It wasn’t until the end of the nineteenth century that scientists finally resolved the confusion. The physicist J. J. Thompson proved the existence of electrons, particles even smaller than atoms. Scientists then understood that what was flowing through nerves and axons were really electrical charges created by the activity of these electrons.
If the discovery of electrons helped physicists understand a bit more about electricity, it also helped neuroscientists get back on track regarding the work of the brain’s neurons by putting to rest the idea that electricity could bring the dead back to life.
Enter Loligo pealei. In the middle of the 1800s, scientists discovered that an electrical impulse travels along an axon at a speed of about 90 feet per second, much more slowly than it would travel through a metal wire. By that time, scientists were able to understand the concept of electrical flow through a wire, and imagined that the body was filled with continuous “wiring” that seemed to have something to do with these long strands of fibers that ran down the spinal cord. It wasn’t until the 1880s that a Spanish scientist was able to draw the neuron and explain what the various parts of the neuron, including the axon, actually did. By finally clarifying that the neuron with its axon is the basic unit of the brain and that the body does not have a continuous system of wires running through it, Santiago Ramón y Cajal became one of neuroscience’s most famous researchers.
Progress continued, although slowly by the standards of modern science. Once science accepted that the neuron had a beginning (the dendrites), a middle (the cell body), and an end (the tip of the axon), researchers were able to learn that all electrical impulses traveling along an axon have exactly the same strength. That is to say, there are not some very powerful electrical pulses and some very weak electrical pulses flowing along an axon. This seemingly uninteresting fact had considerable implications: It meant that the electrical message being sent down the axon was charmingly simple. It was binary, like the telegraph. Either dots or dashes, on or off. Or in terms of computer language, either zeros or ones. The pulse either traveled down the axon—or it didn’t.
When scientists attached some simple technology to human nerve fibers, they could hear a characteristic “buzz” when electrical messages traveled down those nerves. But they still couldn’t understand the details of what was happening. One of their biggest handicaps was that they were not able to look inside a human axon as it was firing. It was simply too small and too delicate for the technology that existed in the decades after Cajal’s momentous discovery. For decades, scientists were stumped. It seemed as though it just wasn’t going to be possible to study the interior workings of a neuron. How the cell did what it did was apparently going to remain a mystery.
Then British biologist and cephalopod fanatic John Zachary Young came across the Atlantic in the summer of 1936 to enjoy Woods Hole. Young had been interested in cephalopod anatomy from the beginning of his career. That summer at the Marine Biological Laboratory, he worked with Loligo.
Young began studying a long, delicate strand of squid tissue believed by most scientists to be a blood vessel. Young stimulated one end of this bit of tissue and heard the characteristic static that showed that electrical impulses were traveling down the pathway. He determined that the tissue was not a blood vessel at all. It was actually a very large axon.
Back in Britain, he continued his research for a while, but not for long enough. Call it a quirk of fate. He decided not to pursue this line of research to its ultimate end—figuring out how the cell managed to create the electrical impulse and send it from one end of the axon to the other. Thus this great scientist gave up an opportunity to earn a Nobel Prize.
He instead handed the research on to Alan Hodgkin and Andrew Huxley. Hodgkin had worked on squid with Young, and he asked Huxley, his onetime student, to work with him to continue to solve the mystery. The two formed the exceptionally powerful bond of two scientists who work well together. Their first job was to develop an appropriate approach. Removing the axon from the squid, they placed it in seawater. They took a finely honed electrical probe and placed it inside the axon and placed another probe outside. They already knew from earlier experiments by other scientists that the inside of the axon, when at rest, had a comparatively negative charge and that the outside of the axon had a comparatively positive charge. Scientific consensus theorized that the charge inside the axon would move from negative to neutral.
Instead, Hodgkin and Huxley discovered, much to their amazement, that there was a big jump inside the axon, much bigger than anyone had anticipated. In fact, the inside of the axon changed to strongly positive. By comparison, the outside became negative. Then, when the axon returned to its resting state, the charges returned to their original charges.
“We have recently succeeded in inserting micro-electrodes into the giant axons of squids,” the scientists wrote triumphantly in a short note to other scientists, published in Nature, a prestigious British science journal. The pair mentioned in the note that although they had succeeded in one respect, there were many questions they still wanted to try to answer.
Ultimately, they were able to watch the flow of electricity down the axon as though they were watching the flow of a twig down a stream. They realized that one type of charged molecule moved from outside the cell axon to inside the cell axon, while the other type moved from inside to outside.
Then the pair found something even more intriguing. While many of the molecules involved in keeping a cell alive are rather large and complicated, those involved in keeping the electricity flowing were comparatively simple and very common: sodium (like the sodium in table salt or seawater) and potassium (found in foods like tomatoes and bananas). Both the sodium and the potassium lacked one electron, so they became positively charged “ions.” When the axon is at rest, the scientists found, there are a lot more positive ions outside the cell than inside the cell. When electricity flows down the axon, some of these ions outside the cell are in fact moving into the cell. When the electrical impulse passes, the ions move back outside. The inside of the axon returns to its original, comparatively negative state.
By studying the giant axon of little Loligo, Hodgkin and Huxley had made this profound discovery: Our ability to think is based on this marvelously simple process—the movement of electrical charges, ions, into and out of the axon.
But like many scientific discoveries, this one raised questions. Why were potassium and sodium moving into and out of the cells at only the appropriate times? Why didn’t they move back and forth randomly?
In turned out that there were gates, or channels, in the axon that opened and closed at only the appropriate times. In science, the more questions you answer, the more questions materialize. This is part of the fun. Once Hodgkin and Huxley revealed the basics of how electricity flows down an axon cell wall, other scientists wanted answers to questions about exactly how these gates or channels operated.
Scientist Clay Armstrong, one of Huxley’s students, tackled the question. Armstrong sometimes used the “giant” axons of the little squid found near Woods Hole, but he also traveled to South America, where fishermen provided him with Humboldt squid. Armstrong discovered that individual ions like potassium have their own specific gates that open and close only for them. These gates control passages through the cell wall that have come to be called “ion channels” and that are voltage-sensitive. In other words, the flow of electricity down the axon involves the opening and closing of these various channels.
This complicated-seeming idea is quite simple: Imagine a field filled with horses and cows. The horses can only enter and leave by one gate; the cows only enter and leave by another gate. “We are what we are because of ion channels,” Armstrong explained to one interviewer. To another, he explained that “every perception is encoded in electrical form. All of our thoughts, all of our emotions, involve the action of millions of ion channels. Billions.”
Since then, scientists have learned that there are many different kin
ds of channels leading into and out of an axon, and, indeed, into and out of all kinds of cells in the body. The reason some tranquilizers work is that they block the flow of ions through these channels, and thus the flow of electricity down the neuron’s axon. The axons or nerves become quiet.
Armstrong’s squid-based discovery has had immense consequences for human medicine. A whole new class of medications—channel blockers—has saved countless human lives. A common channel blocker called a calcium channel blocker is routinely prescribed to lower blood pressure and prevent heart attacks. Other medications help to control some forms of diabetes by influencing the opening and closing of potassium channels. Some forms of epilepsy seem to be the result of the malfunctioning of the ion channels in neurons; researchers hope to eventually find medications to improve life for epileptics by controlling the channel malfunctions.
In fact, Armstrong’s work on squid has led to a whole new field of medical research—the study of channelopathies, or the study of the malfunction of channels in the axon. It’s not hard to see why Hodgkin and Huxley’s discovery using Loligo’s giant axon has been called one of the most important breakthroughs in the twentieth century. The pair received the Nobel Prize in 1963. Many people expected Clay Armstrong also to win a Nobel, but sadly, he was never so honored.
It seems incredible to me that nature has worked out such a system, so consistent across species, at once brilliantly simple—based on the tiny ions of sodium and potassium, and on simple binary code—and yet so complex, in that it controls so many different processes in our bodies. And yet this is why we can think, birds can fly, and cephalopods can change their colors in only milliseconds.
CHAPTER NINE
SERENDIPITOUS SQUID
Chance favors only the prepared mind.
—LOUIS PASTEUR
round the time Ben Franklin was killing wild turkeys with electricity in the colonies, Horace Walpole, an English public intellectual and the Fourth Earl of Orford, was contemplating the phenomenon of accidentally finding out about things you weren’t necessarily trying to understand. Walpole realized that these accidental achievements were more common than you might think—common enough, in fact, to deserve their own unique term.
Thus did Walpole coin the word “serendipity.” There is more serendipitous science than you might at first suspect. Until the early 1950s, scientists mistakenly believed that humans had forty-eight chromosomes in their cell nucleus. Then a solution of chemicals accidentally spilled on a dish of human cells. Soaked by the unique chemical solution, the chromosomes swelled and were each clearly, individually visible for the first time. It turned out that humans have forty-six chromosomes, two less than was thought. Moreover, by making individual chromosomes easily visible, the scientist, T. C. Hsu, paved the way for medical research that would eventually save the lives of countless people suffering from chromosome-based diseases.
The most often cited example of serendipity involves the Scottish biologist Alexander Fleming, who won a Nobel Prize for discovering the curative abilities of penicillin in 1928. The commonly told story is that Fleming discovered the organism from which penicillin is made. He didn’t. Other scientists had seen the fungus before. But it was Fleming who realized the importance of what he was seeing and who did something about it. It was Fleming who discovered that Penicillium fungi could be used to cure an infection of Staphylococcus, a bacterium often deadly to humans. Fleming is therefore considered the founder of the field of antibiotics.
The story goes this way: Returning to his lab after a brief trip, Fleming saw that he had forgotten to put away a petri dish containing the Staph he had been studying. When he looked at the dish, he found that some of the bacteria had been killed. He also saw that some other life-form was growing there instead. It turned out to be a fungus. He began working with this material and, after much persistence, created the world’s first antibiotic medicine—penicillin.
Which goes to show: Serendipitous discovery isn’t entirely accidental. You have to be in tune enough with what you’re looking at to know that you’re seeing something important.
“My brain feels like Jell-O” is sometimes used, tongue in cheek, to describe a feeling of mental exhaustion, but in fact scientists do use the word Jell-O to describe the texture of the goo inside your axons. “You can pick up clumps of it with forceps,” Joe DeGiorgis told me, “and you can squeeze it out of the axon the way you squeeze toothpaste out of a toothpaste tube.”
When Joe was in high school, the axoplasm in a neuron was described as a “soup,” he said, “but it’s not like that really. It’s thicker. You can pick it all up, and it stays together.” The material is a fluid, but a very sticky fluid, perhaps just a bit thicker than Jell-O. It’s so difficult to describe that many scientists have adopted a highly technical description—“goo.” The term appears not uncommonly in the scientific literature.
While some scientists were studying the flow of electricity along the axon, others were looking at what went on in the goo. How did the “Jell-O” function? What, exactly, was this plasma? What kinds of molecules were in there? If most of the manufacturing and maintenance work occurred in the cell body, under the direction of the executive DNA in the nucleus, how did the packages of information get “mailed”? How did food—that is, energy—get from one place in the neuron to another? One purpose of the axon is to send an electrical pulse from one point to another, but many other support functions also need to happen in your neurons in order for you to be able to contemplate the words printed on this page.
Scientists have known for quite a while that the axon was filled with a gelatinous substance, and speculated quite reasonably that the substance must have some important job in helping us think. By the end of the nineteenth century, they were able to use simple materials to stain the insides of the neurons and look at a few of the structures there. They could, for example, see the DNA in the cell nucleus, although they had no idea how it worked.
They could also see, with the proper technology, the strange, tiny, sausagelike mitochondria, where energy is made ready for the cell to use. When you eat a jelly bean for breakfast, your body does all kinds of things with that food, but ultimately some of that energy reaches your neurons. In the neural cell body, a portion of that energy goes into the mitochondria, which are little power plants. In these power plants, the energy of food is changed into ATP, which is the form of energy that your cells need to keep functioning.
Some cells in your body have only a few mitochondria, but neurons contain hundreds. This is why kids need to eat breakfast before they go to school: Without food, the mitochondria remain unemployed and kids don’t have the mental energy—ATP—that helps them think.
Although scientists had known for quite a while that these structures existed inside the neuron, they had little understanding as to what exactly they were or why they were there. The only way to see them was to kill the cell, stain it, then study it under a microscope. You could see the mitochondria along with other structures, but you could not watch them work. As microscopes became more and more powerful and as staining techniques improved, scientists could with ever greater clarity look at the structures inside the neuron. But they could never see those structures moving—never see the living manufacturing plants, or watch their packaged exports travel through the axoplasm.
In the late 1940s, medical research, spurred by the nerve injuries of World War II, concentrated on improving the understanding of how axons worked. A pair of researchers performed an impressively simple experiment. They took some silk and tied it around a bundle of axons, a nerve. After creating this “dam,” they saw that the part of the axons closest to the cell bodies gradually “ballooned.” Looking at this bulge on one side of the silk tie but not on the other, they realized that something inside the axon was flowing, just as the electrical pulse flowed down the cell wall. So it turned out that there were at least two flow systems in the axon—the flow of electricity and a flow of axoplasm, with its various
smaller structures, within the axon itself. The flow of axoplasm inside the axon, however, was much, much slower than the electrical pulse. Researchers estimated that the axoplasmic flow might be only a millimeter or so a day. In comparison, the electrical pulse zips along the cell wall.
By the second half of the twentieth century, scientists could use radioactivity to follow some of the movements. But the details were still mysterious. Exactly how did these packages—tiny organelles, including the sausagelike mitochondria—move? Did they just drift along? Was there some kind of system? It clearly wasn’t just random chance that got essential proteins and energy from one part of the cell to another. But how organized could something like that be?
In the 1970s, the field of cell biology was somewhat stymied, in part because the tools available to researchers were not up to the task. Light microscopy—the traditional kind of microscope that we used in high school that relies on visible light—had gone about as far as it could go, at least when it came to resolution limits. At a certain point, when scientists tried to look at smaller components inside a cell, the image would become confused. It was somewhat as though you were looking at those old-fashioned stereoscopes when the tool wasn’t the right distance from your eyes.
I called up Scott Brady, an expert on the secret life of the axon. Now a senior scientist and lab head at the University of Illinois, Brady in the early 1980s was a young and ambitious researcher spending summers at Woods Hole.
Progress on understanding the axon had come to a standstill, he told me, because the light microscopes of the day were inadequate. “You started not being able to tell whether it was one versus two objects you were looking at. We were basically stuck, because the kinds of questions we wanted to explore were below that size limitation.”
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