Unlike chemistry or physics, where chemicals and atoms can be manipulated in highly controlled environments, biology must deal with living organisms that come with numerous confounding variables. Scientific rigor in such an environment is impossible unless variables can be tightly controlled.
Most biologists don’t study rare or unusual organisms. Biologists, particularly geneticists, biochemists, developmental, and molecular biologists, often use model organisms to test hypotheses about broad scientific truths. Model organisms are used because they are:
1) Inexpensive and quick to grow
2) Straightforward to delete, add, and edit genes
Familiar examples of model organisms include flies and mice. Biologists are typically not interested in the biology of model organisms themselves, but simply use them to study broadly conserved biological processes that are shared across the tree of life. For example, both bacteria and humans contain DNA that is susceptible to damage from radiation, and this sort of damage must be repaired lest it result in heritable mutations. Coincidentally, the way that bacteria repair their DNA has some similarities to how human cells repair DNA (Fukui, 2010). Thus, understanding DNA repair genes in bacteria can be beneficial for improving DNA repair capabilities in humans.
Phylogenetic tree showing evolutionary relationships between some model organisms. Numbers indicate time of divergence in millions of years. Adapted from Wheeler & Brändli 2009 Dev Dyn 238:1287-1308
As you get phylogenetically closer and closer to humans – as in conducting research on animals or especially mammals – it becomes easier and easier to apply those discoveries to improving human health. However, studying bacterial or yeast model organisms can still be incredibly valuable, since even ‘simpler’ organisms have a huge economic impact (the next time you roll your eyes at biologists researching yeast, take a look at your bread, beer, and wine!). This article will describe several model organisms commonly used in biology, their advantages, and labs that utilize them.
Bacteria – Escherichia coli (E. coli)
Most biologists merely use E. coli as a tool. E. coli is a laboratory workhorse that can mass produce proteins and gene-carrying plasmids, even if those proteins and genes are from other organisms. However, some labs use E. coli as a model organism for studying general traits of bacteria, like pathogenicity (the ability to cause disease). For example, strains of E. coli in the lab and in the human gut tend to be relatively harmless. However, pathogenic strains E. coli exist in the wild and these can cause lethal infections of the gastrointestinal tract (Leimbach et al., 2013). Many other species of bacteria have the same Jekyll and Hyde characteristic in that both harmless and dangerous strains of the same species exist.
As another example, the Barrick Lab at UT (barricklab.org) uses E. coli and other bacteria to study bacterial evolution. In industry, Bacteria are often genetically engineered to produce desirable chemical compounds, like insulin and human growth hormones. However, the production of such compounds requires energy and thus slows down bacterial growth. Therefore, bacteria that spontaneously mutate and reduce their production of these compounds can grow faster, outcompete their siblings, and eventually pose a problem for the business.
The Barrick Lab studies ways to reduce the mutation rate of E. coli so that these microbial factories can keep operating (Deatherage et al., 2018). Mechanisms of evolution, such as error-prone DNA polymerases that make mistakes during DNA replication, are broadly shared across most bacteria. Therefore, knowing how to reduce the mutation rate in E. coli could be applied to other bacteria that are used as microbial factories.
Even biologists have a sense of humor. Bacteria (and yeast!) are grown on Petri dishes (stacks behind) and broth-containing flasks.
Yeast – Fission yeast, Schizosaccharomyces pombe (S. pombe)
E. coli are prokaryotes and thus lack many features of human cells, such as membrane-bound nuclei. Studies on the essential characteristics of eukaryotes have sometimes used S. pombe, a type of yeast. S. pombe has been invaluable for understanding mitosis and meiosis since it can undergo either asexual or sexual reproduction based on whether the cells are starving (Hoffman et al., 2015). In the 1970s, many mutants that had problems with cell division were isolated, sparking the beginning of the field of S. pombe genetics. Today, PomBase (https://www.pombase.org/) serves as a massive hub of information on S. pombe genes, proteins, and recent discoveries in the field, helping aspiring biologists build hypotheses and develop new projects.
The Finkelstein Lab (https://finkelsteinlab.org/) developed a technique to image single S. pombe cells over their entire lifespan. Shockingly, they discovered that S. pombe does not age (Spivey et al., 2017). Over their whole lifespan, these yeast show no significant changes in size or health. They simply die without showing any signs of getting older. This is just one example of how research on a seemingly simple organism can challenge conventional scientific wisdom.
Insects – Fruit flies, Drosophila melanogaster (D. melanogaster)
Although yeast are eukaryotes and thus share fundamental similarities with humans, yeast are unicellular fungi and thus lack developmental complexity. Biologists interested in researching multicellular animals may turn to D. melanogaster, the fruit fly, which are easy and quick (less than two weeks) to raise from egg to mature adult. People who keep frogs as pets even grow their own fruit flies as a food source. In addition, males and females with different genetic backgrounds can be easily crossed to study the functions of different genes.
Fly genetics is legendary in biology. FlyBase (https://flybase.org/) contains information on every gene ever studied in flies, and fly geneticists are infamous for giving genes weird names like “Mothers against decapentaplegic” and “Sonic hedgehog”. Fly geneticists have discovered many cell signaling pathways, which is how cells communicate with one another and perform complex behaviors such as migration. For example, the transformation of normal cells into cancer cells is influenced by numerous cell signaling pathways.
One of the most recently discovered signaling pathways is the Hippo pathway, which controls cell growth and migration (Staley and Irvine, 2012). Though initially discovered in flies, it was later found that the Hippo pathway is present in other animals, including humans, and mutations in this pathway can contribute to cancer. The Halder Lab (http://www.vib.be/en/research/scientists/Pages/Georg-Halder-Lab.aspx) uses both Drosophila and mammalian cell culture to understand how the Hippo pathway affects the growth of tumors.
Amphibians – Clawed frog, Xenopus laevis (X. laevis)
Although fruit flies are animals, they are invertebrates (i.e., they lack spinal cords). Their life cycles hardly resemble those of humans. Biologists interested in how animals with spinal cords develop may turn to X. laevis, the clawed frog. Various aspects of embryonic development, such as fertilization and gastrulation (the process by which the embryo forms the germ layers, which later become different organs), are shared among all vertebrates. Conveniently, Xenopus embryos are large, inexpensive to mass produce, and easy to image compared to mammalian embryos. Indeed, an entire database exists for videos of Xenopus embryos during various stages of embryonic development (http://www.xenbase.org/anatomy/static/movies.jsp).
Intriguingly, unlike humans, Xenopus has marvelous powers of regeneration. The Tseng Lab at UNLV recently showed that X. laevis embryos can fully regrow their eyes in five days after surgical removal of most of the eye tissue (Kha et al., 2018). Astoundingly, the regrown eyes are connected to the brain and contain all normal eye structures such as the retina. Thus, biologists studying mechanisms of Xenopus regeneration may accelerate advancements in human tissue regeneration.
The beating heart of a Xenopus tadpole. Since the tadpole is clear, it’s easy to image the heart and detect any problems in heart development which might be linked back to a gene. That gene might have a comparable human gene that is involved in human heart development.
Mammals – House mouse, Mus musculus (M. musculus)
Mammals have many unique traits that set them apart from all model organisms mentioned so far. They produce milk for their young, have unique brain structures like the neocortex, and grow fur or hair. Biologists who study the brain, behavior, as well as how body fights off disease often use mice as their model organism.
For example, the Ehrlich Lab at UT Austin (http://web.biosci.utexas.edu/lauren_ehrlich/Ehrlich_Lab_at_UT_Austin/Research.html) uses mice to understand how T cells develop. T cells are part of the adaptive immune system. Although known for helping other white blood cells function and also killing cells infected with viruses, mistakes in T cell development lead to autoimmune disorders where the body attacks itself. T cells themselves can also become cancerous and cause a form of childhood leukemia known as T-ALL. The Ehrlich Lab investigates the mouse thymus, the site of T cell maturation, to study both autoimmunity and T-ALL.
Although mice are more expensive to maintain and take longer to reproduce than any other organism mentioned before, numerous tools exist for mouse genetics. One of the most notorious is the conditional gene knockout. If a gene is essential for survival of a mouse embryo, then its other roles (for example, during adulthood) cannot be studied by performing a regular knockout, because the embryo will fail to develop. This is unfortunate because most genes have different roles depending on the age of the organism and which organ you may be studying. Conditional knockouts allow a researcher to decide when a gene should be deactivated as well as where it should be deactivated to see if that gene has a specific function, for example, only in the heart and only during adulthood (Kühn and Schwenk, 2002). Though quite laborious and tricky to do, this process has been streamlined by taking advantage of recent genome editing tools, such as using CRISPR/Cas9 to generate targeted breaks in the DNA (Miyasaka et al., 2018).
Mouse being mind controlled by light to overeat. Neuroscience owes a lot to mice, whose brains are somewhat similar to ours, but whose DNA is much easier (especially legally) to manipulate.
In sum, model organisms allow biologists to study biological processes that are shared across the tree of life. The most humble yeast or bacterial cell has more in common with a human cell than one would think. The highly orchestrated events of embryonic development and the immune system’s response to infection share striking similarities between mice and humans. That being said, model organisms are imperfect. The nuances of biological regulation can differ even between two members of the same species. Future research should focus on clarifying those nuances and developing new genetic tools to study non-model organisms.
Deatherage, D.E., Leon, D., Rodriguez, Á.E., Omar, S.K., and Barrick, J.E. (2018). Directed evolution of Escherichia coli with lower-than-natural plasmid mutation rates. Nucleic acids research 46, 9236-9250.
Fukui, K. (2010). DNA mismatch repair in eukaryotes and bacteria. Journal of nucleic acids 2010, 260512.
Hoffman, C.S., Wood, V., and Fantes, P.A. (2015). An Ancient Yeast for Young Geneticists: A Primer on the Schizosaccharomyces pombe Model System. Genetics 201, 403-423.
Kha, C.X., Son, P.H., Lauper, J., and Tseng, K.A.-S. (2018). A model for investigating developmental eye repair in Xenopus laevis. Experimental Eye Research 169, 38-47.
Kühn, R., and Schwenk, F. (2002). Conditional Knockout Mice. In Transgenic Mouse: Methods and Protocols, M.H. Hofker, and J. van Deursen, eds. (Totowa, NJ: Humana Press), pp. 159-185.
Leimbach, A., Hacker, J., and Dobrindt, U. (2013). E. coli as an All-Rounder: The Thin Line Between Commensalism and Pathogenicity. In Between Pathogenicity and Commensalism, U. Dobrindt, J.H. Hacker, and C. Svanborg, eds. (Berlin, Heidelberg: Springer Berlin Heidelberg), pp. 3-32.
Miyasaka, Y., Uno, Y., Yoshimi, K., Kunihiro, Y., Yoshimura, T., Tanaka, T., Ishikubo, H., Hiraoka, Y., Takemoto, N., Tanaka, T., et al. (2018). CLICK: one-step generation of conditional knockout mice. BMC Genomics 19, 318.
Spivey, E.C., Jones, S.K., Jr., Rybarski, J.R., Saifuddin, F.A., and Finkelstein, I.J. (2017). An aging-independent replicative lifespan in a symmetrically dividing eukaryote. eLife 6, e20340.
Staley, B.K., and Irvine, K.D. (2012). Hippo signaling in Drosophila: recent advances and insights. Developmental dynamics : an official publication of the American Association of Anatomists 241, 3-15.