A socratic dialogue over why drugs work at all
1.5k words, 7 minute reading time
Why do drugs work at all?
What do you mean?
Like, how come if I take, say, ibuprofen, it’s able to help with my sore back?
Oh, that’s no mystery. Ibuprofen inhibit enzymes called cyclooxygenases, which are involved in producing prostaglandins. Prostaglandins induce inflammation. A lot of pain — including sore backs — is caused by too much muscular inflammation. So, if you turn down COX, you turn down prostaglandins, which turn down pain. Indirect mechanism.
You aren’t understanding me. Ibuprofen is some external chemical I’m introducing to my body. My question isn’t about the mechanism of action, more how the hell is it able to interact with anything in me at all?
Well…your body functions using a huge collection of biomolecules. As in, enzymes, hormones, and so on.
If you introduce a so-called xenobiotic, or a synthetic chemical, into the system, it will inevitably interact with those natural biomolecules. For example, returning back to the case of ibuprofen, it is small enough to be absorbed into your bloodstream through your digestive system. Once in your blood, it circulates throughout your body. Whenever it encounters any other biomolecule, there’s a chance it reacts with it.
In ibuprofen’s case, it is reactive with the COX enzyme. Ibuprofin affects its ability to contribute to the arachidonic acid pathway, which has prostaglandins as the end output. If we’re being specific, ibuprofen binds specifically at Arg-120 and Tyr-355 of the enzyme. This is the entrance of the ‘cyclooxygenase channel’ of COX, which is the same place where arachidonic acid binds.
So…ibuprofen just blocks arachidonic acid from going where it should be going.
Stop! You still don’t understand! Why does ibuprofen exist at all? Why is it that anything that doesn’t naturally float around in my body is allowed to interact with it at all?
I think it’s helpful to consider that largely all the biomolecules in your body are meant to be multifunctional. Like, dopamine isn’t just involved in making you happy, it’s also involved in motor control. In turn, whatever dopamine is interacting with is also multifunctional, D1-D5 receptors (the primary way dopamine exerts its effects) can also bind to completely unrelated proteins, like COPG, which is involved in coating cellular vesicles. And we don’t even know why!
Because of this multi-layered multi-functionality, you should naturally expect a pretty high probability of cross-talk between biomolecules. It’s actually more surprising that the body doesn’t collapse into tangled spaghetti than it is that an external molecule has some physiological effect.
Okay…that makes some sense. But ibuprofen was created in some lab, right? How come I keep reading these stories about how natural metabolites or molecular byproducts from other species can be used in humans? Why is there any sort of transferability?
There’s a general term for these sorts of things: bioactive compounds.
Lots of bioactive compounds used in human medicine do come from animals, such as ACE inhibitors from pit vipers or penicillin from mold, which is pretty strange. It’s a fair question: why is there such a high level of consistent cross-applicability of drugs from one species to another? Or, if we’re leaning on jargon, why does pharmacophylogenomics exist as a concept?
One important thing to remember: we all evolved together. Everything that is ‘living’ on Earth descended from one another, there are hundreds of millions of years worth of genetic lineage tying humans to dogs, cows, insects, wheat, and even yeast cells together. Cell walls, protein synthesis, DNA replication — the core machinery is remarkably similar whether you're looking at bacteria, fungi, plants or animals.
You can observe this macro version if you ever visit a natural history museum. You’ll see rib cages of whales, shoulder musculature of lions, and hearts of cows that look an awful lot like our rib cages, muscles, and hearts. It’s not a coincidence! We’re all descended from the same stuff.
And, while it’s not naively obvious that these macro similarities imply micro similarities, they do continue at the cellular scale.
We all use DNA as the base genetic material, mitochondria exist in most eukaryotic cells, cell cycle proteins are unchanged across most multicellular organisms, and ATP is the primary energy currency.
Moreover, similarities at the basest levels seem to propagate upwards. More complex, higher-level pathways like the Krebs cycle, glycolysis, and DNA transcription/translation also display an enormous amount of consistency in the general process across species. Why is that? Even if there is such deep evolutionary connections between life, why has little changed in millenia? Nick Lane, a biochemist who has written at length about the origins of life, would likely say that because life is fundamentally a chemical phenomenon, all species are similarily constrained by the chemistry, thermodynamics, and energy availability that the earth provides. Moreover, once these strong constraints are satisifed, there may be relatively little evolutionary incentive for it to massively change.
So, the existence of a common universal ancestor makes it so bioactive compounds from one species have a decent chance of doing something in a different species?
Yes! Not at all guaranteed, but way higher than random chance.
It is worth noting that the limit of this cross-talk is controlled by whether the compound is activating something that an organism is already capable of doing! As in, if you want a cell to perform some task using some external chemical, there must also be some situation in which the cell naturally does that anyway.
A simple example is luciferase. Luciferase is an enzyme that causes bioluminescence in some species, like jellyfish and fireflies, by catalyzing a chemical reaction that produces light. But pushing luciferase into a human cell will not do anything, because the substrate that luciferase operates on (luciferin) isn’t naturally created by humans.
What if we put both luciferase and luciferin in a human cell? Well, okay, that works.
But let’s consider a more complex example, like the process of nitrogen fixation in certain bacteria and archaea. These microorganisms use a complex enzyme called nitrogenase to convert atmospheric nitrogen (N₂) into ammonia (NH₃), which can then be used by plants. However, introducing nitrogenase into human cells wouldn't suddenly give us the ability to fix nitrogen. Human cells lack the entire chemical pathway necessary for nitrogen fixation, nitrogenase alone is insufficient! For example, we don't have the bevy of specialized cellular proteins (like those found in nitrogen-fixing bacteria) that protect nitrogenase from oxygen.
Okay…that makes sense. But this still feels a little…weirdly altruistic of other species. I get that they aren’t building these chemicals purely for us, but ancient tribes did use chemicals derived from plants. And I imagine the plants don’t like being ripped up and ground up. Why haven’t they evolved away from being useful to anybody else?
Okay, fair question.
We’ve set up quite a neat story for why biomolecules should interact with one another but…you’re right, there are incentives for this not to happen. Animals (even beyond humans) are capable of pattern recognition, and if they slowly learn that eating a nearby plant helps with pain, that should hurt plants ability to survive. What incentive is there for plants to be of any assistance to other animals? Wouldn’t they try to evolve away from biomolecules that are compatible with life around them?
Well, they do. The premise we’ve set up is a bit incorrect; the plants do desperately want to deter away animals. Many of their secreted chemicals have neurotoxic properties, they are basically natural pesticides. But humans, and many other animals, likely evolved detoxing mechanisms and neurophysiological defenses to deal with the effects of such chemicals. Caffeine, nicotine, and cocaine are all such examples of technically neurotoxic chemicals that humans just have good defenses against.
Obviously, we’re not immune to everything! Plants have won on some fronts. But we’re an active participant in the evolutionary game they are playing, we’re winning some as well. This part is a fair bit more theoretical than anything else I’ve discussed, since evolutionary history is always a thorny subject, but it does make sense.
TL;DR of your point?
Natural compounds in our bodies often interact with multiple targets, since every layer of our physiology is multifunctional and thus displays molecular promiscuity in what it reacts with. This complexity extends across species due to our shared evolutionary history, allowing biomolecules from diverse life forms to interact with human biology. And, even when it’s disadvantageous for those other species to offer us those therapeutic chemicals, humans (along with other animals) can build up evolutionary defenses against any noxious effects that those chemicals have. Because of all this, drugs exist and will be commonly found in other living organisms.
Weird. Weird weird weird.
I also think so!
I think this is pretty good!
I'd also say something about how some molecules, like dopamine, are evolutionarily conserved because they are broadly useful and very complicated. So, the dopamine in bananas is actually the same as the dopamine in our brains, and there's a fair bet that any tools bananas have to deal with their dopamine will also work on our dopamine.
Also, while caffeine, nicotine, and cocaine originally evolved to deter predation, the plants that produce them have evolved (and been selectively bred) now to encourage predation by humans. Being a useful plant to humans is a really successful evolutionary strategy. So, I think your point about "why don't plants evolve away" only works for that initial brief period that humans were detrimental to these plants' evolutionary success, like what supposedly happened with silphium.
Very interesting topic, there are many implications and questions about pharmacophilogenomy, both at how protein changes truly alter ligand binding (IMHO druggability via permutating variants of a known ligand is considerably simpler than reported, via post translation protein modifications, see e.g how almost all lead to relatively successful phenethylamine substitutes with relatively preserved TAAR1 agonism), the second being that similarly to how flowers or butterflies have emergently evolved to reproduce and maintain e.g. the shape of a face without any feedback from vision that many species have evolved drugs to bind stably to receptors they do not even express themselves (polyphenols, toxins, etc) this tend to argue that druggability is simpler than considered.
Anyway on a pedantic nitpick: ibuprofen main mechanism is not IIRC because of the inflammation caused by COX enzymes which is somewhat mild compared to cytokines but because COX is a key mediator of nociception
https://pubmed.ncbi.nlm.nih.gov/17071117/
IIRC ibuprofen is a major antalgic and a minor antiinflammatory drug (despite antipyretism)
(with off topic roles in the digestive system, and in vasodilation especially of the kidneys, btw other prostaglandins have understudied role in the brain and in chronobiotism)