Natural selection and the regulation of defenses: A signal detection analysis of the smoke detector principle

https://doi.org/10.1016/j.evolhumbehav.2004.08.002Get rights and content

Abstract

Many of the body's adaptive responses, such as pain, fever, and fear, are defenses that remain latent until they are aroused by cues that indicate the presence of a threat. Natural selection should shape regulation mechanisms that express defenses only in situations where their benefits exceed their costs, but defenses are often expressed in situations where they seem unnecessary, with much resulting useless suffering. An explanation emerges from a signal detection analysis of the costs and benefits that shaped defense regulation mechanisms.

Quantitative modeling of optimal regulation for all-or-none defenses and for continuously variable defenses leads to several conclusions. First, an optimal system for regulating inexpensive all-or-none defenses against the uncertain presence of large threats will express many false alarms. Second, the optimum level of expression for graded defenses is not at the point where the costs of the defense and the danger are equal, but is instead where the marginal cost of additional defense exceeds the marginal benefit. Third, in the face of uncertainty and skewed payoff functions, the optimal response threshold may not be the point with the lowest cost. Finally, repeated exposures to certain kinds of danger may adaptively lower response thresholds, making systems vulnerable to runaway positive feedback. While we await quantitative data that can refine such models, a general theoretical perspective on the evolution of defense regulation can help to guide research and assist clinical decision making.

Introduction

Understanding how natural selection shaped the systems that regulate defense responses is obviously important because we want to avoid and alleviate aversive experiences such as pain, nausea, and anxiety. This importance grows as we must decide how to use increasingly powerful drugs that block bodily defenses. Negative emotions such as fear, anger, and depression are also defenses that are ever more susceptible to pharmacological manipulation. Understanding the systems that regulate defenses is a crucial foundation for clinical decision making.

The systems that regulate defenses are distinctive subtypes of the general control systems that make life possible. Control systems shaped by natural selection use negative feedback to maintain stability in the multitude of components and processes at various levels of organization that constitute an organism. From gene expression to biochemical pathways, development, physiological variables, behavior and social relationships, organisms are dynamic systems whose stability is maintained by control mechanisms that regulate their components.

The understanding of control systems is a remarkably recent development. Most introductory biology books mention Bernard's (1872) notion of the “milieu intérieur” and then explain “homeostasis” (Cannon, 1929) using examples such as the regulation of respiration and body temperature. In simple homeostasis, the deviation of a controlled variable from its set point initiates responses that return the variable back towards the set point in a process of stabilizing negative feedback. For instance, increased body temperature initiates sweating, flushing, and decreased activity. When these responses lower the temperature to the set point, the homeostatic system turns them off, and stability is thus maintained.

This simple fundamental principle has provided the foundation for an increasingly sophisticated perspective on living systems. The classic book What is Life? by Schrödinger (1944) emphasized how organisms avoid entropy by using energy to create and maintain order. Shortly thereafter, Wiener (1948) expanded the basic principle of feedback control into cybernetics, and Shannon and Weaver (1949) codified information theory. Grand syntheses followed for systems theory, in general (von Bertalanffy, 1969), and biology, in particular (Miller, 1978). In an elaboration of cybernetics, the “perceptual control theory” of Powers (1973) emphasized that the behavior of organisms is not controlled directly by external variables but by the regulation of internal perceptions that convey data from sensory receptors. Because these perceptions are the focus of regulation, anything that distorts them will disrupt the system. For instance, after taking a drug that makes you feel subjectively hot, you might remove your sweater even in a cool room. In yet another rapidly advancing area, computer modeling is revealing how the behavior of myriad individual agents can give rise to complex systems that exhibit patterns of order that cannot be predicted from their individual control systems (Holland, 1992).

Modern systems theory formalizes the notion of feedback regulation in standardized control system diagrams and nomenclature (see Fig. 1). Such descriptions are applied routinely in physiology, biochemistry, and developmental biology. For behavior, they have been the basis for much work in learning and behavioral ecology (Krebs & Davies, 1997). They are just now being applied systematically to the problem of how natural selection shaped the mechanisms that regulate defenses.

Maintaining homeostasis is, however, only the most fundamental regulation task for life. To survive and compete, organisms must monitor outer and inner environments to not only maintain stability but also to be able to respond effectively to changing circumstances. For instance, as the sun increases the temperature of desert animals, they move to cooler locations, a standard example of homeostasis. However, selection also shapes systems that use other cues that allow an organism to respond before the controlled variable changes. An animal exposed to sunlight may move to the shade even before its body temperature rises. Such “feed-forward” systems give an advantage by initiating adaptive behavior more quickly. For instance, sweet tastes initiate a neural reflex that releases insulin from the pancreas even before blood glucose levels rise, thus speeding sugar utilization and minimizing glucose fluctuations. If the taste is from an artificial sweetener, however, this mechanism will lower glucose levels inappropriately. Far more complex anticipatory capacities have been observed, such as butterflies that use the anticipated heat of each day to forage in the morning hours for the amount of water that they will likely need during that day.

The value of responses that anticipate future events helps to explain why natural selection shaped classical and operant conditioning. In operant conditioning, behaviors followed by a reward become more frequent, and those followed by a punishment become less frequent, with obvious benefits. A cue that indicates the availability of the reward can become a secondary reinforcer whose presence elicits the behavior sooner, or in complex sequences that are necessary to get the reward.

In classical conditioning, an unconditioned reflex response gradually comes to be expressed in response to previously neutral cues that have been paired repeatedly with an unconditioned reflex response. In Pavlov's classic demonstration, dogs that repeatedly heard a bell just before being fed salivated when they heard the bell, even in the absence of food. Classical conditioning gives a selective advantage by expressing useful responses sooner. Animals that salivated only after they tasted food must have been at a selective disadvantage, although the ubiquity of classical conditioning in many orders of organisms suggests its early origins and diverse utility.

Many defensive responses are regulated, in part, by classical conditioning. For instance, anxiety can be conditioned readily by cues that precede a painful stimulus; some people have a conditioned anxiety response to sitting in a classroom, and others become nauseated by the smell of the peppermint schnapps that they once consumed in excess. Such conditioning is more rapid for certain cues, such as snakes and spiders, for which anticipatory defensive arousal was likely especially useful in our evolutionary past (Mineka et al., 1980, Öhman & Mineka, 2001).

Control systems do not necessarily return a system to the previous level; different set points are adaptive in different situations. In fever, for example, a higher set point for body temperature facilitates fighting infection (Kluger, 1979). To describe the many regulation mechanisms that adjust set points adaptively, Mrosovsky (1990) coined the word “rheostasis.”

Not all defenses are regulated. Some, such as the skin, are always present (although callus formation adjusts skin thickness to the local degree of protection needed). Other defenses are aroused or adjusted by early life environmental cues that permanently alter developmental trajectories. In a well-studied example, Daphnia (water fleas) grow sharp protective helmets only if they are exposed early in development to chemicals present when predators are in the vicinity (Tollrian & Harvell, 1999). Recent work shows that the chemical is not from the invertebrate predator itself but consists of products released when it digests Daphnia (Stabell, Ogebebo, & Primicerio, 2003). In bacteria, heat stress proteins and the pathways that regulate them have been studied extensively. In many higher animals, adult body size is influenced by fetal levels of available nutrition. In humans, early exposure to cues that indicate scarce resources initiates a whole suite of possibly protective physiological changes such as weight gain and other components of “Syndrome X,” including hypertension, diabetes, and atherosclerosis (Neel et al., 1998). In many species, early exposure to stress, even in utero, can lower the stress response threshold and result in stress-associated diseases later in life (Sapolsky, 1992). In the behavioral realm, early loss of the father has been suggested to induce different female mating strategies (Belsky, Steinberg, & Draper, 1991).

Many defenses, such as pain, vomiting, fever, cough, and the fight–flight response, respond on a much shorter time scale. In the absence of a relevant stimulus, there is no way to know that some of these defenses even exist. You would not guess that mammals shiver, but reducing body temperature reliably elicits this useful defense. You might guess that organisms would have a way to clear foreign matter from the digestive and respiratory systems, but the exact mechanisms of vomiting and coughing would be hard to predict. The existence of many such systems that are useful only in certain situations may help explain why many lines of genetically manipulated mice appear to be normal although they are completely missing certain knock-out genes.

Some of the body's protective responses are general. For instance, Selye's “general adaptation response,” later called stress, adjusts a variety of physiological parameters in ways that facilitate coping with threats or opportunities that require action (Nesse & Young, 2000). Interestingly, the hypothalamic pituitary adrenal responses that are often taken as synonymous with stress may exist, in part, to protect the body from other aspects of emergency responses (Munck & Narayfejestoth, 1994). Natural selection has also shaped more specific defensive responses to cope with distinct kinds of threat. These are superb examples of domain-specific mechanisms (Cosmides & Tooby, 1987). Threats of injury or infection arouse specific physiological defenses such as pain and inflammation. A threat to the welfare of kin arouses worry. Threats to mating fidelity, friendships, or social status arouse yet more complex special states of emotion and motivation, such as jealousy and anger. Table 1 summarizes some defenses and the situations that arouse them.

While not the main focus here, it is worth noting that natural selection seems to have partially differentiated certain defenses from more generic precursors so that organisms can cope more effectively with particular kinds of challenges. This suggests a possible solution to debates about whether the mind is composed of discrete modules. It also obviates arguments about whether the subtypes of a response like anxiety are all separate or all fundamentally the same—they are neither, they are partially differentiated from a common precursor (Marks & Nesse, 1994). Advances in molecular biology may well help to confirm this if variations in receptors and other regulators do indeed map onto a proposed phylogeny of different subtypes of anxiety.

Defenses against severe threats that are hard to detect reliably pose special regulation challenges that are the focus of this article. Because such defenses have costs, they tend to be held invisibly in reserve until they are needed. Because they tend to be much less expensive than are the dangers they defend against, false alarms are inexpensive compared with the possibly dire consequences of failure to express the defense if the threat is present. Because the cues to such dangers tend to be only probabilistic indicators of the presence of the threat, an effective regulation system needs to assess the likelihood that a stimulus does or does not indicate the presence of the danger.

As already mentioned, there are practical reasons why the regulation of defense responses is worth a detailed investigation. Most of life's suffering arises from defense responses. Pain, aversive in its very essence, is the exemplar. People born without the capacity for pain die in early adulthood, tragically demonstrating the utility of a capacity for suffering (Sternbach, 1963). Cough, nausea, vomiting, diarrhea, and anxiety are all also unpleasant, almost certainly because their aversiveness motivates escape and future avoidance of situations that could have caused the response (Williams & Nesse, 1991). Most of the problems for which people seek medical help are also defenses. In fact, one of the most common and useful interventions offered by general physicians is prescribing drugs that block defenses and their associated suffering. Life is vastly better now that pain, vomiting, cough, diarrhea, fever, anxiety, and other defensive responses can usually be controlled.

The second reason is intimately related to the first. Optimal clinical practice—whether in general medicine, psychotherapy, or public policy—requires understanding how defenses are regulated as a basis for deciding when it is safe to block them, and when it is not. The relative safety of blocking defenses often leads to the “clinician's illusion” of viewing defenses as the problem. While most clinicians realize that cough is useful, fewer recognize fever as a defense, and many have difficulty seeing any utility in anxiety and sadness. Such ignorance about the utility of defenses is usually of little consequence, but on occasion, blocking a defense can be harmful or even fatal, such as when codeine suppresses cough, and pneumonia results. A more rigorous framework for assessing when defenses can and cannot be safely blocked is an important missing foundation for clinical practice.

A comprehensive treatment would be based on a detailed analysis of the specific mechanisms that regulate each defensive system. We have little data to support such an understanding. However, the “phenotypic gambit” of treating behavioral tendencies as if they were components directly shaped by selection has been useful in behavioral ecology and offers a way to proceed (Alexander, 1975, Grafen, 1984). It is especially apt in this case because physiologists have long pursued similar strategies in their assumption that the body's internal regulation mechanisms are somewhere near optimal (Schmidt-Nielsen, 1990). Often, such approaches are conducted under the rubric of homeostasis, rheostasis, symmorphosis (Webel, Taylor, & Bolis, 1998) or optimization theory (Alexander, 1996). But there is a surprising dearth of systematic applications of optimization to the problem of defense regulation.

This article extends a control systems approach to the problem of predicting how optimal defense regulation systems should function. Several somewhat different situations require different models. The simplest model predicts when an all-or-none defense of known cost (such as vomiting at an average cost of, say, 500 kcal) should be expressed given how much it is expected to reduce harm. That model is expanded to consider responses to uncertain cues. A related model covers responses such as fever that are expressed in continuous gradations. A final model considers expectations about how metaregulation mechanisms should adjust thresholds for expression of particular defenses as a function of prior experience and knowledge about the current environment.

Section snippets

All-or-none defenses

Many defensive responses are expressed either fully or not at all. Vomiting and panic attacks are examples. These offer a good starting point because, for the purposes of the model, the cost of such defenses can be considered fixed. Expressing such responses will give a net payoff when the cost of the defense is less than the benefit (amount of harm reduction). If the defense offers perfect protection and the potential harm is 100% certain, then an optimal mechanism will express the defense

Continuously variable responses

A different approach is needed to model defenses that can be expressed at continuously variable intensities, such as fever, rate of cough, and amount of anxiety. The costs increase across a range of increasing investments in defense. A model can be based on the reasonable assumption that greater expression of the defense offers greater protection from the threat, with initial incremental increases usually providing more reduction in harm than identical increments at higher levels. For instance,

Skewed payoff curves

Yet, another factor complicates the picture. Because information is limited and prediction is imperfect, the level of defense expressed will usually deviate somewhat from the optimal level. If the curve that describes net payoffs is symmetrical, then errors on either side have identical consequences. However, if the curve for net cost is much steeper to the left than to the right, as in Fig. 3A, then expressing three units less than the optimal defense will have much worse consequences than

Facultative adjustment of defense thresholds

So far, we have treated the thresholds for expression of a defense as if they are fixed. But experience in a particular environment yields information about the actual CD and CH, how prevalent the harm is, how well its cues can be discriminated from noise, and how effective the organism's defenses are. Organisms use this information to adjust the response threshold and intensity. Such adjustments have been best studied in the capacity for sensitizing or desensitizing responses to certain cues.

Novel cues and defense dysregulation

Defense regulation mechanisms were shaped in an environment very different from the one in which we live. As a result, novel cues acting on normal regulation mechanisms can result in pathology. One important example is the current obesity epidemic that results from the failure of normal body weight limiting mechanisms in our current environment. A more specific example has been suggested by Jennifer Weil (personal communication), who notes that when the heart cannot move enough blood, the

Research implications

Just as quantitative models that predict hypothetical optima have been useful in assessing anatomical structures, physiological regulation, and animal behavior (Alexander, 1975), they can also be useful in examining the regulation of defense responses. That such methods have not already been used extensively may well be because of the difficulty of getting actual quantitative data. For instance, while the costs of an episode of panic flight can be quantified, estimating the cost of not

Clinical implications

Even in the absence of specific quantitative data, an evolutionary perspective on defense regulation is useful in the clinic. The simple conclusion that many instances of defense response are perfectly normal but not useful in the specific instance provides a theoretical framework for physicians who are trying to decide whether it is wise to use a drug to block a defense. In many cases, such as when redundant defenses offer adequate protection or when the defense is being unnecessarily

Acknowledgments

Thanks to Richard Alexander for his enduring inspiration and for his extensive comments on a 1982 draft of these ideas. Edward Rothman offered valuable statistical consultation. Thanks also to Nicholas Mrosovsky and Miles Kimball, who offered useful suggestions, and to the editors and two referees whose comments were very helpful.

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