January 2, 2012
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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.
Bill Parker. Note the slight smirk indicating an idea might be brewing.
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.
Cholera cases by region. The size of a region shows the proportion of all cholera cases found in that region in 2004 (or in some cases slightly earlier, where data were not available).
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.
Pseudomyrmex spinicola ants feeding on Beltian bodies produced by an Acacia tree. In exchange for this food, the ants defend, sometimes ferociously other times a little more lackadaisically (we all have our days), their host tree, much as, Parker imagines, the bacteria in the appendix defend their host from species like the Cholera pathogen, Vibrio cholerae.
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.
Acute Appendicitis.
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.
8-There is a hint of Parker’s direction here, if you are curious; I am a rat and so are you and also in a great recent blog post by Robin (the wise) Smith.
Image credits:
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.
About the Author: Rob Dunn is a science writer and biologist in the Department of Biology at North Carolina State University. His first book, Every Living Thing, told the stories of the sometimes obsessive, occasionally mad, and always determined, biologists who have sought to discover the limits of the living world. His new book, The Wild Life of Our Bodies, explores how changes in our interactions with other species, be they the bacteria on our skin, forehead mites or tigers, have affected our health and well being. Rob lives in Raleigh, North Carolina with his wife, two children, and lots of microbes. Follow on Twitter @RobRDunn.
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Almost 20 years ago a doctor took my appendix out although there was nothing wrong with it. (“I was in there anyway; and you don’t need it.”) I thought she was wrong then and I haven’t changed my mind.
Link to thisThe basic reasoning that the appendix could harbor beneficial bacteria even after some agent killed that bacteria in the rest of the GI tract doesn’t seem to hold water: if the beneficial bacteria could penetrate the appendix, what prevents some toxic agent from also penetrating the appendix and effecting any bacteria within?
Link to thisjtdwyer – I agree with the point about antibiotics penetrating (or not as in this case) the appendix but also, what stops the ‘bad’ bacteria colonizing this organ in the first place? Is it simply that they hold a lot of ‘good’ bacteria?
Link to thisjtdwyer, the usual way – at least before antibiotics – our guts lose bacteria is through diarrhea. The offending agent doesn’t kill the bacteria directly, our body reacts to the toxin and “throw the baby with the bath water”, expelling both the invaders and the good bacteria .The apendix, not being part of the intestinal tract, is not affected by diarrhea, so the bacteria there would be safe to survive and re-colonize the colon (no pun intended). On top of that, the abundant IgA in the appendix induces the bacteria to produce biofilm, which increases their resistence.
Link to thisGreat article!
What do the bacteria in the appendix live on? I would have thought that gut bacteria are more or less specialized in breaking down our food, which (as far as I know) doesn’t get into the appendix. Or does it?
Link to thisExcellent article.
Revolutionary inroads are being made daily concerning the human – microbe symbiosis. Microbe symbiont cells make up ten times more of the cell composition of our bodies than human cells do, and microbial genes make up 99% of the genes in our bodies.
http://powertoxins.blogspot.com/2011/08/hypothesis-microbes-generate-toxins-of.html
Link to thispablo.emanuel: Very good point – I agree.
However, as you suggest, in the case where antibiotics or perhaps other toxic disease agents that kill the good bacteria, the question about how good bacteria would survive unaffected in the appendix still seems valid…
Link to thisA comment for Rob Dunn, I really like your ability to put the maybe back where it is supposed to be, not as some kind of problem with science, but essential to the whole process, from beginning to end.
Link to thisThis is an interesting, perhaps important article. dunn’s quirky revelatory style is maddeningly, and needlessly opaque. Why drag us through a clever labrith? Perhaps others find it entertaining.
Link to thisAnother maybe not mentioned: maybe the same people vulnerable to recurring c diff. are vulnerable to appendicitis. It would be interesting to see a follow-up study comparing the incidence of appendicitis & appendectomies in patients who had previously had c. diff. reinfections to patients who did not have it recur, and to the general population.
My gut tells me the appendix does do what Parker says it does, though. (And I could swear I’d read about this idea some years before the dates on the reference papers, including something about it being known that it does in fact serve that function in gorillas. In fact, I recall having read about it at some point before having my own appendix out in 2000.)
Link to thisI had acute appendicitis 13 years ago and had the appendix removed in an emergency surgery. I’m now plagued by recurrent diverticulitis. Who knows if these two things are connected, but I find this research fascinating.
Link to thisInteresting. I’d love to see a study conducted that compares incidences of stomach ulcer/stomach cancer between those who’ve had the appendix removed vs those who still have it. Surelt this can be done retroactively and on an ongoing basis. There is much evidence to suggest stomach ulcers and cancers may be initiated by bad bacteria, so I would have thought this could be a relavent study.
Link to thisMy family doctor in a small South Texas town in the 40s dropped by the house to check on stomach pains from which I was suffering. He diagnosed them as an inflamed appendix, but took a conservative wait and see approach. I’m 71 and still have my dangling digit. I have a very healthy gut and almost never have intestinal tract infections. I eat all kinds of contraindicated nasties including raw meat and fish and was one of the few that didn’t come down with mild salmonella poisoning after eating some suspect alfalfa spouts at an office party several decades ago. Dr. Johnston, apparently I owe you.
Link to thisI find this really interesting and plausible.
Over the past year our family has used the GAPS diet with the goal of improving our gut health & flora balance. One of the premises in the book about the GAPS diet is that our gut flora is established at birth, and will always tend to return to its original state.
The theory goes that some people have a more beneficial natural balance of gut flora than others, dependent on what they were exposed to in the womb and as infants. The idea that a part of the body serves as a reserve for the flora of our guts is appealing. I’m interested to see more research on this point.
Before doing this diet, my son and I had both landed in the hospital with suspected appendix problems a few times. My son actually was about to be sent for surgery, but then his “attack” subsided and he was able to recover. I’ve been afraid of something like this recurring, so I’m especially interested to see research being done!
If you are interested in our story and the GAPS diet (and find links to how to do it and how to make the foods), you can read about it at http://theliberatedkitchenpdx.com/meet-the-liberators/our-story/
-Joy
Link to thisThe appendix is a finger like pouch attached to the large intestine and located in the lower right area of the abdomen appendix pain is not something to take lightly. If you experience rebound Appendix pain when you press your abdomen in your lower right quadrant, you may suffer an infection of the appendix pain,Location of the appendix in the digestive system. Pain first, vomiting next and fever last has been described as the classic presentation of acute appendicitis.
Link to thisAs Robb Dunn states in his article, c diff is of increasing concern to doctors. It can be fatal if repeated antibiotics do not remove it and it is becoming more resistant to antibiotics. Fortunately, there seems to be a simple and inexpensive cure. It is known as ‘fecal transplant’. Rather than give a potted story, I refer you to the December 2011 issue of Sci Am (page 19, The Science of Health – “Swapping Germs”). Information is also available in Wikipedia where scientific references are provided.
Link to thisvery important article, it explains how appendicitis can be deadly, and how one can be managed with. using antibiotics damage our cells can be still be elaboratedDrupal Performance
Link to thisDoctors need to weigh the need to carry around 10 or more pounds of biomass as a backup in case of cholera or other infection. My appendix was maybe 30 pounds when removed, and I couldn’t trim my stomach. Vain as that may sound, I wasn’t willing to look perpetually pregnant (or perhaps impregnated with some alien lifeform is a more apt description) just to play it safe, that is, if I believed in this theory. Huge appendices (from disease or too many hotel guests using it as a permanent resort) lead of distended guts, I’ve observed, and in our social order that’s not cool. Don’t get me wrong, I’m not knocking the theory, just saying.
Link to thisLike many others here, I’m intrigued by this idea in part for the light it may shed on personal experience. About twenty years ago, I became violently but sporadically ill while traveling in Thailand (symptoms would disappear and erupt anew every three days or so). I eventually had an appendectomy in Singapore, but the surgeon there was surprised to find that my appendix was only moderately inflamed. It was only when I returned to the States, still sick, that a salmonella infection was finally diagnosed, and I later heard from a doctor friend that it and other *noxious* bacteria sometimes made the appendix their refuge, thereby eluding detection and treatment. It’s not clear to me from the article whether this possibility is precluded by or coincident with Parker’s hypothesis.
Link to thisThis is interesting, but the gut is not the only place that bacteria and biofilms occur. Every surface exposed to the external environment is colonized with bacteria, and commensal bacteria are the first line of defense against infection of those surfaces with pathogens.
I focus on autotrophic ammonia oxidizing bacteria, which the Belly Button Project was able to identify on my skin.
http://books.google.com/books?id=a3mwmXzpsjkC&lpg=PP1&pg=PA103#v=onepage&q&f=false
My hypothesis is that non-thermal sweating, by releasing ammonia to a biofilm of ammonia oxidizing bacteria can help to regulate the basal NO/NOx/RSNO status of an organism. Lose the biofilm and you lose that regulation.
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