 I would argue that anesthesia is possibly the most important miracle of modern medicine. You might think of advanced cancer treatments and everything, but the reason we can't treat so many disorders now is that we can't perform surgery. It used to be the case that a good surgeon was a fast surgeon, and that's no longer true. We can operate on nine-year-olds today because we can sedate them controllably and also revive them. This is a picture from the Morton Auditorium at Massachusetts General Hospital in October 1846, when Edward Abbott here is having a tumor removed from his neck, and he survived to tell the world about it. At the time, they didn't know what actually caused you to go unconscious, and I would argue that that was the case for probably over 100 years after this. A very large part of modern anesthetics is mostly trial and error. There was one very important result already 100 years ago that there is a surprising correlation, not just correlation, but almost a perfect correlation over orders of magnitude between how hydrophobic a molecule is and how good it is as an anesthetic. Based on that, everyone assumed that anesthesia must just somehow work on our lipid membranes and change the fluidity or something in our lipid membranes, and then magic happens and then you fall asleep. It's not a bad model based on what we knew about lipid membranes and everything at the time, until some other experiments happened the last 30 years. So first we started to see a few anesthetics that broke these rules, and they were some of the most efficient ones. The second part is that people found the ligand-gated ion channels and noticed that there are certain mutations you can make in these channels that make it impossible to sedate mice with the mutants. It doesn't matter how much anesthetic you have, they are not susceptible to it. And that's of course a very strong indication that we have a binding site for the anesthetic in a particular protein involved in our nervous system rather than acting on the membrane. Today I think we know roughly what those binding sites are based, for instance, on Ryan Hibb's work. But if I draw this membrane, one could argue that both explanations are still kind of relevant. So if I have my membrane, it is definitely clear that if I have an anesthetic that's very hydrophobic, the anesthetic will go in here in no time, no question about it. And then of course I have this ligand-gated ion channel sitting here with some sort of binding site. And depending exactly what happens here, this anesthetic will enter this binding site or not, depending on how large it is, how solubility it is in the lipid bilayer and how easily accessible this site is. That in turn is likely related to, for instance, the cholesterol compounds binding here. So there's a competition for this binding site from cholesterol, anesthetics, other small molecules. It's a wealth of fun information there that I won't have time to go into. Why do I think that's important? Well, because I glossed over one important anesthetic. One of the most efficient anesthetics is actually Xenon. Xenon is known for many things, but not its great binding properties. Xenon is a small, completely hydrophobic molecule that doesn't really want to interact with anything. Xenon will instantly partition into the lipid bilayer. The question is why should Xenon bind? For a long time we thought that there might be some influence of the fluidity of the membrane or local pressure, although Olaf Andersen's group showed some 10 years ago that that's likely not the case. It's hard to measure, but they were one of the groups that used to argue for it. And if even they are giving up on the idea, I wouldn't believe it either. Xenon is subject to an hydrophobic effect though, but once it's already in the membrane, there's not going to be a strong hydrophobic effect to go into the protein. So I think the blind answer here is I don't know why Xenon is so efficient as an anesthetic. Do a PhD with us or somebody else and find out if you're interested. It's a super interesting result that is slightly intimately related to how lipids stabilize proteins and how proteins change their conformations depending on the lipid surrounding.