Research Foundation of Southern California, La Jolla
Thermodynamic and kinetic changes with time (right), during
a competitive replication experiment,  
in silico, devised by       
Kramer et al. (1974) with Qβ221 variants.    
Origin of the genetic code – The ‘universal’ genetic code is now seen to be ordered and, frozen within it, is an imprint of its origin,
more than 3.5 billion years ago. This became apparent more than three decades after base triplet assignments to 20 amino acids
commonly incorporated into proteins, and chain-termination signal, had been identified.
Validation of a direct correlation between the time-order of codon assignments and amino acid synthesis path-length - the longer the
path from the citrate cycle, the later codon assignment – led to this advance (Davis 1999, 2002, 2006, 2008). A set of widely diverse
structural regularities attributed to the code were shown, in this connection, to conform with the correlation, demonstrating it to be a
deep structural feature of the genetic code (Davis, 2011, 2013).
Beyond the intrinsic significance of this finding, it has led, as noted below, to structure-based paradigms for reconstructing other
aspects of pre-LUCA molecular evolution.         
A 23 residue antecedent of ferredoxin, Pro-Fd-5 (above), was the    
most ancient of ten pre-‘Last Common Ancestor’ proteins, based
on the goodness of fit of its residue profile at conserved sites with
the amino acid alphabet at different stages in code formation. Its
origin coincided with a stage 5.6 code - amino acid synthesis.
pathways then extended only 5 to 6 reaction steps from the citrate
cycle. The protein linked a [4Fe:4S] electron transfer center
(green) to an acidic (red residues) N-terminal segment, evidently
to bind it to a cationic mineral surface (Davis, 2002). Spectroscopic
analysis of Pro-Fd-5 reconstructed by Dr Hans Christensen and   
associates at DTU, Lyngby, Denmark, confirmed its structure    
(Norgaard et al. 2009 J. Biol.Inorg.Chem. 14, Supp. 1).
Forces Driving Molecular Evolution – A theory of evolution based on comparative rates of
self-propagation, as a ‘single-agent’ of change, has been applied at biologic (Darwin, 1859;
Wallace, 1859), genetic (Fisher, 1930), and polymeric (Eigen, 1971) scales. Validation of the
fundamental theorem of natural selection by frequency variations in competitively replicating
RNA species, moreover, quantitatively affirmed this theory under defined physical conditions
(Davis, 1978). When self-replicating RNA species, such as Qβ221-β and Qβ221-γ (
), compete in vitro, however, multiple scalar forces are seen to govern evolution: a
thermodynamic force (A) drives nucleotide condensation and a kinetic force (A‡) (counterpart
of natural selection) lowers the effective activation barrier (elevating Qβ221-γ frequency). A
third force drives the formation of stable RNA duplexes, which do not replicate, that also
affects polymer evolution. The notion that evolution was solely the product of 'comparative
rates of propagation' thus gives way to a more general principle that portrays evolution as a
damping response to multiple physicochemical forces that arise within a non-equilibrium
system (Davis, 1996, 1998). Evolution thus involved the search for terrestrial free energy
sources to drive propagation and, subsequently, their efficient utilization.  
Complexity- Functional biopolymers have complex monomer sequences, as Schrodinger (1943) first
noted. The initial eight base pairs of the ferredoxin gene in
Clostridium pasteurinum illustrate this (figure
a, right
): they form a conspicuously more complex (harder to recall) sequence than the highly repetitive
rearrangement at its right. Both are equally ordered, since each is constrained by an identical number of
H- and P-bonds. Duplication of either sequence, or any of 110 other rearrangements (with two
orientations per base pair), necessitates formation of an identical number of H- and P-bonds. Thus, the
chemical work expended in DNA duplication is independent of template complexity. Transmission of this
'ordered-state randomness', accordingly, has no direct thermodynamic cost (Davis, 1965, 1994). No shift
in the reaction equilibrium can result, therefore, from the presence of template complexity. The forces
driving evolution plainly 'pay' for the selection of any given sequence from among all possible sequences.
Complexity has significance beyond the algorithms encoded in DNA, promoting self-propagation. A
force-free state in Newtonian dynamics, either one of rest
(figure b, upper) or constant velocity (lower),
remains unchanged, until acted on by an external force. A trajectory of zero complexity results. This
equates the First Law of Motion to a proposition in complexity theory. When space is curved, force-free
motion proceeds along a geodesic, characterized by an invariant tangent velocity and zero-complexity
trajectory (Davis and Davis, 2010). The conservation laws of dynamics, furthermore, imply complexity
invariance, given the constants of motion are the product of a common cause and unchanged force-  
frame (Davis and Davis, 2014). A transparent explanation for the conservation laws of dynamics results.  
It extends, moreover, to motion with a discontinuity, as in the rotation of the tangent velocity (null incident
and reflected force frames) in an elastic reflection.
Complexity theory thus generalizes the significance of randomness beyond its long recognized role in
orienting order-disorder transitions in time. In particular, it orients order-order transitions in the direction
of decreasing complexity. Departures from order-order transitions, illustrated by random errors in
replication, were, as long recognized, integral to the acquisition of complexity during evolution.  
Emergence of Life- DNA in the deepest branching
Aquifex and Methanopyrus, contains 1.55 to 1.69
million base pairs. How reactions among single C molecules
spontaneously led to cells of this complexity on the early Earth
had remained unexplained. Insights gained into the evolution
of ancient reaction sequences, aided by advances on the
origin of the genetic code (Davis, 1999, 2002, 2006, 2008,
2009, 2012, 2013, 2015), link it to occurrence of pre-RNA
catalysts and ladder replicators, formed from polymeric
phosphorylated-sugars, at a cationic mineral surface. The
spontaneous, autocatalytic synthesis of a 2C sugar (C2H4O2)
from a 1C pre-sugar (CH2O) is the initial sugar source.. Life
emerged with appearance of the first polymer whose monomer
sequence encoded an algorithm for a polymeric structure that
promoted its own propagation.
'Code age' of pre-divergence proteins – All inter-species differences  
between proteins, derived from a common gene, vanish at the Last Universal
Common Ancestor. Reconstructing protein evolution before the divergence of
species, thus requires an alternative to inter-species mutation distances. The
success of the path-distance model in clarifying the origin of the genetic code has
provided a new metric of time-order - furnished by the distinct sets of amino acids
encoded at each stage identified in code formation. Matching the residues
conserved by an ancient protein, from the pre-divergence era, with these stage-
specific amino acids, yields an estimate of protein ‘code age’ (Davis, 2002).
String theory -  This theory replaces point particles with standing waves, or strings, in an attempt to unify the relativity theory of gravity with quantum physics.
Quantum theory has provided a unified description of three forces, electromagnetism and the weak and strong forces in the atomic nucleus. Since gravity remains to
be incorporated to complete the unification of the forces, string theory continues to be the subject of considerable interest.

© RFSC-2018
The above figure (upper-left) shows a pre-RNA ladder-replicator with H-bonded ribulose-P (Ru-
P) monomers, within anti-parallel strands. They flank a ribosylglycine-amide (Ri-NH
2) pair.
Modification converted the ribose from a non-interacting monomer (embedded scaffold) to an
external (closed-form) scaffold for the self-bonded purine-intermediate pair (Davis, 2018). This
replicator is plainly transitional between the poly(pentose-P) replicator of the reductive
pentose-phosphate cycle (RPC) and purine RNA replicator (
home page). As ribose-P forms on
cyclization of ribulose-P, the poly(RPC) replicator emerges as an apparent antecedent of the
external poly(ribose-P) scaffold in an RNA double-helix (
lower-left). A sugar-phosphate era
catalyst, modeled on the Tamura-Schimmel ribozyme (
lower-right), is depicted charging a
poly(pentose-P) mini-helix with an L-amino acid (Davis, 2015). Ribulose (R) monomers in the
binding strand self-interact with anti-parallel monomers of the amino acid (aa)-charged
strand, and mini-helix. An aperiodic distribution of non-interacting ribose monomers
(embedded scaffold, S) imparts sequence complexity
. Ferrous/ferric atoms coordinately   
bonded to sulfur atoms, in a cross-linked thiolated 3C sugar-phosphate membrane (putative
antecedent of phospholipid P-glycerol scaffold; Davis, 2015), are depicted catalyzing
synthesis of a 1C pre-sugar precursor, CH
2O (upper-right). A proton gradient at the interface of
an alkaline hydrothermal vent upwelling and early acidic ocean water drives the reaction
(Russell, Daniel, Hall. 1993). The membrane conceivably coupled this geophysical free
energy source with the self-organizing capacity of a 3C sugar replicator.