What’s Alive in the Superunknown?

Up until now I have talked about diseases and conditions with which all readers are likely familiar, have some experience with, and can conceptualize. I know want to give some attention to a flavor that, to varying degrees, will have the opposite effect on readers and even on physicians and scientists.

I want to introduce the idea—well accepted by the microbiological community—that much of this field is unknown and what we do know is but a sliver of what is yet to be discovered. Throughout the chapter I will introduce interesting, and sometimes provocative, topics that are on the cutting edge of microbiological science. The purpose is not just to merely list all the cool things out there but to begin to sketch out an answer to the question with which I began this book by developing an enhanced framework with which to approach the field of infectious disease.

The Final Frontier

When people contemplate extraterrestrial life, they immediately think of creatures like ET or other Hollywood creations, but a more sober thought would be of microorganisms as the first type of extraterrestrial life that humans might encounter.

Indeed, the panspermia hypothesis argues life on Earth originated after the planet was seeded with microbes from a comet, asteroid, or meteoroid that crashed to the planet. If, and it is still a major if, panspermia is more than a hypothesis, what would that mean?

It may be surprising to many that the US government takes the possibility of extraterrestrial life very seriously—but not in an X-Files Area 51 way.

There have been 6 manned landings on the moon and in each of these situations humans interacted with a vastly different environment than anything before. Not only did the astronauts return to Earth after their heroic adventures, but they also brought back moon rocks and equipment “contaminated” with mysterious dust.

Biosafety (a common buzzword in the modern era due to highly visible lapses involving anthrax, smallpox, and bird flu popularized by the media) was a major component of lunar missions and is a fascinating topic in this context. Not only were astronauts quarantined prior to the mission to minimize the risk that they would contract an earthly infection prior to liftoff, but there were serious concerns regarding what would happen to them upon return.

 The human microbiome—the symbiotic bacteria and other microbes that are part of our bodies—is a fragile thing.  Antibiotics can severely disrupt it and the consequences can be dire (e..g., Clostridiodes difficile infection) as the microbiome is part of our defense against pathogenic microbes. In general, any alteration in the milieu can change the microbiome whether it’s antibiotics, social isolation, or stress hormones.

 Knowing these facts decades ago, scientists conducted simulations of the spaceship environment prior to prolonged spaceflight. The results revealed microbiome changes did occur (including a shift toward more virulent microorganisms) causing many to speculate whether upon return to earth a pathogenic microbe might gain a foothold while the microbiome defenses of the astronaut were still altered, and a fatal “microbial shock” ensue. Thankfully, such an event never came to pass, though certain fungi overgrew in the mouths of returned astronauts—an intriguing finding given that fungi, such as Aspergillus, stowing away from Earth, also flourished on the Russian space station Mir.

In addition to the threat of microbial shock, there was a slight—but real—concern of the astronauts bringing back a moon contagion and quarantine was imposed on the returning astronauts through the Apollo 14 mission. There is even a famous picture of President Nixon visiting the pioneering Apollo 11 astronauts who are safely behind a window in their quarantine trailer. The same sorts of precautions were also taken with lunar rocks. There is even an Outer Space Treaty(1966) and a NASA Policy Directive (8020.7G) that stipulates that care must be taken so as to not contaminate the earth with extraterrestrial material. Various microbiological studies were conducted and did not reveal the presence of any lunar microorganism—one wonders what the results would be with our current microbiological diagnostic tools.

The proposed Mission to Mars has also prompted some concern regarding the threat of Martian microbes, especially given the presence of subsurface ice and possibly organic Martian meteorite contents. There are currently debates about what types of biosafety procedures should be used so as not to damage any potential biological samples yet still render them relatively safe.

The solar system is often described as desolate, radiation-laden, and subject to large variations in temperature. On its face that doesn’t appear to be all that conducive to supporting a fragile organism, even a tiny bacterium. However, tiny microbes—the predominant form of life on Earth—aren’t as invariably dainty as they may seem.

As I have emphasized, ours is a microbial world and in areas of the globe where it would appear inhospitable to life, microbes can be found. Undersea high temperature vents, acid-laden environments, and environs with high levels of ionizing radiation are all home to extremophile – extreme loving -- microorganisms of various types. Extremophiles have even been found in the highest reaches of the Earth’s atmosphere. Such resiliency to harsh conditions argues that microbes don’t require the cozy environment of sweat gym socks or grandma’s potato salad to thrive. In fact, these extremophiles, by flourishing in their respective environments, have evolved traits that make it impossible for them to be displaced from the safety of the nasty places they call home.

Despite the existence of extremophiles, I think it is unlikely that a microbial organism that evolved to survive in an environment entirely disparate from that of Earth’s is unlikely to find our planet hospitable.

 The Third Domain

 Traditionally, pre-1990, the domains of life were broken into two: bacteria and the eukaryotes, which included everything from malaria parasites to humans. The division was based upon the presence of a certain cellular features including a nucleus. Now, the accepted division includes a third domain: the Archaea. Archaea were once included in the bacterial domain and share many features with them, including a one-celled nature and the absence of a nucleus. However, upon deeper investigation, it became apparent that they were as different from bacteria, despite superficial similarities, as the eukaryotes are. These differences include distinct biochemical attributes, such as the structural components of cell walls, as well as a divergent evolutionary lineage.

It is unclear what the full evolutionary relationship is between Archaea, Bacteria, and Eukaryotes. However, I believe the answer will unlock many mysteries of the origin of life on the planet.

Many Archaea are extremophiles, but species of these microbes can also be found living, rather peacefully, inside us. An open question has been whether Archaea can cause human disease and the answer is somewhat mixed. While most Archaea can be thought of as gentle components of the human microbiome there is suggestive evidence of their role in dental disease (periodontitis) where the density of their presence in those with certain dental infections correlates with disease severity.

Biological Dark Matter

 In a way, what I am focusing on in this chapter is the prospect of biological dark matter—though Archaea are by no means dark. By dark matter I mean microorganisms that we are unable to culture or see. More broadly speaking, biological dark matter includes genetic material we recover from various locations (including our own bodies!) that doesn’t match with any known entity. The field of metagenomics explores these haunting sequences.

What might have been considered biological dark matter in infections gets a little brighter when we bring new technologies to bear. From a plain light microscope to routine culture to an electron microscope, the diagnosis and treatment of infectious diseases have gotten both simpler and more complex. As routine culture, with its clean and often binary (growth or no growth) answers is increasingly supplemented with mass spectrometry and genetic sequencing, the clinician is faced with a zoo of organisms some of whose names require the consulting of a reference book. What was once a straightforward case of a Staphylococcal blood stream infection is now a polymicrobial swarm of organisms, as what was dark to routine culture is now blindly bright. In these settings, the clinician—me included—sometimes wishes to be left in the dark because patients did well enough when treated according to ordinary culture results…usually. However, this type of paradigm cannot continue to exist if our species is to become more resilient to microbial threats.

One corner of the biological dark matter world that merits deep exploration are the ordinary infections in which no culprit organism is found. Ranging from pneumonia to encephalitis (infection of the brain) to septic shock, many cases defy a specific microbiologic diagnosis. People get better, or they don’t. Antibiotics are often given empirically with a hope they will counteract whatever is occurring. Part of this gap in diagnosis is due to the fact that pursuing diagnostic testing after a few standard methods come up empty is not the standard of care in many conditions. Hospitals are loathe to incur costs on such endeavors as they falsely believe the answer is likely inconsequential and won’t change treatment. However, I think this is short sighted as having a specific diagnosis for conditions with high mortality such as septic shock provides valuable epidemiological insight, has implications for hospital infection control, and could engender more judicious use of antibiotics. It also saves lives. The continued rise and widely recognized value of antibiotic stewardship programs – which improve outcomes by countering antibiotic resistance trends, preventing antibiotic associated infections such as C.difficile, and optimizing the treatment of infections—will hopefully displace this type of thinking.

The advent of COVID-19 saw many hospitals purchase equipment allowing the identification of many respiratory viruses so, if this equipment continues to be employed routinely, many more viral infections will be identified and add to our knowledge of their circulation and impact. This will increase interest in developing antivirals and vaccines for those seen to have significant impacts. The same trend can be hoped to the rise of at-home diagnostic testing for COVID-19 allowing more individuals to conduct home testing for respiratory infections such as influenza. Prior to the COVID-19 pandemic, only HIV could be tested for in the home. I envision a day when many households have a device in their bathroom that can identify common causes of sniffles, coughs, sexually transmitted infections (STIs) and sore throats allowing expeditious treatment and helping people make judgements about whether to social distance or not.

So far, these pseudo-dark matter infections represent what we can identify, classify and label. However, true biological dark matter is much darker, and, in many cases, there are no clues to its origin. It might represent esoteric members of known life or could be hints of an undiscovered 4th domain of life. The existence of such dark matter, what its origin may be, and what its impact is should give pause to those who devote all their efforts to warning of the dangers of synthetic biology and genetic engineering while ignoring the fact that these techniques operate on what is known while this shadow life operates unbeknownst to all.

Similarly mysterious, within our own human genome exist large gene sequences whose origins are viral. The role and function of these endogenous retroviruses, integrated into our chromosomes, and which compromise nearly 10% of our genetic material, are only beginning to be unraveled. These viral genes are also present in pigs (porcine endogenous retroviruses, PERVs) and the nascent field of xenotransplantation — using organs from pigs in humans— is complicated by their presence.

Existing in this netherworld are even more entities, each more puzzling than the next. There are viroids, the basically naked infectious RNA molecules that have some properties of viruses and can infect plants; satellite and defective viruses that require the presence of another virus to be infectious (the human hepatitis D virus/virusoid is one such example); and virophages, viruses that infect other viruses and cause their function to be altered (an interesting vampire virus has been described). New massively sized (relatively speaking) amoeba-infecting viruses have even been isolated from the desolate tundra—reminiscent of the manner in which scientists recovered the deadly 1918 H1N1 influenza virus from human remains in the permafrost.

For those who think of infectious disease and microbiology as dry and boring subjects this chapter should serve as a concretization for how dynamic and intellectually challenging these fields are. To paraphrase Isaac Newton, we are as children playing on the seashore, diverting ourselves now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before us.

Why it won't be HIV?

If I were to describe a viral illness that infects people surreptitiously, lingers in their bodies for 10 years almost silently, is contagious throughout its silent years, and is uniformly fatal I would be describing a potential human extinction level pathogen. For the astute reader, it is obvious that what I am describing is the human immunodeficiency virus (HIV). For the reasons I enumerate below, I do not believe even this prolific killer has the capacity to cause and extinction level event.

A Snapshot of a Prolific Pathogen

When you look at HIV in terms of its global impact, it has a very impressive record. It has been the #1 infectious disease killer in the world, won major victories in every corner of the planet, made medical science turn on a dime to confront it, prompt society to explore sometimes taboo social mores, and elude—thus far—any and all attempts to cure or prevent it through vaccination, though one vaccine which reduced rates of acquisition by about 30% provides proof-of-concept that an efficacious vaccine may be possible.

But looking at its record in terms of the statistics and facts I just listed does not do this class A killer justice.

HIV as the Perfect “Form” of the Emerging Infectious Disease

When the infectious disease community discusses the need to better deal with emerging infectious diseases, exotic diseases like Hendra, Nipah, and chikungunya spring to mind. HIV is not one that makes the list in 2021. The general public, in many ways, views HIV as passé and a known quantity but, when looked at in the appropriate context, HIV is the emerging infectious disease par excellence, unequivocally demonstrates almost every attribute of this class of disease and dwarfs all other members of the category.

HIV is a zoonosis – an infection that originated in animals –that spilled into humans from other primate species: chimpanzees for HIV-1 and sootey mangabey monkeys for the less common HIV-2 strain.  The precise manner in which this event occurred is something that is lost to history, but through genetic techniques it can be determined when and where this occurred.

Though HIV burst onto the infectious disease main stage in the early 1980s it was, like a small-town comedian, making important advances on second stages around the world since the early 20th century.

The way I explain HIV’s emergence is that it spilled into sentinel humans in Africa, such as bush meat hunters in Cameroon, but had a stultified spread. HIV was unable to make major inroads into the human population until aided and abetted by industrialization that allowed regular contact—especially sexual—between peoples in remote villages where HIV was present and burgeoning metropolitan cities. Even in this brief encapsulation of HIV’s emergence, the crucial actions needed to track emerging infectious diseases (the exotic infectious disease zebras as opposed to the ordinary horses whose hoofbeats we always hear when evaluating patients) become apparent. These include:

1.     Understanding what infectious diseases are prevalent in animal species: Since almost all infectious diseases arise in animal species prior to infecting humans, it is important to know what is out there and will serve as the substrate for future human threats to health. Indeed, the entire “one health” movement, which seeks to meld human and veterinary health and epidemic intelligence, is devoted to this point. This is not a call for what was once derided as “viral stamp collecting” but a need to understand which minute proportion of the countless animal viruses that exist has the capacity to infect humans.

2.     Monitoring sentinel populations: not every human has the same risk of acquiring novel infectious diseases. Just as not everyone skydives, not everyone hunts chimpanzees, works in an abattoir, goes spelunking, injects drugs, or works in a brothel. When an individual’s unique activities place them at the vanguard of what the human species does, they become the tip of the spear that first pokes into new microbial jungles. As such, these special populations are studied in detail in order to predict the next trend in microbial threats to humans as a whole.

3.     The dynamics of social interaction can make or break a disease. If a disease is only present in an isolated society—say a remote village in the DRC—it may have little opportunity to spread beyond that population, especially if it is rapidly fatal and leaves little to no mechanism for widespread contagion to occur. However, if a contagious person has access to larger populations through buses, airplanes, trains, or crowded hospital waiting rooms, the microbe does too. This phenomenon is behind all the (mostly misguided) calls for travel bans, quarantines, vigilance at airports, and emphasis on travel history taking.

While HIV may be a staid representative of an established infectious disease and glossed over by those in the emerging infectious disease field, it can be viewed as, to use a Platonic metaphor, the “Form of the Emerging Infectious Disease” of which others are mere diluted versions.

Blood and Body Fluids

Generally speaking, if a microbe is spread through blood and body fluids it has a major problem it will always need to overcome: how to find easy access to new hosts. Unlike something that can spread through the air or through droplets in a sneeze, a virus like HIV requires close contact between individuals for transmission to occur because it is spread through blood and body fluids.

The ways in which humans exchange blood and body fluids are rather obvious: sexual intercourse, sharing of injection material, blood and blood product transfusions, breast-feeding, and in utero.

Again, the role of technological progress (i.e., blood transfusions) is something that viruses can exploit. HIV, with its long latent period, was able to contaminate blood banks before anyone even knew it existed. The latency period was also instrumental in allowing spread via the sexual route. Asymptomatic yet contagious vectors are a major boon for an ambitious infectious disease that is poised for world dominance.

Marginalized Populations

Who is first infected is almost as important how a person is infected. When the first victims of a disease are those that the world can empathize with, we are quicker to to action. When the first victims are far away, have special risk factors that are not seen as universal, or otherwise stigmatized, it may take longer for the world to notice and even longer for decisive action. All of this applied to the early years of HIV.

Though HIV was silently coursing through the African continent infecting many heterosexually, through birth, and through breast milk, it may have been hard to tease apart from the myriad other infectious diseases that perpetually plague those in non-industrialized settings. Indeed, there are early clues to HIV in African patient logs in certain areas in which mysterious opportunistic infections, a telltale sign of HIV-induced immune deficiency, were clustering.

The first descriptions of HIV occurred in men who had sex with men, injection drug users, Haitian immigrants, and hemophiliacs. Infectious diseases are taboo in many ways, even today, because of who they are thought to infect. When is the last time you say a hospital billboard advertising their infectious disease physician in a manner they do their dermatologists, surgeons, or oncologists? Any billboards that read “Got Hepatitis C, We Have Your Back?” in your hometown?

Such groups as those who doctors first diagnosed with HIV were not considered “mainstream” victims and therefore the outbreak response was slowed. This slowing did not affect all aspects of the management of the HIV pandemic and clearly does not characterize the rapid-fire discovery of the actual virus, the development of the test to diagnose it, and the elucidation of its transmission properties, all of which occurred in record time. The slowing was more of a general lassitude with which the general population and its leaders viewed the disease. Some of this is captured in the musical Rent. Yet, despite this general sentiment, HIV was subject to a travel ban by the United States until 2009.

HIV thrived on this neglect and even in the modern era, with our 5th generation HIV tests and robust anti-retroviral therapies can roar back when societal safeguards such as needle exchange for injection drug users are neglected. The 2015 Indiana HIV and hepatitis C outbreak is one powerful case to keep in mind in which then Governor Mike Pence had to be persuaded about the benefits of harm-reduction and clean needles.

Elusive Maneuvers

In the over 3 decades we have been actively battling this virus, the landscape has changed unrecognizable. HIV is no longer a death sentence, and a normal lifespan can be had if one is on treatment. HIV is a chronic infection that can be, in most cases, easily controlled with medication. Not only does treatment keep a person healthy, but one also becomes less contagious on treatment—treatment is prevention. Treatment can even render someone non-contagious, the U=Uparadigm (undetectable viral load means untransmittable virus sexually). There are even techniques that prevent people from acquiring HIV if they engage in behaviors that place them at risk, almost like pseudo-vaccines. Pre-exposure prophylaxis (PReP) — taking a daily antiviral pill or an injection every few months to prevent infection upon exposure — holds great promise, if implemented correctly, to changing how readily HIV can find new victims.

However, none of the above should be mistaken for a cure. There is currently no cure for HIV and no vaccine available. All attempts at a vaccine have fallen short and ingenious attempts to cure the infected with early treatment and other techniques have failed (save innovative and dangerous bone marrow transplants done for other reasons--the exception that proves the rule). Also, like any microbe, HIV can become drug-resistant if treatment is not judicious and these resistant strains can be transmitted rendering first line therapies ineffectual.

It Isn’t the One to Cause Human Extinction

With all the doom and gloom that is the HIV pandemic, it won’t be an extinction event for the human species for many reasons many of which I discuss above. Current treatment regimens, though not curative, are game-changers allowing a normal lifespan and even the ability for those with diagnosed HIV to give birth to uninfected children. A person with an undetectable viral load is unable to transmit the virus (U=U). Pre-exposure prophylaxis (PrEP) with antiretrovirals can prevent infection and long acting injectable antiretrovirals make treatment much simpler. In many important ways, becoming a diabetic is more life altering than becoming HIV positive (obviously one must ignore the social stigma in this calculation).

Human genetic variation also poses challenges for HIV as a proportion of the population is naturally resistant to infection. A specific human mutation (CCR5-Δ32), for which tantalizing hypotheses are devoted to, is present in a high enough frequency in certain areas of the world to provide a mechanism for the human race to survive HIV even if it were much more widespread. Ingenious physicians exploited the facts surrounding CCR5-Δ32 in the treatment of the Berlin Patient, Timothy Brown. His was the first of just a few durable cures of HIV to have been achieved and was accomplished via a bone marrow transplant for a concomitant leukemia containing the requisite mutation (though there is a hypothesis that a complication known as graft-versus host disease in which the transplanted bone marrow attack the recipient’s cells may be part of the actual curative process). Additionally, and even prior to the advent of therapies, mother to child transmission of the virus was never 100%.

While vaccine progress has been disappointing, there have been important advances. The most promising vaccine candidate today is the RV 144 vaccine (“The Thai vaccine”) that demonstrated a 31% protection rate in those vaccinated. While 31% isn’t perfect, it is substantial (compare it to the 2014-2015 23% efficacy of the seasonal influenza vaccine) and serves as the basis for newer vaccines.

HIV, like Ebola, is delimited in how it spreads. It is not measles. It requires close and intimate contact between individuals. Because of this limitation, behavior change is a key means to prevent infection. Countermeasures as simple as condoms, clean needles, limiting sexual partners—especially concurrent ones—and, in certain contexts, male circumcision (before sexual debut) can significantly make inroads into HIV’s spread.

Chapter 4: The Second Lens—Make Infections Not War

It is somewhat taken to be an axiom that infectious diseases eventually taper in their ability to cause severe disease over time as they evolve to incite less physiological mayhem in the species they infect.

 

This is not an axiom but a complicated phenomenon that is very context dependent, the relevant context being the transmission mode of the pathogen, the teleology (or goal) of the pathogen, and what countermeasures the host species is deploying (either through evolution or consciously when it comes to humans). In this chapter, I am going to explore this concept and, by doing so, give you my second lens for looking at the pandemic, catastrophe, and extinction potential of any agent of infectious disease.

How Transmission Modes Matter

 

Thinking anthropomorphically, an infectious disease pathogen “wants” to flourish, complete its life cycle, and continue the propagation of its genetic lineage. To do so, it will need a suitable environment that is conducive to the completion of these tasks. Such an environment might be the gut of mosquito, the nasopharynx of a human, the digestive system of a cat, or even a combination of multiple hosts for different hosts for different life stages. Some pathogens do not need anything, but the conditions present in a pond, the detritus on the forest floor, or the soil. This last group is a special case I will discuss separately later in the chapter.

 

Pathogens, therefore, need to traverse the chasm from one host to another and, to do so, need to be carried from host A to a suitable place in host B via some medium. Suitable mediums and mechanisms include skin-to-skin contact, body fluids such as saliva, respiratory droplets, blood, sexual-activity related fluid, feces, nasal mucus, ingestion, via a tick or mosquito bite, or through exhaled air.

 

Additionally host A and host B need to be in close enough proximity or networked enough to be above a threshold degree for this to be successful.

 

Differing modes of transmission will lead to different proximity thresholds. For example, a pathogen like measles which spreads efficiently through the air just needs two humans to share the same air, even separated by a couple of hours. By contrast, Ebola requires close proximity for body fluids carrying viral particles to pass fairly directly from one human to another human. Certain other pathogens need humans to be in a network such as one that shares water sources, shares food sources, or shares an environment with the same pool of mosquitoes or ticks.

 

In general, a pathogen that requires people to be in close proximity to be transmitted by blood or body fluids is, in the modern world, going to be constrained in its spread. Additionally, the modern world can be thought of as very pathogen-proof (not foolproof of course) in the sense that modern sanitation, food handling processes, vector control measures against mosquitoes and ticks, and hand washing really make the terrain difficult for many pathogens.

 

What’s left for pandemic prone pathogens, as I concluded in the last chapter, are those that spread via the respiratory route either through respiratory droplets or via exhaled air. A pandemic pathogen not only needs to be able to spread, but it also has to spread prolifically, universally, and uncontainably. It has to easily overwhelm modern societal anti-infection measures. In short, it needs hosts in close proximity who are not apprised or unaffected by the respiratory droplets or contaminated air to which they are exposed.

 

Even though healthcare (or nosocomial) infections are a critical and devastating problem, they are not conducive to starting a global pandemic let alone something worse. This is because a hospitalized patient with a respiratory infection is, by definition, not in the most conducive environment to spread to the majority of the humans on the planet. A bedridden person, in the hospitalize or at home, is going to have less proximity to others and, because of the severity of the illness, is also likely to raise caution level of those that visit with the patient delimiting spread.

 

However, if a person is out and about performing their daily tasks— not changing the landscapes of their contacts with others because of unawareness of their illness, because the severity of the experienced infection insufficient to keep them home, and/or because the illness resembles an every-day baked in risk of daily living like stepping in a mud puddle, getting caught in the rain, or twisting one’s ankle stepping off of a curb, or transmitting or acquiring the common cold—transmission will be efficient and widespread.

 

Therefore, a pandemic prone pathogen is likely to be a respiratory virus that spreads efficiently between humans secondary to causing a spectrum of illness that is heavily weighted towards mild or clinically inapparent — yet contagious — manifestations.

 

A respiratory virus that causes fulminant symptoms too frequently is going to confine a significant portion of its transmissibility period to the bed-bound or hospitalized which is inefficient if a pandemic is the end game. It is also the case that fulminant symptoms occurring too frequently will eventually change enough of the behavior of humans to one that is more avoidant of individual risks.

 

The above is not meant to mean that a pandemic pathogen can’t evolve to be incrementally more dangerous to humans such as the delta variant of SARS-CoV-2 represents, but that a respiratory route-dependent pathogen cannot be on a path to kill all humans if it “wants” to be prolific and join the pantheon of pandemic pathogens. 

 

It is important to recognize that in the above discussion and thought experiment I am confining myself to pandemic pathogens (in the modern era) and this does not apply to epidemic pathogens or outbreak pathogens. Recall the way the fecal-oral spread bacterium that causes cholera can evolve to more ferocity in certain situation when that is conducive to more extensive spread.

 

What about HIV?

An astute reader would be thinking that the above is skirting over probably the most devastating pandemic in our lifetimes — that of the Human Immunodeficiency Virus (HIV). HIV is the subject of a later chapter, but it is important to delineate some aspects its pandemicity now. HIV has killed at least 40 million people in the past 40 years, spread to every habitable niche of the planet, and infected around 100 million. Until around 1996 with the development of potent combination anti-retroviral therapy, it was essentially 100% fatal.

 

Why was HIV with its horrific case fatality ratio of 1.0 able to cause a still ongoing pandemic and defy what I take to be a general rule about pandemic-prone pathogens? It is a legitimate question to ask whether HIV qualifies as a pandemic because it differs from an unequivocal pandemic pathogen such as the 1918 influenza A virus, whose death toll exceeded 40 million plus in about year— not over 40 plus years.

 

Make no mistake, HIV has arguably been the most pressing infectious disease challenge in the past 100 years and its emergence was a seminal event in my profession. HIV was and remains a disruptive event that changed society indelibly (and probably eternally) when it comes to certain practices such as universal precautions, blood supply safety issues, safe sex, and safe injection drug use practices. However, the very attribute that allowed it to infect over 100 million humans is what makes it different than traditional pandemic pathogens (and also the same when viewed in a certain context) — its clinical latency or chronic period.

 

The time period after HIV initially infects someone, the occurrence of which will cause a severe flu-like illness, and when a person has overt symptoms due to the opportunistic infections that HIV predisposes to, involves a period of about a decade. We know that during this time, HIV is not biologically silent and physiologic damage is occurring, but it is often clinically silent..until enough damage is done that the immune system is so wrecked it cannot serve its purpose any longer and AIDS (Acquired Immunodeficiency Syndrome) ensues. Throughout this period of clinical silence a person is contagious to others via their blood and body fluids. This is why the virus spread around the world even before it was first noticed and continues to infect individuals who are asymptomatic and do not know their status. This asymptomatic period is what gave HIV its pandemic potential. However, the clinical latency and its blood/body fluid transmission mode also staggered cases temporally and did not overwhelm society (though some hospitals in the 1980s did have considerable burden of patients at once suffering from HIV) in the manner of 100 million cases occurring over a period of a year or two. Its slow silent spread gave HIV a prolific reach that other blood and body fluid infections could never attain but also did not cause a universal, all-at-once calamitous response or have the same velocity of risk that the 1918 influenza or COVID pandemics did. [A similar analysis could be applied to both hepatitis B and hepatitis C which followed similar trajectories but are even more silent and subtle, causing fatal liver disease and carcinoma over a period of multiple decades].

 

 

The Idea of a perfect pathogen

 

I have argued that pathogens have to “care” about what they do to their hosts if they want to spread. This is known as the host-density theorem: there must be enough density of hosts present for the pathogen to successively infect; if it kills too many it will extinguish itself. But what about a pathogen that just doesn’t care because finding itself in a human or some other species is a detour from its normal lifestyle, just a brief fling, a species to which the host density theorem does not apply?  Think of a fungus, for example, that normally lives on the dying or dead vegetation in a pond. It, through whatever means, now finds itself in the body of a frog which summarily succumbs to the infection that ensues. In fact, imagine that this happens to every frog that happens upon the fungus. The fungus after killing the frog just leeches out if its body and goes back to its ordinary life cycle in the specific environment it is suited for. This type of pathogen can pose extinction level pandemic threats because of its non-relationship with the frog host, it is environmentally stable and can thrive irrespective of a frog being present or not. This is what is known as a sapronoticinfection and they are basically exclusively confined to the realm of fungi, and, in the case of humans, the environmental source can be removed or avoided, and anti-fungal therapies can be developed (many frogs are left without defenses of any sort as attested to the devastation their species has faced from the chytrid fungus). I have already discussed why I don’t think humans face this threat from fungi in an earlier chapter and will return to it again in a later chapter.  

 

*****

 

The two lenses I employ prompt two questions for any outbreak and concretize why an extinction level event from an infectious disease in humans is not plausible. These questions are:

 

1. Is the etiologic agent a respiratory-borne pathogen?

2. Is it efficiently spreading?

 

If the answers are no, it is at most, capable of causing an epidemic and be regionally restricted. If the answers are yes, it will be pandemic capable. However, an efficiently spreading respiratory virus — the only pandemic prone pathogen according to my analysis — will fall far short of an extinction level event. To not fall short would contradict the prerequisite needed to be a pandemic pathogen: an efficient spreader requiring a wide spectrum of illness tilted towards the mild or asymptomatic.

Chapter 3: The Alchemy of a Pandemic Pathogen

When I first started thinking about the ideas contained in this book, one of the questions I was trying to answer for myself was “what does it take for a pathogen to cause a pandemic?”— let alone a GCBR or extinction event. Not everything can cause a pandemic despite how breathless each outbreak, especially post-COVID, renders the press.

In this task, I wanted to go back to first principles and clarify my thinking. I could not just think about scary pathogens that were put on some list without thinking about why they were on the list. Could all bacteria, fungi, parasites, or viruses equally cause a pandemic? What traits would be absolutely necessary?

For an infectious disease to become anything near an extinction level threat it first has to be able to cause infection in a large — very large — swath of the population. This is independent of its ability to cause severe or fatal disease. It must first be capable of infecting a large proportion of the population and causing some degree of symptomatic infection. In essence, an existential risk pathogen would be something that has the characteristics needed to render it pandemic-worthy.

In my estimation a pandemic can only be caused by an agent that transmits between people. I do not think an agent that uses an intermediate animal or insect to get to humans would be able to cause a world-wide pandemic and would be limited to an outbreak or epidemic. This is also true for environmentally acquired pathogens like tetanus. This fact is because all other forms of transmission can be halted much easier than transmission between humans. For example, once a contaminated food was discovered people would stop consuming it or once an animal species was found to be the source of infection people could change their interaction with it or cull it. Though an animal reservoir makes eradication of the pathogen from the planet impossible—and provides a source for new pathogens to enter the human species—this feature is not related to pandemic potential, which is almost entirely related to how efficiently it transmits between humans.

The concept pandemic literally means “all people” and does not denote any level of severity. Pandemics can be relatively mild in the number of deaths such as 2009 H1N1 or intermediate like COVID-19. Although the concept has some psychological connotation or association with severity, it is not part of the concept.

 In this chapter I will detail my thoughts on this question, most of which are derived from a project I led in 2018, The Characteristics of Pandemic Pathogens.

 

Being Agnostic

Most people associate pandemics and viruses together for good reason, but in this exercise, I want to be agnostic about and ask the question if any category of the myriad infectious microbes, in the modern era, has this capacity.  

 Dividing the infectious disease world up into categories yields 7 major categories (by my count):

 

1. Viruses

2. Bacteria

3. Fungi

4. Protozoa

5. Helminths (i.e., worms)

6. Prions

7. Ectoparasites (e.g., lice, botflies, etc.)

 All of these categories are awesome in their own right and each exact a considerable toll on humans, but are all of them equal when it comes to causing a pandemic in the 21st century?

Let’s discuss some of these in turn.

 

Bacteria

Bacterial infections are formidable and today, post-COVID, the number one infectious disease killer of humans is again a bacterial agent: Mycobacterium tuberculosis, the cause of tuberculosis. Antimicrobial resistance continues to be a vexing problem with physicians increasingly being in the situation of having no good anti-bacterial options to treat a patient with due to overwhelming levels of resistance in certain bacterial species. The Black Death, mentioned, earlier wiped out one-third of Europe’s population.

 However, when looked at with a discerning eye one can see that bacterial infections since the advent of penicillin and the age of antibiotics have lost much of their edge. It is true that endemic bacterial infections such as tuberculosis exact a horrific toll on the population of certain parts of the world and antibiotic-resistant bacteria plague the immunocompromised and debilitated with serious and fatal infections. Antibiotic resistance does threaten modern medicine with a hint of the pre-penicillin era as antibiotics to treat and prevent secondary infections facilitate everything from cancer chemotherapy to organ transplantation to joint replacement. But this is a far cry from a pandemic. The U.S. average lifespan in 1944 had already reached over 60 years, before antibiotics were commercialized.

It is also the fact that antibiotics tamed much of the bacterial world of infectious disease that led to bacteria not possessing the pandemic potential they once had. While it is critical to not view the struggle against bacterial infections as anywhere near over and to continue to advocate for a robust antibiotic pipeline, a pandemic is not — in my estimation — possible with a bacterial species any longer. The direst untreatable bacterial infections are not capable of causing disease in most members of the population. These bacteria rely on compromised hosts with little by way of defenses who are often in and out of various medical facilities and, thus, have multiple medical-related exposures (where antimicrobial resistant organisms abound). We are even able to craft together (sometimes not so elegant treatment regimens) for some of these patients.

 So, if not bacteria, what about fungi?

 Fungi can cause a range of infections from the banal athlete’s foot to fulminant necrotizing infections in lungs or sinuses of the immunocompromised. Probably the major fungal threat is the multi-drug resistant fungi Candida auriswhich is currently causing human infections that are extremely difficult to treat. Valley fever, caused by Coccidiodes, has expanded its range likely in response to temperature changes making more of the world hospitable to it. Even the construction of the Panama Canal and the occurrence of tsunamis were exploited by fungi to settle in different environs where humans were infected.  Fungi are also regularly destroying reptilian and amphibian species where they are an existential threat. Despite these facts, and the popularity of the Last of Us television series, I do not believe they have pandemic potential for several reasons.

First, human fungal diseases outside of some minor skin ailments like ring worm or athlete’s foot are not really transmissible between people outside of healthcare facilities. They are not highly communicable, but primarily environmentally acquired through inhalation of spores or sometimes through direct inoculation of the skin (as happened with post tornado debris). Fungi abound in the environment and each of us inhale countless fungal spores daily with no untoward effect. It is really only in the immunocompromised, critically ill, or those with severe lung disease that serious fungal disease is commonly found.

Healthcare facilities themselves confer increased risk of fungal disease as evidenced by the multi-drug resistant C.auris which has become a critical problem in nursing homes that house frail patients. Fungi can also exploit shoddy sterilization procedures be transmitted through medical procedures such as contaminated steroids used for spinal injection (Exserohilum), contaminated anesthetic agents, or via injection drug use.

Why is this the case? Interestingly, fungi thrive at temperature lower than we do. The normal human temperature of around 98.6F/37.5C is not hospitable to most fungal species — they are not thermotolerant. There is even a hypothesis that mammals were provided this temperature by natural selection — a mammalian filter — as a way to avoid fungal infections that had major consequences for our colder amphibian and reptilian relatives. This biological barrier, though not insurmountable (as the evolution and dissemination of the multi-drug resistant and somewhat thermotolerant C.auris demonstrates), coupled to the constrained person to person transmission of most fungal species really delimits pandemic potential from this kingdom of infectious agents.

The cast of others

Protozoa and helminths as more complicated organisms are often geographically restricted and have complex lifecycles for which humans are often a dead-end host. A dead-end host is one from which no further transmission can occur. The infection chain dies with the host. As such, these often lead to a very niche type of infection that is not conducive to a worldwide pandemic. The protozoa that cause malaria are a notable exception worth noting as they are purported to have killed half of all humans that have ever lived. This face alone merits its consideration as an existential or pandemic risk. But, with the understanding of how the disease is transmitted (via mosquitoes) the disease became much more controllable when resources were deployed. For instance, malaria’s reliance on a mosquito vector for transmission opens up another avenue — beyond vaccines and treatment — for control which can be as simple as an insecticide-impregnated bed net. The development of effective anti-malarial compounds, a vaccine, and even genetically modified mosquitoes have considerably delimited malaria’s prowess. Highly drug resistant malaria species spreading out of the Mekong Delta to Africa would be a continent-wide emergency, but still not an existential or pandemic level crisis.

 Prions, the infectious protein particles responsible for bovine spongiform encephalopathy (BSE) or Mad Cow Disease, are probably the most fascinating class of infectious agents to me. They may play a role not only in Creutzfeld-Jakob disease but also Alzheimer’s and Parkinson’s Disease as well as Lewy Body Dementia. But despite these roles, prions are not easily transmissible between people outside of medical procedures or cannibalism, as occurred in Papua New Guinea and was responsible for kuru. If people have resorted to cannibalism on a mass scale, I think a pandemic would be the least of our problems.

 

Viruses, Viruses, Viruses

Surveying the microbial world, it becomes quickly clear that a pandemic pathogen is most likely to be a virus. The reason for this is several-fold and should be no surprise given my treatment of the other classes of infectious agents.

 First, viruses have the ability to quickly spread with shorter generation times — the time it takes an infected person to become contagious — on average than other classes of pathogens. Some viruses replicate into the billions each day and people can become infectious to others in a matter of days. That replication capacity also gives viruses the ability to evolve at a much faster pace than other types of infectious agents that are, comparably, much slower.

 Second, there are no broad-spectrum anti-viral agents the way there are broad-spectrum antibacterial and antifungal and antiparasitic agents. Viruses are bad news coated in protein, to borrow a famous analogy. The “news” they contain is very sparse and very specific to the virus. This means that viruses have just a few targets for antivirals to interfere with as it is host cell machinery that the virus relies on to go through its “life cycle” and host targets are, for obvious reasons, not suitable targets. Additionally, what targets viruses do have are often exquisitely specific to an individual virus type or even a subtype or strain of a virus. For example, some antivirals only work on one subtype of a subtype of a virus and have no cross reactivity against other agents. There are no off-the-shelf antivirals that can be rapidly deployed with large effects on a virus that is genetically distinct. Accordingly, there are very few antivirals that work on multiple viruses in a single family let alone disparate families. 

Respiratory Transmission is Critical

Above, I discussed why transmissibility is critical between humans for an agent to be pandemic capable but not all types of transmission are equal.

 Communicable infectious diseases are transmitted in a variety of ways: surface/mucosal contact, blood/body fluids, fecal-oral, and via the respiratory route. Of these, as has become evident with COVID-19, the ease with which a respiratory spread pathogen can traverse the world is unrivaled. That is not to say major calamities won’t ensue with different transmission modes but in the 21st century it is the respiratory route that is paramount to pandemic causation. For example, blood and body fluid transmission — exemplified by Ebola and HIV — can be interrupted with simple barrier protections and fecal-oral transmission by sanitation. Something transmitted by mosquitoes, flies, ticks, or fleas can be outran as many of these vector species have a geographic range to which they are best suited or the vectors themselves can be targeted.

 It is only the respiratory route which cannot be interrupted by simple measures as talking, coughing, laughing, sneezing, singing, and breathing are not easy to interdict. The respiratory route of transmission is best understood as a continuum that ranges from larger droplets to aerosols with many pathogens alternating between modes based on the context. For example, measles is the paradigmatic airborne pathogen, in which the air in the room in which a measles infected individual was in remains contagious for an extended period of time, while influenza and COVID are better considered to be opportunistically airborne.

Contagious Before Symptoms

It may be an axiom in infectious disease that a pathogen that is able to move from person-to-person before a person knows that they are ill is basically not containable. This is so because if a person does not recognize they are ill or are not disruptively ill, they are able to go about their activities of daily living all the while spreading an infection to their contacts. This explains why respiratory viral illnesses such as the common cold are so prolific. If an infection spreads efficiently between humans via the respiratory route and is contagious during a period when only mild or no symptoms are present, containment becomes a fantastical goal.

 This is a critical trait that evolution would select for in many pathogens especially those that thrive on social interaction which requires people to be well enough to interact. As such, in the early days of an outbreak, a pathogen can be all over the globe before it is even noticed, traveling at the speed of a jet, seeding outbreaks in all corners of the globe. Indeed, this was likely the case with COVID-19 and with the 2009 H1N1 influenza pandemic virus.

No Pharmacologic Countermeasures or Population Immunity

 In the current era, a pandemic pathogen is likely to be something that cannot be met with off-the-shelf antimicrobial agents or vaccines or even with significant immunity in the population. Though the speed with which vaccine platform technologies such as mRNA vaccines, monoclonal antibodies, viral-vectored vaccines (i.e., the Johnson & Johnson and Astra-Zeneca COVID vaccines), and other platform medical countermeasure technologies can be developed is truly revolutionary and the lead time is shrinking, there will always be some lag before vaccines are developed, made in mass quantities, and administered to the population. This last is critical because a vaccine is not a vaccination and if there is sufficient vaccine hesitancy, control may be elusive until widespread antivirals — which take substantially more time to develop — are available.

The Controlling Families

 What the above boils down to is a select cluster of traits that can be mapped onto known viral families spread through the respiratory route. Not every virus can cause a pandemic and many members of high risk viral families may not be capable either. However, I believe it is likely that the next pandemic pathogen will emerge from one of the following families: adenoviridae, picornaviridae, paramyxoviridae, orthomyxoviridae, pneumoviridae, or coronaviridae. These families contain many familiar diseases such as the common cold, RSV, influenza, and smallpox but also many other members (some in animals, some undiscovered), one or more of which could pose a pandemic threat. It is these families that I believe merit special emphasis which will be discussed in detail in later chapters.

 

 The First Lens to View Infectious Diseases

 The above is my first lens when studying an infectious disease outbreak and projecting its potential to cause a pandemic.

 

The question I ask myself is: is this a respiratory-borne virus that spreads efficiently between humans, contagious with mild or no symptoms, to which the population has little immunity without existing vaccines or treatment?

 If yes, there is pandemic potential; if no, it is containable.

 As an exercise apply this rubric to the US 2022 monkeypox outbreak one sees why cases fell so precipitously in the US — despite doomsday predictions in the press - once testing, vaccines, and behavior change recommendations were put in place.

 Using this lens is powerful because it allows one to cut through much of the noise in the early days of an outbreak and focus on the most salient aspects. One develops the ability to have a way to make one of the most important distinctions in the infection disease field which will have cascading impacts on the public, the healthcare industry, and policy makers: pandemic prone or not.

 Next, we will explore my 2nd lens which, when combined with the first, will hopefully relegate the extinction event, or as the hip are wont to call them “X-events”, to apocalyptic science fiction and allow real progress on long neglected but less shiny pandemic preparedness tasks to continue.