Combinatorial chemistry and molecular evolution

Much of Schultz's work consists of finding ways to do a great many similar experiments at the same time, on many different compounds. He is one of the leading pioneers in combinatorial chemistry, screenable molecular libraries, and "high-throughput" chemistry. His interests are extremely wide-ranging, with applications in such diverse areas as catalytic mechanisms, cell-specialization and other complex biological processes (normally studied by biologists, not chemists), basic photochemistry, biophysical probes of all stripes from NMR through positron-emission, and solid-state materials science.

Early in his career Schultz showed that the natural molecular diversity of the immune system could be directed to generate catalytic antibodies. This method enabled the subsequent development of many new selective enzyme-like catalysts for reactions ranging from acyl transfer and redox reactions to pericyclic and metalation reactions. Although their catalytic activities are only rarely strong enough to be of practical use, catalytic antibodies have provided important new insights in our understanding of biocatalysis, structural plasticity of proteins, evolution of biochemical function, and the immune system itself.

Schultz then applied molecular diversity—the strategy of creating a large community of different molecules, plus a method for fishing out and identifying the ones that do what you want—to a range of problems in chemistry, biology and materials science. Along with Richard Lerner, he was one of the critical players in the development of phage-display libraries, and surface-library chips. For high-throughput bioassays which require freely soluble test-compounds, he uses microrobotic fluid-manipulation systems, adapted for 1,536-microwell cell-culture plates, to separately treat very small cell colonies with large numbers (hundreds of thousands) of different compounds.^[10]

Using these various high-throughput and combinatorial experimental approaches, Schultz has identified materials with novel optical, electronic, and catalytic properties; also, proteins and small molecules which control important biological processes such as aging, cancer, autoimmunity, and stem-cell differentiation and de-specialization back to pluripotency.

Unnatural amino acids

Schultz has pioneered a method for adding new building blocks, beyond the common twenty amino acids, to the genetic codes of prokaryotic and eukaryotic organisms. This is accomplished by screening libraries of mutant amino acyl tRNA synthetases for mutants which charge nonsense-codon tRNAs with the desired unnatural amino acid. The organism which expresses such a synthetase can then be genetically programmed to incorporate the unnatural amino acid into a desired protein in the usual way, with the nonsense codon now coding for the unnatural amino acid. Normally, the unnatural amino acid itself must be synthesized in the lab and supplied to the organism by adding it to the organism's growth medium. The unnatural amino acid must also be able to pass through the organism's cell membrane into the interior of the organism.

More than seventy unnatural amino acids have been genetically encoded in bacteria, yeast, and mammalian cells, including photoreactive, chemically reactive, fluorescent, spin-active, sulfated, pre-phosphorylated, and metal-binding amino acids. This technology allows chemists to probe, and change, the properties of proteins, in vitro or in vivo, by directing novel, lab-synthesized chemical moieties specifically into any chosen site of any protein of interest.

A bacterial organism has been generated which biosynthesizes a novel, previously unnatural amino acid (p-aminophenylalanine) from basic carbon sources and includes this amino acid in its genetic code.^[11][12][13] This is the first example of the creation of an autonomous twenty-one-amino-acid organism.

Unnatural genetic information

Schultz's group has recently created bacteria whose chromosomes include unnatural DNA-bases, and bacteria whose chromosomes are hybrids which include both RNA and DNA.^[14][15]

Origins of mitochondria

In order to probe details of the traditionally accepted hypothesis that mitochondria originated when independent bacteria capable of respiratory (oxygen-dependent) metabolism took up residence inside host cells which had previously only been capable of fermentation (metabolism without using oxygen), and evolved to establish a symbiotic relationship with them,^[16] Schultz's group has created bacteria capable of surviving inside yeast cells and maintaining a symbiotic relationship with the host yeast cells by carrying out reactions which the yeast cells cannot catalyze without the bacteria.^[17] One goal of this work is to culture the yeast-bacteria hybrids and see whether the bacterial genome evolves to increase the mutual benefits of its chemical interactions with the host cells, as has happened with mitochondria over time.^[18]