Tag Archives: biology

Maybe Your Zoloft Stopped Working Because A Liver Fluke Tried To Turn Your Nth-Great-Grandmother Into A Zombie

Or at least this is the theory proposed in Brain Evolution Through The Lens Of Parasite Manipulation by Marco del Giudice.

The paper starts with an overview of parasite manipulation of host behavior. These are the stories you hear about toxoplasma-infected rats seeking out cats instead of running away from them, or zombie ants climbing stalks of grass so predators will eat them. The parasite secretes chemicals that alter host neurochemistry in ways that make the host get eaten, helping the parasite transfer itself to a new organism.

Along with rats and ants, there is a dizzying variety of other parasite manipulation cases. They include parasitic wasps who hack spiders into forming protective webs for their pupae, parasitic flies that cause bees to journey far from their hive in order to spread fly larva more widely, and parasitic microorganisms that cause mosquitoes to draw less blood from each victim (since that forces the mosquitoes to feed on more victims, and so spread the parasite more widely). Parasitic nematodes make their ant hosts turn red, which causes (extremely stupid?) birds to mistake them for fruit and eat them. Parasitic worms make crickets seek water; as the cricket drowns, the worms escape into the pond and begin the next stage of their life cycle. Even mere viruses can alter behavior; the most famous example is rabies, which hacks dogs, bats, and other mammals into hyperaggressive moods that usually result in them biting someone and transmitting the rabies virus.

Even our friendly gut microbes might be manipulating us. People talk a lot about the “gut-brain axis” and the effect of gut microbes on behavior, as if this is some sort of beautiful symbiotic circle-of-life style thing. But scientists have found that gut microbes trying to colonize fruit flies will hack the flies’ food preferences to get a leg up – for example, a carb-metabolizing microbe will secrete hormones that make the fly want to eat more carbs than fat in order to outcompete its fat-metabolizing rivals for gut real estate; there are already papers speculating that the same processes might affect humans. Read Alcock 2014 and you will never look at food cravings the same way again.

But del Giudice thinks this is just the tip of the iceberg. Throughout evolutionary history, parasites have been trying to manipulate host behavior and hosts have been trying to avoid manipulation, resulting in an eons-long arms race. The equilibrium is what we see today: parasite manipulation is common in insects, rare in higher animals, and overall of limited importance. But in arms race dynamics, the current size of the problem tells you nothing about the amount of resources invested in preventing the problem. There is zero problem with war between Iran and Saudi Arabia right now, but both sides have invested billions of dollars in military supplies to keep their opponent from getting a leg up. In the same way, just because mammals usually avoid parasite behavior manipulation now doesn’t mean they aren’t on a constant evolutionary war footing.

So if you’re an animal at constant risk of having your behavior hijacked by parasites, what do you do?

First, you make your biological signaling cascades more complicated. You have multiple redundant systems controlling every part of behavior, and have them interact in ways too complicated for any attacker to figure out. You have them sometimes do the opposite of what it looks like they should do, just to keep enemies on their toes. This situation should sound very familiar to anyone who’s ever studied biology.

Del Giudice compares the neurosignaling of the shrimp-like gammarids (small, simple, frequently hijacked by parasites) to rats (large, complex, hard to hijack). Gammarids have very simple signaling: high serotonin means “slow down”, low serotonin means “speed up”. The helminths that parasitize gammarids secrete serotonin, and the gammarids slow down and get eaten, transferring the parasite to a new host. Biologists can replicate this process; if they inject serotonin into a gammarid, the gammarid will slow down in the same way.

Toxoplasma hijacks rats and makes them fearless enough to approach cats. Dopamine seems to be involved somehow. But researchers injecting dopamine into rats don’t get the same result; in fact, this seems to make rats avoid cats more. Maybe toxoplasma started by increasing dopamine, rats evolved a more complicated signaling code, and toxoplasma cracked the code and now increases dopamine plus other things we don’t understand yet.

Aside from the brain, the immune system is the most important target to secure, so this theory should predict that immune signaling will also be unusually inscrutable. Again, this situation should sound very familiar to anyone who’s ever studied biology.

Second, you have a bunch of feedback loops and flexibility ready to deploy at any kind of trouble. If something makes dopamine levels go up, you decrease the number of dopamine receptors, so that overall dopaminergic neurotransmission is the same as always. If something is making you calmer than normal, you have some other system ready to react by making you more anxious again.

Del Giudice makes the obvious connection to psychopharmacology. Many psychoactive drugs build tolerance quickly: for example, heroin addicts constantly need higher and higher doses to get their “hit”. Further, tolerance builds in a pattern weirdly similar to antibody response – it takes a while to build up a cocaine tolerance, and you lose it over time if you don’t use cocaine, but the body “remembers” the process and a single hit of cocaine years later is sufficient to bring you back up to the highest tolerance level you’ve ever had.

The standard explanation for tolerance is that it’s an attempt to maintain homeostasis against the sort of conditions that can cause natural variation in neurotransmitter levels. I never questioned this before. But why is the body prepared to suddenly have all its serotonin reuptake transporters inhibited? Is that something that frequently happens, out in nature? I guess maybe plant toxins could do that, but then how come the body is prepared to deal with this for months or years?

While not denying the value of these standard explanations, Del Giudice thinks defense against parasite behavior manipulation may also play a role. Remember, gammarids absolutely have parasites that try to increase their serotonin levels as a prelude to getting them killed. Is it that surprising that a lot of different animal lineages would develop a reaction of “If something other than normal cognition has started increasing your serotonin levels, it’s a trap and you need to get them back down again”? Does that explain why SSRIs don’t work for some people, or randomly stop working, or need frequent dose escalation?

Third, you encode messages in the timing of pulses. This is a central feature of neuroendocrine communication – an intense pulse of testosterone at 6 AM means something different from tonically high testosterone all day. Parasites cannot do pulses. Remember, these parasites are usually microscopic. Each parasite can only produce a miniscule quantity of neurotransmitter or hormone. Only colonies of thousands or millions of parasites can produce enough chemicals to affect host signaling. This parasites cannot communicate or coordinate with each other, so there’s no way for them to be producing lots of testosterone one minute and none at all the next. That means that when a hormone arrives in a pulse, or better yet a complicated pattern of pulses, that’s a pretty reliable sign that it’s coming from a real gland.

Fourth, you exploit your individuality. The immune system already does this; there are some genes called the major histocompatibility complex that are designed to be especially variable, such that most people (except identical twins) will have different MHCs. These help the immune system differentiate self from other. Because they have such high individual variability, pathogens can’t just evolve around the MHC; they would have to undergo an entire evolutionary process for each new host they invade.

Del Giudice wonders if parasite-host arms races created pressure for increased human variability. SSRIs will make some people less depressed. But some people will get more depressed. A few will even get suicidal. A very few will flip out and become psychotic, or improve much more quickly than the textbooks say should be possible and feel completely reborn on day 3, or have something else even weirder happen. I always assumed God just hated psychiatrists and wanted them to be miserable. But another possibility is that extreme individual variability in neurosignaling pathways is a defense against parasite manipulation. If the effects of serotonin are unpredictable for any individual, no parasite species can devise a universally valid mechanism for controlling its hosts.

Fifth, you let the parasites become part of the furniture. If everybody in your ecosystem is infected with a parasite that raises serotonin, you just evolve a tonically lower serotonin level, and then it all cancels out. This one seems a little bit weird to me – surely this isn’t the stable equilibrium? But:

A downside of preemptive strategies is evolved dependence (de Mazancourtet al. 2005): if brain physiology and behavior are designed to function optimally when the parasite is present, the absence of the parasite will lead to inappropriate or fitness-reducing behaviors (Weinersmith and Earley 2016; see also Johnson and Foster 2018).

I think this is meant to hint at the “hygiene hypothesis”, ie our immune systems are screwed up because we are not getting exposed to the parasites it was built to expect. Suppose lots of parasites try to downregulate the immune system (which sounds logical enough), and the body doesn’t know which ones it’s going to get but expects it to follow a Poisson distribution around some mean. Then it might just upregulate the activity of the immune system that same amount. If you get rid of all the parasites, then your immune system is just set too high and you get autoimmune disorders.

(in case you had the same question I did – yes, the parasitologist Kelly Weinersmith cited above is the same Kelly Weinersmith who co-wrote Soonish with Zach Weinersmith of SMBC fame.)

Sixth, you use antiparasitic drugs as neurotransmitters. This is the kind of murderous-yet-clever solution I expect of evolution, and it does not disappoint. Several neurotransmitters, including neuropeptide Y, neurokinin A, and substance P are pretty good antimicrobials. The assumption has always been that the body kills two birds with one stone, getting its signaling done and also having some antimicrobials around to take out stray bacteria. But Del Giudice proposes that this is to prevent parasites from hijacking the signal; any parasite that tried to produce or secrete an antiparasitic drug would die in the process.

Dopamine is mildly toxic. The body is usually pretty good at protecting itself, but the mechanism fails under stress; this is why too much methamphetamine rots your brain. Why would you use a toxic chemical as a neurotransmitter? For the same reason you would use antiparasitic drugs – because you want to kill anything smaller than you that tries to synthesize it.

People always talk about the body as a beautiful well-oiled machine. But sometimes the body communicates with itself by messages written with radioactive ink on asbestos-laced paper, in the hopes that it’s killing itself slightly more slowly than it’s killing anyone who tries to send it fake messages. Honestly it is a miracle anybody manages to stay alive at all.

All these features together are a pretty effective way of dealing with parasite manipulation. There are a few parasites that can manipulate human behavior – rabies definitely, toxoplasma maybe – but overall we are remarkably safe.

Del Giudice argues that a combination of factors make it easy for parasites to manipulate insects but not large vertebrates. First, insects are small, so you only need a few parasites to produce an insect-sized level of neurotransmitter. Second, insects are so simple that usually one neurotransmitter maps nicely to one behavior; they are too small to support multiple redundant systems or complicated signal cascades. Del Giudice writes:

Although parasites can evolve subtler and more indirect means of manipulation, their computational capabilities are ultimately limited by their size. As the size and complexity of the host’s brain increase relative to the parasite, the disparity may become so extreme that the host is able to “outcompute” its adversary, making complex manipulations effectively impossible. The parasite may still be able to alter the host’s behavior in nonspecific ways (e.g., sickness, brain damage), but is unable to induce the kind of coordinated pattern required for trophic transmission or bodyguard manipulation. Although this argument is admittedly speculative, it is consistent with the fact that complex behavioral manipulations have not been documented in larger, warm-blooded animals (see Lafferty and Kuris 2002).

Finally, almost nothing eats humans, so there aren’t a lot of parasites interested in using us as a vehicle to get to their definitive hosts. If parasites want anything from us, it’s probably STIs wishing we had more risky sex; accordingly, Del Giudice obliquely cites Greg Cochran’s controversial hypothesis that homosexuality may be related to parasites hijacking sexual machinery.

But let’s take a step back: is any of this true?

The strongest evidence against is the dog that didn’t bark. Some systems look heavily defended against parasite manipulation, but others don’t. Amphetamines raise dopamine effectively and without significant tolerance buildup (see part IV here for a defense of this claim); antipsychotics lower dopamine equally effectively and consistently. Since dopamine is one of the most lucrative systems for parasites to hijack, it’s surprising to find it so easy to affect. And what about immune function? Externally administered corticosteroids decrease immune activity and make the body more vulnerable to infection; why don’t parasites secrete them? Why don’t we have some counter against them? These systems look consistent with an evolutionary history in which we don’t expect any threat from parasite manipulation and don’t need to defend ourselves very hard.

But also: homeostasis might be the most basic activity of all living things. Every bodily system can be modeled as a striving for homeostasis in some domain or other, even high-level cognitive functions. So it’s not clear that tolerance to psychiatric drugs needs a complicated evolutionary explanation beyond just “if you increase serotonin, your body is going to try to decrease it again, because that’s what bodies do“.

So I’m not sure how much of an effect this really had. It’s an interesting theory. But whether it explains some things, nothing, or everything, it’s too early to say.

But I like this paper because it takes the complexity of biology seriously. There’s a sense that science is stagnating, and biology is one of the worst offenders. In the 1800s and early 1900s, we were pinning down our mastery of anatomy, discovering all the major hormone systems, learning about microbes and inventing antibiotics. It seemed like the same kind of thing as physics, where you could go out into the world, observe things, and make difficult but fundamentally straightforward discoveries. But for the past fifty years, it’s been kind of a mess. Despite some amazing work by amazing people, we still don’t even understand questions as basic as what depression is. Everything seems bogged down in a million different opaque signaling cascades that fight off any effort to untangle or shift them.

Del Giudice offers a seductive explanation: the perceived perversity of the human blueprint is absolutely real. Parts of it – the parts most involved in health and disease – were sculpted by evolution to be as hard as possible to understand or affect. This makes me feel better about how often the drugs I prescribe fail in surprising ways