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Critics in Decartes' era were also concerned that corpuscular explanation involved hypothetical unobservable entities, and the supposition that this invisibly small world could be understood by analogy with larger objects. Descartes countered that "there is nothing more in keeping with reason that we judge about those things that we do not perceive, because of their small size, by comparison and contrast with those that we see" [[CiteRef::Clarke (1992)|p. 267]] He felt that a plausible model, though potentially incorrect due to the unobservability of its fundamental parts, was better than none at all. The role of unobservably small entities in the physical sciences was to remain a matter of prolonged debate. In modern science, it is an accepted and central practice.

Another notable objection came from Princess Elizabeth of Bohemia (1618-1680), who questioned Descartes’ theory of substance in a letter dated the tenth of May, 1643. In it, she asks “Given that the soul of a human being is only a thinking substance, how can it affect the bodily spirits, in order to bring about voluntary actions?”[[CiteRef::Descartes (2009)]] Descartes would never gives a satisfactory answer to this central question over the course of the correspondence. In 1747, in his ''L'Homme machine''(''Machine Man'') Julien Offray de La Mettrie (1709-1751) raised another simple, but devastating objection to Descartes' supposition that human reason must be due to an immaterial mental substance. He noted that reason can become impaired by material causes such as drunkenness and fever. [[CiteRef::De La Mettrie (1996)]]. In the nineteenth century, Princess Elizabeth's objection became far more poignant with the formulation of the law of the conservation of energy, which implied causal closure of the physical world to influence by a mental substance. In the early twentieth century, the mathematician Alan Turing (1912-1954) showed that it was possible to construct a general purpose machine capable of performing any possible mathematical computation, thereby demonstrating that a general purpose machine was possible and refuting Descartes' core argument against a mechanical understanding of human reason. By the end of the twentieth century, the relevant scientific communities of neuroscience and cognitive science had rejected the idea of a mental substance and sought a mechanistic physical explanation for the mind [[CiteRef::Bechtel (2008)]], though there was still no agreement as to whether consciousness could be explained in this fashion. [[CiteRef::Chalmers (1996)]]