March 28, 2022

How do we know if something is alive? Probably the thing that would first strike us would be the presence or absence of some kind of coordinated movement. This could be the movement of arms and legs or perhaps the muscles of the face, suggesting an internal emotional state. Most of us would consider that movement is a primary characteristic of being alive and this was certainly something that was noted by the great 17th century philosopher Rene Descartes.

Descartes lived a very peripatetic life, joining the army and residing in many different parts of Europe. While on his travels he visited many of the continent’s palaces and gardens. These were the great showplaces of the time with aristocrats trying to outdo one another by transforming their gardens into fabulous theme parks. Many of them exhibited incredible automata designed by brilliant hydraulic engineers. Driven by water engines they displayed famous scenes such as incidents from classical mythology. What impressed Descartes the most was the fact that these automata were not just like clockwork fountains that would spray water on cue at particular times of the day, but that they were responsive to specific inputs, such as the presence of a human visitor that would trigger an action, suggesting sentience and responsiveness. Surely, thought Descartes, the human body must work in exactly the same manner. He wrote “Indeed, one may compare the nerves of the machine I am describing with the pipes in the works of these fountains, its muscles and tendons with the various devices and springs which serve to set them in motion, its animal spirits with the water that drives them, the heart with the source of the water, and the cavaties of the brain with storage tanks.” 

The body, then, was just a machine that worked through a set of reflexes. The behavioral output of the machine could be as simple as the withdrawal of a limb to something much more complex such as an emotion or at least the physical actions associated with it. Descartes didn’t wish to imply that the human machine was inanimate. Far from it. The human body was a machine that was also alive. Understanding the precise mechanisms that contributed to it being alive was an interesting question. And, as Descartes realized, humanity had recently developed experimental approaches for properly investigating this kind of question, pioneered by people like the great William Harvey, who had discovered the circulation of the blood. This scientific discipline, for which Harvey’s work was a powerful example, now had a name given to it by the French scientist Jean Fernel: it was called physiology - the understanding of the mechanisms that enabled living systems to function. Descartes thought that all aspects of the way the human body functioned were accessible through this kind of analysis. It was just that the human machine was much more complicated than anything in the gardens of the Hortus Palatinus or Saint-Germaine-en-Laye because it had a much better designer - almighty God. Descartes realized, as Aristotle had, that living machines had something missing from them and that something was the capability to think rationally so that the machine could receive directions that resulted from thinking and self-reflection, something that was initiated from within. It was the cogito ergo sum of the human being. Descartes envisaged this as the rational human soul, something that was completely disembodied, immaterial and distinct from the human machine but could interact with it and direct it. Indeed, Descartes thought this interaction occurred at a specific point below the brain - the pineal gland.

Incapacitating joint diseases like osteoarthritis (OA), which display symptoms such as degeneration, inflammation, and pain, degrade our ability to move in a coordinated manner and, as intuited by people like Descartes, strike at the heart of what it means to be alive. As biomedical scientists how can we approach such a problem? In 1739, a French natural philosopher proposed a scheme for testing new medical therapies. The appropriately named Claude-Nicolas Le Cat, suggested constructing an automaton that displayed many of the important functions of a human being. It would have “all the operations of a living man…..the circulation of the blood, the movement of the heart, the play of the lungs, the swallowing of food, its digestion, the evacuations, the filling of the blood vessels and their depletion by bleeding……..even speech and the articulation of words.” All of this, of course, was in keeping with Cartesian ideas circulating at the time that the bodies of humans and animals were essentially mechanical. So why not make a machine that reflected these realities and use it for developing and testing novel therapeutic procedures prior to using them on humans? Current research on musculo-skeletal disease is the direct descendent of Le Cat’s approach. We use mechanical, animal, and human models of these diseases to ask questions about pathogenic mechanisms. But what constitutes the best models given the fact that, as the statistician George Box said, “All models are wrong: the question is are they useful?”

A theoretical goal of musculo-skeletal therapeutics is to prevent the deterioration of joints and to allow them to function perfectly forever-in effect to produce a human perpetuum mobile. Therapeutic approaches to declining joint function have traditionally targeted individual sites of action in particular joint tissues. However, results from human patients treated with NGF antibodies for the relief of OA pain have highlighted the fact that OA is a disease of the entire joint, not just one individual component of it. A therapy that targets one aspect of joint disease, such as pain, may well affect another, such as joint integrity. Hence, we need models of joint disease that reflect the realization that the evolution of the joint has been as a thermodynamically efficient structure under the control of an overall program directed by key organizing molecules that regulate all joint functions simultaneously.

Experimentally, we need a multifaceted approach, and that is the goal of C-COMP. Diverse approaches and investigators coming together to investigate joint function holistically, providing models that reflect the interactive complexities of joint function. Like the joint itself, C-COMP will serve to integrate the community of scientists whose goal is to keep us moving. As Curley in Oklahoma sings, our anthem will surely be -

“Don’t you wish you’d go on forever
Don’t you wish you’d go on forever
Don’t you wish you’d go on forever
And you’d never stop?”


Categories: COMPositions