(Image credit – Wikimedia Commons, user: Kristof vt)

Model organisms – biomedical science’s most powerful tools

The zebrafish (Danio rerio) is perhaps the model organism with the fastest rising popularity in science right now. Now, what do we mean by “model organism”? These are not, despite the name, organisms that get dressed up and pose for pictures. Model organisms are certain species commonly used by scientists to better understand biology. Have you ever heard someone say that to truly understand how something works, you have to take it apart and then put it back together? It’s a similar story with disease, except incredibly difficult (both ethically and technically) to manipulate a human just to figure out how his disease works. Instead, scientists study model organisms, organisms that have shared biological properties with humans thanks to evolution, to figure out how diseases work. Model organisms can range from yeast (Saccaromyces cerevisiae) to chimpanzees (Pan troglodytes) and everything in between. There are advantages and disadvantages to every type of model organism, with the overarching caveat that none of them are exactly like humans, so what exactly are the different model organisms and what makes them useful?

What are some classic model organisms, and what makes zebrafish special?

Yeast is one of the most basic model organisms. The same yeast that is used to bake bread and doughnuts has a definitive similarity to us humans – we both have cells that contain a nucleus to hold our genetic information (i.e. yeast and humans are both eukaryotes). For this reason, yeast are useful to study things that happen on a cellular level, such as how cells grow and divide (called the cell cycle). Another model organism that is slightly closer to us evolutionarily is the fruit fly (Drosophila melanogaster). Their cells are also built like ours, and they are multicellular organisms. They also have easily observable physical differences between individuals (like red eyes or white eyes, long wings or short wings), inherited from parents, making them useful for studying the genetics of complex processes like embryo development. Although yeast and fruit flies are inexpensive to keep in the lab and easy to grow, it can be difficult to study certain things in these organisms because they don’t have lungs, vertebrae, or many of the other parts that humans have. This is where a model organism like the mouse comes in.

You’ve probably heard the term “lab rat” at some point in time. Many scientists study rodents because they share so many biological properties with humans. While this may not be obvious on the surface, rats and mice are mammals just like us; they reproduce sexually, go through pregnancy, and feed their babies with mother’s milk. They have essentially the same types of lungs, hearts, livers, and other body parts as humans. A drawback to rodents as model organisms, however, is that they are relatively more expensive to house and feed, and are not as easy to genetically manipulate as, say, yeast. In short, rodents are more complex, because they’re more like us, but their complexity can sometimes make them harder to tinker with and to totally understand how they function.

Somewhere in between the evolutionary distance from yeast and fruit flies to mice and rats, there are zebrafish. Zebrafish serve as a great middle ground as far as model organisms go. Again, it may not be clear at first that you have anything in common with fish, but you do. They are vertebrates like us, which puts them on our side of the significant evolutionary divide between vertebrates and invertebrates. Also, while they may have gills instead of lungs, and externally fertilized eggs, they have strikingly similar hearts, livers, and even skin when compared to humans. In addition, while they may be more expensive to maintain than yeast or fruit flies, they are just a fraction of the cost of larger animals like mice and rats. If you still have doubts about how studying fish could be of any use to people, then let’s discuss some clear examples of how mankind has benefited greatly from the little zebrafish.

Figure 1. A type of zebrafish called “casper,” which has been genetically engineered to be completely transparent, is a powerful tool for studying many aspects of internal development, even into adulthood.

What do zebrafish studies have to do with you?

As stated previously, zebrafish have skin; it’s underneath their scales, but it’s still skin. Under a microscope, it can actually be incredibly difficult to tell human skin from zebrafish skin. This is why it’s not too surprising that when zebrafish get skin cancer (through genetic manipulations performed by researchers), those skin cancers share many properties with human skin cancer. In humans, skin cancer often starts as a mole that begins to grow uncontrollably until it forms a true cancer. The same is true of fish – their skin cancer will start as a dark spot of pigment that eventually grows and grows until it is a full-blown tumor. Cancer cells usually undergo a distinct change in size and shape from healthy cells, and most of these changes are the same or “conserved” between humans and zebrafish. Many of the same genes that are mutated in human skin cancer, when put into zebrafish, will cause the fish to develop skin cancer, despite the fact that the genes originally came from humans.

In fact, in one study (Ceol et al. 2011), scientists were unsure of which gene out of a set of about 40 genes was responsible for some of the rapid growth of human skin cancers. By taking these genes one by one and putting them into zebrafish skin, they found that only one of the many genes was able to accelerate skin cancer formation in the fish, and this provided new genetic knowledge that was directly applicable to human disease. What’s more, a second study from this same lab led to the discovery of a drug that significantly slowed zebrafish skin cancer growth. It was later shown that this effect held true in mice and now, this drug, leflunomide, is in clinical trials to see if it will help fight human skin cancer, specifically melanoma, the most deadly form of skin cancer.

Surprisingly, zebrafish have also proven useful in the study of obesity-related health concerns. Obesity is one of the biggest health threats in Western civilization, and one of its side effects is the build-up of fats in the liver, a condition that lacks effective treatments. Zebrafish transport fats in the same way as humans, and they will develop obesity and fatty liver disease when they are overfed. Because of the small size of zebrafish embryos, just a few millimeters in diameter, it is relatively easy to test hundreds or even thousands of chemicals to see if any of them reduce fatty livers in the zebrafish. Research has already shown that a tomato extract can successfully prevent fatty liver in zebrafish (Tainaka et al. 2011), and may one day be a treatment for the human condition.

There are many other aspects of zebrafish that are surprisingly similar to those of humans: the presence of stem cells, the formation of heart defects, the development of liver and muscle cancers, the existence of blood cells and an immune system that can develop leukemias or blood cancers, all just as in humans. This is only a sampling of features that we share with these fish. It’s no wonder that the use of zebrafish is on the rise when you add the facts that a zebrafish can lay upwards of 1000 eggs a week (compared to the average of 10 mice born after 3 weeks by one mother), are of intermediate cost, and are similar enough to humans that they are already well on their way to giving us insights into new therapies for human disease. Today, the use of zebrafish as a model organism is very much on the rise, and for many good reasons. While every model organism has its specific benefits and limitations, the zebrafish might just be the perfect middle ground for more cost-effective studies that still produce treatments that can treat human diseases.

Kristin Rose is a graduate student in the Biological and Biomedical Sciences Program at Harvard University.

References

Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferré F, Bourque C, Burke CJ, Turner L, Uong A, Johnson LA, Beroukhim R, Mermel CH, Loda M, Ait-Si-Ali S, Garraway LA, Young RA, Zon LI. “The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.” Nature. 2011 Mar 24; 471(7339):513-7.

Tainaka T, Shimada Y, Kuroyanagi J, Zang L, Oka T, Nishimura Y, Nishimura N, Tanaka T. “Transcriptome analysis of anti-fatty liver action by Campari tomato using a zebrafish diet-induced obesity model.” Nutr Metab (Lond). 2011 Dec 13;8:88.