Azra Raza, M.D. Professor of Medicine, Director of the MDS Center, at Columbia University recently wrote the following regarding mouse models of cancer. Azra was answering the question: “What Scientific Idea Is Ready For Retirement?”
An obvious truth that is either being ignored or going unaddressed in cancer research is that mouse models do not mimic human disease well and are essentially worthless for drug development. We cured acute leukemia in mice in 1977 with drugs that we are still using in exactly the same dose and duration today in humans with dreadful results. . . . there are no appropriate mouse models which can mimic the human situation.
Raza quotes Robert Weinberg of the Whitehead Institute at MIT, as stating that the reason people continue to use mouse models are: "Two reasons. First, there's no other model with which to replace that poor mouse. Second, the FDA has created inertia because it continues to recognize these models as the gold standard for predicting the utility of drugs." (See here for more on the comments of Robert Weinberg. I will also address some of his comments on the FAQs section of the new website.) Weinberg’s first reason is fallacious as there are many times when doing nothing is preferred to the status quo of doing something. For example, doing research that is misleading is worse than doing no research at all. Weinberg’s second reason, while true is just an excuse to maintain the status quo. Scientists do not have to use models that do not work just because someone in a different department of the federal government suggests they use mouse models.
But Raza adds a third reason that is more to the point:
There is a third reason related more to the frailties of human nature. Too many eminent laboratories and illustrious researchers have devoted entire lives to studying malignant diseases in mouse models and they are the ones reviewing each other's grants and deciding where the NIH money gets spent. They are not prepared to accept that mouse models are basically valueless for most of cancer therapeutics.
Sound familiar? I wonder if David Gorski MD, PhD agrees with her? (You can read her entire essay at http://www.edge.org/responses/what-scientific-idea-is-ready-for-retirement.) Furthermore, I wonder if any scientists will speak out and support her in this position? I doubt it. Growing a spine could result in their colleagues talking behind their back or the university speaking sternly to them about their tenured position and being a team player. I cannot imagine anyone asking a full professor to endure that kind of horror just to save the lives of few billion human patients.
Raza’s position is consistent with a December 19, 2013 press release from Jackson Laboratory that announced the response to cocaine and methamphetamine differs between 2 substrains of the commonly used Black 6 mouse. The C57BL/6J mice appeared to have a weaker response to the drugs than the C57BL/6N mice. The reason appears to be a single nucleotide polymorphism (SNP) in the gene Cyfip2. The press release states that: “This means that researchers should be very cautious when comparing behavioral data from studies using 6J and 6N strains.” (For more see reference .)
As I have stated many times, when strains of mice differ in their response to drugs and disease and monozygotic human twins do the same, trans-species extrapolation is not going to have any predictive value. (See Trans-Species Modeling Theory for more.) But it will be a hard to convince people of this when they have a vested interest in animal models. And by vested interest I do not just mean a financial interest.
Recently Universities and Science Minister of the UK, David Willetts stated: “Animals are only used when there are no suitable alternatives. But the results we get from research can transform lives and pave the way for new and ground-breaking medical advances.” Needless to say the Science Minister provided no references for this claim and refuses to support a proper debate as I outlined here or even consider the notion that vested interest groups might lie. Willetts supports the status quo as long as he benefits. Moreover, as I have also stated, there are no alternatives to something that is not viable in the first place. There are no alternatives to using animals as predictive models for human response to drugs and disease.
Interestingly, in the same article that Willets was quoted in, Minister Norman Baker was quoted as saying that “the scientific case for developing new techniques that do not involve animals is ‘as strong as the moral one.’ ”
Raza is not the first to point out that mouse models have failed. The list of scientists who have stated more or less the same thing in science journals is long. Despite this, nothing seems to be changing. Perhaps that is because society seems to be under the impression that all scientists support the use of animals as predictive models in drug and disease research. As long as the vested interest groups get to phrase the survey questions, can buy advertising space, have the support of the media, and refuse to debate specific questions in the presence of unbiased experts, this will not change. Must be nice to have that kind of job security.
1. Kumar, V.; Kim, K.; Joseph, C.; Kourrich, S.; Yoo, S.-H.; Huang, H.C.; Vitaterna, M.H.; Pardo-Manuel de Villena, F.; Churchill, G.; Bonci, A.; Takahashi, J.S. C57BL/6N Mutation in Cytoplasmic FMRP interacting protein 2 Regulates Cocaine Response. Science 2013, 342, 1508-1512. http://www.sciencemag.org/content/342/6165/1508.abstract