Is Vitalik going to die because he ate crickets?
An autistic dive into allergy and chitin (Part 1)
Welcome to Science with Shrike! Today we’re going to talk about eating insects, like crickets. We will focus on the immunologic aspects. This discussion is spurred by Ethereum creator Vitalik Buterin eating crickets, and the general push by global elites to normalize insect-eating for the masses as a sustainable alternative to meat. More recently, Tetranode posted the following (paper here):
Up front, this is not a ‘should I eat crickets?’ post. We all know the answer to that one (if you don’t, in the future you may use $XRP to buy your grasshoppers). This post aims to answer the questions, ‘Is eating crickets, or other chitin-containing insects, inflammatory?’ and ‘What impacts on allergy might eating chitin-containing arthropods have?’
Answering these questions are not straightforward, because there are several complications that we need to deal with first. The first complication is that your body has different ways of recognizing things that stimulate immune responses, depending on where they are in the body. The same immunostimulatory protein may be treated differently if it’s found in the lungs, in the gut or circulating in your blood. The reason is that your blood should be free of most foreign substances, whereas your gut is full of them. Your lungs have to expel foreign substances, repair damage, and still allow oxygen to your blood. Different challenges that your immune system must deal with.
The second complication is that how allergy arises remains controversial. Allergy has been increasing in the developed world. One proposed explanation is the hygiene hypothesis. This hypothesis posits that our immune system is not prepared for the increased cleanliness we see today, so we’re missing prior exposure and resolution of immune responses, which leads to allergy.
Finally, we need to dissect allergy responses, chitin responses, and other immunologic risks from both the innate and adaptive immune system. For completeness, there is more than just chitin in insects. However, most of those other components are not universal enough to be worth our innate immune system singling those components out for warning. The microbes/parasites living in insects could harbor human pathogens. However, a recent study found that the parasites reflect the source region. Regions that have endemic tape worms in the water, etc, also have the same tape worms in the insects. Especially when compared to the human pathogens living in suspended animation in honey (Clostridium perfringens, C. botulinum—reminder to NEVER feed your infant raw honey), the potential impact of human pathogens living in edible insects seem to be minimal—region is more important.
While chitin is the main danger signal, to consider allergic responses, we will first consider allergy mechanisms, build in the other complications as we go, and then cover chitin in the next post. Also, there are different kinds of allergy. This discussion is about “Type I” allergy. For a summary of the others, see Shrike’s tweet thread:
Allergy requires both arms of the immune system, innate and adaptive. The innate immune system recognizes a defined list of problems, and has a set of instructions to follow when it encounters those problems. It may help to think of the innate system like a computer program: it can execute with ruthless efficiency, but it can’t operate outside of its parameters, and can be exploited. In contrast, the adaptive immune system figures out novel problems, tailors the response to those new problems, and coordinates the innate response to the problem. With our programming example, the adaptive immune system is more like the programmer. It has to figure out why the program is not solving the problem, and update it to fix it. In both cases, it is the program resolving the problem. This is the case with the immune system, where your innate system does most of the dirty work.
Your immune system has common response plans to deal with pathogens, depending on the type of pathogen. Pathogens that try to hide inside your cells require different responses than ones than small ones like bacteria and fungi that live outside of your cells. Giant pathogens (i.e. worms, or “helminths” as they are often called), need yet another response. The response to worms is the same kind of response plan that causes allergy. For brevity, we call this a Th2 response, short for T helper cell type 2 response (Th1 destroys pathogens inside cells and Th17 destroys small pathogens outside cells). Don’t let ‘helper’ in the name fool you: T helper cells are the cells that organize and drive the adaptive immune response.
Since a Th2 response is aimed at removing giant pathogens, it does 5 key things. First, it tries to sweep the invader out of the body. This is why you get runny nose, runny eyes, coughs, etc during allergy. Second, it opens up your blood vessels and other barriers to help immune cells get to the site of the problem. That’s one reason you puff up like the Stay-puft Marshmallow Man during allergy. Third, it tries to murder the pathogen, or at least make life so unpleasant for the invader that the invader withdraws. Specialized innate immune cells call basophils and eosinophils carry out this task, with the help of mast cells and innate lymphoid cells. Fourth, the immune system orients towards a “wound healing” response, where macrophages help tissues repair damage caused by a giant worm biting its way through, and other collateral damage. This can drive fibrosis and keloid formation when it gets dysregulated. Finally, the immune system “remembers” the pathogen, so that it can rapidly respond the next time it encounters the problem. This immune memory is why you react more potently to allergens after the first encounter or two.
Your body also needs to turn off the immune response when the problem is solved. Parts of the shut-off mechanism relevant to this discussion are “Tregs” and IgG4 antibodies. Tregs are “regulatory T cells”, where “regulatory” is used in the government sense of the word—suppression and elimination. So Tregs shut down the immune response through murder and intimidation. Good thing these are cells and not people!
IgG4, or Immunoglobulin gamma 4, is one particular subtype of antibody. Antibodies, or immunoglobulins, do many different things in the body, and help instruct the innate immune responses. IgG4 activates responses that help shut down the immune response to its target. As expected, this occurs late in the immune response.
The last concept we need to cover is the specificity of the adaptive immune response. The adaptive immune response uses tailor made proteins to recognize specific targets, called antigens. Specificity is not binary, but a spectrum. If two antigens are very similar, the adaptive immune system can still react to the similar antigen. How well the non-target antigen is recognized by the T cell also influences the response. If it recognizes it very well, it drives the same Th1, Th2 or Th17 response the original antigen did. If it is recognized poorly, it can drive a Treg response.
In practice, there are some pathogen-non-pathogen pairs where the similarity happens often in humans. Certain subtypes of strep throat bacteria (especially in Rwanda) look like your heart’s mitral valve. This is how rheumatic fever develops. Relevant to allergy, there are several allergens that are similar to worm antigens. For example, Herring worm proteins look similar to allergens from Bermuda grass, German cockroaches and one of the many cat allergens. Other examples include worms with proteins that look similar to papain (in papayas), dust mites, and shellfish protein.
These similarities and other observations (such as the rise in asthma and hay fever) led to the development of the hygiene hypothesis. The overall idea is that modern environments do not educate the immune system in the same way as occurred 100-300 years ago, and this failure accounts for the increase in allergic reactions. The specifics have been refined and expanded as evidence rules in or rules out different predictions of the hypothesis.
You can see how some of the mechanisms addressed above are consistent with the hygiene hypothesis. Helminth exposures can lead to the development of regulatory T cells and production of IgG4. These may prevent the development of the allergic responses. So it’s possible that exposure to insect antigens, especially early in life, could reduce some allergies, instead of increasing them.
Next, we need to cover routes of administration. You do not develop an immune response to the broccoli you eat, despite it being a foreign antigen. That is due to the route of administration. Since your body expects foreign antigens in the gut, it does not mount an immune response against them. This was demonstrated with a generic antigen (egg white protein, or ovalbumin). When mice were fed ovalbumin, they did not develop an immune response to it when they were later injected with it. Mice not fed ovalbumin did develop an immune response. On the other hand, oral tolerance is not perfect, and not always sufficient to prevent hypersensitivity responses. Shrike suspects most food allergies do not develop in the gut, but due to exposure via other routes (especially lungs). Once sensitized, oral tolerance will not help.
In contrast to eating foods, your lungs seem predisposed to a Th2 response. This may account for the more common allergies being respiratory in nature. If you inhale chitinous organisms (for example, house dust mites), it may sensitize you to other allergens (shellfish).
From an insect-consumption standpoint, eating insects, especially from an early age, may reduce allergy rather than increase it. However, there would likely be occupational exposure to cricket dust if you work in the factory that makes the cricket flour, or otherwise grinds up the insects. We already know how to deal with respiratory hazards in the workplace (eg other toxic dusts), so the main issue would be occupational safety and PPE for the workers.
It is worth noting that with other common foods that drive different kinds of allergic reactions (eg celery-pickers’ disease, mangoes, raw cashews), the occupational risk does not stop us from producing or consuming the foods.
In the next post, we’ll consider chitin itself, and how (or if) it modifies these responses.