Steven Albert Benner

Steven A. Benner is a former V.T. & Louise Jackson Distinguished Professor of Chemistry at the University of Florida Department of Chemistry. He was also a faculty member in the Department of Molecular Cell Biology.

Benner left University of Florida in late December 2005 to found The Westheimer Institute of Science and Technology (TWIST) in Honor of Frank Westheimer. He also created the Foundation For Applied Molecular Evolution (FFAME).[1]

Steve Benner has also founded multiple companies including EraGen Biosciences [2] and FireBird Biomolecular.

Steve Benner joined the faculty at the University of Florida in 1997, after working at Harvard University and the Swiss Federal Institute of Technology. He received his B.S./M.S. in Molecular Biophysics and Biochemistry from Yale University, and his Ph.D. in Chemistry from Harvard University under the supervision of Robert Burns Woodward and Frank Westheimer.

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The Benner Laboratory

The Benner laboratory is an originator of the field of "synthetic biology", which seeks to generate, by chemical synthesis, molecules that reproduce the complex behavior of living systems, including their genetics, inheritance, and evolution. Some high points of past work in chemical genetics are listed below.

Gene synthesis

In 1984, the Benner laboratory was the first to report the chemical synthesis of a gene encoding an enzyme [13], following Khorana's synthesis of a shorter gene for tRNA in 1970. This was the first designed gene of any kind, and the design strategies introduced in this synthesis are now widely used to support protein engineering.

Artificial genetic systems

The Benner laboratory introduced the first expanded DNA alphabets in 1989 [44], and developed these into an Artificially Expanded Genetic Information System (AEGIS), which now has its own supporting molecular biology [51,122,197]. AEGIS enables the synthesis of proteins with more than 20 encoded amino acids [71], and provides insight into how nucleic acids form duplex structures [201], how proteins interact with nucleic acids [71], and how alternative genetic systems might appear in non-terrean life [210].

A "second generation" model for nucleic acids

The first generation model for nucleic acid structure, proposed by Watson and Crick 50 years ago, has proven inadequate to guide modification of the core structure of DNA. The Benner group has used synthetic organic chemistry and biophysics to create a "second generation" model for nucleic acid structure [156]. The model emphasizes the role of the sugar and phosphate backbone in the genetic molecular recognition event, and creates perspectives on how nucleic acids work, tools for diagnostics and nanotechnology, and insights on how extraterrestrial life might be recognized [190,196].

Practical genotyping tools

The FDA has approved two products that use AEGIS in human diagnostics. These monitor the loads of virus in patients infected with hepatitis C and HIV. AEGIS also enables products developed by EraGen Biosciences for multiplexed detection of genetic markers and single nucleotide polymorphisms in patient samples. These tools will allow personalized medicine using "point-of-care" genetic analysis, as well as research tools that measure the level of individual mRNA molecules within single processes of single living neurons.

Astrobiology

The exploration of planets other than Earth seeks signs of non-terrean life. 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. These are "bio-signatures", both for terrean-like life and for "weird" life forms [164, 165,166,196,210]. As a member of the NASA Astrobiology Institute (with the University of Washington), and in collaborations with the Jet Propulsion Laboratory and the University of Michigan, the Benner group is designing the next generation of probes to Mars [178].

Genomics and Interpretive Proteomics

Proteins and genes are nothing more (and nothing less) than organic molecules. In the late 1980s, the Benner group recognized that genome sequencing projects would generate sequences for millions of these in the coming decade, offering more molecular structures than then known to organic chemistry. The group developed computational tools to extract chemical and biological information from these.

Bioinformatics workbenches and databases

In 1990, in collaboration with Prof. Gaston Gonnet, the Benner laboratory introduced DARWIN, the first bioinformatics workbench [57]. DARWIN supported the first exhaustive matching of a modern genomic sequence databases [72], and generated information that showed how natural proteins divergently evolve under functional constraints by accumulating mutations, insertions, and deletions [85,102].

Protein structure prediction

The Benner laboratory provided the first practical tools to predict the three dimensional structure of proteins from sequence data (reviewed in [147]). This has led to a revolution in tools to model protein folds, detect distant homologs [139], enable structural genomics, and join protein sequence, structure, and function [180]. Further, the work has suggested limits to structure prediction by homology, defining what can and cannot be done with this strategy.

Interpretive proteomics

The Benner laboratory introduced a range of "second generation" tools to interpret genomic data [43,184,191,193,194,205]. These include 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 has emerged examples showing how the roles of biomolecules in contemporary life can be understood through models of the historical past [185, 193,204,206,211].

Practical interpretive proteomics

The global proteome is assembled from approximately 100,000 easily recognized families of protein modules. The MasterCatalog, developed in collaboration with EraGen Biosciences, organizes all of these according to their evolutionary histories [180]. Genome Therapeutics Corporation recently selected the Master Catalog as the in­terpretive proteomics platform to distribute its proprietary microbial sequence database, and the combined product today has over $2 MM in annual sales. In addition to offering a manageable version of GenBank, the MasterCatalog supports a variety of evolution-based tools in interpretive proteomics, and suggests therapeutic and diagnostic targets.

Experimental paleogenetics

The Benner laboratory was an originator of the field of experimental paleogenetics, where genes and proteins from ancient organisms are resurrected using bioinformatics and recombinant DNA technology [13]. Experimental work on ancient proteins has tested hypotheses about the evolution of complex biological functions, including the biochemistry of ruminant digestion, the thermophily of ancient bacteria, and the interaction between plants, fruits, and fungi at the time of the Cretaceous extinction [52, 110]. These develop our understanding of biological behavior that extends from the molecule to the cell to the organism, ecosystem, and planet [192,206].

Future work

Synthetic biology

The ultimate goal of a program in synthetic biology is to develop chemical systems capable of self-reproduction and Darwinian-like evolution. Such systems will support a "bottom up" exploration of the chemistry behind life, telling us how catalysts and pathways work, how they are regulated, and how they contribute to overall function in natural systems. From a chemical perspective, this work will also show how chemical reactivity is distributed in "structure space", an understanding key to combinatorial chemistry and the origin of life. Work is ongoing to:

• Chemically synthesize a larger repertoire of artificial genetic components.
• Develop DNA polymerases that better handle artificial genetic systems.
• Incorporate artificial genetic systems into artificial evolution experiments.
• Develop quantitative models for chemical evolution in artificial environments.
• Generate artificial chemical systems capable of Darwinian evolution.
• Improve diagnostics, detection, and genotyping systems for practical application.

Genomics and interpretive proteomics

Planetary Biology

Advances in geology, paleontology, genomics, and experimental genetics make it timely to attempt a broad synthesis of the history of life and the planet [192]. Most susceptible to today's tools are phenotypes emerging in the Phanerozoic, over the last 500 MY. In constructing this synthesis, the Benner group brings only a fraction of the needed knowledge and tools. Therefore, most of these projects rely heavily upon collaborators.

Aplysia

In a project funded by a $1 MM grant from the Packard Foundation, the Benner laboratory is collaborating with the laboratory of Leonid Moroz to exploit over 12,000 ESTs from Aplysia neurons to understand the functioning of the nervous system in this mollusk, which learned to swim upon losing the shell of its ancestors that lived 65 million years ago.

Arabidopsis and Oryza

Plants, especially those that live on land, are closely connected to the global planetary environment. In collaboration with plant molecular biologist Robert Ferl and paleobotanist David Dilcher, the Benner laboratory is examining the Arabidopsis and rice genomes to understand how these plants adapted to the changing ecology of the Cretaceous, the extinction of the dinosaurs, the cataclysmic Oligocene cooling, and the rise of man.

Drosophila and Anopheles

With parasitologists at the University of Florida, the Benner group is initiating a project to study the genetic record of adaptation in the mosquito and the fruit fly. These too suffered adaptive change in response to the emergence of mammals as the dominant land fauna 65 MYA, and the rise of angiosperms as the dominant land flora shortly before.

Animal biology

In collaboration with animal scientists Frank and Rosie Simmen, the Benner laboratory is exploiting its proteomics tools to understand the reproductive endocrinology of livestock animals. Placental reproduction has been a site of extraordinary genetic experimentation in the past 150 million years, and much of this is reflected in the genome [206].

Human biology

With industrial and academic collaborators, the Benner laboratory is seeking to learn more about the genetics behind primate traits and diseases, including obesity, Down syndrome, and Alzheimer's disease, using its planetary biology strategy.

Small molecule combinatorial chemistry and drug lead development.

Chemists who work with small molecules would like to mimic the combinatorial processes (random variation, natural selection) that have produced the impressively diverse function that is found in the genetics of living systems. The Benner group has developed target-assisted combinatorial synthesis (TACS), a strategy that enables exploration of genome-sized molecular diversity - up to 100 million different molecular structures in a single experiment [154]. The TACS technology is a foundation for Therascope, a new biotechnology company that generates small molecules as lead development candidates for drug target validation and therapy.

Biological target validation

Enhanced analytical chemistry for combinatorial chemistry

TACS is being applied to define the minimal structures required to bind to a protein target [154,195]. TACS therefore helps solve a key problem in drug development: obtaining a lead. In collaboration with Prof. John Eyler and Prof. Alan Marshall, the Benner group is developing the analytical tools needed to capture information about pharmacophores using TACS experiments [146,154,195].

Pharmacophore identification

TACS is being applied to define the minimal structures required to bind to a protein target [154,195]. The next phase of research will focus on coordination chemistry as the foundation for the TACS experiment, and target proteins involved in inflammation and cancer.