6 replies to this topic

[giftsplash]

Wondering if anyone came across any studies which showed what percentage of mice studies actually translate successfully to humans? (As well as false negatives)

 

Would love to know the probability I should assign each time I read a mice study I get excited about?

 

While we are at it, vitro/vivo success percentage would be interesting also.

[joelcairo]

An awful lot of successful studies never even go past the in vivo stage, but among drugs that begin clinical development about 10% will make it to market[1]. That's not to say that the research is faulty or that the drug doesn't actually work in humans. Frequently the economic case for investing in the clinical trial process is not there - due to the enormous costs, the perceived odds of success, the potential market for the drug, whether it is likely to be superior to existing alternatives, difficulty obtaining corporate financing, the FDA having its head up its butt, etc.

 

 

1. http://www.clinicall...rials-fail-0001

 

[niner]

Mouse results are a hell of a lot better than worms or flies, and worms or flies are better than cells in a dish, but not wildly better.  Frankly, cells in a dish (in vitro) are nearly useless as predictors of human activity.   The biggest cause of internet idiocy in the health/longevity sphere is people seeing an in vitro result where cells were bathed in a compound for an extended period at concentrations impossible to reach in humans, and proceeding to claim that the compound works in humans.  Animals have evolved many layers of defenses to keep random molecules OUT of their system, and to destroy and eliminate them rapidly if they do manage to get in.  None of this is present in a test tube, and not very much of it is present in worms or flies.   Mice are so much better than in vitro that it's like a different world, but humans are enough different than mice that they are like yet another world.   At least the mouse and human worlds are in the same solar system.  The in vitro world is a different galaxy.   If a drug works in a mouse, it's a good sign that it might work in a human, but there are still a lot of hurdles to overcome.  There can't be any important differences in the target receptor, it has to be absorbed adequately in the human, and there can't be metabolic pathways in the human that would eliminate the drug too quickly.  There also needs to not be any toxicities that show up in the human but not the mouse.  Taken in total, this is pretty tough to quantitate well in the general case.

[Darryl]

Over evolutionary time, the ability of individual genes to perform their function climbed through genomic space to local fitness optima. For basic biochemistry, most of this was accomplished in deep time during the evolution of archaea, the bacterial symbiotes that became our mitochondria, and early eukaryotes. We share a huge amount with yeast (last common ancestor, perhaps 1200 mya). Of 450 genes critical for yeast survival in laboratory conditions, about half can be swapped out for the human version and the yeast can survive and reproduce.

 

I think with model organisms, its useful to consider the time of our lineages' divergence:

 

Escherichia coli: 3-4 billion years ago

Saccharomyces cerevisiae (Baker's yeast): 1200 million years ago

Caenorhabditis elegans (nematode worm): 560 mya

Drosophila melanogaster (fruit fly): 560 mya

Danio rerio (zebrafish): 430 mya

Xenopus tropicalis (Western clawed frog): 340 mya

Canis lupus (wolf, domestic dog): 85 mya

Sus scrofa (domestic pig): 85 mya

Rattus norvegicus (brown Norway rat): 65-75 mya

Mus musculus (house mouse): 65-75 mya

Macaca mulatta (rhesus monkey): 25 mya

Pan troglodytes (chimpanzee): 7 mya

 

In the grand scheme, we and mice are fairly near cousins. With mice, at the genetic level we share pretty much everything but developmental tweaks and hundreds of olfactory receptors that our primate lineage lost. Our genes can generally be freely swapped with mice versions, and the mice are still viable. This is how hundreds of mice models of human diseases have been produced, everything from ApoE-/- to Huntingtons.

 

IMO, compared to mice we certainly differ in the extent to which we're effected by environmental/diet/exercise interventions, but usually not in the direction. If something benefits mice its generally neutral to beneficial in humans, if something harms mice its neutral to harmful in humans.

[jondoeuk]

Experiments on mice or other non-humans for that matter seldom translate to human results.

 

''So how is everyone doing in the clinic? Sheesh, you had to ask. The overall Likelihood of Approval” (LOA) from Phase I is 9.6 per cent. So no, if you were hoping for an upturn in the more recent numbers, it doesn’t seem to be there. Somewhere around ten per cent success has been the estimate for some time now, and here it is again. The worst therapeutic area is oncology, with a 5.6% LOA.'' http://blogs.science...r-in-the-clinic

 

For Alzheimer's it's even worse with a failure rate of 99.6%. It means that none of the disease modifying agents have come to fruition https://www.ncbi.nlm...les/PMC4095696/

[RWhigham]

Difference between humans and mice - example: bioavailability of UA

 

Ursolic Acid (UA) is orally bioavailable in mice but not in humans. UA looks very promising for body composition

mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass " 

• Identification of Ursolic Acid as an Inhibitor of Fasting-Induced Muscle Atrophy
• Ursolic Acid Reduces Denervation-Induced Muscle Atrophy
• Ursolic Acid Induces Skeletal Muscle Hypertrophy
• Ursolic Acid Induces Trophic Changes in Skeletal Muscle Gene Expression
• Ursolic Acid Enhances Skeletal Muscle Insulin/IGF-I Signaling
• In Contrast to Its Effect on Skeletal Muscle, Ursolic Acid Reduces Adiposity

and preventing old-age muscle wasting

Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy  This research finds that ATF4 expresses the genes that cause old-age muscle wasting. and UA blocks ATF4.

 

But has very poor oral bioavailability in humans. A 1g dose given to volunteers was undetectable in 2 out of 9 subjects. A single ascending dose, initial clinical pharmacokinetic and safety study of ursolic acid in healthy adult volunteers (1044.6)

[joelcairo]

That is odd, given the researchers tested 100, 500 and 1,000 mg doses of ursolic acid, since the main supplement Swanson sells for this is Holy Basil standardized to just 2% ursolic acid. With their brand, a dose is considered to be 2 capsules and provides only 16 mg ursolic acid. I've never taken Holy Basil so I have no opinion on whether it works or whether the mechanism is ursolic acid, but the reviewers generally seem to think it has a biological effect.