The standard scientific method requires that you make an interesting observation, generate a hypothesis and then design an experiment to test the hypothesis. In ophthalmology, as in most fields of medicine, the observations and hypotheses tend to have more degrees of freedom, and the interpretation of experiments is also more complicated and often indeterminate. But sometimes it works out, going back and forth from bench to bedside to bench, in reiterative cycles. A successful example of alternating bench and bedside studies was presented (AAS) at the 2012 Alper Memorial given at the Washington Hospital Medical Center, illustrating a series of questions and investigations that pertain to mitochondrial optic neuropathies, beginning two decades ago, before the concept of mitochondrial optic neuropathies had much meaning. Basic science questions are often best answered by that extraordinary experiment of nature that we call clinical disease, and clinical questions are often best tested in the laboratory.