I _do_ JUMP to Conclusions, particularly a 77 page paper. I’ll give the name of it at the end: Conclusions All of the theories we have considered contain some useful features that need to be included in a definitive theory of life (Fig. 49), but all lack some that are important. In particular, none of them incorporate any mechanism of regulation, or any other mechanism to prevent a self-organizing system from growing until it forms a tar (Section 3.1.8). In extreme cases a real living organism may starve to death, or die for some other reason, but, apart from a cancer, which is not a self-organized system, it never forms a tar or otherwise disorganized state. We have not provided all the answers in this review, but we hope that we have pointed to the direction that future research needs to take in the hope of arriving at a definitive theory of life. There are various courses that future research may take: 1. Each individual researcher may a choose a preferred theory from the current ones and try to extend it. That is essentially what has happened until now, and we do not believe that it is the best way forward. 2. One may try to incorporate all the points in Fig. 49 into a single theory, after first identifying and eliminating any logical inconsistencies. The main points that we see are the following: (a) Construction of a membrane needs to be described explicitly, not just left for future development. (b) Thermodynamic requirements need to be satisfied explicitly. For a system at the origin of life it may be sufficient to suppose a supply of energy-rich nutrients, but a more long-term system certainly needs to harness gradients across boundaries. (c) It is not enough to have a cycle labelled “information cycle”: there must be a clear mechanism for collecting, storing and using the information. (d) Any living system must be closed to efficient causation: the catalysts (apart from metal ions) must be produced by the organism in such a way that infinite regress is avoided. (e) There must be regulation of the metabolism, so that organisms cannot grow indefinitely, and metabolites are produced only as needed. 3. One should identify if there are other essential characteristics not mentioned in Fig. 49 that need to be incorporated. We are not aware of essential characteristics apart from metabolic regulation that are missing from all of the current theories. 4. The really adventurous could start with a completely clean plate and develop a new theory that is not derived from any of the existing ones. Contrasting theories of life: Historical context, current theories. In search of an ideal theory Athel Cornish-Bowden María Luz Cárdenas 2019

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“tar”?

3.1.8. Controlled growth A supply of energy alone cannot account for a living organism (Schwartz, 2007; Benner, 2009; Benner et al., 2012). Without a means of regulating the consumption of energy, heating an organic sample never results in growth, but instead results in formation of asphalt, “gunk,” or tar. Living organisms do not normally produce anything resembling tar.84 Unfortunately, however, none of the authors of the theories we are discussing appear to have been aware of the problem of tar production,85 and the lack of a provision for controlled growth is a weak point in all of them.86 (M, R) systems take no account of growth at all: it is not clear how an (M, R) system could grow. The hypercycle does consider growth, but it is unclear what mechanisms prevent uncontrolled growth until the whole system becomes a tarry mess, and that is certainly what we should expect in autocatalytic sets, autopoiesis and the chemoton.

In addition to the authors of general theories of life that we have been considering, others who put most of their emphasis on energy management and thermodynamics, such as Russell et al. (2014), tend to ignore the problem of tar production:

“There is an advantage to be gained from examining the transition from geochemistry to biochemistry from the bottom up, that is, to “look under the hood” at life’s first free energy-converting nanoengines or “mechanocatalysts.” Such an approach encourages us to see life as one of the last in a vast hierarchical cascade of emergent, disequilibria-converting entropy-generating engines in the Universe.”

These points are important, but excessive emphasis on thermodynamics can be misleading: it is not enough to have the capacity to make molecules; it is also necessary to have organization, and regulation to maintain it.

Lack of awareness of the need for controlled growth suggests a lack of awareness of the principles of metabolic control and regulation. Most biochemists today have some knowledge of the mechanisms of regulation: feedback inhibition (Section 4.1.2), allosteric interactions (Monod et al., 1963), cooperativity (Monod et al., 1965; Koshland et al., 1966; Cornish-Bowden, 2014) and so forth, but very little of metabolic control, often thinking of it as the same thing as metabolic regulation (Section 4.1.1).

However, none of the originators of the main theories were biochemists, and seem to have known very little of either regulation or control. Before developing the theory of (M, R) systems, Rosen (1979, 1985) described organisms as anticipatory systems, and his description of how anticipation might be achieved included some rudimentary notions of metabolic regulation, but not enough to constitute an adequate account. For this reason, and the importance of tar production, it is essential to give an account here, as we shall do shortly (Section 4.1). First, however, we need to consider the last of the criteria listed in Table 5.