Authors: This article was written by Martin Laurence (see Martin's comment below). I helped with structuring and reviewing the article.
Update by Martin (November 15th 2018): Following some of your input in the comment section on the impact of this research, the phrase “There are ~2 million Crohn’s disease sufferers worldwide, and many use immunomodulatory injections (such as adalimumab which costs ~50K$ USD/year) to reduce inflammation and symptoms. A back of the envelope calculation suggests this would have a direct economic impact of 50K$ x 2M = ~100B$ USD/year.” was changed to “A cheap cure for Crohn's would save a large fraction of the $33B spent on Crohn's each year, and in turn, these funds could save thousands of lives per year if spent on other causes.” This remains a rough and narrow estimate of the potential impact of this project, and additional help to improve this estimate would be greatly appreciated.
Summary: Recent studies strongly suggest Crohn’s disease is caused by a fungus, most likely a Malassezia species (Laurence et al 2018). The FDA approved antifungal drug itraconazole might cure patients by clearing this fungus from the gut, as reported in a small study (Samuel et al 2010). Since this drug’s patent has expired, there is little financial incentive to formally demonstrate its efficacy in Crohn’s disease—this would be required to change clinical practice. A cheap cure for Crohn's would save a large fraction of the $33B spent on Crohn's each year, and in turn, these funds could save thousands of lives per year if spent on other causes. More information can be found at www.malassezia.org.
Importance
Direct impact
There is currently no known cure for Crohn's disease. Onset usually occurs in young adults, who are then affected for life. Though Crohn’s disease is typically non-fatal, it greatly decreases the quality of life of patients (Norton et al 2012, Benedini 2012) and increases their risk of colon cancer. Curing this disease would improve the life of an estimated 2 million sufferers worldwide. Current interventions include surgical removal of affected regions of the intestines (this can mean defecating into a bag strapped to one’s stomach from then on) and drugs which reduce the aggressivity of the immune system such as adalimumab, infliximab and azathioprine (which increase the risk of various infections). Neither intervention is appealing.
Leverage value
Crohn's disease is part of a group of immunologically similar diseases known as spondyloarthritides. These diseases are the result of abnormal activation of alpha beta T cells, though the specific antigens targeted by these T cells remain a mystery. Spondyloarthritide symptoms include chronic inflammation of the gut, skin, joints, eyes, spine and genitals (Laurence et al 2018); affected organs can flare-up alone or in combination. Common phenotypes include Crohn's disease, ulcerative colitis, ankylosing spondylitis, reactive arthritis, psoriasis, psoriatic arthritis, acute anterior uveitis and oligoarthritis.
Recent studies suggest all these diseases are caused by alpha beta T cells attempting to clear a fungus from affected organs—and failing miserably, making us sick in the process. We strongly suspect this fungus is part of the genus Malassezia (Laurence et al 2018). This means proving beyond all doubt that Crohn's disease is caused by this fungus will very likely lead to a cure for all spondyloarthritide symptoms using antifungal drugs. These symptoms include chronic non-radiographic back pain which is a mild spondyloarthritide symptom affecting a large subset of the adult population.
Though supporting evidence is not as strong as for spondyloarthritides, it is probable that B cell-mediated diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus share the same infectious etiology (Laurence et al 2017, Benito-Leon et al 2017, Benito-Leon et al 2018). If so, antifungal treatments should be effective for these debilitating diseases as well.
Though supporting evidence is weaker than for spondyloarthritides, it is probable that prostate cancer and benign prostatic hyperplasia are caused by the same fungal infection, and antifungal treatments would prevent these two common diseases (Laurence et al 2018).
If an important disease is shown to be caused by Malassezia and is cured using antifungal drugs—Crohn’s is currently the best candidate—then government agencies like the NIH would probably invest billions of dollars to see if the same holds true for other diseases, especially those in bold above.
Tractability
My academic collaborators and I have published many articles making the case for a fungal etiology in spondyloarthritides (including Crohn's disease), multiple sclerosis, prostate cancer and benign prostatic hyperplasia (Sutcliffe et al 2014, Laurence et al 2018, Laurence et al 2017, Benito-Leon et al 2017, Benito-Leon et al 2018). We suspect a single ubiquitous fungal species or genus is causing all these diseases. The only known fungi which fit the bill are Malassezia restricta and Malassezia globosa.
The main open question which pressingly needs an answer is: “Can existing antifungal drugs eliminate this fungus, curing Crohn’s and other diseases listed above?” Antifungal compounds are very effective at treating dandruff and seborrheic dermatitis, two skin conditions known to be caused by Malassezia. The small study run by Samuel et al suggests oral itraconazole is effective in Crohn's disease. This hypothesis is readily testable by replicating Samuel et al in a double-blind placebo-controlled study. This is our primary goal. Thereafter, we'd like to run additional studies to test the efficacy of antifungal drugs in other diseases listed above.
Neglectedness
Why it’s neglected
The vast majority of microbiome studies focus on bacteria, and ignore fungi. There are technical reasons for this: assays to detect bacteria are cheaper and easier to run. There are many more bacterial species in humans than fungal species, so study results seem more interesting when bacteria are included. For historical reasons, bacteria such as Klebsiella and Mycobacteria were considered the prime suspects in spondyloarthritides (including Crohn’s disease). In short, studying fungi has not been an appealing prospect for researchers.
Malassezia restricta and Malassezia globosa were first identified in 1996 using DNA sequencing. The tardiness of this discovery is best explained by the fact that they don’t grow well in culture. This means only recent studies using DNA sequencing have any hope of detecting them. In addition, Malassezia have the thickest cell wall of medically important fungi, which means most kits used to extract DNA to detect microbes can’t crack them open (Vesty 2017). Malassezia are the Brazil nut of microbes!
Drugs currently used to treat spondyloarthritides (including Crohn’s disease) are expensive biologics which depress the patient’s immune system. Imagine if we were treating syphilis with immunosuppressants rather than penicillin! Immunosuppressants would reduce symptoms, but wouldn’t address the root cause of the disease. The correct treatment for syphilis is penicillin, which quickly kills the causative bacterium, permanently resolving symptoms. The correct treatment for spondyloarthritides might well be existing antifungal drugs. We need to test this to be certain. However, there is no financial incentive to do this because patents on most antifungal drugs have already expired.
A similar situation unfolded in the 1980s when Barry Marshall discovered that stomach ulcers were not caused by stress, smoking and acid (as previously thought), but rather by a bacterium in the stomach called Helicobacter pylori. Antibiotics to eliminate Helicobacter pylori had been on the market since the 1950s, we simply did not know how to use them. Instead, we gave patients antacids which reduced their symptoms, but did not address the root cause of their disease. This is well explained here.
Funding gap
This project has been running since 2012, full-time and self-funded. I’d rather not know how much I have invested so far, but it’s in the hundreds of thousands of dollars.
I currently have a quote of 500K$ USD to replicate Samuel et al 2010 with controls (n=20 itraconazole, n=20 placebo, for six months). I would eventually like to run additional clinical trials for each important spondyloarthritide symptom. I cannot fund these clinical trials entirely myself, though this would have been my preference.
I strong-downvoted this post. I had hoped the reasons why would be obvious. Alas not.
Scientific (in)credibility
The comments so far have mainly focused on the cost-effectiveness calculation. Yet it is the science itself that is replete with red flags: from grandiose free-wheeling, to misreporting cited results, to gross medical and scientific misunderstanding. [As background: I am a doctor who has published on the genetics of inflammatory bowel disease]
Several examples before I succumbed:
Intermezzo
I'd also rather not know how much has been spent on this so far. Whatever it is, investing another half a million dollars is profoundly ill-advised (putting the money in a pile and burning it is mildly preferable, even when one factors in climate change impacts). At least an order of magnitude cheaper is buying the time of someone who works in Crohn's to offer their assessment. I doubt it would be less scathing than mine.
Meta moaning
Most EAs had the good judgement to avoid the terrible mistake of a medical degree. One of the few downsides of so doing is (usually) not possessing the background knowledge to appraise something like this. As a community, we might worry about our collective understanding being led astray without the happy accident of someone with specialised knowledge (yet atrocious time-management and prioritisation skills among manifold other relevant personal failings) happening onto the right threads.
Have no fear: I have some handy advice/despairing pleas:
I see these aspects of epistemic culture as an important team sport, with 'amateur' participation encouraged (for my part, implored). I had hoped when I clicked the 'downvote' arrow for a few seconds I could leave this to fade in obscurity thereafter. When instead I find it being both upvoted and discussed like it has been, I become worried that it might actually attract resources from other EAs who might mistakenly take conversation thus-far to represent the balance of reason, and detract from EA's reputation with those who recognise it does not (cf. "The scientific revolution for altruism" aspiration). So I feel I have to am to write something more comprehensive. This took a lot longer than a few seconds, although fortunately my time is essentially worthless. Next time we may not be so lucky.
I mostly agree with this, but I think it's also wrong in a couple of places.
I think this is just restating the hypothesis, that Crohn's shares (most of) its pathophysiology with the spondyloarthritides... Which is a well-known open possibility. The incidence of Crohns is >10% in people with AS and vice versa. They share heredity, HLA-B27. Apparently 2/3 of those with AS also have silent gut signs [1].
Also, I think the following is off the mark:
Note that the author did manage to co-author his latest piece with an ophthalmologist/rheumatologist with a professorship in inflammation research and 20k cites.
Overall, the parts of the objection that I agree most with are i) that it seems very unlikely that one or two fungi would be implicated with all of these 14 various diseases, and that treating the fungus would cure the inflammatory disease (rather than the fungus just acting as an initial trigger), and ii) that there are mistakes, especially semantic ones, and especially on malassezia.org (as opposed to in the papers), with some of the medical science.
The interesting questions seems to me to be whether an overconfident-seeming author could nonetheless be correct about the minimal prediction that some antifungals would work well in at least Crohn's disease. I don't yet see why this is <1% likely.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996322/
2. https://www.ncbi.nlm.nih.gov/pubmed/29675414, https://en.wikipedia.org/wiki/James_T._Rosenbaum
Hi Ryan, Thanks for double checking Seke's impact numbers. Could you help me draft the impact phrase, I'm afraid of getting it wrong again.
Hi Gregory, Thanks for the detailed response. I understand where you are coming from: if tables were turned, I would have posted a similar comment. I’d be happy go over the science in greater detail with you; perhaps we can start another thread to cover this, as I expect our science discussion to be very long, detailed and technical. Right now, we have an important question to answer: is it worth spending 500K$ USD in an attempt to replicate Samuel et al 2010 with more patients and proper controls?
The 500K$ USD figure is from a detailed budget produced by a credible university-affiliated clinical research team eager to start this study. I reviewed this budget with them, and it is reasonable.
Zeke estimates the direct financial upside of a successful replication to be about 33B$/year. This is a 66000:1 ratio (33B/500K = 66000). We need to assign probabilities to the following explanations of Samuel et al 2010’s results:
1. Their results are correct: itraconazole cures Crohn’s.
2. Their results are a fluke: itraconazole isn’t affecting Crohn’s symptoms, and natural waxing and waning of symptoms made it look like itraconazole cures Crohn’s.
Itraconazole is a cheap, widely available off-patent broad-spectrum antifungal drug. The main immunological signature of Crohn’s disease are antibodies against conserved fungal sugars (mannan, beta-glucan, and chitin). By principle of parsimony, this means that Crohn’s patients’ immune systems are likely fighting a fungus which is the root cause of Crohn’s disease. There are a number of other possible explanations for the above observations, but these are more complex and difficult to prove.
(A) What are the odds that Samuel et al 2010’s results will replicate? X
(B) At what odds is this replication project a good candidate for EA funding? Y
(C) If X > Y and X is low, can funding agencies and foundations tolerate the risk of failure, or must we find these funds in a less non-conventional manner?
I am getting a much better understanding of Y with the help of people on this forum, thanks to Seke and Ryan (I have no experience in doing these estimates). I was hoping to get a better idea of the value of X too. In most situations, people round-down the value of X to zero before starting their analysis. This means they consider further effort evaluating X or Y to be largely futile (in Bayesian terms, prior probabilities of zero cannot be changed by further analysis). EA folks are used to dealing with low X values, so I thought they’d be less likely to round down to zero
If X < Y, then I will move on to other things. If X > Y, then I will do all I can to fund this study, as this is likely the highest-impact charitable project available to me.
I'd very much appreciate it if Gregory, Ryan, Seke, Aaron could help me quantify X and Y. Other diseases listed here can somewhat decrease Y, but calculating by how much is complex, so let's stick to Crohn's for now. I included other diseases in this post because they were the main focus of my research for six years, and they might well have the same fungal etiology as Crohn's disease. I realize that despite this prior research *strengthening* the case a fungal etiology in Crohn's, many people instinctively *reduce* the prior probability of any of this being correct due to the unusually large scope of this project.
A cheaper alternative (also by about an order of magnitude) is to do a hospital record study where you look at subsequent Crohn's admissions or similar proxies of disease activity in those recently prescribed antifungals versus those who aren't.
I also imagine it would get better data than a poorly powered RCT.
This might be naive and I have only skimmed this thread, but wouldn't using a cheap study using mouse model be best here? Maybe contact the authors of the papers cited in this paper "Mouse models of inflammatory bowel disease for investigating mucosal immunity in the intestine" to collaborate on such a study.
Hi Hauke, Thank you very much for this suggestion. Yes, animal models would be another category 2 option. You might know that Barry Marshall had much trouble developing animals models of Helicobacter pylori-induced gastritis, so this approach is hit-and-miss at best, and it is hard to know ahead of time what the probability of a "hit" would be. It is also less ethical than the other solutions, and for this reason, I'd prefer avoiding animal models (if possible).
Hi Gregory, Great suggestion! The main issue with this approach is that it seems long-term use of itraconazole is required (>3 months), which rarely occurs in practice. Most on-label uses of itraconazole are for much shorter periods, which is one reason why Samuel et al 2010 was such an exception: histoplasmosis is only prevalent in the mid-West, and requires a very long course of itraconazole.
A second problem is that once treatment is discontinued, Crohn's symptoms seem to return after a few months (again per Samuel et al 2010). This is very much like dandruff (caused by the fungus Malassezia): once antifungal shampoos are discontinued, Malassezia return, and so does dandruff! So we'd have to be able to test using the medical database if these Crohn's patients got a flare or not during the treatment period (as compared to properly selected controls - getting comparable/unbiased controls using this methods is not trivial).
In addition, Samuel et al 2010 was very well positioned to detect the effect of itraconazole, because they stopped giving their patients immunosuppressants - so they were expecting severe flares during treatment. This is not expected to occur in most cases from medical databases.
Finally, I don't think medical database studies like this can be used to change medical practice. Would the FDA allow a new indication without an RCT? I doubt it. So running a database could not reach the stated impact.
How many patients do you think we would need in a RCT to have sufficient power? The researchers I am working with think itra=20, placebo=20 would be sufficient. I don't have the expertise to evaluate this. Samuel et al 2010 noticed a marked effect on 5 patients, although there were no controls, so they were judging this using their clinical experience. FWIW, the last author of Samuel et al 2010 is one of the top Crohn's researchers in the world.
Hi Gregory, here are some more options:
X = odds that Samuel et al 2010’s results will replicate (range 0 - 1).
Category 1 options: studies which can bring X’s value close to 1.
(1a) A well powered RCT testing itraconazole in Crohn’s (success = curing Crohn’s).
Category 2 options: cheaper studies which can increase X, but not bring it close enough to 1 to change clinical practice. However, they would raise awareness that Crohn's might be caused by a fungus, and thus might be cured by itraconazole. Hopefully someone will do (1a) based on the results of these category 2 options.
(2a) Test Samuel et al 2010 by using a larger medical database than that available at the Mayo Clinic in 2010 (ideally in the mid-West where histoplasmosis is endemic).
(2b) Antibodies against Malassezia are associated with psoriasis (Squiquera et al 1994; Liang et al 2003). We could try replicating these studies in Crohn's disease.
(2c) In psoriasis, white blood cells release interferon gamma when exposed to Malassezia antigens (Kanda et al 2002), likely because T cells are specifically targeting Malassezia on the skin. We could replicate this study in Crohn's disease.
(2d) We could replicate Kellermayer et al 2012 or Richard 2018, who found extremely strong associations between Malassezia and IBD.
Note that (2c) will likely be successful because vedolizumab is known to cause psoriasis in ~10% of Crohn's patients by sending T cells from the gut to the skin (Tadbiri et al 2018).
Other ideas are welcome!
The idea of doing an intermediate piece of work is so one can abandon the project if it is negative whilst having spent less than 500k. Even independent of the adverse indicators I note above, the prior on case series finding replicating out in RCT is very low.
Another cheap option would be talking to the original investigators. They may have reasons why they haven't followed this finding up themselves.
I attempted to contact them, but they did not reply. These are top Crohn's researchers, and must be very solicited from all sides, so their lack of response is expected.
(2b) (2c) (2d) are being run right now by different groups. I don't know how long it will take for them to publish (best guess ~1-2 years).
What numerical value do you assign to the probability of replication of Samuel et al 2010 (variable X)?
~3% (Standard significance testing means there's a 2.5% chance of a false positive result favouring the treatment group under the null).
Hi Gregory, Thank you for helping try to establish these probabilities. I am not sure I follow the math (I'm not used to doing these calculations). Could you explain how you calculated it? Thanks again!
If you use a two tailed test and find a positive effect with p<0.05 it's <0.025 likely you'd get a positive effect that big by chance. If you don't understand that then you should look up two tailed tests.
OK, I will. I don't have your input data, nor the assumptions on which you based your analysis to apply the two-tailed test. These are necessary to understand your results.
He's just saying he thinks there's a 0.005 chance of detecting a real effect.
Hi Ryan, I need to know what input data and assumptions he used to be able to verify/replicate/interpret his math. Without this information, I cannot comment further. Thanks!
In hope but little expectation:
You could cast about for various relevant base-rates ("What is the chance of any given proposed conjecture in medical science being true?" "What is the chance of a given medical trial giving a positive result?"). Crisp data on these questions are hard to find, but the proportion for either is comfortably less than even. (Maybe ~5% for the first, ~20% for the second).
From something like this one can make further adjustments based on the particular circumstances, which are generally in the adverse direction:
As Ryan has explained, standard significance testing puts a floor of 2.5% of a (false) positive result in any trial even if the true effect is zero. There is some chance the ground truth really is that itraconazole cures Crohn's (given some evidence of TNFa downstream effects, background knowledge of fungal microbiota disregulation, and the very slender case series), which gives it a small boost above this, although this in itself is somewhat discounted by the limited power of the proposed study (i.e. even if Itraconazole works, the study might miss it).
Hi Gregory, Thanks for the detailed answer. I'm still not clear on how the numbers quoted above (0.005, 3%, 2.5%) were calculated, nor how they affect the probability of Samuel et al 2010 replicating successfully. It is worthwhile to break down the problem in two parts:
(I) Does Samuel et al 2010 give us any information to support the hypothesis that Crohn's might be cured by itraconazole? If so, how much?
(II) How large does an RCT need to be to properly test this hypothesis?
Answering these two questions is essential to determine if Samuel et al 2010 should be replicated or not (obviously with proper controls this time). This is what I am trying to determine with this forum post: should we raise ~500K$ to replicate it or not? What is the expected return on giving for this experiment?
>Zeke estimates the direct financial upside of a successful replication to be about 33B$/year. This is a 66000:1 ratio (33B/500K = 66000).
This is not directly relevant, because the money is being saved by other people and governments, who are not normally using their money very well. EAs' money is much more valuable as it is used much more efficiently than Western people and governments usually do. NB: this is also the reason why EA should generally be considered funders of last resort.
If the study has a 0.5% (??? I have no idea) chance of leading to global approval and effective treatment then it's 35k QALY in expectation per my estimate which means a point estimate of $14/QALY. iirc, that's comparable to global poverty interventions but at a much lower robustness of evidence, some other top EA efforts with a similar degree of robustness will presumably have a much higher EV. Of course the other diseases you can work on may be much worse causes.
Also that $33B comes from a study on the impact of the disease. Just because you replicate well doesn't mean the treatment truly works, and is approved globally, etc. Hence the 0.5% number being very low.
Hi Zeke, Thanks for the clarification and the estimate for Y. If I understand correctly:
(1) Minimum success probability for project viability is ~0.5% (Y=0.5%)
(2) Upside following success is 33B$*10 years = 330B$ (per your earlier estimate, this needs to be adjusted for many different reasons, both up and down, but these adjustments are beyond my capabilities).
(3) Cost is 500K$.
(4) Expected ROI is = (330B$ * 0.5%) / 500K$ = 3300.
So this means if you find a 100$ bill on the sidewalk and giving it away to someone else statistically gives them ~300K$, you will keep it, but if it statistically gives them 400K$ you will give it away. Is that right?
Only if this project is assumed to be the best available use of funds. Other things may be better.