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.