by Rob Dunn
Therein is both the heart of the dilemma and the interesting story. Humans and some apes appear to have a more highly developed, larger, and more structurally elaborate appendix than do most other primates such as monkeys, which suggests that the appendix is likely more important to us than it was to our ancestors.4 The pattern is the opposite of what would be expected if our appendix were vestigial. What could this mean? It seems that the appendix, long seen as useless, does something for us, or at least it did in very recent history. It did so much, in fact, that it allowed those individuals with more distinct and developed appendices to live longer and have more children, who would pass along their genes for a more distinctive appendix. Somehow, we have been getting the story precisely backward. Looking at other primates led to the conclusion that our appendix must, in our recent evolutionary history, have had a value. But what?
For several hundred years, the question of what the appendix did or does hung around, awaiting the right scientist. No one in the world was actively working on the question. Like most questions, it was simply there to be talked about over lunch and then ignored. All across the world, surgeons have spent their entire lives removing appendices, removing so many that the surgery has come to seem mundane, like opening a can of soda or cutting the stem off a tomato. Most stopped wondering at all what the appendix does, not even pausing before they dropped it in the trash. No one had considered the possibility that it played a role in dealing with microbes, but they should have.
Back in the submarine, when Wheeler B. Lipes began to cut toward the intestines of his patient, he knew almost as much as anyone else about the appendix, which is to say very little at all. Knowing he was not the only one who was ignorant would have been little solace to them both. Sweat dripped from Lipes’s head and he asked someone to wipe it. A man’s body cavity was open below him. The surgery was exhausting. For twenty minutes Lipes searched inside Rector for an appendix, in vain. He “tried one side of the caecum,” and then he tried the other. He began to doubt himself.
Then, when all seemed lost, he “got it.” Rector’s appendix had “curled way into the blind gut.” Lipes removed it and put it in a jar, sponged Rector off and, with catgut thread, sewed him back together. Lest it be argued that in any part of the surgery Lipes had actually possessed the appropriate tools, he clipped the thread with fingernail clippers.
Whether Rector lived or died, his appendix was out in a jar for all to consider. Had Lipes taken a good look at the appendix, he would have noticed clues to what it does. He could have seen that the appendix was filled with lymphatic tissue, a sign that it bore some relationship to the immune system. He would have noticed that it was filled with bacteria, a dense carpet of diverse cells that were—like the bacteria on some ants’ backs—linked together in a kind of film. He might have also seen that, in the right light, the appendix looked like a kind of cave. Lipes did not notice any of those things, though. At that moment, he could not have cared less what Rector’s appendix had been meant to do. He had enough on his mind, which by then was addled with secondhand effects of the ether and adrenaline in which he and the other men had been steeped during the hours of the surgery. The appendix in its jar slid back and forth on its shelf as the submarine rocked in the waves. Rector too rocked in his cot, hoping that he had just been saved.
Over the next days, it became clear that Rector was going to survive. Lipes was his improbable hero. He was to be heralded for the rest of his life for his valor and creativeness. But the more recent story of his patient’s or any human’s (yours included) appendix features an equally unlikely character, a man who has seen plenty of appendices in jars and trash cans and, in seeing them there, noticed the clues. Randal Bollinger is an emeritus professor at Duke University in Durham, North Carolina. He claims to be retired. Send him an e-mail and his account responds that he won’t be coming back to the office until 2050.* By standard accounts of the history of science, he is past the prime of his best ideas and innovations. No spring chicken, as they say, nor even a late-summer rooster. But standard accounts have their limits. They tend to ignore the value of experience and observations. Yes, Picasso’s best work came out of the wild flame of his youth, but the talent of his friend Matisse was more like a wine, having taken decades to mature. Matisse painted many of his most influential paintings between the ages of seventy-one and eighty-five,5 and Bollinger, well, he kept working on and thinking about human bodies. They had long been the canvas for his dual arts of mending and discovery. He knew they still had and have a mystery or two left to resolve. One of those mysteries was the appendix.
Through the course of his career, Bollinger had seen thousands of appendices, in bodies, on tables, in jars. He knew the appendix was filled with three things—immune tissue, antibodies, and bacteria. It is the bacteria in the appendix that make its bursting so problematic. When an appendix bursts, the bacteria contained in the intestines and appendix spill into the body cavity and, in doing so, cause infection.
Many people noticed what Bollinger noticed, but most ignored it the way we all must ignore nearly all of what we see. Yet for Bollinger, his simple observations about the natural history of the appendix were about to seem useful. It took the clues he observed and an insight from his colleague Bill Parker at the Duke Medical Center to make the discovery. It was a routine lab meeting in 2005. Parker and Bollinger were talking with students and postdocs about their latest research. The function of the appendix had never been a topic of discussion during meetings, and this day started out as no exception. Parker remembers the lab bench he was sitting at, even which stool. Bollinger, in Parker’s telling, “just got this look like he had figured something out,” and suddenly said, as if to himself but quietly aloud, “I bet that is what the appendix does.” From there, seemingly apropos of nothing, the discussion expanded. The students looked on, excited but dumbstruck. Bollinger and Parker soon believed that they had, in a few minutes on a spring morning, resolved a several-hundred-year-old question. They had figured it out. The answer was suddenly obvious. The appendix, Bollinger and Parker had come to believe, was a house for bacteria. It had evolved to serve as a place where the bacteria could grow, removed from the wash and grind of the intestines themselves. It was a peaceful alley. From that alley, they thought, microbes might also be able to recolonize the gut after an intestinal disease had wiped it clean. Cholera, for example, causes such violent vomiting and diarrhea that much of the bacterial community of the human gut is expelled. For cholera, this effect appears adaptive. When cholera cells are expelled (typically into water supplies), they can then be transmitted to other humans, as predictably as if the water carrying them were a mosquito. Cholera triggers this response by producing a compound in excess that, while not actually toxic, tricks the body into responding as though massive quantities of toxins are present. Under such conditions, perhaps the appendix was a safe house.
At that moment there was little else in the world of which Bollinger and Parker were more sure. Perhaps the bodies of humans were, after all, nearly as sophisticated as those of ants. Now they had to decide what to do. They could try to publish their idea immediately, or they could give themselves some time to better test it. Reluctantly, they decided to wait and test. To do so they would need “to dig up some fresh human colons, with their appendices attached.” Although they did not know it at the time, that would take two long years.
The insight that Bollinger, Parker, and the rest of Parker’s lab came to that day could not have been made by any of them alone. It depended on their combined knowledge and experiences. It required Bollinger’s experiences looking at appendices. Just as importantly, it required a discovery that Parker had made nearly ten years before. Parker was studying antibodies and reading up on how antibodies respond to bacteria. While doing so, he had realized two things: that antibodies sometimes help rather than attack other species, and that the appendix was, for reasons unexplained, full of antibodies. Not only was it strange that this apparently useless
organ existed in the first place. It also seemed to be filled with antibodies that the body produces at great cost. Why this might be the case was ignored.
Antibodies are typically described as being part of the body’s defensive system, a kind of second line of defense once some other attacker makes it into our body and past, for example, the nose’s mucous. This is only part right, though. What antibodies really do is to discriminate our bodies’ cells and parts from those of other organisms. From the perspective of antibodies, the world is populated with two kinds of life, “us” and “them,” and sorting the two and then triggering the appropriate response is how they spend their lives.6 The antibody component of our immune system is old. Our immune system works like the system of a rat or a frog, because in the hundreds of millions of years since we last shared a common ancestor, it has worked well enough.
Parker started by reading up on what other biologists already knew about one particular kind of antibody, IgA, which is the most common antibody in the gut. In looking at IgA, he saw what other scientists saw when they turned to the literature. “The primary function of IgA antibodies is to find and identify bacteria in the gut” so that the other players in the immune system can send them packing down through the colon and out of the body. But something about this story did not make sense.
It should be said in advance that much of science is, at least in some detail, wrong. Fixing what is wrong is a big part of what keeps the hundreds of thousands of us who do science busy. The hope is that truth accumulates and mistakes are beaten back (sent down the colon so to speak), but sometimes it takes a while. Sometimes fiction masquerades as fact for generations, growing ever more difficult to see as it is printed in textbook after textbook and memorized by one young scientist after another.7 Finding these old errors and misconceptions is difficult. But if you can do it, whether through insight, patience, careful reading, good luck, or some combination thereof, it is like nothing so much as finding a door to a secret world right in the middle of Grand Central Station. One wants to stop to ask everyone else, “How did you not see this?”
As Parker looked at the old papers on IgA, he read what every other immunologist had read, but something seemed awkward. The parts were all there, but it was as if they had been put together wrong, the leg glued awkwardly high on the hip. Studies since the 1970s had noted that the bacteria the IgA attacked had a receptor, a kind of microscopic door for the IgA. When the IgA attacked those bacteria, they did so through that door. What, though, were the bacteria doing with a door for the very antibodies whose goal it was to attack and expel them from the body? It was as though the Chinese, after having built the Great Wall, had also left out a giant ladder. Why offer your enemy a door? Then, as Parker read on, he found something even stranger. A recent study had shown that in patients and mice that lack IgA, bacteria with receptors for IgA seem to disappear.
Parker is a medical researcher, studying the xenotransplantation of organs from one animal to another. His job is to find medical solutions, breakthroughs, and applications. Understanding IgA and related antibodies had started out for Parker as a means to an end. If he could temporarily block or change their action, he might get the human body to accept a monkey’s lung or a pig’s heart. (He envisioned, at some moments, the headline “Pig Lung Transplanted into Cleveland Man. . . .”) But in addition to being a medical researcher, Parker has an eye for radical new ideas. He loves them. They rise in him like joy. Now, just as he was supposed to be really buckling down to understand xenotransplantation, a radical new idea was rising in him about IgA. If he was right, whole chapters in textbooks were going to need to change.
So it was that in 1996 Bill Parker found himself sitting in his lab, thinking about what he knew about IgA. Many scientists have these moments when they mentally paw over the facts—like a jaguar with an armadillo—to try to sort out explanations of how things fit together. More often than not, the armadillo proves too difficult to open. It continues to walk around the lab, taunting the researchers, but every so often the jaguar finds a soft spot. Parker thought he had found a way in. He had an explanation that made all his disparate observations make sense. The answer had been there the entire time. It had not even required any new observation, at least not yet. It was a theory that, if right, would change everything we know about the most common antibody in our gut.
In 1996, the epiphany that Bill Parker had was that if his or any other body was, through the production of IgA, trying to get rid of or otherwise control these bacteria, it was doing a really bad job. If the bacteria were trying to avoid the IgA antibodies, they were similarly ineffective. The bacteria had not only left the door open but changed the lock so that it would better fit IgA’s key. In fact, it wasn’t just that the bacteria had a door, a receptor, for the IgA; the reverse was also true. IgA antibodies have sugars that bacteria recognize and respond to. What Parker thought was that everyone who had ever studied IgA in the gut had been wrong about its function. The IgA were actually helping bacteria! They were helping them, more specifically, to clump together and to set up shop in the gut without getting washed away.
The IgA antibodies, he imagined, help the bacteria by providing a kind of scaffolding with which they can link together to form biofilms, a sort of commune of unrelated microbial cells. Biofilms are common in nature. The bacteria that live on leaf-cutter ants form a biofilm. Bill Parker did not yet know about the leaf-cutter ants, but he did know about similar interactions in plants. Parker’s realization was that the bacteria in human guts were remarkably similar to those on plant roots. What if the human body, like plant roots, was producing compounds to help the bacteria adhere? What if IgA was, instead of fighting the bacteria, helping some of them stay put?
In order to test his idea, Parker needed to establish a system for studying IgA interactions with gut microbes in the lab. He began to grow gut cells on a kind of filmlike plastic and layered microbes on those cells. All around the lab were flasks of the awful-looking scum, in some cases primed with human feces. Sometimes a big discovery involves pushing a trail through to a new forest, where great marvels suddenly become apparent. Other times, though, it is a lab filled with bacteria from human poop. To all the world who cared to look, this scene seemed terrible, a little vulgar even—all the world, that is, except Parker, to whom the lab smelled like discovery, potent and yet somehow sweet.
In 1996 all Bill Parker had was an idea, but it seemed to be one with wheels. He needed to test this idea. Those tests would come, albeit slowly, over seven years. Eventually, Parker was able to show in the lab that when IgA was added to biofilms, they formed faster and grew thicker. Bacteria were nearly twice as likely to stick to human cells when IgA was present. When an enzyme was used to break down the IgA, the biofilms fell apart. Yet even when he thought he had the data to support his idea, for a while no one believed him. His wheels spun. No one funded his grants or printed his research papers on the topic. Eventually, in 2003, he was able to publish his paper. But would anyone notice? Or would it drift among the annals of obscure ideas about life? Parker could be both right and ignored.
Then, finally, in 2004, a breakthrough came. Jeffrey Gordon, a more senior scientist than Bill Parker, with millions of dollars in research support and nearly a dozen postdocs, wrote a conceptual paper that supported Parker’s idea.8 Gordon’s paper seems to have been the threshold, the necessary traction, and soon others who had been quiet had been given permission to believe. Almost as quickly as a tide climbs up under the roots of mangroves, Parker’s idea went from heresy to, if not dogma, credibility. IgA, it now seemed evident, performs the primary function of helping bacteria. In Parker’s lab study, the one that initially no one would publish, he found that gut bacteria grow fifteen times as fast when IgA is present than when it is absent. So not only did IgA allow bacteria to do better—it allowed it to do much better.
The transition Parker’s ideas were quietly ushering in was revolutionary. When Parker began his work, it was believed that
the function of the native immune system in our gut was primarily to attack bacteria. Case closed. Now Parker and a growing number of other scientists argued the exact opposite. Our IgA antibodies, in knocking on bacteria’s doors, do not attack them. They help them by providing substrates necessary for them to link to each other and form the commune of bacteria called a biofilm. Such biofilms, Parker and Bollinger have gone on to show, appear to line much of the lower gut, particularly the colon and the appendix. They look, in cross section, like a rug of rod-shaped forms, side by side, tiny soldiers, shoulder to shoulder.9 These biofilms are often thought of as “bad” in a medical context. They grow along the insides of tubes and on equipment. But in our guts, they might not be bad. In our guts they may be good, even necessary. We will return to the question of “good for what,” but first, Bill Parker was not quite done thinking.
It was with Parker’s idea (by now, fully a discovery) in mind that Randal Bollinger offered his hypothesis about what the appendix does. If the immune system was helping bacteria in the gut, and if the appendix was where immune tissue and antibodies were most concentrated (and where cells were sloughing less rapidly, making it a kind of slow pool, rather than a river), it seemed the appendix might be helping bacteria disproportionately. The appendix is a small incubator, removed as it is from the fast flow of the intestines (and the potential from infection by passing pathogens), a Zen garden of microbial life.
