Second thoughts about first principles in biology

First-principles approaches, based on physics or chemistry, are key pillars of biological theory. Despite their value, there are recurrent problems with many first-principles approaches in biology: they often include incomplete physics or are driven by unscrutinised biological assumptions. Meanwhile, debates about biological theories based on first principles usually focus on the fit of predictions to data-we argue such a focus confuses prediction with explanation. A good fit of predictions to data is a necessary, but insufficient condition for a theory to be sound. First-principles approaches in biology will only be effective when the physics and biology are both sufficiently complete. Determining what elements are essential to include is an enduring but exciting challenge of science.