[23] Efforts toward the goal of artificial genetic systems were first reported by Benner and coworkers in 1989, when they developed the first unnatural base pair.
[24][25][26][27] Benner and his colleagues have since developed a six-letter artificially expanded genetic information system called Artificially Expanded Genetic Information System (AEGIS) which includes two additional nonstandard nucleotides (Z and P) in addition to the four standard nucleotides (G, A, C, and T).
[38]: 100–106 Benner has used synthetic organic chemistry and biophysics to create a "second generation" model for nucleic acid structure.
The first generation model of DNA was proposed by James Watson and Francis Crick, based on crystallized X-ray structures being studied by Rosalind Franklin.
[39] Benner's model emphasizes the role of the sugar and phosphate backbone in the genetic molecular recognition event.
It supported the matching of genomic sequences in databases, and generated information that showed how natural proteins could divergently evolve under functional constraints by accumulating mutations, insertions, and deletions.
[45] Building on Darwin, the Benner laboratory provided tools to predict the three dimensional structure of proteins from sequence data.
Information about known protein structures was collected and marketed as a commercial database, the Master Catalog, by Benner's startup EraGen.
[45] The use of multiple sequence information to predict secondary structure of proteins became popular as a result of the work of Benner and Gerloff.
[50] AEGIS has been the basis of the development of tools for multiplexed detection of genetic markers such as cancer cells[51] and single nucleotide polymorphisms in patient samples.
[53] Interpreting genomic data and projecting back to a common genetic ancestor, "Luca", the Benner laboratory has introduced tools that analyze patterns of conservation and variation using structural biology, study variation in these patterns across different branches of an evolutionary tree, and correlate events in the genetic record with events in the history of the biosphere known from geology and fossils.
From this have emerged examples showing how the roles of biomolecules in contemporary life can be understood through models of the historical past.
[54][55] Benner was an originator of the field of experimental paleogenetics, where genes and proteins from ancient organisms are resurrected using bioinformatics and recombinant DNA technology.
[59] He suggested that the planet Mars may have had more desirable conditions than Earth for the initial production of RNA,[60][61] but more recently agreed that models of early Earth showing dry land and intermittent water, developed by Stephen Mojzsis, present sufficient conditions for RNA development.
[12] The Benner group has worked to identify molecular structures likely to be universal features of living systems regardless of their genesis, and not likely products of non-biological processes.
[64] This concept was linked by Benner to the "aperiodic crystal" view of the gene as proposed by Erwin Schrödinger's book "what is life?"