Professor
Center for Cardiovascular and Muscular Diseases
Science is facing a reproducibility crisis. In the biomedical sciences, the inability to validate and reproduce findings is slowing progress in understanding basic principles. Among the fields hindered by irreproducibility is retinoic acid research. Fortunately, new techniques provide a way forward.
Vitamin A (retinol) has been known for more than 100 years to be a nutrient essential for embryonic growth and development, and 35 years ago its metabolite retinoic acid was discovered to function as a ligand for retinoic acid receptors that control gene expression.
A big question since has been: What genes are regulated by retinoic acid and when and where in the embryo does this occur in order to avoid birth defects? Gain-of-function studies based on treatment of cell lines or animals with retinoic acid have often given results not supported by loss-of-function studies in which genes encoding retinoic acid-generating enzymes are deleted genetically in what are called gene knockouts.
After three decades, it is clear that identifying the normal developmental processes and genes controlled by retinoic acid requires the rigor of gene knockouts. If you want to know what it does, don’t add it, remove it! This is what my laboratory has focused upon, leading to novel findings on the requirement of retinoic acid for development of the forelimbs (arms), vertebrae and the eye.
In general, for biomedical studies in any field researchers need to perform genetic loss-of-function studies in order to establish the normal functions for the gene, protein, molecule or DNA control element they plan to examine before they embark on detailed studies to explore the mechanism. Do you want a car mechanic who does not know the function of each part of your car?
With the advent of gene-editing tools such as CRISPR, the generation of gene knockouts are much easier and available to all. A clear distinction between studies that report physiological functions (based on loss-of-function) versus pharmacological functions (based on gain-of-function) will clear the path toward a true understanding of biology while ensuring that pharmacological insights relevant to combatting disease are put into the correct perspective.
With the constant improvement of gene editing tools, biomedical scientists can begin to move beyond the obstacles that have led to reproducibility problems in my field (retinoic acid signaling) as well as most other fields.