Why Drugs That Work in Mice Don't Work in Humans

In my (admittedly indirect) experience, there's always a specific medical issue being targeted, and usually a specific biochemical system (i.e. protein binding partner). Very occasionally, they end up with a drug for a condition completely different from what they were trying to treat, but that's the exception. (Viagra was one of these; I would have loved to have been a fly on the wall when they realized the implications of the side effect profile from the original trial.)

I wonder if a similar proportion of drugs that work in Humans wouldn't work in mice. Are we missing out on a ton of potential?

It's just about every way you could imagine. I work at a large company, where my department has something like 75 people in 25 labs working on one disease area. Anything we think we can build a case for is worth considering, and we'll run down lots of leads that don't turn up anything. We get chemists involved to make tool compounds that might hit your target pathway, and eventually, if you build enough evidence to convince management, you'll put together a team. That team will involve a few biology labs, a chemist (could be a biochemist) or two, a toxicologist, and a pharmacokinetics person (ADME).

Then, if it's a chemical target, they'll make thousands of compounds to test in their preliminary tests to make sure the compound very basically attaches to the target. The ones that make it past that might make it into a cell-based assay then rodents. The path each treatment takes through specific assays is different for every project depending on the specifics, but it generally follows that progression.

This is a huge field of research and development, with a number of different approaches.

Almost always, though, you are starting with a particular medical problem in mind, so the first step is to develop some kind of assay for detecting compounds which might be useful in treating it. Ideally, this would be a simple biochemical reaction, but it might be something involving cell culture.

For example, if you wanted to find new painkillers, you might look for chemicals inhibiting cyclooxygenase (as ibuprofen does). You can buy kits for doing that assay commercially [1], where you prepare a solution of the enzyme, add your test chemical, then add a substrate which emits light when the cyclooxygenase breaks it down, and measure the intensity of light produced.

If you wanted to find new anti-cancer drugs, you might look for drugs which cause proliferating cells to get stuck in the metaphase step of the cell cycle (as paclitaxel does). You would plate out some rapidly proliferating cells, add your test chemical, wait twelve hours, then fix them, stain them with a DNA-specific dye, and use a microscope to count the number of cells in metaphase (which is quite distinctive [2]). This is a lot more tedious than the cyclooxygenase assay, but we have robots that can handle liquids and plates of cells, and operate microscopes, and process images, so it can be highly automated, at a cost.

Then you take your assay and go hunting for molecules.

One approach is indeed just to start with a wide range of compounds. You can get libraries of small molecules [3] [4], so you give them to your robots (or graduate students), and put them all through your assay to find which ones work.

You can also start with mixtures of compounds, perhaps obtained from natural sources. For example, you could go and collect twenty species of fungus or sea sponge, grind them up, and put the extracts of each through your assay. If anything works, you then fractionate the extract somehow (eg by chromatography), and put each fraction through your assay. You pick fractions which work, fractionate them further, assay the sub-fractions, and repeat until you have got a pure substance with some activity, which you then characterise. Here, you can knowledge of ecology and biology to pick likely species - for instance, fungi are a good source of antibiotics, because they have to make antibiotics to defend themselves in their natural habitat.

Or you could start with some knowledge of the structure and function of the target (from X-ray crystallography, NMR, and good old fashioned biochemistry), and try to rationally design a molecule which will bind to and inhibit it. Computer simulations are useful here. Combinatorial methods let you design hundreds of molecules which might work, and then put them all through the assay.

Or you could hope that an antibody will do the job, and inject your target protein into some mice, wait for them to make an immune reaction to it, then collect their blood, extract B-lymphocytes, culture them in bulk, purify antibodies from the culture, then assay the antibodies. If something works, split the lymphocytes into single-cell clones, and assay each clone's antibodies one by one.

I don't work in this field, so my knowledge of these techniques is from undergraduate study, and one relative who grinds up sponges. It's possible some of the approaches i mention are obsolete, or were only ever speculative.

[1] https://www.abcam.com/cyclooxygenase-cox-activity-assay-kit-...

[2] https://www.le.ac.uk/bl/phh4/roottip.htm

[3] https://www.tdi.ox.ac.uk/small-compound-libraries

[4] https://wiki.nci.nih.gov/display/NCIDTPdata/Compound+Sets

The failure in humans of stuff that worked in mice is actually the biggest driver of the cost of drug development

According to a widely cited paper on the cost of drug development [0], phase 2 has the lowest probability of succes of any stage in the funnel at 30-40%. Phase 2 is generally the first time a drugs effectiveness is studied in humans. It can cost $50-100M+ to get a drug through a phase 2 study

One of the major advances in drug development in the last few years is to reduce the "translational risk", i.e. The risk that animal models and other disease models are not predictive of human outcomes. A recent study suggests that we have actually started to make some improvements in this area which is a huge step in lowering drug costs and getting more new medicines

[0] https://www.nature.com/articles/nrd3078