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Eldorado Desperadoes I: Of Mice and Men
Athena Andreadis
Astrogator's Logs
Posted: Jul 18, 2009
About a week ago, the Internet went wild with the announcement that a “fountain of youth” drug had been found that extends life by about 10%. I picked a site at random and read the report, knowing full well what I would find buried somewhere in the story. Sure enough, there it was, tucked at the end of a paragraph halfway down: the study was done on mice.
 The “elixir of life” is rapamycin, an immunosuppressant used to prevent transplanted organ rejection. The maximum human daily dose for rapamycin is 5 mg. To receive the same relative amount as the mice were fed in the study, people would have to ingest 200 mg daily. This means that anyone who takes “longevity” doses of rapamycin had better live in a controlled, sterile environment. It also means that they’ll be prone to developing tumors. This is not a problem for mice, in whom cancer can be easily cured. Not so, by a long shot, for humans.
Mice are extremely useful for dissecting molecular pathways and fairly useful as models for a long list of diseases. Their advantages are many and obvious: they’re mammals, so they share more with humans than the other organisms used in genetics — yeast, flies, worms, fish. Their generation times are short, their litters large. We can totally control their environment, though this affects their health and behavior. We can alter, delete or insert genes in mice and regulate when and where they express. And mouse research is far less emotionally and ethically fraught than experiments on primates.
However, as I never tire of saying, the devil’s in the details. Mice are sufficiently different that drug studies, in particular, are better as proofs of principle than one-on-one mappings. Unlike us, mice are fast-metabolizing and short-lived. Drugs, nutrients and hormones are radically divergent in every mammal in terms of bioavailability, activity, metabolism and toxicity. Many drugs that showed exceptional promise in mice fared no better than placebos or essentially acted as poisons in human clinical trials. The social and behavioral wiring of the two species are totally disparate. For example, mouse sexual arousal and mothering behavior depend on smell pheromones. Mouse models of complex diseases are prone to over- or mis-interpretation. Does a compound stop a mouse from jerking uncontrollably because it’s a pain killer — or is it acting as a muscle relaxant? It’s even harder to correlate such complicated responses as learning, anxiety or depression.
Cartoon credit: Sidney Harris
At the molecular level, many genes that are essential in mice are non-essential in humans and vice versa. Comparisons between the human genome and its recently completed mouse equivalent show that they diverge far more than previously recognized — close to 20%. Not only are there significant numbers of human-specific genes; equally importantly, genes whose structure is identical in the two species are nevertheless differently regulated. And last but decidedly not least, the two species have distinct regulatory RNAs (miRNAs for the truly curious).
All this may sound esoteric, but the conclusion is simple: mouse models, especially those based on highly inbred strains, recapitulate only limited aspects of many human functions and diseases. This is particularly true of metabolism, neoplasty, lifespan and that troublesome jewel in the crown — the brain. Elixirs and panaceas for obesity, cancer, longevity and dementia remain stubbornly species-specific. So next time a brushfire sweeps the Internet with news of yet another miracle cure, the first and last question of non-biologists should be: what were (or when will we know) the results of the human tests?
Athena Andreadis served as a fellow of the IEET from 2007 to 2009, and is an Associate Professor of Cell Biology at the University of Massachusetts Medical School, and the author of To Seek Out New Life: The Biology of Star Trek.
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COMMENTS
Than you, Athena, for countering the undeserved hype this story has been getting.
I first heard about this study on the Nature podcast, and while it was a fascinating result, even then it was made clear that its crippling effect on the human immune system alone meant that we were, at best, a long way off from getting any practical benefit. It never hurts to be reminded of the weaknesses of animal models.
It’s interesting that you say “mouse sexual arousal and mothering behavior depend on smell pheromones.”. There have been numerous, recognized studies at institutions such as Monell Chemical Senses Center, University of Penn, Lafayette, etc that have shown the effects of male axillary pheromones on female ovulation and mating patterns, etc. And the current studies on oxytocin show the effect of cuddling in both male and female parents and their children. Some good links:
http://www.livescience.com/health/060213_attraction_rules.html
http://www.scientificblogging.com/news_releases/pheromones_some_females_can_smell_reproductive_fitness_and_even_ancestry_males
http://www.pheromonefacts.com/science/pheromone-related-links.aspx
http://www.athenainstitute.com/science.html?tab=0
http://blogs.wsj.com/juggle/2009/06/19/fathers-day-why-men-are-hard-wired-to-cuddle-their-babies/
I’m glad you enjoyed the essay, Ben! Indeed, animal models are enormously informative and helpful—but their applications and conclusions are finite.
James, humans are primarily visual and this is true for sexual attraction as well. Two areas of the human brain are disproportionately large: the prefrontal cortical lobe and the regions associated with receiving and processing visual cues.
Anosmic mice do not go into heat and hence cannot mate. Anosmic humans have no such problem (Kallmann syndrome sufferers are anosmic and sterile, but that is due to lack of pituitary hormones, not because the lack of smell abolishes interest in sex). Smell is our weakest sense.
Oxytocin may be the hormone de jour in TH circles for its (largely scifi) potential for happifying drugs. It does turn male voles monogamous. Voles, not humans. In humans, its primary action is to induce smooth muscle contraction, hence its use during labor.
In most of these links (none of which are primary research), the talk starts in humans and soon afterwards veers into other animals, particularly… could it be?... mice!
I agree with Ben that this story has gotten wway more publicity than it deserves. Anthony Serafini in his classic work THE EPIC HISTORY OF BIOLOGY also suggested caution it relying on animal models.
Michael • Philadelphia • Jul 19, 2009
Wickipedia tells us it all about the rodents:
* Sexual arousal. Oxytocin injected into the cerebrospinal fluid causes spontaneous erections in rats,[9] reflecting actions in the hypothalamus and spinal cord.
* Bonding. In the Prairie Vole, oxytocin released into the brain of the female during sexual activity is important for forming a monogamous pair bond with her sexual partner. Vasopressin appears to have a similar effect in males.[10] Oxytocin has a role in social behaviors in many species, and so it seems likely that it has similar roles in humans.
* Maternal behavior. Rat females given oxytocin antagonists after giving birth do not exhibit typical maternal behavior.[13] By contrast, virgin female sheep show maternal behavior towards foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise.[14]
So, with oxytocin being the sexual hormone de jour, there is some validity to the effects it has on maternal behaviors, sexual arousal and smooth muscle contraction in humans. Just out of curiosity, what are your thoughts on the VNO in humans? Thank you.
Michael, humans have a vomeronasal organ (VNO) during development, but then it shrinks and remains (if at all) vestigial. There seem to be no active neurons in humans that correspond to that of the VNO in other mammals. Furthermore, most genes that correspond to the VNO receptors have become pseudogenes in humans, which means they don’t express functional proteins. So the overall evidence so far indicates that olfactory cues from the VNO are either absent or minimal in our species.
As for oxytocin being the sexual hormone du jour, you know Tina Turner’s immortal words: Today cock of the walk, tomorrow a feather duster (*laughs*).
Usually, Creationists are considered science stoppers, but in the case of VNO, we must not let scientists be the science stoppers by definitively calling the VNO a vestigial organ, and hence stop looking for a function. We’ve been burned before. Fortunately we have scientists like Witt and Shirokova looking into VNO very carefully.
Having written a book on oxytocin’s neurochemical effects on bonding, as well as its pivotal role as a hormone in sexual arousal, I agree with James, Michael and Veronica.
There is strong scientific evidence that the human vomeronasal organ functions, from studies at Monell and others. I think it made scientists queasy to think that we huffed each other just like animals, but soon the evidence that we do will be incontrovertible.
For more refs, see: http://www.hugthemonkey.com/2007/10/smells-like-tee.html#_edn2
Athena, I don’t think we know enough about genes and their expression to use a genetic argument that the VNO is not active.
Michael, I’d say there’s a lot more than “some validity” to the effects of oxytocin on sexuality and behavior. I’d say it’s a done deal.
People, pay attention: I said “the overall evidence so far”. Additionally, the vestigial status of the VNO is true not only for humans, but also for most primates. It seems to be an evolutionary event, that’s all. Nothing to do with queasiness about huffing.
Veronica, there may well be other functions for the VNO and nobody is stopping the research just because it’s not “sexy” (literally and metaphorically).
Susan, we know a fair amount about genes and their expression. Not everything by far, but enough to know if a gene we examine is being expressed or not. I know you wrote a book about oxytocin, which is great. But primary research has the disconcerting effect of constantly discovering nuances and exceptions. It would be wonderful if everything fell neatly into place, but that rarely happens in biology. And if something sounds too good to be true, it invariably is.
All this may sound esoteric, but the conclusion is simple: mouse models, especially those based on highly inbred strains, recapitulate only limited aspects of many human functions and diseases. first and last question of non-biologists should be: what were (or when will we know) the results of the human tests
Yes very good! This point was made by Anthony Serafini is his work THE EPIC HISTORY OF BIOLOGY
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