Journalist and author Maryn McKenna talks about fecal transplants, which have proved to be exceptionally effective at restoring a healthy intestinal microbiome and curing C. diff infections, yet remain in regulatory limbo
Podcast Transcription
Steve: Welcome to the Scientific American podcast Science Talk posted on January 31st, 2012. I am Steve Mirsky. On this episode...
McKenna: …They take feces, stool, from someone with a healthy gut and they infuse it into the gut of someone whose microbiome has been disrupted.
Steve: That's journalist and author Maryn McKenna, and she is talking about one of the hottest topics in medicine, the fecal transplant. Maryn and I talked recently about a variety of subjects for almost an hour. I will roll out the other topics in a second episode but here in part 1 we talk almost exclusively about fecal transplants. So grab a milkshake and enjoy.
Steve: Maryn McKenna, fecal transplants—they're inherently fascinating. I mean the name itself. Tell us about them, you have an article in the December issue of Scientific American, still available on our Web site. What's the deal?
McKenna: So, let me tell you first about that article because I am very excited about it. It's the inaugural installment in the reboot of a column in Scientific American called the Science of Health. I am going to be writing this column along with Deborah Franklin, another long-time science and medical journalist. We're going to alternate pretty much and this fecal transplants piece is the first article in the reboot. So fecal transplants—what are they?. Fecal transplants are based on the understanding that all of us carry around in our gut, in our intestines, a complex community of bacteria that are actually larger in aggregate than the rest of us. There are actually more bacterial cells in our intestines than there are cells that belong to us in the rest of our bodies. And most of the time that incredibly complex community works in a really interesting harmony to do all sorts of things for us: to extract nutrients from our food, to tune up our immune systems, to keep our reactions to things in our environment, from revving out of control the way that allergies do, for instance. But every once in a while, that community gets completely out of whack and that happens, for instance, when we take antibiotics. Now I am really interested in antibiotics and antibiotic resistance and that's, kind of, how I got led into this topic. The way this usually happens is that people become, they get an infection, they take antibiotics. Because antibiotics, in a broad spectrum way, often kill lots of different bacteria, they disrupt the bacteria in our intestines, this microbiome as it's come to be called. And then another bacterium, a pathogenic bacteria that's really vicious called Clostridium difficile, or most people just call C. diff, takes over. C. diff is not only really, really persistent, it's really stubborn. If you get an attack of C. diff, even if you take another set of antibiotics to cure it, the chances are about one in five that you'll have a recurrence. Once you've had one recurrence, you're very likely to have others. So, people get into this to descending spiral where that bacterial community within their bodies gets more and more disrupted. They can't digest food properly. They're permanently afflicted by diarrhea. Their lives are just destroyed. They pretty much can't leave the house. So, someone had the idea to take a step back from this endless spiral of treatment, and say, "What would happen if instead of just treating this problem, we tried to replace that unhealthy community of bacteria with a healthy community of bacteria?" And that's what fecal transplants are, really. I mean in their most basic, they take feces, stool, from someone with a healthy gut, and they infuse it in to the gut of someone whose microbiome has been disrupted. That healthy community of bacteria takes over and grows into the sort of ecological niche that's been disrupted and restores intestinal health. The cure rate with fecal transplants is somewhere north of 90 percent. It's astonishing. It's something…
Steve: Which is, like, better than aspirin for headaches.
McKenna: It's better than any drug we have. And yet what's so interesting about it is that it works, just unquestionably works in a clinical sense—there is case series after case series that now shows this; a couple of dozen case series—but it doesn't work in a regulatory sense. It hasn't been approved by the FDA and because it hasn't been approved by the FDA, NIH can't figure out a way to fund further research, because feces are not any of the things that the FDA licenses. They're not a device, they're not a drug, they're not what we call a tissue, really—they're not something like a replacement joint or replacement tendon or the replacement lens of an eye. So they're caught in this kind of regulatory no man's land. The effect of that is that only a few, kind of, brave physicians or physicians whose institutions are pretty relaxed or not too concerned about approvals are going forward with this. So something that's really inexpensive, really safe and really, really effective is only available to people based, kind of, on the inclinations of physicians randomly across the country, and not widely and broadly the way it really should be.
Steve: In your article you point out, I think it's the Journal of Gastroenterology in 2010, came out and said, this treatment works. This should be the treatment of choice, actually, rather than a last resort.
McKenna: Absolutely, in fact there's a guy who is one of the lead authors on a number of those papers that I described. He's one of the longest standing practitioners of this in the U.S.
Steve: Is this Brandt, right?
McKenna: Correct, Lawrence Brandt from here in New York City.
Steve: Of the Albert Einstein College of Medicine up in the Bronx.
McKenna: Right and Montefiore Medical Center. He has pointed out that what happens at this point is that people usually get a fecal transplant as a, kind of, last resort after they've had one or a number of those recurrences that I described; and they've been confined to their house for a year and their nutrition is just, you know, completely disrupted. He is saying, "Look, at the moment, we only do this when we are about to take people's colons out, but we know that it works and we know that it's safe and we know that's cheap, so why don't we do it first thing?" And that is both a really radical proposal, and yet at the same time when you step back and look at it, a really, kind of, obvious and sensible thing to be saying. So, the fact is that though the regulatory authorities and the federal authorities are kind of still not really sure what to do about this, not just individual physicians but really the specialty as a whole of gastroenterology is moving in this direction of saying this is something that we should do. The fascinating thing to me is that if you go back in the medical literature, back into like the 1950s, this is something that people used to do all the time. Now they didn't know at that time they were treating Clostridium difficile because that bacterium wasn't actually identified until the 1970s, I think. But I vividly remember when I was in high school I read a book that my parents had on the shelf call The Making of a Surgeon. It was a narrative of what it was like to do residency at Bellevue here, the public hospital here in New York City, in the 1950s. And in The Making of a Surgeon, there's an account of a patient who was incredibly afflicted with what at that time they called antibiotic-associated diarrhea. And the interns actually sneak a dose of feces into essentially a milk shake for this poor patient, give it to him without telling him what's in it and he's cured. So, they were doing, effectively, fecal transplants back in the 1950s, just no one was admitting to it at that time, and they didn't really know what they were treating. Now the funny thing is, is that 60 years later, we're still sort of, we know what the bacterium is, we know what's going on in the gut microbiome, but we haven't really moved much further along the treatment and we haven't moved much further along with, kind of, official acceptance of it.
Steve: We should point out that the conventional mode of delivery of the transplant today…
McKenna: Is not a milk shake.
Steve: It's not milkshake; it's not oral.
McKenna: Well, in some cases; this is actually practiced much more in Europe and especially in Australia than it is in the Untied States. Australia in particular is just streets ahead of everybody else with it. In the European and the Australian literature it's fairly common to see it delivered by a nasogastric tube, so a thin tube that is sent in through the nose and kind of goes up and then down the esophagus and down through the stomach and into the intestinal tract. However that's still is not, you're not having to drink it, it's not actually going you know over your tongue and through your teeth. But in the United States what most often happens is that a fecal transplant is delivered effectively like a colonoscopy. Whoever is your donor, the person who has agreed to give feces to you as the substance of your, transplant takes a mild laxative, delivers the substance of the transplant; the gastroenterologist takes it, dilutes it usually with saline, strains it and then fills up a bunch of big wide syringes that are good for swirling liquid—not the kind of syringe that would give you a flu shot or something like that but something much more wide bore— and then the person who is going to receive it does the, kind of, prep with a more intensive laxative that you do if you're going to have a colonoscopy; and then they just do it in an endoscopy suite in a hospital. And what that means is that a very flexible tube is being put in from the other end and snaked all the way over to, sort of, the far end of your large intestine effectively going around three sides of a square essentially. The reason that they've always done that is because they figured, that way it's, they're putting the transplant, the liquid, far enough back in the intestinal tract that you're not just going to lose it out again right away. But an interesting thing about that is that, so this does cost money, largely because you have to pay for the doctor's time, and you have to use the endoscopy suite. So there's another really interesting gastroenterologist who has essentially proposed that people can do this at home by themselves. And he lays out a recipe in his article that's pretty much, you know, one blender that you shouldn't use for anything else; one bottle of saline that you could buy out of a drug store and one, just, enema kit. And you mix it up yourself —you find your own donor—you mix it up in the blender, you fill the enema kit, you give yourself an enema. Now the thing about an enema is it only goes to the very near end of the intestinal tract, you know, just very close to the outside of the body. It turns out that that works too. You don't actually have to use that long snaking lit tube that requires you to have had some degree of anesthesia and to be using a suite within a hospital. You can actually do this at home. He also got an almost 90 percent cure rate.
Steve: In the article I think, at that point anyway, he was seven for seven.
McKenna: Right, it was a very small sample. And the thing is none of these case series are very big. But now at this point, we're starting to see, sort of, meta-analyses of the case series. Now I am being careful in saying "case series" because the issue at the moment, because of the sort of lack of official recognition of this, is that no one has been able to do a randomized clinical trial, which would be the gold standard, which would get the more conservative hospitals to accept this and also probably get insurance companies as well to start pain for it. The reason there's been no randomized clinical trial is that NIH can't figure out a way to fund it because the FDA can't figure out a way to confer what would be called investigational status, investigational drug status effectively, on feces, because as I said they're not a drug. And until they fix that going round and round about what do we call this, until we call it something we can't fund something, we can't approve it, we can't fund it, we will still be in the same situation.
Steve: I realized this does not solve the regulatory issue but it seems to me from a marketing point of view, this is a terrible name. Why not call it a microbiome transplant? It makes it sound more hi-tech and who knows what a microbiome is out there?
McKenna: So the funny thing is that this same procedure has actually been used in veterinary medicine for a very long time. They particularly use it for thoroughbred horses. And now thoroughbred horses don't get Clostridium difficile so I haven't actually done enough research to know what it is that they're treating in horses, but in veterinary medicine it's called transfaunation. And so we could call it that maybe, or we could call it a microbiome transplant. I have to say that the thing that people are secretly worried about is not just that people are going to come up with a more hi-tech name for it but that because we're caught in this sort of regulatory stasis with what to call stool or feces and how to license it for use, is that in the meantime some clever pharma company is going to figure out essentially an artificial stool. They're going to figure out what it is in a microbiome that are the essential components of that bacterial community. They're going to figure out a way to deliver it that doesn't involve actually using the freshly delivered feces of someone, and they will really be able to charge hundreds or thousands of dollars for it instead of having it be essentially cheap, available and free.
Steve: Most of which would really be just a solution to what you call the ick factor.
McKenna: Right, exactly.
Steve: It's icky, it's disgusting. But you know, this is just an editorial comment by me. People got to get over this ick business. I mean, surgery is icky. Surgery is, I mean, people take a knife and cut you open; it's disgusting.
McKenna: So, the thing that, I actually said that to one of the people I spoke to for this article, and what was particularly interesting to me is that so few gastroenterologists are actually doing this. Because let's face it, gastroenterologists deal with the intestines. They should have gotten over their ick factor, because they're dealing with poop all the time. And when I said this to one of these physicians she said well, "You know truthfully, it's actually the nurses that are dealing with the poop."
Steve: Right. As it always is. I am also, I think about maggot therapy.
McKenna: Right.
Steve: Which, there was a case, I believe it was on Boston Legal, the TV show, where maggot therapy, a doctor who did maggot therapy was found guilty of malpractice based solely on the ick factor; when the patient discovered, woke up and discovered, what was going on, she was so grossed out that she wound up suing. And basically the whole legal case was decided on the fact that everybody thought it was disgusting. Forget about the fact that it works great for certain things.
McKenna: Maggots are fantastic. They actually, I know I sound incredibly creepy when I say that, they only eat necrotic tissue and they keep wounds really clean. Another, sort of, similar case of the ick factor is leeches. We think of leeches as being incredibly medieval, but in fact, leeches have kind of come back into high tech medicine because they're perfect for the aftermath of microsurgery. When, you know, somebody lops of a couple of their fingers with a saw or something like that and it can be reattached, blood pools in the ends of those reattached digits because they can only reattach blood vessels down to a certain, sort of, bore and that, you know, a certain sort of width; and the very find blood vessels don't get reattached. They will eventually regrow, but in the meantime, blood kind of pools in the ends of those reattached digits. Leeches are fantastic at extracting that and they also, they secrete a kind of anticoagulant, so they keep blood flowing and they keep things from pooling and turning gangrenous. They have become so popular for microsurgery that there are now actually companies that grow, effectively, you know, sterile leeches for use in that kind of surgery. It's one of the strangest sorts of byways of modern surgical medicine that we have sterile leeches being farmed.
Steve: It's true, but they're the best tool for the job. Any institution that does really high-tech microsurgery is going to have leeches on the premises.
McKenna: But if you said that to a, sort of, average member of the public, who wasn't aware of that, you would hear that same ick factor response. It's fascinating.
Steve: Anyway, so we'll change the name to microbiome transplants and hopefully we will get somebody at the FDA, or I am not sure how the regulatory process works but, to understand that, you know, this is a great treatment do something so that this treatment can get used and help people.
McKenna: So, it's important to say that among the folks who have been pushing this the hardest, among the physicians who have been pushing this the hardest in the United States, a bunch of them have actually banded together to, kind of, push this forward. The first thing they did was they wrote a set of guidelines for other physicians who want to try it. And it was published by the clinical journal of one of the gastroenterology societies. So that's both a degree of official recognition, and it's also a recognition, I think, by the entire specialty that people out there are trying this and they need to know how best to try it. The second thing that the same group of physicians did is that they have actually started to work on a proposal to the FDA to effectively confer investigational status on this procedure, and I believe they have actually now sent in their first draft. So, we will see where it goes.
Steve: More from Maryn McKenna in part 2 of our conversation coming up soon. In the meantime get your science news at www.ScientificAmerican.com, where in a related subject, you can check out the video on how new nanocoatings will keep your cell phones dry if—or more likely when—you drop it in the toilet. And follow us on Twitter. You'll get a tweet every time a new item hits our Web site. Our Twitter name is @sciam. For Scientific American's Science Talk, I am Steve Mirsky. Thanks for clicking on us.
Web sites related to this episode include www.marynmckenna.com, Swapping Germs: Should Fecal Transplants Become Routine for Debilitating Diarrhea?
A laboratory-made slurry of healthy bacteria could replace human fecal matter in stool transplants to treat bacterial infections. Gretchen Cuda Kroen reports
When normal populations of healthy bacteria in the gut get out of whack, the result can be the stubborn and recurrent bacterial infection known as Clostridium difficile – C-dif. The main symptom is nearly constant and debilitating diarrhea.
One of the most successful therapies for C-dif is to repopulate the intestines with healthy bacteria that keep that nasty C-dif in check. There’s been only one way to do this: import a small sample of a healthy person’s feces. That’s right. A poop-transplant.
But the “ick” factor of fecal transplants is a hurdle for some, as well as a regulatory conundrum for the FDA. Which is why researchers at the University of Guelph in Canada came up with a synthetic alternative: a laboratory-made slurry of healthy bacteria they’re calling “rePOOPulate.” The research is published in the journal Microbiome. [Elaine O. Petrof et al., Stool substitute transplant therapy for the eradication of Clostridium difficile infection: "RePOOPulating" the gut]
It’s intended to replace human fecal matter in stool transplants, and researchers say it has several advantages. The bacteria are carefully controlled and can be tailored to the patient. It reduces the risk of transmitting disease. And, well, it’s just less gross.
Elaine Petrof i Gregory Gloor z Kingston General Hospital w Ontario zareagowali na zastrzeżenia natury etycznej i proceduralnej, jakie wysuwa się pod adresem przeszczepów fekalnych. Skoro nie da się przeprowadzić randomizowanych badań, procedurę trzeba wdrożyć w ciągu kilku godzin od pobrania materiału, niekiedy trudno znaleźć właściwego dawcę, a w dodatku istnieje ryzyko wprowadzenia do organizmu pacjenta nie tylko korzystnych, ale i chorobotwórczych bakterii, czemu by nie sporządzić gotowej mieszanki do zaimplantowania?
Kując żelazo póki gorące, naukowcy sporządzili koktajl gatunków bakterii ze zdrowego przewodu pokarmowego. Co ważne, wg tego przepisu można sporządzać kolejne porcje o identycznym składzie.
W naszym szpitalu mieliśmy wiele przypadków nawracających zakażeń Clostridium difficile. Pacjenci ci przechodzili terapię fekalną i choć była skuteczna, postrzegaliśmy ją jako dość prymitywną i surową. Stąd pomysł, by ulepszyć metodę, zachowując naukową ideę, która leżała u jej podstaw.
Substytut zdrowej flory jelitowej uzyskano dzięki pewnej 41-latce. Naukowcy wyizolowali od niej 62 gatunki bakterii. Eliminując wszystkie z najsłabszymi nawet oznakami antybiotykooporności, zachowali 33-elementowy zestaw. Petrof i Gloor odtworzyli proporcje, w jakich organizmy te występują w naszym przewodzie pokarmowym. Powstały w ten sposób koktajl można podawać w formie lewatywy.
Dotąd akademicy przetestowali swoją procedurę na dwóch siedemdziesięciokilkuletnich kobietach. Jedna była hospitalizowana przez C. difficile aż przez 1,5 roku, a gdy podano jej substytut fekaliów, prawidłowa perystaltyka jelit powróciła po 10 dniach (bakterie zostały wyeliminowane). Druga pacjentka walczyła z 3. rzutem zakażenia; w jej przypadku powrót do zdrowia nastąpił jeszcze szybciej, bo po zaledwie 3 dniach.
Badania Kanadyjczyków miały na razie pilotażowy charakter. By prawidłowo ocenić skuteczność niby-odchodów, należy zebrać większą próbę i wylosować pacjentów do grup z różnymi procedurami terapeutycznymi. Mając to na uwadze, Petrof i Gloor planują dłuższe studium na zwierzętach. Wspominają też o testowaniu na ludziach mieszanek bakteryjnych o innym składzie. "Ludzie są różni, niewykluczone więc, że optymalna dla nich mikstura także powinna być zindywidualizowana".
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