Why don’t you talk more about the business aspect of using animals in research and testing? Would not the argument that alternatives are cheaper and more predictive be a good place to start the debate of using animals in research and testing? This is a good question and we appreciate the chance to respond as it gives us the opportunity to cover a lot of ground. First, the actual dollar amount spent by companies on using animals as predictive models for humans is unknown and is likely to remain that way. In addition to such data being proprietary, companies do not want society to know how much they spend on such things. So any attempt at comparison is dead before it even begins. But all is not lost. We can look at the paradigm of using animals per se and draw conclusions. As an analogy, we cannot review every patent application claiming the development of a perpetual motion machine but we can study the laws of physics and conclude that a perpetual motion machine (PMM) is not possible. Therefore, money spent on attempts to develop a PMM are wasted and a company would be better off developing more efficient solar technology or a way to use fossil fuels that is less polluting and more efficient. Moreover, examining all the patent applications for a PMM is not necessary, as we know in advance that the applications will have fatal flaws. We do not need to find the individual flaws in every application in order to refuse the patent. Similarly, a thorough study of evolutionary biology and complexity science via Trans-Species Modeling Theory (TSMT) tells us that with respect to drug and disease research animal models will not offer predictive value for humans (see books and article in the Resources section for more). Second, we can conclude from our study of complexity science, evolution, and the empirical evidence that any company using animals as predictive models will probably not do well, at least in so far as it relies on animal data when trying to determine what the disease or drug will do in humans. The cost to the company will be large and the benefit no better than one would expect from using random guessing to determine human response. This is exactly what we are seeing in the pharmaceutical industry (Pharma) currently. Third, this question allows us to point out once again that when people suggest that an alternative to using animals should be developed, they are implying that using animals is a viable means for accomplishing whatever the stated goal is; for example, predicting toxicity. In fact, animals are not viable for predicting human response to drugs and disease, so the practice of using them as predictive models should be abandoned simply because it is ineffective. For more on this go to the section For Animal Protectionists and read the essay How animal protection groups are delaying the end of vivisection. Fourth, rough approximations of the costs to companies conducting animal research are available from Pharma, and Dr. Ray Greek discusses these in his articles in the peer-reviewed literature (see Resources section). The bottom line is that animal studies per se are not that expensive. The expense comes from the cost of developing drugs that go on to fail in clinical trials or after, when the animal-based research or tests indicated that the drugs would succeed. This is called “failing late” by Pharma and is the biggest cost in drug development. Thus the data from Pharma proves how expensive animal modeling is but not in the way many animal protectionists claim. Lastly, do not be taken in by people who claim that all animal modeling can be replaced by non-animal methods that are predictive for humans. First, very few in vitro or in silico methods predict properties like safety or efficacy in terms of drug response for humans. Second, the point to be made regarding the use of animal models is that they offer no predictive value for humans in the first place. Thus animal models that claim to have predictive value but that in reality do not should be abandoned. Requiring tests with predictive value before abandoning animal tests that offer none is like continuing to treat schizophrenia with trephination (cutting a hole in the skull) and justifying the practice based on the fact that there is currently no cure for schizophrenia. One of the first rules in medicine is to not make the situation worse and animal models violate that principle. In summary, we do not have, but neither do we need to have, a monetary cost analysis comparing animal models to other models, such as in vitro and in silico, when trying to determine whether animals should be used as predictive models by industry or academia. The best science we have available today proves that animal models will never offer predictive value for humans in terms of response to drugs and disease. (For more on why this is the case, see the articles in the Resources section.) AFMA has been criticized for promoting an agenda as opposed to merely stating their scientific opinions and letting the facts speak for themselves. Is AFMA’s scientific creditability diminished because it promotes change as opposed to merely stating facts? Merely stating facts is often inadequate. Milner: Darwin was well pleased with Huxley's aggressive campaign to win over public opinion in 1860, just after Huxley had bested Wilberforce. Darwin stressed the "enormous importance of showing the world that a few first-rate men are not afraid of expressing their opinion. . . . I see daily more and more plainly that my unaided book would have done absolutely nothing.” (Milner, Richard. 2009. Darwin's Universe: Evolution from A to Z. University of California Press. P122.) In fact, Darwin was not the first to suggest natural selection as a means for change. Two others, Patrick Matthew in 1831 and William Charles Wells in 1818 had written about it prior to Darwin (Milner p 295-6). But their publications received little attention in part because they had no Huxley to promote their idea. Another example is the monk Gregor Mendel and his discoveries in genetics. Mendel published a paper in 1865 that was ignored for decades. Finally discovered after his death, it went on to become the basis for explaining evolution as well as informing science in many other areas. AFMA is committed to better patient care through better research hence will continue to vigorously point out the implications of using animals as predictive models. Lives depend on it. Where is the data to support your position that using animals as predictive and causal analogical models for human drug and disease response is a scientifically untenable? There is an overwhelming amount of empirical and clinical evidence, not to mention a large number of scholarly and popular publications that have been written, regarding the use of animals as predictive models. Moreover, remarkable advances in the world of biomedicine are being made every day in the United States and around the world that support this position. Any attempt to cull this information into a single website and keep it up-to-date would most certainly fall short. Rather than engaging in a futile attempt to provide exhaustive information to explain our position, we have provided a substantial number of resources for those who wish to explore the issue further. For those wanting details, the books and articles listed in the Resources section offer both empirical evidence and supporting theory. Many people who share AFMA’s position on animals as predictive models for drug and disease response have relied on the data provided in earlier versions of your website to support their beliefs. How can they now prove their point without the appropriate data? Many people who do not have a strong background in science have, in the past, used scientific data that was available on previous versions of the AFMA website in a piecemeal attempt to support their belief that animals should not be used as predictive models for human drug and disease response. To begin with, science is not amenable to a piecemeal approach. Second, if a person currently does not have the educational background to make a scientific case, we suggest he read FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. Familiarity with the contents of this book will allow him to present good, solid science as opposed to fragments in a piecemeal fashion, to others in his peer group (family, friends, and so forth). Finally, with the tremendous advances in science over the last two decade, the arguments being made based on data that was on older version of the website is like using the curvature of the earth on the surface of the moon as seen during an eclipse to prove the earth is round. One can do it that way but a photo of the earth from an Apollo or STS mission is much better. AFMA realizes that the new information coming from research in the 2000s is much more difficult for a non-scientist to assimilate than the old. This is the nature of science. AFMA has expended considerable resources to make this information available to nonscientists via the FAQs book.For those in need of experts on the subject of the scientific merits of the uses of animals in science, we suggest you contact us directly. We would be happy to interact with your questioners. Are Drs. Greek’s first three books wrong or simply outdated? As we stated in the answer to the previous question, the information in the first three books written by the Drs. Greek, along with similar information on older versions of the website, are essentially out of date. The information in them is not wrong, but as more information has become available, the arguments made in these books are not as powerful as the arguments we make in Animal Models in Light of Science, which is a scholarly publication geared for people with doctorates in science. For the non-scientist, we recommend FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed instead of the first three books. For scientists, we strongly recommend the articles listed on the Resources page. AFMA is frequently identified as an animal rights group. Why? Because AFMA opposes the use of animals as predictive/causal analogical models for human drug and disease response, our position intersects the position of animal protectionists in that they too wish to eliminate the use of animal models in drug and disease testing. However, that is where all commonality ends. AFMA’s position is rooted in science. AFMA focuses on the harm that is done to humans when science is ignored. Animal protectionists, on the other hand, hold their position on animal-oriented ethical grounds. There are additional differences. Because we are based purely in science, we do not oppose the use of animals to benefit humans when such use is scientifically sound. We readily acknowledge that in many respects animals have proven to be of great benefit to medicine, just not as predictive models for human drug and disease response. Animal protectionists, however, unilaterally oppose the use of animals in science as part of their philosophy regarding humanity’s relationship with animals. AFMA has both animal activists and people who are not “animal people” on the board. The mistaken belief that AFMA is an animal rights group is sometimes a natural one, since there is a thread of commonality and it is all too easy to make false assumptions. At the same time, AFMA is frequently and purposefully accused of being an animal rights group by those who advocate for animal-based research. Such accusations are examples of ad hominem attacks designed to confuse those who are not familiar with AFMA and the scientific basis for our position. Do you conduct your own biomedical research? AFMA is an educational organization, and we are dedicated to education and improving policy and decision making regarding the use of animals in biomedical research. We do publish in the scientific literature and some, including AFMA, would consider such publications to be the result of “biomedical research.” But we do not currently conduct research in the sense of working in a lab, controlling variables, using equipment commonly found in labs, or working with patients. Do you oppose the use of animals in all scientific endeavors? No. We only oppose the use of animals as predictive/causal analogical models for human response to drugs and disease. The reason we oppose this use of animals is because it is a scientifically untenable practice. As a science-based organization, we know that animals have historically been used successfully in a number of areas to benefit human health. A word of caution, however: Many of the historical examples given by animal modelers to demonstrate the importance of using animals in research do not hold up to scrutiny.AFMA also addresses the use of animals in basic research, but only when people conflate basic and applied research or when the issue of “How effective is basic research that uses animals?” is raised as these topics overlap with the prediction issue. (See Greek, R and Greek, J. Is the use of sentient animals in basic research justifiable? Philosophy, Ethics, and Humanities in Medicine 2010, 5:14.) Dr. Ray Greek and AFMA quote scientists out of context. There are several fallacies and accusations that are routinely used by people without evidence to support their position. Individuals and organizations that have to sell a position in the face of overwhelming evidence against that position also frequently resort to fallacies. We cover some of these in this FAQs section. One attack is to accuse a scholar of quoting out of context. This is a very severe offense in scholarly circles and accusations are taken seriously. The mere allegation has ruined careers, even when the charge was eventually shown to be unsubstantiated. Even though the burden of proof should be on the person making the accusation of “out of context,” the charge is not usually treated that way. We will provide one example of this attack and refute it thoroughly. Obviously, refuting one example does not refute them all but when the same people repeatedly attack Dr. Ray Greek and AFMA with the “out of context” accusation, without providing evidence, this one example should place the burden of proof back where it belongs: on the accusers.Dennis wrote the following in Nature, and Shanks and Greek quoted it in Animal Models in Light of Evolution: It was in 1991 that Bob [Robert] Weinberg first realized he had a problem with mice. He and his postdoc Tyler Jacks were trying to develop a mouse model for retinoblastoma, a childhood cancer of the retina. It results from the loss of a gene called Rb, so the team genetically engineered mice to lack the same gene. But the mice didn’t get retinoblastoma. Instead, they developed tumors in their pituitary glands. The finding shocked Weinberg. “Up until then, I had always believed that all mammals were biologically equivalent,” he says: “This planted the seeds of doubt in my mind.” Weinberg, based at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, is one of the pioneers of the molecular age of cancer research. He was involved in the early work on the first human cancer-causing and cancer-suppressing genes in the early 1980s. But when he saw that mutations in such genes didn’t cause the same kind of cancer in mice and humans, he began to ask himself why. He became aware of other examples that challenged researchers’ faith in how accurately mice could replicate human tumors, and has since sought to bring this to his colleagues’ attention. “There is a laundry list of problems with mouse models of cancer,” he says.1 Rangarajan and Weinberg had previously written in Nature Reviews Cancer: These various observations show the existence of key differences in the signaling requirements for the transformation of mouse and human cells in vitro. In mouse fibroblasts, perturbation of just two signaling pathways—those involving p53 and Raf-MAPK—seems to be sufficient to mediate tumorigenic conversion. In human fibroblasts, perturbations of six or more pathways—those involving p53, RB, telomerase, PP2A, RAL-GEF and one or more additional RAS-effector pathways—seems to be essential for achieving the same outcome.2 Begley wrote the following in Newsweek in 2008, and this was also quoted by Shanks and Greek in Animal Models in Light of Evolution: A widely discussed 2004 article in Fortune magazine (“Why We’re Losing the War on Cancer”) laid the blame for this at the little pawed feet of lab mice and rats, and indeed there is a lot to criticize about animal studies. The basic approach, beginning in the 1970s, was to grow human cancer cells in a lab dish, transplant them into a mouse whose immune system had been tweaked to not reject them, throw experimental drugs at them and see what happened. Unfortunately, few of the successes in mice are relevant to people . . . “Far more than anything else,” says Robert Weinberg of MIT, the lack of good animal models “has become the rate-limiting step in cancer research.” 3 Weinberg, was quoted by Leaf in the aforementioned Fortune article as stating: “And it’s been well known for more than a decade, maybe two decades, that many of these preclinical human cancer models have very little predictive power in terms of how actual human beings—actual human tumors inside patients—will respond . . . preclinical models of human cancer, in large part, stink . . . hundreds of millions of dollars are being wasted every year by drug companies using these [animal] models.”4 Leaf also quotes Homer Pearce, “who once ran cancer research and clinical investigation at Eli Lilly and is now research fellow at the drug company” as stating: mouse models are “woefully inadequate” for determining whether a drug will work in humans. “If you look at the millions and millions and millions of mice that have been cured, and you compare that to the relative success, or lack thereof, that we’ve achieved in the treatment of metastatic disease clinically,” he says, “you realize that there just has to be something wrong with those models.”4 Compare the above quotes with the following from Dario Ringach Ph.D. of UCLA: It is unfortunate that Dr. Greek selectively quotes scientists out of context throughout his book when they acknowledge some failure of animal models and appears to imply their statements support his contentions that animal research will never lead to cures for human ailments.5 Note that Dr. Greek has never stated: “that animal research will never lead to cures for human ailments.”Ringach then quotes Robert Weinberg as stating the following regarding his words as quoted by Shanks and Greek in Animal Models in Light of Evolution: This is clearly a willful and intentional misreading of my intent, since my words were clearly intended by me to indicate that, while mouse models have their limitations, they are by far the best thing we have at present and in the foreseeable future. Indeed, they are indispensable for much of contemporary cancer research. I would emphasize in the strongest and most unambiguous way that as we begin to develop therapies that are increasingly effective in dealing with cancer in humans, we come to appreciate, with ever-increasing clarity, that many of the properties of cancer cells and tumors cannot be and will never be approximated by in vitro culture models, i.e., in which one studies cancer cells growing in the Petri dish. For example, it is truly absurd to argue that it is possible to study clinically important processes such as tumor invasiveness into adjacent tissue and tumor metastasis without using an animal model. I am disappointed that anyone would espouse such a point of view, even for a minute! If the American people wish to support Dr. Greek’s agenda, then they must at the same time give up the hope that future biomedical research will improve the powers of medicine to treat and cure disease—it’s as simple as that.5 AFMA leaves it to the reader to compare and contrast what Dr. Weinberg said in the above with what he stated in the previous quotes and with which he had no objections or corrections for the writers. AFMA also encourages the reader to click on the above links and read the articles in their entirety. The fact that humans and animal respond differently in terms of mechanisms and susceptibilities to cancer is not controversial. Neither is the fact that Weinberg has been instrumental in proving this. Anisimov, Ukraintseva, and Yashin wrote in 2005: Available data indicates that there are similarities in the genes involved in carcinogenesis in humans and rodents. For instance, many proto-oncogenes and tumour suppressors are the same or homologous in humans and rodents. Examples include the p53 and retinoblastoma (RB) tumour suppressors, as well as MYC, RAS and tyrosine-kinase-receptor proto-oncogenes. However, important differences between humans and rodents are evident in the number of genetic events involved in cancer development. Fewer genetic, epigenetic or gene-expression-altering events are required to induce a malignant transformation in murine cells compared with human cells. Hahn and Weinberg3 and Rangarajan and Weinberg4 reviewed this divergence in depth. In brief, the authors showed that at least four to six mutations are required in humans to reach this state, whereas fewer are required in mice. Human cells must break several genetic barriers to achieve immortalization, including telomere shortening and subversion of the RB and p53 tumour-suppressor pathways. By contrast, ablation of the ARF-p53 pathway alone is often sufficient to immortalize murine cells'. The exact reasons for these and other differences in human and murine carcinogenesis are not clear and need further investigation.6 3. Hahn, W. C. & Weinberg, A. A. Modelling the molecular circuitry of cancer. Nature Rev. Cancer 2,331-341(0002). Basic Information on the differences between the genetic events required to induce malignant transformation in human and mouse cells, 4. Rangarajan, A. & Weinberg, P. A. Comparative biology of mouse versus human cells: modelling human cancer In mice. Nature Rev. Cancer 3, 952-959 (2003). Important paper addressing differences in how tumorigenesis occurs In mice and humans. Likewise, Chabner and Roberts wrote in 2005: Certain principles emerged from the cytotoxic era, and are likely to be applied to the new chemotherapies. First, animal models, while instructive, are unreliable predictors for success against human disease. Human tumours of any given histological type have great genetic diversity, as revealed by gene-expression profiling, and in most types of cancer only a subset of patients will prove responsive to any given new agent. Animals imperfectly reflect the pharmacokinetics of drugs in humans, because of more rapid metabolism, greater tolerance for side effects and differences in protein binding. Even specific organ toxicities cannot be extrapolated from mice to humans. As pointed out recently by Douglas Hanahan and Robert Weinberg, the basic biology of murine cells, and the process of transformation, can differ significantly from that of human cells. Attempts to produce genetically engineered mouse models of human cancer in fact lead to models of the specific molecular changes in a mouse cell, and have uncertain relevance to a human counterpart.7 As Shanks and Greek quoted from widely read sources that Weinberg had not previously objected to, and as these sources had come to essentially the same conclusion regarding animal models that Shanks and Greek came to, AFMA can only conclude that Weinberg backtracked and attempted to rationalize his comments when they threatened his standing in the animal model community. 1. Dennis, C., Cancer: off by a whisker. Nature, 2006. 442(7104): p. 739-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=169152612. Rangarajan, A. and R.A. Weinberg, Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer, 2003. 3(12): p. 952-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14737125 3. Begley, Sharon. 2012. We fought cancer. . . and cancer won. Newsweek, September 15 2008 [cited April 24 2012]. Available from http://www.newsweek.com/id/157548 4. Leaf, C., Why we are losing the war on cancer. Fortune, 2004(March 9): p. 77-92. http://money.cnn.com/magazines/fortune/fortune_archive/2004/03/22/365076/index.htm 5. Ringach D (2011) A More Balanced View of Animal Models. In: McNulty M (ed) Opposing Views. Opposing Views, Los Angeles. http://www.opposingviews.com/i/a-more-balanced-view-of-animal-models 6. Anisimov, V.N., S.V. Ukraintseva, and A.I. Yashin, Cancer in rodents: does it tell us about cancer in humans? Nat Rev Cancer, 2005. 5(10): p. 807-19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=161957527. Chabner BA, Roberts TG, Jr. (2005) Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer 5:65-72. nrc1529 [pii] 10.1038/nrc1529. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15630416 Dr. Ray Greek and AFMA rely on fallacious reasoning to make their arguments. AFMA and Dr. Ray Greek support critical thinking and Dr. Greek frequently links to critical thinking websites. If anyone can substantiate the above accusation, AFMA would love to hear from him. So far, no one has offered any such examples. Vivisection activists have accused Dr. Greek of using fallacies many times but have never accepted offers to debate the topic in a public setting or in the scientific literature. Claims and accusations are not evidence. All scientists disagree with AFMA. Actually, they don’t. AFMA’s position is that animal models have no predictive value for human response to drugs and disease. No studies, surveys, or polls have asked what scientists think of this. Several surveys have asked whether scientists think animal-based research is important. For example, a 2010 Pew Research survey conducted in association with the American Association for the Advancement of Science (AAAS) and revealed that: “More than nine-in-ten scientists (93%) favor the use of animals in scientific research, but only about half of the public (52%) agrees.” In 2005, the Guardian (UK) reported that more than 500 leading UK scientists and doctors had signed a declaration supporting animal-based research. Moreover, organizations such as the American Medical Association and the American Physiological Society have position statements supporting animal-based research. The above surveys raise several questions. Who sponsored the poll/study? Who exactly does the organization that advocates for the position represent and, if there are many shareholders, which ones are represented by this position? How was the question phrased? What was really being asked? Is this an example of the bandwagon fallacy? Is there disagreement from other scientists? In reality, scientists openly disagree with the vested interest groups on the use of animal models, as we will see below. Are there reasons to suspect that the responders have an agenda? For example, one Congressman stated at a hearing in 1988 that the U.S. research granting system was: . . . an old boy’s system where program managers rely on trusted friends in the academic community to review their proposals. These friends recommend their friends as reviewers . . . It is an incestuous ‘buddy system.’1 This casts doubt on the objectivity of those receiving research grants from the U.S. taxpayer. Markou, Chiamulera, Geyer, Tricklebank (of Eli Lilly), and Steckler (of Johnson and Johnson) state: Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. . . . Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. . . . Since the founding of the American College of Neuropsychopharmacology (ACNP) in December 1961, there have been tremendous advances in neuroscience knowledge that have greatly improved our understanding of brain functioning in normal and diseased individuals. Unfortunately, however, these scientific advancements have not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders in general, and psychiatric disorders in particular (Hyman and Fenton, 2003; Fenton et al., 2003; Pangalos et al., 2007). . . .2 Cook, et al. wrote: Over many years now there has been a poor correlation between preclinical therapeutic findings and the eventual efficacy of these [anti-cancer] compounds in clinical trials (Johnson et al. 2001; Suggitt and Bibby 2005). . . . The development of antineoplastics is a large investment by the private and public sectors, however, the limited availability of predictive preclinical systems obscures our ability to select the therapeutics that might succeed or fail during clinical investigation. . . . Murine models base become a main part of research in many laboratories as they are the most accessible animal model. There are extensive reports highlighting the advances we have made in cancer biology by employing these systems however, the usefulness of different types of animal models in preclinical compound testing is a much more disputed topic. . . . These models [syngeneic or allograft rodents, xenograft rodents, orthotopic rodent model, and genetically engineered mice] have been used extensively in the academic and pharmaceutical industry research settings to prioritise compounds for clinical testing. Subcutaneous implantable models offer the ability to rapidly examine large cohorts of relatively uniform tumours whose growth and response to drugs can easily be assessed. Unfortunately, while such models are relatively inexpensive, convenient and easy so use, they generally behave differently than the corresponding human cancer. When used in the drug discovery setting many agents show consistent and compelling anticancer activity in specific implantable model systems, but unfortunately oftentimes fail in later stages of clinical development. . . . The primary purpose of preclinical therapeutic efficacy testing is to predict whether a particular compound will be successful in the clinic. Despite encouraging preclinical results, unfortunately most drugs are found to be ineffective late in their development, with only a small percentage (5%) of patients in Phase I clinical trials responding (Roberts et al. 2004). Apart front using inaccurate tumour models, there are many other reasons why preclinical studies fail to predict clinical activity. Species-specific PK, its addition to differences in drug delivery, and tumour heterogeneity might all contribute to discordant results. Such failures are costly to scientists and drug companies and of great consequence to the patients that optimistically enroll in experimental clinical trials.3 Bendtsen and Møller discussing animal models of portal hypertension and the pharmacologic interventions thereof, stated: “In conclusion, the results of this experimental study emphasize that pharmacologic hemodynamic effects are [animal] model specific, and one should therefore be cautious to draw firm conclusions as to the efficacy in humans based on animal studies.”4 Spedding et al. stated: “Animal models often cannot be transposed to Phase I and Phase II clinical testing, and Phase I/II clinical testing is often not transposable to Phase III trials and the general population.”5 Dan Engber wrote three articles about mouse research for Slate magazine.6-8 In the articles, Clifton Barry, chief of the Tuberculosis Research Section at the National Institute of Allergy and Infectious Diseases, discusses the drug development process as going from test tube to mouse to man and is quoted by Engber as saying: “The bad part of that is that no part of it is predictive.” Engber then continues: A new compound that succeeds in the dish might flunk out in the mouse, and something that can cure tuberculosis in a mouse could wash out in people. Take the example of pyrazinamide, one of the front-line drugs in the treatment of tuberculosis. Along with three other antibiotics, it forms the cocktail that remains, despite ongoing research, our only way of defeating the infection. But pyrazinamide didn’t make it through the three Ms: It does nothing in the dish—there’s no MIC whatsoever—and it has a weak effect in mice. According to Barry, if a compound like that were discovered in 2011, it would never make its way into clinical trials. . . . The fact that nothing gets to humans today without first passing the mouse test, says Barry, “has cost us a new generation of medicines.” . . . That’s why we’ve made so little progress using mice to generate new drugs and treatments [against tuberculosis], Barry tells me. In the absence of a clear, granulomatous response upon which to model human disease, the second M has become a massive roadblock in the path to a cure. “The vast majority of the money that we spend in clinical trials based on mouse data is completely wasted,” he says. If you ask Clif Barry why we’re still using the mouse to study tuberculosis, or Mark Mattson why we continue to test new drugs on obese and sedentary rodents, they’ll tell you the same thing: Because that’s what we’ve always done—we’re in a rut. But to an outsider—say, a journalist who’s trying to understand the place of the mouse in the broad enterprise of biomedicine—that explanation doesn’t make sense. The doctors who devised the classic treatment [for tuberculosis] 40 years ago didn’t need detailed mouse data—they found their cure with a methodical, brute-force approach: a series of human trials that spanned the better part of two decades and tested every possible combination of exposures. “The way those four drugs were put together is incredible. It’s never to be seen again.” Since that happened, we’ve had thousands of mouse studies of tuberculosis, yet not one of them has ever been used to pick a new drug regimen that succeeded in clinical trials. This isn’t just true for TB; it’s true for virtually every disease,” he tells me. “We’re spending more and more money and we’re not getting more and more drug candidates.” Several other pain treatments have failed in spectacular ways upon moving from the cage to the clinic. Drugs designed to block substance-P receptors and sodium channels succeeded in rodent models, but had little, if any, effect in people. According to Mogil, there’s really just one commercial analgesic for human patients whose efficacy was first identified and tested in animal models—a derivative of cone snail venom called ziconotide—and it’s not a particularly good drug. Holmes, Solari (of GlaxoSmithKline), and Holgate, writing in Drug Discovery Today state: Asthma remains an area of considerable unmet medical need. Few new drugs have made it to the clinic during the past 50 years, with many that perform well in preclinical animal models of asthma, failing in humans owing to lack of safety and efficacy. The failure to translate promising drug candidates from animal models to humans has led to questions about the utility of in vivo studies and to demand for more predictive models and tools based on the latest technologies. . . . Current strategies rely on cell- and animal-based assays during preclinical and clinical stages of drug development. The predictive power of these assays plays a considerable part in the lack of efficacy and safety seen in human trials of new drugs, (Paul et al. 2010; Collins 2011) including those developed to treat asthma. The scientific literature includes many examples of potential asthma therapies that have been developed on the basis of positive preclinical data, only for them to fail on the grounds of safety and/or efficacy in clinical trials (Box 1). The lack of predictive preclinical models of asthma is contributing to the paucity of efficacious asthma drugs . . . The US Food and Drug Administration (FDA) (FDA 2004) and European Innovative Medicines Initiative (IMI) (Shattock et al. 2011) have acknowledged the limitations of animal models as a major bottleneck in the development of efficacious and safe medicines across many therapeutic areas, including asthma. . . . Further variability is observed within species, with different strains of mouse exhibiting striking differences in the extent to which they develop allergic immunological responses to the same sensitizer.(Wadman 2011; Wilke and Dolan 2011) Similar strain differences have also been observed in rats. (Fauci 2011), (Carroll 2009) 9 Furthermore, arguing that the experts disagree with AFMA and therefore AFMA’s position is wrong is an example of the fallacy known as the argument from authority. The argument from authority basically states that: X is an authority on Y. X says Y is true. Therefore Y is true. This has the advantage of being very straightforward. But the reason this is a fallacy is because no proof or evidence is provided; the proponent relies only on the credentials or reputation of the authority. There is a reason arguments from authority persist. Authorities are often correct. However, history is replete with authorities being wrong. James Watson stated: “Oh sure, I knew it would cause trouble,” says Watson, eyes widening with unabashed glee. “I said most scientists are stupid.” He pauses, furrowing his brow in an effort to quote himself accurately. “The fact is most scientists act as though they are stupid because they are wedded to some approach they can’t change, meaning they are moving sideways or backwards.” 10 Bertrand Russell said: “Even when all the experts agree, they may well be mistaken.” Without evidence, opinions from the authorities mean little. Along these lines, Oreskes and Conway in Merchants of Doubt ask why scientists who knew the truth about issues like second hand smoke and acid rain, did not challenge the nonsense being put out by the vested interest groups: If the skeptical arguments pursued by our protagonists were not about science—if they were politics camouflaged as science—then why didn’t scientists recognize this, and say something? Why did the scientific community stand by while this was happening? With the notable exception of the atmospheric science community’s defense of Ben Santer, scientists fighting back have been conspicuously scarce. Add to the authority equation the fact that many authorities have a vested interest in the issue and the testimony of an authority is worth even less. For example, the following is from the NABR website: Founded in 1979, The National Association for Biomedical Research (NABR) provides the unified voice for the scientific community on legislative and regulatory matters affecting laboratory animal research. (Emphasis added.) That is pretty straightforward. It continues: NABR works to safeguard the future of biomedical research on behalf of its more than 300 public and private universities, medical and veterinary schools, teaching hospitals, voluntary health agencies, professional societies, pharmaceutical and biotech industries, and other animal research-related firms that are: (1) involved directly in the use of animals in biomedical research and are (2) committed to the responsible and humane use of these animals. (Emphasis added.) That should put the following from NABR in context: Virtually every major medical advance of the last century has depended upon research with animals. Data from experiments on humans are obviously the most scientifically reliable; however, in many cases human research is ethically unacceptable. Researchers first must use animals, the living systems most closely related to humans, before humans are asked to participate in experimentation. Animals serve as surrogates in the investigation of human diseases and new ways to treat, cure or prevent them. The health of animals also has improved due to animal research.11 And the following from the Foundation for Biomedical Research, a sister organization to NABR: From the discovery of antibiotics, analgesics, antidepressants, and anesthetics, to the successful development of organ transplants, bypass surgery, heart catheterization, and joint replacement - practically every present-day protocol for the prevention, control, cure of disease and relief of pain is based on knowledge attained—directly or indirectly—through research with animals. In their brochure, Animal Research Fact vs. Myth, the Foundation for Biomedical Research states: “Virtually all medical knowledge and treatment—certainly almost every medical breakthrough of the last century—has involved research with animals. There is a compelling reason for using animals in research. The reason is that we have no other choice . . . There are no alternatives to animal research.” (Emphasis added.) The American Medical Association (AMA) likewise has a vested interest in research using animals as many of its members and supporters depend on animal-based research for monetary support. The 1992 AMA White Paper states: “ . . . virtually every advance in medical science in the 20th century, from antibiotics and vaccines to antidepressant drugs and organ transplantation, has been achieved either directly or indirectly through the use of animals in laboratory experiments.” The American Physiology Society, a society that is synonymous with animal-based research, says: Animals are used in research to develop drugs and medical procedures to treat diseases. Scientists may discover such drugs and procedures using alternative research methods that do not involve animals. If the new therapy seems promising, it is tested in animals to see whether it seems to be safe and effective. If the results of the animal studies are good, then human volunteers are asked to take part in a clinical trial. The animal studies are done first to give medical researchers a better idea of what benefits and complications they are likely to see in humans.12 The American Association for the Advancement of Science is composed of members and supporters that profit from animal modeling. The AAAS states: “ … in order to protect the public, both consumer and medical products must be tested for safety, and such testing may in some cases require the use of animals.” And finally, Marshal Bio Resources, an international breeder of animals for biomedical research states: Animal research has played a vital role in virtually every major medical advance of the last century—for both human and animal health. Thanks to recent medical research breakthroughs, scientists are closer than ever to finding new preventions, therapies, and cures for myriad diseases shared by humans and animals. As yet, there is no complete alternative to biomedical research with animals. The Food and Drug Administration mandates the testing of drugs, medical devices and other promising treatments on animals before they can be safely administered to humans. In the final analysis, theory, facts, data, and empirical evidence are the coins of the realm in science. Not grandiose statements from vested interest groups. See the Resources section for AFMA articles supplying theory, facts, data, and empirical evidence. US Congress: Scientific Fraud and Misconduct and the Federal Response. (Committee on Government Operations Subcommittee on Human Resources and Intergovernmental Relations ed., vol. 100th congress, April 11 edition. Washington DC: US Congress; 1988. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T (2009) Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34:74-89. 10.1038/npp.2008.173. 2651739. http://www.ncbi.nlm.nih.gov/pubmed/18830240 Cook N, Jodrell DI, Tuveson DA (2012) Predictive in vivo animal models and translation to clinical trials. Drug Discovery Today 17:253-260. Bendtsen F, Moller S (2008) Pharmacological effects are model specific in animal models of portal hypertension. Hepatol Int 2:397-398. 10.1007/s12072-008-9097-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19669314 Spedding M, Jay T, Costa E Silva J, Perret L (2005) A pathophysiological paradigm for the therapy of psychiatric disease. Nat Rev Drug Discov 4:467-476. nrd1753 [pii]10.1038/nrd1753. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15931256 Engber D (2011) Lab mice: Are they limiting our understanding of human disease? Slate, November 17 Engber D (2011) Black-6 lab mice and the history of biomedical research. Slate, November 17 Engber D (2011) Naked mole rats: Can they help us cure cancer? Slate, November 17 Holmes AM, Solari R, Holgate ST (2011) Animal models of asthma: value, limitations and opportunities for alternative approaches. Drug Discovery Today 16:659-670. 10.1016/j.drudis.2011.05.014. Conant, J., The New Celebrity. Seed, 2003(February). NABR. The Human Care and Treatment of Laboratory Animals. 1999 [cited 2010 March 10]; Available from: APS. (2001) Why do scientists use animals in research? Last update date: 2001 [cited December 16, 2013]; Available from. AFMA groups all uses of animal together and refuses one specific example or case then claims that they have refuted all animal uses. On the contrary, AFMA separates the use of animals in science and research in nine categories and acknowledges that animals can be successfully used in seven out of the nine. The vested interest groups however, commit the fallacy of equivocation when they give an example of the successful use of animals as bioreactors in order to justify the use of animals as predictive models for human response to drugs and disease. Table. Nine categories of animal use in science and research. (From Greek and Shanks. 2009. FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. University Press of America.) Animals are used as predictive models of humans for research into such diseases as cancer and AIDS. Animals are used as predictive models of humans for testing drugs or other chemicals. Animals are used as “spare parts”, such as when a person receives an aortic valve from a pig. Animals are used as bioreactors or factories, such as for the production of insulin or monoclonal antibodies, or to maintain the supply of a virus. Animals and animal tissues are used to study basic physiological principles. Animals are used in education to educate and train medical students and to teach basic principles of anatomy in high school biology classes. Animals are used as a modality for ideas or as a heuristic device, which is a component of basic science research. Animals are used in research designed to benefit other animals of the same species or breed. Animals are used in research in order to gain knowledge for knowledge’s sake. The 2X2 predictive value table does not apply to what researchers do. AFMA’s definition of prediction is not valid for research. What applies to toxicology does not apply to basic research (e.g., on the brain). The table below is the 2X2 table AFMA frequently cites as providing standard formulas for calculating predictive value. Gold Standard GS+ GS- Test T+ TP FP T- FN TN Sensitivity = TP/(TP+FN) Specificity = TN/(FP+TN) Positive Predictive Value = TP/(TP+FP) Negative Predictive Value = TN/(FN+TN) T- = Test negative T+ = Test positive FP = False positive TP = True positive FN = False negative TN = True negative GS- = Gold standard negative GS+ = Gold standard positive In reality, this table is used for evaluating claims of predictive value in many areas of science and daily life. The reason basic researchers that use animal models do not like this table is that it frustrates their efforts to claim their research offers predictive value for humans. They must make this claim in order to obtain funding. However, they must simultaneously deny that their research is anything except basic research, which is done for the pursuit of knowledge as opposed to having predictive value, because analyses have consistently shown animal models to lack predictive value. (For more, see Greek, R and Greek, J. Is the use of sentient animals in basic research justifiable? Philosophy, Ethics, and Humanities in Medicine 2010, 5:14. Many of the examples AFMA uses to illustrate the lack of predictive value for animal models come from the toxicology and drug development literature. The reasons for this are very straightforward—that literature provides the most examples as many drugs have been studied for effects in humans and animals. Animal models can be evaluated in other areas, however. For example, as of this writing approximately 100 vaccines against HIV or SIV or SHIV have been effective in animals. None have been effective in humans. The predictive value of the animal model in terms of HIV vaccine development is therefore zero. Furthermore, the same theories—evolution and complexity—account for the failure of animal models in all areas where they are used to predict human response to drugs and disease. Why doesn't Dr. Greek and AFMA list all the times animal and humans responded the same way to a drug or disease? Several reasons:1. AFMA is attempting to prove that animal models offer no predictive value for human response to drugs and disease. AFMA accomplished this by a) discussing Trans-Species Modeling Theory and b) citing empirical evidence that supports the TSMT. This is the standard method for supporting a position in science. 2. The burden of proof for proving animal models do offer predictive value is on those making that claim. AFMA has not seen any empirical evidence or theory from those that disagree with us. AFMA has seen numerous anecdotes and retrospective analyses that identified common responses. This is not science. 3. Almost every response in humans can be seen in some animal. The problem is identifying the correct animal model prospectively. Retrospectively identifying such an animal model offers nothing in terms of predictive value. Even when common responses have been noted, further research has identified different mechanisms for the response or the model has not been useful in identifying other responses of the same type. In other words, the model correlated with human response in just one instance (e.g. nonhuman primates suffered phocomelia from thalidomide but when tested with other known teratogens did not offer predictive value). 4. Given the fact that TSMT is based on one of the most established theories in science, the Theory of Evolution, along with Complexity Theory, falsifying TSMT is going to require an extraordinary amount of evidence. Such evidence simply does not exist. Therefore, pointing out where animal model A responded the same as humans to drug B is not helpful to our opponents’ claim and does not falsify or even call into question TSMT, hence there is no reason for us to cite such instances. AFMA is just a shill for animal rights groups. No, we are not. AFMA has received monetary support from animal protection organizations in the past. However, a majority of AFMA’s support has come from individuals. Moreover, AFMA takes positions that are in opposition to those of animal rights groups. If AFMA is being paid by animal rights groups, an argument could be made that animal rights groups are not getting their money’s worth. For more on this, see the above question AFMA is frequently identified as an animal rights group. Why? Predictions about complex systems can be made. Yes, they can, but AFMA addresses the issue of using one evolved, complex system to reliably predict responses for a second evolved, complex system. At higher levels of organization, responses of two different, evolved, complex systems differ a sufficient percentage of the time to falsify the claim of predictive value. Animal models obviously work because of all the past discoveries that have been made using animals. AFMA acknowledges that many past discoveries either were made, or could have been made, using animal models. Exactly which discoveries were dependent upon animals is controversial, in part because the records of such discoveries in the 1800s and early 1900s are suboptimal. Regardless, many discoveries could have been made using animals. Such is the case because animals and humans share a common evolutionary ancestor and this results in conserved processes and commonalities in biochemistry and morphology. Thus, animals can be used for discovering basic physiological principles.None of which is relevant to using animal models for their predictive value for human response to drugs and disease—the main reason animal models continue to be used. These historical facts are also accounted for in Trans-Species Modeling Theory . Dr. Greek and others associated with AFMA are friends with terrorists. To the best of Dr. Greek’s and AFMA’s knowledge this is not true. Dr. Ray Greek is just like Hans Ruesch, Robert Sharpe, Vernon Coleman, and Pietro Croce. The scientific community has refuted all of these arguments before. All of the above authors wrote when they had only empirical evidence to support their claims. As explained in the section on TSMT, the arguments against using animals as models to predict human response to drugs and disease have improved immeasurably since these authors wrote their books. Indeed, the arguments against using animals as models to predict human response to drugs and disease have improved immeasurably since Drs. Greek wrote their first book. AFMA realizes that some of the above authors held positions that were, and still are, inconsistent with scientific knowledge of their era. This section is not a critique of these authors’ writing in general. Rather, AFMA is pointing out that regardless of their other views, the knowledge relevant to animal modeling has increased since the 20th century and AFMA’s position is based on current science. AFMA and Dr Greek want society to just give up on curing diseases. Granted animal experimentation is hard but at least the animal experimentation community is trying. Neither Dr Greek nor AFMA is suggesting anyone give up. AFMA wants to see cures brought to market faster, safer, and cheaper. The current system is not working. Animals do not and cannot offer predictive value for human response to drugs and disease. Society needs human-based research and testing and there are already many ways this can be accomplished. If society stopped funding animal-based research and testing, we would see the cures and treatments we need. Scientists must experiment and test on whole, intact systems because in vitro and in silico does not reflect the entire system. There is no choice but to use animals. This is called the intact systems argument and is the most frequent argument made against AFMA’s position. Dr. Greek has addressed this in his blogs More Misrepresentations, Fallacies, and Other Lies. Part II and Vivisection Or Death: Part III, No Other Options. Briefly, it is true that current in silico and in vitro technology cannot reliably predict safety and efficacy for humans taking drugs. But neither can animal models. The reason for this is that while humans and animals are intact, complex systems, they are differently complex. The electrical grid for the U.S. is also a complex system but no one tests drugs on it in order to learn what they will do in humans. For more on why the intact systems argument is false see the articles in the Resources section.