Failing to Demonstrate Prebiotic Plausibility: Confusing Lab Results with Reality

(See, "Q's Response to Richard Carrier: About the Debate," for context)

(See also, "Q's Open Challenge to Richard Carrier", and "The 'Fatal Flaw' with Richard Carrier's '1 in 10^41' Argument for Abiogenesis")

Experimental results are 'infinitely' better than "toy land" chemistry, but still represent idealized conditions that are frequently not indicative of the real-world. "Prebiotically plausible” is probably one of the most overused phrases in the origin of life field. There are no agreed upon standards, no consensus recognition or understanding of what qualifies as “prebiotically plausible”. What is “prebiotically plausible” to one investigator is “implausible” to another. Thus, just because a study claims to be “prebiotically plausible” doesn’t mean it actually is, and just because a molecule can be synthesized in a controlled laboratory setting, does not mean it can form in a natural setting. Bains aptly explains in his review of David Deamer’s “Assembling Life” (Bains (2020), “Getting Beyond the Toy Domain.  Meditations on David Deamer’s ‘Assembling Life'”):

“In my view, almost all the OOL chemistry that I see is Toy Domain chemistry. It is making single types of biochemicals in a controlled laboratory setting using pure chemicals that might, just might, have been present in trace amounts in a complex mixture of thousands of other chemicals at OOL, under conditions that might have existed and might have persisted long enough, and then stopping the reaction at exactly the right time to maximize the yield of what you want. It neglects that many of the postulated starting materials are themselves unstable. It neglects that they will react with other chemicals present. It neglects that the intermediates will all react with each other, and with the products."

"(The occasional comment that some unstable compound is present in meteorites/Titan/comets and so could have been present on early Earth as feedstock for abiotic chemistry is obviously absurd. Stability is determined by environmental conditions, including temperature and presence of other chemicals, including water. Presence of materials on Titan is no more relevant to the proposed inputs to terrestrial scenarios that the presence of DNA on Earth is precedence for life on Mercury. An unstable compound might be a reactive radical or other fleeting intermediate under terrestrial conditions, but that is a different argument.)"

"Of course OOL chemists understand that 99% pure reagents were not available at OOL. The hope is that by exploring what happens in “clean” chemistry you can gain insight into messier chemistry, and so edge towards more realistic scenarios. Indeed, there is a growing body of work on “messy chemistry”—doing lab chemistry with mixtures and accepting impure products as valid outputs. Most researchers, even some working on such chemical schemes, understand that lab chemistry is only a tiny part of the whole problem. But that is not the primary issue. It is a tiny part solved in an unrealistic way. Only by a tiny, outside chance can lab reactions of specific reagents, even to give “messy” products, be part of a larger solution. The research does tell us something about chemistry. But it is not something that has much relevance to OOL, because if you carry out lab organic chemistry on anything approaching a plausible pre-biotic aqueous organic soup you never get life. You get tar. Even if you do it in vesicles…."

"Deamer admits a lot of this. He points out that, no matter what clever chemistry scheme makes sugars from formaldehyde or adenine from hydrogen cyanide, they form in very low yield and they then break down again under those same conditions.”

And the same applies to ALL the studies Richard cites as ‘proof’ of plausible prebiotic syntheses. Here I give additional examples, starting with Richard's "Lee peptide". Richard claims that the “right environment/right conditions” for the spontaneous formation of a “Lee peptide” have been “empirically” demonstrated to exist, when in reality he has not critically read the primary literature, starting with the Lee et al. (1996) study itself. He needs additional supporting research to demonstrate that a “Lee peptide” is, in fact, prebiotically plausible.

1. McFadden's 1 in 10^41 probability (from whom Richard obtains this figure) assumes we have a copious supply of the 20 canonical amino acids. (McFadden, J. (2000). Quantum Evolution: Life in the Multiverse).

A good summary of *potentially* plausible prebiotic 'building blocks' and the minimum conditions needed for their synthesis is found in Kitadai, N., & Maruyama, S. (2018). Origins of building blocks of life: A review. Geoscience Frontiers, 9, 1117e1153. Twelve of the thirty-two residues (37%) in the “Lee peptide” consist of six types of amino acids that are more restricted in their prebiotic availability (Cf. Figure 2, Lee et al. (1996), and Table 1, Kitadai & Maruyama (2018)). 

Specifically, glutamine (no prebiotic source listed), arginine (only known from hydrothermal synthesis), lysine (restricted to spark discharge and hydrothermal synthesis), tyrosine (only known from extraterrestrial sources), cysteine (known from irradiation and hydrothermal synthesis), and methionine (known from spark discharge, irradiation, and hydrothermal synthesis). Before the “Lee peptide” can be considered a plausible prebiotic molecule Richard must *at minimum* identify one or more plausible environments in which it can form, while accounting for adequate sources of the requisite amino acids and their delivery to said environment(s)—especially the aforementioned six amino acids that make up 37% of the Lee peptide that are more rare and limited in their availability. A more realistic probability calculation would also account for this.

2. McFadden's calculation ignores the amphipathic properties of the "Lee peptide" (LP). 

The “Lee peptide” is a polypeptide chain of 32 amino acids linked together that forms an alpha-helix structure (i.e., it has a coiled, corkscrew-like shape. See, Figure 1 in Lee et al. (1996). A self-replicating peptide. Nature, 382(6591), 525-528). 

The LP is an amphipathic alpha-helix, which means it exists in an aqueous environment and has hydrophilic ('water-loving') and hydrophobic ('water-fearing') sides. Figure 2 (See below) in Lee et al. (1996) includes a helical wheel diagram that shows the position of each of the 32 amino acids in the coiled alpha-helix structure. 

Hydrophilic ('water-loving') amino acids are on the outward, water-facing sides of the coil, while hydrophobic ('water-fearing') amino acids are inward to form a stabilizing hydrophobic core. The alternating pattern of polar-nonpolar amino acids in the linear sequence is critical to forming the a-helix coil, which, in turn, is critical to the functioning of the Lee peptide—without it, it doesn’t work, because the a-helix is specifically designed to 'groove-fit' the 17aa & 15aa fragments (which are also a-helical). 

Furthermore, amphipathic a-helices are extremely sensitive to changes in pH, ion, salt concentrations, temperature, etc.; any change to which disrupts the shape of the alpha helix, and renders it nonfunctional. Lee et al. (1996) don't report the range of conditions in which the LP a-helix can exist, but usually these tolerances are quite narrow. If their laboratory protocol is any indication, then optimal conditions for an LP a-helix requires neutral, dilute aqueous conditions. Specifically, a temperature of 21 C in a pH 7.5 buffered solution of 4.3 M guanidinium hydrochloride. The solution is buffered to resist changes in pH, which would otherwise disrupt the a-helix shape. Guanidinium hydrochloride (in this concentration) is typically used in lab protocols to help proteins fold and maintain their native conformation, and likely served a similar purpose here to help maintain the a-helix shape. However, 4.3 M is a high concentration that is unlikely to occur in nature in pure form. 

The point is controlled laboratory conditions like these rarely exist in nature, and experimental results can’t be assumed to transfer directly to natural environments without corresponding evidence. Richard needs to cite additional research that shows the LP a-helix shape can form, persist, and function in a natural, aqueous environment (i.e., demonstrate it is truly prebiotically plausible).

3. McFadden's calculation ignores competing/interfering side reactions: The amide-bond formation that the “Lee peptide” catalyzes is not the only way the amino acids can link. There are multiple ways amino acids can connect together, but polypeptides require a specific bond that is not inherently more probable than the other possibilities. Lee et al. (1996) explains how they employed a specific "thioester-promot[ing]" protocol "in order to circumvent potential side reactions which may arise from reactions at amino and carboxylic acid side-chain functionalities."  In other words, and in terms of prebiotic plausibility, they employed a “cheat”. Thus, even if an LP “self-replicator” and 15aa & 17aa fragments all formed in the same location of the universe around the same time, there is no guarantee the LP would connect the 15aa & 17aa pieces together the ‘correct’ way, and, in fact, it’s more probable they would incorrectly link together, because there’s more possible ways for this to happen. McFadden’s 1 in 10^41 probability is a “toy model” calculation “on paper” that does not factor in this real-world problem, although McFadden does discuss the problem (McFadden, J. (2000). Quantum Evolution: Life in the Multiverse):

"Another 'just the chicken' hypothesis was proposed in 1996, with the discovery that a small peptide could also replicate itself. David Lee and colleagues of California’s Scripps Research Institute designed a short peptide, thirty-two amino acids long, that could act as an enzyme to stitch two bits of itself together (fifteen and seventeen amino acids long), and replicate. The reaction was however helped along by using activated peptide fragments to minimize the gunk-yielding side-reactions. No prebiotic route to these activated amino acids was suggested."

4. Lee et al. (1996) reported the LP exhibits parabolic growth, instead of exponential. As Lee et al. note, this indicates product inhibition. This is a common problem with many "self-replicating systems" that is usually caused by failure of the product to dissociate from the template strand (Duim, H., & Otto, S. (2017). Towards open-ended evolution in self-replicating molecular systems. Beilstein journal of organic chemistry, 13(1), 1189-1203):

"If [the] complex does not dissociate, the newly formed template molecule cannot lead to further enhancement of the reaction rate, effectively arresting the autocatalytic cycle. Such product inhibition is an important limiting factor in many synthetic replicator systems and prevents them from attaining exponential growth." 

 (Fig. 9, Rubinov et al. (2009). Self‐Replicating Amphiphilic β‐Sheet Peptides. Angewandte Chemie, 121(36), 6811-6814.)

(Figure 5, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 1, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 2, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 3, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 4, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 5, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 6, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 7, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

(Figure 8, Strazewski, P. (2019). The beginning of systems chemistry. Life, 9(1), 11.)

Thus, even if a “Lee peptide” (AND a copious supply of 17aa & 15aa substrates) spontaneously form in the same location around the same time, that is still not enough to “spark” a runaway, exponential growth reaction system that can outcompete via "Darwinian fitness."  And, of course, once we run out of 17aa & 15aa fragments, then we're back to a stopped reaction anyway where nothing happens. The “Lee peptide” is nothing like the type of *sustained*, networked enzyme-mediated reactions we see in even the simplest known, minimal cell. In point of fact, the non-exponential, parabolic reaction kinetics for the “Lee peptide” demonstrate that it is not “a self-sustaining chemical system capable of Darwinian evolution,” and, thus, does not meet NASA’s definition of life, and thus, is not equivalent to the origin of life (Of course, not everyone agrees with NASA’s definition anyway, which has been severely criticized. For example, by NASA’s definition a mule is non-living).

In short, Richard has assumed but not demonstrated that the “Lee peptide” synthesized under controlled laboratory conditions and a protocol that employed “cheats”, could form, persist, and function in a natural setting (and even if it did the reaction kinetics for the “Lee peptide” exhibit parabolic, not exponential growth). Until this is done he cannot claim that it is an empirically-backed plausible prebiotic molecule.