Steven A. Benner

Last updated
Steven Albert Benner
Born (1954-10-23) October 23, 1954 (age 69) [1]
NationalityAmerican
Alma mater Yale University
Harvard University
Scientific career
Fields Chemistry, synthetic biology
Institutions Harvard University
ETH Zurich
University of Florida, Foundation for Applied Molecular Evolution
Doctoral advisor Robert Burns Woodward, Frank Westheimer
Website www.ffame.org

Steven Albert Benner (born October 23, 1954) is an American chemist. He has been a professor at Harvard University, ETH Zurich, and most recently at the University of Florida, where he was the V.T. & Louise Jackson Distinguished Professor of Chemistry. In 2005, he founded The Westheimer Institute of Science and Technology (TWIST) and the Foundation For Applied Molecular Evolution. Benner has also founded the companies EraGen Biosciences and Firebird BioMolecular Sciences LLC.

Contents

Benner and his colleagues were the first to synthesize a gene, beginning the field of synthetic biology. He was instrumental in establishing the field of paleogenetics. He is interested in the origin of life and the chemical conditions and processes needed to produce RNA. Benner has worked with NASA to develop detectors for alien genetic materials, using the definition of life developed by the NASA Exobiology Discipline Working Group in 1992, “a self-sustaining chemical system capable of Darwinian evolution”. [2] [3] [4] [5]

Education

Benner attended Yale University, receiving his B.S./M.S. in molecular biophysics and biochemistry in 1976. He then went to Harvard University, receiving his Ph.D. in chemistry in 1979. [6] He worked under the supervision of Robert Burns Woodward, completing his thesis work with Frank Westheimer after Woodward's death. His Ph.D. thesis was Absolute stereochemistry of acetoacetate decarboxylase, betaine-homocysteine transmethylase, and 3-hydroxybutyrate dehydrogenase. [7]

Career

After graduating from Harvard University, Benner became a fellow at Harvard, receiving the Dreyfus Award for Young Faculty in 1982. He was an assistant professor in the Department of Chemistry at Harvard University from 1982 to 1986. [8]

In 1986, Benner moved to ETH Zurich, the Swiss Federal Institute of Technology in Zurich. [9] He held the positions of associate professor of bio-organic chemistry from 1986 to 1993 and professor of bio-organic chemistry from 1993 to 1996. [8]

By 1996 [10] Benner joined the faculty at the University of Florida, as a professor in both chemistry and cell & molecular biology. He was appointed the V.T. & Louise Jackson Distinguished Professor of Chemistry at the University of Florida's Department of Chemistry in 2004. [11]

Benner left University of Florida in late December 2005 to found The Westheimer Institute of Science and Technology (TWIST) in Honor of Frank Westheimer. It is part of the Foundation For Applied Molecular Evolution (FfAME) in Alachua, Florida, which Benner founded in 2001. [12]

Benner founded EraGen Biosciences in 1999. The company was acquired by Luminex in 2011. [13] [14] He founded Firebird BioMolecular Sciences LLC in 2005. [12] [15] [16]

Research

Benner's research falls into four major areas:

  1. expanding the genetic alphabet by synthesizing artificial structures
  2. pre-biotic chemistry, the recreation of the chemical origin of life
  3. paleogenetics, the study of ancient proteins from long-extinct species
  4. detection of extraterrestrial life [17]

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, Benner's laboratory at Harvard was the first to report the chemical synthesis of a gene encoding an enzyme, [18] [19] [20] following Khorana's synthesis of a shorter gene for tRNA in 1970. [21] This was the first designed gene of any kind, a pioneering achievement that laid the groundwork for protein engineering. [22] The design strategies introduced in this synthesis are now widely used to support protein engineering. [23]

Artificial genetic systems

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). [28] [29] [30] [31] AEGIS has its own supporting molecular biology. [5] It enables the synthesis of proteins with more than the naturally-encoded 20 amino acids, and provides insight into how nucleic acids form duplex structures, how proteins interact with nucleic acids, [32] and how alternative genetic systems might appear in non-terran life. [33]

Benner is one of a number of researchers, including Eric T. Kool, Floyd E. Romesberg, Ichiro Hirao, Mitsuhiko Shionoya and Andrew Ellington, who have created an extended alphabet of synthetic bases that can be incorporated into DNA (as well as RNA) using Watson-Crick bonding (as well as non-Watson-Crick bonding). While most of these synthetic bases are derivatives of the A, C, G, T bases, some are different. While some are in Watson-Crick pairs (A/T, C/G), some are self complementing (X/X). Thus the genetic alphabet has been expanded. [15] [25] [27] [34] [35] [36] [37] [38] : 88–98 

The number of possible nucleotide triplets, or codons, available in protein synthesis depends on the number of nucleotides available. The standard alphabet (G, A, C, and T) yields 43 = 64 possible codons, while an expanded DNA alphabet with 9 DNA bases would have 93 = 729 possible codons, many of them synthetic codons. For these codons to be useful, Aminoacyl tRNA synthetase has been created such that tRNA can code for the possibly synthetic amino acid to be coupled with its corresponding synthetic anti-codon. Benner has described such a system which uses synthetic iso-C/iso-G DNA which uses the synthetic DNA codon [iso-C/A/G] which he calls the 65th codon. Synthetic mRNA with synthetic anti-codon [iso-G/U/C] with synthetic aminoacyl-tRNA synthetase results in an in vivo experiment that can code for a synthetic amino acid incorporated into synthetic polypeptides (synthetic proteomics). [38] : 100–106 

A "second generation" model for nucleic acids

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. According to the double-helix model, DNA is composed of two complementary strands of nucleotides coiled around each other. [39] Benner's model emphasizes the role of the sugar and phosphate backbone in the genetic molecular recognition event. The poly-anionic backbone is important in creating the extended structure that helps DNA to replicate. [40] [41] [42]

In 2004, Benner reported the first successful attempt to design an artificial DNA-like molecule capable of reproducing itself. [22]

Genome sequencing and protein structure prediction

In the late 1980s, Benner recognized the potential for genome sequencing projects to generate millions of sequences and enable researchers to do extensive mapping of molecular structures in organic chemistry. In the early 1990s, Benner met Gaston Gonnet, beginning a collaboration that applied Gonnet's tools for text searching to the management of protein sequences. [43] [44] In 1990, in collaboration with Gaston Gonnet, the Benner laboratory introduced the DARWIN bioinformatics workbench. DARWIN (Data Analysis and Retrieval With Indexed Nucleic acid-peptide sequences) was a high-level programming environment for examining genomic sequences. 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. [46] [47] [48] Predictions of protein secondary structure by Benner and colleagues achieved high accuracy. [49] It became possible to model protein folds, detect distant homologs, enable structural genomics, and join protein sequence, structure, and function. Further, this work suggested limits to structure prediction by homology, defining what can and cannot be done with this strategy. [45]

Practical genotyping tools

Benner's approach opened new perspectives on how nucleic acids work, as well as tools for diagnostics and nanotechnology. The FDA has approved products that use AEGIS DNA in human diagnostics. These monitor the loads of virus in patients infected with hepatitis B, hepatitis C and HIV. [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. These tools will allow personalized medicine using "point-of-care" genetic analysis, [52] as well as research tools that measure the level of individual mRNA molecules within single processes of single living neurons. [53]

Interpretive proteomics

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]

Experimental paleogenetics

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. [56] Experimental work on ancient proteins has tested hypotheses about the evolution of complex biological functions, including the biochemistry of ruminant digestion, [57] [58] : 209  the thermophily of ancient bacteria, and the interaction between plants, fruits, and fungi at the time of the Cretaceous extinction. [58] : 17  These develop our understanding of biological behavior that extends from the molecule to the cell to the organism, ecosystem, and planet, sometimes referred to as planetary biology. [58] : 221 

Astrobiology

Benner is deeply interested in the origin of life, and the conditions necessary to support an RNA-world model in which self-replicating RNA is a precursor to life on Earth. He has identified calcium, borate, and molybdenum as important to the successful formation of carbohydrates and the stabilization of RNA. [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. These are "biosignatures", both for terrean-like life and for "weird" life forms. [3] [62] [63]

One of these universal life identifiers was proposed in the Polyelectrolyte Theory of the Gene. This idea proposes that proposes that for a linear genetic biopolymer dissolved in water, such as DNA, to undergo Darwinian evolution anywhere in the universe, it must be a polyelectrolyte, a polymer containing repeating ionic charges. [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?" to make a robust universally generalizable view of genetic biomolecule. [65] This idea has been suggest as a framework by which scientist may look for life on other solar bodies besides Earth. [66]

Related Research Articles

<span class="mw-page-title-main">Base pair</span> Unit consisting of two nucleobases bound to each other by hydrogen bonds

A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA and RNA. Dictated by specific hydrogen bonding patterns, "Watson–Crick" base pairs allow the DNA helix to maintain a regular helical structure that is subtly dependent on its nucleotide sequence. The complementary nature of this based-paired structure provides a redundant copy of the genetic information encoded within each strand of DNA. The regular structure and data redundancy provided by the DNA double helix make DNA well suited to the storage of genetic information, while base-pairing between DNA and incoming nucleotides provides the mechanism through which DNA polymerase replicates DNA and RNA polymerase transcribes DNA into RNA. Many DNA-binding proteins can recognize specific base-pairing patterns that identify particular regulatory regions of genes.

<span class="mw-page-title-main">DNA</span> Molecule that carries genetic information

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

<span class="mw-page-title-main">Nucleic acid</span> Class of large biomolecules essential to all known life

Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). If the sugar is ribose, the polymer is RNA; if the sugar is deoxyribose, a variant of ribose, the polymer is DNA.

<span class="mw-page-title-main">RNA</span> Family of large biological molecules

Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself or by forming a template for the production of proteins. RNA and deoxyribonucleic acid (DNA) are nucleic acids. The nucleic acids constitute one of the four major macromolecules essential for all known forms of life. RNA is assembled as a chain of nucleotides. Cellular organisms use messenger RNA (mRNA) to convey genetic information that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome.

<span class="mw-page-title-main">RNA world</span> Hypothetical stage in the early evolutionary history of life on Earth

The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence of this stage.

<span class="mw-page-title-main">Stop codon</span> Codon that marks the end of a protein-coding sequence

In molecular biology, a stop codon is a codon that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein; stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain.

<span class="mw-page-title-main">Central dogma of molecular biology</span> Explanation of the flow of genetic information within a biological system

The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein", although this is not its original meaning. It was first stated by Francis Crick in 1957, then published in 1958:

The Central Dogma. This states that once "information" has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information here means the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

<span class="mw-page-title-main">Nirenberg and Matthaei experiment</span>

The Nirenberg and Matthaei experiment was a scientific experiment performed in May 1961 by Marshall W. Nirenberg and his post-doctoral fellow, J. Heinrich Matthaei, at the National Institutes of Health (NIH). The experiment deciphered the first of the 64 triplet codons in the genetic code by using nucleic acid homopolymers to translate specific amino acids.

<span class="mw-page-title-main">Nirenberg and Leder experiment</span>

The Nirenberg and Leder experiment was a scientific experiment performed in 1964 by Marshall W. Nirenberg and Philip Leder. The experiment elucidated the triplet nature of the genetic code and allowed the remaining ambiguous codons in the genetic code to be deciphered.

Xenobiology (XB) is a subfield of synthetic biology, the study of synthesizing and manipulating biological devices and systems. The name "xenobiology" derives from the Greek word xenos, which means "stranger, alien". Xenobiology is a form of biology that is not (yet) familiar to science and is not found in nature. In practice, it describes novel biological systems and biochemistries that differ from the canonical DNA–RNA-20 amino acid system. For example, instead of DNA or RNA, XB explores nucleic acid analogues, termed xeno nucleic acid (XNA) as information carriers. It also focuses on an expanded genetic code and the incorporation of non-proteinogenic amino acids, or “xeno amino acids” into proteins.

<span class="mw-page-title-main">Nucleic acid analogue</span> Compound analogous to naturally occurring RNA and DNA

Nucleic acid analogues are compounds which are analogous to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered. Typically the analogue nucleobases confer, among other things, different base pairing and base stacking properties. Examples include universal bases, which can pair with all four canonical bases, and phosphate-sugar backbone analogues such as PNA, which affect the properties of the chain . Nucleic acid analogues are also called xeno nucleic acids and represent one of the main pillars of xenobiology, the design of new-to-nature forms of life based on alternative biochemistries.

<span class="mw-page-title-main">Expanded genetic code</span> Modified genetic code

An expanded genetic code is an artificially modified genetic code in which one or more specific codons have been re-allocated to encode an amino acid that is not among the 22 common naturally-encoded proteinogenic amino acids.

The RNA Tie Club was an informal scientific club, meant partly to be humorous, of select scientists who were interested in how proteins were synthesised from genes, specifically the genetic code. It was created by George Gamow upon a suggestion by James Watson in 1954 when the relationship between nucleic acids and amino acids in genetic information was unknown. The club consisted of 20 full members, each representing an amino acid, and four honorary members, representing the four nucleotides. The function of the club members was to think up possible solutions and share with the other members.

<span class="mw-page-title-main">DNA and RNA codon tables</span> List of standard rules to translate DNA encoded information into proteins

A codon table can be used to translate a sex code into a sequence of amino acids. The standard genetic code is traditionally represented as an RNA codon table, because when proteins are made in a cell by ribosomes, it is messenger RNA (mRNA) that directs protein synthesis. The mRNA sequence is determined by the sequence of genomic DNA. In this context, the standard genetic code is referred to as translation table 1. It can also be represented in a DNA codon table. The DNA codons in such tables occur on the sense DNA strand and are arranged in a 5′-to-3′ direction. Different tables with alternate codons are used depending on the source of the genetic code, such as from a cell nucleus, mitochondrion, plastid, or hydrogenosome.

Numerous key discoveries in biology have emerged from studies of RNA, including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.

<span class="mw-page-title-main">Xeno nucleic acid</span> Synthetic nucleic acid analogues

Xeno nucleic acids (XNA) are synthetic nucleic acid analogues that have a different backbone than the ribose and deoxyribose found in the nucleic acids of naturally occurring RNA and DNA.

<span class="mw-page-title-main">Hachimoji DNA</span> Synthetic DNA

Hachimoji DNA is a synthetic nucleic acid analog that uses four synthetic nucleotides in addition to the four present in the natural nucleic acids, DNA and RNA. This leads to four allowed base pairs: two unnatural base pairs formed by the synthetic nucleobases in addition to the two normal pairs. Hachimoji bases have been demonstrated in both DNA and RNA analogs, using deoxyribose and ribose respectively as the backbone sugar.

<span class="mw-page-title-main">Philipp Holliger</span> Swiss molecular biologist

Philipp Holliger is a Swiss molecular biologist best known for his work on xeno nucleic acids (XNAs) and RNA engineering. Holliger is a program leader at the MRC Laboratory of Molecular Biology.

The polyelectrolyte theory of the gene proposes that for a linear genetic biopolymer dissolved in water, such as DNA, to undergo Darwinian evolution anywhere in the universe, it must be a polyelectrolyte, a polymer containing repeating ionic charges. These charges maintain the uniform physical properties needed for Darwinian evolution, regardless of the information encoded in the genetic biopolymer. DNA is such a molecule. Regardless of its nucleic acid sequence, the negative charges on its backbone dominate the physical interactions of the molecule to such a degree that it maintains uniform physical properties such as its aqueous solubility and double-helix structure.

References

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