Some researchers suggested adopting the newest video technology, but many of the older scientists remained skeptical. “The reigning paradigm was that TV would never be something you would want to use,” cell biologist Nina Strömgren Allen told me. Strömgren Allen was part of a group of researchers who would overturn that paradigm. Her father, a Danish astrophysicist and formerly a student of Neils Bohr, told her about the new high-powered, high-resolution telescopes that had recently been developed for astronomy. Could some of that technology be transferred to the world of microscopy? Strömgren Allen and her husband, Robert Day Allen, began working on a new idea—Video-Enhanced Microscopy—that they hoped would be able to show the inner life of a living neuron. By 1979, they had made some progress, and by 1981 they had published a paper on their breakthrough.
Then one of those key moments of serendipitous science occurred. The couple was teaching a course in Woods Hole about how to use microscopes. They placed a common Loligo squid axon under a light microscope, to which was connected a video camera and a television screen. When they switched on the technology, the image didn’t seem quite clear.
Allen turned a knob, hoping to bring the image into focus. Twisting the knob controlled how much light was let in and, therefore, how much you could see. Allen was explaining this principle to his students, and he wanted them to see the problem.
Continuing to look through his microscope, he twisted the knob.
“See,” he said. “You can’t see anything anymore.”
Hands waved in the audience of students.
“The image isn’t washed out. We’re looking right at it,” the students said. “In fact,” they continued, “we can see it better than before.”
“Of course it goes away,” Allen said. “I can’t see anything.”
Then he stepped away from the eyepiece of his microscope and looked at the image on the television screen.
Suddenly, right in front of everyone, appeared the movement of tiny little components inside the squid axon. A whole new world was revealed. Word of the amazing sight spread quickly on the streets of Woods Hole. Scientists passing each other on the sidewalks buzzed with excitement.
“Suddenly, the veil was lifted,” Strömgren Allen remembered when we spoke on the phone. “We knew they were there, but we couldn’t see them before this.”
When Allen followed up on what had happened, he found out that the new microscope that had been sent to him had been tuned incorrectly by the manufacturer. Serendipitously, it was this incorrect tuning that revealed for the first time this whole new avenue of exciting scientific research.
The accident created a revolution in medicine, just as the creation of penicillin had decades earlier. Scott Brady was there the day it happened. He said: “It provided us with a means to visualize these very tiny objects in living preparations. You could resolve things that were smaller with electron microscopy, but you also had to impregnate what you wanted to see with metals, so that you weren’t then seeing much in the way of direct objects, but depositions of metal stains. All of that was dead, and if you’re interested in movement, it’s not going to do you much good. It was really quite remarkable. No one knew there was so much movement. And no one had realized that all this movement was almost continuous.”
Suddenly you could look at a lot more than the electrical pulse flowing along the squid axon. You could see that inside little Loligo’s axon was a beehive of activity. Or, to use the analogy provided in one scientific paper, it was “as engrossing as the ant farms of our childhood.”
Scientists had never imagined that the world inside the axon was so dynamic. And the first thing they noticed—what was stunningly obvious—was that this activity was much more than just a lackadaisical “drift” of organelles. There seemed to be roadways and pathways, lots of stop-and-go traffic, and much more organization that anyone had previously imagined. There was a whole universe in there. It was as though you were looking at a model train set, the very elaborate kind you see in department stores at Christmas. There were engines going in all sorts of directions, lots of different tracks, and loaded-up flatbed cars and stop-and-go points where things were loaded and unloaded. It was all highly orchestrated so that (usually) none of the moving parts, the molecules, collided with each other. Some of the engines seemed to be zipping along, much faster than the one millimeter a day that had been estimated. Others crept along at a pace that would have made a snail look high-powered.
There were even, occasionally, accidents. Sometimes scientists could see collisions. Every once in a while, the molecules pulling their loads would inexplicably (or so it seemed) jump the tracks.
The movements the scientists saw that day were breathtakingly sophisticated. “It was a jaw-dropping experience for those guys, and started a whole new flurry of activity. It’s a very famous story,” Joe DeGiorgis explained. Worlds within worlds, right there, in each and every neuron. Many of these organelles were being tugged along trackways, out of the cell body and into the axon, traveling some-times all the way to the axon tip. In the 60-foot blue whale axon, this is quite a trip.
What soon became obvious was that various molecules had specific jobs. Using the new technology, a number of younger scientists began studying the intricacies of the activity. Intriguingly, they learned that they could squeeze the axoplasm out of the squid axon, and that, under proper conditions, it would continue to do its job of shuttling the tiny packages around for quite a while. This made their task much easier, because they could look directly at the tracks and cars, rather than having to look at them through the semitranslucent cell wall.
Almost immediately the scientists began looking at the chemistry of the miniature railroad system. Scott Brady was in on the action right from the beginning. The senior scientist he was working with in Woods Hole told him about the news as soon as it happened. For a young scientist, to be present at a revolution is like receiving manna from heaven. This moment of video-enhanced clarity provided Brady, in an instant, with his life’s work, with a whole new wide-open field of research where no other scientist had yet staked out territory.
It was like being the first prospector to find gold at Sutter’s Mill.
“There was so much excitement,” Brady remembered. “Then we started asking questions: How can we make use of this?”
The race was on among the young scientists in Woods Hole that summer to be the first to find out what the various molecules inside the squid axon were up to. Thrilled with the new technology, Brady set about trying to find how the larger molecules were pulled along the tracks in the axon.
Both Brady and a competing young researcher, Ron Vale, found a kind of “motor,” eventually called “kinesin,” that was responsible for moving packages up and down the axon. It turned out that kinesin was a kind of “slave” molecule that “walked” along one of the tracks, putting one foot in front of the other, pulling its loads behind it.
Eventually, after decades of research, researchers, including Joe DeGiorgis, had found many different kinds of hardworking kinesins in squid and other animals, including humans.
There are multiple motors in the same neuron. Humans may have nearly fifty different kinds.
I asked Joe why we need so many.
“We’re trying to figure that out,” he answered. “We don’t know yet what all these motors do. We know it’s a trafficking issue. We want to know that if there’s a problem with some of this transport, does that lead to neurological disease?”
So, inside the axon is a city that never sleeps.
Thanks to the squid, we understand this. But how does an axon die? What happens to brain cells when we develop diseases like Alzheimer’s or Parkinson’s? Brady and a number of colleagues across the country and around the world have devoted much of their research during the first decade of the twenty-first century to answering that question. And once again, they’ve used the squid axon in some of their research.
“Neurons have some very special challenges,”
Brady explained. “You have to remember that neurons are, many of them, extremely long. When you start stretching a cell over a meter [a meter is a bit more than three feet] or more, we’re talking about large as well as long. Especially when all the proteins needed all along the axon have to be packaged and transported to where they’re going.”
Recently, scientists have learned that the trackways inside the axon run in both directions. Packages put together in the cell body must sometimes travel all the way to the end of the axon. And materials at the far end of the axon sometimes must travel all the way back to the cell body. This two-way transport is mandatory. It’s also sometimes mandatory for the packages to be dropped off at points in between both ends. “These things are essential for the survival of the cell. It turns out that you have to have particular proteins at particular places all along the neuron,” Brady said.
So, Brady and others wondered, what makes the proteins inside the neurons start and stop? How do the kinesins “know” when to dump their loads and relax? How do they know when to keep on truckin’ just a little bit farther? One of the triggers, or switches, that flips the kinesins on and off turned out to be another molecule, called a “kinase.” It’s the kinase’s job to give kinesins their marching orders. Kinases are like the switchmen positioned along railroad tracks, managing traffic.
“What happens when the kinase doesn’t do its job?” I asked.
“You get a perfect storm,” Brady answered. “The axon starts dying back. And if the axon dies back far enough, then the whole neuron dies.”
In 2009, Brady and others published papers that tied at least part of the problem in patients suffering from various types of neurological diseases to the malfunction of the kinases in the neuron that give the kinesins their orders.
It reminded me of the story Yale’s Vincent Pieribone had told me about the different characters—“amazing little guys”—inside the axon. Using squid and other animals, scientists keep finding more and more such characters, all with their own individual, highly specialized jobs to do.
By studying kinases, the switchmen, Brady and his lab team believe they have discovered an important part of what happens in the human axon when Huntington’s disease debilitates a human body. Researchers have long known that the disease has a genetic, inherited basis. Because of this genetic problem, a long chain reaction or a cascade of errors occurs. The kinase does not do its job properly. Which means the kinesins do not keep on truckin’. The packages that need to be carried back and forth between the tip of the axon and the cell body do not get where they need to go in the correct quantities or in the correct time frames. Eventually, the very existence of the neuron itself becomes an issue.
Brady believes that there are a number of common neurological malfunctions that have their roots in the malfunction of the axon’s shuttle system, and that Alzheimer’s and Parkinson’s disease may be among them. He and his lab have even created a name for this group of illnesses: dysferopathy.
It took several decades and many, many scientists to decipher this puzzle, and the success of the endeavor stretches all the way back to J. Z. Young and the discovery of the giant axon in little Loligo pealei. It’s been nearly a century of scientists standing upon the shoulders of the generation that preceded them.
I asked Brady about that history, and about how odd it seemed to me that so much of our own brains have been revealed by studying an animal that’s so incredibly different from us.
“The squid was designed by Mother Nature for neuroscientists by making everything so big that it allows us to see things and have access to things that we just really can’t get to in an intact mammalian system,” he answered. “These kinds of experiments can only be done with squid. We share a surprisingly large number of features with the squid. The kinesin motors, for example. There are big chunks of our kinesin motors that are remarkably similar to those of the squid. We both have the same basic mechanisms. The choices [about how the neuron would develop] were made before we split [on the evolutionary tree], perhaps 700 million years ago. And we both took advantage of those choices to recreate the remarkable signaling that is the nervous system. So far, everything that we’ve identified in the squid, we’ve been able to confirm in the mammalian system.”
I asked him the question I asked everyone: If squid have such complex brains, are they smart?
“Squid are the jocks of the cephalopod world. They swim very fast. They’re designed for speed,” he said. “The octopus is the intellectual. They can solve problems and learn quite remarkable things.”
We may share many things with squid—a similar eye, a similar neuron, neurotransmitters like dopamine, perhaps even certain intellectual proclivities—but there is one biological area in which our styles decidedly differ: sex.
CHAPTER TEN
HEURE D’AMOUR
Amoebas at the start
Were not complex;
They tore themselves apart
And started Sex.
—ARTHUR GUITERMAN, POET
t wasn’t until live worms—long and white and writhing—emerged from the carcass of the two-years-dead Dosidicus gigas that shrieks of joyful terror filled the Newburyport High School dissecting lab.
“What’s this?” one student asked commercial-fisherman-turned-teacher Rob Yeomans. He was holding a white mass in his hands. It was about six months before Rob met me to go Dosidicus fishing on the West Coast, and he was helping his marine biology students dig into the innards of a carcass sent to him by Bill Gilly. I was up there, too, watching, along with several other adults.
When Rob heard the shrills, he turned to look. Already the things had managed to spread. At about three inches in length, they looked like short tapeworms. The lab table was covered with these squirrelly, hopping things that seemed to be able to stand up on their tips and cavort along the metallic surface, like weird animation creatures. One adult decided it was as though you’d been sitting at a bar and had one too many and the bartender’s cocktail straws started crawling toward you like inchworms and then stood up and danced. To me, they looked like huge, distorted jumping beans.
The unofficial consensus was that they were some kind of unidentified parasites that had stowed away in the squid and managed to survive two years in deep freeze. Then, like something from a B-movie horror flick, they’d reawakened on the other side of the American continent in this high school dissecting lab.
Before starting to carve up the carcass, Rob had carefully instructed the kids to put on latex gloves. Most complied. One boy, though, declined. He wasn’t worried. His dad was a scientist. He was experienced at this sort of thing. When the jumping started, he’d been holding a pile of the white things in his hands.
A student holding the mass of “worms”
Warmed by his palms, the mass came to life and began squirming in his hands. The boy’s face turned ashen. He put the mess down, headed over to the faucet, picked up the soap, and began scrubbing. Minutes later, he was still scrubbing. Whatever the things were, he didn’t want them burrowing into his skin. Which, in reality, is what they might have done if he’d held them long enough.
The kids could thank Rob’s intrepid curiosity for the presence of Dosidicus that day. Having seen several television programs about Humboldt squid that featured the work of Gilly’s lab, Rob had poked around on the Internet, found the lab’s Web site, and e-mailed, asking for a Humboldt carcass for his students to dissect. Rob became the first schoolteacher to take official advantage of Gilly’s Squids4Kids educational project. This dissection was the result of that request.
Yeomans helping to dissect in classroom
You wouldn’t think that a biology lab class would be The Main Event in a high school, but all day long kids not in Rob’s marine biology class had begged him to be allowed to attend. Their excitement was fueled by the long string of docudramas on a variety of cable stations about how dangerous and horrific Dosidicus is. Rob had had to adopt a very stern voice—“No! No, please!”
—to keep the class from being mobbed by party crashers. By the time the late afternoon class began, Rob had had to recruit his department head, a physics teacher, to guard the door.
The dissection started out smoothly enough. Several boys lifted the thawed carcass out of its container and put it on the lab table. Then a line of girls elbowed their way in to form a phalanx at the dissecting table. They looked like groupies in a mosh pit. There was no room in the front line for the boys, who stood behind and watched, arms folded across their chests.
The girls reveled in the yin and yang of their loathing and fascination. The frenzy mounted. Various bits and pieces of anatomy were pulled out—the stomach (it turned out there was a whole, not-quite-thawed, not-yet-digested fish inside), the heart, the gladius (a.k.a. the pen), the eyes, the ink sac (ink flowed out), and various bits and pieces of brains. One girl spent most of her time in a trancelike state picking the sharp little rings out of the squid’s suckers. She was deeply intent on trying to harvest as many of the toothed rings as possible. Later that day she went home and shocked her mother by saying she wanted to switch her career goal from baking to marine science.
After pulling the beak out and cleaning it off, the kids passed the thing around in triumph, like a war souvenir. Only a few students stood far to the back, squeamish. Rob didn’t force them to come up and participate, as long as they took good notes. It may have been the most intently focused high school lab dissecting class in the history of Newburyport High School.
But when the translucent white things began to shiver and quiver and crawl and jump, even Rob was taken aback.
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