Review
DOI: 10.1002/ijch.201500073
Physical Organic Chemistry and the Origin of Life
Problem: A Personal Perspective
Addy Pross*[a, b]
Abstract: The origin of life (OOL) question might be consid-
ered physical organic chemistry’s ultimate challenge, yet de-
spite continuing efforts over close to a century, the problem
remains unresolved. In this personal perspective, I discuss
some aspects of that challenge, and argue that notwith-
standing the general perception that physical organic
chemistry is a research area in decline, the discipline was,
Keywords: Darwinism · history of science · origin of life · thermodynamics
1 Introduction
Formally, one might think of physical organic chemistry
(POC) as that scientific discipline, which applies physical
techniques and principles to problems of organic struc-
ture and reactivity. But that rather dry description belies
a more subtle, more ambitious, less easily defined charac-
ter: a methodology for exploring the organic chemistry
landscape – seeking broad patterns of behavior with
regard to both structure and reactivity characteristics.
Though the field was formally established after Louis
HammettÏs landmark text of the same title,[1] the POC
way of thinking was utilized well before then, strikingly
by VanÏt Hoff and Le Bel in 1874, when the basic struc-
ture of tetravalent carbon was unknown. Was tetravalent
carbon planar, or tetrahedral? Without some physical
means to “see” the molecule, how was one to know? The
physical organic approach to a solution: count isomers.
The fact that CH2Cl2 consisted of one isomeric form, not
two, the fact that carbon bonded to four different groups
could exist in two distinct isomeric forms, not three, dif-
fering just in the direction of their optical rotation, solved
the problem well before physical techniques were avail-
able to confirm that logical deduction. That kind of intel-
lectual versatility has been the mainstay of physical or-
ganic chemical thinking ever since, contributing to the es-
tablishment of a coherent structural and mechanistic
framework for the subject.
Given the scope and range of physical organic chemis-
try methodology, it would seem a foregone conclusion
that the origin of life (OOL) problem, one of the most
tantalizing scientific questions ever, and physical organic
chemistry would make for a happy marriage. After all,
the building blocks of life are organic, and life processes
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
and continues to be, the most relevant one for tackling the
OOL problem. Systems chemistry, a newly emergent branch
of physical organic chemistry, which, inter alia, deals with
replicating chemical systems and the networks they estab-
lish, reveals that physical organic chemistry, though in differ-
ent guise, is alive and kicking. The broad direction ahead
seems illuminated.
are largely chemical in nature. So what methodology
could be right for considering this vital question – how in-
animate matter self-assembled into the dynamic, far from
equilibrium, energy consuming, highly organized, material
entity that is a living cell – if not that of physical organic
chemistry? But, strangely, the voice of POC in this ongo-
ing debate became increasingly mute. A general percep-
tion seemed to have set in that the OOL problem was
beyond the reach of physical organic chemistry, that
other more “sophisticated” approaches must be sought.
But, as IÏll discuss, to date none of these alternative ap-
proaches have bagged the Holy Grail, and we continue to
await the heralded breakthrough.
Applying POC thinking to the OOL problem can be
traced back to one of the fathers of theoretical biology,
Alfred Lotka. Almost a century ago, he sought to place
Darwinian theory within a broader physicochemical
framework. And, indeed, his early attempt to reformulate
natural selection in physical terms, as articulated in one
of his two classic 1922 PNAS papers,[2] was years ahead of
its time and appeared to point the way forward. But a cen-
[a] A. Pross
Department of Chemistry
Ben Gurion University of the Negev
Beer Sheva, 84105 (Israel)
e-mail: pross@bgu.ac.il
ap148@nyu.edu
[b] A. Pross
NYU Shanghai
1555 Century Avenue
Pudong New Area
Shanghai 200122 (China)
83
Review
tury has passed, and while some progress has been made,
particularly through the development of nonequilibrium
thermodynamics,[3] the OOL question remains unre-
solved. The two grand theories of the 19th century – Dar-
winian natural selection and the second law of thermody-
namics – remain the odd couple, awkwardly out of step
with one another. The former unified biology and ex-
plains its irrepressible direction, seemingly towards in-
creasingly complex, dynamic, energy gathering, far-from-
equilibrium systems; the latter downhill, towards equilib-
rium and uniformity – towards what the physicists call
heat death. That anomalous situation has troubled biolo-
gists and physicists alike. But as Woese and Goldenfeld
recently pointed out, understanding biologyÏs essence en-
tails understanding how the remarkable transformation
from inanimate to animate came about. In their words,
“biology is a study, not in being, but in becoming”.[4]
Indeed, in an almost messianic cry for redemption, Woese
claimed that biology of the 20th century, with its current
focus on the genome and associated molecular mecha-
nisms, had lost its way and needed to be rediscovered,
just like physics at the turn of the 20th century.[5] We have
here a shrill wake-up call from one of the 20th centuryÏs
leading biologists, though one that seems to be studiously
ignored.
The POC-OOL story I present is very much a personal
perspective. POC, as applied to traditional organic prob-
lems, was my scientific field for some three decades
before the siren call of biology jolted me out of my chem-
ical tranquility. The realization that initially there was no
biology, that some 3.5 to 4 billion years ago chemistry
became biology, that evolution must have started with
a chemical system, and therefore, that biology must ulti-
mately be just a very special kind of chemistry, struck me
like a thunderbolt. To me, a conceptual framework based
on physics and chemistry was the way to proceed, and
that realization has been my focus for the past 15 years.
My goal: based on years of applying POC methodology
to chemical problems, to attempt to apply that methodol-
ogy to WoeseÏs “becoming” question, to continue on
Addy Pross received a PhD in organic
chemistry from Sydney University in
1970 and took up a lectureship in
Chemistry at Ben Gurion University of
the Negev in 1973, where he is now
Professor Emeritus. He currently holds
a visiting professorship at NYU Shang-
hai, China. His research interests are in
theoretical organic chemistry and
chemical reactivity with recent empha-
sis on systems chemistry and the
origin of life. He has authored two
books: Theoretical and Physical Princi-
ples of Organic Reactivity, Wiley, 1995, and What is Life: How Chemis-
try Becomes Biology, Oxford University Press, 2012.
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
from where Lotka took leave, to work towards a physico-
chemical framework able to accommodate both chemical
and biological systems, one that is hopefully able to inte-
grate DarwinÏs biological theory of evolution and the
ubiquitous second law. Happily, a newly emergent area of
chemistry, termed systems chemistry, established and
named less than a decade ago by Gînter von Kiedrowski
and colleagues, is providing valuable experimental data
and is now beginning to fill the void.[6,7] In the following
discussion, I outline what I believe to be the central chal-
lenge, the achievements to date, and the way forward.
Some of the main ideas summarized here are discussed in
my recently published book.[8]
2 Discussion
2.1 Historic and Ahistoric Facets
In addressing the OOL problem, a necessary starting
point is the recognition that the problem has two facets –
historic and ahistoric.[8,9] The historic facet would seek to
reveal the pathway by which life on earth emerged;
namely, the central molecular building blocks from which
the process was initiated, key intermediate forms, and the
primal energy source that would have enabled the trans-
formation to simple life to take place. However, this goal
is not achievable, not even remotely. Simply, the historic
record of lifeÏs chemical emergence has long been lost (in
contrast to the historic pathway for biological evolution,
where paleontological and phylogenetic studies offer sub-
stantial historic information). But, of even more concern,
attempts to simulate the historic reaction conditions
thought to have existed at various sites on the prebiotic
earth, even if feasible, would not prove that life started
out that way, as such theories are not falsifiable. So while
the chemistry that could be discovered in this way would
be of interest, experiments of this kind cannot impact di-
rectly on the OOL question. In fact, the plethora of un-
falsifiable mechanistic speculation surrounding the OOL
question in the latter part of the last century may well
have contributed to the decline in the status of OOL re-
search as a legitimate scientific pursuit.
A momentÏs thought however suggests that the more
fundamental OOL question is the ahistoric one, namely,
why would any mixture of chemical materials lead to the
process of material complexification towards life? It is
the resolution of the ahistoric question that is the real
challenge. Rather than how did life emerge?, the more
pertinent question is why did life emerge?, or for those
uncomfortable with “why” questions, how could life have
emerged? If the ahistoric principles, necessarily independ-
ent of time and place, could be identified, then the histor-
ic path, though still interesting in its own right, would be
of secondary importance – presumably just one of many
feasible pathways. And, indeed, only when that process of
emergence is finally understood can we seriously hope to
www.ijc.wiley-vch.de 84
Review
duplicate the process – to attempt the synthesis of proto-
life, that ultimate synthetic challenge.
2.2 Darwinian Selection or the Second Law?
Before the question of process can be addressed, we need
to consider the possibility that lifeÏs emergence occurred
by chance, that in fact no process was involved at all. But
as Morowitz pointed out some time ago,[10] the likelihood
of a chance sequence of events leading to life can be
safely dismissed. The probability of the chance formation
of a bacterial cell from its components was estimated to
be of the order of 10¢100 000 000 000. That being the case,
there had to be a process, one able to overcome the effec-
tively zero probability of a chance series of events leading
to life.[11]
The two central theories which have been utilized, di-
rectly or indirectly, to explain the process underlying
OOL are well known – Darwinian natural selection and
the second law. But despite their profoundly important
place in scientific thought for over a century, both have
come up short. Consider first Darwinian selection, which
also forms the basis for the replication-first view of
OOL.[12] In his classic work on RNA in-vitro replication,
Sol Spiegelman discovered that biologyÏs sine qua non –
the sequence: replication-variation-selection-evolution –
can take place at the molecular level.[13] In other words,
the chemical equivalent of (biological) natural selection
already operates on molecules; natural selection is not re-
stricted to living organisms. The implication of that land-
mark experiment conducted almost 50 years ago is pro-
found: the roots of biological evolution lie in chemistry;
a connection between change in the chemical and biologi-
cal worlds had been discovered. Since SpiegelmanÏs dis-
covery many elegant molecular replication experiments
have been carried out, and SpiegelmanÏs early finding
that a process akin to Darwinian selection operates at the
chemical level has been reaffirmed.[14] Thus according to
this Darwinian perspective, once some replicating entity
(or replicating molecular system) emerges, the evolution-
ary process, based on natural selection, begins to operate,
leading ultimately to simple life.
Yes, but how? Despite that appealing Darwinian inter-
pretation, a number of difficulties arise. In the first in-
stance, how were the energy requirements of replication
accommodated? The driving force for all chemical pro-
cesses, OOL related or not, is thermodynamic, as ex-
pressed by the second law, so it is not clear how natural
selection was able to transform a relatively simple molec-
ular system into the staggering complexity of even the
simplest life form. How would selection at the molecular
level lead in a direction seemingly opposed to the ther-
modynamic directive – towards complexity and the main-
tenance of a far-from-equilibrium, metabolic state –
rather than downhill towards the “dead” equilibrium
state? After all, even kinetically directed processes must,
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
and do, lead toward thermodynamically more stable
products. For this and other reasons (associated with the
likely availability of lifeÏs essential abiotic building
blocks), the replication-first approach to the OOL prob-
lem continues to encounter opposition.
The second law, as the primary law governing the OOL
process, enjoys widespread support, but also has its diffi-
culties. According to this way of thinking, and based on
subsequent developments in nonequilibrium thermody-
namics, life is a thermodynamically induced phenomenon,
a so-called dissipative structure. Thus lifeÏs nonequilibri-
um character emerged to facilitate natureÏs drive towards
energy dissipation, an additional means of reaching ther-
modynamically stable states.[3] But here also there are
concerns. If living systems are simply nonequilibrium dis-
sipative structures and life is merely one of natureÏs fa-
vored ways of dissipating energy, then why did cells
evolve to minimize energy dissipation? Why is the pro-
cess of cell replication so exquisitely efficient in replica-
tion, but so miserly in dissipation?[15] Why, for example,
donÏt cells dissipate energy deliberately and expeditiously
when resources are plentiful? LifeÏs extraordinarily inno-
vative and versatile character could easily have come up
with a mechanism for that. But it didnÏt. Examination of
cell replication makes it evident that the cellÏs “agenda”
is to optimize replication, not energy dissipation. So life
processes are consistent with the second law, but not ex-
plained by the second law. A strict thermodynamic view
of evolution appears to have reversed cause and effect:
replication induces dissipation, not the other way around.
Indeed, Lotka, already almost a century ago, recognized
that thermodynamics is unable to tell us what will
happen, just what cannot happen; thermodynamics is only
part of the story.[2]
Two additional perspectives on the life phenomenon,
much in vogue in recent times, are complexity theory and
information theory, and given their fundamental nature,
one might dare hope they could offer insights into OOL.
After all, OOL is the process by which biocomplexity and
bioinformation were created. But despite the considera-
ble interest in these approaches, the OOL problem does
not appear to have benefited. Even though life could be
considered as the ultimate emergent complex system, any
underlying rules of complexity governing the emergence
and evolution of living things continue to remain ob-
scure.[16] And the claim that biological complexity has
more to do with those rules of complexity than with Dar-
winian principles[17] remains unproven.[16]
A similar conclusion is forthcoming regarding informa-
tion theory and OOL, as no direct connection between
the two has been proposed to date. In fact, a recently pro-
posed view that informational imperatives may be able to
transcend the laws of physics and chemistry[18] remains
unsubstantiated, and in the OOL context, merely serves
to muddy the waters. If life is but an information manage-
ment and control process, how does that manifest itself in
www.ijc.wiley-vch.de 85
Review
the early (chemical) phase of lifeÏs emergence? In sum-
mary, to the best of my understanding, no practical in-
sights into OOL have come about through complexity or
informational considerations, as, for example, in being
able to suggest possible strategies for synthesizing simple
protolife.
So given the above comments, how are we to proceed?
In my view, it is time for the OOL problem to return to
its natural home – physical organic chemistry. The OOL
problem is a physical/chemical problem and its solution
needs to be sought within the established rules of physics
and chemistry. In fact, this appears to be taking place, as
the recently emergent area of systems chemistry[6,7] re-
flects this way of thinking. Systems chemistry is physical
organic chemistry par excellence, just focusing more on
the relatively unknown chemistry of replicative sys-
tems.[19] In the classic physical organic chemical perspec-
tive, chemical process are seen as being governed by
a combination of kinetic and thermodynamic factors, and
there may be no need to forsake that fundamental and
proven approach when dealing with the OOL issue.
Indeed, it is precisely through a deeper understanding of
that kinetic-thermodynamic interplay in the context of
replicative systems where we suspect the solution to the
OOL problem may lie. In recent work, Robert Pascal and
I have pointed out that there are two mathematical en-
gines for change in the universe – one based on Boltz-
mannÏs probabilistic considerations, the other on Malthu-
sian exponential growth.[20] It is within the chemical world
of Malthusian exponential growth that the relative impor-
tance of kinetic and thermodynamic factors changes dra-
matically, and in fact, can invert. Thus the kinetic power
associated with replicative systems is able, under certain
circumstances, to subsume thermodynamics, leading to
the emergence of a qualitatively different kind of chemis-
try – biology. That kinetic-thermodynamic reversion is
readily understood through an extension of the stability
concept; specifically, through the characterization of an
alternative stability kind: dynamic kinetic stability
(DKS).
2.3 A Different Stability Kind: Dynamic Kinetic Stability
Dynamic kinetic stability, a particular kind of kinetic sta-
bility, is distinctly different to the (static) kinetic stability
that pervades chemical reactivity thinking.[8,11,21] In sim-
plest terms, DKS is the stability kind associated with enti-
ties able to self-replicate, but able to do so at an exponen-
tial growth rate, to enable a nonequilibrium steady-state
population of replicating entities to be maintained over
time – stability (in the sense of persistence) through self-
replication. And being in a nonequilibrium state, DK (dy-
namic kinetic) stable systems are inherently thermody-
namically unstable, as they depend on a continuing inflow
of energy to maintain that replicator steady-state. But to
the central point: once the existence of this other stability
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
kind is established, it leads directly to a different selection
rule to the one that normally operates in chemistry –
from DK less stable to DK more stable. The math gov-
erning the kinetics is explicit – competing exponential
replicators cannot coexist; better replicators drive poorer
ones into extinction.[22–24] The result – evolution. Howev-
er, based on the existence of two stability kinds, two evo-
lutionary processes for governing change in the universe
naturally follow – in the “regular” chemical world,
change is directed towards greater thermodynamic stabili-
ty; in the replicator world (once DK states have been ac-
cessed), change is directed towards greater DKS.
Importantly, recognition of the existence of this alter-
native stability kind enables the two seemingly distinct
phases within the replicative world – the emergence of
simple life from abiotic beginnings (abiogenesis), and the
biotic phase, so-called Darwinian evolution, to be unified
and understood as a single continuous physicochemical
process.[8,11,21d] That process is able to operate within the
entire world of persistent replicating systems, both chemi-
cal and biological, thereby offering a conceptual basis for
the replication-first view that rested (somewhat problem-
atically) on the (biological) idea of natural selection at
the molecular level. Thus the DKS formulation allows the
conceptual integration of biological evolution within
a more general physicochemical framework. A more rig-
orous physicochemical analysis of that process of emer-
gence, with particular emphasis on irreversibility and its
energy requirements, has recently been described by
Robert Pascal.[21e,g,h]
2.4 Unifying Darwinian Selection and the Second Law
While the formulation of another stability kind, DKS, is
helpful in unifying the OOL process and biological evolu-
tion, the question may be asked: why two stability kinds?
Could there be others? What is actually meant by the
“stability” term? I now offer some recent thoughts that
bear on these general questions. Central to those ideas is
the proposal of a logical principle of nature, the persis-
tence principle,[20] very much in tune with the physical or-
ganic way of thinking, and which may offer further in-
sights into the animate-inanimate connection.
Though we typically think of stability in energy terms,
the stability concept has another facet – a time facet, one
quite unrelated to energy. A system is considered stable if
it is able to persist over time, even if it is thermodynami-
cally unstable, and DKS exemplifies such a stability kind.
A biological population is stable in that persistence sense
since it can maintain a continuing presence over millions
of years, even though the individuals that comprise that
population have a limited life span and continually turn
over. But time stability and energy stability can be relat-
ed, as illustrated in the Venn diagram in Figure 1.
Inspection of the diagram leads to the surprising con-
clusion that the time facet is more general than the
www.ijc.wiley-vch.de 86
Review
Figure 1. Diagram illustrating the set of thermodynamically stable
systems as a subset of the more general set of persistent systems.
energy facet. A thermodynamically stable system is nec-
essarily persistent, but a persistent system does not have
to be thermodynamically stable, as the DK stability kind
demonstrates. But it is this connection between stability
in the replicative world and in the “regular” physico-
chemical world which allows the formulation of a general
principle governing persistence. Grand recently noted in-
sightfully that “things that persist, persist, things that
donÏt, donÏt”.[25] But that simple truism can be extended
and reformulated into a principle which describes change
in the world: systems will tend from less stable (persistent)
to more stable (persistent) forms, or, more concisely:
nature seeks persistent forms. Note the principle is logical-
ly derived, as the truism can also be expressed as: chang-
ing things will change, until they change into things that
donÏt.
Importantly, however, the persistence principle, by con-
sidering both thermodynamic stability and DKS in the
same “persistence” terms, offers a unifying framework for
the two stability kinds. Material change towards greater
persistence takes place in both worlds – “regular” and
replicative. It is just the physical/mathematical basis for
change that differs. Within the physiochemical world, the
driving force is dictated by the second law with its proba-
bilistic directive (towards increasing entropy), while in
the replicative world, change is governed by replicative
variation and the math of exponential growth. But two
distinct maths mean two distinct evolutionary processes,
each leading to its corresponding material form – living
and nonliving – each tending towards increasing persis-
tence. If these ideas prove fruitful, the value of the physi-
cal organic chemical way of thinking will again have
proven itself.
3 Concluding Remarks
The “what is life?” question continues to torment. Like
the blind men of Hindustan attempting to describe an ele-
phant, the different sciences “see” different life aspects
and reach strikingly different conclusions as to lifeÏs es-
sence. But, as the late and great Carl Woese pointed out,
life is more a process than a series of things, and there-
fore, to understand those “things”, we need first to under-
stand the process.[4] And that brings us right back to the
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
OOL problem: the key to understanding the process is to
understand its driving force, why it got started. Why
would abiotic material of any kind, in any combination,
under any feasible conditions, start out on the long chem-
ical journey towards that highly complex, far from equi-
librium, energy consuming, chemical assembly, that is
life? That question, as posed, is a physical organic
chemistry question, maybe the ultimate one.
While much remains to be discovered, I believe an out-
line of a resolution is beginning to materialize. Life is
a self-sustained, dynamic, nonequilibrium, extended repli-
cative chemical network, which was initiated by the
chance emergence of a simple, but persistent, replicative
chemical system. Replication is not a common chemical
reaction, but it does take place with the right materials
under the right conditions. Once such an entity was able
to emerge and access that nonequilibrium DK state, its
road to greater stability – replicative stability – com-
menced. How? Primarily through a process of complexifi-
cation, that is to say, network formation and its subse-
quent extension. Greater complexity for greater stability.
Indeed, complexity in the replicative world may be
thought of as the analog of entropy in the “regular”
world. Thus in its broadest sense, life can be understood
as a logically dictated process, a direct expression of the
persistence principle – from less persistent to more persis-
tent, but within the replicative world. Physicochemical
change, whether in the “regular” or the replicative
worlds, reflects the same basic truism: nature seeks persis-
tent forms.[20]
A final point regarding the relative kinetic powers op-
erating in the two worlds. Due to the awesome Malthusi-
an power of exponential growth, replicative persistence is
able to out-compete Boltzmann thermodynamic persis-
tence, and overwhelmingly so. ThatÏs why life has taken
over our planet, inhabiting almost every conceivable eco-
logical niche. The Malthusian power of exponential
growth overwhelms the Boltzmann asymptotic slide to-
wards equilibrium, engulfing all that stands in its way.
Thus the physics of life is explicit and unambiguous. The
uncertainty lies within chemistry, within that new area of
physical organic chemistry, systems chemistry.
The challenge ahead: to discover which chemical
groups are able to facilitate the replication process within
the general framework of nonequilibrium systems, to ex-
plore how energy sources can couple up with and sustain
such systems, and to explore their potential for network
formation and possible evolution. Recent work by van
Esch et al., demonstrating unusual chemically-fueled dy-
namic nonequilibrium self-assembly processes akin to cer-
tain biological ones, is pointing the way forward.[26] For
those ready to eulogize classical physical organic chemis-
try, the challenge posed by the OOL question is a gentle
reminder that, like Mark Twain, rumors of its demise are
premature. The ultimate physical organic chemistry ques-
tion is very much alive, and beckons.
www.ijc.wiley-vch.de 87
Review
Acknowledgements
I thank Robert Pascal for the productive collaboration
which contributed to the ideas expressed here and Leo
Radom for helpful comments on an earlier draft of the
manuscript. Thanks are also due to COST Actions
TD1308 and CM1304 for the exchanges they have facili-
tated.
References
[1] L. P. Hammett, Physical Organic Chemistry, McGraw-Hill,
New York, 1940.
[2] A. J. Lotka, Proc. Natl. Acad. Sci. U.S.A. 1922, 8, 151 – 154.
[3] G. Nicolis, I. Prigogine, Self-organization in nonequilibrium
system: From dissipative structures to order through fluctua-
tions, Wiley, New York, 1977.
[4] C. R. Woese, N. Goldenfeld, Microbiol. Mol. Biol. Rev.
2009, 73, 14 – 21.
[5] C. R. Woese, Microbiol. Mol. Biol. Rev. 2004, 68, 173 – 186.
[6] G. von Kiedrowski, S. Otto, P. Herdewijn, J. Syst. Chem.
2010, 1, 1.
[7] a) R. F. Ludlow, S. Otto, Chem. Soc. Rev. 2008, 37, 101 – 108;
b) J. J. P. Peyralans, S. Otto, Curr. Opin. Chem. Biol. 2009,
13, 705 – 713; c) E. Mattia, S. Otto, Nat. Nanotechnol. 2015,
10, 111 – 119.
[8] A. Pross, What is life? How chemistry becomes biology,
Oxford University Press, Oxford, 2012.
[9] M. Eigen, Steps towards Life: A Perspective on Evolution,
Oxford University Press, Oxford, 1996.
[10] H. J. Morowitz, Beginnings of cellular life: Metabolism reca-
pitulates biogenesis, Yale University Press, New Haven,
1992.
[11] R. Pascal, A. Pross, J. D. Sutherland, Open Biol. 2013, 3,
130156.
[12] A. Pross, Origins Life Evol. Biospheres 2004, 34, 307 – 321.
Isr. J. Chem. 2016, 56, 83 – 88 Ó 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[13] D. R. Mills, R. L. Peterson, S. Spiegelman, Proc. Natl. Acad.
Sci. U.S.A. 1967, 58, 217 – 224.
[14] For detailed reviews, see: a) K. Ruiz-Mirazo, C. Briones, A.
de la Escosura, Chem. Rev. 2014, 114, 285 – 366; b) G. F.
Joyce, Angew. Chem. Int. Ed. 2007, 46, 6420 – 6436.
[15] J. Monod, Chance and necessity, Vintage, New York, 1972,
pp. 19 – 20.
[16] S. Weinberg, New York Rev. Books, Oct. 24, 2002.
[17] S. Wolfram, A New Kind of Science, Wolfram Media, Cham-
paign IL, 2002.
[18] S. I. Walker, P. C. W. Davies, J. R. Soc. Interface 2013, 10,
20120869.
[19] Z. Dadon, N. Wagner, G. Ashkenasy, Angew. Chem. Int. Ed.
2008, 47, 6128 – 6136.
[20] a) R. Pascal, A. Pross, Chem. Commun. 2015, 5, 16160–
16165; b) R. Pascal, A. Pross, J. Syst. Chem. 2014, 5, 3.
[21] a) A. Pross, V. Khodorkovsky, J. Phys. Org. Chem. 2004, 17,
312 – 316; b) A. Pross, Pure Appl. Chem. 2005, 77, 1905 –
1921; c) A. Pross, Chem. Eur. J. 2009, 15, 8374 – 8381; d) A.
Pross, J. Syst. Chem. 2011, 2, 1; e) R. Pascal, J. Syst. Chem.
2012, 3, 3; f) A. Pross, R. Pascal, Open Biol. 2013, 3,
120190; g) R. Pascal, in Astrochemistry and Astrobiology:
Physical Chemistry in Action (Eds.: I. W. L Smith, C. S.
Cockell, S. Leach), Springer, Berlin, 2013, pp. 243 – 269;
h) R. Pascal, Isr. J. Chem. 2015, 55, 865 – 874.
[22] M. Eigen, P. Schuster, The hypercycle: A principle of natural
self-organization, Springer, Berlin, 1979.
[23] E. Szathm‚ry, I. Gladkih, J. Theor. Biol. 1989, 138, 55 – 58.
[24] S. Lifson, J. Mol. Evol. 1997, 44, 1 – 8.
[25] S. Grand, Creation: Life and how to make it, Harvard Uni-
versity Press, Cambridge MA, 2003.
[26] a) J. Boekhoven, W. E. Hendriksen, G. J. M. Koper, R. Eel-
kema, J. H. van Esch, Science 2015, 349, 1075 – 1079; b) D.
van der Zwaag, E. W. Meijer, Science 2015, 349, 1056 – 1057.
Received: October 12, 2015
Published online: November 6, 2015
www.ijc.wiley-vch.de 88