Mark Crislip is on vacation, but through an arduous series of shakings and succussions (beating his head against the wall?) we have channeled part of his essence: This post mostly concerns itself with infectious diseases, thanks to several recent posts on SBM that discussed the plausibility of health claims† and that touched on the recent discovery that most peptic ulcer disease (PUD) is caused by a bacterium, Helicobacter pylori. Several comments and statements quoted in those posts reveal recurrent questions regarding both plausibility itself and the history of the H. pylori hypothesis. In this post I’ll attempt to answer some of those questions, but I’ll also insert some new confusion.
Plausibility ≠ Knowing the Mechanism
Let’s first dispense with a simple misunderstanding: We, by which I mean We Supreme Arbiters of Plausibility (We SAPs) here at SBM, do not require knowing the mechanism of some putative effect in order to deem it plausible. This seems so obvious that it ought not be necessary to repeat it over and over again, and yet the topic can’t be broached without some nebbishy South Park do-gooder chanting a litany of “just because you don’t know how it works doesn’t mean it can’t work,” as if that were a compelling or even relevant rebuttal. Let’s get this straight once and for all: IT ISN’T.
Steve Novella explained why at the Yale conference and again here. We talked about it at TAM7 last summer. For a particularly annoying example, read the three paragraphs beginning with “Mr. Gagnier’s understanding of biological plausibility” .
OK, I’ll admit that I’m beginning to learn something from such frustration. Perhaps we’ve not been so good at explaining what we mean by plausibility. The point is not that we don’t know a particular mechanism for homeopathy, for example; the point is that any proposed mechanism would necessarily violate scientific principles that rest on far more solid ground than any number of equivocal, bias-and-error-prone clinical trials could hope to overturn. The same is true for “energy medicine” and for claims based on non-existent anatomical structures (iridology, reflexology, auricular acupuncture, meridians, chiropractic “subluxations”), non-existent physiologic functions (““), or non-existent anatomic-physiologic relations (“neurocranial restructuring,” “detoxification” with coffee enemas, dissolving tumors with orally administered pancreatic enzymes). The spectrum of implausible health claims euphemistically dubbed “CAM” is full of such nonsense.
Reader daedalus2u proposed a useful way to clarify the point:
I think the idea of prior plausibility should actually be reframed into one of a lack of prior implausibility. It isn’t that one should have reasons to positively think that something is plausible before testing it, but rather that one should not be able to come up with reasons (actually data) why it is fatally implausible.
Some of what We deem implausible will not be fatally so, of course. Implausibility can be based not only on established physical and biological knowledge, but also on studies, as is the case for sticking needles into people, injecting them with chelating agents, or claiming that autism is caused by childhood immunizations.
Plausibility and History
A second theme, though not as simple, concerns the historical role of plausibility. Reader anoopbal introduced the point:
am not sure if you can apply biological plausibility to every situation. It is usually considered as a weak criterion because it is limited by our knowledge.
If we used plausibility 300 years back, nobody would have used citrus fruits for scurvy nor people would have believed mosquitoes are linked with black water fever.
I think that daedalus’s “reframing” proposal deals with that objection to a large extent. I also don’t think that anoopbal’s examples are all that revealing. It seems to me that empiricism was the main source, other than myth, for plausibility at the time. Plausibility in the biomedical sense is not something that can be usefully discussed for the period prior to about the mid-19th century, when enough was finally known about biology and chemistry to hatch science-based medicine in its full form. Prior to that, most useful diagnostic and treatment methods had been discovered empirically (accidentally).
This is not to say that someone living before the mid-19th century could not have applied plausibility to a medical question—obviously that could happen at any time—but that to attempt to do so, when so much was still mysterious (how cowpox pus worked, microbiology, Avagadro’s number, energy flux in living organisms, physiology, pharmacology, etc.) or (the Vital Force, miasmas, sympathetic magic, the 4 humors, etc.) would have meant very little by today’s standards. And I do believe that there is a fundamental difference—not merely a foolish conceit about modernity—between what we know today and what we knew 300 years ago. Thus I don’t think that biological plausibility is a weak criterion now, even if it was then.
To give anoopbal his or her due, he seemed to partially agree when he later noted:
And that‘s exactly the limitation of biological plausibility. It is limited by what we currently know. Centuries back our knowledge about earth was limited, and you can’t blame them for believing the earth [was] a flat disc.
On to H. Pylori
Daedalus offered another interesting take on plausibility:
An idea does not have low prior plausibility if it does not agree with prior explanations, it has low prior plausibility if it does not agree with prior data.
Many (most?) scientists make this confusion too. That is because they are thinking on the level of the explanations, not on the level of the data that led to those explanations. The explanations may be wrong, the data that led to them is not.
Given the presumption that the data are accurate, we would all probably agree with this. Daedalus, however, then got a little tripped up:
The idea of using antibiotics to treat ulcers was incompatible with the idea that ulcers were due to too much acid. It was not incompatible with any of the data surrounding ulcer treatment.
So did Harriet Hall:
The idea of treating ulcers with antibiotics was not incompatible with any of the data about ulcers; it was only incompatible with the idea that ulcers were caused by too much acid.
At the time that Barry Marshall and Robin Warren proposed their bacterial hypothesis, there were that ulcers were caused by too much acid: acid neutralization or suppression of acid formation resulted in better than 90% healing of peptic ulcers, compared with about 30% for placebo. If such therapies were discontinued after healing, the ulcers typically relapsed, only to be healed again by renewed acid suppression. This did not rule out the possibility of some other factor also being involved, of course, but it would seem to have come pretty close to throwing down the gauntlet of .
Why not just Treat with Antibiotics?
What might it have taken prior to 1984, short of what was subsequently done, to convince the world that peptic ulcer disease could be effectively treated with antibacterial agents? A reader sent just such a question to Steve Novella:
What would Science Based Medicine do if H. pylori was not known, but a study showed that antibiotics given to patients with stomach ulcers eliminated symptoms? I assume that SBM wouldn’t dismiss it outright saying that it couldn’t possibly be helping because antibiotics don’t reduce stomach acid. I assume a SBM approach would do further studies trying to discover why antibiotics work. But, in the meantime, would a SBM practitioner refuse to give antibiotics to patients because he doesn’t have a scientific explanation as to why it works?
A straightforward answer is as follows. Although the question may raise an interesting general point about plausibility, the example is not a good one. Antibiotics are not one medicine but many. They all have side effects, some quite serious. Bacteria are also not one species but many; they have widely differing sensitivities to various antibiotics. Which antibiotic(s) would the study have used, and on what basis? Responsible MDs would not have accepted such a scheme for PUD, because they would have needed to know what they were treating and how to treat it (H. pylori turns out to require three different antibiotics given simultaneously).
A predictable rejoinder to this is that many physicians routinely treat upper respiratory tract infections, most commonly caused by viruses, with an antibiotic. Without going into detail, let me assure you that this does not refute my point: in many cases MDs should not be treating these URIs with antibiotics, and in cases where it makes a bit of sense to do so it is done with a single, short-term antibiotic with a benign risk/benefit profile, known to be effective against the most common community-acquired bacterial culprits of the respiratory tract. This is quite different from attempting to treat a mysterious bacterium that might not even exist, for a disease that already has effective treatments that are safer and have fewer side effects than antibiotics.
Mikerattlesnake got the point:
I think it’s a wise addendum to directly address the logical misstep in the question you received. Those who understand SBM would get the answer from the broad approach taken in your post, but those people aren’t the ones likely to parrot the fallacy.
To put it simply: finding that an antibiotic was effective against an ulcer would indicate a bacterial cause for ulcers that would warrant further study. The reason for that has entirely to do with prior plausibility. Antibiotics are known to fight bacteria. If an antibiotic cures ulcers, it gives us a plausible answer for the mechanism causing ulcers. The questioner makes the mistake of assuming that we would never abandon the assumed cause of ulcers, but SBM looks for mechanisms of action for ailments as well as cures.
So did BillyJoe, with the appropriate caveat:
I like it.
Only one thing though: this could never have happened. As I understand it, the treatment involves taking three different tablets – two antibiotics and an acid suppressing drug – twice a day for a week. How likely is that to have happened by chance?
Discoveries Require Context
Some might assume that Robin Warren and Barry Marshall were the first to discover bacteria apparently living in the human stomach and duodenum, and the first to propose that the bacteria might be involved in diseases of these tissues, but this isn’t the case. Such bacteria were first observed in the 19th century. Over subsequent decades there were sporadic reports of similar bacteria, but they were not necessarily associated with diseases and their presence . The table of contents of , edited by Barry Marshall, gives a hint of just how close some investigators came to the truth:
- Helicobacters were discovered in Italy in 1892: An episode in the scientific life of an eclectic pathlogist, Giulio Bizzozero. Natale Figura and Laura Bianciardi
- The discovery of Helicobacter pylori in Japan. Yoshihiro Fukuda, Tadashi Shimoyama, Takahashi Shimoyana and Barry J Marshall
- An early study of human stomach bacteria. A. Stone Freedberg
- Gastric urease in ulcer patients in the 1940’s: The Irish connection. Humphrey J O’Connor and Colm A O’Morian
- How it was discovered in Belgium and the USA (1955 -1976) that gastric urease was caused by a bacterial infection. Charles S Lieber
- A personal history of giving birth to the cohort phenomenon of peptic ulcer disease. Amnon Sonnenberg
- John Lykoudis: The general practitioner in Greece who in 1958 discovered the etiology and a treatment of peptic ulcer disease. Basil Rigas and Efstathios D Papavassiliou
- How I discovered helicobacters in Boston in 1967. Susumu Ito
- How we discovered in China in 1972 that antibiotics cure peptic ulcer. Shu-Dong Xiao, Yao Shi and Wen-Zheng Liu
- Helicobacter pylori was discovered in Russia in 1974. Igor A Morozov
- The discovery of Helicobacter pylori in England in the 1970’s. Howard W Steer
- We grew the first Helicobacter and didn’t even know it!. Adrian Lee, Michael Phillips and Jani O’Rourke
- The Dallas experience with acute Helicobacter pylori infection. Walter L Peterson, William Harford and Barry J Marshall
- The discovery of Helicobacter pylori in Perth, Western Australia. J Robin Warren
- The discovery of Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease. Barry J Marshall
- Helicobacter pylori treatment in the past and in the 21st Century. Peter Unge
Prior to Marshall and Warren, human gastric bacteria were not only inconsistently seen, but were never cultured and hence never characterized in a useful way (for a more basic treatment of this topic, please see my 2004 ). At least two distinct technological advances were necessary to set the stage for the discovery and characterization of H. pylori in humans: first, a simple and safe method for obtaining gastric mucosa specimens from live patients had to be devised; second, the field of bacteriology had to appreciate the existence of highly fastidious organisms and devise methods for growing them in culture. The first of these requirements was satisfied only by the late 1970s, when flexible, fiberoptic endoscopy became widely available.
I am not enough of an historian of bacteriology to state, with certainty, when H. pylori might have first been cultured, if only its existence had been fully appreciated, but it is doubtful that it could have occurred much sooner than it did. Helicobacter Pioneers reports that the first successful culture of any helicobacter species—isolated from mice—occurred in 1968. Other examples of fastidious bacteria have also been characterized relatively recently: and , two organisms that cause atypical pneumonia, were still thought to be viruses until the 1960s; several new species of helicobacter and campylobacter, some of which are human pathogens, have been discovered only in the last 10-15 years.
The culture requirements of H. pylori, moreover, are esoteric: it grows best in an atmosphere of 5% oxygen and is helped by the presence of certain antibiotics to discourage overgrowth by more hardy contaminants, which are almost impossible to avoid when collecting specimens from the stomach via the mouth. Helicobacter takes much longer to grow than most bacteria, and but for serendipity Warren and Marshall might have missed it. They abandoned their first 34 culture attempts (or, more precisely, “junior microbiology staff” abandoned them) in spite of multiple variations of media and temperatures, after no growth had occurred within 48 hours. It was only after a five-day Easter vacation, during which the 35th attempt was left undisturbed, that tiny, transparent colonies appeared.
John Lykoudis: the Real Galileo of PUD?
An intriguing story in Helicobacter Pioneers is found in chapter 7: John Lykoudis: The general practitioner in Greece who in 1958 discovered the etiology and a treatment of peptic ulcer disease. You can read most of this chapter at the website. If it is accurate, it makes the answer to the question that the reader posed to Dr. Novella not so straightforward as Mikerattlesnake, BillyJoe, and I argued above: it inserts the “new confusion” that I promised at the beginning of this post. Lykoudis’s story has all the necessary tragic elements:
a general practitioner in a small, isolated town in Greece, prompted by a single clinical observation, developed on his own the concept that PUD and gastritis had an infectious etiology. As if this was not enough, this most unlikely student of PUD proceeded to devise an apparently effective treatment, based on the antibiotics of his time.
Lykoudis’s treatment, apparently developed by trial and error, consisted of 3 antibiotics (2 quinolines and streptomycin, for you microbiology/infectious disease enthusiasts out there) and vitamin A, taken orally. He patented this regimen in a pill that he named Elgaco, “from the Greek word for ulcer (= elkos), gastritis and colitis” (for which he also asserted that his treatment was effective). He eventually claimed to have treated 30,000 patients with nearly perfect results and no toxicity. According to the authors of the chapter,
The success of Elgaco cannot be quantified from extant notes on thousands of patients, because the outcome of each patient is not recorded. We have concluded, however, that his treatment was successful, based on the following considerations. First, our current understanding of the etiology and treatment of PUD makes it plausible that his treatment was effective. Second, there is the written testimony (some of it sworn, as explained later) of many of the patients who were treated by Lykoudis. All report prompt responses to his therapy. In some cases, patients even detail that radiographically proven ulcers were cured following treatment with Elgaco and that such cure was confirmed by repeat radiological series. Third, Lykoudis had a large following and despite fierce opposition from the establishment, patients flocked to him from all over Greece.
In spite of this, his attempts to make his discovery known to the world were rebuffed at every turn:
He encounter[ed] formidable obstacles in convincing the medical establishment, the Greek regulatory authorities and the pharmaceutical industry. In fact, Lykoudis spent the rest of his life engaged in incessant activity to propagate his treatment of PUD and gastritis. His archives, some made recently available by his family, make it clear that he was fully aware of the importance of his discoveries. They also convey an almost suffocating sense of frustration…
[He was] completely shunned by the medical establishment of his time, or at best, considered an eccentric provincial physician…
In 1966, Lykoudis attempted to publish his observations in the Journal of the American Medical Association, but his manuscript entitled “Ulcer of the Stomach and Duodenum” was rejected…Unfortunately, no copy of this manuscript survives for re-evaluation in the light of current knowledge.
Lykoudis did, however, publish his own booklet, “The Truth about Gastric and Duodenal Ulcer.” In it he wrote:
There is no doubt that gastritis and duodenitis, which have gastric and duodenal ulcer as their complication, are inflammations due to an infectious agent…
Lykoudis made numerous attempts to get his remedy approved by the Greek Drug and Pharmacies Administration, to no avail. He even managed to enlist the aid of influential politicians:
In 1967, Lykoudis succeeded in getting the attention of the Prime Minister’s office. His correspondence with the Minister of Health on 21 August, 1967, a sad document indeed, is revealing. He registers his frustration that medications with apparently no effect on PUD were approved, whereas Elgaco was repeatedly rejected. He proposes, in essence, a phase III trial: 100 PUD patients to be treated at a State hospital by the eminent professors, 50 with conventional treatment and 50 with Elgaco. ‘Their refusal to approve it is understandable, but their refusal to test it is not!’ he writes.
If the study proves them correct, they will be vindicated and I will become a laughing stock…It is dramatically urgent to clarify this issue…Too much, endless talking, which leads nowhere, while it is simple to resolve this in a practical way. Only facts constitute the truth.
Yet again he was refused. Lykoudis also tried, unsuccessfully, to interest several drug companies in his regimen. The final insults were these:
…he was referred for disciplinary action to the Athens Medical Association, of which he was a member, ‘because (a) he prepared and distributed an unapproved medicinal preparation…and (b) he made his method publicly known to attract patients’…On 6 November 1968…the Disciplinary Committee, presided over by a neurology professor, fined him 4000 drachmas…
A more serious problem for Lykoudis was his indictment in the Greek Courts…
In the latter instance numerous former patients came to his support; one of them testified that Lykoudis “treated also many poor ulcer patients free of charge.” We are not told the outcome of the indictment.
Lykoudis died in 1980 without knowing that he would soon be vindicated. His story is disturbing because it is an almost perfect hybrid of two entirely different possibilities: on the one hand, a legitimate innovator who is unfairly rejected and persecuted, in spite of heroic efforts over more than 2 decades to prove his theory; on the other, a classical example of unwitting foolishness, bordering upon quackery or sociopathy.
It is only in hindsight that we can grant that there is a good chance that it wasn’t the latter. Consider the striking parallels, however, to Nicholas Gonzalez, whose main arguments have consisted of patient testimonials and case reports selected by himself, who claims that his regimen is nontoxic, who claims to treat some patients for free, who was hounded by regulatory boards for a time, who found political allies to help defend him, and who for years pleaded that all he wanted was a chance to :
I believe in research. I don’t want this to be out there until we prove it works by the strictest standards of orthodox medicine. What I have wanted from the day I began researching this under Dr. Goode at Cornell in 1981, was to do appropriate clinical trials.
Again: Discoveries Require Context
My sense, reading the story of John Lykoudis, is that he was treated unfairly, and I think that most people would agree. A major caveat is that the authors of the chapter are clearly sympathetic to him, and it’s quite possible that another account would read differently.
Whether fair or not, it seems to me that the major weakness in Lykoudis’s case is that he never characterized the putative bacteria in any way: he didn’t see them, he didn’t provide direct evidence of them for others to examine, and he didn’t culture them.
Even his sympathetic biographers recognized this. Although they attributed his failure to “his lack of academic credentials” and even more to “his thesis [being] contrary to established, albeit unsubstantiated, dogma,” they also observed:
Unfortunately, when he was compelled to identify these elusive organisms, particularly when dealing with regulatory agencies, he meandered around known pathogens, unable to build a strong case for any of them. His main argument, and the strongest one he could marshal in all his writings in favor of the infectious etiology of these clinical entities, was the response to treatment that he had witnessed.
A good argument can be made that characterizing the “bug” not only is, but ought to be a sine qua non for treating a putative infectious disease with drugs. This is true because the drugs are not benign or universally effective, as argued above, but also because there are precedents suggesting that to do otherwise opens the door to mistreatments. Bacteria or viruses are frequently offered as potential etiologic agents for all sorts of diseases whose causes are poorly understood, particularly when there is an inflammatory component (that is one reason that the H. pylori hypothesis didn’t represent a new “paradigm”). Osteoarthritis and rheumatoid arthritis are examples, but these have, so far, eluded attempts at proof.
When I first learned about and in medical school in the 1970s, I would have bet dollars-to-donuts that they, and rheumatoid arthritis and a few other diseases for that matter, would eventually be shown to have infectious etiologies. I would still almost make that bet, my only hesitation being that after 30+ more years of investigations and impressive advances in microbiology (including vastly more powerful methods of detecting well-veiled foreign invaders, from electron microscopy to nucleic acid amplification), no apparent culprits have feen found.
During that same time, moreover, not only peptic ulcer disease but also Lyme disease, Legionnaire’s disease, and Toxic Shock Syndrome were shown to have bacterial origins, and AIDS was shown to be caused by a virus. Thus on the basis of what has been learned about infectious diseases it can’t be argued, with a straight face, that biomedical progress is hampered by stodginess or petty jealousies or dogmatic thinking or conflicts of interest or any of the other usual suspects, even though they certainly all exist among individual scientists. What hampers progress, in cases such as Likoudis’s, is what hampers all scientific progress: the context is not prepared.
Instances in which at least some people have become convinced of a spurious infectious etiology, on the other hand, have not been pretty. In the early 20th century, prior to the discovery of antibiotics, became convinced that “insanity” was caused by bacteria in the mouth and that the appropriate treatment was “surgical bacteriology”: tooth extractions, tonsillectomies, and in intractable cases removal of “testicles, ovaries, gall bladders, stomachs, spleens, cervixes, and especially colons.” More recently a putative has spawned a small .
Even if any of the diseases mentioned above is eventually found to be infectious in origin, this will not necessarily vindicate those whose premature exuberance put patients in harm’s way. Such exuberance ought to motivate legitimate investigations, not half-assed, ill-conceived treatments. Still, I seem to hear a ghostly voice in my ear, speaking Italian with a thick Greek accent…
E pur si muove!
† The Prior Probability, Bayesian vs. Frequentist Inference, and EBM Series:
16. What is Science?