- Rob Stadler
A Dose of Reality for Miller/Urey and Their Disciples
If the first life ever to exist began through purely natural processes, the first step must have been production of the basic building blocks: amino acids, nucleotides, carbohydrates, and lipids. Although modern laboratory experiments can produce these basic building blocks, there are three ways that these experiments bypass reality.
1. Use of Unnaturally Pure, Concentrated Reagents
Experiments to produce the building blocks of life always begin with unnaturally pure, concentrated reagents, purchased from laboratory supply shops and produced through sophisticated, intelligently designed processes. For example, Stanley Miller and his graduate student Jeff Bada used a mixture of nitrogen gas and CO2 to produce some amino acids. They described the starting materials as:
"Medical grade nitrogen gas (purity > 99.99% N2 and industrial grade carbon dioxide (claimed by the manufacturer to contain no more than 10 ppm impurities) were purchased from Airgas."
Where on a prebiotic Earth could you find gasses with no more than 10 parts-per-million impurities? We recognize that the initial motivation to work with such unnaturally pure reagents was to avoid criticism that their experiment was contaminated. But, after succeeding in producing some amino acids from these ingredients, they claimed success and moved on, never stopping to inject reality into their work. In my own research on heart disease, the gap between an initial proof-of-concept (e.g., success in a petri dish experiment) and the practical, widespread application of a new heart failure therapy can be enormous. If I stopped working after proof-of-concept, publishing only the initial findings but extrapolating my results to claim sweeping success in curing heart failure, I could rightly be accused of academic fraud. The origin-of-life research community is clearly held to a different standard.
In chemical reactions, the amount of product produced commonly depends on the concentration of the reagents (this is known as Le Chatelier’s Principle). Unnaturally concentrated reagents therefore drive the reaction to produce more product. As said by origin-of-life researcher Pier Luigi Luisi: “concentration can indeed be seen as a chemical constraint in the origin of life, since chemistry cannot operate below a certain threshold of concentration.” On a prebiotic earth, with lower concentration of reagents and plenty of impurities, Miller and Bada’s reaction may not have produced any appreciable amino acid product.
2. Production of Interfering or Toxic Products
Origin-of-life researchers stop their reactions at optimal times, and scan through the products of their reactions with sensitive high-tech equipment to find trace amounts of the product they seek. When the product is located, they claim success, publish a paper, and move on. But, what about the other products of the reaction? And, what if the reaction was not artificially stopped, but was allowed naturally to continue?
Agnieszka Wotos and colleagues built a computer simulation called “Allchemy” to simulate chemical reactions in a prebiotic world. They started with just 6 pure ingredients (H2O, N2, HCN, NH3, CH4, and H2S). After only 7 rounds of chemical reactions between the reagents, the simulation produced 36,603 different molecules that are not found in living organisms and only 82 different molecules that are found in living organisms.  Thus, 99.776% of the molecules that they produced were not biotic. This is not only a problem of dilution of the desired (biotic) molecules, but many of the undesired molecules will cross-react, block, or otherwise destroy the molecules that are desired for life. Imagine if a concrete mixer contained only 0.224% of the items needed to make concrete (limestone, clay, gypsum, gravel, sand, and water) and 99.776% random items that are not found in concrete (e.g., toothbrushes, basketballs, Cheetos, cockroaches, and some random items that are detrimental to concrete production: sugar and sulfuric acid). In the Wotos study, this very unfavorable ratio of non-biotic to biotic molecules occurred after only 7 rounds of chemical reactions to produce rather simple molecules. With more rounds of reactions and addition of other biologically relevant starting molecules like phosphate, the situation grows exponentially worse. As stated by the authors:
“because the masses of molecules like ATP, ADP or dinucleotides are high (above 400 g/mol), creating them from very basic substrates (HCN, H2O, CH4, N2, H3PO4) takes 9-13 synthetic generations within which extremely large numbers of other, not-very-interesting molecules are created” 
Some may be thinking that this is only a computer simulation, not reality. However, as a general principle, prebiotic processes will always produce vast arrays of molecules that fill the chemical “space” of all possible molecular configurations, whereas life is built upon a relatively small set of very select molecules. The chemical constituents of carbonaceous chondrite meteorites provide a confirmatory reality check. These meteorites contain organic compounds produced by purely natural processes in outer space. The Murchison meteorite contained “tens of thousands of different molecular compositions, and likely millions of diverse structures,” which “suggests that the extraterrestrial chemodiversity is high compared to terrestrial relevant biological- and biogeochemical-driven chemical space” 
Origin-of-life researchers conveniently overlook this unpleasant reality. They artificially stop reactions when production of the desired product is maximized and they maintain laser-focus on detecting only their desired product and ignoring the implications of the vastly predominant undesired molecules that they produced.
3. Relay Synthesis
After performing a first experiment to produce a building block of life, then claiming success and publishing a paper, origin-of-life researchers always start the next experiment toward life by purchasing pure, concentrated building blocks. For example, having successfully shown that the first experiment can produce any amount of an amino acid, the researchers dispose of the results from the first experiment and start the next experiment with a new, clean flask and pure, concentrated amino acids purchased from a laboratory supply.
This “relay synthesis” approach is essentially a silent confession that the products of their first experiment are not of practical use. A relay synthesis approach is required because of the poor concentration of product and the preponderance of impurities resulting from the first reaction. As said by origin-of-life researcher Pier Luigi Luisi: “concentration can indeed be seen as a chemical constraint in the origin of life, since chemistry cannot operate below a certain threshold of concentration.” The poor yields of origin-of-life chemical reactions simply forbid sequential reactions. This is not a question of scale – even if the “chemist’s flask” was the entire Earth, the relatively large mass of desired product would be hopelessly dispersed amongst the unwanted, interfering products. As shown by the Allchemy simulation, such reactions can be expected to produce 99.776% unwanted molecules and only 0.224% of desired molecules. 
Abiogenesis would require a natural method to stop the reaction when the yield of desired molecules is high, followed by a prebiotically plausible filter that could remove the 99.776% of undesired products, followed by a natural means to concentrate the remaining desired molecules, and a means of repeating this process for each successive step toward life. These requirements are far from being recognized in laboratory experiments.
For those who want to learn more, my recent book, The Stairway to Life, describes a list of 12 required steps to advance from chemistry to the simplest forms of life. The production and concentration of the basic building blocks is only the first of the 12 required steps, and the remaining 11 steps are substantially more difficult than the first.
1 Cleaves HJ, Chalmers AL, Miller SL, Bada JL. A Reassessment of Prebiotic Organic Synthesis in Neutral Planetary Atmospheres. Orig Life Evol Biosph. 2008; 38: 105-115.
2 Luigi Luisi P. Chemistry Constraints on the Origin of Life DOI: 10.1002/ijch.201300177.
3 A. Wotos el al., "Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry," Science (2020). https://science.sciencemag.org/content/369/6511/eaaw1955.
4 Schmitt-Kopplin, P., et al., High molecular diversity of extraterrestrial organic matter in Murchison meteorite revealed forty years after its fall. Proc Natl Acad Sci U S A, 2010. 107(7): 2763–2768.