After posting New Drugs and Animal Testing on January 17, I was not planning on another installment but that same day I noticed that Speaking of Research (SoR) had posted on the same topic and decided to examine their essay.
The essay by Juan Carlos Marvizon is titled: Animal research is not “animal testing.” As I have stated many times, there is a difference between testing drugs and devices on animals and performing basic research on animals. By categorizing the various uses of animals in science, we can intelligently discuss the distinct uses without committing the equivocation fallacy. Lumping all uses of animals in science under the banner of animal research or animal experimentation is not helpful for a science-based discussion although a discussion revolving around philosophy might use those general terms in a productive manner. The fact that such an essay has appeared on the SoR site is puzzling as most vivisection activists are the very ones that conflate the terms and oppose classification of animal use. (See this entire exchange, for example.) But lets get to the essay.
Animal rights ideologues like to refer to animal research as “animal testing”. This seems to be part of their new strategy of arguing that animal research is worthless because they claim that testing new medications on animals has no predictive value on their effects on humans.
There are several problems in these first two sentences. Technically, what most scientists do with animals in labs is best designated animal experimentation not animal research. Research is a word that can be applied broadly to anything done in order to advance knowledge, but in biomedical studies it usually means something that is ethically conducted for the benefit of the individual, or at least where the harm to the individual participating in the research is minimal. For example, allowing my genome to be sequenced might necessitate a swap being rubbed against the inside of my cheek to collect cells containing DNA. Such an action is unlikely to result in harm even though my participation in the project is equally unlikely to result in something positive for me in the immediate future.
Experimentation however, offers nothing positive for the individual, is usually (although not always) performed against the will of the individual, and is usually painful, debilitating, and or might result in death. Willful participation in human experimentation is usually accompanied by reimbursement, such as when humans who are not suffering from the disease the drug is supposed to treat, volunteer for drug trials. (For more on the differences between these two terms and the implications thereof, see here, here, here, and here. This distinction is universally acknowledged.)
What happened at Auschwitz was not human research! It was research and it was performed on humans but it was specifically the type of research that is termed experimentation as opposed to the more benign, general use of the word research. So, if SoR wants to be precise, an objective I support, what they address and defend is animal experimentation not animal research.
Second, I am about the only person that addresses the predictive value of animal models and, as I have gone to great lengths to differentiate the various uses of animals in research and science in general (see just about any article or book I have published, including here), accusing me of conflating the term is like an uneducated Hollywood actress and antivaccine activist accusing an infectious disease physician of not having enough education (zero years after high school as opposed to about 15 years) to understand vaccines. This is good strategy on their part however as, if facts and truth and irrelevant and all you want to do is sell your product, accusing your opponent of all the things you are doing wrong is a good way to confuse the masses.
In any event, some animal-based research, or other animal uses in science, claims to be of predictive value for human response to drugs and disease and some does not. The research that makes such claims, however, is subject to evaluation in order to assess how well such practices really do perform. The research that does not claim to be of predictive value should not be judged in the same manner. In my writings, I have pointed out that research that makes no claim for predictive value—for example, using animals for spare parts or as a heuristic—successfully fulfills it's function. Drug testing on animals clearly claims predictive value as do grant applications for using animals in research for human disease. (See Animal Models in Light of Evolution for more.)
Marvizon continues by discussing drug discovery in general as an example of “animal research” as opposed to animal testing. Marvizon also calls this basic research and states: “it absolutely requires experiments on animals.” This is THE problem, as we will see. Marvizon explains:
This is what is normally called “basic research”, as opposed to “clinical research”, which is research done on humans by directly studying our diseases and the efficacy of treatments to cure them. In between basic and clinical research there is “translational research”, whose goal is to take the knowledge acquired in basic research and to apply it to clinical practice. Basic research is critically important. Without it we would get stuck with the medications and treatments that we currently have and would be unable to create anything new. . . . Because any new advance in medicine has to be rooted in knowledge about the basic functioning of living beings.
Once again, this is misleading if not completely false. First, the basic versus clinical research line is a false dichotomy. It is true that basic research is different from clinical research but there are other types of research that are distinct from both. For example, applied research in the physical sciences occurs when a scientists is attempting to develop a product or technology based on math equations, basic research in physics or chemistry, or other knowledge. Moreover, basic research in any area of science is not confined to using animals or animal tissues. Human tissue has been used in basic research and is still being used. Finally, clinical research involves more than studying disease and treatments.
Second, many medications and or new classes of drugs have been discovered secondary to serendipity. Numerous books have been written on this subject and we give some examples in our book What Will We Do If We Don't Experiment On Animals? Medical Research for the Twenty-first Century. (More examples can be found in Happy Accidents: Serendipity in Modern Medical Breakthroughs by Morton Meyers and Who Goes First?: The Story of Self-Experimentation in Medicine by Lawrence Altman.) I have no data to support this, but I think more new drug classes have been discovered through serendipity than any other single activity. Reading the history of drug discovery one cannot help but be impressed by how many classes of drugs were discovered because of chance factors, usually seen in humans or petri dishes.
Third, and related to number two, the mechanisms of most of the drugs discovered through serendipity were simply unknown at the time of discovery (and some still are unknown). Claiming that “any new advance in medicine has to be rooted in knowledge about the basic functioning of living beings,” is simply refuted by history. Further, some drugs whose mechanisms were worked out on animals did end up helping patients, but by entirely different mechanisms and sometimes for entirely different diseases than the scientists thought the drugs were going to treat.
Marvizon then resorts to the intact systems argument (ISA), which has been addressed by myself and others. See:
- More Misrepresentations, Fallacies, and Other Lies. Part II
- Complexity and Animal Models
- Brute Science
I will therefore refrain from repeating the points here. But the ISA is the bread and butter argument for the vivisection activist, so please read the links if you are up to it.
So what is THE problem with this essay? What Marvizon is attempting to say is that not all research (defined broadly) claims predictive value and should not be judged as if it were. Fair enough! I have stated that many times, as well. But he then makes claims regarding basic research that uses animals that either a) have no factual support, or b) turn out to be claims for such animal models actually having predictive value. If he is going to claim that basic research identifies druggable targets that could not have been identified with animal-based research then he needs to provide studies, not anecdotes, that support that claim. This will be difficult however since, as I pointed out in New Drugs and Animal Testing on January 17, the attrition rate of drug whose targets were identified based on animal models is atrocious. Just to remind you of what scientists are saying in this regard:
Speaking of rodent models of sepsis, Kathleen Raven of Nature Medicine quotes Shaw Warren, an infectious disease specialist at the Massachusetts General Hospital in Boston: “The mouse models really don't reflect the human condition.” She also quotes Mitchell Fink, a surgeon at the University of California–Los Angeles: “Clearly, current animal models seem to be incapable of predicting results in human trials of new agents.” (Raven 2012)
Elias Zerhouni, former director of NIH and current head of R&D at Sanofi was quoted in the June 25, 2012 issue of Forbes as saying: “R&D in pharma has been isolating itself for 20 years, thinking that animal models would be enough and highly predictive, and I think I want to just bring back the discipline of outstanding translational science, which means understand the disease in humans before I even touch a patient.”
Kevin Mullane of Profectus Pharma Consulting and Michael Williams of the Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University authored an article published in Drug Discovery Today.(Mullane and Williams 2012) They acknowledge, just as I have acknowledged, that advances have been made by using reductionism to study human disease and develop drugs to treat those diseases. However the main theme of the article is that Pharma and society are facing crisis in terms of developing new drugs that are safe, effective, and inexpensive. They cite the decrease in number of new chemical entities entering the market and late failure of many drugs in development, for example a success rate of only 5% for drugs that enter clinical trials (Munos and Chin 2011) and an 82% failure of drugs in Phase II proof of concept trials (Arrowsmith 2011), to illustrate the problem.(Munos 2009; Pammolli, Magazzini, and Riccaboni 2011) They note that this is ironic since the total investment in biomedical research in the US reached $150 billion in 2010 (Munos and Chin 2011) and the amount of knowledge regarding knowledge of life has also increased substantially in the recent past. Much of this money went to basic research with animals and the knowledge referred to is also about mechanisms in animals. Mullane and Williams state:
The difficulties in predicting drug efficacy from preclinical models have been of concern for more than two decades . . . Thus, novel findings apparently related to the systems and targets involved in disease causality; the delineation of the efficacy, selectivity and safety of NCEs; and the predictive relevance of biomarkers and animal model data to the human disease state, even when there is evidence for target engagement in humans, all frequently fail to enhance the success rate for new drug applications (NDAs). (Mullane and Williams 2012) (Emphasis added.)
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. (Markou et al. 2009)
But perhaps the most damning evidence that animal models are extremely limited in what they can inform regarding druggable targets comes from Contopoulos-Ioannidis et al (Contopoulos-Ioannidis, Ntzani, and Ioannidis 2003) and Crowley commenting on the Contopoulos-Ioannidis et al article:
The article by Contopoulos-Ioannidis et al. (1) in this issue of the journal addresses a much-discussed but rarely quantified issue: the frequency with which basic research findings translate into clinical utility. The authors performed an algorithmic computer search of all articles published in six leading basic science journals (Nature, Cell, Science, the Journal of Biological Chemistry, the Journal of Clinical Investigation, the Journal Experimental Medicine) from 1979 to 1983. Of the 25,000 articles searched, about 500 (2%) contained some potential claim to future applicability in humans, about 100 (0.4%) resulted in a clinical trial, and, according to the authors, only 1 (0.004%) led to the development of a clinically useful class of drugs (angiotensin-converting enzyme inhibitors) in the 30 years following their publication of the basic science finding. They also found that the presence of industrial support increased the likelihood of translating a basic finding into a clinical trial by eightfold.
Still, regardless of the study's limitations, and even if the authors were to underestimate the frequency of successful translation into clinical use by 10-fold, their findings strongly suggest that, as most observers suspected, the transfer rate of basic research into clinical use is very low. (Crowley 2003)
An editorial in Nature supports the above:
The readers of Nature should be an optimistic bunch. Every week we publish encouraging dispatches from the continuing war against disease and ill health. Genetic pathways are unravelled, promising drug targets are identified and sickly animal models are brought back to rude health. Yet the number of human diseases that can be efficiently treated remains low — a concerning impotency given the looming health burden of the developed world's ageing population. The uncomfortable truth is that scientists and clinicians have been unable to convert basic biology advances into therapies or resolve why these conversion attempts so often don't succeed. Together, these failures are hampering clinical research at a time when it should be expanding. (Editorial 2010)
Based on the evidence, if you want to find druggable targets, basic research using animals is not the way to go about it. If I wanted to sell the importance of basic research, I would not use drug development as an example.
Moreover, there are better ways to help patients. Rothwell stated in the Lancet in 2006:
Indeed, most major therapeutic developments over the past few decades have been due to simple clinical innovation coupled with advances in physics and engineering rather than to laboratory-based medical research. The clinical benefits of advances in surgery, for example, such as joint replacement, cataract removal, endoscopic treatment of gastrointestinal or urological disease, endovascular interventions (eg, coronary and peripheral angioplasty/stenting or coiling of cerebral aneurysms), minimally invasive surgery, and stereotactic neurosurgery, to name but a few, have been incalculable. Yet only a fraction of non-industry research funding has been targeted at such clinical innovation. How much more might otherwise have been achieved? (Rothwell 2006)
So why all the vitriol if basic research makes no claims for predictive value? Why not just say that scientists using animals want money from taxpayers in order to discover more knowledge about the material universe? Because society will not fund such endeavors and the scientists asking for money know this.(Giles 2006) Therefore, they want to link their research to a future drug that will cure Grandma of Parkinson’s and babies of brain cancer then sell this notion to Congress and society in general. Once again, all this revolves around money. (And ego.)
Certainly, it [biomedical research] can be improved and, in fact, it will be improved, given the self-correcting nature of science. But tampering with it by imposing over-zealous and ideological restrictions, like a prohibition of using animals for research, would have far-reaching consequences in our ability to cure human suffering.
I have no issues with tampering with a system that results in a new class of drugs somewhere in the neighborhood of 0.004% of the time. Evolved complex systems theory explains why animal models fail and will continue to fail. But until competent and ethical physicians and scientists get involved in the discussion, society will be stuck with 0.004%.
Arrowsmith, John. 2011. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Discov 10 (5):328-329.
Contopoulos-Ioannidis, D. G., E. Ntzani, and J. P. Ioannidis. 2003. Translation of highly promising basic science research into clinical applications. Am J Med 114 (6):477-84.
Crowley, W. F., Jr. 2003. Translation of basic research into useful treatments: how often does it occur? Am J Med 114 (6):503-5.
Editorial. 2010. Hope in translation. Nature 467 (7315):499.
Giles, J. 2006. Animal experiments under fire for poor design. Nature 444 (7122):981.
Markou, A., C. Chiamulera, M. A. Geyer, M. Tricklebank, and T. Steckler. 2009. Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 (1):74-89.
Mullane, Kevin, and Michael Williams. 2012. Translational semantics and infrastructure: another search for the emperor’s new clothes? Drug Discovery Today 17 (9/10):459-468.
Munos, B. 2009. Lessons from 60 years of pharmaceutical innovation. Nature reviews. Drug discovery 8 (12):959-68.
Munos, B. H., and W. W. Chin. 2011. How to revive breakthrough innovation in the pharmaceutical industry. Science Translational Medicine 3 (89):89cm16.
Pammolli, Fabio, Laura Magazzini, and Massimo Riccaboni. 2011. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10 (6):428-438.
Raven, Kathleen. 2012. Rodent models of sepsis found shockingly lacking. Nat Med 18 (7):998-998.
Rothwell, P. M. 2006. Funding for practice-oriented clinical research. Lancet 368 (9532):262-6.