As the academic system is slowly imploding, my career followed suit and I recently found myself licking my wounds in a cushy industry job (read: adult daycare) and dreaming of startups. This was one of my brainstorms, but for the life of me, I can’t figure out a way that it could ever be profitable, so I’m releasing it into the wild.
You’ve probably heard of the hygiene hypothesis; in a nutshell, our immune systems ‘evolved’ to deal with lives that were, immunologically speaking, nasty, brutish and short. Consequently, the dial on the thermostat got turned up a bit too high for our fully [immunologically] automated gay space communism with pesky luxuries like vaccines, soap and plumbing. The incidences of immune conditions like asthma, allergies, MS, Crohn’s, T1D have gone up three to four fold in the last 70 odd years in developed nations which is too rapid for dysgenics as an explanation. Some interesting pieces of evidence hinting at a deeper truth;
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Adult immigrants from developing nations to the first world are by and large unaffected, but their children do have increases. This suggests an environmental rather than genetic etiology, and furthermore, that the environmental influences have to happen while the immune system is developing (though the evidence for this latter point is not particularly strong in my opinion). 1 2 3 4 5
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Abiotic mice (no bacteria or fungi in their gut, skin, esophagus, etc) have very defective immune systems. Whole compartments of the immune system fail to develop properly, suggesting that interplay between pathogens, benign commensals and the immune system is required.
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A number of studies have shown that even within developed nations, individuals raised on farms or exposed to animals at very young ages have lower incidences of atopy and autoimmunity.
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Your immune system develops in ‘waves’ and is ‘educated’ throughout your development (and almost certainly beyond!). Furthermore, there is substantial variation in our immune systems due to infectious history/environment. (Note that some competing papers took similar approaches with significantly different conclusions). These all point towards significant environmental influences* on these complex immunological diseases.
You’ve probably also heard of Alex Jones claiming that the US government is turning the frogs gay. With this audience, you probably also know that, uh, ‘turning the frogs gay’ isn’t a very honest description, but it is a real problem. Indeed, the process for dumping a new chemical into the environment is labyrinthine, but it probably isn’t particularly effective at screening substances that might influence the immune system. They seem largely focused on chemicals that mimic hormones (see: declining sperm counts and the aforementioned gay frogs).
The crux of this post: Why isn’t more effort expended towards identifying environmental factors, preferably added in the last 70 odd years in the developed world, that modify the immune system?
The hypothesis: Increased exposure to certain chemicals in our environment (food, makeup, air pollution, water contamination), when intersecting with susceptible genotypes, has led to an increase in allergy and autoimmune disease in the developed world.
So, to test it, you’d want to screen large numbers of chemicals in some kind of high-throughput immune assays. Good news: The dataset exists, and you can download it yourself! Bad news: It’s crap! Half-good-half-bad news: Nobody (as far as I know) talks about it or uses it for anything.
About 10 years ago the EPA decided to modernize environmental toxicology and generate The Dataset to end all datasets. They spent (wasted?) tens (hundreds?) of millions of dollars building the data architecture, contracting an army of adult daycare inmates like myself to carry out the assays all to generate a half-dozen low-impact publications nobody has ever read (don’t trust their publications page, it’s padded with anyone who uses the data for any purpose) and this monstrous dataset. Here’s a 728 page pdf some poor soul generated to describe the in vitro assays.
I fiddled around with the data about a year ago at this point, and generated this list of compounds if anyone is interested. I mostly focused on assays relevant to T cells (due to personal biases - B cells are Boring, T cells are Terrific) that came up with a Ka < 10uM, although keep in mind that the majority of these things will be false positives*. Tldr; pesticides are really, really bad and you shouldn’t eat them; they light up every assay like a roman candle. Triclosan was an interesting hit as it’s been (weakly) shown to influence autoimmunity in some mouse models as well as an association with allergy development. Here it came up as a potentiator of lck activity, which is one of the major stimulatory proteins in T cells.
So…who cares? I suppose one might imagine mining some of these molecules as precursors to new drugs after the medicinal chemists have their way with them, although that kind of ‘pharma 1.0’ thinking never really appealed to me. Then again, everyone tells me to just try to make something work, and then your second company can be your vanity project/moonshot. Alternatively, I’ve got to assume that such a large database is amenable to machine learning, maybe along the lines of this paper? I think the largest problem is that the majority of the data here is without a doubt crap. Less relevant to the startup perspective is what the EPA actually wants to do, which is regulate some of these compounds. This would probably be prosocial, but then, if you wanted me to do prosocial stuff you should have given me my academic lab, ja?
*Note that, as complex traits, there are obviously genetic influences on the development of atopy and autoimmunity. The intersection of susceptible genetics and environment leads to disease.
**Cons: - Tons of false positives as many of these compounds won’t be bioavailable or aren’t present in quantities large enough to be relevant
Dataset sucks and others have claimed it to be unreliable
Unclear that people suddenly started being exposed to these things in the last 70 years
Assays poorly optimized and either cell-free (very prone to false positives) or done artificial overexpression systems
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I remember going to a panel about virology and biology as it relates to fiction at a comic convention one year. One of the panelists, who studied at ASU, talked about the allergy thing and Red Queen Syndrome(?), and how one of their colleagues, who suffered from a peanut allergy, had the ballsy idea to fly to some African country and intentionally contract a hookworm(!). It actually worked, and they could eat a peanut butter sandwich without suffering an allergic shock.
But then, I don't suppose we could ever think of trying to treat allergic and autoimmune conditions by having people deliberately infect themselves with something their immune systems can focus on.
I'm assuming they meant the Red Queen hypothesis? We're in an evolutionary arms race with pathogens and we have to run as fast as possible just to avoid losing ground.
Yeah, people have seen this kind of thing for a while. There's been some efforts to identify the molecular bits that mediate the immunomodulation, but my impression the last time I looked into it (probably nearly a decade ago to be fair) is that there's something about live worms that's required to get the immune system going, much like how live attenuated vaccines are normally better. I doubt live worms as a treatment would make it past an IRB, or be very appealing for most people.
Why can't we just make a worm smoothie? (as disgusting as that sounds. I'm sure the nice folks at Biotechnica could devise a way to make it in pill form.)
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It wasn't a peanut allergy, it was some fairly crippling gut related autoimmune disease.
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Why not? I mean the problem is obviously having ourselves a permanently active immune system with nothing to do so it keeps lowering its standards for what is a threat until it gets something. At least that's my interpretation. Maybe not a hookworm, but probably give it something to work with. Maybe they should have a disease vaccine, but it just gives you mild variants of diseases with an immune response in humans in general. Then you go home get two days of fever and voila, eat a peanut butter sandwich without choking to death and your face veins exploding.
Not a scientist, most of what i said is conjuncture based on limited understanding.
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Why not? Treatment of syphilis by deliberately induced malaria used to be a thing. It worked.
https://en.wikipedia.org/wiki/Pyrotherapy
https://en.wikipedia.org/wiki/Malaria_therapy
Injecting bacteria into tumors too!
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