BSL-4 lab in Hamilton Montana must be weighed against the baseline risk of monkeypox that is already circulating within the human population and that Vincent’s lab is one of the safest labs in the world and one of the only places where we can test countermeasures in live animals to make sure we have a cure for monkeypox before the ongoing pandemic gets worse.

Some critiques may rightfully argue that transporting live viruses poses a risk of infections during transportation. This would be true if samples of live viruses were being transported, but most often samples transported abroad for sequencing are placed in preservatives that inactivate (kill) viruses both for biosafety and data quality. The dangers of transporting clinical samples are real and alternative options are desirable even with suitable inactivation/preservation media. In fact, this was part of the reason USAID funded capacity-building efforts abroad aiming to distribute the responsibility of sequencing clinical samples of emerging infectious diseases, allowing us to move inactivated samples faster over shorter distances for local sequencing, letting reverse genetic methods like those believed to have resurrected SARS-CoV-2 to resurrect live viruses from the DNA sequence only in qualified, secure facilities.

With USAID shut down, with no sequencing capabilities abroad for US scientists to use, the only options that remain are either (a) inactivate samples and bring them home in the most secure way possible, such as luggage whose chain-of-custody you can be sure of at all times, or (b) don’t study any pathogens abroad until other countries choose to share the sequences, including emerging infectious diseases with a high likelihood of finding their ways onto US-bound planes.

These arguments of wildlife and foreign clinical sampling are separate from the questions about dangerous Gain of Function. The research discussed here assumes we are only getting samples from animals or patients for studies of countermeasure efficacy and epidemiology, not for targeted enhancements, passaging, or other modifications that fall under the dangerous Gain of Function policy. Infectious disease biology of native samples is valuable because it helps us understand routes of transmission, test the efficacy of existing countermeasures, develop new countermeasures such as monoclonal antibodies that can neutralize the diversity of pathogens found in humans or animals (and not be one, pre-existing mutation away from evolved resistance), and more.

The risks of such work can be managed with proper protocols, from inactivation of field samples and proper custody of samples during transport to use of capacity developed abroad for local sample processing.

Wildlife virology is essential for bioattribution

This is perhaps the least-appreciated point, something that epizootiology researchers aren’t aware of because they typically don’t do forensic or intelligence work, and something that lab origin theorists and biosafety advocates overlook because they haven’t done wildlife infectious disease biology.

In order to know that a pathogen is non-natural, we need a verifiable natural baseline.

In order to attribute non-natural pathogens as such, such as SARS-CoV-2, we rely on genomes of close relatives sampled around the world to contextualize what we see in the pathogen under forensic investigation. The furin cleavage site of SARS-CoV-2 is only “inconsistent with the expectations of evolutionary theory”, as one scientist put it, thanks to the baseline context of wildlife virological evolution we can study under the assumption that pre-COVID wildlife viral genome databases were not tampered with, that the genomic record therein is accurate and trustworthy.

Consider a world where the pendulum swings too far without wise consideration of these things. Wildlife virological labs at home are defunded, limiting our capacity at home. USAID was gutted, removing US scientists’ access to capacity abroad. Paperwork for such research is not approved on account of transportation risks and no combination of sample inactivation or chain-of-custody protocols can move paperwork through.

In this scenario, the US will be completely reliant on foreign scientists and foreign governments for our genomic, natural baselines. If the Chinese government were to modify another virus, such as a Nipah virus, and such a virus were to be intentionally or unintentionally released, we would likely be even more blind and unable to attribute that non-natural virus as such because we wouldn’t be able to verify the genomic baselines we need to identify any inconsistencies with evolutionary theory.

It’s not just the Chinese government, or the Russian, Iranian, and North Korean governments we need to monitor, attribute, and deter. It’s also foreign research labs and bioterrorists who could procure wildlife, domestic animal, or clinical pathogen samples, possibly enhance these pathogens, and intentionally or unintentionally release them.

Simply put, without verifiable and voluminous natural baselines, we will be unable to attribute non-natural pathogens as such. If we can’t even determine that a pathogen is non-natural, we certainly can’t attribute it to a responsible party, and thus we will be unable to deter intentional and unintentional releases of potentially catastrophic pathogens. Adversaries trying to plan bad actions could very well try to poison the data with fabricated genomes, confusing evolutionary analyses without any of our own samples enabling us to identify fabricated genomes as such.

Thankfully, it’s possible to cooperate with others on verifiable natural baselines, bolstering many countries’ abilities to attribute non-natural pathogens as such.

All we need to do is fund sample collection, sequencing, and possibly capacity development abroad for sample processing and sequencing under the condition that chain-of-custody protocols are strictly followed, allowing us to have 100% assurances that the data we collected came from the animal, place, and time we collected it with sequences generated in the exact manner described.

Wildlife infectious disease biology can be done safely & improve health security

The best most cost-effective way to generate such samples is to support epizootiological research with better risk-management oversight than we had pre-COVID. Ensure field workers wear PPE. Evaluate the relative risks of sample collection versus baseline rates of spillover. Ensure samples are inactivated prior to transport. Ensure chain-of-custody protocols are followed during transport. Ensure downstream laboratory work adheres to the dangerous Gain of Function EO by conducting work in facilities certified at the proper biosafety level, by prohibiting enhancement and passaging except in cases approved by procedures laid out in the dGOF EO, and ensuring any live viral samples are recorded, access strictly controlled, and facilities monitored to deter any unauthorized transport of samples outside their designated facility.

Done well, wildlife infectious disease biology can even improve our ability to monitor and deter biological weapons development. By expanding capacity for disease surveillance abroad and cooperating with other governments to monitor stockpiles of pathogens studied (and not enhanced) for countermeasure development, the statistical power of our bioattribution capabilities will dramatically improve. Such agreements may be possible to arrange multilaterally: refuse to acknowledge patents on countermeasures for pandemic pathogens coming from any country outside this cooperative biosafety agreement, allow neutral observers to witness sample collection, transport, and sequencing (or fund international teams doing this), and otherwise increase the streetlights on natural and laboratory pathogens around the world so we can easily identify a laboratory accident or unauthorized pathogen stockpile as such.

We don’t know what will cause the next pandemic, but international cooperation on epidemiology has been essential to domestic health security. The drug Remdesivir, for example, was useful (with significant limitations) during the COVID-19 pandemic, and that same drug passed clinical trials years prior in the Ebola pandemic. Our studies of Ebola and access to public health systems abroad helped us test countermeasures in humans in Africa, not requiring samples be transported at home. During the COVID-19 pandemic, early samples collected by travelers from Wuhan were shipped to Vincent Munster’s labs, where he, Kwe, and others put on positive-pressure space suits to study the efficacy of countermeasures like Remdesivir in macaques infected with SARS-CoV-2 in a BSL-4 lab in a small town in Montana.

There may seem like there are no good choices, but that’s not true. Yes, some virologists have engaged in reckless research practices, enhancing the transmissibility and virulence of pathogens, exposing the world to the risks of research-related pandemics with zero plausible benefits. At the same time, there are many virologists who have conducted life-saving work, who collect samples from infected animals and humans without any intentions to modify them and make them worse, who study such samples to better understand what causes severe diseases and what drugs or vaccines could prevent transmission or reduce the burden of disease of circulating viruses.

The international threat landscape of pathogens means most pathogens that enter the human population will originate in human populations outside our borders, having previously spent their time circulating in animals outside our borders. Our ability to develop countermeasures depends on our situational awareness of pathogens circulating in humans, and both countermeasure development and attribution rely on verifiable sequences to map out the extant natural variation of pathogens.

We can make good choices balancing biosafety with biodefense (countermeasure development + attribution) by focusing on the largest problems - dangerous Gain of Function research - and for lesser risks find risk-management protocols that maximize the benefit while improving our management of the lesser risks. From a dynamical systems perspective, these finer, quicker iterations on science policy are likely to lead to more stable, lasting solutions than infrequent, large changes that cause their own problems and force the pendulum to swing wildly in the other direction in future administrations.

Biosafety and biodefense are non-partisan issues and it’s possible for this administration to win lasting policy victories, much like Nixon’s victory in the Biological Weapons Convention, if they utilize experts they can trust and avoid overcorrections. While I may have my own political beliefs that differ on some issues, the non-partisan nature of biodefense is an opportunity for all of us. I believe the Trump Admin could win a Nobel Prize for biosecurity, but it will take a deliberate, coordinated effort with the best of the best leading the charge, setting up multilateral frameworks for biosecurity that turbocharge cooperative biodefense, protect and even center American biopharmaceutical industry, and deter bad actors from even thinking about bad bio.