This chapter is about the misunderstood topic of pathogens. Organisms that cause disease affect all living things, sometimes causing death. Many have argued that their ability to cause disease is uniquely defining and somehow sui generis. We must continue to treat all living things including humans as self-organizing physical systems that dissipate entropy. This enables them to grow, interact, and robustly actuate biological functions in changing environments. Thus, human pathogens are the physical vehicles of our interactions with our environment. They are viruses, bacteria, protists, fungi, and other animals that gain access to our bodies. Our waste is their food. Our disease is their growth. We need to relate the evolutionary history of organisms that cause disease to the physical processes by which they come to interact with their hosts.
Earliest microbial life on our planet probably obtained electronic energy from hydrogen, accumulated in the atmosphere from volcanic eruptions. As volcanoes released heat from our newly formed planet about 4 billion years ago—merely a few billion years after the universe is thought to have formed in the first place—sulfur and hydrogen boiled from our planet’s core into the atmosphere. For aerobes like ourselves, this was an inhospitable environment initially. However, these simple molecules had what the simplest living cells needed, energy-rich electrons, which can be stripped from this atmospheric food to provide energy for self-organization and growth, producing hydrogen sulfide (H2S) as waste. Today, this process can still be detected in prokaryotes that live near hydrothermal volcanic vents. They are the current descendants of the first immortal electrons.
As the Earth continued to cool and atmospheric sulfur became scarce either from diminished release or excessive consumption, blue-green bacteria evolved to use water (H2O) as the energy source, with oxygen released as waste. As Margulis insightfully noted, this oxygen release from cyanobacteria resulted in death on a planetary scale, probably poisoning and killing most of the sulfate-reducing living things. In this way, cyanobacteria were pathogens for chemolithoautrophic organisms that constituted the first biosphere. Just as much, today they are also nitrogen-fixing organisms essential for the production of oxygen that defines our current planetary atmosphere. All organisms have similarly dynamic and pleiotropic relationships with each other. Our planet is host to diverse species that fix carbon and nitrogen from the atmosphere. Among them are humans who obtain electronic energy by eating other plants and animals. Disease and pathogenicity are byproducts of the physical interactions between newly formed co-evolutionary relationships.
It is impossible for humans not to think about pathogens in the year 2020. As I write today, every aspect of human life has been shaped by the pandemic coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent molecular clock estimates based on the nucleotide sequencing of coronaviruses that currently infect humans and various animals such as birds and rodents suggest that they diverged from a common virus ancestor more than 10,000 years ago. Many other viruses that infect our bodies have similar evolutionary histories. Thus, human history is the co-evolution of our bodies as they physically interact with other organisms, including viruses, bacteria, and other living things that comprise our microbiome and ecosphere.
Many organisms in our bodies primarily reside in our gut, with more than 100 trillion symbiotic bacteria living in our intestines. With the development of single molecule DNA sequencing, non-human genetic material has also been detected on our skin, and may even be in some visceral organs such as the liver. In the case of viruses, their direct relationship with human biology is inescapable considering that nearly half of the human genome is derived from sequences related to mobile genetic elements, or transposons.
Some transposon sequences in the human genome are related to retroviruses, distant cousins to the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). By and large, endogenous human retroviruses and retrotransposons are not pathogenic. For example, the majority of DNA sequences that regulate tissue-specific expression of genes essential body development in primates are derived from retrotransposons. While the majority of our genetic elements are related to retroviruses and retrotransposons, many are derived from other RNA viruses, such as bornaviruses, and other DNA elements, including DNA transposons.
The origin and evolution of these genetic elements are largely a mystery today. We can postulate that some of these genetic elements became incorporated into the genomes of our evolutionary ancestors as a result of infections. This is highly probable given the frequent and pervasive nature of microbial colonization. It is impossible to know what fraction of these genetic transfers were pathogenic and associated with disease, and which were functionally neutral, a kind of genetic echo of interactions between us and our living neighbors. However, the evidence that many of the “domesticated” mobile genetic elements and viruses can become physiologically essential is mounting.
We already discussed the domestication of the Transib transposable element during evolution of vertebrate animals to generate the adaptive immune system using RAG1/2-mediated somatic DNA rearrangements of immunoglobulin receptor genes. In lancelets, which are relatively simple vertebrates thought to be related to the evolutionary predecessor of fishes, transposons with similarity to our RAG1/2 are likely still genetically mobile—as remarkably observed by David Schatz and colleagues—with different genomic locations in different species. Human PGBD5 gene that has evolutionarily conserved functions in brain development is genetically related to the piggyBac transposon. Originally discovered by Malcolm Fraser and colleagues, and named for its ‘piggybacking’ activity through Baculoviruses used for genetic manipulation of insect cells, genetic sequences with similarity to piggyBac transposons are present in most living things, from bacteria to humans.
How these “jumping genes” managed to spread through the genomes of diverse organisms is currently unknown. However, recent finding of transposition of mobile genetic elements from infectious viruses in zebrafish provides a plausible mechanism. We must now search for viruses that can infect animal germ cells, either oocytes in females or spermatocytes in males. There should be evidence of horizontal gene transfer, if this mechanism for the evolution of our genomes is correct.
The coronavirus disease (COVID-19) pandemic also illustrates how evolutionary processes can start with viruses that infect some species with relatively mild effects on fitness (birds and bats), and lead to those that cause death of others (humans). The molecular basis for this transformation is beginning to be elucidated, and at least in part involves changes in the amino acid sequence of the coronavirus spike protein. The newly evolved Spike protein of SARS-CoV-2 has higher affinity for the human ACE2 receptor that is highly expressed on nasal and lung epithelial cells, as well as immune macrophage cells, and is more efficiently cleaved by human cellular proteases. This increases its infectivity with respect to its ability to spread among cells and individuals, and disease severity, including dysregulation of the human immune response.
Recent studies of individuals with life-threatening SARS-CoV-2 infections have identified inborn loss-of-function mutations of genes encoding type I interferon immune response in a subset of individuals. Many other individuals with life-threatening infections had antibodies that neutralized type I interferons. Importantly, neither group had experienced severe infections by other viruses, such as influenza, even though influenza has been endemic in humans now for more than sixty years.
The current coronavirus COVID-19 pandemic thought to have originated in Asian bats, the HIV epidemic causing AIDS that originated in African monkeys, and many other pathogens that spread from animals into human populations causing disease illustrate that viruses and other microbes becomes pathogens initially as a result of changing environmental conditions. As genetic replicators and energetic organizers, pathogens begin their evolution as neutral or symbiotic ecological neighbors. This is simply because at inception, they are derived from other living things. Viruses likely originated from transposons and other mobile genetic elements, which acquired physical mechanisms for horizontal transfer between cells. Commensal bacteria evolved from environmental prokaryotes, transferred at birth, from food, and neighbors. Both transformations required a changing environment to provide the necessary physical contact. In the case of COVID-19 and AIDS epidemics, current evidence indicates that the change was driven by the increased contact between humans and animals as a result of human population growth and food scarcity (bats are eaten in Asia, and monkeys in Africa).
Cooperative interactions among potentially pathogenic organisms are widespread in nature. For example, grasses that survive otherwise deadly hot desert temperatures require fungal endophytes to mediate cooling, which in turn need a virus for their own thermal tolerance. We and human viruses are no different. For example, Epstein-Barr virus which can cause infectious mononucleosis, and which is pandemic in large parts of human populations, also protects against infections by Listeria and Yersinia, which cause food poisoning and plague, respectively. Future studies should reveal symbiotic effects among coronaviruses in birds and rodents, retroviruses in primates, and other living things that became human pathogens.
In addition to symbiosis, the host-microbe relationship can also reach another dynamic equilibrium in the form of an arms race. This results from fluctuating selection dynamics, in which the host population is infected by a pathogen, leading to its constriction, followed by the pathogen’s collapse. This can produce either directional evolution of increasing resistance and infectivity, or alternatively, a dynamic attractor. Originally described by Leigh Van Valen as the Red Queen effect—referring to the character from Lewis Carroll’s novel who runs to keep in the same place in a moving world—this dynamical equilibrium explains the joint evolution of organisms, where mutual selective pressures promote evolutionary innovation and co-adaptation. Van Valen developed this idea to explain the need for ongoing genetic innovation to keep up with the changing environments. Continued exposure to new animal viruses that can infect and cause disease in humans should lead to the evolution and selection of more effective anti-viral immunity, such as the type I interferon response needed for effective clearance of SARS-CoV-2 infections. While most of the individuals who succumbed to lethal COVID-19 disease were adults beyond their reproductive age, sufficiently long selective pressures like this have been found to lead to adaptive evolution in other social organisms.
“Animated water,” that’s what Vernadsky and other chemists used to call the source of life in microorganisms. Besides echoing Romantic ideas and the dependency of earthly living things on water, little remains of this poetic construct today. However, living things do share fundamental properties. Modern evolutionary biology describes them as genetic replicators. Elaboration of the physical basis of living things shows them as physical structures that consume energy to self-organize. Change and instability are essential features of both. As a result, all organisms fluctuate, with diversification of molecular and genetic structure subject to functional selection.
For organisms that gain physical access to a new environment, such as a transposons in prokaryotes or viruses in multicellular organisms, molecular and genetic fluctuations inevitably lead to new activities. In the case of HIV, recent introduction of this retrovirus into human populations has caused the epidemic of AIDS. Retroviruses are composed of several proteins, including the Gag protein that mediates their self-assembly into capsid particles that assemble viral RNA genome and bud from cells to infect others. Humans also have several evolutionarily conserved genes derived from retroviral Gag.
For example, ARC is an essential human gene that is required for synaptic plasticity and memory. Arc-deficient mice are unable to retain newly formed memories. Remarkably, mammalian ARC forms capsid-like structures in neurons that are indistinguishable from retroviral Gag, binds to neuronal RNA molecules, and mediates their transfer in capsid-like particles to neighboring neurons. Evolutionary analysis suggests that our ARC is derived from a distinct vertebrate lineage of Gypsy retrotransposons, which themselves are ancestors to modern retroviruses like HIV. The insect lineage of Gypsy retrotransposons still mediates horizontal gene transfer in Drosophila flies, where it is thought to protect flies from infection by other retroviruses. Remarkably, the vertical transmission of Gypsy from parents to offspring insects is itself regulated by the endosymbiotic Wolbachia bacteria.
Thus, there is no inherent distinction between pathogenic, commensal, or symbiotic organisms. All three relationships are shared outcomes of a fluctuating and dynamic evolutionary physical process. Indeed, recent microscopic and genome sequencing studies of viruses show that each isolate is composed of extraordinarily diverse populations of viral particles, both structurally with respect to the fluctuant molecular architectures of viral particles, and genetically in terms of mutants and variants. Many viruses, and HIV in particular, exist on a kind of evolutionary precipice, with mutational rates that would be lethal for our cells, forced into Red Queen’s sprint by entropic and selective pressures.
Lovelock proposed that our entire planetary system is metastable because of the accumulation of reactive gases like methane, produced by bacterial fermentation or decay of organic material. This metastability is the defining feature of all living systems. Life on Earth is directly linked to the absorption, consumption, and dissipation of solar energy by photosynthetic organisms, which provide sustenance for the rest of us. Viruses, bacteria, and other organisms that cause disease are similarly reactive products, intermediates, and food that link humans with our ecosphere. So long as humans continue to proliferate and encounter new environments, we will continue to encounter new organisms. Insofar as at least some of the new encounters between organisms are truly new, without any preceding functional co-adaptation, disease from pathogens is inevitable. It is the spark when immortal electrons first collide.