Ask HN: How close are we to replace animal models with software?

In pre-clinical trials for some diseases, animal models are notoriously nearly useless. The story of the C9orf72 mice model (a familial ALS/MND model) who lived healthily in a Broad lab, while their counterparts at Harvard died quickly [0, 1] has been widely discussed.

In general, for nervous system diseases, mice models are not translatable to humans. One reason might be that their nervous system is quite different from those of primates/humans, for example, great primates have direct motor neuron connections (no interneurons) for complex manipulations.

So scientists often try to develop animal models closer to primates, see for example [1]. But their methodology for validating animal models intrigues me.

Basically, they seek to disrupt to some extent some biological function, and if the behavior/phenotype of the animal model looks like that of human patients, then it is assumed the animal model is correct.

I wonder if it's not possible to use a software model of a human being with the same level of effectiveness. For example, there are very complex software models of human beings (see Biogears engine and similar [3]).

If we apply the same methodology to human software models and if when we disrupt a biological function, and if then the software model displays the pathological behavior, isn't as valid as an animal model?

I would be interested to know your advice.

[0] https://www.alzforum.org/news/research-news/gut-microbes-dif...

[1] https://pubmed.ncbi.nlm.nih.gov/32483373/

[2] https://pubmed.ncbi.nlm.nih.gov/39343009/

[3] https://www.biogearsengine.com

Biologist here. We're definitely not close to replacing animal models with software. However, many aspects of animal models can be studied using cell culture systems. I work on ovarian organoids, which can be used to develop fertility therapies.

Still, organoids will merely reduce the number of animals used in drug development rather than eliminating them entirely. Before giving a drug to humans, testing whether it's safe to give to animals is a step that can't be skipped for the foreseeable future.

I took a look at the Biogears website that you linked, and it looks like a physiology simulator, i.e. more of a model of a plumbing system than a full organism. Something that can model heart rate and blood pressure won't be able to say if a cancer drug will work (or if it will have a toxic side effect).

There's a huge difference between when we know how an organ system behaves in a particular circumstance vs. when we don't. Take, for example, the hepatic function in biogears: https://github.com/BioGearsEngine/core/blob/trunk/projects/b... If you know all the constants and how the liver reacts to a given stimulus, then sure, you don't need to test anything out in vivo. But the reason we do experiments is that we don't know how the liver will react in a given circumstance, so we can't rely on known equations to tell us the answer.

I also think that while there are circumstances where animal models are not helpful, those tend to make the news because they are the exception rather than the rule. There are many, many diseases where animal models were critical for figuring out at least where to look for human disease processes. In addition, a lot of the issues with mouse models are not due to the fact that mice are inherently a poor substitute for humans, but that the models (the specific genes mutated) were a poor mimic of human diseases. For example: "Measurements of gait and grip strength showed that their muscle deficits were in fact mild, and post-mortem examination found that the animals died not of progressive muscle atrophy, but of acute bowel obstruction caused by deterioration of smooth muscles in the gut." [https://www.nature.com/articles/507423a]

Modeling a creature is so damned hard. Take a single celled organism and break it down to the most basic one you can imagine: I'm willing to bet a model of its interaction with drugs would take decades to be useful in any manner. We're only just getting __ok__ models of how protiens fold and even then within specific temperature boundaries. Even then the error rate is high enough that they'd be a lot of issues. You cant just have 5% of your protiens being wrong. Even if we assume perfect protien folding models it's another problem to model correctly how they'll interact wit X drug or eachother. If you want to start somewhere, try modeling hemoglobin. It's got a simple job: Move oxygen through blood, dump it, and pick up CO2. Yet it's fussy as hell. if the protien is slightly off it'll become useless. And you can't cheat because plenty of diseases that are all about homoglobin being "slightly off" so you can't just hack it so all your homoglobins are perfect magic carriers, you'd have to model it perfectly and watch how drugs may interact with it.

Every step of this modeling would be hellish. Not to mention just how much stuff you'd need to model and have simulated in parallel for even the most basic of creature simulation. Parallelization is trivial for nature. Once it figured out how to create one cell the the next 2 or a trillion was easy. In computer simulations the first model just as resource intensive to simulate as the next... simulating a trillion cells? Ooofff. You'd be lucky to get a second of simulated time after a months run.

Not close. This might be the best whole-animal sim available, and it is a for a worm: https://openworm.org/