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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 13, 2013

Mouse Models of Inflammation Are Basically Worthless. Now We Know.

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Posted by Derek

We go through a lot of mice in this business. They're generally the first animal that a potential drug runs up against: in almost every case, you dose mice to check pharmacokinetics (blood levels and duration), and many areas have key disease models that run in mice as well. That's because we know a lot about mouse genetics (compared to other animals), and we have a wide range of natural mutants, engineered gene-knockout animals (difficult or impossible to do with most other species), and chimeric strains with all sorts of human proteins substituted back in. I would not wish to hazard a guess as to how many types of mice have been developed in biomedical labs over the years; it is a large number representing a huge amount of effort.

But are mice always telling us the right thing? I've written about this problem before, and it certainly hasn't gone away. The key things to remember about any animal model is that (1) it's a model, and (2) it's in an animal. Not a human. But it can be surprisingly hard to keep these in mind, because there's no other way for a compound to become a drug other than going through the mice, rats, etc. No regulatory agency on Earth (OK, with the possible exception of North Korea) will let a compound through unless it's been through numerous well-controlled animal studies, for short- and long-term toxicity at the very least.

These thoughts are prompted by an interesting and alarming paper that's come out in PNAS: "Genomic responses in mouse models poorly mimic human inflammatory diseases". And that's the take-away right there, which is demonstrated comprehensively and with attention to detail.

Murine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials. However, few of these human trials have shown success. The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed. Despite commentaries that question the merit of an overreliance of animal systems to model human immunology, in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.

What this large multicenter team has found is that while various inflammation stresses (trauma, burns, endotoxins) in humans tend to go through pretty much the same pathways, the same is not true for mice. Not only do they show very different responses from humans (as measured by gene up- and down-regulation, among other things), they show different responses to each sort of stress. Humans and mice differ in what genes are called on, in their timing and duration of expression, and in what general pathways these gene products are found. Mice are completely inappropriate models for any study of human inflammation.

And there are a lot of potential reasons why this turns out to be so:

There are multiple considerations to our finding that transcriptional response in mouse models reflects human diseases so poorly, including the evolutional distance between mice and humans, the complexity of the human disease, the inbred nature of the mouse model, and often, the use of single mechanistic models. In addition, differences in cellular composition between mouse and human tissues can contribute to the differences seen in the molecular response. Additionally, the different temporal spans of recovery from disease between patients and mouse models are an inherent problem in the use of mouse models. Late events related to the clinical care of the patients (such as fluids, drugs, surgery, and life support) likely alter genomic responses that are not captured in murine models.

But even with all the variables inherent in the human data, our inflammation response seems to be remarkably coherent. It's just not what you see in mice. Mice have had different evolutionary pressures over the years than we have; their heterogeneous response to various sorts of stress is what's served them well, for whatever reasons.

There are several very large and ugly questions raised by this work. All of us who do biomedical research know that mice are not humans (nor are rats, nor are dogs, etc.) But, as mentioned above, it's easy to take this as a truism - sure, sure, knew that - because all our paths to human go through mice and the like. The New York Times article on this paper illustrates the sort of habits that you get into (emphasis below added):

The new study, which took 10 years and involved 39 researchers from across the country, began by studying white blood cells from hundreds of patients with severe burns, trauma or sepsis to see what genes are being used by white blood cells when responding to these danger signals.

The researchers found some interesting patterns and accumulated a large, rigorously collected data set that should help move the field forward, said Ronald W. Davis, a genomics expert at Stanford University and a lead author of the new paper. Some patterns seemed to predict who would survive and who would end up in intensive care, clinging to life and, often, dying.

The group had tried to publish its findings in several papers. One objection, Dr. Davis said, was that the researchers had not shown the same gene response had happened in mice.

“They were so used to doing mouse studies that they thought that was how you validate things,” he said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?”

What's more, the article says that this paper was rejected from Science and Nature, among other venues. And one of the lead authors says that the reviewers mostly seemed to be saying that the paper had to be wrong. They weren't sure where things had gone wrong, but a paper saying that murine models were just totally inappropriate had to be wrong somehow.

We need to stop being afraid of the obvious, if we can. "Mice aren't humans" is about as obvious a statement as you can get, but the limitations of animal models are taken so much for granted that we actually dislike being told that they're even worse than we thought. We aren't trying to cure mice. We aren't trying to make perfect diseases models and beautiful screening cascades. We aren't trying to perfectly match molecular targets with diseases, and targets with compounds. Not all the time, we aren't. We're trying to find therapies that work, and that goal doesn't always line up with those others. As painful as it is to admit.

Comments (50) + TrackBacks (0) | Category: Animal Testing | Biological News | Drug Assays | Infectious Diseases


COMMENTS

1. Iridium on February 13, 2013 9:57 AM writes...

"What's more, the article says that this paper was rejected from Science and Nature, among other venues. And one of the lead authors says that the reviewers mostly seemed to be saying that the paper had to be wrong. They weren't sure where things had gone wrong, but a paper saying that murine models were just totally inappropriate had to be wrong somehow."

I love it.

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2. PPedroso on February 13, 2013 10:00 AM writes...

I haven't had the opportunity to read this paper but my first question is, what do we do with know, effective drugs in humans that also work in mice models? (some of them were discovered in such models!)

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3. luysii on February 13, 2013 10:02 AM writes...

This goes in spades for the mouse (or rat) brain vs. the human brain. It is so different anatomically that it doesn't look like the same organ, and functionally it's in a different universe.

It probably explains why rodent models of stroke have led to the testing of over 50 treatments of stroke, none of which have worked in man.

This is exactly why drug development for human brain diseases is so hard.

All is not lost -- a recent paper [ Neuron vol. 77 pp. 440 - 456 '13 ] developed cortical pyramidal neurons (which make up 80% of the neurons in our cerebral cortex) from human embryonic stem cells or human induced pluripotent stem cells (iPSCs) ex vivo. This is amazing in itself, but then they injected them into neonatal mouse brain. The cells didn't die, but formed dendritic spines, synapses with mouse neurons, and axonal projections typical of human cortical pyramidal neurons (and the projections of individual neurons were typical of the cortical layer they were found in (there are 6). Amazing !

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4. bhip on February 13, 2013 10:02 AM writes...

Having thrashed around for ~ 10 years trying to develop anti-inflammatory/immunomodulatory drugs, it is very gratifying to see actual data supporting what we all knew- the models suck.
On the other hand, animal models to test pain drugs may suck more, so take heart Immunology!

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5. luysii on February 13, 2013 10:02 AM writes...

This goes in spades for the mouse (or rat) brain vs. the human brain. It is so different anatomically that it doesn't look like the same organ, and functionally it's in a different universe.

It probably explains why rodent models of stroke have led to the testing of over 50 treatments of stroke, none of which have worked in man.

This is exactly why drug development for human brain diseases is so hard.

All is not lost -- a recent paper [ Neuron vol. 77 pp. 440 - 456 '13 ] developed cortical pyramidal neurons (which make up 80% of the neurons in our cerebral cortex) from human embryonic stem cells or human induced pluripotent stem cells (iPSCs) ex vivo. This is amazing in itself, but then they injected them into neonatal mouse brain. The cells didn't die, but formed dendritic spines, synapses with mouse neurons, and axonal projections typical of human cortical pyramidal neurons (and the projections of individual neurons were typical of the cortical layer they were found in (there are 6). Amazing !

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6. mass_speccer on February 13, 2013 10:03 AM writes...

We've had a paper rejected by journals for a lack of mouse data - all of our work was from human volunteers. The mouse model for the mutation we're interested in has a completely different phenotype from the human - it basically doesn't get sick. Still, we've done a load of mouse work now to keep the reviewers happy - doesn't really add anything to the original data though!

Like Derek says, "a mouse is not a human" seems to get forgotton a lot.

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7. Hap on February 13, 2013 10:29 AM writes...

1) Extraordinary claims require extraordinary evidence.

2) If such evidence is provided, not liking the result is irrelevant.

This doesn't mean anything good for publication - if cool results are accepted without sufficient evidence, uncool results aren't accepted even with it, and most people generally can't analyze the data (they don't know enough) but take peer review as important evidence of accuracy, then the rejection of this paper would seem to indicate a problem.

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8. bacillus on February 13, 2013 10:29 AM writes...

A major reason for the widespread adoption of rodent models of human disease was to get away from using nonhuman primates or other large mammals that brought with them massive welfare issues as well as the most vicious attention of the animal rights movement. It was the path of least resistance. One can only wonder how many millions of rodents might have been spared by using far fewer scientifically more appropriate animal models. Given PETA's claim that "a rat is a pig is a dog is a boy" then they must shoulder at least some of the blame for the unnecessary deaths of millions of souls.

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9. KissTheChemist on February 13, 2013 10:42 AM writes...

OK, animal models, beware.......but where do we go from here? And I mean that as a real question. Anyone have any better ideas? I've been down the road with mouse models for inflammation so if there's an alternative waiting in the wings, I'm listening!!

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10. Curious Wavefunction on February 13, 2013 10:50 AM writes...

The important caveat about differences between mice and humans is well-taken. But I am still a little skeptical regarding the generality of these conclusions since the study seems to have looked mainly at burns and trauma. What percentage of the inflammatory response in these conditions is shared by other inflammation-related disorders, including autoimmune disorders like psoriasis and arthritis?

In addition I think the translation of responses between mice and humans will depend on the specific target. Surely there are some inflammatory targets for which the two responses tracked? So in general yes, this paper is quite valuable, but I suspect that the number of exceptions might still make anti-inflammatory drug testing in mice worthwhile. As we all know, a lot of success stories in drug discovery come from the exceptions.

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11. passionlessDrone on February 13, 2013 11:15 AM writes...

Can some smart people help a dumb person out?

It seems like 'inflammation' is being used pretty casually in the title and some of the press, but the details are involving highly acute conditions. While the fact that all of the trials for 'critically ill' patients have failed and gene expression after extensive burning and/or trauma doesn't match up, does this really tell us that "Mice are completely inappropriate models for any study of human inflammation."?

The FDA looks to have approved bunches of drugs lately for arthritis, COPD, or other conditions with significant inflammatory contributions. For example, tocilizumab got the FDA nod in 2011. Its mechanism of action is inhibition of IL-6. My take from reading this blog is that lots of mice were sacrificed to get there. The tnf-alpha inhibitor class of drugs would seem to be largely similar.

I'm not saying we understand everything (or much) about everything that happens underneath the hood when a human takes infliximab; but didn't drugs like this get identified and progressed through development based on mouse models of what happens if you interfere with tnf-alpha signalling?

?


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12. The Iron Chemist on February 13, 2013 11:23 AM writes...

This might be amended to "Massively inbred mice aren't humans." It might even be a stretch to compare them to regular, fresh of the field mice.

At the risk of opening Pandora's Box, one might even extend these concerns to cell culture-based studies. Do HeLa cells, for instance, even remotely resemble any cells actually found in humans after sixty-plus years of culturing?

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13. FatSquirrels on February 13, 2013 11:43 AM writes...

I realize many of the readers here might not be avid webcomic readers, but I thought it was interesting that the cartoonist Zach Weiner drew a comic based on the problems with mice models about a week ago. Since it reminded me so strongly of his joke I thought I would share it with you all. No real scientific merit here, but some humor you might appreciate.

http://www.smbc-comics.com/index.php?db=comics&id=2881#comic

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14. aman on February 13, 2013 12:22 PM writes...

I find it scary less funny that reviewers: be saying that the paper had to be wrong.
Without bashing I am wondering if some of the reviewers actually work in industry.
#2 Drugs are normally not discoverd in mice models (maybe some fiew exceptions from the 60ies), but they are more often validated in them (or in rat).
#11 Models are only as good as their validation and the questions one tries to answer with them. In Asthma mice models are relativelly well studied especially their limitations in contrast to COPD. COPD is a wild guess and crossing fingers. Often drugs against asthma are tried to place in the COPD segment because of competition and market size. Because of size the chance to find something positive is higher.

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15. Anonymous on February 13, 2013 12:42 PM writes...

Unless I'm mistaken they are only using circulating blood leukocytes as their target. My understanding is that in many inflammatory diseases the changes in expression at the gene and protein level are very different locally vs. systemically, and very different in the chronic vs. acute setting.

I'm not disagreeing that they may be onto something (the idea that there are profound immunological differences between mice and man is hardly a novel concept), but there could be alternative explanations here. Perhaps their method of inducing inflammation and/or the target tissue for measuring genomic changes are not appropriate. Or maybe they should look at epigenetic or post-translational changes.

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16. Anonymous on February 13, 2013 12:51 PM writes...

Also, isn't the title and conclusion a little broad considering they used a single mouse strain and a single method for generating inflammation? Is an acute injury model of inflammation appropriate for studying Crohn's, for example?

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17. barry on February 13, 2013 12:53 PM writes...

mice are overwhelmingly the first animal model for disease for several reasons. One is circular--we know a lot about them so we go on studying them. Another is regulatory. U.S. statute defines rats and mice as "laboratory equipment" rather than as "animals". That makes it vastly cheaper to breed, keep and use them than other species.
There are cases (leprosy in armadillos, asthma in sheep...) where we use other models. But each such case requires an expensive uphill struggle.

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18. MarkW on February 13, 2013 12:58 PM writes...

KissTheChemist - Where we go from here is to leverage improved research capabilities and use pre-clinical models more effectively. The more we understand about mice and how they do differ both from us and between strains, the better we'll be able to interpret the data produced.

Using a single inbred strain, C57BL/6J, to make sweeping statements about shock response is like taking a single person's drug reaction and calling it good for the entire population. It's an important discussion, but use the genetically diverse mouse populations now available to make your case.

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19. petros on February 13, 2013 1:07 PM writes...

A damning indictment of the reviewers but perhaps not totally unexpected given the many discrepancies between animal models and man.

In the comments on respiratory models. Guinea pigs used to be almost universally used until technology improved to the extent where mouse models were usable, even if no more predictive. Rats generally produced very different results.

#17 Barry mentions the sheep model of asthma which is also useless except for showing a drug produces effects in a large animal. Many classes of putative anti-asthma drugs have worked in the sheep but not man.

COPD models are even more problematic, with smoking mice probably the best mimic for this long term degenerative, inflammatory, disease. But then all the animals develop lung disease not the 15-20% as in the human disease!

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20. a. nonymaus on February 13, 2013 1:25 PM writes...

Re: #12,
I'd think that by this many generations of cell culture of what was already a mutated tissue (it was, after all from a tumor), that HeLa isn't a direct mimic of any bodily cell. In fact, I think it could be safely, and correctly, renamed as a unicellular organism, Homo helacksia.

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21. David P on February 13, 2013 1:26 PM writes...

@13: I was going to mention the exact same thing.

I liked best the part where the rats were controlling the NIH - by telepathy.

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22. newnickname on February 13, 2013 1:33 PM writes...

@12, re: cell testing. Gerald B Dermer made the case against cancer screening in cell culture in "The Immortal Cell" (Avery Press, 1995). Dermer is a pathologist who has been looking at cells from cultures and from real tumors his whole life. He said that cultured cancer cells are really screwed up and almost irrelevant to finding a cancer treatment in vitro. He favored testing in whole animals. Maybe he'll update THAT opinion in light of more recent animal v human studies.

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23. Diver dude on February 13, 2013 1:38 PM writes...

All animal models are misleading because they are the wrong species. If you want to develop drugs for humans, work in humans. Cell cultures, explants, whole intact people even - at least you are in the correct species. Not-so-co-incidentally, this is how productive experimental medicine used to be done before the smoke and mirrors of models became de rigeur.

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24. Carl Lumma on February 13, 2013 1:54 PM writes...

> the inbred nature of the mouse model

I don't think this gets nearly enough attention. It's time for some serious trials comparing wild and laboratory mice.

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25. barry on February 13, 2013 1:55 PM writes...

@17: animal models go back at least to Emil Roux modeling human diphtheria in guinea pigs in the 19th century. Scarcely "smoke and mirrors". That's how science advanced.

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26. RKN on February 13, 2013 2:29 PM writes...

Another hangover from too much Koolaid: "Look, mice and humans have >95% of DNA in common. It's all going to be sooo easy now!"

Oops.

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27. Ethan Perlstein on February 13, 2013 2:47 PM writes...

Good thing "organs on a chip" are in development: http://wyss.harvard.edu/viewpage/121/donald-e-ingber

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28. Anonymous on February 13, 2013 2:59 PM writes...

Horrobin (2003) Nat Rev Drug Disc 2:51 has raised this using many examples. His solution? More whole animal work, and more healthy animal work (in order to see what the baseline is) and finally more study of human disease, i.e., more experimental medicine studies.

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29. Ani-nymous on February 13, 2013 3:05 PM writes...

Two comment inspired by my years long attempts to harness the issue of predictability of inflammatory models.
A) Every inflammatory model is specific and its predictability to a given pathology should be tested with so called "gold standard" drugs if available. How about the plethora of other inflammatory diseases and model (RO, OA, COPD, Asthma, IBD etc...)
B) This blog had a post a few days ago arguing the use of bioinformatics in predictig any biological scenario, given, among other things, the paucity of data quality.
Now, how comparable is the quality of ER samples, taken over a few years within 12 hours of injury, likely to be to that of lab animals'?
I'll add a third one.
C) the human endot data were derived from eight healthy subjects given standard LPS. To be able to compare, these should have been octuplets derived from in-bred relationship that have been kept in the same cage, sorry room, for 25 years.Clones might have been even better.

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30. hibob on February 13, 2013 4:02 PM writes...

I wonder how many of of those 150 trials were part of the steroids/sepsis back and forth and back and forth?

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31. darwinsdog on February 13, 2013 4:47 PM writes...

DL, have you ever reported blog response rate vs. topic for trends. Predictably no valentines day overtures to animal models; what else causes big responses (CEO pay, in silico hype etc).

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32. luigi on February 13, 2013 5:17 PM writes...

@14 Aman
Many are using the various transgenic amyloid overexpressing mice as screens for new compounds - and the clinical data - failure after failure - indicates that they are either irrelevant like the inflammatory mice - or that amyloid is not causal. Reductionism is a major road block - echo sentiments on Horrabin - 10 years later!

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33. okemist on February 13, 2013 5:25 PM writes...

The best thing I ever heard in a meeting was from a toxicoligist stating this non-equivalence: Rats are not big mice, and people are not big rats; ... except for senior managment.

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34. Shazza on February 13, 2013 6:16 PM writes...

If pharma was going to go back to discovering and developing drugs in humans how would they go about it?

One possibility that springs to mind is that we have a whole range of new biotech tools that can measure tiny changes in human physiology before anything obvious is observed (e.g. symptoms).

Would it be possible to put test patients on a ridiculously low dose of a drug and gradually ramp up from there, with a keen eye on any unacceptable side effects vs intended therapeutic effect?

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35. srp on February 13, 2013 7:03 PM writes...

I'm more worried about missing stuff that would work in humans but doesn't in mice than I am about all the stuff that works in mice but not in humans. The former represent a potential vast galaxy of safe and effective treatments that our current regulatory and institutional setup places forever beyond our reach.

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36. Brent Morse on February 13, 2013 7:54 PM writes...

Take a look at this article:

http://ccforum.com/content/9/2/R157

This seems to suggest that the difficulty in mimicking sepsis may extend beyond the choice of model organism. If you can't mimic the disease when injecting healthy humans with endotoxin, then maybe you shouldn't expect to be able to do so by injecting a mouse.

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37. John C. Hodge on February 13, 2013 8:13 PM writes...

An important note about inflammation is that it controls all aspects of stem cells. Their creation, use, adaptation to their new role, and destruction of all leftovers. It is also highly interactive with the internal flora (and even the vast number of human parasites we used to have.) Thus much of our future study of inflammation might be through floral manipulation and parasite studies.

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38. Bill Barrington on February 13, 2013 9:18 PM writes...

The problem with this study is that the researchers only investigated one strain of mice (B6), yet generalized their findings to all mouse models of inflammation.

After talking with other geneticists, I've written a response to the study http://wp.me/p2Fl7o-8y

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39. Anonymous on February 13, 2013 11:04 PM writes...

Anyone working in animal models knows the limitations, and the need to take a stepwise approach to translation back to humans. No rational researcher thinks you show efficacy in a mouse then start injecting humans.. That only works in X-files..

LPS is a decent model of endotoxemia, not sepsis, and was used extensively 20 years ago; likely when these folks started their project. Increasingly complex models (of sepsis and other inflammatory diseases) can provide a starting point for new targets.

On another note, how many new drugs have been discovered (or brought to market) as a result of gene expression (microarray) profiling?

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40. Anonymous on February 14, 2013 7:10 AM writes...

I would like to challenge bioinformatics and data analysts to check the analysis of these data. The data appears to have been generated by a large NIH collaborative project. Thus, the data files are available.

Also, the experiments were not designed to be directly compared. The mice that were used were inbred and the cell preparation was different for patients versus mice.

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41. pharmacologyrules on February 14, 2013 7:43 AM writes...

I think there is almost on obsession from the medicinal chemists to test in an 'efficacy' model even if the model does not translate to the human disease. Statins don't lower cholesterol in rodents, ApoE and LDL KO mice don't have the human histopathology, almost no human diabetics have a leptin signalling deficiency (db/db and ob/ob mice), subcutaneous tumours using cell lines carried for multiple generations are the norm, bleomycin pulmonary moels, CCL4 liver fibrosis... I could go on. Also, consider that most mouse models utilise inbred mouse strains-- and I think the humans are much more heterogeneous.

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42. Lyle Langley on February 14, 2013 8:57 AM writes...

@41, pharmacologyrules...
Let's not single out the medicinal chemists and their "obsession with 'efficacy' models". You would be remiss not to mention that it is the pharmacologists/behavioral biologists that "validate" these models in the pre-clinical discovery project. Your comment brings to mind a medicinal chemist forcing a pharmacologist to run a model; when in fact, we (medicinal chemists) are probably the ones more skeptical of these models being translational than anyone else. Anyone going into any mouse/rat model without appreciating the fact that these are clearly not human models is naive, at best.

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43. ctchemist on February 14, 2013 12:50 PM writes...

Mice and rats are incapable of vomiting, yes? If so, what animals are used to test antiemetics?

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44. smurf on February 14, 2013 1:14 PM writes...

ad 43: Ferrets I think.

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45. In Vivo Veritas on February 14, 2013 3:04 PM writes...

@43 & 44. Ferrets and dogs.
Ferrets are under predictive, and dogs puke when you look at them. Together, they make pretty good models.

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46. Cellbio on February 15, 2013 10:06 PM writes...

@10 & 11

Regarding the similarity of other conditions and the utility of animal models, I's say the paper is close to accurate for all settings rather than drawing narrow conclusions that fail to acknowledge prior success.

I spent well more than a decade sending compounds into animal models, both small molecules and biologics, and the data are very clear. The animal models and intervention methods can be designed to the point that the same molecule in the same species is either wildly potent or totally inactive. Further, evaluation of the model itself shows a very dynamic situation, involving acute response to agents like LPS, or immunization with collagen in adjuvant driving an acute and synchronized immune response that looks nothing like autoimmune disease in humans.

Regarding the role of animal research, certainly information generated from genetic or pharmacological interventions led to an understanding of the fundamental role of factors like TNF or IL-6 in immune cell development and function. The utility of the animal models can't really be argued either, even if only from the point of providing a piece of data that enable a calculation of a therapeutic index, or providing comfort for investing in clinical trials.

Whether "validation" or safety assessment in animal models are scientifically valid is really open for debate, in my opinion. I am convinced that they are not useful to assess potential activity in human disease, nor predictive of adverse events.

Can we forgo them and move into the clinic without them? I would argue yes we can. We still need empirical tox testing, as limited as it is, but we can base a human dosing regimen off of drug levels associated with measured pharmacological effects and observed adverse events. (like what Shazza suggests, using dosing at MABEL, minimal anticipated biological effect level as a starting point).

Rationale for targets will still be strongly influenced by mouse biology, and I think this is a problem, but we should move away from rodent models as required elements of drug development.

For those that have been involved in portfolio risk assessment, you've probably witnessed discussion around topics like not aiming everything at one disease, or one target class for the purpose of diversifying risk. I once asked about changing our selection scheme so we did not make like decisions across the board, regardless of target or disease indication. It did not fly, so animal models still ruled. Most potent and selective compound advanced to animal models... the most impressive animal model results generated the clinical candidate....if no train wreck in tox, then into trials...similar selection schemes...similar outcome, trial failures. But hey, no one could say we took a crazy risk!

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47. Chris on February 16, 2013 6:53 PM writes...

I work in preclinical development for small pharmaceutical companies. I have always known that mice are different than humans -- you can tell, actually -- they are alot smaller, have longer tails and bigger ears!

Another question if you get to this e-mail -- what do you think about the Adam Fuerstein - Mark Ratain rule on phase III studies by small market cap companies? Have you commented on this before?

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48. Chris on February 16, 2013 6:53 PM writes...

I work in preclinical development for small pharmaceutical companies. I have always known that mice are different than humans -- you can tell, actually -- they are alot smaller, have longer tails and bigger ears!

Another question if you get to this e-mail -- what do you think about the Adam Fuerstein - Mark Ratain rule on phase III studies by small market cap companies? Have you commented on this before?

Permalink to Comment

49. Chris on February 16, 2013 6:53 PM writes...

I work in preclinical development for small pharmaceutical companies. I have always known that mice are different than humans -- you can tell, actually -- they are alot smaller, have longer tails and bigger ears!

Another question if you get to this e-mail -- what do you think about the Adam Fuerstein - Mark Ratain rule on phase III studies by small market cap companies? Have you commented on this before?

Permalink to Comment

50. Peter Liu on October 7, 2013 10:03 PM writes...

Does anybody know that there is custom service for Rat knockin? Check numerous facilities'websites, look like no one say yes?

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