Science’s Unsung Heroes: The Importance Of Model Organisms
- Monday, 20th May 2013
- Core Concepts
Model organisms play a central role in scientific research as they allow us to manipulate, analyse and understand a huge assortment of variables in an in vivo setting. Model organisms generally possess three main characteristics: rapid growth and short generation time, minimal creation and maintenance costs, and ease of manipulation. In scientific research a wide spectrum of different model organisms can be used depending on the requirements of the researcher and his experiments. These model systems can range from bacteria, such as E. coli, to large mammals, like chimps. The reason why we have such variety is due to the fact that all the basal biological processes and principles are nearly the same in all living things. Therefore, even a simple system such as yeast can be useful to study the molecular basis of processes that work the same way in humans. At the same time, the availability of complex systems that are genetically closer to humans enables researchers to either project the results obtained from a simple organism (to confirm and progress the study undertaken) or to direct specific questions onto them. This allows scientists to choose which organism best fits with the questions/purposes of their study.
What are the main model organisms used in science?
C. elegans is a very small nematode (1 mm length) that is normally found in the soil; it grows very easily and it is very cheap to breed. Sydney Brenner was the first to recognise the genetic potential of this tiny organism and in 1974, decided to study it to understand the genetics of organ development and apoptosis, or programmed cell death (Nobel Prize in 2002). Since then, C. elegans has become widely used as a model organism and in 1998 Andrew Fire and Craig C. Mello took advantage of it to elucidate the RNA interference process (Nobel Prize in 2006). RNA interference (RNAi) is a process by which small RNA molecules are able to inhibit the expression of genes by causing the degradation of specific messenger RNAs. RNAi is a fundamental mechanism in the control of gene expression in eukaryotic organisms, humans included. RNAi has become an important tool in research and it has been used for large-scale screening with the aim at identify components of specific cellular processes such as cell cycle or morphogenetic and metabolic pathways.
Recently, RNAi has been used in C. elegans for the first genetic suppressor screen for antipsychotic (APS) drug targets. Antipsychotics are medical treatments used to manage psychosis, such as schizophrenia and bipolar disorders. So far, Clozapine is the most effective antipsychotic though it produces severe toxic side effects through an unknown mechanism. With this genetic screen, researchers were able to delineate novel molecular mechanism of action of specific APD targets through which Clozapine may produce its toxic effects. Similar studies could facilitate the design of better targeted treatments in psychiatric neurobiology and help researchers better understand the pathogenesis of such diseases. Another invertebrate model commonly used by researchers is the fruit fly, Drosophila melanogaster.
D. melanogaster is a small fly with a very short generation time (10 days at room temperature). Surprisingly, Drosophila shares high sequence homology with humans, making it one of the top organisms for genetic studies. Drosophila was first used as model organism at the beginning of the 20th century, when Thomas Hunt Morgan studied mechanisms of heredity and evolution. From his experiments he deduced that genes are carried on chromosomes, and that there are specific traits that are linked to genes on the sex-determining chromosomes. For these discoveries he was awarded a Nobel Prize in 1933 and since then Drosophila has been used for the study of several medical conditions, including Parkinson’s disease, Alzheimer’s and various types of cancer. Moreover, Drosophila intestinal pathology provides a model for the study of intestinal stem cells, tissue regeneration and inflammatory responses. Despite morphological differences, the intestines of Drosophila and humans share highly conserved signalling pathways, which control intestinal development. For instance, recent studies have highlighted the pathogenic role of several pathways, (such as those including the JAK/STAT, Wnt and Notch signalling molecules), in the intestinal regeneration and homeostasis, making each pathway component a potential target for therapies. These kinds of therapies can be used in patients with Inflammatory Bowl Diseases (such as ulcerative colitis and Crohn’s disease); conditions in which the colon is inflamed over a long period of time increasing the risk of developing colorectal cancer. Although useful, researchers also have need for vertebrate systems as well. One of these systems is a species of frog native to Sub-Saharan Africa named Xenopus leavis.
Although X. leavis does not share some of the more common characteristics of a model organism, with its slow progression to sexual maturity (1 or 2 years) and complex genetic make-up, it does however produce an enormous amount of large eggs, which are easily manipulated experimentally. Only 13 years ago, Janet Heasman used Xenopus embryos to develop gene knock-down in vertebrates by injecting the embryos with morpholino-antisense oligonucleotides. Morpholino oligomers bind to complementary nucleic acid sequences on the RNA, ultimately resulting in reduced expression of a target protein. This has become a very common technique in research and can be applied to several model systems, many of which have played an important role in the study of Human Genetic diseases. Recent studies have demonstrated that phosphorodiamidate morpholino oligomers (PMOs) can be used to re-direct the splicing of myostatin, a negative regulator of skeletal muscle mass that could be involved in muscle mass loss diseases such as Duchenne muscular dystrophy (DMD). By reducing the amount of myostatin protein, this morpholino technique has the potential to become a therapeutic strategy to counteract muscle-wasting conditions for DMD. Another species commonly used in developmental studies is the small tropical fish Danio rerio.
Zebrafish are used for the study of vertebrate development and gene function because their embryos develop outside of the mother and remain transparent until most of the organs have fully developed. This peculiarity means that Zebrafish larvae can be used for in vivo imaging studies. ‘Casper’ is a mutant form of Zebrafish developed in 2008 at the Boston Children’s Hospital that is ghostly transparent. This transparency allows cancer cells to be visualised and tracked through the developing body. By combining laser scanning confocal microscopy (LSCM) and in vivo flow cytometer (IVFC) techniques, researchers are able to capture real-time 3D images and perform quantitative analysis of circulating cells. This type of analysis has yet to be finalized but it will enable both stationary and circulating cells to be tracked non-invasively over time. This type of techniques will be applied not only to monitor tumour growth and metastases, but also to follow hematopoietic stem cell engraftment after transplantation without affecting the physiology of the fish. Scientists may also opt for a system more physiologically similar to humans, such as the common house mouse, Mus musculus.
Mus musculus handles easily, reproduces quickly, and has a short lifespan (2 or 3 years). Mice necessitate specific facilities and expert caretakers. Due to their close genetic resemblance to humans, mice are one of the most important model organisms in biomedical sciences as scientists are able to produce genetically modified mice that imitate human diseases. For instance, researchers are able to produce mice in which the Sonic Hedgehog pathway is impaired. Sonic Hedgehog (SHH) is a signalling molecule that drives cell differentiation during development. Defects in SHH pathway regulation lead to different types of developmental disorders and cancer. Thanks to the observations conducted in mutated mice, researchers were able to distinguish three types of signalling defect models, each characterised by aberrant pathway activation. This has allowed scientists to start developing targeted therapies with the aim of controlling and stopping the over proliferation of the cancer cells.
However, the use for experimental purposes of animals that are capable of feeling pain raises several ethical issues. To regulate the use of laboratory animals, the Parliament of the United Kingdom approved the Animals (Scientific Procedure) Act 1986 (A(SP)A86). The Act has the purpose of regulating the use of laboratory animals, permitting animal experiments only when certain criteria are met. The Act comes from the necessity to control animal experiments that could potentially cause pain, suffering, distress and lasting harm under the responsibility of humans. Interestingly, the Act protects all living vertebrates other than humans and only a single invertebrate species, the Octopus vulgaris (due to its high intelligence).
The organisms described here are just a few examples among all those available for scientific purposes. For instance, bacteria are highly used in the genetic engineering, rabbits and goats are some of the organisms that are highly used for the production of antibodies, and apes are extremely important for the advancement of therapies against HIV. Model organisms are fundamental for scientific progress and their use in research has enabled major advancements in science. This scientific progression would have not been possible otherwise.
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