Time Out

James Tour

In 1952, Stanley Miller and Harold Urey derived a number of racemic amino acids from a handful of small molecules. These were electrifying results because they suggested that the methods of synthetic chemistry might finally explain the origins of life. The excitement was justified, but premature.¹ Origins of life (OOL) research has, to be sure, become progressively more sophisticated, but its goal—to explain the origins of life—remains as distant today as it was in 1952. This is not surprising. The protocols in use have remained unchanged: buy highly purified chemicals; mix them together in high concentrations and in a specific order under carefully devised laboratory conditions; derive a mixture of compounds; and publish a paper making bold claims about OOL. These protocols are as unrealistic as they are unimproved.

This essay comprises an argument, but it also contains an appeal to the OOL community. The history of science suggests that on occasion what is required for research to flourish is not further research—at least to the extent that further research involves doing the same thing. This is one of those times.

Needed for Life

Four molecules are needed for life: nucleotides, carbohydrates, proteins, and lipids. Nucleotides are composed of a trimeric nucleobase-carbohydrate-phosphate combination, and once polymerized, constitute DNA and RNA. Five different nucleobases comprise the entire alphabet for DNA and RNA. The nucleotides and their subsequent DNA and RNA structures are homochiral, yielding one of two possible enantiomers. Amino acids are most often homochiral. When amino acids are polymerized, they form proteins and enzymes. Proteins and enzymes also display a tertiary homochirality. Lipids are dipolar molecules with a polar water-soluble head and a non-polar water-insoluble tail. They, too, are most often homochiral. Cells use carbohydrates for energy, and carbohydrates, along with proteins, are identification-receptors. Carbohydrates are also homochiral, and their polymeric forms take on tertiary homochiral shapes. OOL researchers have spent a great deal of time trying to make these four classes of molecules, but with scant success.

Constructing the molecules necessary for life from their prebiotic precursors represents one goal of OOL research; putting them together, another. Some of synthetic chemistry is pedestrian, and some ingenious. Fundamental questions remain unaddressed. Claims that these structures could be prepared under prebiotic conditions in high enantiomeric purity using inorganic templates, or any presumed templates, have never been realized. The carbohydrates, amino acids, lipids, and other compounds within each of these classes require specific methods in order to control their regiochemistry and stereochemistry. The differences in reaction rates often require chiral systems acting upon chiral molecules. If this were possible under prebiotic conditions, it is odd that it cannot be replicated by synthetic chemists.

They have, after all, had 67 years to try.

Synthetic Hyperbole

Consider the class of experiments that deal with the assembly of chemicals into what are referred to as protocells—“a self-organized, endogenously ordered, spherical collection of lipids proposed as a stepping-stone to the origin of life.”² In 2017, a team from the Origins of Life Initiative at Harvard University performed a type of polymerization reaction in water known as the reversible addition–fragmentation chain transfer.³ This reaction type is not seen in nature, and neither are the monomers that figure in the experiment. Still, this is standard chemistry. Polymers are made by a controlled radical polymerization reaction, where two different monomer types are added sequentially to a chain bearing both a hydrophobic and a hydrophilic block. Researchers observed polymeric vesicles forming during polymerization—interesting, but not extraordinary. The vesicles grew to bursting as researchers kept the radical chain growing through ultraviolet light activation. There is, in this, nothing surprising: the forces between the growing vesicle and the surrounding water dictate a critical growth volume before the vesicle ruptures.

The claims should have ended there.

Here is how the work was portrayed in the published article:

The observed net oscillatory vesicle population grows in a manner that reminds one of some elementary modes of sustainable (while there is available “food”!) population growth seen among living systems. The data supports an interpretation in terms of a micron scale self-assembled molecular system capable of embodying and mimicking some aspects of “simple” extant life, including self-assembly from a homogenous but active chemical medium, membrane formation, metabolism, a primitive form of self-replication, and hints of elementary system selection due to a spontaneous light triggered Marangoni instability [provoked by surface tension gradients].⁴

These claims were then rephrased and presented to the public by the Harvard Gazette:

A Harvard researcher seeking a model for the earliest cells has created a system that self-assembles from a chemical soup into cell-like structures that grow, move in response to light, replicate, and exhibit signs of rudimentary evolutionary selection [emphasis added].⁵

This degree of hyperbole is excessive.⁶ Nothing in this experiment had growing cell-like structures with replication, or that exhibited aspects of evolutionary selection.

Teams from the University of California and the University of New South Wales recently conducted lipid bilayer assembly experiments, publishing a summary of their work in 2017.⁷ They combined nucleotides and lipids in water to form lamellae, with the nucleotides sandwiched between the layers. Nucleotides are trimers of nucleobase-carbohydrate-phosphate, and, in this case, both nucleotides and lipids were purchased in pure homochiral form. Both teams then demonstrated that a condensation polymerization of the nucleotides can take place within the lamella upon dehydration. Polymerization takes place by means of a reaction between pre-loaded phosphate and the purchased stereo-defined alcohol moiety found on a neighboring nucleotide. Similar reactions, they conjectured, may have occurred at the edge of hydrothermal fields, volcanic landmasses providing the necessary heat for reactions.

The chemistry that figures in these experiments is unremarkable. Bear in mind that derivatives were all pre-loaded. To provide the essential concentrations for the reactions, researchers removed the water, thus driving the intermolecular reactions to form oligomers that resembled nucleic acids. The problem with condensation polymerization is obvious: any alcohol can compete for the reactive electrophilic site. In the case under consideration, researchers added no other alcohols. They were scrupulous, but the system was stacked. Condensation polymerization reactions need to be very pure, free of competing nucleophilic and electrophilic components. Witness the Carothers equation, which defines degrees of polymerization based upon monomer purity.⁸ If there happened to be amino acids or carbohydrates mixed with the nucleotides, they would terminate or interrupt the growth of the oligonucleotides. What is more, the researchers did not confirm the integrity of the structures they claimed to have derived. If carefully analyzed, these structures would likely have shown attacks from unintended hydroxyl sites. Since their sequences are essentially random, short oligonucleotides are not realistic precursors to RNA. An alphabet soup is not a precursor to a poem. The authors go on to suggest that the lamella sandwiching oligonucleotides eventually break off to form lipid bilayer vesicles. These contain the oligonucleotide-within-vesicle constructs, which they call protocells. The conversion of planar lamella into multilamellar vesicles as they hydrate is well established, but shearing forces are generally required to form the requisite lipid bilayer vesicle. For this reason, yields were likely to be low.⁹ It is hard to imagine finding highly purified homochiral nucleotides trapped in a pure lipid lamella on the prebiotic earth.

But set all that aside. These vesicles bear almost no resemblance to cellular lipid bilayers. Lipid bilayer balls are not cellular lipid bilayers. One would never know this from reading the authors’ account. “Then, in the gel phase,” they write, “protocells pack together in a system called a progenote and exchange sets of polymers, selecting those that enhance survival during many cycles.”¹⁰ Chemicals, of course, are indifferent to their survival. No mechanism is described to demonstrate how protocells would bear different sets of polymers or exchange polymers among them. Terms from biology have generally been misappropriated in a way that makes no chemical sense. This is not an isolated or incidental defect. It reappears when the authors write that “[t]he best-adapted protocells spread to other pools or streams, moving by wind and water…”¹¹ Best-adapted? Microbial communities apparently “evolve into a primitive metabolism required by the earliest forms of life.” Molecules do not evolve, and nothing is being metabolized. Condensation polymerization is a simple chemical reaction based upon the addition of nucleophiles to electrophiles with loss of water. Such a reaction is never referred to as a form of metabolism within synthetic chemistry.

Terminology is one thing, non-sequiturs quite another. “After much trial and error,” the authors write, “one protocell assembles the complicated molecular machinery that enables it to divide into daughter cells. This paves the way for the first living microbial community.” How is the molecular machinery made? They do not say. The mechanisms needed for cellular division are complex, requiring cascades of precisely functioning enzymes. There is nothing between what the authors demonstrate and what they claim to have established, and nothing they propose “paves the way for the first living microbial community.”

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