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IN SEARCH OF MECHANISMS
Discoveries across the Life Sciences
By CARL F. CRAVER, LINDLEY DARDEN
THE UNIVERSITY OF CHICAGO PRESSCopyright © 2013 The University of Chicago
All rights reserved.
INTRODUCTION DISCOVERING MECHANISMS
LEARNING HOW CURARE KILLS
In 1804, many years before Darwin boarded the Beagle, the explorer Charles Waterton (1782–1865) traveled to British Guiana to take over an estate left to him by his uncle. From there he launched expeditions into the rest of Guiana and into Brazil. He reported his findings in a book, Wanderings in South America, and introduced many new types of animals and plants to Great Britain. In one story, Waterton describes joining a bow-hunting expedition for monkeys with some native people.
Having spotted a monkey in a nearby tree, one of the natives draws his bow and fires. The tiny arrow goes wildly off course and lodges in the arm of another member of the hunt. Recognizing that he's been hit, he announces, "Never will I bend this bow again," lays on the ground, and, without further ceremony, dies. The hunter knew, as every member of the party knew, that the tip of the arrow had been dipped in wouralia, the local name for a residue made from local plants. And the hunter knew, as every member of the party knew, that once the poison entered his body, nothing could be done to prevent his demise.
Although everyone was quite familiar with the fact that wouralia means certain death, no member of the party could say precisely how the plant residue kills its victims. The answer would not begin to appear until nearly forty years later in the 1850s, when Claude Bernard (1813–1878) published his reports describing experiments to discover the mechanism by which that poison, more commonly known as curare, kills its victims. Bernard and his students discovered, for example, that curare does not kill the victim unless it enters the bloodstream and that it does not efficiently do so through the stomach. He determined that curare is a crystalloid and that it can pass through a semi-permeable membrane by dialysis, showing that the poison might be absorbed from the prick of a pin or an arrow. After placing a small piece of curare under a frog's skin, Bernard found that the frog's heart continued to beat long after the frog stopped breathing. He concluded from this that the poison kills the animal by interfering with its ability to breathe. He further showed that if one maintains the frog with artificial respiration, it will eventually live to hop another day.
Bernard began to think that perhaps the poison interferes with the nerves or the muscles required for breathing. He found that curare clearly blocks the ability of motor neurons to cause muscular contractions, but that it leaves the sensory nerves relatively unaffected. After showing that the muscle continues to contract in response to electrical stimulation (that is, that the muscle itself still works), Bernard initially concluded that curare deadened the motor neuron itself. In later publications however Bernard reported that both the muscle and the motor neuron continue to function after the application of curare. The natural conclusion to draw is that curare somehow blocks communication between the motor neuron and the muscle.
Precisely how curare blocks synaptic communication at the neuromuscular junction was not determined until nearly a hundred years after Bernard's pioneering studies in the frog. Neuroscientists have subsequently learned that the neuromuscular junction works through chemical transmission: the electrical signal in the motor nerve causes the nerve to release a chemical neurotransmitter, acetylcholine (ACh). This transmitter diffuses across the gap to the muscle, where it binds to specific receptors for ACh. In the bound state, ACh receptors open to expose a pore through the muscular membrane, allowing passage to charged ions that constitute an electrical signal. Curare acts by interfering with this mechanism. It mimics the shape of ACh, and so binds to the places on the receptor that ACh would occupy, but it does so without opening the channels.
How does curare kill its victims? It enters the bloodstream and makes its way to the neuromuscular junction. There, it blocks chemical transmission from motor neurons, effectively paralyzing the victim. When the diaphragm is paralyzed, the victim cannot breathe, and animals that cannot breathe do not get the oxygen required to maintain basic biological functions. Thus is hunter's lore about the irrevocable effects of curare transformed into scientific knowledge of mechanisms: knowledge of the entities and activities organized together such that they produce, underlie, or maintain the phenomenon in question.
LEARNING TO LOOK FOR MECHANISMS
The search for mechanisms is one of the grand achievements in the history of science. The achievement is first and foremost conceptual: it is the very idea that scientific activity should be organized to advance the discovery of mechanisms that produce, underlie, or maintain the diverse manifest phenomena of our world. The achievement is, second, methodological: it involves the increasing acceptance and refinement of a set of tools for constructing, evaluating, and revising descriptions of mechanisms. No one person created this mechanistic view or the experimental approach characteristic of its champions. In The New Atlantis, a work that inspired the social organization of science in the seventeenth century and beyond, Francis Bacon (1561–1626) described a utopian society sustained through the efforts of specialized scientists organized to discover and control nature's hidden causes. During that period, commonly referred to as the Scientific Revolution, thinkers came to see the natural world as a world of mechanisms, just as they came to see science as fundamentally organized around the search for mechanisms. As a consequence, the methods of science came increasingly to be evaluated in terms of their efficiency and reliability as tools in the search for mechanisms. The scientific project, in turn, was justified in many domains by the fact that knowledge of the hidden mechanisms of the natural world offers humans power over the forces of nature that dominate their lives.
Just when and how this mechanistic view of science entered the different fields of biology, specifically, and precisely how the idea of mechanism came to so thoroughly triumph as a way of thinking about explanation in biology, we shall not venture opinions. That it has so triumphed is indisputable. Neuroscientists study the mechanisms of spatial memory, the propagation of action potentials, and the opening and closing of ion channels in the neuronal membrane. Molecular biologists discovered the basic mechanisms of DNA replication and protein synthesis, and they continue to elucidate the myriad mechanisms of gene regulation. Medical researchers probe the genetic basis of cystic fibrosis and how nutrient deficiencies give rise to somatic symptoms. Evolutionary biologists study the mechanism of natural selection and the isolating mechanisms leading to speciation. Ecologists study nutrient cycling mechanisms and the way imbalances in nutrient cycling produce dead zones in places such as the Chesapeake Bay. Across the life sciences the goal is to open black boxes and to learn through experiment and observation which entities and activities are components in a mechanism and how those components are organized together to do something that none of them does in isolation.
Yet there is no tidy story to tell about how this idea took hold in biology. Some of the features of mechanistic biology are discussed in Aristotle's Parts of Animals, although we hesitate to call Aristotle (384–322 BC) a mechanist. Certainly, the break from Galen's theories of anatomy during the Renaissance, such as Vesalius's corrections to Galen's human anatomical diagrams and Harvey's demonstration that the blood circulates, share many of the marks of a commitment to the search for mechanisms and of the effort to codify experimental and observational methods for discovering mechanisms. In other respects, however, such theorists were decidedly nonmechanistic, making frequent appeals to Aristotelian notions that would come to be seen as the very antithesis of mechanism in the sixteenth century. René Descartes (1596–1650) imagined a world of small corpuscles colliding with one another and, in Le Monde, fashioned innumerable models of mechanisms to explain diverse features of the biological and nonbiological world in terms of this basic activity. Yet Descartes famously left room in his world for nonmechanical causal interactions to explain the relationships between minds and brains. Perhaps one could point to the nineteenth century, to Claude Bernard or perhaps to Emil du Bois-Reymond (1818–1896), as powerful figures in part responsible for the stunning extent to which biologists understand what they are doing in terms of the search for mechanisms. Certainly their insistence upon the search for mechanisms fit nicely within the nascent worldview of Charles Darwin (1809–1882), according to which the exquisite adaptedness and diversity of living systems are in fact produced by nothing more than the purposeless mechanism of natural selection.
The mechanical philosophy has been expressed in many ways by many different authors, but one fundamental metaphysical theme is that all phenomena in nature are ultimately explained in terms of a very restricted set of basic, non-occult, non-vital, non-emergent activities. Descartes envisioned the mechanical universe as a billiard-ball universe, made only of things that take up space moving about and clacking into one another. He advanced the bold thesis that everything (except human minds and God) runs by one fundamental activity: movement conserved through collision. It is as if God arranged everything in the world just so and then kicked it. Collision upon collision propagated motion through time, making rivers flow, moving planets about the sun, and sending blood in a circuit about the body. Other mechanical philosophers chose different fundamental, non-occult activities to bottom-out their mechanisms: for some, attraction and repulsion are fundamental; for others, conservation of energy and matter are on the bottom rung. Sometimes the name "the mechanical philosophy" is intended to pick out precisely this kind of austere and materialistic metaphysical commitment.
Although very few contemporary biologists admit to the existence of occult or vital forces in the biological world, it would be false to assume that they embrace anything so austere as these pristine worldviews. Such austere and materialistic forms of the mechanical philosophy are now largely historical curiosities. Contemporary science, let alone biology, is not so restricted in the number and kinds of activities that might appear in its descriptions of mechanisms. The number of acceptable activities, while not unrestricted, is too large to list or count. Some argue that Descartes' austere mechanical philosophy ended once and for all with Newton's introduction of forces and his (reluctant) embrace of action at a distance. Thermodynamic mechanisms were added to the list of activities in the nineteenth century to explain transfer of energy and tendencies to equilibrium. Electromagnetic activities were put on a solid foundation around the same time. Diverse types of chemical bonding discovered in the nineteenth and early twentieth centuries compose biochemical, molecular biological, and metabolic mechanisms. Physiological systems often contain proprietary activities: neurons generate action potentials, hearts and muscles contract, circadian clocks entrain, and the primary somatosensory cortex forms a topographical map of the body. Organisms as a whole engage in diverse kinds of behaviors (such as mating and drinking), and populations of organisms grow, migrate, and divide. The list of non-occult activities acceptable for inclusion in descriptions of biological mechanisms has thus expanded considerably since the austere mechanism of Descartes. Many kinds of activities have been discovered, characterized, and placed on a solid epistemic foundation (using methods that we discuss in later chapters). All these activities are potentially available for inclusion in one's understanding of how a mechanism works.
Whatever the origins of this mechanistic perspective, and however it is related to the austere forms of mechanism that developed in the sixteenth and seventeenth centuries, it is now so thoroughly woven into the fabric of contemporary biology one might easily forget that biology could have taken a different form. Instead of mechanism, one might find a biology of more thoroughly Aristotelian orientation. Such a biology would place particular emphasis on explanations in terms of the goals or functions of organisms, the "that for the sake of which," final, or teleological explanations in Aristotle's four causes. Perhaps it would also emphasize Aristotelian formal causes: this cat has four legs because it has the form of a cat. While mechanists of the sixteenth and seventeenth centuries would allow that considerations of formal and final causes might play a heuristic role in discovering biological mechanisms, they generally insisted that such causes were not to be included among the acceptable explanations for biological phenomena. For the mechanist, the ability to perform a function is a phenomenon that requires a mechanistic explanation; it is not an explanation in its own right. For the mechanist, the form of a cat is either a filler term for mechanisms-we-know-not-what (i.e., the mechanisms producing the various traits and behaviors characteristic of cats) or it is an empty nothing that can do no explanatory work.
Instead of mechanism, biology might have followed the form of the bestiaries of the late Middle Ages, finding in the menagerie of life-forms on earth certain allegorical lessons from a god about how to live our lives. The beaver (castor in Latin) instructs us through its namesake behavior to cast off the temptation to sin, lest we suffer. Herbalists might still be studying plants by using their color, for example, to indicate a god's plan for their medicinal effects on humans. For the mechanists, the biological systems of our world are not messages from a creator but fascinating collections of mechanisms that perform the most complicated tasks, as it were, automatically. These systems behave as they do because they are made of components of particular sorts that engage in specific sorts of activities and are organized together such that the organism exhibits its behavior. The mechanistic biologist is not a decoder of theological texts but a kind of curious mechanic, an engineer building a blueprint for the mechanism working in a target system. The goal is not salvation but knowledge of mechanisms and the power that such knowledge promises.
The fact that biology has become a search for mechanisms is not merely a matter of fashion. Biologists look for mechanisms because they serve the three central aims of science: prediction, explanation, and control. First, knowing the mechanism usually allows one to predict how the phenomenon will behave. If one knows how a mechanism works, one can say how it would work if it were placed in different conditions or given different inputs. Second, and related, describing the mechanism for a phenomenon serves to explain the phenomenon. In some cases one can literally see how the mechanism works from beginning to end. Finally, knowing the mechanism potentially allows one to intervene into the mechanism in order to produce, eliminate, or change the phenomenon of interest. Biological mechanisms, in other words, are of interest because we want to bring them under our control: for production (as in agriculture and farming), for healing (for the purposes of medicine and pharmacology), and for environmental management and protection (in ecology). Examples abound: One's understanding of how a normal mechanism fails in disease can guide one in the search for cures and preventions. One's understanding of how a natural ecosystem works might suggest interventions to control or ameliorate the effects of an invasive species.
In saying that the search for mechanisms has come to dominate biological research, we do not intend to suggest that biology is only concerned with the discovery of mechanisms. Some biological research programs are not particularly driven by the search for mechanisms. A taxonomist might be interested in cataloguing the diversity of life in an Amazonian rain forest with no interest in mechanisms whatsoever. An epidemiologist might be interested in modeling or predicting how a disease will spread in a population without knowing the precise mechanisms by which the disease spreads. A developmental psychiatrist might be interested in the frequency with which individuals with autism fail to understand what (or that) other people are thinking without a concern for why individuals with autism have these characteristics. A molecular neurobiologist might be interested in the structure of an ion channel with no regard to the mechanisms by which the channel opens and closes, just as an anatomist can (in principal at least) study how parts are arranged spatially within the body independently of any consideration about what those parts do and how they are organized together. Categorization, generalization, modeling, observation, and prediction are, in fact, often useful in the search for mechanisms, but the value of these scientific practices is not exhausted by their contribution to the search for mechanisms. Science, in short, is not defined as the search for mechanisms; still, much of biology is in fact driven by the search for mechanisms. This is a detail worthy of our sustained, isolated attention. For this reason we focus here on the search for mechanisms, and we discuss these other practices only in so far as they contribute to that search.
Excerpted from IN SEARCH OF MECHANISMS by CARL F. CRAVER, LINDLEY DARDEN. Copyright © 2013 The University of Chicago. Excerpted by permission of THE UNIVERSITY OF CHICAGO PRESS.
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Table of ContentsTable of Contents
List of Illustrations
Chapter 1 Introduction: Discovering Mechanisms
Chapter 2 Biological Mechanisms
Chapter 3 Representing Biological Mechanisms
Chapter 4 Characterizing the Phenomenon
Chapter 5 Strategies for Mechanism Schema Construction
Chapter 6 Virtues and Vices of Mechanism Schemas
Chapter 7 Constraints on Mechanism Schemas
Chapter 8 Experiments and the Search for Mechanisms
Chapter 9 Strategies for Revising Mechanism Schemas
Chapter 10 Interfield and Interlevel Integration
Chapter 11 The Pragmatic Value of Knowing How Something Works
Chapter 12 Conclusion