[4][5][6][7][8] Noble established The Third Way of Evolution (TWE) project with James A. Shapiro which predicts that the entire framework of the modern synthesis will be replaced.

This led to two seminal papers in Nature in 1960[10][11] giving the first experimentally-based mathematical simulation of the electrical rhythm of the heart,[12] extensively developed with Richard Tsien in 1975,[13] and with Dario DiFrancesco in 1985.

[15] From this work it became clear that there was not a single oscillator which controlled heartbeat, but rather this was an emergent property of the feedback loops involving the various ion channels.

[18][19] As secretary-general of the International Union of Physiological Sciences 1993–2001, he played a major role, together with Peter Hunter, in launching the Physiome Project, an international project to use computer simulations to create the quantitative physiological models necessary to interpret the genome, and he was elected president of the IUPS at its world congress in Kyoto in 2009.

He points out that there are many examples of feedback loops and "downward causation" in biology, and that it is not reasonable to privilege one level of understanding over all others.

He also explains that genes in fact work in groups and systems, so that the genome is more like a set of organ pipes than a "blueprint for life".

[9][27][28] He has argued that from research in epigenetics, acquired characteristics can be inherited and in contrast to the modern synthesis, genetic change is "far from random" and not always gradual.

[9] Shapiro's natural genetic engineering, a process described to account for novelty created in biological evolution is also important for the TWE.

He has shown that therapeutic levels of cardiac glycosides may increase, rather than decrease, potassium gradients in the heart, and has published an analytical treatment of membrane excitation theory and cable theory that provides a modern basis for the concepts of safety factor, liminal length, excitation time constants and the phenomenon of repetitive firing.

In addition to English, he has lectured in French, Italian, Performance with Nadau & Peiraguda Occitan,[69][70] Japanese and Korean.