Why Human Gene Therapy Scientists Should Care About Model Organisms

Ever since Gregor Mendel developed the principles of inheritance in experiments using Pisum sativum (pea plants), scientists have recognized that many discoveries made in one living organism may have implications that can be generalized to other organisms, including humans. This has led to the recognition that most of the fundamental mechanisms of biology are held in common among vertebrate and invertebrate animals, plants, fungi, and protists, and to some extent even with prokaryotes and archaea. It seems that once nature has solved a common biological problem, this solution is either conserved or recapitulated across evolutionary time.

Certain organisms have particular traits that have lent themselves well to laboratory study. Most have short replication times and nutritional and environmental requirements that are easy to reproduce. Organisms that survive well in ambient air and between room temperature and human body temperature (37°C) are obviously easier to cultivate than are extremophiles, such as thermophilic bacteria native to undersea volcanic vents. Supplying simple carbohydrate-rich media to insects and nematodes is considerably more scalable than supplying live prey to obligate carnivores. Additionally, model organisms that are transparent or nearly transparent are quite useful in studying morphologic changes over time in living organisms during development, differentiation, and aging.

Seminal discoveries in biochemistry and molecular biology were initially made in bacteria, such as Escherichia coli, and yeast, such as Saccharomyces cerevisiae. Somewhat more complex eukaryotic models that have risen to prominence include Caenorhabditis elegans (round worm), Drosophila melanogaster (fruit fly), and Danio rerio (zebrafish). Fundamental discoveries made in C. elegans include the central pathways involved in axonal development, intestinal organogenesis, programmed cell death and senescence, and RNA inhibition. ^{1 –3} D. melanogaster experiments have led to breakthroughs in the understanding of chromosome structure and function, development of polarity and embryonic segmentation, innate immunity, and special sensory systems. Similarly, D. rerio has proven to be useful in the study of the organ regeneration and of the developmental biology of blood vessels, neurons, hematopoietic stem cells, and other tissues and organs ⁴ .

One might have supposed that improvements in the technological ability to manipulate murine embryonic stem (ES) cells to create knockout and knock-in mice would have eroded interest in the use of model organisms for studying human disease-related genes and therapies. Overall, this has not proven to be the case. Increasingly, disease-specific phenotypes have been produced in model organisms by mutating genes identified directly in humans. These genetically determined phenotypes are now being used to screen and develop pharmaceuticals and even nucleotide-based therapies. The advent of efficient and specific tools for genome editing, such as the Zn finger nuclease (ZFN), TALEN, and CRISPR/Cas9 system has accelerated and expanded the role of model organisms.

The relationship between research in model organisms and gene therapy research promises to be mutually beneficial. Gene mutations targeted for augmentation or knockdown by a potential gene therapeutic can rapidly be reproduced in model organisms and confirmed. This could allow for validation of such targets and serve as initial proof-of-concept for the advancement of gene therapies. Such studies can generally be completed more quickly and inexpensively than comparable studies in mice or larger animals. Thus, studies in model organisms have enhanced rather than replaced other nonclinical gene therapy trials.

In the final analysis, paradigm shifts in the treatment of human disease come from breakthrough discoveries rather than from incremental advances. These breakthrough discoveries can come from many different quarters: model organisms, field biology, rodent models, direct human studies, and population studies, just to name a few. Keeping in mind the overarching goal of advancing the human condition, including humanity's ability to maintain a healthy world, scientists should ever seek to avoid partisanship in their advocacy for one form of science over another.