When animal modelers use terms like similar to and resembles to describe the relationship between animal models and humans, and express confidence that their model is excellent because it shares some genes with humans, they are declaring to the world that they have little knowledge and understanding of evolution and molecular biology. Consider that just one nucleotide substitution out of hundreds can mean the difference between a person with cystic fibrosis, sickle cell anemia, or beta-thalassemia and one without. Furthermore, genes act in networks, interact with proteins, and are acted upon by the environment. There are regulatory genes, gene expression profiles, background genes and modifier genes and all of these things influence what a gene does.
Convergent evolution can result in the same trait developing in two different species by entirely different mechanisms. For example, insects from the Arctic and Antarctic “have developed distinct . . . mechanisms to cope with similar desiccating conditions.” Researchers discovered that the insects use very different gene expression patterns to survive in the very dry environment. Likewise, blind mole rats fight off cancer using a different mechanism from naked mole rats. Combine all this with the fact that the same gene can cause disease in one species but not another [3, 4] and the concept of modeling humans with different species appears nonsensical. Why would anyone do this?
An answer is suggested by Randall S. Prather, of the National Swine Resource and Research Center, Division of Animal Sciences, at the University of Missouri in Columbia:
The US National Institutes of Health deemed the pig so important for biomedical research that it established the National Swine Resource and Research Center to serve as a genetic resource and repository for disease models and as a core facility to create new genetic mutants (http://nsrrc.missouri.edu/). Swine have long been recognized as an especially good model for certain human diseases. For example, modification of the CFTR gene results in a phenotype resembling human cystic fibrosis in pigs but not in mice. Pigs develop atherosclerosis and lay down plaques in a manner similar to humans. And owing to the similarity of photoreceptor distribution and of the size of pig and human eyes, these animals are an excellent model of human eye disease. The advantages of pigs as disease models likely derive from their genetic similarity to humans; at the nucleotide level their identity to humans is three times higher compared with mice, and porcine-human synteny blocks are farther along the phylogenetic tree compared with those of mouse and human.
So far, the above is pretty much boilerplate propaganda from the vested interest groups. Prather is ignoring essentially the last half-century of advances in biology when he uses the word similar and implies similar is adequate for using pigs to discover cures for humans. We are also similar to stars. We are identical on the subatomic particle level! He is also completely discounting complexity science and empirical evidence.
But what I found more interesting was what followed. Under the section regarding “competing financial interests,” Prather stated: “The author declares no competing financial interests.” Seriously?! The guy works for the National Swine Resource and Research Center and is touting research with swine in order to get more grant money to do research with swine, but he sees no conflict of interest! This is the mindset of the animal model industry. And it is an industry: a multibillion-dollar industry, complete with lobbyists and multiple stakeholders that include universities, animal sellers, equipment sellers, and doctors. So when an animal modeler is writing about his righteous endeavors, there is nothing wrong (in his view) with claiming he does not have a vested interest because that being truthful would just confuse the ignorant masses about how important his work is. And how important is his work? It’s righteous! Therefore, the usual rules do not apply to him.
I have written many times that almost any animal experiment can be sold to society by promising cures to dreaded diseases. The following is another example. Scientists at the Marine Biological Laboratory (MBL) have conducted research on the lamprey and discovered genes that might be related to human diseases like Alzheimer's and Parkinson's disease as well as spinal cord injury. Jennifer Morgan of the Eugene Bell Center for Regenerative Biology and Tissue Engineering at MBL states: “This means that we can use the sea lamprey as a powerful model to drive forward our molecular understanding of human neurodegenerative disease and neurological disorders.” In case there was any doubt that lampreys are significantly different from humans, consider that the lamprey can regenerate its nervous system in addition to not having any myelin. If Smith et al want to conduct comparative research, there is no doubt they will be successful. However, learning something that will cure neurological diseases is highly unlikely.
Genes act in specific environments and networks. One cannot isolate a gene and treat it like it was a piston—a part that is interchangeable between cars of the same year and model. Fugger et al discuss genetic mutations in humans:
The diagnostic and prognostic value of identifying such mutations is unequivocal. In contrast, the study of the genetics of complex diseases has largely, at least in recent years, entailed efforts to find variants whose prevalence differs only slightly between persons with a given disease and those without it. On its own, such variation has little or no predictive utility, and even if a moderate fraction of a trait's genetic variance (or heritability) can be accounted for by adding up the effects over many loci, the diagnostic utility is limited by the substantial environmental component in the causation of most complex traits.
There are other reasons what appears to be the same gene does different things in different species. Scientists at the University of Toronto Faculty of Medicine “sequenced and compared the composition of hundreds of thousands of genetic messages in equivalent organs, such as brain, heart and liver, from 10 different vertebrate species, ranging from human to frog. They found that alternative splicing -- a process by which a single gene can give rise to multiple proteins -- has dramatically changed the structure and complexity of genetic messages during vertebrate evolution.” They also discovered that alternative splicing was more complex in humans and nonhuman primates than other species. But even the author of this study stated: “Our research may lead to the design of improved approaches to study and treat human diseases.” So keep the grant money coming! This is a poor reflection on the scientific community. It is a realistic reflection, but unfortunate nonetheless.
Humans and animals have a genome, proteome, transcriptome, interactome, metabolome, regulome, and epigenome and they all interact. Modifying a mouse by adding or subtracting a gene has no predictive value for what that gene does in humans. There are genes that perform more or less the same function, but the occasional correlation does not imply predictive value. If it did, fortune-tellers would be scientists. Although, considering their professional standards and lack of experiences in committing fallacies, I doubt they would be as successful in obtaining grant money as animal modelers.
1. Teets, NM, JT Peyton, H Colinet et al. (2012) Gene expression changes governing extreme dehydration tolerance in an Antarctic insect. Proceedings of the National Academy of Sciences 109:20744-20749. 10.1073/pnas.1218661109. http://www.pnas.org/content/109/50/20744.abstract.
2. Gorbunova, V, C Hine, X Tian et al. (2012) Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism. Proceedings of the National Academy of Sciences of the United States of America 109:19392-19396. 10.1073/pnas.1217211109. 3511137. http://www.ncbi.nlm.nih.gov/pubmed/23129611.
3. Gibbs, RA, J Rogers, MG Katze et al. (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316:222-234. 316/5822/222 [pii]
4. Holmes, B (2007) Monkey genome springs surprise for human origins. New Scientist:15.
5. Prather, RS (2013) Pig genomics for biomedicine. Nature Biotechnology 31:122-124. 10.1038/nbt.2490. http://www.ncbi.nlm.nih.gov/pubmed/23392511.
6. Smith, JJ, S Kuraku, C Holt et al. (2013) Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. Nature Genetics 10.1038/ng.2568. http://www.ncbi.nlm.nih.gov/pubmed/23435085.
7. Greek, R, J Greek (2010) Is the use of sentient animals in basic research justifiable? Philos Ethics Humanit Med 5:14. 1747-5341-5-14 [pii]
10.1186/1747-5341-5-14. 2949619. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20825676.
8. Fugger, L, G Mcvean, JI Bell (2012) Genomewide association studies and common disease--realizing clinical utility. The New England journal of medicine 367:2370-2371. 10.1056/NEJMp1212285. http://www.ncbi.nlm.nih.gov/pubmed/23252523.
9. Barbosa-Morais, NL, M Irimia, Q Pan et al. (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587-1593. 10.1126/science.1230612. http://www.ncbi.nlm.nih.gov/pubmed/23258890.