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Validity of malaria models: need for a less circular, more secular, argument
Letter
Validity of malaria models: need for a less circular, more secular, argument Andrew Taylor-Robinson Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK
Reading the authoritative review by Stephens et al. [1], on how study of Plasmodium chabaudi has furthered our knowledge of the many facets of malaria infection, brought to mind how secular societies endeavour to separate religion from politics. In my opinion, an analogy may be drawn between acceptance of malaria models and religious belief in that both have a basis in fact but lack the empirical evidence required for unequivocal substantiation. Therefore, recognition of either demands a leap of faith due to the paradoxes that exist. I shall explain. Those of us who work with rodent models of malaria, whether on chemotherapy, immunity, pathology or vaccine development, are always conscious of the suitability of their chosen experimental system and its relevance to the condition in humans which it purports to reflect. As scientists we are trained to be objective but often we can appear defensive in support of our models, and therefore, by extension, of the grounds for our research. Researchers of P. chabaudi and other rodent models of malaria will be familiar with the perceived need to justify not simply their latest findings but the whole basis for their body of work. This requirement for validation comes at all stages of the research process – from writing a grant proposal to presenting the findings in person or in print. Criticism of the use of P. chabaudi to study blood-stage malaria infection has focused principally on two issues. First, infection is initiated routinely by introduction of parasitised erythrocytes directly into the bloodstream via intravenous injection and thus bypasses the first phase of mosquito-inoculated infection in the liver. It is fair to say that this aspect of the life cycle has been underutilised by the model as it is perfectly feasible, where facilities permit, for this work to be performed. Second, the laboratory mouse is not the natural host and therefore, for instance, the fine specificity of antigen–receptor binding may not be sufficiently representative. This unquestionable weakness exposes the model to the charge surrounding its fundamental suitability over which justification becomes that leap of faith to which I refer. Modelling is necessary because understanding protective immunity to blood-stage P. falciparum in humans has proved intractable. Observations under field conditions invariably lack any detailed parasitological history of the individual and their current parasitological and immune status. It is fair to say that vaccine development, in particular, has been hampered by our poor knowledge of the correlates of natural immunity and of vaccine-induced immunity. While improved comprehension at a human Corresponding author: Taylor-Robinson, A. ([email protected]).
population level will come only from further field studies [2], a greater understanding of the regulatory and effector mechanisms of the immune response may continue to emerge from judicious application of rodent models that are experimentally pliable. However, as recently acknowledged, when it comes to vaccine design the current crop of models are useful tools to exclude failures, but less so to predict successes [3]. My anecdotal impression is that colleagues who throw brickbats at malaria models do so to play Devil’s advocate since they realise that if a better system existed it would be used. In this light, it is gratifying to note a recent move to experimental refinement that acknowledges and seeks to address the perceived flaws of previous generations of models. For instance, two opposite approaches illustrate how more sophisticated models could be informative to the human condition. First, the laboratory mouse is being forsaken in favour of the African thicket rat, Thamnomys rutilans, the natural host of most laboratory-adapted species of rodent malaria parasite, and from which they were isolated [4]. If colonies can be established successfully in rodent facilities, these rats, which have naturally coevolved with P. chabaudi, will better replicate the human-malaria system and thus provide a more relevant model. Second, immunodeficient mice bearing an IL2rgnull mutation have been engineered that permit engraftment of a functional human immune system [5]. Such ‘humanised’ mice support infection with both the liver and blood stages of P. falciparum [6,7]. Although there are still technical issues to resolve [4], this should provide a powerful tool to dissect the human immune response to human malaria infection in a controlled environment. A further advance is the generation of chimeric rhesus macaques which would help to bridge the gap between mice and humans [8]. Infection with a primate malaria species such as P. knowlesi would appear the obvious next step. This is supported by the current call for greater use of primates in research [9]. If a malaria model is not accepted for what it is, warts and all, the argument becomes circular as to its validity. However, once that act of acceptance is made, one is liberated to discuss the detail of a specific piece of work within the acknowledged constraints of the model in which it was performed. A balanced case for using models is welldocumented, both by Stephens et al. [1] and in other recent reviews [10,11]. Wykes and Good [10] summarise well the ethos which I suggest should be adopted: ‘animal models have a role in the study of malaria but the experimental conditions used for testing must reflect the environment of infected individuals’. Even though we strive to improve 259
Letter each model, it does not have to be perfect for it to be valued. To borrow a quotation applied to human emotions: ‘We come to love not by finding a perfect person, but by learning to see an imperfect person perfectly’ [12]. References 1 Stephens, R. et al. (2012) The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol. 28, 73–82 2 Todryk, S. and Bejon, P. (2009) Malaria vaccine development: lessons from the field. Eur. J. Immunol. 39, 2007–2010 3 Langhorne, J. et al. (2011) The relevance of non-human primate and rodent malaria models for humans. Malaria J. 10, 23 4 Waters, H. (2011) Better animal models needed for malaria vaccine development, experts say. Nat. Med. Blog 21 October. (http://blogs. nature.com/spoonful/2011/10/better_animal_models_needed_fo_1.html) 5 Shultz, L.D. et al. (2010) Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rgnull humanized mice. Proc. Natl. Acad. Sci. U.S.A. 107, 13022–13027
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6 Jime´nez-Dı´az, M.B. et al. (2009) Improved murine model of malaria using Plasmodium falciparum competent strains and nonmyelodepleted NOD-scid IL2rgnull mice engrafted with human erythrocytes. Antimicrob. Agents Chemother. 53, 4533–4536 7 Shultz, L.D. et al. (2011) Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann. N. Y. Acad. Sci. 1245, 50–54 8 Tachibana, M. et al. (2012) Generation of chimeric rhesus monkeys. Cell 148, 285–295 9 Craig, A.G. et al. (2012) The role of animal models for research on severe malaria. PLoS Pathog. 8, e1002401 10 Wykes, M.N. and Good, M.F. (2009) What have we learnt from mouse models for the study of malaria? Eur. J. Immunol. 39, 2004–2007 11 Taylor-Robinson, A.W. (2010) Regulation of immunity to Plasmodium: implications from mouse models for blood stage malaria vaccine design. Exp. Parasitol. 126, 406–414 12 Keen, S. (2000) To Love and Be Loved, Bantam (USA) 1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.04.001 Trends in Parasitology, July 2012, Vol. 28, No. 7
Validity of malaria models: need for a less circular, more secular, argument Andrew Taylor-Robinson Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK
Reading the authoritative review by Stephens et al. [1], on how study of Plasmodium chabaudi has furthered our knowledge of the many facets of malaria infection, brought to mind how secular societies endeavour to separate religion from politics. In my opinion, an analogy may be drawn between acceptance of malaria models and religious belief in that both have a basis in fact but lack the empirical evidence required for unequivocal substantiation. Therefore, recognition of either demands a leap of faith due to the paradoxes that exist. I shall explain. Those of us who work with rodent models of malaria, whether on chemotherapy, immunity, pathology or vaccine development, are always conscious of the suitability of their chosen experimental system and its relevance to the condition in humans which it purports to reflect. As scientists we are trained to be objective but often we can appear defensive in support of our models, and therefore, by extension, of the grounds for our research. Researchers of P. chabaudi and other rodent models of malaria will be familiar with the perceived need to justify not simply their latest findings but the whole basis for their body of work. This requirement for validation comes at all stages of the research process – from writing a grant proposal to presenting the findings in person or in print. Criticism of the use of P. chabaudi to study blood-stage malaria infection has focused principally on two issues. First, infection is initiated routinely by introduction of parasitised erythrocytes directly into the bloodstream via intravenous injection and thus bypasses the first phase of mosquito-inoculated infection in the liver. It is fair to say that this aspect of the life cycle has been underutilised by the model as it is perfectly feasible, where facilities permit, for this work to be performed. Second, the laboratory mouse is not the natural host and therefore, for instance, the fine specificity of antigen–receptor binding may not be sufficiently representative. This unquestionable weakness exposes the model to the charge surrounding its fundamental suitability over which justification becomes that leap of faith to which I refer. Modelling is necessary because understanding protective immunity to blood-stage P. falciparum in humans has proved intractable. Observations under field conditions invariably lack any detailed parasitological history of the individual and their current parasitological and immune status. It is fair to say that vaccine development, in particular, has been hampered by our poor knowledge of the correlates of natural immunity and of vaccine-induced immunity. While improved comprehension at a human Corresponding author: Taylor-Robinson, A. ([email protected]).
population level will come only from further field studies [2], a greater understanding of the regulatory and effector mechanisms of the immune response may continue to emerge from judicious application of rodent models that are experimentally pliable. However, as recently acknowledged, when it comes to vaccine design the current crop of models are useful tools to exclude failures, but less so to predict successes [3]. My anecdotal impression is that colleagues who throw brickbats at malaria models do so to play Devil’s advocate since they realise that if a better system existed it would be used. In this light, it is gratifying to note a recent move to experimental refinement that acknowledges and seeks to address the perceived flaws of previous generations of models. For instance, two opposite approaches illustrate how more sophisticated models could be informative to the human condition. First, the laboratory mouse is being forsaken in favour of the African thicket rat, Thamnomys rutilans, the natural host of most laboratory-adapted species of rodent malaria parasite, and from which they were isolated [4]. If colonies can be established successfully in rodent facilities, these rats, which have naturally coevolved with P. chabaudi, will better replicate the human-malaria system and thus provide a more relevant model. Second, immunodeficient mice bearing an IL2rgnull mutation have been engineered that permit engraftment of a functional human immune system [5]. Such ‘humanised’ mice support infection with both the liver and blood stages of P. falciparum [6,7]. Although there are still technical issues to resolve [4], this should provide a powerful tool to dissect the human immune response to human malaria infection in a controlled environment. A further advance is the generation of chimeric rhesus macaques which would help to bridge the gap between mice and humans [8]. Infection with a primate malaria species such as P. knowlesi would appear the obvious next step. This is supported by the current call for greater use of primates in research [9]. If a malaria model is not accepted for what it is, warts and all, the argument becomes circular as to its validity. However, once that act of acceptance is made, one is liberated to discuss the detail of a specific piece of work within the acknowledged constraints of the model in which it was performed. A balanced case for using models is welldocumented, both by Stephens et al. [1] and in other recent reviews [10,11]. Wykes and Good [10] summarise well the ethos which I suggest should be adopted: ‘animal models have a role in the study of malaria but the experimental conditions used for testing must reflect the environment of infected individuals’. Even though we strive to improve 259
Letter each model, it does not have to be perfect for it to be valued. To borrow a quotation applied to human emotions: ‘We come to love not by finding a perfect person, but by learning to see an imperfect person perfectly’ [12]. References 1 Stephens, R. et al. (2012) The contribution of Plasmodium chabaudi to our understanding of malaria. Trends Parasitol. 28, 73–82 2 Todryk, S. and Bejon, P. (2009) Malaria vaccine development: lessons from the field. Eur. J. Immunol. 39, 2007–2010 3 Langhorne, J. et al. (2011) The relevance of non-human primate and rodent malaria models for humans. Malaria J. 10, 23 4 Waters, H. (2011) Better animal models needed for malaria vaccine development, experts say. Nat. Med. Blog 21 October. (http://blogs. nature.com/spoonful/2011/10/better_animal_models_needed_fo_1.html) 5 Shultz, L.D. et al. (2010) Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rgnull humanized mice. Proc. Natl. Acad. Sci. U.S.A. 107, 13022–13027
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Trends in Parasitology July 2012, Vol. 28, No. 7
6 Jime´nez-Dı´az, M.B. et al. (2009) Improved murine model of malaria using Plasmodium falciparum competent strains and nonmyelodepleted NOD-scid IL2rgnull mice engrafted with human erythrocytes. Antimicrob. Agents Chemother. 53, 4533–4536 7 Shultz, L.D. et al. (2011) Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann. N. Y. Acad. Sci. 1245, 50–54 8 Tachibana, M. et al. (2012) Generation of chimeric rhesus monkeys. Cell 148, 285–295 9 Craig, A.G. et al. (2012) The role of animal models for research on severe malaria. PLoS Pathog. 8, e1002401 10 Wykes, M.N. and Good, M.F. (2009) What have we learnt from mouse models for the study of malaria? Eur. J. Immunol. 39, 2004–2007 11 Taylor-Robinson, A.W. (2010) Regulation of immunity to Plasmodium: implications from mouse models for blood stage malaria vaccine design. Exp. Parasitol. 126, 406–414 12 Keen, S. (2000) To Love and Be Loved, Bantam (USA) 1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.04.001 Trends in Parasitology, July 2012, Vol. 28, No. 7