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Human-Based Research Advances Medicine While Animal Studies Confound

Human genetics is revealing more clues for curing or preventing disease. A study in the Journal of Leukocyte Biology suggests that two mutations in the TLR1 gene might explain why some people are resistant to tuberculosis. In this human-based study scientists tested 71 people. An abstract of the article can be accessed here

.According to a press release from the University of Montreal, genome-wide association studies once again revealed relevant human data. Scientists studied 9,772 people with multiple sclerosis (MS) and compared their genomes with 17,376 controls. They found 52 genes associated with MS. Compston, one of the co-authors stated: "Identifying the basis for genetic susceptibility to any medical condition provides reliable insights into the disease mechanisms. Our research settles a longstanding debate on what happens first in the complex sequence of events that leads to disability in multiple sclerosis. It is now clear that multiple sclerosis is primarily an immunological disease. This has important implications for future treatment strategies." Donnelly, another co-author said: "Our findings highlight the value of large genetic studies in uncovering key biological mechanisms underlying common human diseases. This would simply not have been possible without a large international network of collaborators, and the participation of many thousands of patients suffering from this debilitating disease." The Nature article can be found here.

Contrast the above with what is happening to drug development based on animal models in the neurosciences. Kaitin and Milne 2011:


Schizophrenia, depression, addiction and other mental disorders cause suffering and cost billions of dollars every year in lost productivity. Neurological and psychiatric conditions account for 13 percent of the global burden of disease, a measure of years of life lost because of premature mortality and living in a state of less than full health, according to the World Health Organization. Despite the critical need for newer and better medications to treat a range of psychiatric and neurodegenerative diseases, including Alzheimer’s and Parkinson’s, drugs to treat these diseases are just too complex and costly for big pharmaceutical companies to develop. The risk of spending millions on new drugs only to have them fail in the pipeline is too great. That’s why many big drug companies are pulling the plug on R&D for neuropsychiatric and other central nervous system (CNS) medicines. (1)


Enna and Williams state:


A major hurdle in the translational medicine undertaking is the fact that most preclinical animal models of disease generally lack predictive value with respect to the human condition under study. Indeed, the false positives that result from the present generation of animal assays are a major cause of NCE attrition in the clinic either because of lack of efficacy or the appearance of unacceptable side effects that were not detected preclinically. While there are notable, albeit retrospective, exceptions (Zambrowicz & Sands, 2003), this weakness in the conventional drug discovery process has not been resolved with the use of transgenic animals which themselves contribute additional confounds that further complicate data interpretation. In therapeutic areas as diverse as pain (Rice et al., 2008), stroke (O'Collins et al., 2006), neurodegeneration (Lindner, McArthur, Deadwyler, Hampson, & Tariot, 2008), and substance abuse (Gardner, 2008), numerous agents that displayed substantial efficacy and safety in animal models, have failed in the clinic (Hackam & Redelmeier, 2006). Similarly, animal models used to interrogate the PK and PD effects of NCEs are in need of further refinement so they have predictive value with regard to human use. The poor translational record from animal models to humans has been attributed to poor preclinical methodologies (Green, 2008; Hackam, 2007; Perel et al., 2007), which include a lack of blinding and randomization, adequate powering/size, and an "optimization bias"; in that very often only positive results are reported. (2)


Geerts 2009: “The successful development of new innovative drugs for chronic CNS diseases is in jeopardy and new paradigms need to be explored. The current drug-discovery paradigm is based upon detection of activity and toxicity in animal models; however, these models show a rather limited predictability for the clinical situation. This report presented a number of less appreciated and underestimated limitations of animal models that could explain, in part, the substantial number of failures in the clinic.” (3)

Roger Morris, head of biomedical sciences at Kings College London, was quoted in the Guardian on July 13, 2011, as stating: "But real diseases are diseases of the whole body, and can only be studied in the whole body. To take the example of Parkinson's – a disease that is very common and devastating. Part of this disease is a dopamine deficiency in the neurons, but the underlying cause is a complex set of interactive problems, that probably involves an inflammatory or autoimmune component. Thus we need to understand the interaction between two very complex bodily systems – the brain, and the immune system, to understand the defects causing this multi–tissue, multi–step disease. We can't study that in tissue culture of individual cells." (4)

Morris is correct in what he affirms—diseases must be studied in the whole body—but is wrong in what he denies—that there are no causal disanalogies between species.(5) The intact mouse or monkey is not the same as the intact human suffering from neurological diseases. Nor is the intact mouse similar enough to humans allow for a high enough predictive value to be relied on in drug development. See my blog Vivisection Or Death: Part III, No Other Options for more on the intact systems argument.

MacLennan and Amos of Clinical Science Research Ltd, UK, had it right in 1990, when they stated: “There is no doubt that the best test species for Man is Man. This is based on the fact that it is not possible to directly extrapolate animal data to Man, due to inter species variation in anatomy, physiology and biochemistry.”(6)


1.            Kaitin KI, Milne CP. A Dearth of New Meds. Scientific American. 2011(August):16.

2.            Enna SJ, Williams M. Defining the role of pharmacology in the emerging world of translational research. Advances in pharmacology. [Historical Article]. 2009;57:1-30.

3.            Geerts H. Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS Drugs. 2009 Nov 1;23(11):915-26.

4.            Jha A. Animal experiments rise by 1%.  London: Guardian; 2011 [updated July 13; cited 2011 July 29]; Available from:

5.            LaFollette H, Shanks N. Brute Science: Dilemmas of animal experimentation. London and New York: Routledge; 1996.

6.            MacLennan and Amos. Cosmetics and Toiletries Manufacturers and Suppliers Clinical Sciences Research Ltd. 1990;XVII:24.


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