Particles of Thought

HAKEEM: So given how advanced we are with our capabilities, I wonder why there's a certain capability that we don't have, and here's what that is. I constantly hear about researchers going to the Amazon, finding some plant or animal that creates some novel molecule that's useful for us. But why can't we say, "Oh, here's a problem we have. I'm going to use my computational powers to calculate what molecule I need to deal with that problem, then I'm going to synthesize that"? So instead of searching for it in nature, take on that role ourselves, but in a direct way.

SEAN: We do both. We really do both, and I'll give an example. So for example, we have so much better control of AIDS now than we did in the beginning or even the middle of the AIDS crisis, and a lot of those drugs are designed by humans out of thin air. We're saying, "Okay, I need to design a drug that's going to fit into a pocket of an enzyme and shut that thing down," and we design that on computers and we make it in the lab, and then we test it, and there you go.

HAKEEM: Oh wow.

SEAN: So that's drug design sort of from scratch. We do it.

HAKEEM: Okay.

SEAN: At the same time, nature has had millions and millions and millions of years to work on some of these things and come up with sometimes pretty complicated chemistry, a lot of antibiotics, et cetera, those aren't things that a chemist would synthesize just in their spare time someday? They're fancy looking molecules when you first look at them and you're like, "Yeah, nature's has come up with it," and sometimes they're made by sort of longer pathways, lots of chemical modifications, because those arms races that have been happening between, say, a fungus and bacterium in the soil, oh my gosh, those are so old. So let's exploit what nature's been tinkering with for millions and millions of years, while we also-

HAKEEM: And when say millions and millions, you mean tens of millions of millions and hundreds of millions.

SEAN: Tens of millions and hundred of millions of years, et cetera, yeah. I mean, a great example of that, underappreciated story is the first statin.

HAKEEM: What is a statin?

SEAN: Statin. Everybody's-

HAKEEM: Staten Island?

No. People aren't staying.

SEAN: That's where the Wu-Tang Clan is from.

People are on statins to control their cholesterol.

HAKEEM: Oh, right, yeah, yeah, yeah, yeah.

SEAN: The first statin came from a fungus because a Japanese researcher, I'm going to say back in the early '80s, thought, "You know, if I can stop the cholesterol metabolism, if I can get involved with cholesterol metabolism, I could really benefit, for example, cholesterol levels in humans. Well, I'm betting that somewhere out there in nature that's a strategy that some fungus used to stop an invader," and he screened like 6,000 strains of fungi.

HAKEEM: Wait a minute, how did he make that connection, human cholesterol, a fungus stopping bacteria?

SEAN: Yeah. Well, it was kind of the same strategy people use to find antibiotics. A lot of these things are fungal products are antibiotics. So he thought, "There must be like an antibiotic I can use for cholesterol." Because cholesterol is used in making membranes, he thought, "Okay, that might be a target that fungus would use." I think he screened like 6,000 strains of fungi, and that launched a drug revolution.

HAKEEM: And he found what?

SEAN: The first statin, and once you got the first statin, you got the first principle, and then the chemist came along and they said, "Okay, we'll modify this. We'll modify that. We'll make this a little more potent. We'll make this a little easier on the stomach," whatever. But the first statin was pulled out of nature. So there's two strategies going, use nature if you can. I feel the same way with anti-venoms. These animals have had tens of millions of years to work on these defense mechanisms. Let's exploit that knowledge, while at the same time, the laboratory, we can also use our... we got ever more powerful tools for designing drugs.

HAKEEM: So you want to do both.

SEAN: We live in a time where we can do both, we do do both, and let the competition begin. Because very often in drug development, there's a first generation where you didn't have something, then you have something. But this was true for AIDS. I mean, you had to take so many different pills and they were so big and there were side effects and all that stuff. So over the years, what you work on are more potent drugs operating off those first principles, less toxic, more convenient to take. It's the same thing going on with weight loss drugs right now. You know the root of this weight loss-

HAKEEM: Right, right. Yeah, yeah, yeah, Ozempic and such.

SEAN: Yeah. You know the root of this?

HAKEEM: No.

SEAN: The root of this-

HAKEEM: Tell me.

SEAN: ... it's the Gila monsters.

HAKEEM: What? No way.

SEAN: Yeah. This is a discovery. The weight loss drugs are based on a discovery made in Gila monsters. So reptiles can go a long time between meals.

HAKEEM: Yeah, yeah.

SEAN: How do they do that? How do they control their body physiology in these long periods?

HAKEEM: They're cold-blooded.

SEAN: No, they're doing a little more than that.

HAKEEM: They do a [inaudible], yeah.

SEAN: So the lead to what became Ozempic and Mounjaro and all that kind of stuff were discoveries in Gila monsters.

HAKEEM: Wow.

SEAN: This is why when you talk to biologists, we plead for the support of basic research because the more we learn about how nature works, we come up with new ideas of how to, for example, intervene in human medicine. If it weren't for people studying how Gila monsters regulate their physiology in the long gaps between meals, we wouldn't have these weight loss drugs which we now start to understand are helping cardiovascular health, liver health, all this kind of stuff, and we're going from injectables because you're watching the evolution of the drug making to now oral which is a lot more convenient, easier for compliance, we're all also reducing side effects, et cetera. It's the same story being told, a lead from nature, a first in class drug, then the collective human creativity gets involved, and we come up with things that are more potent, safer to take, et cetera, et cetera.