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How useful are animal models of human disease?
Seminars in Cell & Developmental Biology 14 (2003) 1–2
How useful are animal models of human disease?
We live in a world of contradictions. In England, foxhunting is currently legal and is widely supported, fishing is a popular sport and horse racing is the sport of kings. However, this country has an extremely vocal and occasionally violent antivivisection movement that appears to receive significant support from many in the general population and the media. Furthermore, licensing and regulation of animal experimentation (including frogs and fish) for medical research in England is among the strictest in the world, frequently involving more justification, administration and regulation than experiments on humans. I believe that medical researchers must justify their experiments on animals and aim to restrict any suffering. I also believe that animal research and the development of animal models is crucial for our quest as medical scientists to ultimately find cures for disease. The reviews in this issue of Seminars in Cell and Developmental Biology provide a series of examples of different animal models that are powerful and essential tools for studying diseases. These reviews also elucidate a number of elegant approaches that allow insights into the biology of human diseases that could not be achieved without animals. O’Kane reviews the uses of Drosophila and C. elegans, which are particularly useful for studying the many pathways that are well conserved between these organisms and humans. Furthermore, the ease and speed with which one can genetically manipulate these animals makes the dissection of in vivo pathways particularly tractable, e.g. modifier screens. Goldsmith and Harris review the use of zebrafish in the specific context of retinal degeneration. They argue that the zebrafish may be a better model for a human retina than the mouse. Furthermore, they highlight the potential of zebrafish as a generic model—this vertebrate combines many of the strengths of Drosophila (ease of genetic manipulation) with a closer evolutionary distance with humans. Brown and Hardisty focus on the uses of ENU mutagenesis in mice. They describe how one can study and identify many of the genetic loci (and hence pathways) contributing to Mendelian traits by performing ENU mutagenesis on male mice and cloning the mutations that cause the resulting dominant and recessive phenotypes of interest in subsequent generations. They point out that ENU mutagenesis can also be used to identify modifiers for existing mouse diseases and also describe a new gene-driven approach where
one can use ENU mutagenesis to study the phenotypes of different allelic variants in a gene as a primary strategy. One of the great challenges facing modern medicine is the understanding of complex diseases. Marschang and Herz have comprehensively reviewed transgenic and knockout approaches that have been used to dissect lipoprotein metabolism in mice. Their review highlights the power of single and double knockout strategies for understanding the genetic control of complex metabolic pathways, in general. Their review demonstrates why such approaches are crucial if we want to understand how gene products act in vivo in complex pathways, as opposed to in biochemical or cell culture contexts where the fluxes through pathways are often not physiological and the full complement of proteins in the appropriate tissues are not present. Their review also highlights how genetically modified mice can serve as human disease models, allowing testing of pharmaceutical and gene therapeutic approaches to hyperlipidemias and coronary artery disease, one of the major killer diseases in Westernised societies. The understanding of the biology of psychiatric diseases is crucial because of their high incidence and morbidity. It is difficult to see how anyone could study psychiatric diseases meaningfully in a test tube or in tissue culture. Flint considers how one can use mice to understand the biology of anxiety—such models, once validated, may also provide tools for therapeutic development. Ferguson-Smith and coworkers have reviewed the biology of genomic imprinting, an epigenetic mechanism that organisms use to switch expression of genes on or off, depending if they are on paternally or maternally derived chromosomes. Abnormalities of this process are features of a number of inherited human diseases (e.g. Prader–Willi syndrome). The understanding of epigenetic control of gene expression is also relevant to cancer biology, X-chromosome inactivation, silencing of parasitic genetic elements including retroviruses, etc. This review considers how mouse studies have advanced the field and why they will continue to be essential in order to allow further progress. The successes of genome projects and the development of related technologies have dramatically simplified the identification of disease genes. This, coupled with allied progress in basic biological sciences has led to an expanding catalogue of allelic variants and combinations of variants that are
1084-9521/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 1 0 8 4 - 9 5 2 1 ( 0 2 ) 0 0 1 5 9 - 3
2
D.C. Rubinsztein / Seminars in Cell & Developmental Biology 14 (2003) 1–2
likely to have important biological roles in health and disease. In order to test and understand the in vivo relevance of such variants/mutations, these need to be studied in appropriate animal models—many of these models will provide critical insights into disease processes, or be models of disease that can be used as tools for therapeutic development. I believe that one should encourage the development of such models, in order to take the current progress closer to a stage where medical scientists can use such knowledge as a platform for rational therapeutic approaches. If the number of important target loci identified each year increases (as has been the case over the last decade), then the scientific community should be expected and encouraged to make more use of such animal models over time. I hope that this reality (and
responsibility) will be accepted and encouraged by society, with the understanding that scientists and society should also act to minimize unnecessary use and suffering of animals in research. David C. Rubinsztein Department of Medical Genetics Cambridge Institute for Medical Research University of Cambridge, Wellcome/MRC Building Addenbrooke’s Hospital, Hills Road Cambridge, CB2 2XY, UK Tel.: +44-01223-762608 fax: +44-01223-331206 E-mail address: [email protected]
How useful are animal models of human disease?
We live in a world of contradictions. In England, foxhunting is currently legal and is widely supported, fishing is a popular sport and horse racing is the sport of kings. However, this country has an extremely vocal and occasionally violent antivivisection movement that appears to receive significant support from many in the general population and the media. Furthermore, licensing and regulation of animal experimentation (including frogs and fish) for medical research in England is among the strictest in the world, frequently involving more justification, administration and regulation than experiments on humans. I believe that medical researchers must justify their experiments on animals and aim to restrict any suffering. I also believe that animal research and the development of animal models is crucial for our quest as medical scientists to ultimately find cures for disease. The reviews in this issue of Seminars in Cell and Developmental Biology provide a series of examples of different animal models that are powerful and essential tools for studying diseases. These reviews also elucidate a number of elegant approaches that allow insights into the biology of human diseases that could not be achieved without animals. O’Kane reviews the uses of Drosophila and C. elegans, which are particularly useful for studying the many pathways that are well conserved between these organisms and humans. Furthermore, the ease and speed with which one can genetically manipulate these animals makes the dissection of in vivo pathways particularly tractable, e.g. modifier screens. Goldsmith and Harris review the use of zebrafish in the specific context of retinal degeneration. They argue that the zebrafish may be a better model for a human retina than the mouse. Furthermore, they highlight the potential of zebrafish as a generic model—this vertebrate combines many of the strengths of Drosophila (ease of genetic manipulation) with a closer evolutionary distance with humans. Brown and Hardisty focus on the uses of ENU mutagenesis in mice. They describe how one can study and identify many of the genetic loci (and hence pathways) contributing to Mendelian traits by performing ENU mutagenesis on male mice and cloning the mutations that cause the resulting dominant and recessive phenotypes of interest in subsequent generations. They point out that ENU mutagenesis can also be used to identify modifiers for existing mouse diseases and also describe a new gene-driven approach where
one can use ENU mutagenesis to study the phenotypes of different allelic variants in a gene as a primary strategy. One of the great challenges facing modern medicine is the understanding of complex diseases. Marschang and Herz have comprehensively reviewed transgenic and knockout approaches that have been used to dissect lipoprotein metabolism in mice. Their review highlights the power of single and double knockout strategies for understanding the genetic control of complex metabolic pathways, in general. Their review demonstrates why such approaches are crucial if we want to understand how gene products act in vivo in complex pathways, as opposed to in biochemical or cell culture contexts where the fluxes through pathways are often not physiological and the full complement of proteins in the appropriate tissues are not present. Their review also highlights how genetically modified mice can serve as human disease models, allowing testing of pharmaceutical and gene therapeutic approaches to hyperlipidemias and coronary artery disease, one of the major killer diseases in Westernised societies. The understanding of the biology of psychiatric diseases is crucial because of their high incidence and morbidity. It is difficult to see how anyone could study psychiatric diseases meaningfully in a test tube or in tissue culture. Flint considers how one can use mice to understand the biology of anxiety—such models, once validated, may also provide tools for therapeutic development. Ferguson-Smith and coworkers have reviewed the biology of genomic imprinting, an epigenetic mechanism that organisms use to switch expression of genes on or off, depending if they are on paternally or maternally derived chromosomes. Abnormalities of this process are features of a number of inherited human diseases (e.g. Prader–Willi syndrome). The understanding of epigenetic control of gene expression is also relevant to cancer biology, X-chromosome inactivation, silencing of parasitic genetic elements including retroviruses, etc. This review considers how mouse studies have advanced the field and why they will continue to be essential in order to allow further progress. The successes of genome projects and the development of related technologies have dramatically simplified the identification of disease genes. This, coupled with allied progress in basic biological sciences has led to an expanding catalogue of allelic variants and combinations of variants that are
1084-9521/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 1 0 8 4 - 9 5 2 1 ( 0 2 ) 0 0 1 5 9 - 3
2
D.C. Rubinsztein / Seminars in Cell & Developmental Biology 14 (2003) 1–2
likely to have important biological roles in health and disease. In order to test and understand the in vivo relevance of such variants/mutations, these need to be studied in appropriate animal models—many of these models will provide critical insights into disease processes, or be models of disease that can be used as tools for therapeutic development. I believe that one should encourage the development of such models, in order to take the current progress closer to a stage where medical scientists can use such knowledge as a platform for rational therapeutic approaches. If the number of important target loci identified each year increases (as has been the case over the last decade), then the scientific community should be expected and encouraged to make more use of such animal models over time. I hope that this reality (and
responsibility) will be accepted and encouraged by society, with the understanding that scientists and society should also act to minimize unnecessary use and suffering of animals in research. David C. Rubinsztein Department of Medical Genetics Cambridge Institute for Medical Research University of Cambridge, Wellcome/MRC Building Addenbrooke’s Hospital, Hills Road Cambridge, CB2 2XY, UK Tel.: +44-01223-762608 fax: +44-01223-331206 E-mail address: [email protected]