GSA: 'Cardinal' Organisms to Human Biology
15/06/10 00:47 Filed in: GenomeWeb Daily Scan
Submitted by S. Pelech - Kinexus on Tue, 06/15/2010 - 00:47.
Dr. Ruvkun's suggestion to the already converted at the Genetics 2010: Model Organisms to Human Biology meeting in Boston to rename "model organisms" as "cardinal organisms" is rather self-serving and markedly overstates the real value of the study of invertebrates for understanding human pathology. It aims to further perpetuate the mythology that genomics analyses of organisms, such as the budding yeast, the fruit fly and the nematode worm, provide continuing breakthroughs in clinical research. While there are clearly compelling arguments to support basic research in these "simple" model organisms, a huge proportion of grant-funded disease-related research dollars has been inappropriately directed towards these creatures with the long shot chance that something applicable to the human condition will emerge.
In various dictionaries, amongst its many meanings, "cardinal" refers to something that is "of fore-most importance," "first importance" or "paramount." There are millions of different species on this planet. Our choice of the established model organisms for life science research is really based more on accident and the evangelical zeal of a just a few individuals who were seeking organisms that might be amenable to genomics analysis with relatively little forethought about their limitations for proteomics studies. With its tough cell wall, enzymology in the budding yeast is a nightmare. The biomass available from breeding fruit flies and microscopic worms is too cost prohibitive for practical protein biochemistry. Instead, we are stuck producing recombinant proteins from these species in other organisms such as bacteria which poorly recapitulate if at all the post-translation modifications that are required for their full functionality.
Nearly three decades of research with these simple model organisms has actually revealed how misleading the interpretation of findings from their genetic analysis can be when extrapolated to higher organisms. In fundamental processes such as mitosis and apoptosis, which apply at the cellular level, it is not surprising that there is reasonable good conservation. But this is more the exception rather than the rule, and the generalities rapidly breakdown when examined in vertebrate species. Even cell division in the budding yeast and in the early D. melanogaster embryo are actually very atypical.
Apparently cognant proteins in very divergent species are commonly utilized for very different purposes, despite similarities in amino acid sequences. For just one example, MAP kinases are one of the most conserved of the protein kinases in eukaryotes. In S. cerevisiae, they mediate mating in response to pheromones, in C. elegans they regulate vuval development, and in D. melanogaster, they control compound eye development. These are not processes found in humans. While some important protein-protein interactions can be maintained across evolution of the species, the vast majority do not appear to be.
Defects in protein kinase-based signalling systems have been linked with nearly 400 different human diseases. Budding yeast have about 130 protein kinases, but only about a third have even distantly related human counterparts. Meanwhile, there are about 515 human protein kinases. Across the species, protein kinase-substrate interactions appear to be about 100-fold more conserved in evolution than transcription protein-gene promoter interactions. The 23,000 human proteins feature about 500,000 phosphorylation sites. Based on published mass spectrometry analysis of phosphorylation sites in S. cerevisiae, C. elegans and D. melanogaster, it appears that only about 1%, 6% and 5%, respectively, of the phospho-sites in these organisms have remotely similar counterparts in humans. It should be plainly obvious that the signalling systems in these model organisms are extremely distinct from mammals. With such vast differences at the protein level, it is small wonder that there are also huge differences in their physiology compared to each other and humans. Consequently, these simple model organisms are very poor surrogates for understanding the complexities of human disease. Those that suggest otherwise are fooling themselves and may in fact be performing a disservice to the broader scientific community by leading others less critical down blind alleys.
Link to the original blog post.
Dr. Ruvkun's suggestion to the already converted at the Genetics 2010: Model Organisms to Human Biology meeting in Boston to rename "model organisms" as "cardinal organisms" is rather self-serving and markedly overstates the real value of the study of invertebrates for understanding human pathology. It aims to further perpetuate the mythology that genomics analyses of organisms, such as the budding yeast, the fruit fly and the nematode worm, provide continuing breakthroughs in clinical research. While there are clearly compelling arguments to support basic research in these "simple" model organisms, a huge proportion of grant-funded disease-related research dollars has been inappropriately directed towards these creatures with the long shot chance that something applicable to the human condition will emerge.
In various dictionaries, amongst its many meanings, "cardinal" refers to something that is "of fore-most importance," "first importance" or "paramount." There are millions of different species on this planet. Our choice of the established model organisms for life science research is really based more on accident and the evangelical zeal of a just a few individuals who were seeking organisms that might be amenable to genomics analysis with relatively little forethought about their limitations for proteomics studies. With its tough cell wall, enzymology in the budding yeast is a nightmare. The biomass available from breeding fruit flies and microscopic worms is too cost prohibitive for practical protein biochemistry. Instead, we are stuck producing recombinant proteins from these species in other organisms such as bacteria which poorly recapitulate if at all the post-translation modifications that are required for their full functionality.
Nearly three decades of research with these simple model organisms has actually revealed how misleading the interpretation of findings from their genetic analysis can be when extrapolated to higher organisms. In fundamental processes such as mitosis and apoptosis, which apply at the cellular level, it is not surprising that there is reasonable good conservation. But this is more the exception rather than the rule, and the generalities rapidly breakdown when examined in vertebrate species. Even cell division in the budding yeast and in the early D. melanogaster embryo are actually very atypical.
Apparently cognant proteins in very divergent species are commonly utilized for very different purposes, despite similarities in amino acid sequences. For just one example, MAP kinases are one of the most conserved of the protein kinases in eukaryotes. In S. cerevisiae, they mediate mating in response to pheromones, in C. elegans they regulate vuval development, and in D. melanogaster, they control compound eye development. These are not processes found in humans. While some important protein-protein interactions can be maintained across evolution of the species, the vast majority do not appear to be.
Defects in protein kinase-based signalling systems have been linked with nearly 400 different human diseases. Budding yeast have about 130 protein kinases, but only about a third have even distantly related human counterparts. Meanwhile, there are about 515 human protein kinases. Across the species, protein kinase-substrate interactions appear to be about 100-fold more conserved in evolution than transcription protein-gene promoter interactions. The 23,000 human proteins feature about 500,000 phosphorylation sites. Based on published mass spectrometry analysis of phosphorylation sites in S. cerevisiae, C. elegans and D. melanogaster, it appears that only about 1%, 6% and 5%, respectively, of the phospho-sites in these organisms have remotely similar counterparts in humans. It should be plainly obvious that the signalling systems in these model organisms are extremely distinct from mammals. With such vast differences at the protein level, it is small wonder that there are also huge differences in their physiology compared to each other and humans. Consequently, these simple model organisms are very poor surrogates for understanding the complexities of human disease. Those that suggest otherwise are fooling themselves and may in fact be performing a disservice to the broader scientific community by leading others less critical down blind alleys.
Link to the original blog post.