What was Leslie Orgel saying?

Well, my first impression on reading Leslie Orgel's recent (posthumous) essay in PLoS Biology was that it was just the sort of rich quote-ore that creationists and cdesign proponentsists cannot resist mining. Indeed, it was not long before famous cdesign proponentsist Casey Luskin began distorting the article in a way that served his personal beliefs. Others have dissected the failures of Mr. Luskin's analysis, and of course volumes were written about his putative misuse of the Research Blogging icon. In all the clamor condemning Mr. Luskin, Orgel's actual paper seems to have gotten lost. I thought I might write about it.

Orgel's article itself doesn't contain any new research, and those who are keeping track might notice similarities to a previous essay on the same topic from 2000. The issue at hand is the origin of life, which owing to our inability to travel back in time is one of the most difficult subjects in biochemical research. It is almost impossible to know exactly what chemicals were present in the prebiotic milieu, what minerals and surfaces were available to perform catalysis, and which of the many possible environments was the one in which life actually arose. As such, the field is highly speculative. Orgel's essay is something of a reaction to this.

It is popular to speak of an "RNA world" of primitive organisms in which most or all of the functions currently performed by proteins were instead performed by RNA. This model has the advantage that RNA can have both informational content and catalytic activity, but it demands the question of where the RNA came from. Some elements of nucleic acids can form nonenzymatically from simple chemicals likely to be present in the prebiotic milieu, but the transition from adenine and ribose to a diverse oligosaccharide with a phosphate backbone is not trivial. If, however, enormous autocatalytic cycles existed on the prebiotic Earth, that would resolve many of these objections.

In his essay, Orgel seemingly meant to quell enthusiasm (I use the term in its pejorative sense) for this idea, not because he believes it is intrinsically false, but because it doesn't really make things easier for us. He takes as an example the reverse citric acid cycle, pointing out that although it is extremely useful, and moreover is autocatalytic, it requires numerous and diverse chemical activities, many of which could go awry if the wrong substrate were used for a step. The assertion that this cycle underpins the existence of life requires appropriate colocal catalysts acting with sufficient efficiency to keep the cycle running. Moreover, it requires that unproductive (or toxic) side-reactions not drain away the reactants at any step. That is, the catalysts present must discriminate between different possible reactants, so as not to break down components inappropriately before they advance in the cycle. It is not immediately apparent that this is possible (certainly it does not appear to be probable), and Orgel was not convinced by several of the attempts to justify prebiotic catalytic cycles. This article summarized his reasons for skepticism.

This attitude has been misrepresented as meaning that Orgel believed (A) that prebiotic autocatalytic cycles were impossible, and (B) that important life cycles are irreducibly complex. Both propositions are false, and it is also false that Orgel believed them.

Part of the rebuttal to proposition A is referenced in Orgel's paper itself, when he mentions Arthur Weber's recent work in which a reaction of various trioses with ammonia gave autocatalytic products. Although the cycle at work in that instance is not yet understood, Orgel points to it as being particularly promising, in part because it requires no additional catalyst, and in part because it yields high-energy carbon compounds of a kind that might be useful substrates for life.

Granted, the reactions of the Weber experiment may not be directly analogous to anything observed in modern organisms, but I feel that this should not be seen as a problem. After all, why would a primitive organism evolve an activity to perform catalysis already occurring naturally? Rather, one would expect that primitive organisms, whatever their informational and structural characteristics, used the products of autocatalytic cycles as raw material for more exotic activities, which were later repurposed to the production of raw materials as a way to gain a competitive edge or to respond to resource scarcity. If, additionally, very complex abiotic cycles similar to the TCA cycle existed to produce more exotic or useful substrates, it ceases to be quite as problematic if they are not highly efficient or specific. Indeed, these sorts of shortcomings would likely serve as a basis for establishing selective advantage for those organisms that evolved compensating protein catalytic activities.

It is not necessary that abiotic cycles intended to serve as a metabolic origin of life work perfectly, or even that they involve products and intermediates similar to those used by contemporary organisms. They need only be efficient and specific enough for life to get started, with intermediates and products that are useful enough for primitive organisms to benefit from them. Orgel's objection is not that this latter situation is impossible; rather he feels that it is sufficiently implausible that actual evidence is needed, rather than hopefulness and modeling.

The sharp-eyed will (hopefully) note the influence of Orgel's rules in the above, especially the First Rule: "Whenever a spontaneous process is too slow or too inefficient a protein will evolve to speed it up or make it more efficient." The rebuttal to proposition B, of course, comes in the form of Orgel's Second Rule: "Evolution is smarter than you are." The belief that any biological systems are irreducibly complex results merely from a failure to understand the enormous problem-solving potential of selection combined with random mutation and millions upon millions of years of time to work. Certainly Orgel would never have accepted that evolution could not produce these complicated cycles once given a chance, or that these cycles could not be broken down in a useful way for primitive organisms. Orgel's point is not that any of this is impossible, it is that it must be shown to be plausible:

The most serious challenge to proponents of metabolic cycle theories—the problems presented by the lack of specificity of most nonenzymatic catalysts—has, in general, not been appreciated. If it has, it has been ignored. Theories of the origin of life based on metabolic cycles cannot be justified by the inadequacy of competing theories: they must stand on their own.

Orgel's paper does not rule out the possibility of autocatalytic cycles, nor does it assert or even imply that some mystical intervention is necessary to explain how life came about. Orgel's paper is a demand for evidence. It is not enough to say that autocatalytic cycles solve the problem of biogenesis, nor even that they are more plausible than other explanations. Negative arguments do not suffice; a positive argument must be made and backed up by simulations, reconstructions, and experimental evidence. Orgel points favorably to several promising avenues of research in this regard.

Intelligent design is not among those avenues, and it is certain that Orgel would reject it. Having only a (flimsy) negative case in its favor, lacking even the virtue of plausibility, and ignoring his second rule, ID must be seen as weaker than any extant metabolic or genetic theories, which at least are not based on magic. Orgel's overall point is a valuable one. It is disgusting and disgraceful that, with flagrant disregard for his thinking, Orgel's essay should be misrepresented as supporting "if pigs could fly" views of the origin of life.

Primary citation:
Orgel, L.E. (2008). The Implausibility of Metabolic Cycles on the Prebiotic Earth. PLoS Biology, 6(1), e18. DOI: 10.1371/journal.pbio.0060018 OPEN ACCESS

Other peer-reviewed articles referenced:
Orgel, L.E. (2000). Self-organizing biochemical cycles. Proceedings of the National Academy of Sciences, 97(23), 12503-12507. DOI: 10.1073/pnas.220406697 OPEN ACCESS
Roy, D., Najafian, K., von Rague Schleyer, P. (2007). Chemical evolution: The mechanism of the formation of adenine under prebiotic conditions. Proceedings of the National Academy of Sciences, 104(44), 17272-17277. DOI: 10.1073/pnas.0708434104
Weber, A.L. (2007). The Sugar Model: Autocatalytic Activity of the Triose-Ammonia Reaction. Origins of Life and Evolution of Biospheres, 37(2), 105-111. DOI: 10.1007/s11084-006-9059-9