Studying rare diseases can help many
Increasingly, model organisms such as fruit flies and worms are being used to find the correct diagnosis and to develop new therapies for patients with rare diseases
Drs. Shinya Yamamoto, Oguz Kanca, Michael F. Wangler, and Hugo J. Bellen who lead the Model Organism Screening Center (Drosophila Core) at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine, recently published a comprehensive review in Nature Reviews Genetics highlighting the growing importance of non-mammalian animal models in rare disease research and the wide range of opportunities they offer in speeding up gene discovery and therapy development.
In the past decade, state-of-the-art next-generation sequencing technologies have rapidly accelerated the discovery of genetic mutations/variants observed in patients with rare diseases. However, identifying the genetic culprit is sometimes challenging and unequivocal demonstration that the variants are the primary cause of the disease can be a complex process. Often, these studies require several experimental studies to validate their biological functions.
In recent years, a new approach pioneered by the authors in collaboration with physicians and researchers in the National Institutes of Health’s Undiagnosed Diseases Network (UDN) program has proven to be time-and cost-effective in discovering and studying novel gene variants implicated in rare diseases. In this new approach, non-mammalian model organisms — mainly fruit flies (Drosophila melanogaster), nematode worms (Caenorhabditis elegans), and zebrafish (Danio rerio) — are used in a systematic manner to rapidly and cost-effectively assess the functional effects of identified genetic variants on various biological processes.
“This new collaborative and targeted approach has proved to be very successful and has led to the discovery and validation of the underlying genetic variants for more than forty new disorders in just a few years,” said Dr. Bellen. “In addition, probing mechanisms of gene action and identifying interacting genes and proteins in vivo using fruit flies has not only facilitated the diagnosis of numerous genetic diseases but has also enabled the screening and identification of effective FDA-approved drugs for patients. We feel gratified by the immediate positive impact these studies have had on the lives of these patients. Families of rare disease patients who have participated in these studies have unanimously shared the sentiment that getting the correct diagnosis empowered them to seek the right care and resources for their loved ones and connect with similarly affected families, which often significantly eased their psychological and financial burdens.”
“Moreover, studies in non-mammalian model organisms have also shown that the biological processes underlying rare diseases can provide deeper insights into fundamental questions such as the mechanism of action of various genes and pathways. Insights obtained from rare diseases provide us with valuable new information that can be leveraged for other common diseases. Thus, the knowledge we gain from studying rare diseases has broad applicability and has the potential to have a marked impact on public health,” Dr. Wangler said.
“With thousands of genes in the human genome not yet functionally annotated, the effect of this research on medical genetics will continue, and the full consequences of model organism-based approaches to studying human diseases are anticipated to be highly impactful,” added Dr. Oguz Kanca.
“Moreover, this model exemplifies the emerging culture of ‘team science’, in which clinicians and scientists collaborate closely with experts from various disciplines and with individuals suffering rare diseases and their families,” Dr. Yamamoto said. “It recognizes the value of integrating a patient and their families’ lived experiences to advance research and these interactions provided us with important insights that we would not have been aware of otherwise. In short, this interdisciplinary and inclusive approach has significantly accelerated our research by directing us to biological questions that are highly clinically relevant.”
Finally, this review emphasized the pivotal need for continued support for such efforts, whether they are in the form of individual or large research studies or building and maintaining centralized repositories or databases because studying one individual with a rare disease often leads to a better medical future for many.