Notes on Engineering Health, July 2021

Some Notes on Model Organisms

In 1859, Charles Darwin published the first edition of his seminal work On the Origin of Species By Means of Natural Selection or the Preservation of Favoured Races in the Struggle for Life which laid out the theory of natural selection. As people reckoned with the ideas of heredity and a common lineage for all organisms suggested by Darwin, the question of how to study these phenomena arose. 

Unbeknownst to most of the scientific world at that time, while Darwin was unveiling his revolutionary theory, Gregor Mendel and his (now) famous pea plants were simultaneously laying down the foundations of modern genetics, and providing an answer to the question of how to acquire new biologic knowledge proving the incredible power and importance of “model organisms” in understanding biology.

What Mendel somehow intuited well ahead of the rest of the field was that if every organism has a shared origin, then there must be some basic biological principles that are at play in humans as well as in much “simpler” organisms. The idea that certain organisms can be studied and used to acquire knowledge on other organisms led the way to new fields of research and the development of a myriad of the models (zebrafish, yeasts, bacteria, phages, and, of course, mice and monkeys to name a few) that drive much of modern biology. 

Three models have had an outsized impact on research (note, we absolutely acknowledge the importance and the contribution of other models and do not mean to insult our readers with a passion for other organisms). 

The fruit fly, or Drosophila melanogaster, became a lab animal in 1901 at Harvard University as scientists were looking for an animal they could keep easily in the lab and reproduce in large numbers. These flies were key for Thomas Hunt Morgan, considered the father of all drosophilists and inspired by Mendel’s experiments, to establish that chromosomes were the basis of heredity, for Eric Wieschaus and Christiane Nüsslein-Volhard to discover genes controlling embryonic development (those same genes are conserved in humans!) and, more recently, Michael Rosbash to uncover some of the mechanisms controlling the circadian rhythm. In a 2001 survey, it was shown that 75% of known human disease genes had an identifiable match in Drosophila and the immense set of genetic tools developed for this model continue to make it an essential part of many biologists’ experimental arsenal. 

The round worm, or Caenorhabditis elegans, was the first multicellular organism to have its whole genome sequenced (a partial genome in 1998 and a complete one in 2002). With leadership from Sydney Brenner beginning in the 1970s, the round worm became a perfect screening tool where every gene could be knocked down using silencing RNA (siRNA) and thereby reveal its function. Silencing genes using this techniques has worked remarkably well in worms as they absorb the siRNA through their food and bodies in their normal living environment. Thanks to large screening efforts over the years, many discoveries were made via the worm including elucidating mechanisms in areas as diverse as programmed cell death (apoptosis), aging (development of Alzheimer’s disease, role of oxidative stress and lifespan) and sleep. Overall flies and worms have been tremendous models to study cell cycle and developmental processes. 

The mouse, or Mus musculus, combines features that make them the perfect proverbial lab workhorse—ease of maintenance and handling, high reproduction rate, and proximity to human biology. If fruit flies are humans’ first cousins, then mice are their brothers sharing 99% of protein-coding genes. Mice are thus far better models than yeasts, worms, and flies to interrogate the immune, endocrine, nervous, cardiovascular, skeletal and other complex mammalian physiological systems. Mice get sick with many similar diseases as humans do, and researchers have managed to create models for diseases that normally do not affect the rodent. The Jackson Laboratory has played a crucial role in the development of the mouse into the leading model for biomedical research developing breeds to study conditions as diverse as multiple types of cancers, Down syndrome, Cystic Fibrosis, diabetes, and many more. 

While many, many mice have been cured of all sorts of inflicted ailments, the translation to human biology and disease has often been more haphazard than is optimal. No model is perfect and, as useful a tool mice have been, there are species differences that have been hard to reconcile. As one example, although Dr. Valina Dawson managed to create a parkin knockout mouse, mimicking a mutation that causes some cases of Parkinson’s disease, the mice did not display the disease’s hallmark features - no trembling limbs, no rigid body movements, no unsteady gait. 

Despite the glorious past (and noted shortcomings) of these model organisms, one can wonder about their future. From peas to flies to mice, is the next frontier of the model organism its complete virtualization? Some argue that the increasing use of AI will replace the need to experiment on animals, going directly from in vitro to in silico without the burdensome in vivo step. It is true that, while they enabled truly remarkable biological discoveries, many of these models fall short of clearly predicting how a drug will behave in humans. A complementarity of approaches however seems to yield more promising results, with this massive effort aiming at improving the translation from mouse to human an interesting effort in this direction. 

– Jonathan Friedlander, PhD & Geoffrey W. Smith