Leslie Orgel’s Last Testament: Pigs Don’t Fly, and Life Doesn’t Just Happen

Leslie Orgel’s last written article before his death shows
no patience for hypothetical scenarios for the origin of life.

A veteran origin-of-life researcher died last October: Leslie E. Orgel of the Salk Institute for Biological Studies. Orgel had co-authored Origins of Life on the Earth (1973) with Stanley Miller, the man whose spark-discharge experiment launched the modern origin-of-life craze in the 1950s (05/02/2003). Orgel worked in the field for decades and was familiar with all the different approaches.

Apparently Orgel was working on an essay when he died. Gerald Joyce [Scripps Institute], who wrote a eulogy to Orgel in Nature last November (11/29/2007) submitted Orgel’s manuscript to PLoS Biology. It was published posthumously this week on January 22. Origin-of-life [OOL] researchers will not find much encouragement in Orgel’s last scientific will and testament. It bears careful reading, however, coming from someone who spent a lifetime working on and thinking about chemical evolution.

The essay is entitled, “The Implausibility of Metabolic Cycles on the Prebiotic Earth.” The caption states, “In this essay, the final contribution of his scientific career, Leslie Orgel explores the severe difficulties that arise when these proposals are scrutinized from the standpoint of chemical plausibility.”

To understand his critique, the reader should be aware that OOL research bifurcated into two disparate approaches in the 1990s. The “genetic” party, endorsed by Stanley Miller, Leslie Orgel, Jeffrey Bada (06/14/2002), Steven Benner (11/05/2004) and others, looks for prebiotic macromolecules able to carry genetic information: DNA, RNA, PNA (12/17/2005), TNA and other candidates. The newer “metabolic” party is less ambitious than to expect such complex polymers to arise naturally. They propose that self-sustaining cycles of simpler compounds might arise, to be “co-opted” later by information-storing RNA and DNA. Champions of this approach have included Gunter Wachterschauser, Michael Russell (12/03/2004), Harold Morowitz (03/23/2005), Stuart Kauffman (05/09/2006), and Robert Shapiro (02/15/2007). Robert Hazen gave it good press in the Teaching Company lecture series Origins of Life while comparing and contrasting both schools of thought and describing them as somewhat spirited and adamant rivals.

While Orgel might be expected to be partial to the genetic school, his final criticisms of the field are broad enough to raise serious concerns about the ability of natural processes to produce life at all by any method. Combining this essay with Shapiro’s devastating critique of genetic approaches last year (q.v., 02/15/2007), it seems that both approaches, like warriors in close combat, have both given and received mortal wounds, falling down together.

Orgel was not entirely dismissive of the metabolic approach on theoretical grounds. Indeed, he said, “If complex cycles analogous to metabolic cycles could have operated on the primitive Earth, before the appearance of enzymes or other informational polymers, many of the obstacles to the construction of a plausible scenario for the origin of life would disappear.” No obstinacy here; he would welcome such a discovery. It’s the implausibility of metabolic scenarios that, to him, render them useless in the real world.  Scenarios cannot be merely clever and imaginative. They have to obey the laws of chemistry. They need to be experimentally demonstrable.

Orgel’s essay is open for public reading. He stated, “The main purpose of this Essay is to examine the plausibility of these and some related hypothetical nonenzymatic cycles. Could prebiotic molecules and catalysts plausibly have the attributes that must be assigned to them in order to make the self-organization of the cycles possible?” Those without an organic chemistry background can wade through the jargon and decipher his main criticisms:

1. Could is not good enough:  “It must be recognized that assessment of the feasibility of any particular proposed prebiotic cycle must depend on arguments about chemical plausibility, rather than on a decision about logical possibility.” To claim a chemical reaction is possible does not mean it will ever happen. What are the specific reactants? How efficient are they? Researchers must present ideas that are chemically plausible, not just possible.
2. Paper is not good enough:  “It is a catalytic cycle in which a complicated sequence of enzymatic reactions is used to bring about indirectly a reaction that looks simple on paper, but is not easily achieved in practice.” A researcher needs to think about chemical cofactors required, and the possibility of damaging cross-reactions, for instance, or whether reactions in a cycle are likely to proceed in a realistic time frame.
3. Time is not enough:  A metabolic cycle on the primitive earth may have had eons longer to work than a chemist in a lab. “However, the identification of a cycle of plausible prebiotic reactions is a necessary but not a sufficient step toward the formulation of a plausible self-organizing prebiotic cycle.”
4. Where are the exits?  Every step in a metabolic cycle needs to be efficient enough to keep the whole cycle going. “The cycle could not survive if side reactions funneled off more than half of the cycle components irreversibly, because then the concentration of the cycle components would decline exponentially to zero.”
5. Weakest link breaks the chain:  A researcher might be able to propose that each step in a metabolic cycle, say the 11 steps in the reverse citric acid cycle, is plausible in a prebiotic environment. “However, the reactions are not independent because each reaction is pulled toward completion by the use of its product as the input for the subsequent reaction of the cycle.”
6. Don’t forget thermodynamics:  Because reactions are reversible, it is likely the input of a step will be depleted. “Whatever the original input, one would finish with an equilibrium mixture, the composition of which is determined by thermodynamics.” Equilibrium means you are at a standstill and nothing more will happen.
7. Not all reactions are created equal:  Orgel lists seven reactions in the reverse citric acid cycle (one popular scenario for a self-organizing metabolic scenario) that are completely different. “The reverse citric acid cycle involves a number of fundamentally different kinds of chemical transformations,” he said; “At the very least, six different catalytic activities would have been needed to complete the reverse citric acid cycle.” What would this require: six different environments on the early earth? This “could be argued, but with questionable plausibility,” he remarked.
8. Beware of thieves:  Damaging side reactions are often more likely to occur than the desired ones. Orgel gives examples, such as difficult carboxylation reactions. “This reaction would move material irreversibly out of the cycle, so one must postulate a specific catalyst that discriminates between succinic and malic acid.”
9. Inspectors required:   Biological enzymes in living cells are experts at discriminating between similar substrates. The same cannot be assumed in a prebiotic environment: “One needs, therefore, to postulate highly specific catalysts for these reactions. It is likely that such catalysts could be constructed by a skilled synthetic chemist, but questionable that they could be found among naturally occurring minerals or prebiotic organic molecules.”
10. Minerals are not enough:  Clay surfaces and other substrates have been popular ingredients in metabolic cycle scenarios. The necessary reactions might occur on these natural lab tables, they say. Orgel discusses two leading scenarios. “While the details of the two proposals are different, the difficulty of achieving all of the required reactions while avoiding all of the likely side reactions seems at least as formidable” in both of them.
11. Hand-waving is not enough:  Orgel criticizes a recent proposal by Wachtershauser that describes self-organization by “metabolic reproduction, evolution, and inheritance by ligand feedback.” Suggestive words. “Unfortunately he never explains, even in outline, how this mechanism could lead to the synthesis of the aminoacyl-nucleotide conjugates that seem to be an essential feature of the proposal.”
12. One example is not enough:  “The only autocatalytic cycle that has been demonstrated experimentally is that involved in the formose reaction—the polymerization of formaldehyde to give a notoriously complex mixture of products, including ribose, the organic component of the backbone of RNA.” Well, this must be the path to explore! Indeed, researchers have explored this path since it was discovered in the 19th century. Is it the holy grail? Not exactly; the mix must be seeded with certain impurities to get started, and “Despite some successes, it is still not possible to channel the formose reaction in such a way as to produce ribose in substantial yield.”
    Ribose, of course, is one of the most difficult essential parts of RNA to imagine forming on the prebiotic earth – especially in the presence of water (see Benner, 11/05/2004). The proposed hopeful cycles, unfortunately, produce a host of other unhelpful reaction products.
13. Simple is not enough:  Orgel begins a section on “Cycles and the Evolution of Complexity.” Assume a cycle begins. That does not mean that complexity will evolve. “A cycle … does not seem capable of evolving in any interesting way without becoming more complex.” The scenarios that suggest a substantial amount of “information content” will emerge from a simple cycle, with genetic macromolecules coming in late to add stability, are little more than “intuitions” – not schemes that can be examined critically.
14. Variation is not enough:  Suggesting that a change in temperature or concentration is a form of evolution is a play on words. For instance, “one could not usefully claim that the dependence of the rate of a reaction such as ester hydrolysis on reaction conditions is a form of evolution.” At some point you have to add complexity to the picture. “The evolution of any substantial additional complexity of a cycle, therefore, must depend on the appending of further reaction sequences to those present in the core cycle.”
15. The law of diminishing returns:  “Given the difficulty of finding an ensemble of catalysts that are sufficiently specific to enable the original cycle, it is hard to see how one could hope to find an ensemble capable of enabling two or more.” The further the scenario gets from the original simple cycle, the more the problems arise. Orgel has heard many proposals in his career. None of them “explains how a complex interconnected family of cycles capable of evolution could arise or why it should be stable.”

Orgel spent several paragraphs dismantling Kauffman’s mathematical proposal for a peptide cycle, which is interesting to read for those with an appetite for details.² Even more interesting are some off-the-cuff remarks he made that, like an overheard microphone in wartime, reveal weaknesses to the enemy:

• By faith:  The discovery of a feasible, evolvable cycle would be a real breakthrough, but…
  

  What is essential, therefore, is a reasonably detailed description, hopefully supported by experimental evidence, of how an evolvable family of cycles might operate. The scheme should not make unreasonable demands on the efficiency and specificity of the various external and internally generated catalysts that are supposed to be involved. Without such a description, acceptance of the possibility of complex nonenzymatic cyclic organizations that are capable of evolution can only be based on faith, a notoriously dangerous route to scientific progress.

• By intelligent design:  You can get fantastic experimental results if you add design to the equation:
  

  Ghadiri and his coworkers have demonstrated experimentally that peptide cycles of the type envisaged in Kauffman’s theory are possible. They first showed that peptides of length 32 that have been carefully designed to self-associate to form stable coiled-coils will facilitate the ligation of their N-terminal and C-terminal subsequences. This shows that the self-replication of peptides is possible. In later work they demonstrated the self-organization of networks of ligation reactions when more than two carefully designed input peptides are used. These findings, however, cannot support Kauffman’s theory unless the prebiotic synthesis of the specific 15mer and 17mer input peptides from monomeric amino acids can be explained. Otherwise, Ghadiri’s experiments illustrate “intelligent design” of input peptides, not spontaneous self-organization of polymerizing amino acids.

  Those words must surely sting in the ears of researchers trying to avoid the D word design. He presses the point: can these long chains necessary for autocatalytic cycles form spontaneously? In several paragraphs, he explains why not. The short answer invokes words that sound like Dembski’s criterion of specified complexity for design: “Clearly, self-organization requires catalysis that is not only sufficiently efficient but also sufficiently sequence-specific.”

• Let us bow our heads. No worship leader, Orgel pauses to marvel at how life does what it does:
  

  The catalytic properties of enzymes are remarkable. They not only accelerate reaction rates by many orders of magnitude, but they also discriminate between potential substrates that differ very slightly in structure. Would one expect similar discrimination in the catalytic potential of peptides of length ten or less? The answer is clearly “no,” and it is this conclusion that ultimately undermines the peptide cycle theory.”

  For a few more paragraphs, Orgel entertained various attempts to rescue Kauffman’s theory. Alas; “Even if such systems exist, their relevance to the origin of life is unclear,” he said mercifully. “It is unlikely, therefore, that Kauffman’s theory describes any system relevant to the origin of life.”

In the conclusion of the essay, Orgel laid down the rules that all origin-of-life researchers must obey: in a phrase, get real. “In view of the importance of the topic, it is essential to subject metabolist proposals to the same kind of detailed examination and criticism that has rightly been applied to genetic theories.” (Here he referred to critiques by Shapiro; cf. 02/15/2007).  At least the genetic theorists, like himself, have a “substantial body of experimental work” in their resumes. Orgel let the storytellers have it between the eyes:

Almost all proposals of hypothetical metabolic cycles have recognized that each of the steps involved must occur rapidly enough for the cycle to be useful in the time available for its operation. It is always assumed that this condition is met, but in no case have persuasive supporting arguments been presented. Why should one believe that an ensemble of minerals that are capable of catalyzing each of the many steps of the reverse citric acid cycle was present anywhere on the primitive Earth, or that the cycle mysteriously organized itself topographically on a metal sulfide surface? The lack of a supporting background in chemistry is even more evident in proposals that metabolic cycles can evolve to “life-like” complexity. 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 tried to soften this blow with suggestions that plausible cycles might some day be discovered, for instance around hydrothermal events, and these deserve further investigation. “It is important to realize,” however, “that recognition of the possible importance of prebiotic syntheses that could occur hydrothermally does not necessitate a belief in their ability to self-organize.”

…scenarios that are dependent on “if pigs could fly” hypothetical chemistry are unlikely to help.

In the final paragraph, the final words of his final essay, he generalized to all kinds of origin-of-life theories. You need pure building blocks to get polymers that might replicate themselves. You need to sift the good from the bad in the complex mixtures that result from experiments. “No solution of the origin-of-life problem will be possible until the gap between the two kinds of chemistry is closed.” Then, he uttered his last scientific writing with the most stinging words of all, aimed at the whole OOL community:

Simplification of product mixtures through the self-organization of organic reaction sequences, whether cyclic or not, would help enormously, as would the discovery of very simple replicating polymers. However, solutions offered by supporters of geneticist or metabolist scenarios that are dependent on “if pigs could fly” hypothetical chemistry are unlikely to help.

Rest in peace, Dr. Orgel.

1.  Leslie E. Orgel, “The Implausibility of Metabolic Cycles on the Prebiotic Earth,” Public Library of Science: Biology, 6(1): e18, Jan 22, 2008, doi:10.1371/journal.pbio.0060018.
2.  Kauffman’s model depends on peptides growing to a certain length that can autocatalyze one another.  Orgel shows additional factors that would be required, reducing the plausibility of his hypothesis, which is more mathematical than experimental to begin with.  Kauffman misunderstands the thermodynamics of peptide bond formation.  He thinks amino acids will be plentiful and will spontaneously form long polypeptides, Orgel complains, “In practice, this would not happen.”  In fact, the need for coupling agents becomes a problem for all origin-of-life theories that depend on the formation of polypeptides or polynucleotides.  The problem “could only be avoided by proposing a series of monomers, such as aminoaldehydes, that polymerize spontaneously, but the difficulty of finding a prebiotic synthesis of suitable monomers then becomes severe.”

Ouch! Or should we shout, Amen! What a way to go. No more spark-discharging simple gases for him. Orgel has just tased everyone in the OOL community with shocks of realism. Does it get any better than this?

We spent a lot of time on this entry because of its significance. Evolution’s theory of the origin of life is the fulcrum on which the entire evolutionary worldview rests, like an inverted pyramid at the tipping point. The news media, and children’s textbooks, make it all look so easy. NASA repeatedly insinuates that the mere presence of water on some planet or moon means that life can’t be far behind. For over 50 years now, textbooks have been decorated with Miller’s spark-discharge experiment, that useful lie, that icon of the Darwin Party propaganda machine (05/02/2003). The propaganda has deceived the public into thinking scientists have essentially solved the puzzle of the origin of life, and God is out of business.

Orgel has been in the thick of actual OOL research and, thank God, did not lose his scientific realism completely like so many of the others have. Practically on his deathbed he has preached a final hellfire sermon against researchers who substitute imagination for reality, faith for experimentation. He reprimanded those who unscrupulously insert that foreign, despised, prohibited ingredient into their equations: intelligent design! You may go speculate about flying pigs, Orgel says, but don’t claim that by doing so you are doing science, or helping the evolution movement.

Read this article, then read Shapiro’s critique of the genetics-first approach (02/15/2007). Here you have two champions both collapsing in the ring with fatal wounds. Creationists and Intelligent Design debaters need do nothing but show the tape. The evolution advocates have falsified each other, the flying pig circus tent has collapsed, and the pyramid has tipped toward intelligent design, never to point toward evolution again.

Thanks for hanging in there with this long entry. We just thought our readers would like to know what the silly TV shows and kiddie books aren’t telling you. As Porky (the flying) Pig always ended his Looney Tunes, “Th-Th-Th-That’s all, folks!” Cartoons are over. Get off the couch, go outside, and have a great day in the real world – the world of Creation.