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Neuroimmunity
A New Science That Will Revolutionize How We Keep Our Brains Healthy and Young
By Michal Schwartz, Anat London Yale UNIVERSITY PRESS
Copyright © 2015 Michal Schwartz
All rights reserved.
ISBN: 978-0-300-21656-1
CHAPTER 1
A New Player in the Body-Mind Connection The Immune System
In the early 1630s, René Descartes was wandering the streets of Amsterdam, calling at various butcher shops. He wasn't shopping for dinner. Rather, he took home the haunches of beef and other cuts of meat to dissect. Descartes, a Frenchman famous for his contributions to philosophy and mathematics, was also a keen student of anatomy. When he could get them, he also dissected human cadavers. On his mind was the question, Where does the soul reside? Does it animate the body? Or is the body more like a machine?
In his Treatise of Man, published posthumously in 1664, Descartes argues that human physiology and behavior follow the same principles as the physical universe. He saw the body as a machine similar to "clocks, artificial fountains, and mills," which operated according to physical rules dependent "solely on the disposition of our organs." He set out an explanation of a system of nerve fibers transmitting messages to and from the brain, and was the first person to propose that an involuntary action could be produced by sensory stimulation — a revolutionary idea that would acquire the name "reflex" a century later.
But with respect to complex behaviors, Descartes was still a product of the seventeenth century. His science was deeply influenced by the Catholic Church's doctrine of the soul. From his point of view, we pick up a pencil only after our soul decides to do so and orders the muscles to perform the action. Descartes coined the term "dualism" as a way of describing the mind and body as two different entities, which interact in a small structure in the brain, the pineal gland. Although his concept of a complex system that delivers and receives sensory stimulation and accordingly dictates the body's response was correct, he erroneously described this system as one that is dominated by "animal spirits" that transfer the sensory information — a belief that Gilbert Ryle three hundred years later called "the dogma of the ghost in the machine."
The pendulum of thought about where our consciousness resides has shifted throughout the years: from viewing the "soul" as being located outside the physical body, we have come to find consciousness part of our physical existence residing in the brain, which is separated from the rest of the body but controls it. This question of where the self resides has been a contentious subject for many centuries. In this chapter we will see how philosophers and physicians addressed the brain and mind throughout history and how they viewed the body-mind interaction. We will offer a twist in the adventure story by suggesting a new and unexpected player in the body-mind equation — the immune system. If, we now understand, the brain controls our intellectual, emotional, and physical performance through its network of neurons, the immune system resets the "workplace" in which these neurons are operating, the brain's milieu, in order to provide an optimal framework for proper brain function without interference. In other words, the immune system is not part of the brain's network of neurons but is the body's orchestrating system, which controls the brain. We have proposed that the immune system is the central coordinating mechanism that enables the entire physiology of mind and body to function in harmony.
HISTORICAL PERSPECTIVE: WHERE DOES THE MIND RESIDE?
In the late 1700s, German physician and neuroanatomist Franz Joseph Gall was among the first to propose that each behavior is controlled by specific brain regions. According to his view there was a spot in the brain linked to any behavior you could think of, including generosity, the sense of satire and wit, the ability to keep secrets, and the talents for mathematics, architecture, and music. Gall's view was controversial, as some philosophers and intellectuals were reluctant to accept the idea that each mental function had a specific physiological basis. The concept of no soul, no spirits in the machine, was too much for them to bear.
The desire to unravel the way our behavior is controlled did not start with Descartes or Gall. The Edwin Smith papyrus (c. 1600 bc) contains the earliest known reference to the brain, describing the symptoms and prognosis of patients with head injuries. However, the Egyptians and some of the Greek philosophers in the centuries to follow did not think much of the brain. This may explain why Egyptian priests carefully preserved the heart and other organs during mummification while disposing of the brain. Philosophers such as Aristotle perceived the heart as the seat of the mind, responsible for our emotions and thoughts. The heart has retained a metaphorical connection to our emotional states, in expressions like "broken heart" or "change of heart." Other philosophers, such as Pythagoras, Hippocrates, and Plato, viewed the brain, rather than the heart, as the source of our intellect, emotions, and reasoning.
The scholastic tradition in which Descartes was educated was largely based on the biomedical texts written by the Greek surgeon Galen, the most influential and appreciated philosopher at the time. Galen served as the in-house physician for school of Roman gladiators, a job that provided the young doctor with extensive experience in treating head trauma. Galen witnessed the supreme role of the brain in controlling both movement and behavior. He himself was among the Greeks who believed that the mind and body were a single entity. By the time Descartes was making his first steps in deciphering the relationship between the mind and the body, these issues of the mind or soul versus the physical body, and what role the brain played in the interaction between the two, were still a matter of contention.
Since Descartes's doctrine, breakthroughs in technique and technology have allowed researchers to understand that the nervous system is responsible for our behavior and to decipher the way it works. In the nineteenth century, Camillo Golgi, an Italian scientist, developed a silver stain that provided the breakthrough needed to visualize neurons in the brain. Later, Santiago Ramón y Cajal, the Spanish anatomist who became the father of contemporary neuroscience, improved Golgi's method and mapped an individual nerve cell. Ramón y Cajal showed that neurons were single, complete cells, though of a complex physical nature. He showed that each neuron contained a cell body, fingerlike dendrites that collect the information and deliver it into the cell body, and a long axon that extends from the cell body and carries information to the edge of the neuron toward the next target cell (figure 1).
Ramón y Cajal's discoveries made him perhaps the greatest neuroscientist of all time. His findings became the basis for all brain research that followed. As a young man, he had wanted to be an artist, and, using Golgi's silver stain, he produced a series of drawings of nerve cells that are striking in their beauty.
In 1923 he wrote an elegant description of his search for the secrets of the inner workings of the brain in which he described the "cells of delicate and elegant forms" as "the mysterious butterflies of the soul, whose fluttering wings would some day — who knows? — enlighten the secret of mental life." In the same spirit, if the neurons are the mysterious butterflies of the soul, our findings led me to suggest that the immune cells are the nectar of these butterflies — maintaining their functions and keeping them safe.
Contemporary with Ramón y Cajal was the Austrian neurologist Sigmund Freud, the founding father of psychoanalysis and a highly skilled physician with a deep understanding of the physical structure of the brain. One of Freud's early scientific papers, published in 1882, was a study of the nerve cells of crayfish; without knowing the Spanish scientist, he independently reached the same conclusion as Ramón y Cajal: that the nerve cell is a single unit.
Freud's deep insight into human psychology was to recognize that our current emotional life and personality are intimately connected to our parents, to our past experience, and to our environment. He claimed that he was able to treat patients' problems by encouraging them to freely discuss their thoughts and memories, a practice that led to the establishment of what was then an entirely new branch of medicine. In the current age of drug therapies for every mental condition, classical Freudian psychoanalysis may have lost some of its prestige. Despite his background as a physician and the fact that he was an expert in neuroanatomy, Freud could not explain his observations and consequential hypotheses in physical terms. The id, ego, and superego could not be located in the brain. Two hundred years after Descartes, Freud had still not recognized the body-mind connection. The ghost had still not been exorcised from the machine.
The attribution of specific behaviors to different brain parts was advanced in the mid-nineteenth century by British neurologist J. Hughlings Jackson. While studying epilepsy, he provided evidence that different parts of the brain controlled diverse motor and sensory functions. Later on, Ramón y Cajal and others showed that different mental functions are regulated by certain groups of neurons within the brain that are connected to one another.
With the help of new tools and techniques that were not available to Ramón y Cajal and Freud, contemporary neuroscience has developed a much deeper understanding of the physical processes involved in brain activity, which are responsible for many activities of the mind. The American neuropsychiatrist Eric Kandel, who was awarded the Nobel Prize in physiology and medicine in 2000, has studied the interactions of neurons in the humble central nervous system of a marine snail. Together with many scientists of his generation, he has provided new insights into the cellular and molecular mechanisms that underlie learning and memory formation. Advances in technology allow scientists to listen to the electrical impulse as it travels along an axon and identify the molecules that enable neurons to transmit signals along neural pathways. Particular mental functions have been associated with specific areas of the brain; at the same time, researchers have seen how an injured brain can shift these functions to another area. New techniques have enabled us to trace firing neurons in real time in the brains of living animals and humans in a technique called functional magnetic resonance imaging, or fMRI.
DOES THE IMMUNE SYSTEM LINK BODY AND MIND?
This philosophical debate continued for centuries over the concept of a body-mind dualism and the question as to whether the mind/soul was contained within the body's physical properties. Now that, thanks to the major development in neurosciences, many functions of the mind have been discovered to be located within the brain, and body-mind dualism has taken on new meaning. Researchers are currently conducting experiments to tease apart how the brain is able to perform so many sophisticated and diverse tasks, accurately, precisely, and over the lifespan of the individual. New questions emerge: Is the mind assisted by the body outside the brain to maintain its health for so many decades? Does the body outside the brain affect the brain, or is the brain totally autonomous?
Descartes and his contemporaries, and many others to follow, in debating the body-mind connection, never considered the immune system in this equation. This is not surprising; at that time in the history of science, the immune system had not been identified. Research that would lead to germ theory was still in its infancy, and recognition of the role of the immune system in tissue maintenance was far in the future. As late as the mid-nineteenth century, people believed "miasmas" caused disease. Progress came slowly. In the early eighteenth century, Mary Wortley Montagu, the wife of the British ambassador to Turkey, inoculated her own children after witnessing local doctors in Istanbul inoculating children with pus from mild smallpox cases against the deadly smallpox epidemic. In the 1790s Edward Jenner noted that milkmaids infected with cowpox were largely immune to smallpox, and he used the abscess of their cowpox lesions to vaccinate healthy individuals, who, when they were later exposed to smallpox, did not develop the disease.
Later, Louis Pasteur and Robert Koch demonstrated that microbes can cause diseases. Their insights in turn led to the understanding of cellular immunity, antibody function, and the development of synthetic antibiotic therapy.
For most of the twentieth century, immunologists still continued to view the immune system as one that is solely designed by nature to protect us against invading threatening pathogens. Toward the end of the century additional roles of the immune system have been revealed, including its roles in normal maintenance of tissues, healing noninfectious "sterile" wounds, and coping with internal enemies, such as hazardous molecules produced by our own bodies, or our own cells if they become cancerous. Step by step, more elements of the immune system were identified, and its role in maintaining and defending the body was revealed. Yet the brain was completely excluded from this discussion, largely because of its unique anatomy as a tissue behind barriers.
When I entered the field of neuroscience as a young post-doc after earning my Ph.D. in immunology, I felt that it was highly unlikely that such a precious and sophisticated system as the central nervous system would have given up the maintenance of the immune system.
My students and I were the first to ask, Could the immune system also protect the brain? Could it affect the way we think and feel, or even the way we adapt to the endless changes and challenges that we encounter throughout our life? Could it be the system that repairs the brain, the most crucial organ, from the wear and tear that accumulates throughout life?
Even when the immune system was recognized as the ultimate system of maintenance and repair, it was not thought to be shared among all organs. It was long believed that some parts of our body are not assisted by immune cells so readily. Among these restricted organs, also called immune privileged sites, are the brain, the spinal cord, and the neural retina: the components of the central nervous system. Experiments in the early 1920s demonstrated that tumor cells transplanted into the brain can grow and survive for prolonged periods, compared with tumors placed beneath the skin, which are rapidly attacked by immune cells. These experiments further supported the idea that immune cells, which generally act to reject foreign transplants, are not active in the brain under normal conditions. A generation after these experiments, the brain still was considered a sealed system, surrounded by barriers that screened out most blood-borne cells and molecules.
Because scientists used to believe that immune cells were kept out of the brain, the fields of neuroscience and immunology long remained separate. At its outset, the study of brain and immunity was a field that focused solely on how to prevent immune cells from attacking the brain and other parts of the central nervous system in various pathologies, as in the case of multiple sclerosis, a disease in which immune cells attack the brain. Thus the possible benefits of the immune system in the central nervous system were not even considered. Instead, the immune system was viewed as a major threat to the brain.
However, my team began to ask questions. Had evolution really left the brain walled off and deprived of help from the immune system? This question opened up new avenues in the research of brain-immune interactions.
My students and I were the team that overturned this tenet in 1998, by proposing that the brain had retained the ability to be assisted by the immune system. At that time, it was already accepted that the mind is part of the physical body. We were adding another key component to the body-mind puzzle, showing that the immune system is the way our body keeps the brain and mind in good condition.
(Continues...)
Excerpted from Neuroimmunity by Michal Schwartz, Anat London. Copyright © 2015 Michal Schwartz. Excerpted by permission of Yale UNIVERSITY PRESS.
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