WEBVTT

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All right, so today we're diving into drug discovery.

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And more specifically, how scientists actually

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validate a target. Yeah, it's like, you know,

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before you build a house, you got to make sure

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you have like a solid foundation, right? Exactly.

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You don't want to spend years developing a drug

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that's aimed at the wrong thing. And you've brought

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in some really interesting research on this.

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Oh, yeah. From like classic lab techniques to

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AI. To AI, exactly. And all of it burrows down

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to this one key question. How do scientists confirm

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that a specific molecule is actually involved

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in a disease? Right. Because it's not enough

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to just kind of have a hunch. No, not at all.

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You need evidence. Hard evidence. Hard evidence

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to avoid wasting time and resources. So let's

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start with the traditional methods. Okay, I'm

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seeing kind of like two main approaches here

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genetic and chemical Yeah, those are the two

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big ones So genetic methods so genetic methods

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involve manipulating genes to see what happens

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like actually like tweaking the blueprint of

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a cell Yeah, think of it like you're an engineer

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and you're tinkering with the design So one of

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the classic techniques is the knockout study

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the knockout study where scientists essentially

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silence a gene. So they just like turn it off.

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They turn it off and then they see what happens.

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And from that, they could tell that that gene

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was doing. Exactly. It's like removing a cog

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from a machine. You take out a specific gene

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and you observe what stops working. OK, so it

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helps you pinpoint what goes wrong in a disease

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when that gene isn't functioning properly. Right.

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Our sources talk about PEP2 knockout mouse models.

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PEP2. Yeah, they've been really helpful in understanding

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how the PEP2 transporter affects drug absorption.

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Interesting, so like how well a drug gets into

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the body? Precisely. OK. But I imagine there

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are limitations to these genetic techniques.

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Oh, absolutely. Even with powerful tools like

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CRISPR, there's always a chance of what we call

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off -target effects. Off -target. Off -target

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effects. It's like you're trying to edit one

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specific gene. OK. But you accidentally end up

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editing another gene. Oh, so you get like misleading

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results. Exactly. So you always have to be careful

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with the interpretation. It's like needing a

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double check system just to make sure you didn't

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accidentally delete something important. Exactly.

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Now let's move on to chemical meth. Chemical

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methods. These use something called tool compounds,

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which are basically small molecules designed

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to interact with the target of interest. So each

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tool compound is designed for a specific target.

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Yeah, like a key fitting into a lock. Key and

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a lock, OK. So by observing the effects of blocking

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or activating the target with these keys, researchers

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can kind of tease out its role in the disease.

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It's like seeing what happens when you throw

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a wrench into the machinery. Precisely. And,

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you know, tool compounds are also used in lead

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optimization. Lead optimization. So that's where

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researchers are actually fine -tuning promising

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drug candidates. Right. They're assessing things

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like metabolic stability. Metabolic stability.

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How quickly a compound gets broken down in the

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body. OK. So does it hang around long enough

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to do its job or? Exactly. Or does it disappear?

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Right. If it disappears too quickly, there's

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no point in developing it further. Makes sense.

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So these tool compounds, do they always behave

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perfectly? Sadly, no. No. Sometimes it can be

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a little bit tricky. Tricky how so? Well, sometimes

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they interact with other molecules besides the

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intended target. OK. And that can lead to false

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positives. So it's like the key fitting into

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the wrong lock. Exactly. You might think you've

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found the right target, but you're actually looking

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at something else entirely. So how do researchers

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avoid getting tricked by these false positives?

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It all comes back to rigorous experimentation.

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You know, using multiple methods to really confirm

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a target's role. OK, so it's a gathering evidence

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from different sources. Exactly. You want to

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build a really strong case. Yeah, you don't want

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to jump to conclusions. No, definitely not. And

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that's actually a perfect segue into the world

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of AI -driven target validation. Ooh, now we're

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talking. I've heard so much about how AI is revolutionizing

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drug discovery. It's pretty amazing. Imagine

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having this super -powered research assistant

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that can analyze massive data sets. Like a supercomputer.

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Way faster than any human could. And what kind

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of data are we talking about here? Oh, everything,

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you know, genomic information, protein structures,

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scientific literature, all of it. Wow. And so

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AI can sift through all of that and find potential

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targets. Exactly. And it can even predict how

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drugs might interact with those targets. So could

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it actually help us avoid those accidental delete

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moments we talked about earlier? In a way, yes.

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AI can flag potential issues early on. That's

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incredible. It must save researchers so much

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time and effort. Oh, absolutely. Our sources

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mention AtomWise. AtomWise. Yeah, and their AtomNet

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platform. AtomNet. It's a really great example

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of how AI is changing the game. So how does it

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work? Well, AtomNet uses deep learning to sift

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through enormous chemical libraries. OK. And

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it looks for molecules that could bind to species.

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specific targets. So it's like a matchmaking

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service for drugs and targets. Exactly. And they've

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even used it to identify potential drug candidates

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for neglected tropical diseases. Oh, wow. So

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AI is giving these diseases a fighting chance.

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It really is. It's a really exciting development.

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But even with all of his promise, AI and drug

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discovery... is still in its early stages, right?

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It's right. So we still need those traditional

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methods for validation. Absolutely. It's about

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using the best of both worlds. I like the best

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of both worlds. AI can provide really powerful

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insights and accelerate the process. but we still

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need that rigorous experimental validation. Exactly,

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to confirm those findings and make sure we're

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on the right track. This is all so fascinating.

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It really highlights the complexity and the ingenuity

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involved in drug development. Absolutely. And

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we've only just scratched the surface. Oh, I

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bet there's so much more to uncover. Oh, yeah.

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Maybe we should pause here, let our listeners

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absorb all this. That's a good idea. Take a break,

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and we'll be right back. Okay, so we're back

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and we were just talking about how AI is really

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like shaking things up in the world of target

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validation Yeah, it's really exciting to see

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how fast things are moving. Yeah, it is. But

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um, you know, even AI can't solve every problem,

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right? That's right. It can help us find those

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targets, but Doesn't mean drug development is

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suddenly easy Right, like there are still challenges.

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Big challenges, and one of the biggest is what

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happens during the metabolism process. Oh yeah,

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you're talking about those reactive metabolites.

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Exactly, even when a drug binds perfectly to

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its target, things can still go wrong. And these

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metabolites, they can cause some serious problems,

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right? Oh yeah, from drug reactions to liver

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damage, even DNA damage. That's scary. So it's

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not just about finding the right target. No,

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it's also about what happens to the drug once

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it's in the body. And like how it breaks down.

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Exactly. Researchers need to figure out if a

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drug is going to be metabolized into something

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harmful. That sounds like a super complicated

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puzzle. It is. It's like trying to predict all

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the possible moves in a chess game. So how do

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scientists even begin to predict and mitigate

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these risks? Well, there are a few different

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strategies. One approach is to design drugs that

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are less likely to form those reactive metabolites.

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So it's like designing drugs that are more body

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-friendly. Exactly. And AI can actually play

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a role here, too. Really? Yeah. Some AI algorithms

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can actually predict the metabolic fate of a

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drug candidate. Wow. So it's like having a sneak

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peek into the future. That's a great way to put

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it. It helps researchers identify potential problems

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early on. But even with AI... I'm guessing scientists

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still need to do a lot of real world testing.

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Oh, absolutely. Prediction is just the first

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step. They use a combination of in vitro and

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in vivo models. OK, what does that mean? So in

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vitro means they're testing the drug outside

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of a living organism, like in a test tube. OK.

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And in vivo means they're testing it in a living

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organism, like an animal model. Got it. So they're

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basically testing it at different levels of complexity.

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Exactly. It's like a dress rehearsal before the

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main performance. Yeah, you want to make sure

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everything works properly before you test it

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on humans. Exactly. And speaking of complexity,

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we haven't even talked about protein interactions.

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Oh, yeah. Those are super important, too, right?

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Absolutely. Remember, proteins rarely act alone.

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They're constantly interacting with each other.

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They're like little social butterflies. Yeah,

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exactly. They form these intricate networks that

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influence cellular behavior. So even if a drug

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hits its intent, target perfectly, it could still

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trigger unintended consequences elsewhere in

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the network. Exactly. It's like throwing a pebble

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into a pond. Oh yeah, the ripple spread out.

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Exactly. Affecting the whole ecosystem. So understanding

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those protein interactions is really crucial.

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So how do scientists go about mapping out these

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intricate protein networks? Well, they use a

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combination of experimental techniques and computational

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approaches. One common method is called yeast

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-to -hybrid screening. Yeast -to -hybrid screening.

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I remember reading about that. Yeah, it helps

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scientists figure out which proteins interact

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with each other. So it's like solving a cellular

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puzzle. Exactly. And there are other techniques,

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too, like co -immuno precipitation and mass spectrometry.

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They all sound so complicated. They can be, but

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they all help identify the different protein

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partners that interact with a target. But I bet

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all of that data can be really overwhelming.

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Oh, it definitely is. That's where computational

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biology comes in. OK, so how does that help?

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Well, scientists use sophisticated algorithms

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to analyze these huge data sets and create detailed

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maps of the molecular networks. So it's like

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having a Google Maps for the cellular world.

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Exactly. And those maps can show how a drug might

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affect not just its target, but also its target's

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friends and their friends and so on. It's like

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a chain reaction. Exactly. And it helps researchers

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understand the bigger picture and anticipate

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potential ripple effects. It's pretty amazing

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to realize that cells are such complex ecosystems.

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It is. And it highlights why drug development

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is such a challenging endeavor. But as we learn

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more about these cellular processes, we get closer

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to developing safer and more effective therapies.

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Absolutely. So where do we go from here? What

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does the future hold for target validation? Yeah.

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What's next? I think we're going to see even

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more integration of AI and computational biology

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into every stage of drug development. So those

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technologies are going to become even more powerful.

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Exactly. And that means scientists can predict

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and prioritize targets with even greater accuracy.

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So it's all about working smarter, not harder.

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Precisely. And we're also seeing the rise of

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new approaches like phenotypic screening. Phenotypic

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screening that rings a bell. Yeah. It's a different

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way of looking at target validation. So remind

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me, how does that work again? So instead of starting

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with a specific target in mind, you start by

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observing the effects of a drug on cells or organisms.

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So you're kind of working backwards. Exactly.

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You see a desired effect and then you try to

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figure out how it happened. It's like being a

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detective searching for clues. That's a great

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analogy. And you know what? Phenotypic screening

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has actually led to the discovery of drugs that

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are on the market today. Really? So it's a proven

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approach. It is. It's been really valuable, especially

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when those traditional target -based approaches

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have hit a wall. It's really encouraging to know

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that scientists are always exploring new ways

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to solve these complex puzzles. It is. And I

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think we're just scratching the surface of what's

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possible. Yeah. As our understanding of cellular

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processes grows, so too will our ability to develop.

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even more effective in targeted therapies? Absolutely.

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All right, so we're back. And we've been on this

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deep dive into target validation. And it's definitely

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been ajourner, right? It has. It's clear that

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this is like a really critical step in drug discovery.

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Yeah, you could say it's the foundation of the

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whole process. Yeah, like you were saying before,

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if you're building a skyscraper, you got to make

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sure that foundation is solid. Exactly. You don't

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want to cut corners when it comes to target validation.

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And we've seen how researchers are using all

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these different tools to do it. from traditional

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lab techniques to AI to, you know, a deep understanding

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of how cells work. It's really amazing to see

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how it all comes together. It's a really cool

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blend of science and technology. But I think

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throughout our conversation there's been this

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one theme that keeps coming up. Oh yeah, what's

00:12:04.820 --> 00:12:07.059
that? The importance of context. Context, okay.

00:12:07.159 --> 00:12:09.340
It's not enough to just find a target and hit

00:12:09.340 --> 00:12:11.059
it with a drug. Right, it's like you need to

00:12:11.059 --> 00:12:12.940
see the bigger picture. Exactly, like what's

00:12:12.940 --> 00:12:15.139
the target's role in the cell? How does it interact

00:12:15.139 --> 00:12:19.379
with other molecules? And even how might different

00:12:19.379 --> 00:12:21.259
patients respond differently? Right, because

00:12:21.259 --> 00:12:23.179
everyone's different. Yeah, exactly. So it's

00:12:23.179 --> 00:12:25.580
about appreciating the complexity of biology

00:12:25.580 --> 00:12:28.759
and understanding that there's rarely a simple

00:12:28.759 --> 00:12:31.320
solution. Right, like those protein networks

00:12:31.320 --> 00:12:33.320
we talked about. Oh, yeah. Those are a great

00:12:33.320 --> 00:12:35.580
example. They're so intricate and interconnected.

00:12:35.799 --> 00:12:37.940
Yeah, disrupting those connections can have a

00:12:37.940 --> 00:12:40.620
domino effect. Even if a drug is doing what it's

00:12:40.620 --> 00:12:43.049
supposed to be doing. Exactly. And that's why

00:12:43.049 --> 00:12:45.309
researchers are really starting to focus on systems

00:12:45.309 --> 00:12:48.210
biology. Systems biology. Yeah, it's this holistic

00:12:48.210 --> 00:12:51.370
approach that considers the whole system. Okay,

00:12:51.409 --> 00:12:53.710
so instead of looking at just one protein, you're

00:12:53.710 --> 00:12:55.950
looking at the entire network. Exactly. It's

00:12:55.950 --> 00:12:57.649
like the difference between looking at a single

00:12:57.649 --> 00:12:59.750
tree and then stepping back and seeing the whole

00:12:59.750 --> 00:13:03.090
forest. That's a great analogy. So systems biology

00:13:03.090 --> 00:13:06.250
helps us see how a drug might affect not just

00:13:06.250 --> 00:13:09.129
its target, but also like everything around it.

00:13:09.269 --> 00:13:12.409
Right. It allows us to anticipate potential side

00:13:12.409 --> 00:13:15.029
effects and develop therapies that are more targeted.

00:13:15.309 --> 00:13:17.210
And speaking of targeted therapies, we also talked

00:13:17.210 --> 00:13:19.389
about personalized medicine. Oh, yeah, that's

00:13:19.389 --> 00:13:21.450
super exciting. It's like the idea that treatments

00:13:21.450 --> 00:13:24.250
can be tailored to each individual patient. Exactly.

00:13:24.330 --> 00:13:26.590
Based on their genetic makeup. So we can predict

00:13:26.590 --> 00:13:30.330
how they might respond to a drug or even identify

00:13:30.330 --> 00:13:32.730
potential risks. It's like moving away from this

00:13:32.730 --> 00:13:35.330
one size fits all approach to medicine. Yeah,

00:13:35.470 --> 00:13:37.529
and creating treatments that are truly customized.

00:13:37.750 --> 00:13:39.990
Right. It's about finding the right drug for

00:13:39.990 --> 00:13:42.330
the right patient. This has been a really eye

00:13:42.330 --> 00:13:44.070
-opening conversation. We've covered so much

00:13:44.070 --> 00:13:46.769
ground. We have. It's been great. But I think

00:13:46.769 --> 00:13:49.590
as we wrap up our deep dive into target validation,

00:13:50.450 --> 00:13:52.529
there's one question I keep coming back to. OK,

00:13:52.629 --> 00:13:55.309
what's that? What does all of this mean for,

00:13:55.309 --> 00:13:57.879
like, the average person? Right, why should they

00:13:57.879 --> 00:14:01.019
care about this really complex science? Exactly.

00:14:01.080 --> 00:14:03.379
Well, the answer is actually pretty simple. Target

00:14:03.379 --> 00:14:06.259
validation impacts all of our lives. How so?

00:14:06.320 --> 00:14:08.419
Think about all the medications we take every

00:14:08.419 --> 00:14:11.360
day. For everything. For everything. Headaches,

00:14:11.539 --> 00:14:13.820
heart disease, infections, you name it. So those

00:14:13.820 --> 00:14:15.879
scientists working in labs, they're the ones

00:14:15.879 --> 00:14:18.120
who make those medications possible. Exactly.

00:14:18.360 --> 00:14:20.779
They're the unsung heroes of our health. It's

00:14:20.779 --> 00:14:23.639
a powerful reminder that science isn't just about

00:14:23.639 --> 00:14:25.919
knowledge. No, it's about making a difference

00:14:25.919 --> 00:14:28.669
in the world. and target validation is a huge

00:14:28.669 --> 00:14:30.970
part of that. It really is. It's about developing

00:14:30.970 --> 00:14:34.230
drugs that are more effective, safer, and more

00:14:34.230 --> 00:14:36.830
personalized. It's about taking those scientific

00:14:36.830 --> 00:14:39.289
discoveries and turning them into real benefits

00:14:39.289 --> 00:14:42.250
for people. Absolutely. This has been an absolutely

00:14:42.250 --> 00:14:44.429
fascinating deep dive. I've learned so much.

00:14:44.590 --> 00:14:47.190
Me too. It's been a pleasure. And for our listeners

00:14:47.190 --> 00:14:49.460
who want to learn even more, We've got links

00:14:49.460 --> 00:14:51.120
to some of the research articles we've discussed

00:14:51.120 --> 00:14:53.120
in the show notes. Yeah, definitely check those

00:14:53.120 --> 00:14:54.820
out if you're interested in learning more about

00:14:54.820 --> 00:14:57.059
this really important topic. And with that, we'll

00:14:57.059 --> 00:14:59.220
wrap up this episode of the Deep Dive. Thanks

00:14:59.220 --> 00:15:02.059
for joining us. And until next time, stay curious.
