Chemistry / Critical Notes

Vol. 3, NO. 2 / August 2017

An Open Letter to My Colleagues

James Tour

Letters to the Editors

In response to “An Open Letter to My Colleagues

Life should not exist. This much we know from chemistry. In contrast to the ubiquity of life on earth, the lifelessness of other planets makes far better chemical sense. Synthetic chemists know what it takes to build just one molecular compound. The compound must be designed, the stereochemistry controlled. Yield optimization, purification, and characterization are needed. An elaborate supply is required to control synthesis from start to finish. None of this is easy. Few researchers from other disciplines understand how molecules are synthesized.

Synthetic constraints must be taken into account when considering the prebiotic preparation of the four classes of compounds needed for life: the amino acids, the nucleotides, the saccharides, and the lipids.1 The next level beyond synthesis involves the components needed for the construction of nanosystems, which are then assembled into a microsystem. Composed of many nanosystems, the cell is nature’s fundamental microsystem. If the first cells were relatively simple, they still required at least 256 protein-coding genes. This requirement is as close to an absolute as we find in synthetic chemistry. A bacterium which encodes 1,354 proteins contains one of the smallest genomes currently known.2

Consider the following Gedankenexperiment. Let us assume that all the molecules we think may be needed to construct a cell are available in the requisite chemical and stereochemical purities. Let us assume that these molecules can be separated and delivered to a well-equipped laboratory. Let us also assume that the millions of articles comprising the chemical and biochemical literature are readily accessible.

How might we build a cell?

It is not enough to have the chemicals on hand. The relationship between the nucleotides and everything else must be specified and, for this, coding information is essential. DNA and RNA are the primary informational carriers of the cell. No matter the medium life might have adopted at the very beginning, its information had to come from somewhere. A string of nucleotides does not inherently encode anything. Let us assume that DNA and RNA are available in whatever sequence we desire.

A cell, as defined in synthetic biological terms, is a system that can maintain ion gradients, capture and process energy, store information, and mutate.3 Can we build a cell from the raw materials?4 We are synthetic chemists, after all. If we cannot do it, nobody can. Lipids of an appropriate length can spontaneously form lipid bilayers.

Molecular biology textbooks say as much. A lipid bilayer bubble can contain water, and was a likely precursor to the modern cell membrane.5 Lipid assembly into a lipid bilayer membrane can easily be provoked by agitation, or sonication in a lab.

Et voilà. The required lipid bilayer then forms. Right?

Not so fast. A few concerns should give us pause:6

  • Researchers have identified thousands of different lipid structures in modern cell membranes. These include glycerolipids, sphingolipids, sterols, prenols, saccharolipids, and polyketides.7 For this reason, selecting the bilayer composition for our synthetic membrane target is far from straightforward. When making synthetic vesicles—synthetic lipid bilayer membranes—mixtures of lipids can, it should be noted, destabilize the system.
  • Lipid bilayers surround subcellular organelles, such as nuclei and mitochondria, which are themselves nanosystems and microsystems. Each of these has their own lipid composition.
  • Lipids have a non-symmetric distribution. The outer and inner faces of the lipid bilayer are chemically inequivalent and cannot be interchanged.

The lipids are just the beginning. Protein–lipid complexes are the required passive transport sites and active pumps for the passage of ions and molecules through bilayer membranes, often with high specificity. Some allow passage for substrates into the compartment, and others their exit. The complexity increases further because all lipid bilayers have vast numbers of polysaccharide (sugar) appendages, known as glycans, and the sugars are no joke. These are important for nanosystem and microsystem regulation. The inherent complexity of these saccharides is daunting. Six repeat units of the saccharide D-pyranose can form more than one trillion different hexasaccharides through branching (constitutional) and glycosidic (stereochemical) diversity.8 Imagine the breadth of the library!

Polysaccharides are the most abundant organic molecules on the planet. Their importance is reflected in the fact that they are produced by and are essential to all natural systems. Every cell membrane is coated with a complex array of polysaccharides, and all cell-to-cell interactions take place through saccharide participation on the lipid bilayer membrane surface. Eliminating any class of saccharides from an organism results in its death, and every cellular dysfunction involves saccharides.

In a report entitled “Transforming Glycoscience,” the US National Research Council recently noted that,

very little is known about glycan diversification during evolution. Over three billion years of evolution has failed to generate any kind of living cell that is not covered with a dense and complex array of glycans.9

What is more, Vlatka Zoldoš, Tomislav Horvat, and Gordan Lauc observed: “A peculiarity of glycan moieties of glycoproteins is that they are not synthesized using a direct genetic template. Instead, they result from the activity of several hundreds of enzymes organized in complex pathways.”10

Saccharides are information-rich molecules. Glycosyl transferases encode information into glycans and saccharide binding proteins decode the information stored in the glycan structures. This process is repeated according to polysaccharide branching and coupling patterns.11 Saccharides encode and transfer information long after their initial enzymatic construction.12 Polysaccharides carry more potential information than any other macromolecule, including DNA and RNA. For this reason, lipid-associated polysaccharides are proving enigmatic.13

Cellular and organelle bilayers, which were once thought of as simple vesicles, are anything but. They are highly functional gatekeepers. By virtue of their glycans, lipid bilayers become enormous banks of stored, readable, and re-writable information. The sonication of a few random lipids, polysaccharides, and proteins in a lab will not yield cellular lipid bilayer membranes.

Mes frères, mes semblables, with these complexities in mind, how can we build the microsystem of a simple cell? Would we be able to build even the lipid bilayers? These diminutive cellular microsystems—which are, in turn, composed of thousands of nanosystems—are beyond our comprehension. Yet we are led to believe that 3.8 billion years ago the requisite compounds could be found in some cave, or undersea vent, and somehow or other they assembled themselves into the first cell.

Could time really have worked such magic?

Many of the molecular structures needed for life are not thermodynamically favored by their syntheses. Formed by the formose reaction, the saccharides undergo further condensation under the very reaction conditions in which they form. The result is polymeric material, not to mention its stereo-randomness at every stereogenic center, therefore doubly useless.14 Time is the enemy. The reaction must be stopped soon after the desired product is formed. If we run out of synthetic intermediates in the laboratory, we have to go back to the beginning. Nature does not keep a laboratory notebook. How does she bring up more material from the rear?

If one understands the second law of thermodynamics, according to some physicists,15 “You [can] start with a random clump of atoms, and if you shine light on it for long enough, it should not be so surprising that you get a plant.”16 The interactions of light with small molecules is well understood. The experiment has been performed. The outcome is known. Regardless of the wavelength of the light, no plant ever forms.

We synthetic chemists should state the obvious. The appearance of life on earth is a mystery. We are nowhere near solving this problem. The proposals offered thus far to explain life’s origin make no scientific sense.

Beyond our planet, all the others that have been probed are lifeless, a result in accord with our chemical expectations. The laws of physics and chemistry’s Periodic Table are universal, suggesting that life based upon amino acids, nucleotides, saccharides and lipids is an anomaly. Life should not exist anywhere in our universe. Life should not even exist on the surface of the earth.17


  1. See James Tour, “Animadversions of a Synthetic Chemist,” Inference: International Review of Science 2, no. 2 (2016); James Tour, “Two Experiments in Abiogenesis,” Inference: International Review of Science 2, no. 3 (2016). 
  2. See Wikipedia, “Minimal Genome.” 
  3. David Dearner, “A Giant Step Towards Artificial Life?Trends in Biotechnology 23, no. 7 (2008): 336–38, doi:10.1016/j.tibtech.2005.05.008. 
  4. A small towards this goal was achieved when a synthetic genome was inserted into a host cell from which the original genome had been removed. The bilayer membrane of the host cell and all of its cytoplasmic constituents had already been created by natural biological processes. See Daniel Gibson et al., “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome,” Science 329, no. 5,987 (2010): 52–56, doi:10.1126/science.1190719. 
  5. Bruce Alberts et al., Molecular Biology of the Cell, 4th ed. (New York: Garland Science, 2002). 
  6. See F. Xabier Contreras et al., “Molecular Recognition of a Single Sphingolipid Species by a Protein’s Transmembrane Domain,” Nature 481 (2012): 525–29, doi:10.1038/nature10742; Yoshiyuki Norimatsu et al., “Protein–Phospholipid Interplay Revealed with Crystals of a Calcium Pump,” Nature 545 (2017): 193–98, doi:10.1038/nature22357. 
  7. See Lipidomics Gateway, “LIPID MAPS Structure Database.” 
  8. Roger Laine, “Invited Commentary: A Calculation of All Possible Oligosaccharide Isomers Both Branched and Linear Yields 1.05 × 1012 Structures for a Reducing Hexasaccharide: The Isomer Barrier to Development of Single-Method Saccharide Sequencing or Synthesis Systems,” Glycobiology 4, no. 6 (1994): 759–67, doi:10.1093/glycob/4.6.759. 
  9. National Research Council, Transforming Glycoscience: A Roadmap for the Future (Washington, DC: The National Academies Press, 2012), 72, doi:10.17226/13446. 
  10. Vlatka Zoldoš, Tomislav Horvat and Gordan Lauc, “Glycomics Meets Genomics, Epigenomics and Other High Throughput Omics for System Biology Studies,” Current Opinion in Chemical Biology 17, no. 1 (2012): 33–40, doi:10.1016/j.cbpa.2012.12.007. 
  11. Adapted from Maureen Taylor and Kurt Drickamer, Introduction to Glycobiology (Oxford: Oxford University Press, 2006). 
  12. Gordan Lauc, Aleksandar Vojta and Vlatka Zoldoš, “Epigenetic Regulation of Glycosylation Is the Quantum Mechanics of Biology,” Biochimica et Biophysica Acta – General Subjects 1,840, no. 1 (2014): 65–70, doi:10.1016/j.bbagen.2013.08.017. 
  13. Claus-Wilhelm von der Lieth, Thomas Luetteke, and Martin Frank, eds., Bioinformatics for Glycobiology and Glycomics: An Introduction (Chichester: Wiley-Blackwell, 2009). 
  14. James Tour, “Animadversions of a Synthetic Chemist,” Inference: International Review of Science 2, no. 2 (2016). 
  15. See Jeremy England, “Statistical Physics of Self-Replication,” Journal of Chemical Physics 139 (2013), doi:10.1063/1.4818538; Paul Rosenberg, “God is on the Ropes: The Brilliant New Science That Has Creationists and the Christian Right Terrified,” Salon, January 3, 2015. 
  16. Natalie Wolchover, “A New Physics Theory of Life,” Quanta, January 22, 2014. 
  17. The author wishes to thank Anthony Futerman of the Weizmann Institute and Russell Carlson of the University of Georgia for information on lipids and saccharides, respectively. 

James Tour is a synthetic organic chemist at Rice University.

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