12. The Human Mutualist: Guidelines for symbionts (whether mutualists or pathogens)

Updated: Jun 9, 2021

The origin of mutualistic systems, such as our microbiome, is lost to the very distant past, but it almost certainly did not begin as a friendly encounter. Let’s define a mutualism as a symbiotic relationship between two organisms that provides a benefit for both species and leads to increased survival and successful reproduction (fitness). Like all adaptations, the formation of a mutualism is an adaptation to alleviate environmental stress. Such an outcome would only occur in a situation where an environmental stress was lowering survival and fitness for the individuals in a population and the formation of a mutualism provided relief from that stress.

To be clear, the process of adapting is not a desirable or welcome process because it involves high mortality in the population over a relatively short period of time. That is, if a population is adapting to its environment, that means an intense stress is killing a large portion of the population and only the strong are surviving. Those survivors must pass on traits to their offspring that help them survive the stress and a larger proportion of the next generation is therefore more capable of tolerating the stress. In this way, the population recovers from the stress by producing new generations of stronger and more tolerant individuals.

In other words, a population that has successfully adapted to an intense environmental stress has just experienced a traumatic episode that involved significant mortality and at an early age for the victims. No population wants to adapt because the process of adaptation requires very high mortality (i.e. only the strong survive). On the other hand, adaptation is a positive outcome because it means the individuals in the subsequent generations are better able to survive under the conditions experienced in that particular environment that were previously lethal to much of the population.

The formation of bacterial mutualisms certainly dates back to the simplest of organisms living in the early oceans on Earth and involved bacteria forming associations with other bacteria and simple multi-cellular organisms forming associations with single-celled organisms. Environmental stress, whether through competition for resources or protection from predators, leads to adaptive responses in the stressed organisms, but which is easier? A mutation for tolerance of the stress or forming a mutualism?

If we consider protection from predation, it could very well be that a series of fortunate mutations leading to a positive physical change is more difficult or time consuming than a favorable association with another organism already possessing such a defense. The severity of the stress may be a critical component in favoring mutualisms over gene-based shifts in body morphology. If the time available for “adapting or dying” is very short, the mutations for survival must already exist in the population, and the probability of this is based on the population being very large and genetically diverse. In contrast, the creation of a mutualism with another species may be facilitated by having two genomes to draw on and by previous ecological interactions between the two species. A mutualism is favored by simply shifting the cost of an association from negative or neutral to positive.

Larger organisms, such as humans, are faced with the need for adapting to shifting climates or colonizing unfamiliar habitats such as high elevation or high latitude regions with very unfamiliar types of food or novel diseases. As an example of the possible pathway that leads to bacterial symbiosis and possibly a mutualism with human biology, let’s consider infection by a lethal pathogen.

After infection by a pathogen, our body experiences the rapid growth of the pathogenic species, perhaps a bacterium, and we are unable to control that growth; it overwhelms our defense systems and we get sick. When we, a naïve population, encounter a new pathogen, the bacterium is likely to be highly virulent meaning it has a very high growth rate once it has infected one of us because we have no specific mechanism for slowing that growth. It’s a dangerous situation because we have no history with the bacterium and therefore no way to defend against it. We get sick, we cannot prevent it from spreading through the population, we have an epidemic on our hands. The bacteria grow rapidly and in huge numbers within each infected individual and, as the disease spreads through the population, large numbers of people die prematurely.

Epidemics spread for three main reasons. First, a large and dense population will have a large number of people susceptible to a new disease or a new strain of an old disease. The new bacteria spread easily in large populations because so many people come into contact with each other and few of them have any defenses against the infection. Disease outbreaks are far more likely to occur in cities where aggregations of people occur for many different reasons and where transportation hubs bring people together from around the region and the country. Thus, a new disease is more likely to appear in places where it is easy to spread, that is, in dense populations with lots of susceptible people.

Second, if transmission is quick or uncomplicated, the bacteria will spread from one person to another readily. For example, if a handshake or a kiss on the cheek is sufficient, then the disease spreads quickly. If contact with saliva or sputum is necessary and a sick person must cough on another person, the rate of spread is slower because that contact is less likely. If blood or lymph contact or exchange is a requirement, then the pathogen will spread even more slowly because such contact only occurs under rather specific conditions. Thus, the manner and likelihood of transmission is critical. For this reason, medical researchers are often more concerned about diseases that are easy to spread even if the difficult-to-spread diseases are far more lethal.

Third, the period of time that an infected person is infectious to other people determines the window of opportunity for the bacteria to move from one person to another. For example, in the case of the flu, my family doctor may advise me to remain at home for 24 hours after the symptoms disappear. At that point there is very low likelihood of being infectious. Those flu-sufferers who insist on going to work or to public places while they are infectious will continue to spread the disease when they make contact with susceptible individuals.

Diseases that are infectious before the symptoms appear or after the symptoms have disappeared are the most dangerous. Thus, diseases spread most rapidly and epidemics occur most commonly when there is frequent contact between people, transmission is uncomplicated, and infectious periods are long or the infection is hard to detect.

When a disease is spreading rapidly, the bacterium is having no difficulty moving from one host to another. Transmission is rapid among the many susceptible hosts and this favors the strains of the bacteria that are capable of reproducing and growing the fastest, which is to say the most virulent strains are favored. Conditions that favor virulence are favoring the dangerous strains of the bacteria, which will come to dominate the bacterial population because the conditions favor their spread the most.

Think of it as a race in which the strain that reproduces the fastest is the winner. If the number of susceptible individuals is large or if the contact rate between individuals is high or if the rate of transmission of the bacterium between individuals is high, then those bacteria that spread easily and grow rapidly in number will dominate the population.

From the bacterial point of view, it really doesn’t matter if the sick individual dies as a result of the infection as long as the disease has been transmitted to the next person before the victim dies. This is a key element in epidemic situations; when conditions support an epidemic, the conditions are favoring the most dangerous strains of the pathogen.

However, all epidemics peak and subside. As the epidemic progresses, the number of susceptible individuals goes down, because more and more of the population have already had the disease (and survived or died) and the spread of the bacterium from one host to another becomes a much slower process. That is, the encounter rate with susceptible individuals goes down and the prospect of transmission of the disease goes down and therefore the likelihood of an infectious individual coming in contact with a susceptible individual goes down.

A key element to this process is that the bacteria must remain in each host a longer period of time before being transmitted to a new host. As these conditions develop, which they do in every serious epidemic, those fast-growing strains of bacteria that were favored initially and that kill the host quickly now face a critical obstacle: they might kill their host before they are able to jump to a new host and when the current host dies, the highly virulent strains of bacteria die too. As an epidemic matures, the strains of bacteria that are favored are those that grow somewhat slower, kill their host more slowly, and are able to stay in their host longer before being transmitted to a new host.

There are two variables interacting as this goes on. First, the bacterial strains that come to dominate the population are those that are slower growing and less lethal. That is, the dominant strains are not causing disease to occur as rapidly in the host. A second variable is that the host’s immune and defense systems are not as easily overwhelmed by the weaker infection and are able to mount a counterattack or at least hold off the assault. Essentially, the slower growing bacterial strains experience an environment that fights back.

Under these conditions the infection becomes a sort of cat-and-mouse game where the bacteria must persist long enough to be transmitted to a new host while the current host’s defense systems are attempting to control the bacteria before they kill the host.

In short, the longer it takes for the bacteria to be transmitted, the more benign the infection becomes because it cannot afford to kill the host before transmission happens. If it does, that strain of the bacteria eliminates itself from the population and only the weaker strains that do not kill their host as quickly can survive. If we understand the evolutionary tug-of-war in host and pathogens, it is easy to see why new diseases with which we have no experience are very dangerous, but diseases that have been around for many years, even centuries, tend to be relatively benign or only problematic for people with weakened immune systems.

While this change does not necessarily result in a mutualism between the host and the pathogen, it is useful to remember that the less-virulent pathogen remains in a battle with the host. The pathogen remains in the host population, exacting an energetic cost by forcing a defensive response, and the host cannot completely eliminate the pathogen, which is adapting to the host defenses. Nonetheless, the eventual détente that evolves creates a situation wherein the host and the pathogen are in an uneasy partnership. If the external conditions change such that the number of susceptible hosts in the population increases and the contact rate between hosts increases, the conditions are right for more virulent strains of the pathogen to proliferate and start a new epidemic. Indeed, the conditions are right for virulent stains of other pathogens to proliferate as well.

This resident-pathogen situation creates conditions that could favor a mutualistic relationship between the host and the pathogen if the conditions were to change. Low level infections take an energetic toll on the host because of the need to constantly fight off the pathogen and because the pathogen takes energy from us. If the environmental conditions were to change, the balance of power would also change: we could lose the fight and get sick or we could vanquish the enemy.

However, if the environment were to change such that a new dangerous pathogen was introduced, the cost of having the resident pathogen could become a benefit if its presence protected its host from infection from the newly arriving, more lethal pathogen. If a pathogen is highly competitive against other pathogens, and by doing so protects the host to some degree from new infections, the result is by definition a mutualism.

The pathogen benefits by protecting the host and the host benefits by having higher survival, lower costs, and higher eventual fitness. Such a mutualism does not require novel mutations and genetic adaptation on the part of the host, but just a shift in the net value of a previously existing association. (The reasons why this will work best in large organisms, such as humans, is discussed in the section called “Of Bigs and Bugs”.)

By the way, what is a Mutualism?

A mutualism is defined as any interaction between two species where both sides benefit from the interaction. Mutualisms are not necessarily constant and many depend on the conditions experienced by each side of the equation. “Obligate” mutualisms are so close and integral to survival that the two species cannot be separated and each species depends on the relationship. For example, Symbiodinium algae live in the tissues and provide nutrients to tropical corals while receiving physical protection from the coral.

Such tight associations are probably very old and the two species have evolved to the point that critical functions have been assumed by one of the species and have been lost by the other species. The Theory of Endosymbiosis suggests that the mitochondria in all animals and plants and the chloroplasts in plants are examples of ancient mutualisms formed by single-celled organisms and that these mutualisms are now fundamental to the biochemical processes of both organisms.

On the other hand, there are “facultative” mutualisms in which the association between the species is not a requirement for survival, but the interaction provides a benefit that increases the probability of survival under certain conditions. Under the right conditions, those individuals participating in the mutualism are more likely to survive or prosper than those that do not.

Facultative mutualisms are very interesting from ecological and evolutionary perspectives because they tend to vary in space and time. There will be times when the mutualism is a good idea and times when it is not and there will be places where it is a good idea and places where it is not. That is, under certain environmental conditions, the benefit of the association will outweigh the cost, but that ratio may change as the environmental conditions change.

For example, certain spiders form social aggregations when food is very abundant. This has been explained this way: when food is very abundant, the cost of spinning an individual web to catch one’s own food is outweighed by the benefits obtained from a much larger collectively spun web, but having to share the food. However, when the food resources become scarce, fewer prey are captured in the communal web and the cost-benefit ratio shifts back to favoring the individual web and not sharing the food. The spiders disperse, become solitary, and do not share their webs or their prey.

Some plants, particularly legumes, will form nodules on their roots in low nutrient soils. Colonies of bacteria in the nodules provide nitrogen compounds to the plant and the plant provides carbon to the bacteria. However, in very fertile soils, the plants will resist colonization of the roots by the bacteria because nitrogen is readily available in the soil. Having the bacteria in the roots is beneficial when nitrogen is needed, but becomes an unnecessary burden (i.e., the plant still loses energy to the bacteria) when nitrogen is available at no cost to the plant.

Mutualistic interactions are the subject of a great deal of fascinating research. Essentially, facultative mutualisms are based on cost-benefit analyses in the sense that organisms must evaluate the benefit received against the cost that must be borne. Those organisms with adaptations for making the best choices as conditions change from being more costly to more beneficial, and vice versa, are more likely to thrive and produce more offspring.

Natural selection helps organisms make adaptive economic choices in a world of limited resources. When conditions remain stable for long periods of time and the costs are predictable, obligate mutualisms are favored because the benefits derived from the mutualism are stable. Understanding the give and take of mutualistic relationships has interesting applications in many areas of human and non-human research such as sociality, philanthropy, shared risk, predation avoidance, mating choices, herd size, genetic relatedness, and food sharing.

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