[Question] Are parasitic worms an effective weapon against MS?

[Demeter]

I’m in the process of acquiring hookworms to trial within my own body. While I’m doing that, I’m researching the effectiveness of using immune modulating parasites to treat rheumatoid arthritis and multiple sclerosis, and I’d love a little help. My reasons for doing all this are given below. But first, some background on what the hell I’m talking about.

Some research groups are running clinical trials where helminths (intestinal worms) are administered to patients with autoimmune disease and other inflammatory conditions (University of Wisconsin School of Medicine and Public Health, University of Nottingham, Australian Institute of Tropical Health & Medicine). As a result of increasing activity within this field over the last ten years, a small online community has formed around helminthic therapy, with the aim of making parasitic worms widely accessible to people with inflammatory conditions ranging from severe allergies to MS.

Proponents of worm therapy have a long list of references not only demonstrating that helminths counter the inflammatory response, but also theorizing that the elevated frequency of inflammatory disease in higher-latitude and more developed nations is due in large part to the absence of immune mediating parasites that co-evolved with humanity near the equator (this concept is related to the hygiene hypothesis—see this PNAS article for an update regarding they hygiene hypothesis, where helminths are specifically discussed).

However, not everyone is on board with the parasites-for-all initiative touted on pro-worm websites. Even when research teams have observed a positive effect, they have been reluctant to recommend live parasites as a long term treatment option, preferring to study the anti inflammatory secretions of the parasites for drug development. This strategy avoids the risks of parasite infection gone wrong, but proponents of helminth therapy are doubtful that a pharmaceutical approach will capture the full effect of live parasites. They are also concerned that the drugs may not arrive for a long time, whereas patients with progressive illnesses have time-sensitive needs.

Where I’m coming from and what I’m after:

I have casually followed the occasional news regarding helminth clinical trials for years, having a mother who lives with the chronic pain of rheumatoid arthritis. I’m getting serious about it now because the stakes just rose dramatically. My fraternal twin is in the process of having a diagnosis of progressive multiple sclerosis confirmed (that’s the especially disabling and unstoppable MS that afflicts about 10% of really unlucky MS patients).

That makes two women in my immediate family with seriously debilitating inflammatory conditions. I’ve read in the past that families can display a genetic predisposition toward developing autoimmune disease (I plan to investigate this idea further as part of this review). I’m not feeling optimistic about my own future right now, so I’m motivated to act on an idea I have been toying with for a very long time: get worms in order to reduce the risk of getting something much worse than worms.

If my own helminth trial goes well and my research provides enough evidence in favor, I will bring this option to my family’s attention. My specific questions on this topic are thus shaped by personal motivations:

1. What’s the evidence for/​against helminth therapy preventing the development of inflammatory conditions in adults who did not grow up with worms?

2. What’s the evidence for/​against helminth therapy as a treatment for progressive MS and rheumatoid arthritis?

3. How significant is the genetic factor regarding an individual’s likelihood of developing MS or RA?

4. What evidence favors helminth-inspired pharmaceuticals vs. living organisms?

Why am I getting worms now, before I’ve finished the review?

I don’t have them yet and I might change my mind on this, but here’s my explanation

This review might take a while, and I believe it’s wise to occupy a safe default state in the meantime before allowing the evidence to convince me to switch to a more risky experimental state. The thing is, the evidence so far indicates that everyone in western society is living in a risky experimental state (sterility) and the results in my family have been very bad.

I’m being careful not to fall into the naturalistic fallacy here; western hygiene has lots of benefits, such as reduced infectious disease across the board. But considering the fact that necator americanus species is benign enough for research groups to give carefully limited quantities to their patients, I’m inclined to occupy worm state as my default (risks of intestinal upset during adjustment period, null results, unexpected consequences of altered immunity), while remaining open to evidence that I should switch to western state (elevated risk of awful things like MS). If things go wrong, I’ll kill the worms with de-worming medication.

I’ll declare a bias here: seeing my sister’s ability to walk become rapidly impaired over the last few months, I feel like my body is a ticking time bomb that must be disarmed as soon as possible.

Why I might change my mind on this bit: COVID19. The whole point of worm therapy is to modulate my immune system. This can potentially lead to an under active immune system. I’ll continue to assess the risks and may switch positions if helminths seem to be a risk factor for worse COVID19 outcomes (while still social distancing and wearing a mask in public etc so I don’t get COVID19 in the first place).

Who might be interested in collaborating:

Anyone with an inflammatory condition, including asthma, allergies, and autoimmune disease. Anyone at risk of getting an inflammatory condition. Anyone who studies this stuff. Anyone who thinks worms are cool and this could be a really successful strategy for preventing autoimmune disease, and anyone who thinks this is a terrible idea and the author must be discouraged from moving forward.

A Review of the Risks and Benefits of Helminth Therapy

Why does anyone think worms are a good thing? The Hygiene Hypothesis and old friends...

You’ve probably heard of the Hygiene Hypothesis, which proposes that an increase in sanitation instigated a rise in allergies and autoimmune disorders over the last century in developed nations. The original idea was that the immune system is trained, so to speak, by early exposures to pathogens. In such a model, a childhood without pathogen exposure was expected to result in dysfunctional immunity, potentially leading to disorders where the immune system is over reactive to benign triggers (allergies) or inappropriately reactive to molecules originating within the body (autoimmunity).

The Hygiene Hypothesis has been updated in recent years, and this article in PNAS (also referenced above) provides a good summary of the new model: our immune systems are not suffering from lack of pathogen exposure, but rather from a loss of exposure to microscopic “old friends” with which our immune systems co-evolved, including microbiota of the gut. This development his been driven by many factors, including sanitation and hygiene, antibiotic medications and cleaners, and dietary changes.

Various studies inspired the shift in focus from pathogens to “old friends”. One such study involved parasites: Gabonese children with chronic Schistosoma haematobium (not a parasite anyone recommends self-inoculating with) infection were less reactive to dust mite allergens (Biggelaar et al, 2000). The authors observed evidence of immune modulation by the parasites: higher concentrations of the anti inflammatory cytokine interleukin 10.

A new picture of parasites emerged as scientists investigated their impact on immunity further. To protect themselves from immune attack, parasites modify the host’s system. They stimulate the proliferation of regulatory immune cells and the release of various anti inflammatory cytokines (Smallwood et al, 2017). They are also extremely common in equatorial regions. A recent report by the WHO states that soil-transmitted helminths continue to inhabit the bodies of 1.5 billion people worldwide, or 24% of people alive today. The WHO and other sources (T. Smallwood et al 2017, S. Navarro et al 2012 plus references contained therein) also note that morbidity results from an excessive worm population, and that people with light infections usually do not appear to suffer from them. This fits with an equilibrium-driven model of the parasite/​host relationship.

As Navarro et al explains:

″ A successful parasite–host relationship is one that borders on commensalism, where the parasite causes little to no overt damage or loss of fitness to its host, thus ensuring its continued transmission. ”

These facts- the ubiquity of parasites in our ancestral environment plus their clear immune modulating activity and the idea that they benefit from a comfy long term relationship with the host- combine with the “old friends” model of immunity to suggest that the ancestral human immune system may have been profoundly affected by co-evolution with parasites. When we lost our “old friends”, were hookworms among them? Many scientists now believe the answer is yes.

At some point, lots of research groups jumped on the “maybe worms are the new frontier for treating inflammatory disease” bandwagon. This has become an area of intense research, where the predominant goal is to figure out the pathways of immune modulation by parasites and to recreate the same benefits with low-risk therapies.

I’m currently working my way through a review article that sums up recent results in both animal models and clinical trials, Helminth Immunomodulation in Autoimmune Disease (published in Frontiers in Immunology in 2017), and here’s my own summary of what’s been done lately...

Damn what a cliff-hanger. I’m taking a break before I write more. Check back later.

Infecting yourself with worms: what could possibly go wrong?

Worms can do all sorts of nightmarish things, but really it depends on the species. I will focus on the species currently being utilized by research groups and garage helminth enthusiasts: Necator americanus, Trichuris trichiuria, Trichuris suis, and Hymenolepis diminuta.

Here are some categories I intend to research, which I’ll fill in as I go along:

Excessive worm populations

Unauthorized worm migration (this would all be a little ironic if worms migrated to my brain)

Helminths as vectors for other parasites, viruses, or bacteria

Incompatibility with medications

Accidentally infecting people who really don’t need worms in their lives

Experimenting with your immune system in the age of COVID19

Adults getting worms as prevention: is it already too late?

This section is a work in progress

What sets off Multiple Sclerosis? Twin studies and the viral-onset hypothesis.

In my quest to identify actions that will reduce my MS risk, I feel it’s important to note that MS isn’t simply the product of bad genes and worm-free modern life. Twin studies indicate that the inflammatory response is initiated by an additional environmental factor.

You might say my sister and I are a twin study, but we’re not the special kind of twins that all the attention in those studies. You know the kind. They start as a single zygote and turn into Fred and George Weasley. Identical twins are known for being the bestest of best friends, doing everything together, occupying similar professions, and marrying people who look and act the same. And, due to the fact that they originated from the same zygotic genome, they are much more likely to end up with the same medical conditions than your run-of-the-mill siblings. Twin studies help scientists sort out nature vs. nurture for lots of traits and conditions where we have uncertainty about the role of genes vs. environment.

In a twin study Sophia and I would be more like the control group: we share no more DNA than any two siblings, but like any other pair of twins not separated at birth, we also shared a womb environment and had common childhood experiences within our family: same diet, same parenting style, same early childhood activities.

Despite the shared environment, we are perhaps the most-different set of fraternal twins who ever emerged from the same womb. I have seriously wondered if there was a hospital twin-swap. When we were kids, most strangers didn’t think we were siblings. I was small for my age, a wiry little bean pole who ate everyone else’s leftovers and never gained any weight, feisty and full of energy, and didn’t hit puberty until 14. She was a calm and gentle kid, took naps during the day, had to watch her weight from the time she hit puberty at 11 ¹⁄₂, and was often mistaken for being a couple years older than she really was. While I double-majored in biology and biochem and took philosophy to round out my education, she studied sociology and gender and took dance to round out her education. We never expected to be the same in any regard.

Over the years, some similarities have emerged, small reminders that we share parents and, long ago, a womb. We have the same allergic reaction to vicodin. We both experience a lifelong elevated baseline anxiety that we’ve both worked hard to manage during our lives. We both love women (I also love men). She presents as gender non-binary while I swing wildly back and forth between androgyny and femininity. We both have flaky scalps that get irritated by all sorts of things people put in their hair.

At a time like this, it’s hard not to wonder: why is she the one struggling to walk?

Why her and not me?

And why now, at the age of 33?

It turns out we’re not the only twins asking ourselves those questions. Identical twins are faced with the same conundrum. According to the National MS Society, twin studies have demonstrated that the identical twin of someone with MS has only a one in four chance of developing it too. Epidemiological data indicate that MS may be set off when an environmental stimulus strikes individuals who are already predisposed to inflammatory disorders, initiating a war in the brain and spinal cord that damages myelin in the crossfire.

This observation has lead some research groups to search for a viral trigger. Epstiein Barr Virus (EBV) is a leading candidate listed by the National MS Society...

More to come. Working on it.

Anecdotal: another trigger for one patient’s MS symptoms was… parasites that had migrated to the central nervous system! This actually happened to a college friend’s father. He had a diagnosis of MS for over 40 years and had lost most of ability to move. When his daughter was in medical school, she requested a test for salivary antibodies and detected Ascaris lumbricoides, taenia solinum, and trichinella. He was treated with four rounds of Albendazole. Laura reports that, with time, “95% of his positive attributes came back” (I don’t know what this means first hand because I haven’t seen him in about 10 years, but it sounds like a great improvement).

A little ironic? As I said above, parasites can do all sorts of nightmarish things, but it really depends on the species. None of those species is being used to treat anyone for anything, as far as I can tell, aside from a few people’s ill-informed attempts to lose weight by getting tapeworms.

This section is a work in progress

Alternatives for someone in my position

I’m getting a lot of recommendations for additional preventative measures against MS et al, and I thank everyone for contributing. I will take all actions that seem likely to reduce my risk. All actions. I might still end up getting worms.

That said, are there any currently available alternative strategies that do what worms reputedly do, or do it better? I’m looking. If I find them, I’ll list them here.

I’m adding more to this post as I gather information, and I intend to incorporate information provided by collaborators. Join me. Read about worms. You know you want to.

References

Formatted for legibility and linked so you can find them

Secondary: Research updates, web sites, and scientific press

A. Gasper 2010. Fleming’s worm egg research entering second phase. National MS Society publication.

Australian Research Council 2018. Combatting autoimmune disease with the humble hookworm. Published online.

Helminthic Therapy Wiki.

The Hygiene Hypothesis according to Wikipedia.

Schistosoma haematobium according to Wikipedia.

M. Scudellari 2017. News feature: cleaning up the hygiene hypothesis. PNAS 114 (7) 1433-1436

Soil-transmitted helminth infections according to the WHO.

S. Navarro et al 2012. The hookworm pharmacopoeia for inflammatory diseases. Current Opinion section of the International Journal for Parasitology.

Twin studies according to Wikipedia.

Secondary: review articles

T. Smallwood et al 2017. Helminth immunomodulation in autoimmune disease. Frontiers in Immunology https://​​doi.org/​​10.3389/​​fimmu.2017.00453

Primary literature

R. Tanasescu et al 2020. Hookworm treatment for relapsing multiple sclerosis, a randomized double-blinded placebo-controlled trial. JAMA Neurology, published online.

A. van den Biggelaar et al 2000. Decreased atopy in children infected with Schistosomahaematobium: a role for parasite-induced interleukin-10. The Lancet, 356, 1723-1727.

More references not yet incorporated into my review

P. Gregersen et al 2009. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol. 2009; 27: 363–391.

[Stuart Anderson]

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[Demeter]

Thanks for the additional recommendations. I’m looking into various means of prevention and don’t expect to find any silver bullets, but rather feel like I’m packing a cartridge with lead shot, piece by tiny piece. If/​when I move forward with worms, I intend to notify my doctor and keep a whole notebook of observations.

In my own case, I do see this approach as potentially being preventative, if not for MS then perhaps for RA. But if additional research indicates that the preventative effect is insignificant in adults (compared to children whose immune systems are still developing), I’ll abandon the idea for myself and may continue to research worm-related therapies for the people in my family who do already have inflammatory conditions.

[herv]

You have already found the only published randomized trial of worms in MS (the JAMA neurology paper). If I were in your position, worms would not be the first option I would look into.

One meta-reason to be skeptical: one often sees worms touted as a solution for all autoimmune diseases. But therapies are not trivially transferable across autoimmune diseases. For example, anti-TNF therapies are effective in RA, but exacerbate MS; natalizumab is effective in MS, but exacerbates neuromyelitis optica. The latter case is especially shocking, as NMO is clinically nearly identical to MS, and was in fact considered a variant of MS for a long time. The biology is distinct across different autoimmune diseases. The concept of “autoimmune disease” has been of limited help in understanding the biology or treatment of MS.

(One further note: it’s not even clear that MS is an autoimmune disease. It’s definitely immune-mediated, but unlike in RA, nobody has been able to identify an antigen.)

In order of options that I would pursue in your situation:

1. Get an MRI. People with MS typically have radiological activity for years before their first clinical episode. Use a high-resolution MRI, which can spot lesions which are smaller or outside of white matter. 7T is the highest resolution, but (last I checked) is only available in research trials. You might be able to get into a trial related to familial MS. Otherwise get a 3T, which is widely available.

2. Get a test for serum neurofilament light levels. This measures the concentration of degraded proteins from the nervous system floating around in your blood. After MRI, this is the second-best validated biomarker of neuronal damage in MS, and likely can measure ongoing damage which is too diffuse to spot on MRI. Not in widespread clinical use in the US, but it is being used in the UK and Scandinavia, and likely to be widely available in the US soon.

3. Sunlight/​vitamin D. Lots of evidence that low levels of sunlight exposure/​vitamin D are associated with development of MS. The literature here is a mess, and there’s less evidence that this is causal, but still some evidence. For example, people who move from high sunlight to low sunlight environments early in life have higher rates of MS than those who move later in life (https://​jnnp.bmj.com/​content/​jnnp/​63/​5/​565.full.pdf) and vice-versa. The causal evidence is largely confounded with the hygiene hypothesis, but there is much more associative evidence for Vitamin D (for example, people with MS typically have extremely low Vitamin D levels at diagnosis).

The reason to get more sunlight or supplement with vitamin D is that these are simple and safe in moderation.

There is another point here which is relevant to worms. The causal evidence points to MS risk being modifiable by early-life environment but not later life (post-teenage) environment. If the hygiene hypothesis is correct, I am not sure that exposure to worms will be useful to you now.

4. Minocycline. Probably going too far given the information you currently have, but it’s widely used to treat acne, and has at least been shown to reduce the probability of MS onset in high-risk individuals (https://​www.nejm.org/​doi/​full/​10.1056/​NEJMoa1608889).

[Demeter]

Thanks! I like your point about the low transferability of therapies across inflammatory disease, and I share your concern that exposure to helminths may not reduce risk in adults whose immune systems are all grown up. I’m looking into those recommendations.

[remizidae]

Have you quantified the risk that deworming medication might not work?

[Demeter]

I haven’t quantified any risks because I’m not practiced in doing that. That’s one reason I’m posting here—as I compile more information, I’d love a little help with formal assessment of risk.

[romeostevensit]

I’ve been thinking of doing this and would love to piggyback some of your investigation/​logistics. Will you be posting updates to LW?

[Demeter]

Yes! I will update this post. I’m not sure if updates rise to the top of the list...? If not, I’ll re-post when I have a significant update.

[Perverse Transcriptase]

You may want to first look into oral tolerization/​desensitization with myelin oligodendrocyte glycoprotein (or peptide fragments thereof) or other possible self-antigens associated with MS. IIRC the data for oral tolerization has not held-up well in human trials, but if you’re looking for a Yudkowsky-style inadequate equilibria solution then it might be worth attempting a very steep dose escalation of a variety of antigens (or all you can find). This approach, at face value, seems that it would be less risky than helminth inoculation.

Another approach or fallback to consider preparing for is banking a stock of very pure haemopoietic stem-cells (HSCs) for a possible Immunoablation and subsequent transplantation (see, e.g., Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85.). I have not followed-up on the Atkins study or looked at it in several years, but I’d imagine that isolating HSCs from the patient at an earliest low/​non-symptomatic phase of the disease (or prior to possible disease as in your case) would decrease the chances of contamination with autoreactive immune cells.

While you are performing your literature review, keep in mind that animal models of MS (such as EAE) are very deficient in their predictive capacity (even much more so than its reference class of autoinflammatory/​autoimmune animal models).

[Demeter]

Thanks! I’ll look into both those options. I’m also curious about stem cell transplantation for my sister. Speaking of animal models- I assume your point about animals is they are not always predictive the drug and treatment effectiveness in humans, but I’m curious to know what you think of the viral-onset hypothesis inspired by observations in monkeys. It’s referenced on the OHSU research web site and I was planning to read more about it.

[snog toddgrass]

My response

1. Ew gross worms

2. That logic holds up, Greater expected value in worm world.