The Many Successes in Mice that Fail to Translate to Human Medicine

There are many failures on the path from early study in cells to successful medical technology applied to humans. A success in cell cultures often turns out to be infeasible in animals, as cells in culture are not a part of a larger tissue and organism and thus not subject to the same signals, stresses, and influences. Work in organoids, tiny sections of living tissue, can certainly help to bridge this gap, but even an organoid that accurately reflects the structure and function of an organ is still not subject to the real ebb and flow of a living animal, all of the interactions with other tissues and systems.

Success in animal studies, usually carried out in mice, can fail in larger mammals for any number of reasons. While there are many similarities between mammals, there are just as many differences. The popular science article below focuses on the biochemical differences between species as a reason for the leap between mice and humans to fail so often. I think it overemphasizes the point, and fails to offer viable suggestions for an alternative. In the field of aging, I'd have to say that there are two important factors for a high failure rate, only one of which is really an issue of species differences, and both can be traced back to a poor high level strategy for the development of means to treat aging and age-related disease.

The first is that short-lived species exhibit vastly greater slowing of aging and life extension when stress response mechanisms are upregulated. So calorie restriction, increased autophagy, heat stress, and other hormetic effects produce sizable gains in life span, up to 40% or more in mice. Where direct comparisons can be made, we know that these methods produce no such result in humans. While beneficial for health, the existence of effect sizes of larger than five years of additional life is very implausible given the existing data. Yet members of the aging research community continue to put the majority of their effort into developing therapies that boost these stress responses. Results fail to translate because effect sizes in humans are much smaller and much less reliable, and clinical trials are looking for sizable, reliable outcomes.

The second issue is that most of the work on age-related conditions starts with the end stage disease state and works backward. Researchers end up trying to develop therapies based on manipulating proximate causes that are very late in the development of pathology, far removed from root causes. This tinkering with the operation of the disease state is far more vulnerable to small differences in cellular biochemistry between species, and tends to produce marginal results at the best of times. Small benefits based on tinkering with a complex, disarrayed biochemistry have a way of vanishing or becoming highly unreliable firstly in the move between species, and secondly in clinical trials once larger numbers of people and their individuals differences become involved. Again, this is a problem that exists because of the way in which research and development is conducted: it is the result of a poor choice of strategy.

The right approach to aging is to target and repair the known root causes. Many of these are the same in their important aspects in all mammals, such as the accumulation of senescent cells, or the class is the same and only the importance of different members of the class varies, such as accumulation of cross-links or lipofuscin, in which the specific molecules to target are different in mice and humans. Further, the effect sizes resulting from successfully reversing root causes of aging and age-related disease should be larger and more reliable in any species: it covers many downstream consequences, and even if those consequences are different in different species, they will still be reduced. This gives a greater expectation of success in future human clinical trials based on the existence of mouse data only.

Don't believe the mice

When you read that a lab animal with a human disease has been cured with a new drug candidate, do not get your hopes up. The stats for converting these successes into human patients are appalling. Results in animals are often the opposite of those seen in humans. For example: corticosteroids were shown to treat head injuries in animals, but then increase deaths in new-born babies in trials. This is a big deal. A staggering 95% of drugs tested in patients fail to reach the market, despite all the promising animal studies that precede their use in humans. "There are lots of reasons why, but in essence we are not 70 kilogram rats and we are not inbred strains."

Mice are the most popular lab animals, but their brains and biology are quite different from our own. Surprisingly, rats and mice predict each other for complex measures with only 60%. Different animals, different effects. Newspapers headlines heralding cures for Alzheimer's to autism, on the back of rodent studies, can be taken with a pinch of salt. Neurodegenerative disorders such as Alzheimer's were one of the first areas to turn against the animal models. "It was shown that the animal tests were misleading with respect to what is a cure and what is not." After hundreds of human trials for promising treatments for Alzheimer's, almost none helped patients. This is a colossal waste of money. Industry has noticed. "The pharma industry is now using about one-sixth the number of animals that they used in the past for drug studies. They go very late into these models."

One problem is that scientists often take a simple approach to mimicking a disease in mice, by just finding a gene that when knocked out stamps the mice with hallmarks of the human disease. This is how the first Alzheimer's disease mouse was created, but the animal did not reflect the true Alzheimer's condition of most patients. "Single gene mouse models are different from the illness that we experience in humans. This has been a failed strategy."

Sometimes scientists discover therapies to cure mice, but not people. The record for inflammatory disease is especially striking. More than 150 trials have tested agents to block inflammation in critically ill patients. The candidates worked in animals, but all failed in patients. With this in mind, researchers decided to compare how all genes in mice and all genes in people react when they encounter trauma, burns or bacterial toxins. There was almost no connection whatsoever. Mice genes did one thing; human genes did another.


we are probably way, way further away from life extension then anyone wants to admit.

Posted by: randomperson at August 24th, 2018 6:19 PM

Yes. We are quite far from life extension. But we are invited in the right direction. But even if we don't increase the Max LS, there are still a lot of things to be gained with the health span. So if we just increase the median life expectancy, that is already a big thing.
It is assumed that the human lifespan is 120-125 years. The life expectancy is, on average , around 80. The is a lot of room there.

But again, in 10 years we have a good chance to l have widely available first generation senolitic therapies. How much LS will they bring? Probably, no more than 10 years. But that would be many orders of magnitude better than what we have today; fasting, calorie restriction, and avoiding risk factors...

Posted by: Cuberat at August 24th, 2018 8:09 PM

I take a slightly different view. We could be quite close, its just, as the article states, we're basically oriented in the wrong direction of research. I chalk that up, mostly, to the distorting effects of government funded research, and the piles of government regulation.

Posted by: Another Random at August 24th, 2018 8:11 PM

@randomperson: And you conclude that from exactly what?

Posted by: Antonio at August 25th, 2018 1:49 AM

@randomperson and what is your basis on that claim? senolytics and a number of other therapies are in human trials already. you shoucl check out the rejuvenation roadmap if you want to know exactly where each stage is.

Posted by: scott emptage at August 25th, 2018 4:28 AM

@John C., haha, surely you cannot be that naive to believe such nonsense? She supposedly extended her telomeres in a small muscle tissue or something like that.. It was a proof of principle and it did absolutely nothing for her longevity.

Posted by: DarwiN at August 25th, 2018 4:47 PM

Doesn't it logically follow that, conversely, just because an experiment fails in mice, doesn't mean that it won't work in large mammals? Seems like we've cornered ourselves into an incomplete methodology.

Posted by: A Country Farmer at August 26th, 2018 11:33 AM

We can't say anything conclusive about Liz Parrish's longevity at this point, and let's hope we can't for a very long time (or at least until we find a really accurate aging biomarker). She should be lauded for her bold initiative and for providing evidence that the gene therapies she tried won't outright kill a human 100% of the time. The before and after MRIs of her muscle were encouraging and I'd like to see updates. I'd also like to know about her ovarian function (follistatin is produced in the liver and ovaries), but I don't use Facebook - so if anyone else wants to ask...

As Reason pointed out in a recent post, telomere length isn't a good aging biomarker. The Outside magazine article draws a nice straight line from the Haylick limit to telomere length to aging, but unfortunately it is not that simple. Here's an abstract that explains why and also points out some of the limitations of cell culture studies:

@A Country Farmer
Yup, but on the other hand studies of rodents and other model organisms have also generated a great deal of knowledge about biology, as have cell culture studies. We need to develop other methods, though. While I really enjoyed the article (thanks, Reason), it might have discussed newer alternatives such as in silico and organoid models. Also, I was a bit annoyed by the suggestion that the money would have been better spent on lifestyle interventions rather than research. I'm all for lifestyle interventions and prevention, but resource allocation to research and promoting healthful lifestyles does not need to be viewed as a zero sum game. There's spending that can be re-directed to both from other, arguably less important things [e.g., artificial flowers - $650 million spent annually].

Posted by: CD at August 27th, 2018 9:59 AM

Two things seem a shame to me:
(1) That we have so many examples of therapies that work great in mice and yet we still haven't managed to keep mice alive for 2x normal lifespan, let alone indefinitely analogous to a well maintained classic car.
(2) We have so many positive and negative examples of therapies that worked in mice and then did or didn't in humans, and so much understanding of the differences in biology of the species and we still can't accurately predict which new treatments will or won't translate, or even explain in many (most?) cases why a given example failed to translate.

These both seem like areas that deserve a higher fraction of the total research resource pie.

Posted by: Karl Pfleger at August 27th, 2018 10:39 PM
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