Despite everything that has been written about the brain, a potentially critical part of this vital organ has been overlooked—until now. The Other Brain examines the growing importance of glia, which make up approximately 85 percent of the cells in the brain, and the role they play in how the brain functions, malfunctions, and heals itself. Long neglected as little more than cerebral packing material, glia (meaning "glue") are now known to regulate the flow of information between neurons and to repair the brain and spinal cord after injury and stroke. But scientists are also discovering that diseased and damaged glia play a significant role in psychiatric illnesses such as schizophrenia and depression, and in neurodegenerative diseases such as Parkinson's and Alzheimer's. Diseased glia cause brain cancer and multiple sclerosis and are linked to infectious diseases such as HIV and prion disease (mad cow disease, for example) and to chronic pain. The more we learn about these cells that make up the "other" brain, the more important they seem to be. Written by a neuroscientist who is a leader in glial research, The Other Brain gives readers a much more complete understanding of how the brain works and an intriguing look at potentially revolutionary developments in brain science and medicine.
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With a final slice he dropped the scalpel into the stainless steel tray, and reaching into the open skull with both hands, he carefully scooped out the brain. Cradling a human brain in his hands always released a torrent of thoughts and emotions over mortality, individuality, biology, spirituality, and the mystery of one’s own place in the world. Only hours before, everything that was this unique human being had been embodied in these three pounds of convoluted tissue. Although the pathologist had felt these emotions countless times before, this time was different. The corpse laid out on the stainless steel table before him was Albert Einstein, and in his hands he held Einstein’s brain.
Scrutinizing the brain under the bright examination lights he stared with profound wonder at how this brain, slumping under its own weight like Jell-O and looking identical to any other human brain, could have created one of the most extraordinary minds of the last century. Suddenly, Dr. Thomas Harvey saw in this brain his own destiny and purpose. It was meant for him.
Rinsing blood from the brain carefully in saline solution, he weighed and measured it and then placed it in a freshly made 10 percent solution of formaldehyde, the toxic fumes stinging his nose and eyes. When this great man’s body was laid to rest, his phenomenal brain lay sunken in a jar of preservative, like a curious museum specimen, hidden away for the next forty years by a pathologist who felt an overwhelming compulsion to keep it for himself. It was an unethical and illegal desecration, but Harvey felt it was his fate and duty to science and humanity to unlock the secrets that had enabled this brain to give birth to such an extraordinary scientific mind.
The task was far beyond the ability of this pathologist, who saw his role as guardian of this priceless scientific treasure. Over the next four decades, Harvey doled out small slices of Einstein’s brain to scientists and pseudoscientists around the world to probe in different ways for clues to Einstein’s genius.1
Here was a mind so extraordinary it conceived thoughts beyond the ability of any other mind to imagine, and beyond the capacity of many minds to understand even after the theory of relativity was fully formulated and articulated to them. A mind that could conceive the idea that time itself was flexible. Time and space, matter and energy lost their identity and freely morphed from one to the other, and time contracted or dilated to frame events fluidly. And to reach that revelation through no other means than the power of thought—a mind imagining itself riding a beam of light.
Thirty years after Einstein’s brain was stolen, four pieces of it reached a distinguished neuroanatomist at the University of California, Berkeley. She now held in her hands vials containing four bits of tissue selected from carefully chosen regions of Einstein’s cerebral cortex. Dr. Marian Diamond reasoned that since Einstein’s genius related to extraordinary abilities of imagination, abstraction, and higher-level cognitive function, any physical basis for Einstein’s genius would be found in the regions of cerebral cortex serving these cognitive functions, rather than regions of cortex handling other functions such as hearing, sight, or motor control, which were not extraordinarily different in Einstein. Harvey had cut up Einstein’s cortex, numbered the blocks, and embedded them in celloidin, a nitrocellulose compound that, when hardened, encased the tissue like insects in amber. Diamond wanted to examine two samples of association cortex, parts of the cerebral cortex where information is brought together for analysis and synthesis. She requested that Harvey send her samples from the prefrontal region, which lies just under the forehead, and one from the inferior parietal region, located slightly behind and above the ears. It was important to have samples from both left and right sides of the brain, because in most people, the left and right hemispheres tend to dominate in different cognitive functions, just as we engage the world differently with our left and right hands. The prefrontal cortex is involved in planning, recent memory, abstracting, and categorizing information. The infamous prefrontal lobotomy procedure severs this region from the brain, leaving basic mental functions unimpaired but rendering patients docile by the loss of higher level cognitive abilities to make mental abstractions and syntheses from their experiences. Diamond also requested samples from Einstein’s inferior parietal cortex, because this region is associated with imagery, memory, and attention. People with damage to this area, especially on the dominant (usually left) side of the brain, lose the ability to recognize words and letters and cannot spell or calculate. Medical literature documents the story of a mathematician who found it difficult to formulate mathematical problems after damage to this area of his cortex.
A career of studying human cortical anatomy could not diminish the wonder, excitement, and anticipation Diamond now felt as she held these four cream-colored bits of human brain, the size of sugar cubes, up to the light. These were different—at least the mind that had emerged from them was. If she could discover the secrets that had enabled this brain tissue to produce Einstein’s genius, that discovery could give insight into the cellular mechanisms linking mind and brain. It could tell us how our own brain operates and how the diseased minds of those less fortunate fail.
Diamond would need to compare these samples with appropriate control samples. Her excitement was tempered by doubt, for while she was surrounded in her lab by boxes of microscope slides containing tissue samples from many different human brains, there is but one of Einstein’s brain. The truly extraordinary nature of Einstein’s brain meant that no matter what result she obtained, the experiment could never be replicated. The gnawing uncertainty that faces every scientist at the conclusion of an experiment would be harder to vanquish without the possibility of replication. Conclusions from any data can be fallible, but science progresses through observation, data collection, and assembly of the facts. Would it be better not to look?
Scientists deal with the uncertainty of experimental results by making measurements and calculating mathematically the odds that the difference between the data from the control group and the experimental group could have come about due to chance alone. Similarly the significance of a single blond hair found at a crime scene can be partly evaluated knowing the probability of finding a blond hair in the population.
Diamond and her associates prepared to study the cellular structure of the samples. To do this, the brain tissue had to be sliced thinner than the diameter of a cell and stained with dyes, so that individual neurons could be discerned in detail among the jumble of cells forming the tissue. So thin are these slices that a stack of fifteen would only equal the thickness of a human hair. Laid out before her was a series of glass dishes filled with brilliantly colored solutions, ranging from deep purple to a shimmering pink that changed to green depending on how light struck it, like an oil slick on water. After she had collected a series of tissue sections, she transferred each one carefully with an artist’s fine paintbrush to a small glass dish of staining solution.
The next day, when she studied the sections under the microscope, shadows appeared through the formless fog; suddenly, as from an airplane descending through the clouds, the image came into sharp focus and detail like the panorama of a city. The cell she was viewing was a neuron from a region of Albert Einstein’s cortex. Perhaps this very neuron had imagined riding a beam of light. What was the difference between it and an ordinary neuron in another region of Einstein’s cortex that sparked commands to Einstein’s fingers, perhaps to write out on paper the mathematical symbols that brought this imagination to a tangible reality? How similar was this neuron to one in the same part of her cortex now sparking images and thoughts through circuits in her own mind as she contemplated the priceless treasure and mystery before her? How could a microscopic cell have so radically changed the world? How would this cell compare to a neuron in the same part of Isaac Newton’s brain? Science and technology progress through the combined action of thousands of small steps, but scientific advance is sometimes punctuated by great conceptual leaps, like the Copernican view of the solar system, Newton’s laws of gravitation and motion, Darwin’s theory of evolution of species, and Einstein’s theory of relativity. The number of such leaps can be counted on the fingers of both hands, and this neuron had come from a mind that had changed the world.
After days of carefully measuring and counting cells, Diamond added up the data and compared it with the identical regions from eleven control brains, from men ranging in age from forty-seven to eighty. There was no difference.
A neuron from the brain of a genius was indistinguishable from one taken from a typical brain. And on average, there were just as many neurons in Einstein’s creative cerebral cortex as in the cortex of men not noted for being unusually creative. But there was one difference in the data. The number of cells that were not neurons was off the charts in all four areas of Einstein’s brain. On average, the samples from normal brain tissue had one cell that was not a neuron for every two neurons counted, but the samples from Einstein’s brain had nearly twice as many nonneuronal cells, about one for every neuron. The biggest difference was seen in the sample of parietal cortex from the dominant side of Einstein’s brain, the region where abstract concepts, visual imagery, and complex thinking take place. Was this a fluke? Diamond calculated the mathematical odds that this difference could have happened by chance, considering the range of variation in the control tissue samples. In all the regions sampled from Einstein’s brain the odds that the difference could have occurred by chance were small.
The only difference Diamond could see between Einstein’s brain and an average brain was in these nonneuronal cells. Could this be the cellular basis of genius? How? What were these nonneuronal cells—called “glia”—doing? For decades these glial cells had been considered little more than mental bubble wrap, connective tissue that physically and perhaps nutritionally supported the neurons, but Einstein’s brain had more. Speculating that glia could be involved in mental function was well outside the conceptual box of most neuroscientists. Their very name sealed this box for a century: neuroglia—Latin for “neuro glue.”
INTELLECTUAL BLIND SPOT: GLIA HIDDEN IN PLAIN SIGHT
To appreciate the implications of Dr. Diamond’s findings, it is important to understand some basic facts about glia and to consider the origins of our current view of the way the brain works. The image most people have of the nervous system resembles something like the jumble of wires in a telephone network. This image has changed little in the last one hundred years. So deeply ingrained is this concept that it is difficult to imagine the nervous system working in any other way or to imagine that when this view was first conceived, it was seen as radical, and the controversy and debate about it would rage for a quarter century.
Santiago was an artistic boy, born in 1852, the son of a medical doctor in Spain. He excelled in drawing and enjoyed the new art of photography, but these pursuits did not lend themselves readily to a prosperous profession. Studying for his medical degree, he spent hours making anatomical drawings of the cadavers his father carefully dissected.
At the age of thirty-three, Santiago Ramón y Cajal (pronounced Ca-hall) held the position of professor of anatomy at Zaragoza, Spain. In 1887 on a visit to Madrid, Ramón y Cajal saw a microscope slide of nervous tissue stained with a procedure developed by the Italian anatomist Camillo Golgi fourteen years earlier. That image transformed Ramón y Cajal’s life. Abandoning his previous and highly regarded research in bacteriology, Ramón y Cajal assumed the chair of Normal and Pathological Histology in Barcelona and applied himself to improving and exploiting the Golgi method of staining to uncover the cellular structure of the brain. The Golgi method had not attracted attention for fourteen years because it was capricious. Often the staining failed, but when it worked properly, the results were stunning.
The staining method shares the same chemical reaction used in the brand-new method of black and white photography that so interested Ramón y Cajal. For reasons that are still a mystery, only a small number of neurons take up the stain, perhaps one in a hundred. But those that do become stained in their entirety, causing them to stand out in fine detail like the black silhouette of an oak tree against a yellow winter sunset. If the method stained all the neurons in the sample, it would be useless, because the branches of nerve cells packed together in any slice of brain tissue would form a thicket of incomprehensible tangles. Instead Ramón y Cajal saw individual neurons exposed bare and in their entirety like fossils cleaved from stone.
Today we tend to think of the brain by analogy with computers and electronics, but before the electronic age a different model prevailed. Nineteenth-century mills and factories harnessed the power of water diverted from rivers and streams to waterwheels, then channeled it back through canals and streams to the river that was the original source. Hydraulics were the most advanced mechanism for transmitting force over distance. Power could be applied where needed by control valves connecting the plumbing lines and hoses to direct the force. At the time, this was the analogous view to how the nervous system functioned. The nerves in our bodies were thought to be plumbed together so that their force could be applied to any muscle. Through a microscope lens one could see hundreds of tiny tubes inside nerves, presumably all interconnected with control valves and leading to the master cylinder in the brain. Inside the brain, thousands of tangled microscopic tubes, called axons, could also be seen under the microscope, coursing through tracts of white matter streaking through brain tissue.
The headwater for these tracts was in the grey matter, which formed a thick rind over the convoluted surface of the brain, like the stem of a broccoli plant dividing into finer branches to terminate among the green florets. The Golgi staining method revealed the individual nerve cells, called neurons, in exquisite detail, but these details were interpreted differently by two groups of scientists. Golgi saw the axon, the slender tube emerging from the body of each neuron, projecting great distances and branching to interconnect with other axons through countless connections. This network of interconnected fibers would allow tremendous facility in directing nervous commands or routing incoming messages from our sense organs. At the opposite end of the nerve cell, Golgi saw the highly branched and tapering rootlets called dendrites, because they resembled trees. These, he surmised, were for extracting nutrients to sustain the nerve cell and power the flow of nervous energy, now understood to be electrical current, through the network of axons. Ramón y Cajal looked at the same material, using the very staining method Golgi invented, and saw something completely different. Ramón y Cajal proposed a new theory, which came to be known as the “neuron doctrine.”
Ramón y Cajal worked feverishly, sixteen hours a day, seven days a week, examining pieces of brain tissue from animals of all kinds and of all ages, and in all regions of the brain and body. He looked at samples from humans, rabbits, dogs, guinea pigs, rats, chicks, fish, frogs, mice, and fetal animals. With an artist’s precise observation he drew out the silhouetted neurons, and studying them, he began to see a logic in the structure. Although the axons, those wire-like extensions of nerve cells, could travel over tremendous distances in the brain, they always terminated among fields of dendrites, the finely branched rootlets of neurons. In a conceptual leap, Ramón y Cajal realized that a neuron was not a node in a net, it was an independent unit! Moreover, the neuron had a functional polarity. He perceived that signals were not radiated through neural networks in all directions, like vibrations through a spider’s web. Instead the signals were conducted through each neuron in one direction, like horse-drawn buggies on a one-way street. Information came into a neuron through its root-like dendrites and commands exited through the axon, emerging from the opposite side of the cell. The axon did not connect into a meshwork of other axons, but instead ended at the dendrite of another neuron. Somehow, nervous signals were passed across the threshold between axon and dendrite into the next neuron, like boxes left on the doorstep of the recipient neuron to pick up. The cellular contents (protoplasm) of the two nerve cells were not plumbed together like fluid in hydraulic couplings.
This separation between an axon and a dendrite is called the synapse. By passing or not passing a message from axon to dendrite at each synapse, the brain directs information flow with great complexity, just as switchboards direct telephone calls.
Ramón y Cajal became the most renowned neuroanatomist of the twentieth century, receiving the Nobel Prize in Physiology or Medicine in 1906 together with Camillo Golgi, his rival, who had developed the essential staining method, but who disagreed with Ramón y Cajal’s neuron doctrine. Working prodigiously, Ramón y Cajal made discovery after discovery and published volumes of scientific papers and books on the cellular structure of the brain that are still a rich and valuable source of accurate information today. But what he left out of his drawings is an equal measure of his genius.
The wilderness of cellular structure in each microscope slide is refracted through the discerning lens of an artist’s eye in each of Ramón y Cajal’s drawings to isolate the essential information. Pioneering his way through this wilderness of complex brain structure, Ramón y Cajal never failed by drawing something that was not really there— no Martian canals, no homunculus inside the head of a sperm. He was deliberate and careful never to mix things that did not seem to belong together.
Among the things he saw clearly and always left out of his neuron drawings were glia. These he drew separately, filling volumes of notebooks over years of research with the strange-looking cells. These cells fascinated him, but their structure as revealed by the Golgi stain gave no clues to their function. Glial cells lacked both wire-like axons and root-like dendrites. Through a microscope most of them resembled a bullet hole shot through glass: a circular middle with fine fracture-like extensions radiating outward in a halo. Ramón y Cajal called them “spider cells” because of the many protoplasmic legs extending in all directions from their corpulent cell body. Other scientists thought these cells resembled stars and called them “astrocytes.” That name prevails today for one of four major types of glial cells now recognized. But Ramón y Cajal saw that glial cells came in an endless variety of bizarre forms. Some looked like grotesque fan corals, and others like sausages strung up on axons. Most authorities considered these nonneuronal cells some form of cerebral connective tissue, filling the space between neurons. If these peculiar brain cells had a higher function, Ramón y Cajal knew that their secrets would not be cracked with the primitive tools at his disposal. So he wisely drew these cells separately, and in dividing them out in this way in his notebooks, he called implicitly to neurobiologists of the future to answer the question, What is this other half of the brain?
GLIA ARE LISTENING: SHINING LIGHT ON RAMóN Y CAJAL’S MYSTERY
Ninety years later I sit in a tiny room, my face illuminated by the cold blue glow of computer monitors. To my left is a massive pool-table-sized stainless steel table, eight inches thick, floating on air pistons inside massive steel legs to provide a precise, optically flat, and v...
