Journal of Theoretical Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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journal homepage: www.elsevier.com/locate/yjtbi
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Tibor Gánti and Robert Rosen: Contrasting approaches
13 to the same problem
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Q1 Athel Cornish-Bowden n
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17 Unité de Bioénergétique et Ingénierie des Protéines, Institut de Microbiologie de la Méditerranée, Centre National de la Recherche Scientifique, Aix-Marseille
Université, 31 chemin Joseph-Aiguier, 13402 Marseille Cedex 20, France
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21 H I G H L I G H T S
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Tibor Gánti's chemoton and Robert Rosen's (M,R) systems are attempts to capture the essence of life.
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The chemoton is practical whereas (M; R) systems are highly abstract.
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Despite the apparent differences there are important points in common.
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28 art ic l e i nf o a b s t r a c t
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30 Article history: Of the various theories of life that appeared in the second half of the 20th century the chemoton of Tibor
31 Received 24 February 2015 Gánti and the (M,R)-systems of Robert Rosen are among the most important, of which the former is
32 Received in revised form rooted in chemical engineering and the latter is highly abstract. Despite apparent differences, in part due
22 April 2015
33 to very different ways of presenting them, these two approaches share some important characteristics:
Accepted 8 May 2015
34 both are “closed to efficient causation”, which means that they require nothing from their environment,
35 and in particular not catalysts, apart from “food”, or chemical species that allow for the production of
Keywords: energy. On the other hand Rosen insisted that a living organism cannot be regarded as a machine,
36 Chemoton whereas Gánti explicitly discussed its mechanical nature, and the enclosing boundary is explicitly
37 (MR)-systems
created by the system itself in the chemoton, but is (at best) simply implicit in (M,R)-systems.
38 Theories of life
& 2015 Published by Elsevier Ltd.
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42 69
43 1. Introduction Two of the people who did most to define the nature of life in
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44 the half century after Schrödinger (1944) saw it in very different
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45 ways. In the first quotation above Gánti emphasized the functional
In the second half of the twentieth century, people have 72
46 nature of life: a living organism must do something, and its
forgotten that programme control must control a functional 73
47 enzymes need to be regulated to allow that. Rosen, in sharp
system and enzymatic regulation must also regulate a func- 74
48 contrast, wanted to eliminate the messy details of how function
tional system. What this functional system is has not been 75
49 is achieved by keeping only the underlying organization.
studied in the second half of the twentieth century. However, 76
50 Is there a middle ground between these two positions? I think so,
the secret of life is hidden in these systems—in their organiza- 77
51 but finding it is not made easier by the tendency of the different
tion and functioning. Chemoton theory is concerned primarily 78
52 schools to talk past one another. Referring to the early history of
with this machinery aspect (Gánti, 2003). 79
53 epigenetic marks, Morange (2013) has written as follows:
80
54 81
55 What is most striking … is the total absence of communication
I can epitomize a reductionist approach to organization in 82
56 between researchers working on histone modification and
general, and to life in particular, as follows: throw away the 83
57 those studying DNA methylation. The two groups of research-
organization and keep the underlying matter. The relational 84
58 ers were completely separate. This is redolent of the well-
alternative to this says the exact opposite, namely: throw away 85
59 known opposition between molecular biologists, more inter-
the matter and keep the underlying organization (Rosen, 1991). 86
60 ested by DNA, and biochemists studying proteins.
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61 88
62 n
Tel.: þ 33 491 16 41 38. It is even more redolent of the lack of cross-fertilization
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63 E-mail address: acornish@imm.cnrs.fr between the different theories of life that emerged in the 70 years
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64 http://dx.doi.org/10.1016/j.jtbi.2015.05.015 91
65 0022-5193/& 2015 Published by Elsevier Ltd. 92
66

Please cite this article as: Cornish-Bowden, A., Tibor Gánti and Robert Rosen: Contrasting approaches to the same problem. J. Theor.
Biol. (2015), http://dx.doi.org/10.1016/j.jtbi.2015.05.015i
 2 A. Cornish-Bowden / Journal of Theoretical Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 since Schrödinger's seminal book (Schrödinger, 1944): the chemo- 67

2 ton (Gánti, 2003), the hypercycle (Eigen and Schuster, 1977), 68
3 autocatalytic sets (Kauffman, 1986), (M; R) systems (Rosen, 1991), 69
4 autopoiesis (Maturana and Varela, 1980) and others. These can 70
5 appear more different from one another than they really are 71
6 (Letelier et al., 2011), as the various authors almost never men- 72
7 tioned one another's work, let alone discussed it, and made no 73
8 attempt to adopt a common language for presenting the same or 74
9 similar concepts. Several of them were probably barely aware of 75
10 one another's existence, as they came from very different intellec- 76
11 tual backgrounds: chemical engineering (Gánti, 2003), fast- 77
12 reaction kinetics (Eigen and Schuster, 1977), genetic networks 78
13 (Kauffman, 1986), mathematical biology (Rosen, 1991) and neuro- 79
14 physiology (Maturana and Varela, 1980). Rosen certainly knew of 80
15 the existence of autopoiesis, and Matrura and Varela knew of 81
16 (M; R) systems, but on the only occasion that Rosen and Varela are 82
17 known to have met one another they found no point of contact. 83
18 Nonetheless, despite the different backgrounds of the pioneers, Fig. 1. The chemoton. All arrows represent chemical reactions, reversible in the 84
19 the subject cannot advance if no attempt is made to bring the case of double-headed arrows, irreversible otherwise. The diagram is based on 85
20 different threads together, but a recent book (Louie, 2009) of Fig. 1.1 of Gánti (2003) redrawn to represent reactions involving multiple substrates 86
in a more conventional way. The internal system shown against a grey background
21 nearly 400 pages seeking to extend Rosen's work made no 87
is separated from the external environment by a boundary formed from monomer
22 mention at all of Gánti, Eigen, Schuster, Kauffman, Maturana or units T that are fabricated by the system itself. 88
23 Varela. It is thus hard to see this book as other than a paean of 89
24 praise to Rosen, with no attempt to broaden the subject or to 90
25 expand it in a useful way. In a special journal issue devoted to a 91
26 discussion of it, one (Gutiérrez et al., 2011) of the five articles that Bowden et al., 2004). The metabolic sub-system 92
27 it contained referred to all of these other authors apart from Eigen A1 ⇄A2 ⇄A3 ⇄A4 ⇄A5 ⇄A1 93
28 and Schuster, another (Kineman, 2011) mentioned Maturana and 94
29 Varela, and the other three (Prideaux, 2011; Mikulecky, 2011; is an autocatalytic cycle of chemical reactions that obtains chemi- 95
30 Louie, 2011) mentioned none of them. cal energy by converting food X into waste Y, and produces three 96
31 Tibor Gánti and Robert Rosen, in particular, appear to have other products: V0 , T0 and A1, this last being responsible for the 97
32 been diametrically opposed in their approaches to how life should autocatalytic character of the cycle. V0 enters the information sub- 98
33 to be defined. Gánti was a chemical engineer, and was certainly system, which a product R, which reacts with the metabolic 99
34 the most down-to-earth and practical of all of the authors referred product T0 to produce T, the monomer unit of the enclosing 100
35 to, more interested in getting things to work than in abstract membrane that constitutes the third sub-system, structural closure. 101
36 theoretical arguments. Rosen, on the other hand, was the most In the simplest form of the model the membrane grows without 102
37 remote from everyday reality, interested in creating a formalism requiring a catalyst, as it is assumed that T inserts itself sponta- 103
38 that would capture the nature of life without worrying too much neously. This is of course a reasonable assumption if T is a lipid, as 104
39 (or at all) about details, often choosing to express his ideas in lipids generated in an aqueous environment do indeed insert 105
40 terms of more difficult mathematics than they required. In this themselves spontaneously into suitable lipid membranes. 106
41 paper I shall discuss the similarities and differences between their It would be wrong to think of Gánti as wholly uninterested in 107
42 two approaches. abstract theory. In particular, Section 3.5 (pp. 74–80) of his book 108
43 The test of an engineering device is, of course whether it works (Gánti, 2003) is a theoretical discussion of the criteria of life. There 109
44 reliably as designed, and, given that no working chemoton (or he asserts that a living system must inherently be an individual 110
45 other form of synthetic life) has yet been constructed one could unit (structural closure), that it must perform metabolism, that it 111
46 argue on this criterion that the chemoton is not yet a success. must be inherently stable (organizational invariance) and that it 112
47 However, that would be unjust, as everyone agrees that the must have a subsystem carrying information. The second and third 113
48 creation of a self-organizing system is an extremely difficult of these criteria correspond to similar ideas in Rosen's work. 114
49 problem, and if a theory built on Gánti's foundation eventually 115
50 succeeds it will be due in large measure to his work. We cannot 2.2. Metabolism-replacement systems 116
51 judge Rosen on the same basis, as he never claimed to present a 117
52 detailed description of a working system. However, if we reach a Rosen's theory of life needs much more explanation than 118
53 much higher level of understanding of life than we have at present Gánti's, because he never considered it necessary to present it in 119
54 we shall be able to judge if his ideas have been useful for a way that ordinary biologists would find intelligible. The funda- 120
55 getting there. mental concept is the metabolism-replacement system1 or 121
56 (M; R)-system. It can be summed up in Rosen's phrase that 122
57 organisms are closed to efficient causation: this is a reference to 123
58 2. Essential features of the models of life considered Aristotle's definition of four types of cause, the material, formal, 124
59 efficient and final causes. Of these we need to be concerned here 125
60 2.1. The chemoton with the material and efficient causes. The material cause refers to 126
61 the chemical transformations: in the metabolic formation of 127
62 The essential features of the chemoton are shown in Fig. 1. It glucose 6-phosphate, for example, the material causes are glucose 128
63 consists of three sub-systems, all of them essential for the whole. 129
64 Indeed, none of the theories of life, except perhaps autocatalytic 1
Rosen spoke of repair rather than replacement, but as this has no relationship
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65 sets (Kauffman, 1986), can be understood by regarding a self- with more usual ideas of repair in biological systems, such as DNA repair or the 131
66 organizing system just as a collection of components (Cornish- action of chaperones, it is liable to be confusing. 132

Please cite this article as: Cornish-Bowden, A., Tibor Gánti and Robert Rosen: Contrasting approaches to the same problem. J. Theor.
Biol. (2015), http://dx.doi.org/10.1016/j.jtbi.2015.05.015i
 A. Cornish-Bowden / Journal of Theoretical Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 3

1 and ATP. The efficient cause—the only one that really corresponds each catalytic cycle is expanded into three uncatalysed chemical 67
2 to the modern idea of a cause—is the catalyst, in this case the reactions: this full form is needed for computer simulation, 68
3 enzyme hexokinase. Thus Rosen's statement means that all of the because the catalysts are metabolites as well as catalysts, and so 69
4 catalysts, or efficient causes, needed by a living organism are the reactions cannot be represented by conventional kinetic 70
5 produced by the organism itself. It is important to be clear here equations for catalysed reactions (such as the Michaelis–Menten 71
6 that there is no idea of closure to material causation, which would equation). However, it makes the whole scheme appear much 72
7 contradict the important principle that organisms must obey the more complicated than it is: imagine how complicated even a 73
8 laws of thermodynamics, i.e. that organisms must be open systems relatively simple metabolic pathway, such as the urea cycle, would 74
9 in the thermodynamic sense. look if all of the intermediates in all of the four enzyme-catalysed 75
10 Rosen (1971) himself never described an (M; R)-system in reactions needed to be shown. It is important to emphasize that 76
11 chemically clear terms, and, except in one paper, he did not Fig. 2a and b do not represent two different models: they both 77
12 express his ideas with ordinary kinetic equations. A recent book represent the same model, but drawn with different degrees of 78
13 by one of his students (Louie, 2009) tries to develop his vision in detail. 79
14 terms no less abstract and mathematical. However, his ideas can 80
15 never be brought to a wider public if they are not expressed in 2.3. Similarities 81
16 more concrete and familiar terms, though that incurs the risk of 82
17 deviating from his intentions and changing his meaning. Our own At first sight Figs. 1 and 2 seem to be very different from one 83
18 attempt to do this has been refined since we first proposed it another. Nonetheless, they have major features in common, and 84
19 (Letelier et al., 2006), to take account of two objections: we both of them are closed to efficient causation, in Rosen's terminol- 85
20 originally paid no attention to structural closure (no enclosing ogy, as they require nothing from their environment apart from 86
21 membrane), and we made an artificial assumption that metabolic chemical molecules assumed to be available in unlimited amounts, 87
22 products with catalytic properties would decompose sponta- “food” in the case of Fig. 1, which presumably consists of more 88
23 neously, whereas otherwise similar products would not. The than one chemical species, and S, T and U in the case of Fig. 2. In 89
24 version shown in Fig. 2 (Piedrafita et al., 2012) is more complete, particular, the cycles in Fig. 1 are autocatalytic, as the starting 90
25 therefore. The external food metabolites S, T and U are assumed to materials A1 and pVn are regenerated by the cycles that consume 91
26 be available from the external environment and to be maintained them. Although no catalyst is shown for the reaction R þT-T we 92
27 at sufficient concentrations by mechanisms independent of the can suppose that this reaction arises spontaneously from the 93
28 (M; R)-system itself, diffusing passively into the internal compart- properties of the two components. Likewise, in Fig. 2 the three 94
29 ment. In recent simulations (Piedrafita et al., 2012) the rate intertwined cycles are all autocatalytic, and require no additional 95
30 constants for the two directions were assumed to be equal, so catalysts. In both cases the thermodynamic driving force comes 96
31 that the internal concentrations of the different molecules would from the conversion of food into waste, and in both cases the food 97
32 be the same as the external concentrations. This would not and waste molecules are assumed to diffuse passively into and out 98
33 necessarily be true in a more complex version of the model, as of the system through the enclosing membrane. 99
34 the internal metabolism could maintain the compartment at a 100
35 different pH, for example, and that could affect the rate constants. 2.4. Differences 101
36 In Fig. 2a each of the three cycles is shown as a single catalysed 102
37 reaction, the chemical details of the process being left implicit, as There are also some important differences between Figs. 1 103
38 in the usual way metabolic maps are drawn. However, in Fig. 2b and 2. Most notably, in Fig. 1 the membrane enclosing the 104
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63 Fig. 2. A model of an ðM; RÞ system, rearranged and redrawn from Piedrafita et al. (2012). (a) The three catalytic cycles are shown in the conventional way for metabolic 129
reactions, without showing the mechanisms of catalysis explicitly. STU catalyses metabolism, S þ T-ST, as ST is the metabolic end-product; SU catalyses the replacement of
64 the catalyst STU, ST þ U-STU; and STU catalyses a second reaction, S þ U-SU, allowing replacement of the replacement catalyst, thus ensuring organizational invariance.
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65 (b) For computer simulation of the model the mechanisms of catalysis need to be defined explicitly, and here each catalysed reaction is shown as a cycle of three chemical 131
66 reactions. This gives the impression that the model is more complicated than it really is. 132

Please cite this article as: Cornish-Bowden, A., Tibor Gánti and Robert Rosen: Contrasting approaches to the same problem. J. Theor.
Biol. (2015), http://dx.doi.org/10.1016/j.jtbi.2015.05.015i
 4 A. Cornish-Bowden / Journal of Theoretical Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 system is explicitly shown as a product of the system, which other physical barrier.3 This is explicitly recognized in the chemo- 67
2 produces the building blocks T that insert themselves into the ton, and also in autopoiesis (Maturana and Varela, 1980), but is at 68
3 membrane. In Fig. 2, on the other hand, the boundary is shown best only implied in (M; R)-systems as presented by Rosen (1991) 69
4 as existing independently of the (M; R)-system. Indeed, Rosen or autocatalytic sets (Kauffman, 1986). As noted already, this 70
5 does not appear to have mentioned the boundary at all, and it omission is repaired in Fig. 2 by drawing a boundary around 71
6 was missing from the first version of Fig. 2 (Letelier et al., 2006). “the system” to separate it from its environment, but the origin of 72
7 Ignoring it altogether is clearly not acceptable for a realistic this boundary is left undefined. However, all the organisms we 73
8 model of an organism; whether treating it as independent of the know today construct their own containers (even if some, like 74
9 system is acceptable is a point that will be discussed below. hermit crabs, also use containers that they find), so it is necessary 75
10 Another aspect that Fig. 2 lacks is anything that could be called to consider the plausibility of “organisms” that are separated from 76
11 an information-processing system. This is clearly necessary for one another only by pre-existing containers. Martin and Russell 77
12 reproduction and evolution, but it is arguable whether these (2003) have argued that life originated in mineral cavities close to 78
13 should be considered as part of the definition of life. Many ocean vents, and if each such cavity contained just one “organism” 79
14 biologists have accepted Joyce's definition that “Life is a self- individuals living sufficiently close to one another could compete 80
15 sustained chemical system capable of undergoing Darwinian for the same nutrients, and hence compete with one another in an 81
16 evolution” (Joyce et al., 1994), which has been adopted by NASA, evolutionary sense. 82
17 but we (Letelier et al., 2011) regard evolution (and reproduction) A different possibility is that the compartments that separate 83
18 as secondary to the fundamental requirement that a living different individuals could have been self-assembling lipid vesicles 84
19 organism be capable of maintaining its identity and organiza- (Chen and Walde, 2010; Ruiz-Mirazo et al., 2011): unlike the mineral 85
20 tion—or “staying alive”—in the face of changes in its environ- compartments these would need the building blocks to be produced 86
21 ment. This is also consistent with Gánti's view: he regarded by the proto-metabolism, but on the other hand they make it easier 87
22 evolution and reproduction as potential rather than absolute to imagine multiple individuals occupying the same space. 88
23 criteria for life, as they were necessary only for a living world, 89
24 not for living organism for its own sake. 2.6. Other theories of life 90
25 Fig. 1 does contain a cycle designated Information, though 91
26 exactly how this stores and processes information is not very Although in this paper I am primarily concerned with Gánti and 92
27 clear, either in the version shown here or in Gánti's original. Rosen's views of life we should also spend a moment on other 93
28 However, this shows only the simplest type of chemoton with just current theories. Autopoiesis (Maturana and Varela, 1980) is 94
29 one informational monomer V0 , and in his text Gánti discusses perhaps the most similar to (M; R)-systems, especially if we 95
30 various modes of information coding. recognize that the latter need an enclosing container if they are 96
31 From the point of view of (M; R)-systems the most important to describe life as it exists now, and if we fill the gap in autopoiesis 97
32 point lacking from Fig. 1 is a set of specific catalysts for the made by the absence of specific catalysts. Autocatalytic sets 98
33 different steps (Hofmeyr et al., 2007). The cycle (Kauffman, 1986) are the most different, because all of the others 99
34 incorporate, at least implicitly, the idea that a minimal self- 100
A1 ⇄A2 ⇄A3 ⇄A4 ⇄A5 ⇄A1
35 organizing system must be small, i.e. that it must have a minimum 101
36 is autocatalytic, but as drawn it consists of five distinct reactions of components. Kauffman, in contrast, made no such condition, 102
37 with different properties, and in the absence of individual catalysts but instead imagined self-organization as a property that might 103
38 it is not clear why these reactions should take place, and if they do arise spontaneously in a system with enough weakly interacting 104
39 take place it is not clear why there should not also be parasitic components. As he assumed (reasonably) that the probability that 105
40 reactions that compromise the integrity of the whole system.2 any given component might catalyse a particular condensation 106
41 However, this cycle is not the only process in Fig. 1, and in all there reaction would be very small, this inevitably leads to the conclu- 107
42 are nine distinct reactions, or 11 if we include the diffusion of food sion that the total number of components must be very large (at 108
43 and waste. By contrast, in Fig. 2b the three chemical reactions are least millions) in order to have certainty that every reaction will 109
44 explicitly catalysed by just two products of the system itself. It may have a catalyst. 110
45 be unlikely that two molecules produced by random chemistry These are not the only theories of life that exist today, but I 111
46 would just happen to give them the capacity to catalyse exactly shall not discuss the others, which include the hypercycle of Eigen 112
47 three reactions and no others, but a vast amount of time was and Schuster (1977), “symbiosis”4 as understood by King (1977a,b, 113
48 available before the necessary unlikely event had to occur, and in 1982), RAF sets, a development from autocatalytic sets that is being 114
49 any case requiring two unlikely molecules to appear is far less extensively studied at present (Hordijk et al., 2012; Steel et al., 115
50 unlikely than requiring a whole series of highly specific reactions 2013), and Sysers, or systems of self-reproduction (White, 1980; 116
51 to appear. Ratner and Shamin, 1980; Feistel, 1983). We have discussed these 117
52 else where (Letelier et al., 2011). 118
53 2.5. Independently existing compartments 119
54 120
55 3. Discussion 121
Regardless of whether one agrees that the only essential
56 criterion of life is the capacity for staying alive, it is clear that 122
57 It would be absurd to claim that in this short paper I have 123
competition between individuals, and hence reproduction and
58 integrated Gánti's and Rosen's ideas into a coherent whole, or that 124
evolution, is only possible if there are distinct individuals with
59 definite identities. This in turn requires spatial closure, so that 125
60 each individual is separated from its neighbours by a membrane or 3
Vasas et al. (2012), quoting Gánti (2003) and Wächtershäuser (1988), 126
61 Wächtershäuser, 1992, say that “if distinct, organizational different, alternative 127
62 autocatalytic networks can exist in the same environment then they could compete 128
2
63 The notes included in Gánti (2003) recognize the existence of this problem. with each other and the ‘fittest’ would eventually prevail.” However, although that 129
For example, in note G55 Griesemer wrote that “producing all the required raw could be a realistic scenario for the dawn of life it seems hardly conceivable for
64 materials as outputs of the system without harmful side reactions and without the life today.
130
65 use of highly specific is a problem that goes far beyond the connectability of the 4
This is a misnomer, as it has nothing to do with symbiosis as understood in 131
66 three subsystems”, and in note S38 Szathmáry made a similar point. ecology. 132

Please cite this article as: Cornish-Bowden, A., Tibor Gánti and Robert Rosen: Contrasting approaches to the same problem. J. Theor.
Biol. (2015), http://dx.doi.org/10.1016/j.jtbi.2015.05.015i
 A. Cornish-Bowden / Journal of Theoretical Biology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 5

1 I have explored all the differences between them. Critics of the Joyce, G.F., 1994. Foreword. In: Deamer, D.W., Fleischacker, G.R. (Eds.), Origins of 49
2 chemoton, such as Hofmeyr et al. (2007), will feel that I have been Life. Jones and Bartlett, Boston, pp. xi–xii. 50
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3 too kind to Gánti, whereas some of the other contributors to this //dx.doi.org/10.1016/ S0022-5193(86)80047-9. 51
4 issue of the Journal of Theoretical Biology will feel that I have not Kineman, J.J., 2011. Relational science: a synthesis. Axiomathes 21, 393–437. http: 52
5 been critical enough of Rosen's abstractions. However, I hope that I //dx.doi.org/10.1007/s10516-010-9154-z. 53
King, G.A.M., 1977a. Symbiosis and the evolution of prokaryotes. BioSystems 9,
6 have pointed the direction that all of the research in this area 35–42. http://dx.doi.org/10.1016/0303-2647(77)90030-2.
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7 should take, that instead of all of the different participants King, G.A.M., 1977b. Symbiosis and the origin of life. Orig. Life Evol. Biosphere 8, 55
8 remaining in separate and unrelated playing fields as Morange 39–53. 56
King, G.A.M., 1982. Recycling, reproduction, and life's origins. BioSystems 15, 89–97.
9 (2013) lamented for another one at the beginning of the paper, http://dx.doi.org/10.1016/0303-2647(82)90022-3.
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10 there needs to be a real effort to work towards a synthesis, not Letelier, J.-C., Cárdenas, M.L., Cornish-Bowden, A., 2011. From L'Homme machine to 58
11 only of the chemoton and (M; R)-systems, but also covering metabolic closure: steps towards understanding life. J. Theor. Biol. 286, 59
100–113. http://dx.doi.org/10.1016/j.jtbi.2011.06.033.
12 autopoiesis, hypercycles, autocatalyic sets, and probably also 60
Letelier, J.-C., Soto-Andrade, J., Guíñez Abarzua, F., Cornish-Bowden, A., Cárdenas,
13 “symbiosis” as understood by King (1977a,b, 1982) and extended M.L., 2006. Organizational invariance and metabolic closure: analysis in terms 61
14 by Fernando et al. (2005), Sysers (White, 1980; Ratner and Shamin, of (M,R) systems. J. Theor. Biol. 238, 949–961. http://dx.doi.org/10.1016/j. 62
15 1980; Feistel, 1983), and RAF sets (Hordijk et al., 2012; Steel et al., jtbi.2005.07.007. 63
Louie, A.H., 2009. More Than Life Itself. Ontos Verlag, Frankfurt.
16 2013). We have tried to make a start on this (Letelier et al., 2011) Louie, A.H., 2011. Essays on more than life itself. Axiomathes 21, 473–489. http://dx. 64
17 but there is a long road ahead. doi.org/10.1007/s10516-010-9153-0. 65
18 Martin, W., Russell, M.J., 2003. On the origins of cells: a hypothesis for the 66
evolutionary transitions from abiotic geochemistry to chemoautotrophic pro-
19 karyotes, and from prokaryotes to nucleated cells. Philos. Trans. R. Soc. B 358, 67
20 Acknowledgements 59–83. http://dx.doi.org/10.1098/rstb.2002.1183. 68
21 Maturana, H., Varela, F., 1980. Autopoiesis and Cognition: The Realisation of the 69
Living. D. Reidel Publishing Company, Dordrecht.
22 This work was supported by the Centre National de la 70
Mikulecky, D.C., 2011. Even more than life itself: beyond complexity. Axiomathes
23 Recherche Scientifique and by Aix-Marseille Université. In addition 21, 455–471. http://dx.doi.org/10.1007/s10516-010-9119-7. 71
24 I thank Eörs Szathmáry for organizing the meeting in Badacsony Morange, M., 2013. What history tells us XXXII. The long and tortuous history of 72
that gave rise to the various papers in this issue. epigenetic marks. J. Biosci. 38, 451–454. http://dx.doi.org/10.1007/s12038-013-
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Please cite this article as: Cornish-Bowden, A., Tibor Gánti and Robert Rosen: Contrasting approaches to the same problem. J. Theor.
Biol. (2015), http://dx.doi.org/10.1016/j.jtbi.2015.05.015i