Since Newton, classical and quantum physics depend upon the ‘Newtonian paradigm’. The relevant variables of the system are identified. For example, we identify the position and momentum of classical particles. Laws of motion in differential form connecting the variables are formulated. An example is Newton’s three laws of motion. The boundary conditions creating the phase space of all possible values of the variables are defined. Then, given any initial condition, the differential equations of motion are integrated to yield an entailed trajectory in the prestated phase space. It is fundamental to the Newtonian paradigm that the set of possibilities that constitute the phase space is always definable and fixed ahead of time. This fails for the diachronic evolution of ever-new adaptations in any biosphere. Living cells achieve constraint closure and construct themselves. Thus, living cells, evolving via heritable variation and natural selection, adaptively construct new-in-the-universe possibilities. We can neither define nor deduce the evolving phase space: we can use no mathematics based on set theory to do so. We cannot write or solve differential equations for the diachronic evolution of ever-new adaptations in a biosphere. Evolving biospheres are outside the Newtonian paradigm. There can be no theory of everything that entails all that comes to exist. We face a third major transition in science beyond the Pythagorean dream that ‘all is number’ echoed by Newtonian physics. However, we begin to understand the emergent creativity of an evolving biosphere: emergence is not engineering.