Model Organisms in Rare Disease Research

By Quirine Eijkenboom

What do tiny winged flies and zebrafish have in common with humans -- and how could these small organisms possibly be helpful in human rare disease research?

To answer this question, let’s start with some background information. Despite the rapid advancement of scientific technology, such as whole-exome sequencing and comparative genomic hybridization methods, rare disease diagnosis remains one of the greatest challenges of modern medicine. According to Global Genes, the mean time from symptom onset to accurate diagnosis is around 5 years for rare disease patients. Patients with undiagnosed diseases and their families face great burdens and frustrations seeking out a correct diagnosis. One of several reasons for this is due to gaps in knowledge regarding gene function and effects of gene variation on protein functions. As many undiagnosed diseases have genetic origins, clinicians are mainly searching for affected genes and mutations. Once such gene variants have been uncovered, the new challenge researchers face is figuring out how the gene functions in the body and how the genetic variation actually impacts this.

Luckily, such diagnostic challenges have been increasingly facilitated through work in model organisms and collaborations between clinicians and model organism researchers. Potential gene candidates identified by clinicians can be studied in model organisms and used to identify orthologues in humans that may play a role in the disease. For instance, “Knocking-out” or disabling the gene in a model organism and observing whether a similar disease phenotype arises can help validate whether the suspected gene is the main driver of the disease.

Recently, candidate genes involved in human disease have been studied and confirmed as being causative for specific disease through the help of Drosophila (fly) studies, such as the NRD1 and OGDHL genes, which were known to be associated with abnormal nervous system phenotypes in humans (Yamamato et al. 2014; Yoon et al. 2017). Zebrafish and mice have also contributed to the identification of genes associated with abnormal brain structure or function, such as the FAT1 gene (Ciani et al. 2003; Skouloudaki et al. 2009; Gee et al. 2016).

What makes these connections between model organisms and human disease genes possible? The main reason model organisms are so helpful in studying human disease is because a vast number of genes, biological processes and pathways are evolutionarily conserved between species, from the single-celled yeast to humans.  Most notably, several studies performed in yeast indicate many yeast genes required for its viability (33-47%) can be directly replaced by their human counterparts (Hamza et al. 2015; Kachroo et al. 2015); that is, the human gene can substitute for the yeast gene as it performs the same required function in the cell.

This conservation of function between genes in model organisms and humans means information gleaned from species such as yeast, worms, flies, zebrafish and mice could be directly applicable to human biology. Because it is much easier to decipher the function of genes in model organisms, this makes them a powerful research tool.

For example, genetic machinery regulating wing patterning in Drosophila (flies) also regulates skeletal and craniofacial features in humans (Wangler et al., 2017). However, because Drosophila is an invertebrate, not all of its genes are relevant to humans (vertebrates). Because zebrafish and mice share many vertebrate-like features with humans, they can provide very useful information in addition to Drosophila and serve to answer organ-specific questions.

In addition to accelerating disease diagnosis and increasing knowledge about disease pathogenesis, model organisms can also facilitate the discovery of potentially useful therapeutics, by serving as efficient systems to screen for and test possible drugs and other therapeutic strategies. All this information can potentially be translated to humans.

We are pleased that many of our scientists at Grace Science employ model organism research to try to understand NGLY1’s function and importance to cellular processes and development. Using Drosophila, mice, zebrafish, yeast, and C.elegans (worms) as model systems, they seek to shed light on the pathophysiology of NGLY1 deficiency in human patients and identify possible drug targets for the disease.

It is essential to continue to foster collaborations between model organism and clinical research in order to understand the normal function of a gene and apply this knowledge to uncovering and understanding rare disease pathogenesis and potential therapeutic options.