Medicine is conservative,  favoring stability over change. We breathe a sigh of relief when a patient’s vital signs are stable. We worry about labile (changing) emotions, mood, or blood pressure. We have an inordinate fondness for homeostasis; we grow concerned when we detect outliers or departures from “normal” homeostasis. However, a case can be made that evolution favors the flexible. The ability to change, and the machinery that permits this flexibility, have been favored by natural selection and should be considered adaptive in themselves.

As a prosaic example, exercise causes an increase in cardiac output and heart rate. Here are the heart rate distributions of people hiking the ~25 miles rim to rim across the Grand Canyon, work that I helped to conduct:

We are not surprised that this cohort of canyon hikers has a higher heart rate when undertaking a bout of extreme exercise (all measurements were taken at rest by the way). We expect that sort of increase, and understand how it is beneficial for those athletes. In addition to adaptive physiologic flexibility, developmental plasticity evolved to permit adjustment to longer term environmental differences. These have been termed norms of reaction, evolved changes in morphology depending on early life exposures.

The capacity for phenotypic flexibility in humans and other organisms is built into our genomes. Depending on the environment, bodies are exposed to different signals or cues in early life that shape the trajectory of development. In other animals, these changes can result in completely different body forms. One extreme example of a reaction norm occurs in bees and wasps. Larvae that eat royal jelly develop into queens that are relatively huge in size and able to lay eggs. Larvae starting life identical genetically and otherwise as future queens become sterile workers if they don’t get royal jelly diet.

In another instance, when the water flea Daphnia detects the presence of a predator in the water they grow a spiky helmet that makes them slightly harder to be eaten. The helmet is expensive to make, so they don’t bother when the predator is absent. These life history changes are adaptive for the organism. The capacity to grow differently depending on signals in the water, and the alteration of body plan give water fleas higher fitness (and reproductive success) than if they did not have this ability.

A somewhat similar flexibility exists in humans. Babies born small undergo a variety of developmental changes that have important implications for future adult disease. The mechanism for this flexibility is epigenetic, a topic that we have covered in previous posts and podcasts. This phenotypic flexibility is controlled by environmental inputs, meaning that individuals with the exact same genome can develop quite differently. Some have wrongly concluded from this that the phenomenon of epigenetics poses a challenge to evolution by natural selection. If the observed changes are environmental, how could selection produce those traits? This notion misses the point. Evolution by natural selection explains the capacity for plasticity. The changes themselves are adaptive on average for individuals showing them. This is evidence of past selection that shaped and established boundary conditions on the trait (guardrails on that flexibility), a process called canalization.

The range of possible traits that occur within the boundaries of a developmental program is called a reaction norm. The take home point is that natural selection has operated on many reaction norms to maximize fitness benefits and reduce harms. Often, then, the resulting changes to body shape or function have some benefit to the organism. Like the water flea helmet example, some changes also come with costs.

When should we expect reaction norms to evolve? They should evolve when variable conditions encountered by an organism require different adaptive responses. We’d expect them to evolve when the condition has a big impact on survival and fitness. Being eaten has an undeniable impact on survival and fitness after all. Thus the Daphnia water flea benefits by altering its developmental program in a way that protects against predation. Despite the caricature of a ancient human fighting off a saber toothed tiger, miniature predators, pathogens and parasites, probably had a more important impact on fitness. A 2011 genetic analysis of human adaptive genetic variation shows that pressure from pathogens show the greatest signature of selection on the human genome.

Is there evidence that physiologic flexibility helps us fend off pathogens? Yes. Bhavani and colleagues showed that a phenotype they described as “hyperthermic fast resolvers” (very high early fever, followed by a decrease) fared best when suffering COVID-19.  Bhavani et al.‘s previous work in sepsis showed an even more striking benefit to patients able to generate a high fever:

Similarly, having a high fever was associated with increases in inflammatory cytokines. Although we are conditioned to think that these increased pro-inflammatory mediators are harmful in sepsis and in COVID-19, evidence suggests that high initial values are associated with the best survival:

On the other hand, the speed with which cytokines fall towards baseline is also associated with better outcomes. These examples shows that flexible regulation is associated with the best outcomes. Similarly, the ability to rapidly up-regulate the host defense protein interferon has been associated with good outcomes in COVID-19. Pierce and colleagues showed that brisk up-regulation of nasal interferon and pro-inflammatory cytokines results in a more effective immune response against SARS-CoV-2, especially in children. Cranking up immune defenses early prevented unrestrained viral replication and avoided later hyper-inflammation. Timing may be everything, but flexibility and robustness in the response to COVID-19 also seem to be vitally important.  Being able to ramp up a costly immune defense and then shut it off flexibly preserves life during infections and almost certainly promotes fitness too.

For infections like COVID-19 and bacterial sepsis, having the right kind of flexibility can be life saving.

Copyright © Joe Alcock MD

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine