Why humans are likely to be the most diseased organisms on the planet with entire classes of parasites that few other organisms face.

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I recently finished the excellent introduction to immunology: How the Immune System Works, by Lauren Sompayrac. A major part of the human immune system (and that of all vertebrates) is the adaptive system, which unlike the innate system, is able to mount a defense against almost any parasite¹. While “How the Immune System Works” does talk about some of the disadvantages of having such a powerful system, the big one being autoimmune disorders, it paints an awe inspiring picture of a highly sophisticated and versatile system crucial to keeping us alive.

However, a series of articles² by Stephen Hedrick leverage evolution and viral ecology to make a fascinating argument that, while our immune system is indeed sophisticated, it doesn’t keep us any more protected from parasites than the more simple immune system of an ant, oak tree or lobster. Moreover, because of the agricultural revolution, domestication of animals, and urbanisation, humans are in fact likely to be the most diseased organisms on the planet with entire classes of parasites that few other organisms face.

These arguments, which I will be summarizing, present important considerations for immunology, epidemiological modelling, zoonotic spillovers, and viral ecology. More broadly, these pieces have reminded me of the importance of first principles thinking and how crucial it is to account for evolution when thinking about systems, before getting lost in the minutiae. Even more broadly, these pieces are a reminder that we as humans remain stuck on the evolutionary treadmill. It is crucial that we deliberately take actions to hop off before it is too late. If our current rate of technological progress continues and we lack caution about what we develop, humanity looks en route to kill itself and it is somewhat of a miracle that we haven’t already.

The Red Queen

Dr. Hedrick in “The Acquired Immune System: A Vantage from Beneath” argues that because of the sheer number and diversity of parasites, and the fact that no immune system is invincible to every threat³, it is the parasites, not the immune system that are in the driver’s seat. However, while the power is with the parasites, they lack the freedom to decide how to wield it. This is because of their fundamental dependence on the host, meaning they can only be so virulent or else cause their own extinction. As a result, the parasitic burden a population faces is calibrated to, and independent of, the sophistication of its immune system (on evolutionary timescales). The burden an individual host faces is only dependent on how strong their immune system is in relation to the rest of its population: “A zebra doesn’t have to outrun the lion, just the slowest member of the herd.” This is why immunocompromised people can succumb to parasites that those with a normal immune system combat or tolerate effortlessly. David Vetter, the Bubble Boy, died tragically because he lacked an adaptive immune system, but more fundamentally because human co-evolved parasites expected that he would have one.

It is an ancient, ancestral species of “jawed fish” that we have to blame for first evolving a primordial adaptive immune system of the sort we now have, approximately 500 million years ago (Flajnik and Kasahara, 2011). This novel invention allowed it to enjoy a golden period likely free of parasitic infection, with the ability to outcompete friends and foes, and proliferate extensively (such that all vertebrates “from sharks to aardvarks” have the same adaptive immunity). However, this period was short lived as the parasites quickly evolved to catch up and the co-evolutionary race between host and parasite was back on the treadmill again. As Dr. Hedrick eloquently states: “By selecting for ever-more-devious parasites, the immune system is the cause of its own necessity”.

Unfortunately, this race is also not without its consequences as the adaptive immune system has immense energy requirements and causes auto-immune disorders and immunopathology. For example, “more than 3% of people in the United States experience a form of autoimmune disease” that can be debilitating or life threatening (Cooper and Stroehla, 2003).

It may be helpful to know that this form of evolutionary lock-in is often referred to as the “Red Queen Hypothesis”, a reference to Lewis Carroll’s Red Queen in Alice in Wonderland: “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that.” (Van Valen, 1973).

Invertebrate Immunity

Dr. Hedrick supports his argument with interesting examples of invertebrates that don’t suffer a level of parasitic infection that would be expected if the sophistication of their immune system mattered. This is shown by exploring invertebrate lifespan, causes of death and invertebrate parasites.

Regarding lifespan: “red sea urchins and ocean quahogs can live to be more than 200 years of age.” (I thought ocean quahogs would be something highly exotic… sadly it is just another name for a clam!). “Lobsters can live to be at least 30 years of age.” Outside of invertebrates, “the giant sequoia can live 2000 years and the bristlecone pine can live past 4000 years.” Dr. Hedrick notes that these examples of longevity in the wild are unlikely to be rare cases but rather the average longevity of the species. He leverages the power of evolution again to briefly explain why and cites interesting papers on the topic⁴.

Performing direct comparisons between vertebrate and invertebrate lifespans he notes:

A species of subsocial dung beetles (Passalidae) has an average lifespan of greater than 2 years in the wild (hardly a clean environment!), and approximately 5 years in captivity (Cambefort and Hanski, 1991). This is not so different from our favorite species for studying acquired immunity, the house mouse, mus musculus, which has an average lifespan in the wild of approximately 1 year and a lifespan in captivity of 2–5 years. A second example is the lobster (Homarus americanus), which has been studied extensively due to its commercial importance. Lobsters reach sexual maturity at 5-8 years. Including predation, disease, and storm damage, the natural mortality rate of juveniles and adults (excluding human harvesting) is very low with estimates ranging from 2%–8% per year (Thomas, 1973; Ennis et al., 1986; Fogarty, 1995).

Examples of parasites that change their virulence in response to their host are also abundant. For example, malaria (Nash, 2002) and trypanosomes(Turner and Barry, 1989).

As a final example of parasitic co-evolution, a study on “invertebrate iridescent viruses” showed that infections were nonlethal and that “the frequency of infection was directly correlated with species proportion, a hallmark of frequency-dependent coevolution.” (Hernandez et al., 2000).

In light of this evidence, Dr. Hedrick rightly raises the question:

“Perhaps the question is not why invertebrates manage to succeed in the absence of an acquired immune system, but rather, why do we vertebrates have pathogens that necessitate acquired immunity?”

I believe that the underlying evolutionary theory behind our adaptive immunity not protecting us any better from co-evolved parasites is compelling and the above evidence is helpful. However, since the writing of “The Acquired Immune System: A Vantage from Beneath” in 2004, I am curious what additional evidence has been discovered on both parasitic infection and excess mortality due to parasites compared across organisms with different immune systems. Progress in metagenomic sequencing should be helpful with this.

Parasitic Optimization

What are the constraints and considerations of the parasites in their careful co-evolutionary balance with their hosts? The parasites are maximizing for reproduction. This is often called R0 (pronounced “R naught”), the number of new infections caused by an infected host. The factors influencing reproduction are transmission rate and virulence:

Transmission rate is “simply the rate at which a parasite is successfully spread from host to host, and transmission can occur over the length of infection that is determined by a combination of the host life span, the death rate due to infection, and the rate of parasite clearance.” This is \(\frac{\mathit{N_I}}{Time}\) where \(N_I\) is the number of infections and depends not only on the aforementioned features like host life span but also how mobile the host remains during infection and how often an interaction with a naive host leads to transmission (how contagious).

Virulence is “the cost of infection to the host … it is assumed to be associated with the rapidity and extent of in-host parasite replication.” I like to think of this in abstract terms as the raw amount of energy the parasite is taking from its host in order to replicate.

With a few exceptions, transmission rate depends upon virulence. Without sufficiently high virulence, there cannot be transmission. However, if virulence is too high then it is likely the host will no longer have interactions with naive hosts (because of incapacitation or death) and the immune system will try to clear the parasite, both lowering transmission rate and, by proxy, parasitic fitness.

Interesting exceptions to this interdependence between transmission rate and virulence occur when the parasite transmits via third party vectors. This includes malaria (mosquitoes), cholera (water supply) and anthrax (incredibly hardy spores). For malaria, host incapacitation due to high virulence is in fact likely to be advantageous because it makes them an easier target for mosquito bites.

This balance between transmissibility and virulence is referred to in the literature as trade-off theory (Anderson and May, 1982). Its predictions have been replicated in laboratory and natural experiments. In the lab, an incredible experiment started in the 1920s and lasting over 15 years involved between 100,000 and 200,000 mice, which were used to study the evolution of viral and bacterial virulence and mortality rates as the rate at which naive hosts were introduced was altered (Greenwood et al., 1936; Anderson and May, 1979). This evolution of virulence means that when a parasite encounters many naive hosts, there is a reduced fitness cost to high virulence and the most virulent, with the highest transmission rates, spreads the fastest. Meanwhile, with fewer naive hosts available, the opposite is true (Lively, 2006). In a similar fashion, bacteria that have acquired antibiotic resistance genes will lose them over time if they are not exposed to the antibiotics. This is because these genes are extra genetic baggage that require energy to replicate and variants free of them will outcompete those that remain encumbered (Bingle and Thomas, 2001). Applying this phenomenon to the ongoing SARS-CoV-2 pandemic, before global lockdown measures were introduced there was selection for more virulent strains of the virus. Now, with lockdown in place there is selection for less virulent, longer lived strains.

The Most Generous of Hosts

After Dr. Hedrick undermined the advantages of our adaptive immune system, he goes further in “Understanding Immunity through the Lens of Disease Ecology” by arguing that since the domestication of animals and the agricultural revolution, humans have likely been the best parasitic hosts on the planet.

Previously, hunter-gatherer tribes were too small to sustain acute, infectious agents that have high virulence and transmission rates but that the host eventually resolves through sterilizing immunity. Either the parasite would run out of naive hosts to infect, or kill the whole tribe, in either case going extinct. As a result, these tribes could only support parasites with low virulence that persist over a lifetime and could pass across generations. These include the Epstein-Barr and Hepatitis B viruses, supported by studies on indigenous tribes in the Amazon who displayed infection by persistent parasites, but not acute and transient ones that come to mind for most people (Black, 1975).

Urbanization, supported by agriculture and the domestication of animals, led to populations large and dense enough to create the class of acute, resolving infectious agents we are all too familiar with⁵. You may already be familiar with the rule that everyone is at most 6 people away from being connected to each other (Milgram, 1967). These infectious agents such as flu, measles, and smallpox, have killed on the order of billions over the centuries. In the 20th century alone, smallpox is estimated to have killed 300 million, over double that of both World Wars combined (Fenner, 1993). These parasites most often spread through respiratory droplets and are under no selective pressure to reduce their virulence because of the constant supply of naive hosts in the form of immigrants, babies, and immune evading mutations. “As evidence of the success of this pathogen strategy, there are more than 200 different viruses from at least 6 different virus families (adenovirus, coronaviruses, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus) that cause “cold” symptoms: sneezing, coughing, and runny nose.” (Hedrick, 2018) Moreover, measles has been suggested to only have evolved within the last 6,000 years (Black, 1966) and “fades-out” in communities of less than 200,000 to 500,000 people (Bartlett, 1960).

The attentive reader should note the discrepancy between this argument that humans are the most infected and the earlier argument that the human immune system had no influence on parasite infection rates. Hedrick does not directly address this conflict but I have ideas for the answer. One is that we are still at disequilibrium in co-evolving with our new parasites since the agricultural revolution happened only around 10,000 BC the blink of an eye in evolutionary time. Another answer is that we have created entirely new niches for short transient infections which have little to no competition with our previous (and continued) persistent infections. This does raise an interesting question about what the upper bound on the number of infections a host can maintain is. It would be interesting to take an energy-based immunology approach to this in a “Biology by the Numbers” fashion.

An interesting consequence of these transient, acute infections is that people think persistent infections that can last a lifetime are unusual when from an evolutionary perspective humanity is much better acquainted with them. For example, most people don’t know that Epstein-Barr virus infects ~90% of people. Personally, I still remember the horror of learning that an HIV infection can’t be cured, which Dr. Hedrick argues has been the biggest motivator for more recent research into parasitic persisters.

A paragraph that really caught my attention on just how susceptible modern society is to acute, resolving infectious agents because of the way we are interconnected is (emphasis mine):

A second attribute of modern society is that the number of interactions that characterize each individual (the degree distribution) does not follow a normal distribution. Rather, the number of ‘friends’ or ‘connections’ possessed by each person is extremely heterogeneous and more closely follows a (truncated) power law (an example of a ‘heavy-tailed’ distribution). That is, most people have small number of connections, whereas some directly interact with many people [72,77]. A simplified way of looking at this is that for disease spread there would exist highly connected individuals who would be sure to propagate an epidemic [78–81]. Mathematical modeling indicates that no matter how inefficient the transmission of a disease, in a network with a heavy-tailed distribution, an epidemic is likely to permanently take hold (Hedrick, 2017).

In addition to these new infectious agents, close continual contact with wildlife has led to increased rates of zoonotic spillovers. These are the X-Factor in that “rarely do different species experience the same infectious agent with exactly the same pathology”. The parasite is calibrated to a different host and as a result the new infection can be incredibly deadly or inconsequential. Zoonoses can be deadly not only from a parasite that is too virulent and kills quickly, but also from immunopathology where, like in an allergic reaction, the immune system becomes over stimulated. This can cause death, for example, via cytokine storms or encephalitis. An interesting example of this variance in the effects of different zoonoses even within the same viral strain is:

Of the 31 species of the genus Mammarena virus, most cause mild pathology in their natural murid hosts and do not cause an apparent infection in human beings. However, seven of the 31 species are known to cause hemorrhagic fever in human beings with mortality rates between 15% and 30%. The other Mammarena viruses either do not replicate in human cells or, like lymphocytic choriomeningitis virus, cause moderate pathology and are eventually cleared (Zapata and Salvato, 2013).

There are a few consequences of these arguments. Firstly, in order to understand the virulence of a parasite, knowing about the immune system is insufficient. Host population density, size, and spatial structure in addition to viral features like its origins, transmission mechanism, and mutation rate are far more important for predicting its virulence and infection time. Secondly, zoonotic spillovers are in dis-equilibrium with human immunity and forecasting their effects will continue to be the most difficult challenge. Finally, we need to have a much deeper understanding of, and respect for, persistent infections. I think this respect has grown over time with our continuing failed attempts to vaccinate against long co-evolved parasites such as malaria, tuberculosis and HIV (co-evolved in our primate cousins).

If an increase in technology is to blame for all of our infections, it must also be our solution. With vaccines and other treatments, our technology is now de facto part of the human immune system and we need to continue leveraging it to catch up in our parasitic disequilibrium and stay ahead. However, I believe it is helpful to remember that our technology is both the cause and solution to this problem. Yes, sanitation has been wonderful for reducing infection rates dramatically, but it was only necessary in the first place because of urbanization and the infectious agents that it created.

Conclusion

I believe there is much to learn from an evolutionary and parasite oriented approach to immunology. Our adaptive immune system is no optimal solution, we should not expect to ever be truly free of parasites, some parasites will be far more difficult to eradicate than smallpox, and technological advancements have put us in a very precarious position with entire new classes of infection both known, and yet to spillover.

More research should be done on persistent infections and immune tolerance. We must also acknowledge that a perfect mechanistic understanding of the human immune system is insufficient to predict and combat parasites. A great deal of predictive power seems to come from parasite ecology and epidemiology. More of a priority should also be made towards the study of infectious agents that have co-evolved with their hosts. Dr. Hedrick notes that we spend a great deal of time studying human pathogens in mice, but why not study mice pathogens in mice? Looking at host pathogen co-evolution may even help answer questions about why our biology is often so Byzantine.

On a broader level, just like the jawed fish that developed the primordial immune system, the virus that gains greater virulence, and our agriculture-inventing ancestors, humanity remains on the evolutionary treadmill. The treadmill acts not only on our biology but also throughout society wherever there is competition, foremost in capitalism which continues to incentivize technological developments. At a fundamental level, technology is power and a double edged sword. Tyler Cowen has said that he does not think a large number of humans will ever leave Earth to travel the galaxy. This is because the amount of technology and raw power that would be required is so much that any individual would be able to acquire sufficient power to destroy Earth and everyone on it upon a whim. The morbid and amusing thought experiment he presents is, and I paraphrase: “if everyone on earth had their own big red button and if pressing it would kill everyone alive, how much time would pass before someone pressed their button?” I will leave you to answer this yourself because I don’t want to write my answer…

As a society, we must acknowledge that we are on the evolutionary treadmill and face many coordination problems in order to all get off it at the same time. The ongoing SARS-CoV-2 pandemic should make it clear just how tenuous human existence is. We need to think hard about and support ways to both directly reduce existential risks like through nuclear disarmament and better biosecurity, and indirectly, through boosting our cooperation, intelligence, and decision making.

If my summary of Dr. Hedrick’s ideas has resonated, I encourage you to read his work which is far more eloquent and provides many interesting citations. If the general enslavement to evolution I have spoken about interests you then Meditations on Moloch is one of my favourite pieces from my favourite blog. If you are into sci-fi, The Mote in God’s Eye is the most accurate depiction of evolution and aliens in any book I’ve read.

Open Questions:

• Do vertebrates have pathogens that necessitate acquired immunity?
• What additional evidence since Dr. Hedrick’s pieces has been discovered on both parasitic infection and excess mortality due to parasites compared across organisms with different immune systems?
• Where do non-parasitic, commensal viruses and bacteria fit into trade-off theory? How do they transmit well enough without being virulent?
• How are persistent parasites able to evade and induce tolerance in the immune system? How do they maintain enough virulence to remain a high enough transmission rate?
• What are violations to trade-off theory and how has it developed since its introduction in 1982?
• What is the upper bound on the number of infections a host can maintain? It would be interesting to take an energy-based immunology approach to this in a “Biology by the Numbers” fashion.
• What are the cellular/molecular biology correlates of virulence and transmissibility? For example, if a parasite replicates in the respiratory tract, which seems like it would significantly increase its transmission rate, does this have a higher virulence than infecting a toe? If so, by how much?
• Relating the above question to SARS-CoV-2, We know from biochemistry that the receptor binding domain of Spike protein (necessary for viral entry) binds ~10 to 20x tighter to human ACE2 (Wrapp et al., 2020). How does this affect virulence vs transmissibility? Why does this still make SARS ~10x more lethal and MERS ~30x more lethal (Ruan, 2020)? Especially as these coronaviruses are all from the same family with the same tradeoff theory? Surely they also aren’t too far away on the fitness landscape, clearly SARS-CoV-2 is much closer to the local maxima for R0 but why?
• Also can bats sustain the “acute, resolving infectious agents” that we have made ourselves so susceptible to because of their high and dense populations that are mostly stationary inside caves? If so, then what other species also have modern human like population dynamics? Aside from being fellow vertebrates and mammals, what is it about bats that make them such zoonotic threats?

Thanks to Andrew Liu, Alexander Bricken, Joe Choo-Choy and Michael McLaren, for the helpful edits, comments and suggestions.

Footnotes