Studies of human disease-causing genes can often be performed in model organisms like yeast, fruit flies, and mice, leading to breakthroughs in diagnoses and treatment.
It is estimated that there are more than 10,000 to 12,000 rare diseases affecting more than 20 million people in the United States and 400 million worldwide. An estimated 80% of these rare diseases are caused by mutations in our genes. As of today, approximately 4,600 disease-causing genes are known, and scientists are still working to identify the mutations underlying the remaining thousands of unsolved rare diseases.
Prior to 2010, it was very difficult to pinpoint the specific genes and genetic mutations that cause rare human diseases. However, extraordinary advancements in technology have completely changed the landscape of human genetics, and today, scientists can sequence the entire human genome for less than $1,000. By sequencing the genomes of individuals who have rare diseases, geneticists are able to identify genetic variants that could be causing disease, which are then studied in follow-up experiments.
The experimental power of model organisms
All over the world, scientists are capitalizing on new technologies to advance discovery for rare genetic diseases. In North America, the Canadian Institutes of Health Research launched the Rare Disease Models and Mechanisms Network, and in the United States, the National Institutes of Health supports the Undiagnosed Diseases Program (UDP) and Undiagnosed Diseases Network (UDN). Similar approaches are being pursued in Japan (J-RDMM), the European Union (SolveRD), and Australia (AFGN).
These networks are all driven by a fundamental underlying principle: By using the experimental power of model organisms, scientists can conduct studies to determine the genetic basis of disease and help provide individuals suffering from rare diseases with a diagnosis for the first time. The UDP and UDN support clinical sites, sequencing centers, and model organism researchers, with the goal of diagnosing as many individuals as possible. They see patients with some of the most challenging cases in medicine, typically seeking a diagnosis for years. To date, more than 8,000 patients have applied to the UDN, with about 40% accepted. Through human genetic studies and studies in model organisms, approximately 30% of the accepted patients have been diagnosed.
Functional studies of human disease-causing genes can often be performed in genetic model organisms, such as yeast, worms, fruit flies, zebrafish, and mice/rats. Indeed, a comparison of the genomic structures between these organisms and humans reveals that all organisms are built from a similar set of genes. For example, fruit flies share 75% of human disease-causing genes. Thus, experimental manipulations of model organisms can be used to understand the biological effects of a disease-causing mutation. This approach allows scientists to determine whether, and how, the human genetic variants affect the normal function of the gene.
Unlocking new therapeutic approaches
While a precise DNA molecular diagnosis provides some relief to patients who have undergone a diagnostic odyssey, it is just the beginning. Identifying the cellular and biochemical pathways that are at the root of a patient’s symptoms is the most straightforward way to develop potential new therapies. In these endeavors, the model organisms provide unmatched tools to dissect the disease mechanisms. By rapidly assessing the precise expression pattern of the genes, the dynamics of the proteins they encode, and the affected biological pathway, researchers can identify potential therapeutic targets. Furthermore, by unraveling the molecular players in the disease, scientists can, in some cases, identify FDA-approved drugs that can be repurposed to target the molecular pathway.
These discoveries have already led to new therapeutic approaches, and physicians have applied for compassionate use of drugs when appropriate for their patients. Further, the functional studies of rare genetic diseases in children (more than 60% of the submitted cases of the UDN) have provided deeper insight into adult-onset diseases caused by similar mechanisms, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Going forward, it is essential to maintain robust levels of research funding to support scientists’ functional studies on the genetic causes of disease using model organisms. These critical discoveries can then be translated into new therapeutic strategies and clinical studies to help as many patients as possible. Continuing to expand connections, collaborations, and crosstalk between basic scientists, clinicians, and patients will also be key in advancing discovery for rare genetic diseases.
