The evolution of ideas about brain function.

No less a luminary than Sir Charles Sherrington, pioneering 20th-century neurophysiologist and Nobel laureate, called the 17th-century physician Thomas Willis “the inventor of the nervous system.” This is an interesting exaggeration, at first glance grandiose but implying that, even as a theory describes reality, it may also set new boundaries for thought, in effect constructing a new conceptual entity. One can ask, after all: As our own knowledge of brain, mind, and consciousness keeps enlarging, will the concept of “the nervous system”—the “invention” bequeathed to us four centuries ago by Willis—always seem as central and satisfactory as it does today? The question is not irrelevant to Soul Made Flesh: The Discovery of the Brain—and How It Changed the World, a new book by science writer Carl Zimmer, author of At The Water’s Edge, Parasite Rex, and Evolution. Willis, the protagonist of Soul Made Flesh, spent his career in Oxford and later London at a time when the basic function of the brain was controversial, when questioning the concept of the mind as immaterial and immortal could be fatal, and when centuries-old conceptions of anatomy were virtually sanctified. Willis persisted over decades in making his multifarious observations on disease, physiology, and anatomy—rooting them in dissection, careful notes from his own medical practice, and a determination to question traditional notions—as the English Civil War, then Restoration, raged around him. In the cauldron of the struggle between the Royalists and the Parliamentarians, families were sundered and old friendships shattered. Toleration was minimal, and one could be imprisoned or worse, depending on what faction was in the ascendancy in that area. Soul Made Flesh begins with two short chapters that trace the evolution of ideas about brain function from the Egyptians to the mid-17th century and ends with a chapter that looks at the present state of investigation into brain function. But these chapters only establish the context for this careful history of the illustrious Willis and the spectacular group of intellectual giants who worked together in Oxford during that time. Their devotion to gaining knowledge by devising experiments, not by clinging to the ideas put forward by ancient Greek and Roman scholars, was remarkable. Certainly, part of this change was the doctrine of the scientific method advanced by Francis Bacon at the beginning of the century, but mostly it was due to the insatiable curiosity of the members of the Oxford Experimental Philosophy Club, as they called themselves. This club, which later became the Royal Society, still exists today. Zimmer’s historical recreation of the men and the era is vivid. Here is how Willis strides onto the stage: An inner circle of men stands closest to the body. Christopher Wren, thirty years old and not yet England’s great architect, studies the exposed flanges and curves of the skull. He can sketch bowels and hearts as beautifully as he will later sketch a cathedral dome. Richard Lower, who in a few years will perform the first successful blood transfusion in history, severs the nobleman’s carotid arteries and slices the gristly cartilage between his cervical vertebrae. The finest dissector in all Europe, he serves as assistant to another man in the inner circle, the owner of Beam Hall, the man who assembled his herd of natural philosophers within its walls—a short, stammering physician with hair that one neighbor describes in his diary as being “like a dark red pigge.” His name is Thomas Willis. HEART? HEAD? PINEAL GLAND? Thomas Willis was born in 1621 at Great Bedwyn in Wiltshire, the son of a farmer who was steward of an estate. The family was staunchly Royalist and members of the Church of England. In 1638, at the age of 17, Willis went to Oxford to study theology. Given his humble station in life, he was classified as a servitor and required to work to earn his education. Willis soon became more interested in medicine than theology, seeking to develop various cures by following the methods of the Swiss physician Paracelsus, who a century earlier had started the science called alchemy. In 1642, Willis’s education was disrupted by the English Civil War, when Oxford was attacked by the Parliament forces. Willis fought as a soldier in the Royalist army, but eventually Oxford was taken by the Parliament forces and, after a time, Willis was able to resume his studies. After another four years, in 1646, he obtained his medical degree— actually somewhat prematurely, as the remaining Royalist faction at Oxford recognized Willis’s exemplary service to the Royalist cause. In his studies, Willis was influenced by work of William Harvey, who had described the action of the heart and the circulation of the blood. Harvey talked about “the divine banquet of the brain” but held that the heart was the body’s leading organ. Harvey also rejected the idea that animal spirits initiated nerve action, a theory advanced by his contemporary, the French philosopher René Descartes. Descartes believed that the animal spirits were in the brain ventricles (cavities) and moved into the brain a substance establishing memories. He also thought that nerves were hollow tubes through which animal spirits were transmitted to the muscles to initiate movement. Descartes placed what he called the rational soul in the center of the brain, in the pineal gland, and maintained that only humans had such a rational soul. Still another system prevalent at the time was first put forward in the previous century by Jan Baptista van Helmont, a follower of Paracelsus. Van Helmont held that each organ had a soul, and the body was a “hive of souls.” The principal such soul was in the stomach, where food was separated into what was good and what was bad. But yet another major thinker writing at about the same time as Willis, the English philosopher Thomas Hobbes, called the heart “the fountain of all senses.” A great strength of Soul Made Flesh is how we can step into the world of these complex ideas and so understand what Willis had to contend with in his research and teaching. These competing theories of the locus of thought, memory, emotion, and the soul were aptly described by Shakespeare in The Merchant of Venice (1596): Tell me where is fancy bred, Or in the heart or in the head? How begot, how nourished? Reply, reply. It is a worthy summary of the confusing state of knowledge at the time of Willis’s education. THE NEW ANATOMISTS After the victory of Parliament’s forces, there were visitations to prominent citizens to be sure they were no longer harboring Royalist tendencies. Willis, now in an active medical practice, was not deemed important enough to warrant inquiry. But throughout this unsettling time, he arranged for church services to be held in his house, which, if discovered, would be a cause for severe reprisals. The strength of the Puritans and dissident Protestants was growing; Oliver Cromwell was assuming more and more power. He supported the execution of King Charles I in 1649, led successful campaigns in Ireland and Scotland, and was named Lord Protector in 1653. The Parliament and its backers were being ignored. All of it was distasteful to Willis, a Royalist and faithful member of the Church of England, but he continued to work and his medical practice flourished. In 1640, John Wilkins, a mathematician and astronomer who had become well connected with Parliament, was installed in an influential Oxford post. He began recruiting great minds to the university, placing no restriction on the background of his recruits, although he was a Puritan and favorable to the new regime. Eventually, Wilkins assembled an astounding collection of scholars. Christopher Wren was interested in astronomy, biology, and architecture. Robert Boyle was involved in animal experiments and, later, in investigating physical phenomena such as the behavior of gases. Robert Hooke developed the compound microscope, coined the word “cell,” and worked on physical principles such as elasticity. Later, the philosopher John Locke joined the group and developed his ideas on language and philosophy. Willis was an early participant in this astounding assemblage of talent and collaborated with its members in many experiments. Willis’s particular interest was dissection and description of anatomy. Most of the anatomy taught at that time went back to the 2nd-century Greek physician Galen, who had dissected only animals but presented his findings as human anatomy. Then, in the first half of the 16th century, knowledge of human anatomy was greatly improved by Andreas Vesalius. Working in the latter half of the 17th century, Willis described the anatomy of various animals but also dissected humans. He was one of the first to correlate the illnesses he observed and treated with the results of his autopsies. Here, Zimmer shows us the roots of modern neurology in the reliance on anatomy and the increasing technical skill that enabled Willis and his colleagues to seek empirical confirmation of speculative theories about the brain. This work anticipated the development of anatomical-clinical correlation that dramatically changed medicine two centuries later. In his anatomical studies, Willis was assisted by William Petty, Lower, and Wren, with Wren making the sketches of the anatomical specimens. Petty and Willis achieved a certain local celebrity when they revived one of their “corpses”—a woman accused of murdering her baby and hanged. She was pronounced dead, placed in a coffin, and moved to Petty’s rooms for dissection. Petty and Willis noted that she was still alive, treated her, and she recovered. She was due to be hanged again, but the two men pleaded that the baby had been stillborn, not murdered, and she was freed. Many patients treated by Willis had infections, accompanied by fever. He made detailed observations of these cases and, in 1659, published his first book, Fever— a popular but also controversial volume, because Willis attacked Galen’s theory of disease at a time when Galen’s ancient concepts were still being taught in most medical schools. “A DETRIMENT TO THE VERY FACULTY OF PHYSICK” Fortune changed for Willis in 1660. Oliver Cromwell died in 1658, and his son, Richard, took over as Lord Protector. Inept from the start, Richard raised the wrath of the army and was overthrown and banished. Now, with no reigning government, there was a movement to reinstate the monarchy. The son of Charles I was brought to the throne. Although profligate in many ways, Charles II did take an interest in science and gave a royal charter to the Oxford group, which, with a few additions, formed the Royal Society for Promoting Natural Knowledge. The founding members promised the king that it was formed for “the riches and ornament of our kingdom.” With a new government that appreciated his lifelong Royalist credentials, Willis was appointed Sedleian Professor of Natural Philosophy at Oxford. Willis continued his research, now with still more brilliant collaborators. Boyle had invented a vacuum pump, and he and Willis put animals into the chamber, removed the air, and noted their behavior. Willis’s magnificent book, Cerebri anatome or The Anatomy of the Brain and Nerves, published in 1664, synthesized all his work on anatomy and physiology of the nervous system. The illustrations were done by his friend and coworker Wren, who was gaining stature as an architect. It was at this time that Willis advanced the term, “neurologie, a doctrine of the nerves.” He published other books, including Cerebral Pathology, and other papers on various diseases, describing for the first time the signs and symptoms of typhus fever. In 1666, Willis moved to London at the urging of his friend and patron Gilbert Sheldon, the Archbishop of Canterbury. With the help of such friends, and the publication of his books, Willis’s medical practice flourished. He became one of the richest men in London. But in 1670, personal tragedy struck with the death of his wife, Mary. Previously, he had lost four of his eight children. Seeking to assuage his sorrow, he wrote Two Discourses Concerning the Soul of Brutes, in which he discussed his ideas on the soul, or souls, and their location and function. Willis always maintained that humans were “blessed with a material soul and an immaterial soul.” The rational soul, placed in the brain by God, was immaterial; it did not die. By contrast, the sensitive soul, with connections to the outer world, could be subject to madness and idiocy (he explained mental illness in this way), and it died at the death of the body. Willis wrote his last book, Rational Therapeutics, as he was dying. It summed up his medical observations and practice. After a funeral that his grandson characterized as “ridiculously sumptuous,” Willis was buried in Westminster Abbey. A Royal Society statement said that Willis’s death “may certainly be reputed a public loss, and a detriment to the very Faculty of Physick.” WILLIS’S FUNDAMENTAL DISCOVERIES What, then, was Willis’s lasting contribution? It was certainly not locating the rational soul in the brain. Philosophers, theologians, scientists, and physicians who wrote before Willis seemed obsessed with the proper placement of the soul. But as Willis pointed out, the soul was immaterial and immortal, and, as such, could not be identified by science. No, his greatest contribution, as Zimmer’s title suggests, was that he was the first to declare that thoughts, emotions, sensory impressions, voluntary actions, and memories—all that we now know has a neural basis—are the properties of the brain. After Willis, there was really no serious dissent about the role of the brain. His was, as Zimmer puts it, “the most shattering triumph” of the 17th century—a century jam packed with new scientific insights. Willis’s careful observations, logical deductions, and extensive writings swept aside previous notions and became the starting point for more serious work on explaining brain function. In view of his lifelong, settled commitment to scientific method, why did Willis emphasize the role of the rational soul and ascribe to the Creator the marvels of the nervous system? Was he courting favor with the authorities so his writings would not be suppressed? After all, this was an age of religious intolerance on all sides, with the Inquisition, the Index, the trial of Galileo, the visitations to root out the Royalists, the expulsion of Jews from Spain and Portugal, the exclusion of Catholics from the English universities, and the brutal treatment by Cromwell of Irish and Scots for their religious beliefs. Even Descartes, a faithful Catholic, curbed some of his ideas for fear of reprisal by Rome. Yet, it seems likely that Willis was not dissembling. His actions throughout his life testified to his firm Christian beliefs, as did his last action before his death, when he made peace with his Creator and took Holy Communion. Zimmer succeeds in capturing the essence of what he calls the “Neurocentric Age,” for after Harvey, the focus of anatomists shifted to the nervous system. But I am not sure that he highlights sufficiently the fundamental discoveries made by Willis. In identifying them, we must keep in mind that the base of knowledge with which Willis started was several centuries old, with distorted and incomplete anatomy and fanciful notions of vital spirits and the origin of thought, memories, and emotion. First, Willis dispensed with the ventricular theory of brain function, which had existed since the ancient Greek and Roman philosophers and continued by Galen, who in Willis’s time was still the accepted authority on anatomy and medicine. Willis pointed out in Cerebri Anatome that the ventricles were only a hollow space formed by the folding of the developing brain and played no part in its function. Second, Willis corrected the scheme, put forward by Descartes, that the peripheral nerves were hollow. To demonstrate this, Willis microscopically examined the nerves with the instrument devised by his friend Hooke. Third, his work on the blood supply of the brain was the result of careful dissections and injecting colored fluids to follow the course of the vessels. The meticulous description of the circle of blood vessels at the base of the brain, now called the Circle of Willis, replaced the old description of the rete mirabile, or marvelous network, put forth by Galen. Fourth—likely one of Willis’s most prescient observations—was the dividing of brain function into separate parts. Willis said sensory impressions were gathered into the corpus striatum, passed through the corpus callosum where imagination was added, and then moved into the cortex of the brain where memories were stored. His notion was counter to most current theories, which avoided a mechanistic view of brain function. Zimmer properly points out Willis’s importance in our thinking about the brain and its functions, but he pays less attention to the importance of his contributions to anatomy and physiology of the nervous system. CHOOSING OUR METAPHOR FOR THE BRAIN Although Zimmer does not mention it, historians of neuroscience have noted another interesting point about Willis’s ideas. The conception of brain function often mirrors the technology of the day. The ventricular concept of brain function could be likened to the elaborate engineering of the Greeks and Romans, with its highly developed construction of aqueducts, channels, sewers, hypocausts, and irrigation networks. Willis, growing up with the alchemy of Paracelsus, described the brain as “the serpentine channels of an alembic” (a device to distill and mix chemicals). He also saw the brain as a machine and asserted that it should be possible “to explore the brain according to the rules, cannons, and laws of the mechanick.” Willis’s case for localizing brain function was not fully accepted during his lifetime. Opposition focused on the idea that localization was mechanistic and thus not in keeping with the concept of an immortal soul. Indeed, even at the beginning of the 19th century, the notion that the brain functioned as a unified whole was still largely accepted, mainly because of the influence of Marie-Jean-Pierre Flourens, the leading physiologist of the time. Brain scientists conceived of the brain as a bowl of porridge; if parts were removed or damaged, function was not affected by where the spoonful was removed but by how many spoonfuls were taken. The movement toward localization of brain function actually arrived in the 18th century with the pseudoscience of phrenology, an attempt by Austrian anatomist Franz Joseph Gall to divide the brain into functional centers. Gall placed personality attributes in different areas of the brain, largely on the basis of skull size and configuration. Localization did not get a firm scientific foundation until the work of Paul Broca in the 1860s. Using anatomical-clinical methods, Broca localized the language center in the frontal lobes, and, later, lateralized it to the left side. This launched a new model of brain function, with various centers connecting with others as in a telegraph network—the hot new technology of that day. More recently, the brain has been viewed as a computer. Certainly, the all-or-none response of a nerve cell, reaching or failing to reach the point of firing an action potential, fits with the binary basis of modern computing. The analogy may work less well, however, as neuroscience wrestles with neurotransmitters and cells that activate, inhibit, and modulate other cells. Will our next model be the quantum computer? The last chapter of Soul Made Flesh is a lively look at modern techniques for investigating brain function. Zimmer describes functional magnetic resonance imaging (fMRI), a tool that produces a dynamic profile of brain function by distinguishing brain areas that at a given moment are calling for the most blood to satisfy their metabolic demands. Thus, the brain areas involved in producing language, for example, can be delineated by watching the changes when the subject speaks. Zimmer tells of a series of experiments that used fMRI on human subjects during the process of making ethical decisions. Is this the beginning of the modern scientific investigation of the human soul? If we contemplate knowledge of how ethical decisions are made being used for employment or, perhaps, in a court of law, we might well wonder how much we really want to know about the brain. Will we be asking these same questions a hundred years from now? Is this what Willis intended?

neuroscience, history, ed willis, zimmer, sherrington, wilkins, boyle, broca