by Rob Dunn
Then, very clearly, Debora got worse. New symptoms turned up: arthritis and swollen ankles along with the old symptoms.1 Then she got better, much better. For a while she was in total remission. She was, amazingly, no longer, for those days, a Crohn’s patient. Then things got worse again. Ultimately, she was reinoculated with worms. It seems that after each inoculation, she feels better for a few months, and then symptoms return, creeping back, perhaps as her worms die. As of June 2010, she was preparing to go back again, to get more worms. She goes on living like this, day to day, rewilding her body and while not yet cured, better. That is all she had asked.
We want medicine to be sophisticated and effective and informed by knowledge. In the old days, both the Egyptians and the Incans augured holes in people’s skulls to heal them.2 Sometimes it worked. In other instances, the patient died with a drill stuck in his head. All surgeons have good days and bad days, but ideally we want to know what distinguishes the two, and to err in the direction of the former. Debora Wade’s story makes clear that, as often as not, what we know about treatments is that they work—sometimes. We still view our bodies like machines, in need of a little hammering here, some welding there, and the occasional drop of some chemicals to clean us out. They are not machines. They are organisms that evolved in the context of other wild species, organisms full of particulars, organisms that, despite several centuries of medical science, remain fundamentally full of mystery. We need more information, but in particular we need more information about the evolutionary and ecological conditions that have led to a problem in the first place.
Our prevailing form of treatment for difficult illnesses like Crohn’s is to use medicines that treat the symptoms—but this is, at best, a thumb in the levee. Consequently, when it comes to the question of whether or not one should get treated with worms when one has Crohn’s or diabetes or something else, we are still in the Wild West. We know so little that the medical community can’t really provide a good answer. The worms, it is clear, are not a simple panacea. The worms don’t seem to work for everyone. Jasper Lawrence estimated that about two thirds of his treatments are successful, though with imperfect follow-up (some patients simply go home and disappear), it is hard to know. Debora Wade thinks that 70 percent or so of the patients she has talked to seem to have improved. There are, among those patients, miracle stories. Two multiple sclerosis patients have been in total remission for two years. Many of the allergy and asthma sufferers seem to be healed. On the other hand, other individuals, some with the same diseases, have had less success. Patients with ulcerative colitis seem to have had little luck with the treatment. Debora Wade is in contact with several of the Crohn’s patients. Three of the patients, like Debora, initially felt much better, but after six months the effect had worn off, perhaps because the worms died. Reinoculation seems to help.
Debora Wade, though she has had more ambiguous results than many who have been treated, still swears by her worms. She goes on reinfecting herself. Most days she feels better. She now has new symptoms, the cause of which she can’t discern, but the same thing would have been true had she tried the new pill or injection or whatever chemical was about to come next. Meanwhile, she and others wait for more research. As Debora told me, “It is all very new and we have no idea what we are doing, if more is better,” no idea what the required frequency of reinfection is, or anything else. Other research is ongoing, though from Debora’s perspective, too slowly. The Nottingham study in which she first thought to enroll has finished. They have not yet published their results.
Dr. David Pritchard, the biologist in charge of that study, is moving forward with trepidation. The fact that so many people are being treated before the treatment is well understood is worrisome to Pritchard. Yet so few people work on the effects of helminths or other parasites and diseases on the immune system, particularly in a clinical setting, that patients who take matters into their own hands might also be doing what is reasonable. Outside of Lawrence’s treatments and the experiments in Nottingham, there is ongoing research in Edinburgh and London, work by Weinstock in the United States and a new project in Australia. There are two more sites in Mexico where worm treatments are being done, at Ovamed and Wormtherapy, the latter run by Garin Aglietti, one of Jasper Lawrence’s former collaborators who broke ranks.
In a way, Dr. Pritchard in Nottingham is undoubtedly right: What is happening south of the border, in Mexico, is wild. What Jasper Lawrence is doing is unproven but is not an experiment in the scientific sense. In other words, there is no control, no real monitoring of results, and no comparison to what happens to patients that go untreated.
So if you have Crohn’s, what should you do? If you have allergies or diabetes or inflammatory bowel syndrome or MS and are desperate for a healthier life, is there hope? It seems clear that parasites and these diseases are related, but it is less clear how they are related. It seems we need, somehow, to get back to some version of the old days, but the old days are gone, and we need to come up with a new way of restoring elements of what once was. We need, in a way, to domesticate our worms, to make their effects more predictable and their consequences more controlled. For now, for those who are suffering versions of the diseases related to the loss of worms, diseases that are recalcitrant to standard treatments, there are few choices. What would I do in that situation? I would probably travel barefoot to one of those regions where worms are the norm, but I would choose carefully. Or maybe I’m lucky; I’ve traveled enough and walked barefoot enough, so that I might already have some. There are no perfect options. These are the dirty realities of our situation, where we remain bound to our history in webs so complicated that we can’t quite untangle them, not yet anyway.
The lesson that the worms clearly offer, though, is that the old medical model, in which we just scrub the rest of life off our bodies, is wrong. Major systems of our bodies, including our immune system, evolved to work best when other species lived on us. We are not simply hosts to other species; we live lives intimately linked to them, and even the boundaries between the simplest categories of “us” and “them” and “good” and “bad” are blurry to the tools we have so far. And the worms are just the beginning. On our bodies are thousands of species, a kind of living wonderland. There are more bacterial cells on you right now than there ever were bison on the Great Plains, more microbial cells, in fact, than human cells. It is to the question of those cells, each one of them tiny but perhaps consequential, and their relationship to our well-being, that we turn now. No human is an island, not even when she is free of worms.
Part III
What Your Appendix Does and How It Has Changed
5
Several Things the Gut Knows and the Brain Ignores
Once we learn how to kill something, we tend to do so. We enjoy the hunt. With stone-tipped spears, we stabbed at mastodons. We chased saber-toothed tigers, dire wolves, and the American cheetahs that once ate pronghorn. There was a rush in the pursuit. With guns, we did the same job even more exhaustively, until eventually we moved on to smaller prey such as the passenger pigeon, animals that we would sometimes eat, but more often not. The urge to hunt can be greater than our needs. After the invention of pesticides, we sprayed millions of acres for smaller quarry. We even sprayed our bodies. DDT was rubbed lovingly into the hair of hundreds of thousands of children. Once we learned to harness compounds that would kill microbes, we filled ourselves with these concoctions. As much as we might love landscape paintings and fleeting glimpses of wildlife, nothing seems more natural to our brains than getting rid of nature.
Each of the technologies we have used against other species is a kind of anti-biotic (literally, “against life”)—though seldom does a technology actually kill all of the life we are after. Instead, each tends to favor some over others, the strong or weedy over the weak and slow growing. When we stoned, speared, or shot big predators, smaller predators did better.1 We used DDT to kill the pests on our crops and in our homes, and favored the
resistant and insidious. We sprayed our crops and yards to kill the weeds and left the super-weeds to grow up between our rows of corn and out of the cracks in our cement. All around us we find these species, like dandelions and ragweed, species that blossom out of hardship and persistence, growing toward the sun even as they shake the asphalt from their leaves.
If the pronghorn is an experiment on the effects of removing a predator from its prey, we are the broader experiment. We are a case study in the effects of removing not only predators but also snakes, intestinal worms, and even microbes, to see what happens and who remains. The extent of this experiment is greatest at its most intimate, in and on our bodies. We have removed our worms, but more recently we have also begun to remove, or try to remove, our bacteria and other single-celled life-forms, this time with antimicrobial agents. These agents are what we most often think of when we say “antibiotic,” the compounds originally produced by fungi like bread mold and discovered by Alexander Fleming, the haphazard visionary of life. It would be fair to wonder which species they kill and which they favor. After all, you have probably used antibiotics. Even if you have not intentionally used them, you have ingested them. They are in our food and drinks. They are used on crops, in cows, pigs, and other domestic animals both to treat bacterial diseases and to prevent their occurring in the first place. Antibiotics are nearly everywhere. More than 200,000 tons of antibiotics are consumed annually,2 with more consumed both per person and overall each year. Scrub. Wash your hands. Scrub again. Kill what grows before it spreads and then kill it again. This is what we long have done, what our ancestors did, and, without vision or change, what we will do in the future. It is what comes naturally.
We began using antibiotics because we needed them, desperately. Their discovery yielded a trio of Nobel Prizes and cured our gonorrhea, tuberculosis, and syphilis in the process.3 Penicillin was the most effective life-saving drug in the history of the world, rivaled only by other antibiotics. But the use of antibiotics for the treatment of deadly diseases now represents a tiny proportion of all uses—most are for sniffles, earaches, or even preemptive attempts to ward off microbial evil. (“Doctor, I’m feeling a little funny. I think I might be getting, well, I don’t know, something that needs antibiotics . . .”) or so the story, again and again, goes. We turn easily to pills or spoonfuls of amoxicillin, ampicillin, good ole penicillin and all the rest. We turn to them as we once turned to our guns, in self-defense. The question is not whether our antibiotics, in the most general use of the term, have helped us, but instead, when we pull the trigger, how well we are able to aim.
For most of the long history of antibiotics, no one studied the details of how they affected the bacteria in our guts. The approach of medical research is often to see what helps us first and then, only secondarily, to understand how and why it works. It was known that antibiotics kill pathogens such as syphilis (we know that because when patients are given the antibiotic, the syphilis goes away). But what actually happened to the other microbes in and on us when the syphilis was dying was never studied. The appropriate technology did not exist. And, more to the point, for the medical research community the goal was curing diseases. Many diseases were bacterial in origin and so all bacteria came to be considered bad (an idea perpetuated by James Reyniers, the bubble rat king, to whom we will return). They were as bad as the leopards and wolves that once ate our animals and children or as the pests that consumed our crops and sustenance. “Kill them all now and ask questions later” was the medical solution. At least initially, this approach seemed reasonable.
I understand our urge to go a little rogue when we first invent a new tool, particularly when it is in the interest of survival. When some kind of life is discovered to be both controllable and at the root of some ill, we control it. Yet at the same time, when we learn to distinguish the riff from the raff, the deadly from the innocuous or even beneficial, we also ought to try to kill with nuance. The problem in our guts is that until very recently we could not distinguish riff from raff, nor did we even know which species our weapons—in this case antibiotics—were killing. Or perhaps I should say that our brains could not make these distinctions, because it would turn out that our guts (and in particular our appendices) knew what was going on the whole time. They just couldn’t say anything.
The reasons for our ignorance of the goings on inside our bodies are straightforward. Our guts may be as unknown as tropical forest canopies, but they lack in both scenic beauty and romance. If you work in the rainforest, people you bump into at dinner parties will mention their plans to someday travel to Brazil or Costa Rica. Work in the colon and people will mention, at best, their lunch. At worst, well, you can imagine. . . . But it is not just that the gut is unsexy. It is also difficult. The species that live in the rainforest canopy can be taken back to the lab or the field station to be observed, poked, and prodded. We can see what they eat and even watch how they behave. Not so for the gut microbes, most of which are both invisible and unculturable. More than a thousand species of microbes have been found in human guts. A thousand more may live on your other parts. Most of them we cannot grow at all, except where we find them. We know too little about them to get them to live in the lab. They are alive and in us, yet inscrutably difficult to see or understand.
In the last decade, a little of this changed. With innovations in genetics, we gained a set of new tools for seeing, a kind of “geneoscope,” every bit as powerful and revolutionary as a telescope, though to see the worlds within us rather than around us. This set of tools made it possible to examine the RNA (kin to DNA and intermediary, in your cells, between DNA and protein) found in a sample as a measure of which species are present. One can take a scoop of rainwater and using this approach identify the life in it, or take a sample of feces and at least indirectly look at the slew of genes present and what they tell us about who abounds. Now that microbes can be identified based on their RNA, we do not have to culture them to know whether they are present (though it is still helpful). Such genetic techniques are becoming easy and cheap, so much so that a young student or technician might hope to use them to answer a question of relevance to all of humanity as Amy Croswell, working with her mentor, Nita Salzman, and three other colleagues recently did.
Croswell was a technician in the lab of Salzman, a microbiologist and immunologist in the Department of Pediatrics at the Medical College of Wisconsin. Together, Croswell and Salzman planned the first study of what happens to microbes in our guts when we apply antibiotics. The two and their research group took ordinary lab mice with guts full of wiggling microbes. They then gave some of those mice, and not others, antibiotics. The mice treated with antibiotics received one of a variety of possible cocktails of drugs. The “high antibiotic” mice received a dose of four antibiotics in line with what was “known” by other scientists to kill all the bacteria in the gut. The “low dose” antibiotics mice received a single antibiotic, similar to what your child might receive for an ear infection.4 The whole project was simple and small relative to the scale of the problem, a mouse-sized gem.
Much of what Salzman and Croswell did was relatively easy. Mice are experimented upon in labs all over the world. Generations of breeding and tinkering have led to cages and protocols that are, if not always elegant, perfectly functional. The mice that Salzman and Croswell would study were the descendants of a mouse family that had been in the lab for tens of generations. It was, in many ways, their native environment, one more like our modern human environment, in some ways, than the environment of their (or our) ancestors. They were born via C-section in the lab, raised on formula, and then, at the age of five weeks, treated with their appointed antibiotics.
Let us pause for a second to consider the possible results of their experiment. Perhaps our collective intuition is that those mice that had been treated with antibiotics would have fewer “bad” bacteria and the same or even more “good” bacteria than they had started with. In the context of human medicine, that is what
our hope has long been. What did you think was happening when you took antibiotics? It is always easiest to assume someone else knows the answer, but in this case no one did. At the opposite extreme, other biologists working on mice thought that the antibiotic cocktail that Croswell and Salzman applied should kill all of the microbes. Croswell and Salzman added the antibiotics to the water and waited. After a few days, the scientists then took tiny stool samples from each mouse and, as though to add insult to injury, killed them, sampled them exhaustively, and then whisked them away to a large plastic bin at one end of the lab.
When they looked at the samples from the mice, as expected they found that the individuals that had been given clean water with no antibiotics had a full complement of microbes. Their guts were, like yours, gooey with life, grams of life. The mice that had been treated with antibiotics, however, were another story. The antibiotic-treated mice, mice that by analogy to our own medical system were the medicated, healthy ones, had microbes in their intestines (that is an important result in and of itself), but far fewer, particularly in their large intestines and colons. The effect was greatest for the mice treated with all four antibiotics, but present even in the mice treated with just one antibiotic, streptomycin. In essence, the antibiotics were capable of wiping out billions of cells from those treated animals’ guts. While the different antibiotics tended to kill slightly different microbes, none simply killed “the bad bacteria.”5 Many different kinds of bacteria were affected. Since mouse guts are like human guts, this means that when you or I use antibiotics, the same thing is happening to us. When we kill our microbes with antibiotics, we are leaving behind the relatively few weedy species from which a new microscopic empire of life rebuilds. Nobody knew, but now that we do, it seems even more important to understand what it is that those microbes—the ones that we mostly (though not totally) wipe out every time we take antibiotics—really do. The answer involves a young man, a giant steel bubble, and a mistake.