Progress in Biology Is Slow – Here's How We Can Speed It Up
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Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#2A few comments:
* We already have good PK/PD models, PBTK, human physiology models based on differential equations, and toxicity prediction servers. If it was integrated in a smart and easy to use software suite, it would do a lot to reduce the cost of clinical trials. We could even incrementally improve this with toxicicity prediction servers that would be aware of physiology [0].
* You can certainly try to make a good model of mice physiology, as dr Guyton did for humans 50 years ago. But how can you answer a medical question with this model? Let say you want to create a drug for type II diabetes. How can any kind of biology model help you in this task? You would need to run some kind of genetic algorithm on this model, so it would be extremely slow and costly.
* Instead of scaling with mice, you can use organoids, it will be much more realistic, and you will not have the effect that drugs work on mice model but not on humans. Which brings this question: To design organoids you need to have a very good understanding of their biology, but this is what you want to discover!
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#3> If we care about blood pressure, for example, why have we not given every drug, at every dosage, every regiment, and in every combination to a mouse and actually seen what happens?
One of the answers is hidden behind this question: Ethics.
We could make a ton of progress if we started growing humans for lab testing. Then we could run massively parallel tests and get data much quicker. I mean, think about how much we could learn grom the brain if we had a large lab full of humans whose brains we could arbitrarily poke and prod at. Direct access would make us so much faster. But... is this something we will ever want to do?
Ethics force us to attack problems of (human) biology indirectly.
If we're talking about biology in general, though, I think we have made enormous progress in the last 10-20 years. In fact, I don't think we are in any way prepared for how accessible DIY biology is becoming. You can engineer viruses in your basement now. Once gene synthesis can be done in a garage, anyone could engineer anything they wanted (anthrax, ebola, whatever). Progress in biology is accelerating.
My guess is that in the future "learning how to live forever" will be seen as alchemy's goal of turning lead into gold. In theory, you could slam a bunch of subatomic particles together to do it, but that's not really worth doing. We've found other ways to get what we want from nature (shininess, gold color, conductivity, etc.) without using gold. The "living forever" argument also runs very quickly into philosophy (ship of Theseus) and away from biology.
I think it's much more interesting to consider the biological factories that we're building. Directed evolution, CRISPR, BIL Gates, gene drives, etc. We're making real headway into playing god.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#4Why does hn love every low effort, low information blog post on biology? Basically this boils down to just throw more resources at the problem + machine learning.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#5There are 3 major flaws in this thesis:
1. The number of synthesizable, drug like molecules is enormous
2. To have a sufficiently powered experiment, you need to run it multiple times
3. Drugs don't work in a vacuum, it also interacts with the specific genetic/epigenetic/proteomic/microbiomic makeup of the organism. You can't really control for all of that.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#6The possible chemical space is incredibly vast. Even a large collections of potentially interesting molecules at hundreds of thousands or millions of molecules isn't even scratching the surface.
Going directly to mice is certainly problematic in an ethical terms, you're going to kill many millions of mice for something that has very low odds of succeeding.
Biological systems are noisy, the chance that one of your hits is just doing something funny, but not useful is very high. Going directly to mice is only making this worse, as that is a much more complex system as an assay that simply measures binding to a protein.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#7There are 3 major flaws in this thesis: 1. The number of synthesizable, drug like molecules is enormous 2. To have a sufficiently powered experiment, you need to run it multiple times 3. Drugs don't work in a vacuum, it also interacts with the specific genetic/epigenetic/proteomic/microbiomic makeup of the organism. You can't really control for all of that.
There's so much more missing that makes me think this is an engineer writing about how biological research should be in theory, without the understanding and experience the complicated nature of biological research. Well, suppose we want to give "every drug, at every dosage, every regiment, and in every combination to a mouse". Well, that's a combinatorially large search space and one reason drug companies focus on high throughput screening of drugs before applying them to mice. Then even for the promising ones you have other effects that will skew your results, like handler effects (e.g. https://www.nature.com/news/male-researchers-stress-out-rode...). If we want to apply the drugs to that many mice, are we only gonna use female mice because males tend to fight and kill each other when placed in the same cage? Then what do we do about the sex skew? Then there's the fact that 96 million years separate humans from mice, which is relatively short in a genetic perspective but not that much from an epigenetic perspective. How well will results translate?
This is just off the top of my head, and I'm not a biologist. I'm sure actual experienced biological researchers can come up with a whole bunch of other issues. Because more often than not biology is whole lot messier than we can imagine.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#8There are 3 major flaws in this thesis: 1. The number of synthesizable, drug like molecules is enormous 2. To have a sufficiently powered experiment, you need to run it multiple times 3. Drugs don't work in a vacuum, it also interacts with the specific genetic/epigenetic/proteomic/microbiomic makeup of the organism. You can't really control for all of that.
Agreed, I don't know much about biology but I can see many limitations with this brute-force approach.
We live in a finite world, the infinite monkeys metaphor has no value.
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#9There's an interesting article on the topic published in 2012 [0, 1, 2]. One aspect the paper talks about different causes for the current situation. One of them being, "The ‘basic research–brute force’ bias".
> The ‘basic research–brute force’ bias is the ten- dency to overestimate the ability of advances in basic research (particularly in molecular biology) and brute force screening methods (embodied in the first few steps of the standard discovery and preclinical research process) to increase the probability that a molecule will be safe and effective in clinical trials
[0] https://www.nature.com/articles/nrd3681
[1] https://blogs.sciencemag.org/pipeline/archives/2012/03/08/er...
Re: Progress in Biology Is Slow – Here's How We Can Speed It Up
#10For anyone interested in biology's slow advance, I'd highly recommend checking out the 2003 study that coined the term "Synthetic Biology"[0].
TL;DR is that we've known that dropping costs and scaling collaboration is how to make biotech better for many years now. This time span is also a testament to how hard it actually is.
As someone who works in synthetic biology on tools, I think a major problem is that the incentives are wrong for making the field better (they're stuck in a local maximum). The incentives of pharma + selling to academics doesn't really select for lower prices or increased collaboration.