3 ms·

The short answer here is yes. We're constantly working to get more complete models, but surprisingly big effects can come from surprisingly small pieces of the

The short answer here is yes. We're constantly working to get more complete models, but surprisingly big effects can come from surprisingly small pieces of the puzzle. We still don't even really understand how Tylenol/Paracetamol/Acetaminophen works! A great example of the gap between our current models and what would be sufficient comes from the COX-2 inhibitors (Vioxx/Celebrex). Ibuprofin (Motrin/Advil) and other NSAIDs modulate both COX-1 and COX-2 receptors in the body to reduce inflammation, but inhibiting COX-1 also causes stomach damage. The early COX-2-specific inhibitors were designed from the ground up using our best models, which were thought to be well-understood. Unfortunately, after several years on the market, it was discovered that this also came with a large increased risk of heart attacks and strokes. The body just has so so many moving pieces, and while we're getting better, it's going to be some time before we are able to base these studies entirely on theory, and when we get there we'll be able to skip the mice entirely!

ethbro 9y ago
As my dad (pathologist) put it, "Nature is a lazy bitch. She'd rather repurpose the same thing 50 times than develop something novel." So add up random biochemical pathway * X million years of evoltion, and one begins to understand the fun of drug discovery and testing. "We know this is the pathway involved in heart disease. We know this chemical compound is effective against that pathway. ... Now why are all our mouse models getting erections?"
amelius 9y ago
Is somebody maintaining the relationships between compounds, genes, and their high-level effects somewhere? I'm aware of biological pathway diagrams (e.g. KEGG), but they seem so unreadable, and for me they don't connect the dots between substance and effect.
- toolbox 9y ago
  The relationships and high-level effects are maintained in our body of literature. It's hard to resist wanting to put it all in some sort of megachart, but even the pathway diagrams vastly simplify the real interactions. The reason they don't seem to connect substance and effect is because often the substances are very far removed from effect, or may not lie on a known pathway at all. It's still very much a "we don't know what we don't know" situation, which is both intimidating and exciting. There's a lot to be done before our models are even adequate, but we at least get to be part of that learning process.

ethbro 9y ago

As my dad (pathologist) put it, "Nature is a lazy bitch. She'd rather repurpose the same thing 50 times than develop something novel." So add up random biochemical pathway * X million years of evoltion, and one begins to understand the fun of drug discovery and testing. "We know this is the pathway involved in heart disease. We know this chemical compound is effective against that pathway. ... Now why are all our mouse models getting erections?"

amelius 9y ago

Is somebody maintaining the relationships between compounds, genes, and their high-level effects somewhere? I'm aware of biological pathway diagrams (e.g. KEGG), but they seem so unreadable, and for me they don't connect the dots between substance and effect.

toolbox 9y ago
The relationships and high-level effects are maintained in our body of literature. It's hard to resist wanting to put it all in some sort of megachart, but even the pathway diagrams vastly simplify the real interactions. The reason they don't seem to connect substance and effect is because often the substances are very far removed from effect, or may not lie on a known pathway at all. It's still very much a "we don't know what we don't know" situation, which is both intimidating and exciting. There's a lot to be done before our models are even adequate, but we at least get to be part of that learning process.