Neuroblastoma is notoriously difficult to treat secondary to the genetic variation of the tumor. Pediatric oncologist Sholler is studying neuroblastoma and is creating mice that have the tumour of the particular patient injected so that she can “model” each child she studies. (Couzin-Frankel 2011) She then tests potential treatments on the mouse models.
Contrast this with the fact that Dempster et al studied 22 pairs of monozygotic twins, one of which suffered from schizophrenia or bipolar disorder and found epigenetic changes associated with the disease in the affected twin.(Dempster et al. 2011) Scientists will never make mouse that has more, genetically, in common with humans than monozygotic twins have with each other. This fact will not, however, stop them from trying.
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The following is from a press release from NSF September 14, 2011:
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Scientists have sequenced the genomes (genetic codes) of 17 strains of common lab mice--an achievement that lays the groundwork for the identification of genes responsible for important traits, including diseases that afflict both mice and humans. Mice represent the premier genetic model system for studying human diseases. What's more, the 17 strains of mice included in this study are the most common strains used in lab studies of human diseases. By enabling scientists to list all DNA differences between the 17 strains, the new genome sequences will speed the identification of subsets of mutations and genes that contribute to disease. . . . Results reveal striking variations in strain relationships across the genome. (National Science Foundation 2011)(Emphasis added)
A similar press release from the University of WI-Madison, which participated in the research: BEGIN QUOTE
“Mice are the premier model organism for human disease. We’ve made a lot of progress in understanding the genetics of common human diseases by studying mice,” says Payseur, an associate professor of medical genetics in the UW–Madison School of Medicine and Public Health. “Although we’ve been able to map genomic regions that contribute to disease risk, we haven't known the full spectrum of mutations involved.” (University of WI-Madison 2011)(Emphasis added)
The Sanger Institute was also involved in the research and their press release stated:
“We are living in an era where we have thousands of human genomes at our fingertips,” says David Adams from the Wellcome Trust Sanger Institute, who led the project. “The mouse, and the genome sequences we have generated, will play a critical role in understanding of how genetic variation contributes to disease and will lead us towards new therapies.” (Wellcome Trust Sanger Institute 2011)(Emphasis added)
The above clearly reveals that animal experimenters and their representatives claim that animal models are predictive for human response to drugs and disease and that there is a one to one correlation. This attitude completely ignores the fact that animals are complex evolved systems.
A brochure for the conference “Animal Models and Relevance/Predictivity: how to better leverage the knowledge of the veterinarian field” held in France October 10-12, 2011 states the following:
Biomedical research, as an experimental science, has been relying on animal models. Some people claim that these animal-based models are not relevant and not ethical. However, by working on comparative anatomy and physiology, major progress in medicine has occurred. Infectious agents, which ignore species boundaries, can be equally studied in animals and in humans. The deciphering of the human genome and those of several animal and vegetal species provide a tremendous development of biological science. But as any models, predictivity does not mean direct transposition of results. Nonetheless, similarities between species are relevant enough to permit translational research, from the cells and tissues to animals, then to humans. Despite the efforts and the successes to reduce the use of animals in research, it is not possible to avoid completely using animals to improve human health. Whole organisms are still necessary to explore physiology and pathology, to evaluate the interactions between organs and functions, and to assess the efficacy and safety of novel drugs and vaccines. The combination of several models is done to increase the predictivity of models and the confidence in the scientific outcomes. In this context, basic and applied biomedical research benefits to both humans and animals.(Buzoni-Gatel et al. 2011)(Emphasis added)
The above is a combination of the false dichotomy fallacy and the intact systems argument. It also completely misrepresents what the word prediction means and the track record of using animals to predict drug and disease response.
George Phillip Willis, Lord Willis of Knaresborough, is the head of the Association of Medical Research Charities (AMRC) and member of the House of Lords in the UK. He spoke before that body on October 4, 2011 stating:
. . . if the UK wishes to remain a world leader in health and medical research, it requires its scientists to have access to good animal models that are well regulated and well cared for. . . . what steps will he or the Government take on campaigns such as those led by Animal Aid, which tend to persuade the public that you can go straight to human trials rather than trial new devices and products through using animals? That is quite wrong and could be incredibly dangerous to the health of our research base.
The above is an example of the fallacy known as appeal to fear in addition to presenting the false dichotomy of testing on animals or exposing humans to excessive risks.
Dr. Jacques Messier, currently of the Toronto Humane Society came under fire for being involved in animal-based research at Nuvo Research. He was quoted as stating: “The animal testing is done because it is mandated by the government agencies who want to be sure these products are safe for human use. Nuvo doesn’t carry out that testing. It’s contracted out to specific research places that have to meet the animal handling and safety mandates of the Animal Research Council of Canada.”(Yuen 2011)
Again we see the appeal to fear along with the false argument that testing on animals makes drugs safer.
British veterinarian, Pete Wedderburn stated: “We live in a meat-eating society where it’s normal for animals to be used for human benefit; it’s difficult to argue against the humane use of animals in science if it’s certain to significantly reduce human suffering.” (Wedderburn 2011) I would argue that the only thing that is certain about animal models is that they will not predict human response to drugs and disease.
Again, all of the above clearly reveal that animal experimenters and their representatives claim that animal models are predictive for human response to drugs and disease. Compare the above with the following.
A Reuters article on MSNBC discuses a computer-based method for predicting drug toxicity. The chip would test for activation of genes and proteins in various human tissues:
"If things are going to fail, you want them to fail early," Dr. Francis Collins, the director of the National Institutes of Health (NIH), told Reuters on Friday. "Now you'll be able to find out much quicker if something isn't going to work."
Collins said a drug's toxicity is one of the most common reasons why promising compounds fail. But animal tests -- the usual method of checking a drug before trying it on humans -- can be misleading. He said about half of drugs that work in animals may turn out to be toxic for people. And some drugs may in fact work in people even if they fail in animals, meaning potentially important medicines could be rejected.(Reuters 2011) (Emphasis added.)
Once again we are back to the fact that tossing a coin would yield results that are just accurate as animal testing is for toxicity.
Well-conducted Phase II clinical trials provide the data required to determine whether there is a case to be made, both scientifically and commercially, for progressing a drug candidate into Phase III trials. At present, however, Phase II success rates are lower than at any other phase of development. Analysis by the Centre for Medicines Research (CMR) of projects from a group of 16 companies (representing approximately 60% of global R&D spending) in the CMR International Global R&D database reveals that the Phase II success rates for new development projects have fallen from 28% (2006–2007) to 18% (2008–2009), although these success rates do vary between therapeutic areas and between small molecules and biologics. As the current likelihood of a drug successfully progressing through Phase III to launch is 50% (Nature Rev. Drug Discov. 10, 87; 2011), the overall attrition of late-stage drug development seems to be unsustainably high. To help understand these trends, Thomson Reuters Life Science Consulting analysed the 108 reported Phase II failures from 2008 to 2010 for new drugs and major new indications of existing drugs (Drug News Perspect. 22, 39–51; 2009; Drug News Perspect. 23, 48–63; 2010; Drugs Today, 47, 27–51; 2011). Out of these, 87 reported the reasons for failure (Fig. 1a): 51% (44 out of 87) were due to insufficient efficacy, 29% (25 out of 87) were due to strategic reasons and 19% (17 out of 87) were due to clinical or preclinical safety reasons. (Arrowsmith 2011) (Emphasis added.)
In other words, a vast majority of failures, efficacy and safety, were in areas where animal-based research is relied upon.
The future will be in personalized medicine for the above reasons and the following. Andrew Grove, former Chief Executive Officer of Intel Corporation
The biomedical industry spends over $50 billion per year on research and development and produces some 20 new drugs. One reason for this disappointing output is the byzantine U.S. clinical trial system that requires large numbers of patients. Half of all trials are delayed, 80 to 90% of them because of a shortage of trial participants. Patient limitations also cause large and unpredicted expenses to pharmaceutical and biotech companies as they are forced to tread water. As the industry moves toward biologics and personalized medicine, this limitation will become even greater. A breakthrough in regulation is needed to create a system that does more with fewer patients. (Grove 2011)
Personalized medicine will allow for smaller clinical trials as the drugs will used based on genetic make-up. This will reduce the cost of drugs in several ways.
A press release from Mayo Clinic, dated September 22, 2011
Researchers at Mayo Clinic are hacking the genetic code that controls the human response to disease vaccination, and they are using this new cipher to answer many of the deep-seated questions that plague vaccinology, including why patients respond so differently to identical vaccines and how to minimize the side effects to vaccination. . . . Doctors and epidemiologists have long been puzzled about the genetic underpinnings to the fact that up to 10 percent of recipients fail to respond to the first dose of the measles vaccine, while another 10 percent generate extremely high levels of measles antibodies. The remaining 80 percent fall somewhere in the middle.
The abstract of the article referred to above can be accessed here but the article is pay per view.
By studying tissues from human cancer patients, researchers at Duke-National University of Singapore Graduate Medical School discovered that stomach cancer is actually two different diseases and that response to therapy depends on the genome of the cancer.(Tan et al. 2011)
In light of the emphasis being placed on pharmacogenetics and personalized medicine, the fact that basic research using animals translated to new treatments in the neighborhood of 0.004% of the time, and the fact that results from animal models misleads scientists and harms patients, one is forced to ask why the practice persists. As I have said many times, money is the main reason.
Arrowsmith, John. 2011. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Discov 10 (5):328-329.
Buzoni-Gatel, Dominique, Thierry Decelle, Patrick Hardy, Xavier Montagutelli, and Jacques Louis. 2011. Animal Models and Relevance/Predictivity: how to better leverage the knowledge of the veterinarian field. Fondation Mérieux 2011 [cited October 6 2011]. Available from http://www.fondation-merieux.org/documents/conferences-and-events/2011/animal-models-and-relevance-predictivity-10-12-october-2011-programme.pdf.
Couzin-Frankel, J. 2011. Personalized medicine. Pushing the envelope in neuroblastoma therapy. Science 333 (6049):1569-71.
Dempster, E. L., R. Pidsley, L. C. Schalkwyk, S. Owens, A. Georgiades, F. Kane, S. Kalidindi, M. Picchioni, E. Kravariti, T. Toulopoulou, R. M. Murray, and J. Mill. 2011. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Human molecular genetics.
Grove, Andrew. 2011. Rethinking Clinical Trials. Science 333 (6050):1679.
National Science Foundation. 2011. Press release: Of Mice and Men. NSF, September 14 2011 [cited October 6 2011]. Available from http://www.nsf.gov/news/news_summ.jsp?cntn_id=121653&org=NSF&from=news.
Reuters. 2011. U.S. to develop chip that tests if a drug is toxic. Reuters, September 16 2011 [cited October 6 2011]. Available from http://www.msnbc.msn.com/id/44554007/ns/health-health_care/ - .To5AMnPaixF.
Tan, Iain Beehuat, Tatiana Ivanova, Kiat Hon Lim, Chee Wee Ong, Niantao Deng, Julian Lee, Sze Huey Tan, Jeanie Wu, Ming Hui Lee, Chia Huey Ooi, Sun Young Rha, Wai Keong Wong, Alex Boussioutas, Khay Guan Yeoh, Jimmy So, Wei Peng Yong, Akira Tsuburaya, Heike Grabsch, Han Chong Toh, Steven Rozen, Jae Ho Cheong, Sung Hoon Noh, Wei Kiat Wan, Jaffer A. Ajani, Ju‚ÄìSeog Lee, Manuel Salto Tellez, and Patrick Tan. 2011. Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy. Gastroenterology 141 (2):476-485.e11.
University of WI-Madison. 2011. Mouse genome sequences reveal variability, complex evolutionary history. UW-Madison, September 15 2011 [cited October 15 2011]. Available from http://www.news.wisc.edu/19771.
Wedderburn, Pete. 2011. It's hard to argue with experimenting on animals if it will reduce human suffering. The Telegraph, July 14, 2011 2011 [cited July 29 2011]. Available from http://blogs.telegraph.co.uk/news/peterwedderburn/100096887/its-hard-to-argue-with-experimenting-on-animals-if-it-will-reduce-human-suffering/.
Wellcome Trust Sanger Institute. 2011. Researchers develop mouse genetic blueprint. Mouse study drives forward understanding of human biology. Wellcome Trust Sanger Institute, September 14 2011 [cited October 6 2011]. Available from http://www.sanger.ac.uk/about/press/2011/110914.html.
Yuen, Jenny. 2011. THS CEO criticized for links to animal testing. Toronto Sun, September 23 2011 [cited October 2 2011]. Available from http://m.torontosun.com/2011/09/23/ths-ceo-criticized-for-links-to-animal-testing?noimage.