Aside from established genetic evidence, the best proof of a model for disease pathogenesis rests on predicted perturbation via targeted medicines in clinical trials. Here, I discuss the strategy of performing exploratory first-in-human clinical studies on mechanistically homogeneous populations (often small groups of patients with rare diseases) as a routine entrance to full-registration clinical trials. Over the past decade, this approach has proved some pathogenic theories, disproved others, and guided investigators in new scientific directions. The immediate advantages have been smaller trials and provision of new treatments for rare diseases. Later, indications often can be expanded to subsets of more common diseases.

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Photo of Mark C. Fishman

Mark C. Fishman’s group studies the heart-brain connection. They employ a range of genetic, developmental, and neurobiological tools in zebrafish to understand what the heart tells the brain, and how critical internal sensory systems adjust homeostatic and somatic behaviors, including social interactions.

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