NAE Perspectives offer practitioners, scholars, and policy leaders a platform to comment on developments and issues relating to engineering. 

Randolph Nesse, MD, is a research professor of life sciences at Arizona State University. For more about evolutionary medicine, see the International Society for Evolution, Medicine and Public Health.

Engineering has made vast contributions to health and medicine, from designing water and sewer systems that have saved millions of lives to optimizing healthcare delivery systems and creating ever more sophisticated medical devices. New applications of evolutionary biology to medicine are now giving rise to new opportunities for engineering to enhance understanding of disease. Projects that bring engineering expertise to bear on the questions addressed by evolutionary medicine promise major advances.

What Is Evolutionary Medicine?

Evolutionary medicine is the field that uses the principles of evolutionary biology to better understand, prevent, and treat disease. Medicine has made great progress by viewing the body from a mechanic’s point of view—asking how it works, what has gone wrong, and how to fix it. Evolutionary medicine adds an engineer’s point of view by also asking why natural selection left so many aspects of the body vulnerable to disease.

Naïve attempts to answer such questions sometimes suggest that diseases like cancer, schizophrenia, and diabetes somehow give advantages, but such explanations are almost always wrong. Diseases are not adaptations shaped by natural selection, so they do not have direct evolutionary explanations.

The correct objects of evolutionary explanation are traits that leave humans vulnerable to diseases and problems. Why is the windpipe located where food can block it? Why is the birth passage obstructed by a narrow ring of bone? Why hasn’t natural selection provided better protection against infection? Can an answer to that question help to explain the prevalence of excessive inflammation that causes autoimmune diseases, atherosclerosis, and Alzheimer’s disease? Why are pain, anxiety, and depression often excessive? Why are people vulnerable to obesity, eating disorders, and addiction? And why hasn’t natural selection provided better protection against cancer?

Why Aren’t Bodies More Robust?

The limited power of natural selection has been the main explanation for traits that leave bodies vulnerable. Mutations cannot all be prevented or repaired. Development cannot be perfectly controlled. And natural selection cannot start fresh to correct flawed designs, such as the eye’s blind spot and the nerves and blood vessels that come between the lens and the surface of the retina. While the limitations of natural selection provide important explanations for vulnerability, the rapid growth of evolutionary medicine has been spurred by recognizing the importance of other possible explanations.

Mismatch between the human body and modern environments accounts for most obesity, atherosclerosis, and autoimmune disease.[1] Like machines, bodies are likely to malfunction in environments different from those they were designed for, such as the new availability of unlimited sugar, alcohol, drugs, and social media.

Trade-offs, especially those that pit robustness against performance, offer potent explanations for vulnerability.[2] The robustness of high-performance cars is compromised by the necessity of minimizing weight. Humans can run fast, at the cost of leg and foot problems. Higher blood pressure increases vigor at the cost of more agitated blood flow that can cause atherosclerosis. Mechanisms for eliminating dysfunctional cells protect against cancer at the cost of cell losses that contribute to aging and the premature death of cells, a likely explanation for the reduced risk of cancer associated with Parkinson’s disease. Anxiety is useful but, because it is inexpensive compared to the cost of failing to warn against danger, false alarms are common, just as they are from smoke detectors. Engineering expertise can be invaluable in understanding trade-offs that maximize Darwinian fitness at the expense of health.

Control systems make life possible, but their failures cause disease. Thousands of them interact to keep bodies alive and functioning. The expression of each gene is regulated by systems with multiple inputs and controllers far more complex than simple feedback loops.

Cells grow, replicate, move, and eliminate themselves in response to control systems whose malfunction can cause

cancer or cell death. During embryonic development, control systems differentiate 200 different cell types and guide them to their appropriate locations and connections by gradients of substances that are themselves regulated. The synthesis and release of each hormone is regulated by myriad intertwined neural and chemical signals and effectors. Neurotransmitter synthesis, storage, release, recycling, and metabolism are controlled by multiple interacting systems, as are their receptors. Additional mechanisms control perception, emotion, cognition, and, of course, behavior. The difficulty of grasping how only 20,000 genes can give rise to tens of thousands of intermeshed control systems reveals how poorly the nature of organic complexity is understood.[3]

A team of engineers and evolutionary medicine experts could discover why some organic control systems are prone to certain failure modes. The most obvious is runaway positive feedback. Limited ability to control vicious cycles accounts for much disease; the itch → scratch → damage → itch cycle is a simple example. Similarly, a ruptured coronary artery plaque causes agitated blood flow that causes a clot that causes more turbulence and more clotting that culminates in a myocardial infarction. Obesity makes exercise difficult and thus further weight gain likely. Restrictive dieting causes binge eating that motivates more restrictive dieting and more bingeing. Cytokines released during infection can damage tissues that release more cytokines, causing a potentially fatal storm. Repeated arousal of pain and anxiety increases the sensitivity of those systems, an adaptive response to dangerous situations, but one that risks initiating vicious cycles of chronic pain or anxiety.

A more common and subtle failure mode results when a set point is too high or too low. Enormous effort has gone into describing the mechanisms that regulate blood pressure—baroreceptors, brain mechanisms, neural, renal, and cardiac responses—but exactly what accounts for the pandemic of hypertension remains uncertain. The same is true for blood glucose and type II diabetes. Control theory offers a way to frame and study such problems at levels higher than genes and physiological mechanisms.

Excessively wide fluctuations are characteristic of hypoglycemia and cyclothymic mood disorders. Home thermostats show the same pattern when the anticipator fails to dampen swings, but anticipators pose their own risks. For instance, taste receptors in the mouth and stomach initiate insulin release before blood glucose levels change. This blunts glucose peaks, but if artificial sweeteners set off this system, insulin lowers blood glucose in anticipation of a glucose surge that never arrives.

A control system with very high gain can cause wild swings of the sort observed in bipolar disorder. Can that also help explain why the system can get stuck at one extreme, usually depression? What trade-offs shaped the gain and damping mechanisms of the mood control system?

An initial burst of positive feedback helps to ensure a quick and complete shift of a system from one state to another, like the flip of an electrical switch. Biological on/off control systems are essential, but vulnerable to dysregulation. During childbirth, the hormone oxytocin initiates uterine contractions that release more oxytocin to ensure the process goes through to completion, but at the risk of premature birth. Related feedback systems ensure the completion of swallowing, coughing, sneezing, vomiting, defecation, urination, and sexual intercourse, with implications for understanding problems in those systems.

Overcoming Tacit Creationism

Engineering insights have much to offer evolutionary medicine, but there are good reasons why they have not been incorporated. The obvious one is that each science silo has vast specialized knowledge that is inaccessible to outsiders.

The other problem is tacit creationism, the pervasive tendency to view biological systems as if they were designed. It would be lovely if natural systems had parts like those of machines, with clear boundaries, specific functions, and just a few sensible connections to other parts! Alas, the complexity of evolved systems is not only greater than that of designed systems, but also different in kind and vastly harder to describe.

These obstacles are, however, also opportunities for creating a more sophisticated view of bodily systems and using engineering expertise to better understand why some are prone to failure.

The time is ripe for initiatives that bring engineers and evolutionary medicine experts together. The resulting synergies are likely to offer major benefits for human health.

[1] Recognition of the role of mismatch is central to evolutionary medicine. For a readable book, see Gluckman PD, Hanson M. 2006. Mismatch: Why Our World No Longer Fits Our Bodies. New York: Oxford University Press. For a comprehensive article, see Bourrat P, Griffiths P. 2021. The idea of mismatch in evolutionary medicine. British Journal for the Philosophy of Science 27.

[2] Trade-off analysis is also central to evolutionary medicine. See especially interesting work by Crespi BJ, Go MC. 2015. Diametrical diseases reflect evolutionary-genetic tradeoffs: Evidence from psychiatry, neurology, rheumatology, oncology and immunology. Evolution, Medicine, and Public Health 2015(1):216–53.

[3] The evolution of control systems has generated substantial interest, especially how robust systems allow the accumulation of mutations that can speed evolution. Frank SA. 2019. Evolutionary design of regulatory control. I. A robust control theory analysis of tradeoffs. Journal of Theoretical Biology 463:121–37; and Frank SA. 2019. Evolutionary design of regulatory control. II. Robust error-correcting feedback increases genetic and phenotypic variability. Journal of Theoretical Biology 468:72–81.

Disclaimer

The views expressed in this perspective are those of the author and not necessarily of the author’s organizations, the National Academy of Engineering (NAE), or the National Academies of Sciences, Engineering, and Medicine (the National Academies). This perspective is intended to help inform and stimulate discussion. It is not a report of the NAE or the National Academies. Copyright by the National Academy of Sciences. All rights reserved.