January 2, 2012 | 31
Your appendix may save your life…that is, if you have one. If you don’t, well, I will get to that. First I want to tell you about a guy I know, Bill Parker
Bill Parker grew up in Arkansas and is, by my precise calculation, fifty percent pure backwoods Arkansan and fifty percent intellectual wild man. Throw a little seminary training on top and you have a decent measure of the guy—complicated, interested, clever and unbounded. You are as likely to encounter him out on the streets of Durham trying to catch a rat as you are in his lab at the Duke University School of Medicine. He is one of a kind. If you want to keep an eye on someone who is likely to come up with an idea that will change things, I’d keep an eye on Bill Parker. He is also, for the record, the guy to keep an eye on if you want to know how to catch a rat.
In the last five years, Parker, who is a professor of surgery, has published important papers on how proteins fold1, details of the challenges of getting a lung from a pig into a person2, and the function of the most common antibody in our guts (IgA)3. His interests and ideas are unusually catholic. They include the question of what the appendix does.
You may have heard the appendix is vestigial, a relict of our past like the hind leg bones of a whale. Parker heard that too, he just disagrees. Parker thinks the appendix serves as a nature reserve for beneficial bacteria in our guts. When we get a severe gut infection such as cholera (which happened often during much of our history and happens often in many regions even today), the beneficial bacteria in our gut are depleted. The appendix allows them to be restored. In essence, Parker sees the appendix as a sanctuary for our tiny mutualist friends, a place where there is always room at the inn4. If he is right, the appendix nurtures beneficial bacteria even as our conscious brains and cultures tell us to kill, kill, kill them with wipes and pills.
Parker’s hypothesis is a fundamentally new idea about how an organ in our bodies – let me repeat that, an organ in our bodies – works. It is an idea Parker developed on the basis of sitting and thinking. At least initially, he did not have new data, experiments or models. The idea just came to him one day when he was on a stool in his lab with his buddy and collaborator Randall Bollinger. For all these reasons, I wrote about his idea at length in my book, The Wild Life of Our Bodies. I was not sure at the time whether Parker was right, but I knew that he and his ideas were interesting. No one else, for the record, had any better ideas.
At the time I wrote The Wild Life of Our Bodies, Parker and his colleague Randall Bollinger had offered up the mutualist-appendix hypothesis to the world but no one had tested any of its predictions. No one had criticized it. In some ways, no one except an excitable science writer here and there had taken enough notice to respond. There are more details — a bit of drama and a few other characters—but, until recently, no more resolution. Then, in December of 2011, a new study published in the journal Clinical Gastroenterology and Hepatology reported to have tested Parker’s idea head on. When I heard about the study, I will admit to feeling a little nervous, perhaps on Parker’s behalf, but also because I liked his idea.
In my mind, whether or not Parker’s idea held up to this new study, it was still an elegant idea, an idea that tied the human body to trees producing food for ants that protect them, fruits for animals that disperse them, and root chemicals that attract the fungi that help them find food. But the idea needed to be tested. It was plausible, given what we know and yet maybe it is just too radical this late in the story of the study of the human body to posit a totally new explanation for an organ’s existence.
Parker’s idea, his hypothesis, predicts individuals with their appendix should be more likely to recover from severe gut infections than those without. To test this prediction, one could compare the fate of individuals with and without their appendixes after being experimentally infected with a gut pathogen. Easier said than done. Not even college students will voluntarily sign up for a dose of cholera, and lab rats, those time honored guinea pigs5 who never object to being poked, do not have an appendix.
There was one way forward… Scientists could compare the fates of individuals who suffer gut infections and have an appendix to those of individuals who suffer the same gut infections and do not have an appendix. They could, in other words, take advantage of the natural, albeit terrible, experiment created by the spread of human disease. The trouble was such a study would be easiest in developing countries where Cholera and other similar diseases are prevalent, but those are the same regions where medical records (of appendectomies, for example) tend to be the worst.
James Grendell, chief of the division of Gastroenterology, Hepatology and Nutrition, at Winthrop University-Hospital, solved the problem, along with his colleagues6. They studied a pathogen, Clostridium difficile, common even in places with good medical systems, even, it so happened, at Winthrop University-Hospital. Clostridium difficile, or “C. diff.” as it is known among the hip medical in crowd, is a deadly pathogen often encountered in hospitals, particularly when patients must be treated by prolonged courses of antibiotics. C. diff. does not appear to compete well with the native biota of patients’ guts, but when the native biota is depleted (as is the case after several courses of antibiotics) C. diff. can grow quickly and take over. It is the hare to the good bacteria’s tortoise, a weed in the plowed field. C. diff is most dangerous when, after treatment, it recurs, which is to say when the native fauna of the gut and immune system cannot, together, prevent it from reinvading. If Parker’s idea is right, individuals without an appendix should be more likely to have a recurrence of C. diff than those individuals with an appendix.
James Grendell and his team were able to find 254 patients at Winthrop-University Hospital who met the requirements of their study. Each needed to be older than 18 with evidence of having been infected by C. difficile. The team then focused on the subset of patients for whom the presence/absence of an appendix was known or discernible. The rest was easy. They compared whether individuals without their appendix were at a higher risk of recurrence from C. diff and whether the risk of recurrence varied as a function of whether patients were younger or older than sixty (it was thought to).
Even if the study found no effect of an appendix on C. diff recurrence, it would not necessarily reject Parker’s idea completely. Maybe James Grendell and collaborators failed to consider enough samples. Maybe the effect of an appendix is more subtle than the study was able to consider, i.e. it affects the extent of recurrence and not its presence or absence. Or maybe C. diff is just different from the pathogens such as cholera that (may have) shaped the evolution of our guts.
When Grendell looked at the results, two things became clear. First, patients older than sixty were more likely to have recurrences of C. diff, independent of any other factors. Maybe gut bacterial communities age too and make older guts easier to colonize. Maybe something else. And then, second, the big result…. Individuals without an appendix were four times more likely to have a recurrence of Clostridium difficile, exactly as Parker’s hypothesis predicted. Recurrence in individuals with their appendix intact occurred in 11% of cases. Recurrence in individuals without their appendix occurred in 48% of cases.
Grendell’s results do not prove Parker is right. Science does not work that way. More tests, even true experiments, need to be done. Maybe there was something else that differed between individuals with and without their appendixes. Maybe the result only applies to the mostly white population Winthrop hospital serves. Maybe the immune system plays a more important or different role than Parker envisions. These “maybes” are part of what make science beautiful — the idea that each question, each test, and each day, lead to more questions. Every good question is a road that goes on forever, diverging and bounding forward, sometimes quickly, other times more slowly, as new paths emerge and some of the old ones run straight into brick walls.
Where does this leave us? In your body is an organ that appears to be/may be/could be helping out the bacteria in your life so they can, in turn, help keep you alive. If you do not have your appendix anymore, you may be at an increased risk of recurrence and even death when confronted with a pathogen like C. diff., cholera or any of a wild kingdom of other pathogens. This possibility raises the question of what to do if your appendix (or your child’s appendix) becomes inflamed. First things first, you should seek medical attention. As for what the treatment should be, while appendicitis can be deadly, recent studies suggest some, but not the majority, of cases of appendicitis can be resolved using antibiotics, though the topic is an active area of research and little is known about the prognosis for individuals treated with antibiotics for appendicitis later in life7. Might there, some day, be solutions other than surgery and antibiotics, solutions that aim at restoring the sanctuary of the appendix? Maybe. Until then, doctors keep cutting infected appendixes out. When they do, when they hold them up, they hold up a symbol — a somewhat gross, pinky-finger-sized symbol –both of our complex relationship with other species and of how little we know.
As for Bill Parker, he continues down his road. You can read more about his story in The Wild Life of Our Bodies, but only up to a point, because, like all stories, Parker’s has moved on. He has gone back to catching wild rats. With the approval of Duke University, he has even built a special house for them. He has a new idea, a big idea, an idea he doesn’t want me to share with the public just yet. I will give a hint though. The idea requires him to catch more wild rats. He thinks they hold secrets lost on domestic rats and humans,8 secrets that might help to explain autism, asthma and, knowing Bill, a fair bit more. And so he hammers on the cage and when everyone else goes to sleep he puts out dog food to bait his traps that they might yield his quarry, whether that is the rats or just more of the ideas that flash like lightning across the grasslands of his fertile mind.
1-Chen E, Everett ML, Holzknecht ZE, Holzknecht RA, Lin SS, Bowles DE, Parker W. Short-lived alpha-helical intermediates in the folding of beta-sheet proteins. Biochemistry. 2010 Jul 6;49(26):5609-19.
2-Gaca JG, Lesher A, Aksoy O, Gonzalez-Stawinski GV, Platt JL, Lawson JH, Parker W, Davis RD. Disseminated intravascular coagulation in association with pig-to-primate pulmonary xenotransplantation. Transplantation. 2002 Jun 15;73(11):1717-23
3-Bollinger RR, Everett ML, Wahl SD, Lee YH, Orndorff PE, Parker W. Secretory IgA and mucin-mediated biofilm formation by environmental strains of Escherichia coli: role of type 1 pili. Mol Immunol. 2006 Feb;43(4):378-87
4-Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol. 2007 Dec 21;249(4):826-31.
5-Or is it the guinea pigs that are time-honored lab rats?
6-Im GY, Modayil RJ, Lin CT, et al. The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol and Hepatol 2011; 9:1072–1077.
7-For example, see… C Vons, C Barry and S Maitre, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet, 377 (2011), pp. 1573–1579.
1. Photo by Duke Medicine.
2. Map from WorldMapper (http://www.worldmapper.org/display.php?selected=231)
3. One of many amazing, amazing, Alex Wild images. This and other images of the relationship between Pseudomyrmex ants and Acacia trees can be found here: http://www.alexanderwild.com/Ants/Taxonomic-List-of-Ant-Genera/Pseudomyrmex/8709998_bQRJk8/3/575648446_WG23w#575653353_cfNBf
4. Ed Uthman, MD, at Wikimedia Commons and Flickr.