by Rob Dunn
The question of how much and what the microbes in our guts do for us is nearly as old as the study of microbes. Although Pasteur would become a strong advocate for killing the living creatures in our milk (hence pasteurization) and other foods, he believed that the creatures that live in and on our bodies are so necessary that without them, we would die. They evolved, he thought, to depend on us and us on them. Kill the microbes, he said, and you kill the man. In other words, he thought that the microbes in our guts are our obligate mutualist partners, where “obligate” means they are necessary and “mutualist” simply means that they and we both benefit from the relationship. The germ theory of disease, on the other hand, was based on the opposite idea—that some or perhaps even most of the species on us are more likely to do harm than good. No one had ever done the necessary test to see who was right, and yet clearly the answer mattered. In a world in which we continue to scrub off many (though almost never all) of our microbes, the answer matters now more than it ever has. What really happens when you use antibiotic wipes on your hands?
It is worth being reminded here that this question is similar to the one that John Byers asked about the pronghorn: What happens when you take away the predators? It is the same question that Weinstock would come to ask about the worms: What happens when you take them away? It is the same question repeated with different life-forms, by different scientists, as they look at each of the many parts of our bodies.
Born in 1909, James Reyniers, “Art” to his friends, was an ordinary young man—the good Catholic son of a machine-shop worker. He was ordinary until, that is, he became interested, beyond reason, in Pasteur’s question. He wanted to know if it was possible to scrub all of the bacteria off a rat or maybe a guinea pig. The idea that every animal in the world was covered in microbes, but that no one seemed to know if they were good, bad, or otherwise irked Reyniers.6 Rephrased, the question was whether or not the species that live in and on us in great abundance are mutualists (that both benefit from and benefit us), commensals (that benefit from us, but don’t otherwise affect us), or pathogens (that benefit from us at our expense). There must be, he came to believe, a yes or no answer, white or black, mutualist or pathogen. No shades of gray were necessary; either the microbes helped or they did not, and if they did not, they could and should be removed. If they did not, then dosing the gut with antibiotics would be good and just. It would be progress, just as the invention of agriculture, the removal of worms, or the taming of the cow seemed to be.
To Reyniers, the problem was a mechanical one. His challenge was to divide humans from germs in the way you might separate gold from sand. He dreamed of germless rats and, with them, grandeur. By 1928 he was convinced he could figure out how to make a germ-free animal. Everyone before Reyniers who had tried to do the same had done so by scrubbing the germs off, one way or another—a kind of Mr. Clean approach.7 It is the approach each of us uses on our bodies every day and that, in learning that you have trillions of microbial cells on your body (a hundredfold more than your human cells), you might feel compelled to try. Those attempts had failed in the same way they fail you when you scrub. Removing “nearly all” the microbes from an animal is a very different thing from removing them all. From even a single overlooked or persistent cell, billions can rise.
Reyniers, though, was a machinist by training and family tradition, not a biologist, and so he chose a different route. He decided to try to use metal, plastic, rubber, and industrial tools to separate animal from germ. The iron lung had just been invented, as had the first robot. What if, Reyniers thought, he used the same sorts of technologies to construct a microbe-free world, and then allowed mothers to give birth inside that world? Noah put the animals two by two onto the ark. Reyniers thought he could pull them back apart.
If Reyniers could accomplish his goal, he might prove to be the first person in history to produce an animal devoid of germs—bacteria, archaea, protists, fungi, and even viruses. Such an animal would be fascinating and modern. It would also be useful. It would allow scientists to add microbes back, one by one, to understand their effects in ways that had never before been possible. At the time, many hundreds, perhaps thousands, of experiments on guinea pigs, rats, mice, and even chickens had been done in which those animals were given pathogens (such was and is the laboratory industrial complex). But the animals given such pathogens already had on and in their bodies unknowable slurries of other microbes, with unknowable effects. Reyniers thought that he could change what we know about how our own bodies work and in the process usher in a new way of studying disease.
It soon became clear that Reyniers planned to do more than just make the first germ-free animal. He wanted to make thousands of them, hundreds of thousands even. Even before he had ever touched a laboratory guinea pig or a rat, he imagined an entire biological realm populated with animals free of germs. It would be a kind of zoo of germless life. When he proposed the project to the faculty and administrators at his home institution of the University of Notre Dame, he argued that it would take fifty years to accomplish, fifty years not just to make the first germ-free animals but to produce them en masse and to study them over generations. Such was his dream, a dream that seems all the more improbable once one learns that he was not yet a full professor. He was not even an assistant professor, a postdoctoral fellow, or a graduate student. He was a nineteen-year-old undergraduate student, a thin boy in man’s clothes.
I am not sure what I would say if an undergraduate student asked me for permission to use a big room and thousands of pounds of metal to do a fifty-year-long experiment in which he was going to remove germs from guinea pigs, rats, chickens, and monkeys. None of the responses that first comes to mind includes the words “yes” or “OK.” (The phrase “When guinea pigs fly” does, on the other hand, come to mind.) Reyniers, though, was apparently far from ordinary, enough so that when he asked for a room in Notre Dame’s Science Hall, metal, and a blowtorch, a dean in the university administration said, “yes.” Maybe the dean had not been paying attention; maybe he thought Reyniers was a professor. However those first days played out, they were the beginning. So it was that a boy began what was arguably the most ambitious project in the history of microbiology.
Reyniers’s plan was to try to deliver babies by C-section, guinea pigs to start with, without allowing them to come in contact with any germs, including those on his hands, in his mouth, and even in his breath. Reyniers knew that unborn animals, be they human or otherwise, are free of microbes. He thought he might be able to maintain this status, rather than the alternative of trying to kill the microbes once they were established. The animals would then be allowed to live, mate, and die in a world without microbes. Reyniers began what he saw as his life’s work aware that if things went according to his most optimistic expectations, he would be at it until the age of sixty-nine.
Using skills he had learned in his father’s machine shop, alongside his two brothers, both of whom would become machinists,8 Reyniers started in on metal structures, great chambers into which he installed gloves for reaching in and doing surgeries. He built many of these chambers, sometimes with his family’s help, but often alone. They were half-submarine, half-hospital room. Day or night, when one walked past his small room, he might be seen, welding torch in hand. He was like a sculptor or a visionary artist. He stood back from what he was making every so often to admire his work. “Look at that curve, that smooth airtight seal!” He must have had doubts, but if so they have gone unrecorded. Things failed more often than they worked, often for years. Reyniers was, at least on average, undismayed. Sometimes he even slept beside his creations—a small man next to big metal spheres, each one resembling an Earth.
Some parts of Reyniers’s plan were easy to implement. Early on, he found he was able to more or less sterilize the outsides of the mother animals, for example. The mothers would be shaved and plucked (germs love fur, a reality to which we will return), dipped in antiseptic fluid, and then covered in an ant
ibiotic-treated envelope. That much was easy. Anybody could do it, though I suppose it is an uncommon urge. Harder was what Reyniers proposed to do next. He wanted to take the envelope-cloaked mother and transfer her into a metal cylinder where her babies would be delivered by C-section. Making the cylinder in such a way that it would be devoid of bacteria was nearly impossible. The gloves had to be sealed completely airtight, which took fiddling. The gaskets leaked. Then the air inside the chamber needed to be sterilized too. Finally, there was the question of which animal to use. Reyniers tried to use cats, but they scratched through the gloves, breaking the seal of the cylinder and Reyniers’s skin, but not his resolve. He was in too deep to go back.
History records only bits and pieces of Reyniers’s emotional well-being while all of this was going on. It is easy to imagine that, as he tried to do what he had long planned, he would have become depressed. By the age of twenty, he had not yet produced a single functional chamber. By twenty-six, he had chambers, but had not yet produced a single germ-free animal—though hardly for lack of effort. Many guinea pigs died. Cats died. Mice died. Rats died. Even chickens died. They died because the surgery was difficult and tedious (among other difficulties, in the early years it had to be done through thick rubber gloves), and because at each stage in the process some individuals had to be checked, to make sure they were germ-free. The whole ordeal was exhausting for the animals and for the surgeons/machinists/biologists alike. The odds of failure of any particular attempt were simply far greater than those of success. In these circumstances, I would have gone mad, but Reyniers kept on, and in 1935, at the age of twenty-seven, he succeeded. Based on the successful “production” of a cohort of germ-free guinea pigs, he went public. He did not even bother to write a paper. He just made an announcement to Time magazine,9 and so it was noted that on June 10, 1935, James Arthur Reyniers produced the first germ-free animals in the world. Now the question was whether these germless babies would die.
Reyniers had been working on the project so long that he had, in the process, finished his undergraduate degree and, without a PhD, been hired as a professor.10 In that time, one would be forgiven for imagining that he had forgotten about the question he wanted to answer when it all began. He had not. The first thing he did when everything was finally working was to compare the guinea pigs in the chambers to those outside. If Pasteur were right, the guinea pigs inside the chambers would die. The microbes in their guts and on their bodies would be so vital a part of them that, in their absence, life would fail.
But the germless guinea pigs did not die, not once he had their diet right. In fact, they seemed hungrier and more active than did those on the outside with microbes. Success! As time passed, the animals in the chambers seemed to live longer too, and they never developed tooth decay.11 To Reyniers they were a model of what was possible, even for humans. An article in the magazine Popular Science in 1960 highlighted the chambers as a futuristic world in miniature, in which animals are no longer susceptible to the whimsy of germs. The matter was, it seemed, settled unequivocally.12 Mention was made of sending germ-free humans to space, and, if not germ-free humans, germ-free monkeys. The idea that we might make our own living spaces like those of Reyniers’s guinea pigs’ was so obvious to anyone reading, so implicitly a part of the story, that it barely required mention. Here in these chambers was the future, not just of science, but also of our lives. It was not biodiversity, not the ark of life two by two into the future, but instead the opposite, just us. Reyniers had not only achieved the first set of his goals; he had inspired the imagination of the masses, inspired them to believe that we all might live like his guinea pigs, germ-free and nearly forever.
With time, the scope of Reyniers’s work continued to expand, unabated. Notre Dame gave him bigger and bigger spaces in which to work, and then it gave him an institute. He and his father patented a series of germ-free chambers that are still in use, and perhaps most significantly, his approach spread around the world and, with it his animals. Today there are hundreds of thousands if not millions of germ-free animals alive at any time in the world, in thousands of chambers. The chambers have become more sophisticated (they now look more like bubbles and less like submarines), but the basics are the same. They are the descendants of Reyniers’s chambers and so are simultaneously nautical and monstrous.
Reyniers was fabulously successful in carrying out what he envisioned at the age of nineteen, thanks both to his own vision and to the capable (and by their own rights visionary) people he hired to work around him, individuals like Philip Trexler, who would go on to make far smaller, cheaper, and easier-to-use chambers than Reyniers’s submarines. Reyniers would not live to the age of sixty-nine to see fifty years’ worth of his project, but it did not matter. He had succeeded. His germ-free animals would save millions of lives by allowing the study of diseases in isolation from other factors. However, they also had the broader effect of leading biologists all over the world to the conclusion that the microbes in our guts are, on balance, bad. But Reyniers had overlooked something. His oversight was irrelevant (or largely so anyway) for the use of germ-free animals to study diseases. In the end, that was and continues to be their great value. But the mistake mattered when it came to Pasteur’s question of what happens when you remove microbes from a guinea pig or, for that matter, a man.
In the context of Pasteur’s question—a question germane to any of our bodies of what our microbes do and what we are to do with them—the flaws were not in Reyniers’s experiments so much as in his interpretation of his results. Reyniers was a machinist. He was trained in hammers and metal, not flesh and cells. He had no background in evolution, ecology, or any of the fields that would have given his work context. To the extent to which his skills expanded with time, they expanded into management and fund-raising, not the particulars of life. We can forgive him, in this context, for not paying attention to the nuances of his results, ignoring a dead guinea pig or cat here and there. The trouble was that biologists came to see the world of germ-free animals through Reyniers’s lens. Reyniers spoke often and with the weight of his institute and accomplishments. His voice came to dominate the field to such an extent that his interpretation became repeated as truth. Each new talk or study added punctuation until one could almost hear it, a drumming chorus of “Kill the germs!” “Kill the germs!” and we would be free of our past. Kill the germs and we would be healthier and happier, just like the guinea pigs in their giant metal worlds.
On the basis of Reyniers’s work and other work like it, we came to believe that all microbes were bad and so we continued cleaning ourselves, to make our lives more like the lives in those guinea pig chambers. If Reyniers’s original experiment was planned for fifty years, the societal experiment, in which we were the guinea pigs, took even less time to get under way. We went from using no antibiotics on our bodies to using thousands of tons of them in just a few decades. The antibiotics were no bubble. They never killed—or kill—all of the microbes, but we imagined they did. The guinea pigs and rats inside the chambers lived longer, and we wanted that too, to be like them. We wanted to step into the chambers of the future, where we were completely removed from the plagues of our past. Such was our confidence in our germ-free future that several children were even raised germ-free (and bereft of physical interactions with other humans) for a while. They were children who lacked immune systems and so, otherwise, stood no chance of survival. We cleaned them of microbes so that they might live at all. We did so on the hope, the assumption even, that such a germ-free life was what we were all headed for. The bubble was, if not necessary, inevitable, a future into which these children would step first. So it seemed.
Reyniers knew of some of the problems with his experiment, vexing realities of life’s evolving persistence. It turned out that some viruses are passed from mother to offspring directly and so are impossible to remove consistently. Some life-forms are even embedded in the mother’s DNA. In other words, the guinea pigs, mice, and chicken
s were germ-free, except for those germs of which they were not free.* In the strict sense, there are still no totally germ-free animals, with the possible exception of one strain of rats. More to the point, some elements of the microbial DNA passed from one generation to the next are necessary. Without the microbial DNA in our mitochondria, each and every one of us would die. Our mitochondria are the descendants of ancient bacteria, descendants that live in and help to power each of our cells. At the very least, in this regard, Pasteur was right.
Then there was the issue that even the animals that seemed germ-free did not always stay that way. Every so often a germ of one sort or another would sneak into the chambers. A single bacterial or mold cell was enough to contaminate the chambers. There were and are a thousand ways for such a cell to sneak in, and once in to divide and conquer. Nature loves a vacuum. Microbes love a vacuum-sealed guinea pig chamber. In some cases, perhaps most, the animals did worse when the germs sneaked in. But every so often a germ would arrive and the health of the animals would improve. These differences were interesting, but they also served as a constant reminder that with improvements in technology there might also come improvements in the ability of microbes, whether good or bad, to get in. At one point, Reyniers lost ten years of his research when a bacterial pathogen made its way into his chambers and killed all of his animals (at which point he remarked to a journalist that he, like most people, did not have many whole decades to lose). It was such sneaky germs that ultimately killed the bubble boy, the most famous of the children brought into germ-free chambers. The bubble boy had been transferred antiseptically into a chamber at birth because he lacked an immune system. Inside his chamber, he was raised by doctors until the age of twelve. At twelve, he wanted out. At twelve, something needed to change and so he was given a bone marrow transplant in an attempt to restore his immune system. The operation went well, and hope held out that this would be a case of the triumph of ego and medicine over disease. But then the boy grew sick. His mother’s bone marrow contained a virus, which quickly killed the boy. The persistence of pathogens nearly everywhere, be they viruses, bacteria, or something larger, should have, on its own, ruled out the idea that we might achieve some germ-free utopia for ourselves. We could build bigger and bigger chambers (or larger and larger houses filled with more and more antibiotics), but the larger the world from which we wanted to exclude microbes became, the harder it became to exclude them. What is worse, although the species that sneaked into Reyniers’s chambers were sometimes innocuous, the species that sneak past the barriers we attempt to erect with antibiotic wipes, antibiotic sprays, and the like almost never are. Sneaky germs, though, were not the only problem.
