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A review of Addy Pross
'What is Life?'

How chemistry becomes biology
How biology becomes chemistry

by Gert Korthof   first published 6 Oct 2014

Addy Pross What is Life?
Addy Pross (2012, 2014)
What is Life? How chemistry becomes biology.
Oxford University Press
free download chapter 1
I used the ebook version. Paperback: 2016.


Seventy years after Erwin Schrödinger's famous and influential What is Life? (1944), theoretical chemist Addy Pross takes up the question again. According to Addy Pross "we still do not understand what life is, how it relates to the inanimate world, and how it emerged." (Prologue). This looks quite pessimistic. However, in the last chapter we read: "Thanks to systems chemistry, the origin of life problem, at least in its ahistorical sense, may be largely resolved" (Chapter 8). That is a strong claim. This review is an attempt to summarize the book and add some critical notes. The ebook version appeared to be very useful. It made it possible to search for words throughout the book, and as a side effect uncover some potential inconsistencies in his views.

Chapter 1: Living things are so Very Strange

In the first chapter Pross outlines 5 remarkable characteristics of life. His approach gives a fresh look at life. Living things are so very strange when compared to physical and chemical systems. These are the basis for the rest of his book. At this point in his story Pross has not yet defined life explicitly, but those five characteristics could be viewed as a working definition of life:
  1. Complexity of life is highly specific contrary to random complexity of non-living matter
  2. Life's purposeful character (teleonomy)
  3. Living systems are dynamic
  4. Life's far-from-equilibrium state
  5. Life's chiral nature
Maybe, cellularity is too unremarkable to be included in this list?

Chapter 2: The Quest for a Theory of Life

Pross asserts that we do not need a definition of life, as well as a theory of life. Attempting to formulate a definition of life is hopeless as long as we have no comprehensive theory of life (1). According to Pross, the attempts to define life have resulted in many incompatible or even contradictory definitions (2)

Chapter 3: Understanding 'Understanding'

Chapter 4: Stability and Instability

In this chapter Pross explains the laws that govern all chemical reactions. Until recently molecular replication in isolation, without all the cellular machinery to facilitate it, was unknown. In 1986 chemist Von Kiedrowski however was able to carry out the first molecular replication reaction without any enzyme present. This is: molecular self-replication, pure replicative chemistry (12). In this chapter Pross explains the crucial concept 'dynamic kinetic stability' (later abbreviated to: DKS and appears frequently in chapter 7 and 8). DKS is a kind of stability characteristic for life and not found in all other kind of stable systems (mountains, waterfalls). There are two kinds of chemistry: regular chemistry and 'replicative chemistry'. The world of replicative chemistry is governed by dynamic kinetic stability, which seemingly contradicts The Second Law of Thermodynamics. The replicating world is governed by the drive toward greater dynamic kinetic stability. This is an important and sometimes difficult theme (Entropy, free energy, Second Law, autocatalysis), but rather well explained in the book. Impossible to summarize here.

Chapter 5: The Knotty Origin of Life Problem

Pross makes a very important distinction: historical and ahistorical approaches to the origin of life:
  • The historical question is the how question: how did life emerge? Where on earth did life emerge? What chemical and physical conditions?
  • The ahistorical question is the why question: why would inanimate matter of any kind follow a pathway of complexification leading to simple forms of life? What is the driving force? In other words, the search for general laws.
How the two problems interrelate is illustrated with a nice analogy (boulder, see book!).
The historical question is is a very difficult problem, because there is hardly any solid evidence obtainable about the circumstances of the early Earth. Proposed solutions for the place of origin of life contradict each other dramatically: one is the hydrothermal vents on the ocean floor and another is clay surfaces. "Differences don't get much greater than that!" Pross warns the reader, that published hypotheses about the historical paths to life are often untestable, unfalsifiable. "No one is ever likely to prove you wrong!" (8).
"The ahistorical question is the more significant one scientifically, and also the inherently more tractable one, and the one that is less difficult to resolve". This is because the laws of physics and chemistry now are the same as 4 billions years ago. Nonetheless, the fact that two incompatible hypotheses exist, the replication-first (the RNA-world hypothesis), and the metabolism-first, shows that neither school is compelling, each having its inherent weakness. "Both scenarios for the origin of life have fundamental difficulties with the Second Law. We need to come up with a mechanism for the process of complexification toward a far-from-equilibrium system that does not contravene the Second Law."(3)

Chapter 6: Biology's Crisis of Identity

Monod defined teleonomy as the central problem of biology: how could purposeful systems have emerged in a purposeless universe? Darwinism did bring about a sense of unity within biology, but isolated itself from physics and chemistry! This chapter with the dramatic, pessimistic title Biology's Crisis of Identity was strongly influenced by Carl Woese (4).
Pross' three related questions
Fig. 5 (chapter 6) three interconnected problems

Pross examines different solutions to the three interconnected questions: What is Life? How did life emerge? How to make life? (see figure 5). It makes no sense to define life when one doesn't have a good theory of life. Further, if one has no good theory of what life is, it is impossible to make it. The Non-equilibrium Thermodynamics theory (Prigogine) and the mathematical solution (systems biology) of John Conway both failed to produce useful insights (5). In this chapter Pross quotes a 1975 article of Tibor Gánti (6)

Chapter 7: Biology is Chemistry

Fig. 6
Fig 6. Two-phase (chemical and biological) transformation of non-life
into complex life (chapter 7).

Traditionally, the origin and evolution of life has been subdivided in a chemical phase and in biological phase. According to Pross there is fundamentally only one process with two phases, a low and a high-complexity phase. Pross argues that the entire process can be described in chemical terms:

replication » mutation » complexification/simplification » selection » evolution

These Darwinian processes also operate in the chemical world (RNA-world for example). This establishes the 'complexity continuum'. Pross does not want to erase the distinction, but argues for continuity on a deeper level. Pross makes a step further: he redefines natural selection and fitness in chemical terms. In that way he shows the continuity of the two phases. Later he distinguishes between the physical-chemical world of The Second Law and the replicative world of living systems. Both worlds have their own kind of stability (see chapter 4). The first is governed by the Second Law of Thermodynamics and the second by the laws of replicative chemistry (replicating molecules). Pross vision could be described as: living systems do not contradict The Second Law, but outsmart it. Replicative systems use external energy. Just as a car without a motor and energy can only go downhill, a car with a motor and energy can go uphill. This does not contradict the Second Law of Thermodynamics, but outsmarts it!
In the end biology is a sub-branch of chemistry; biology is replicative chemistry. Biology is just an elaborate extension of replicative chemistry. See the subtitle of this review: 'How chemistry becomes biology' means how molecules become life. And 'How biology becomes chemistry' obviously points to Pross' view 'biology is replicative chemistry'.
Although Pross claims to reject the dichotomy replication-first/metabolism-fist, he clearly belongs to the replication-first school of the Origin of Life problem (7).

Chapter 8: What is Life?

For Pross "replication is the essence of life". This is not unexpected. It follows from his earlier views (replicative chemistry). A more elaborate definition is: 'life is a self-sustaining kinetically stable dynamic reaction network derived from the replication reaction',
Nice thing: Pross does not propose an arbitrary definition of life, but a theory of life that can be tested. Which facts exactly does a theory of life have to explain? In principle these are the five properties mentioned in chapter 1. This list looks somewhat different:
  1. life's complexity
  2. life's instability (far-from-equilibrium state ?)
  3. life's dynamic nature
  4. life's homochirality
  5. life's teleonomic character (purposeful)
Is the list complete? If cellularity is a universal characteristic of life, shouldn't cellularity (a membrane) be included? Did Pross explain the properties in the list? Maybe, but I am not sure.

My criticism: life cannot be defined without cells and membranes

Pross is serious about the idea that 'the individual' and 'individuality' does not exist:
  • "What is an individual living entity and do they actually exist?"
  • "Biologically speaking, our individuality is actually non-existent"
  • "If you focus on the individual entity, you are missing the essence of what defines life–its dynamical nature"
  • "evolution does not operate on individuals, ... individuals are just born and then die"
  • "evolution is a process that populations undergo, not individuals."
However, if one digs deeper (with the help of the ebook search function) one can also find statements that demonstrate the importance of cells and individuals:
"I have stated that life is a network of chemical reactions, but merely inspecting the world around us we see that the network seems to be composed of individual units–the cells. Cells are the smallest discrete entities that we unambiguously term to be 'living'." (chapter 8)
The statement is found in the beginning of the last chapter. The appearance of the cell is certainly unexpected in his book. When checking out his working definition of life: 'life is a self-sustaining kinetically stable dynamic reaction network derived from the replication reaction', there is nothing that leads us to expect the necessity of any sort of physical or chemical boundary. Also, cells are absent from a more elaborate definitions of life (9). This seems wrong. If cells are the smallest and simplest discrete entities unambiguously termed 'living', shouldn't cellularity be included in the definition of life? Obviously, it should. On closer inspection one finds more subtle hints (Freudian slips?) earlier in the book:
  • "Yes, we now know that all life is cell based!" (chapter 2),
  • "the system as a whole is replicating, that's what cells do when they replicate–the system as a whole makes copies of itself, as opposed to each individual component within the cell copying itself" (chapter 7)
The first statement is important, because it points to cellularity as a universal characteristic of life. The second statement is important because it is part of a theory of life. So, if (1) all life is cell-based, and if (2) the cell is the unit of replication, then one would expect cellularity to be part of the definition of life. Moreover, cellularity should be an expected outcome of the evolutionary process, not an arbitrary later addition.
Consider his statement about evolution: "Evolution does not operate on individuals". All right. But, does this imply that individuals are not alive? Do we need to include evolution in the definition of life? No. Consider this statement: "individuals are just born and then die". Clearly, individuals that die must have been alive. Consider this poetic pronouncement in the Prologue: "Every cell is ultimately a highly organized and efficient factory for making more cells!" and "the dream of every cell, to become two cells' (Francois Jacob).
Based on Pross' own statements, it is clear, that cellularity should appear in the definition and the theory of life (11). Are membranes absent because they are a hindrance for replicative chemistry? If cells add more stability, they should be present in the definition and theory of life.
Finally, one last argument for the membrane: how could replicating systems compete with each other and evolve, when they could not exclusively profit from their own beneficial mutations when they have no boundaries that separate them from others? (14)

Reply of Addy Pross by email:

"The cell was not the starting point of life but rather a highly successful intermediate point, the evolutionary outcome of a process seeking ever increasing stability - DKS. (...)
Clearly then the life phenomenon must be underpinned by principles that do not include cell existence as part of those principles. The cell and its boundary is an evolutionary adaptation, an extraordinarily successful one. (...)
Yes, cells are central entities in life without doubt, but still just one further link in the complexification process, unable in themselves to offer insight into the central questions in biology: what is life, how did it emerge, and how (in principle) could one make it? Life is the process by which those cells emerged." [5 Oct 2014]

Conclusion

Pross wrote a fascinating book about the interrelated questions of the origin of life, the definition of life and how to make life. It is packed with insightful examples, analogies, and metaphors to explain scientific findings which would otherwise be inaccessible to non-specialists. He hardly uses any technical jargon. For example, one doesn't find the names of the bases Cytosine, Guanine, Adenine, Thymine, they are abbreviated as C,G,A,T. There is only one technical term, DKS, and it happens to be a core concept in the book. It is not easy for a non-chemist, but crucial to understand it.
Pross discusses the origin of life question on a conceptual level. No technical details. The reader is taken on a helicopter flight high above the landscape of scientists in their labs with often incompatible approaches, assumptions, and successes and failures. Where scientific publications drown readers under a flood of technical jargon, Pross succeeds in communicating complex issues in jargon-free language with the additional benefit that the reader is able to see clearly the limitations of current Origin of Life research, as well as (rare) promising research findings.
Sometimes in a pessimistic, sometimes in an optimistic mood, in the end Pross solves the What is life? question in principle: replication is the essence of life. Pross' definition of life is firmly based on his theory of life. This is superior to the more philosophical attempts which are just dictionary definitions. However, Pross is not the first one to give a definition of life based on a sound theory of life (10).
At the same time, Pross also addresses practising scientists (evolutionary biologists, Origin of Life researchers) for example when arguing for his view that hypotheses about the historical conditions and the exact prebiotic steps can never be known (13). So, in his eyes, these efforts are waste of time. His advice to researchers is to focus on the general, ahistoric laws that drive molecules to become those special replicating chemical systems we call life.

I am not sure whether Pross solved the central theoretical problem of the Origin of Life. Did he successfully propose a mechanism for the process of complexification toward a far-from-equilibrium system that does not contravene the Second Law? Is replicative chemistry really able to outsmart the Second Law? Is replicative chemistry able to produce the first RNA template out of pure buildings blocks? Does replicative chemistry require energy capture systems to get started in the first place or could energy capture be a later addition? Similarly, could membranes be a later addition? If he solved these questions he deserves without any doubt a Nobel Prize.

       Notes  

  1. The point of view of Cleland and Chyba is simply too extreme. Understanding life increases gradual. We can define life along with developing a theory of life. An example is Tibor Gánti who defined life very precisely, and has a very detailed theory of life! Do we really have no idea what life is? Consider this: "We see life as cellular, with a nucleic acid genome that is translated to a protein machinery. Life self-reproduces, transmits heritable information to its progeny, and undergoes Darwinian evolution based on natural selection. Life captures high-energy starting materials and converts them to lower-energy products to drive metabolic processes". (Gerald F. Joyce)
  2. This is not fair: an information based definition can be combined with a metabolism based definition. Further: many definitions simply fail at being a definition of life, and cannot be taken seriously.
  3. Replication-first scenario appears to be incompatible with the Second Law of Thermodynamics, since those self-replicating and complexificating systems proceed uphill, they do not seem to complexify to far-from-equilibrium systems. The task is to show "how a simple replicating system would be induced to complexify and 'climb uphill'."
  4. Carl R. Woese (2004) A New Biology for a New Century, Microbiol. Mol. Biol. Rev. June 2004 vol. 68 no. 2 173-186
  5. Did Carl Woese produce solutions? Did he solve the origin of life? I am afraid not. However, he has a good critique.
  6. Tibor Gánti (1975) 'Organization of chemical reactions into dividing and metabolizing units: the chemotons', Biosystems 7 189-195. Pross seems to have ignored the "three subsystems, i.e. into the cytoplasma, the genetic material and the cell membrane". It is not clear why Pross ignores this. Gánti had a completely chemical theory of life. Just like Pross. See for details of Gánti's theory and definition of life my review.
  7. "... that a replicating molecule that underwent some chance mutation that enabled it to capture energy, say, light energy, in a primitive kind of photosynthesis, would be able to out-compete a molecular replicator that lacked such a capability." (chapter7). This assumes replication-fist and metabolism (energy capture) later. Furthermore, in chapter 4: "But there is something special about this self-replication reaction that leads us to believe it was the likely starting point of life."
  8. To sum up the situation: when a particular 'prebiotic' chemical reaction succeeds in the lab, one cannot be certain that it happened under conditions of the prebiotic earth and when a particular chemical synthesis fails in the lab, one can never exclude that it happened at the prebiotic earth. These are a pretty serious criticisms.
  9. A more elaborate definition: "In fact, the moment some non-metabolic (downhill) replicator acquired an energy-gathering capability, could be thought of as the moment life began."
  10. Tibor Gánti has done just that. Also: Radu Popa (2004) Between Necessity and Probability: Searching for the Definition and Origin of Life devotes a whole chapter to The Origin of Cell Boundaries and Metabolism. Popa included Gánti's Chemoton model in Appendix A.6 p. 183. Further: Gerald F. Joyce gives also an argument for the membrane: "One way to avoid complex mixtures would be for each replicating RNA, together with its corresponding building blocks, to be spatially isolated within a separate compartment. ... to allow the fruits of their labor to accumulate locally for their own benefit." Exactly!
  11. The reason why cell boundaries do not easily fit into his replicative chemistry views could be that chemistry knows no boundaries and no cells. Boundaries are the elephant in the room. Chemists have eliminated those boundaries from their theories because they are the boundaries of reaction vessels and test tubes (Sol Spiegelman's test tube experiment).
  12. As far as I understand, an RNA molecule needs to be present at the start of the experiment (to function as a template). Spiegelman started with an RNA molecule of 4000 nucleotides long. Could that RNA molecule self-assemble? Extremely unlikely. Did anybody perform an experiment starting with only RNA building blocks?
  13. An example of a 'historic' Origin of Life model is: Nick Lane et al (2014) A Bioenergetic Basis for Membrane Divergence in Archaea and Bacteria. Pross could criticise this model for being 'historic' and therefore unfalsifiable, but one could also see it as a theory of life; a theory about the origin of energy production and capture, together with the origin of membranes. The Lane energy and membrane theory needs to be integrated with the RNA-world to have a complete theory of life.
  14. For example, here the usefulness for membranes is defended: New Szostak protocell is closest approximation to origin of life and Darwinian evolution so far is a guest post at Panda's Thumb blog. December 13 2013. Quote: "But the membrane is important because chemicals can be kept at high concentrations inside the cell. They are not diluted. The protocell is a unit which is spatially separated from its environment. It also is the beginning of a unit with its own internal environment. Furthermore, a unit could behave differently from other such units. For example, one unit could be more stable than another. Or it could divide more efficiently than others. So it is a good idea that the system has a primitive membrane. More advantages of a membrane will appear later."

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Copyright ©G. Korthof First published: 6 Oct 2014 Updated: 16 Oct 2014 F.R./N: 2 Apr 18