Crohn's disease

by Mati_Roy13th Nov 201848 comments

-12

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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.

48 comments, sorted by Highlighting new comments since Today at 11:36 AM
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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:

  • Samuel et al. 2010 is a retrospective database review of 6 patients treated with itraconazole for histoplasmosis in Crohn's Disease (CD) (N.B. Observational, not controlled, and as a letter, editor- rather than peer-reviewed). It did not "report it cured patients with CD by clearing fungus from the gut": the authors' own (appropriately tentative - unlike the OP) conjecture was any therapeutic effect was mediated by immunomodulatory effects of azole drugs downstream of TNF-a. It emphatically didn't "suggest oral itraconazole may be effective against Malassezia in the gut" (as claimed in the linked website's FAQ) as the presence or subsequent elimination of Malassezia was never assessed - nor was Malassezia mentioned.
  • Crohn's disease is not a spondyloarthritis! (and neither is psoriasis, ulcerative colitis, or acute anterior uveitis). As the name suggests, spondyloarthritides are arthritides (i.e. diseases principally of joints - the 'spondylo' prefix points to joints between vertebrae); Crohn's a disease of the GI tract. Crohn's can be associated with a spondyloarthritis (enteropathic spondyloarthritis). As the word 'associated' suggests, these are not one and the same: only a minority of those with Crohn's develop joint sequelae. (cf. Standard lists of spondyloarthrides - note Crohn's simpliciter isn't on them).
  • Chronic inflammation isn't a symptom ('spondoyloarthritide' or otherwise), and symptoms (rather than diseases) are only cured in the colloquial use of the term.
  • However one parses "[P]roving 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." ('Merely' relieving all back pain from spondyloarthritides? Relieving all symptoms that arise from the set of (correctly defined) spondyloarthritides? Curing all spondyloarthritides? Curing (and/or relieving all symptoms) from the author's grab bag of symptoms/diseases which include CD, Ulcerative Collitis, Ankylosing spondylitis, Psoriasis and chronic back pain?) The antecedent (one n=40 therapeutic study won't prove Malassezia causes Crohn's, especially with a competing immunomodulatory mechanism already proposed); the consequent (anti-fungal drugs as some autoimmune disease panacea of uncertain scope); and the implication (even if Malasezzia is proven to cause Crohn's, the likelihood of this result (and therapy) generalising is basically nil) are all absurd.
  • The 'I love details!' page notes at then end "These findings satisfy Koch’s postulates for disease causation, albeit scattered across several related diseases." Which demonstrate the author doesn't understand Koch's postulates: you can't 'mix and match' across diseases, and the postulates need to be satisfied in sequence (i.e. you find the microorganism only present in cases of the disease (1), culture it (2), induce the disease in a healthy individual with such a culture (3), and extract the organism again from such individuals (4)).
  • The work reported in that page, here, and elsewhere also directly contradict Koch's first postulate. Malasezzia is not found in abundance in cases of disease (pick any of them) and not in healthy individuals (postulate 1): the author himself states Malasezzia is ubiquitous across individuals, diseased or not (and this ubiquity is cited as why this genus is being proposed in the first place).

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:

  • Medical science isn't completely civilizationally inadequate, and thus projects that resort to being pitched directly to inexpert funders have a pretty poor base rate (cf. DRACO)
  • Although these are imperfect, if the person behind the project doesn't have credentials in a relevant field (bioinformatics rather than gastroenterology, say), and/or a fairly slender relevant publication record, and scant/no interest from recognised experts, these are also adverse indicators. (Remember the nobel-prize winner endorsed Vit C megadosing?)
  • It can be hard to set the right incredulity prior: we all want take advantage of our risk neutrality to chase hits, but not all upsides that vindicate a low likelihood are credible. A rule-of-thumb I commend is 10^-(3+n(miracles)). So when someone suggests they have discovered the key mechanism of action (and consequent fix) for Crohn's disease, and ulcerative colitis, and ankylosing spondylitis, and reactive arthritis, and psoriasis, and psoriatic arthritis, and acute anterior uveitis, and oligoarthritis, and multiple sclerosis, and rheumatoid arthritis, and systemic lupus erythematosus, and prostate cancer, and benign prostatic hyperplasia, and chronic back pain (n~14), there may be some cause for concern.
  • Spot-checking bits of the write-up can be a great 'sniff test', especially in key areas where one isn't sure of one's ground ("Well, the fermi seems reasonable, but I wonder what this extra-sensory perception thing is all about").
  • Post value tends to be multiplicative (e.g. the antecedent of "If we have a cure for Crohn's, how good would it be?" may be the crucial consideration), and so its key to have an to develop an understanding across the key topics. Otherwise one risks conversational bikeshedding. Worse, there could be Sokal-hoax-esque effects where nonsense can end up well-received (say, moderately upvoted) provided it sends the right signals on non-substantive metrics like style, approach, sentiment, etc.

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.

Crohn's disease is not a spondyloarthritis! (and neither is psoriasis, ulcerative colitis, or acute anterior uveitis). As the name suggests, spondyloarthritides are arthritides (i.e. diseases principally of joints - the 'spondylo' prefix points to joints between vertebrae); Crohn's a disease of the GI tract.

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:

Although these are imperfect, if the person behind the project doesn't have credentials in a relevant field (bioinformatics rather than gastroenterology, say), and/or a fairly slender relevant publication record, and scant/no interest from recognised experts, these are also adverse indicators. (Remember the nobel-prize winner endorsed Vit C megadosing?)

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.

>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.

Interesting post, thanks for sharing. Although I am skeptical for some reasons I note below, the potential upside to such a cheap treatment for a very unpleasant disease seems highly worth pursuing. For context, I'm viewing this post as an academic biologist who develops methods for microbiome data analysis and collaborates with some clinicians, though my background is ecology and evolution rather than medicine.

While reading the post, I struck by how the referenced evidence for the author's (Martin Laurence) hypothesis is entirely from citations to his own papers and a short reply to a journal article (I don't think peer reviewed) about anecdotal observations from six IBD patients. The author's papers referenced take the form of reviews and argued hypotheses from research done by others, rather than original experiments, and seem to be about spondyloarthritis, prostate cancer and MS rather than Crohn's directly. Given that IBD and Crohns disease are popular research topics in biomedical research and specifically in microbiome research, I found this lack of reference to others in support of the main hypothesis suspicious, and it made me think the hypothesis is controversial or not well subscribed to in the field. That is not to say it is unfounded, but I would have expected some acknowledgement if this is an "out there" view and discussion of why that included some references to the mainstream view and coverage of the controversy. I would also expect that building further evidence that would convince other researchers and mainstream funders in the field would be the next step, rather than crowd funding a clinical trial, and so would have liked to see an explanation for why this strategy isn't being taken.

I also felt that the reasons under Neglectedness and Funding Gap didn't explain why other biomedical researchers aren't pursuing this, or why the author isn't soliciting funds through standard biomedical funding agencies. The lack of incentive for private drug companies mentioned does not explain why standard agencies and organizations aren't funding it. It is true that fungi are often neglected over bacteria in microbiome studies, but if there is good evidence that fungi are playing a role in Crohn's and they've been historically neglected, they I would expect researchers to be jumping on this hypothesis, and for standard biomedical funders to be glad to fund it, unless for reasons mentioned above.

After reading the FAQ on the author's website, I suspect the author is forgoing the mainstream route and soliciting small private donations because he is operating outside academia and lacks academic or hospital collaborators who can apply for the needed grants. But without these collaborators, I don't see how the proposed clinical trial could be orchestrated. This is not to say that I think the author is wrong in pursuing this work or not credible, but I feel that ignoring these issues makes the post seem less credible than it might otherwise be.

Hi Mike,

Thanks for the comments and suggestions. Several studies are currently being run with academics, but it would not be fair for me leak their results in this forum. These results will be published in due time. Replicating Samuel et al 2010 is quite expensive, and is currently beyond my means (to fund it personally).

As you mentioned, the standard way to study this is to first replicate Kellermayer et al 2012, and Kanda et al 2002 in Crohn's, and Richard 2018. You can see the full list of projects which are running right now at the bottom of this page: https://www.malassezia.org/how-can-i-help

Once these results are published, I think it will be possible to apply for NIH funding to replicate Samuel et al 2010. This will delay replication by 1-2 years. I am sensitive to Crohn's patients who will suffer in the interim, which is why I wanted to replicate Samuel et al 2010 earlier (if possible).

I came very close to starting the replication of Samuel et al 2010 with funding from private sources, but a key philanthropist dropped out at the last minute. I have a detailed project plan from credible researchers who are willing to run this study. They told me they could not get institutional funding until Kellermayer et al 2012, and Kanda et al 2002 in Crohn's are replicated. I think they told me the truth, but perhaps not.

If you think we can get NIH funding with the current level of evidence, then by all means direct me to a Crohn's research group who is willing/capable of going this route now.

Hmmm.. this post seems overconfident. Also it's a seriously way out there hypothesis. But between RA+AS+IBD+prostate Ca we're probably talking about a few percent of first-world morbidity, or at least health expenditures. The authors' include some folks with great credentials, and the written argument in Laurence 2018 is seemingly reasonable (on a skim). Very plausible that I've missed glaring mistakes in their analysis, but if not this seems like a high EV experiment.

Hi Ryan, Your analysis is correct: either this project will have a large impact, or the hypothesis on which it is based is wrong. Finding out is important. Laurence et al 2018 concludes by saying: "Since the evidence available at this time is insufficient to definitely confirm the Catterall–King hypothesis, microbiome studies similar to that performed by Kellermayer et al (138) should be performed to test this hypothesis." When we wrote this phrase a year ago, we did not know that IBD had been strongly associated with Malassezia by a second research group. Check Dr. Richard's presentation here: https://www.isham2018.org/resources/uploads/sites/2/Full-program-including-abstracts-.pdf

Hm, RA + Prostate Ca seems to be 0.3% of all DALYs and 1.2% of those in rich North America, based on Table A2 here. So the important matter seems to be evaluating the plausibility of the fungal hypothesis.

If you would like to better understand the scientific details, I suggest reading the "Details" page on www.malassezia.org .

Hm, I don't have enough expertise to efficiently evaluate this. But I think someone should.

This is an interesting project! I hope you're able to show it to people who are in a good position to evaluate whether it's really such a promising idea (Open Phil has certainly made some grants for research on health issues not specific to the developing world), and that you'll post about further updates on the Forum.

I think that this post gets off slightly on the wrong foot with this analysis:

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.

The back-of-the-envelope calculation assumes that the drugs reach every person with the disease, that all of those people were already using the expensive injections (I assume the drug wouldn't be as useful to people who've already had stomach surgery, but maybe it would be?), and that the drugs will replace the expensive injections entirely. The analysis also ignores the cost of getting the drug to patients worldwide (including getting past each country's equivalent of the FDA) and the chance that it might not be approved in some countries.

Of course, if a cure can really be developed and marketed for a cost in, say, the tens-of-millions-of-dollars range, this would still be a very good opportunity for impact. But the oversimplified impact calculation looks a bit like "gilding the lily" (trying to exaggerate the benefits of something that, even with a more realistic calculation, still looks good).

On the other hand, a true "cure" would also bring benefits to all future sufferers of Crohn's, so in another sense, the impact calculation may be somewhat understated. I'd love to see a more comprehensive analysis at some point, as Zeke suggested.

Hi Aaron,

Thanks for your feedback. You raise many valid points. I would have liked to replace the impact by a more detailed analysis, but I don't know how to go about doing this (measuring utility and adjusting for PPP is hard!). The impact math in the summary can be improved in many ways.

One important point which I seemed to have not explained well is that itraconazole is one of the most used antifungal drugs right now. It has been on the market for 30 years. It is already approved in most jurisdictions to treat various fungal infections. It is inexpensive, in part because there are now many generic manufacturers.

Thanks Aaron! I suppose OpenPhil and other people interested in funding projects monitor this forum? If you think we should do something else to get it to people in a position to provide funding, I'm all ears!

I don't know whether any employees of grant-making organizations monitor the Forum. Open Phil rarely funds unsolicited proposals and has no formal process for accepting them. You can sign up here to be notified when the next round of the Effective Altruism Grants program begins, though I don't know whether your project would be a good candidate for funding.

Have you spoken to any nonprofits that specialize in funding Crohn's research? The Crohn's and Colitis Foundation seems to be a prominent example of that category.

Hi Aaron, Thank you very much for looking into possible funding sources. I met with the Canadian foundation six months ago (I'm Canadian). They told me they were tapped out (funding-wise) for the foreseeable future, and did not have time to look into this in detail. I did not reach out to the American foundation. In a continued attempt to fund the replication of Samuel et al 2010, I then looked for wealthy donors in the Montreal area. I did not manage to get the full sum by mid-October, after three months of trying very hard to put this sum together, and the private funding effort stalled.

I'm curious why this got downvoted. Although I personally suspect there's very little impact to be had by addressing Crohn's disease, this post seems an okay starting point for discussing the issue. I don't see anything here that makes me think this is low-quality content, just maybe discussing an issue that is below the threshold of concern for many EAs? I'm really not sure.

Mati and I wrote this post together (thanks for your help Mati!). You can find more information, including animated videos, at www.malassezia.org . I’d be happy to read your comments, suggestions or questions, either here or at ea@malassezia.org . I’m looking forward to working with the EA community on this project!

To summarize:

1. I would really appreciate it if the impact analysis for this project could be improved. I don't like the "back of the envelope" calculation that I put in the summary, but I don't know how to improve it.

2. Will Samuel et al 2010 replicate? In other words, does the cheap and widely available antifungal drug itraconazole cause remission in Crohn's patients? We have to find out.

3. It is worth mentioning that the main immunological biomarker of Crohn's disease is antibodies against fungal sugars (mannan, beta-glucan and chitin). https://www.ncbi.nlm.nih.gov/pubmed/16890590 This means the efficacy of an antifungal compound for Crohn's is plausible.

Hi Zeke, I would have liked to do a more detailed analysis of impact, but QALY/WALYs are not my expertise, and I would have made many mistakes. This analysis would be very valuable, both for the narrow scope (Crohn's disease), and the full potential scope of the project (the other diseases shown in bold). Crohn's affects young adults for life. Total worldwide prevalence is not know precisely due to poor monitoring in many countries. Many studies report Crohn's and ulcerative colitis prevalence combined.

Going from moderate disease to remission seems to be an increase of about 0.25 QALY/year (https://academic.oup.com/ecco-jcc/article-pdf/9/12/1138/984265/jjv167.pdf). If this research accelerates treatment for sufferers by an average of 10 years then that's an impact of 5 million QALY.

Crohn's also costs $33B per year in the US + major European countries (https://www.ncbi.nlm.nih.gov/pubmed/25258034). If we convert that at a typical Western cost-per-statistical-life-saved of $7M, and the average life saved is +25 QALY, that's another 1.2 million. Maybe 2 million worldwide because Crohn's is mostly a Western phenomenon (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32448-0/fulltext?code=lancet-site). So that's 7 million QALY overall. Which of course we discount by whatever the probability of failure is.

It's very rough but it's a step forward, don't let the perfect be the enemy of the good.

33000/7 * 25 is 120k not 1.2M.

I know. It's ten years of savings, because curing is accelerated by ten years.

Hi Zeke, Thank you very much for the detailed analysis! Wow, great work!

What phrase should we place in the summary?:

"Crohn's is estimated to cost 33B$/year in developed countries, and a cure would represent approximately ? QALY."

"A cheap cure for Crohn's could save some large fraction of the $33B spent on Crohn's per year, and these funds could save thousands of lives per year if spent on other diseases."

Thanks, very much appreciated! I will ask Mati to change the summary.

We need to factor in QALY or WALY benefits of health improvement in addition to the money saved by users, but we also need to discount for how many people won't get the new treatment.

I’m not familiar with this field, so I cannot comment on the technical details of the project. But thanks to everyone who has provided constructive feedback to Martin! I think this is a big part of the value this forum provides. I hope this is useful to Martin as he went to great length to make progress on this problem.