Steven A. Benner

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.{{cite book|editor-last1=Impey|editor-first1=Chris Impey|editor-last2=Spitz|editor-first2=Anna H.|editor-last3=Stoeger|editor-first3=William|title=Encountering life in the universe : ethical foundations and social implications of astrobiology|date=2013|publisher=University of Arizona Press|location=Tucson|isbn=978-0-8165-2870-7|page=259|url=https://books.google.com/books?id=LUt5AAAAQBAJ&pg=PA259|access-date=30 June 2016}} 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.{{cite web|title=Steven A. Benner|url=http://academictree.org/chemistry/peopleinfo.php?pid=66098|website=Chemistry Tree|access-date=30 June 2016}}

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.{{cite web|title=Events at Rice|url=http://events.rice.edu/index.cfm?EventRecord=322|website=Rice University|access-date=1 July 2016|url-status=dead|archive-url=https://web.archive.org/web/20160919210641/http://events.rice.edu/index.cfm?EventRecord=322|archive-date=19 September 2016}}

In 1986, Benner moved to ETH Zurich, the Swiss Federal Institute of Technology in Zurich.{{cite journal|last1=Kwok|first1=Roberta|title=Chemical biology: DNA's new alphabet|journal=Nature|date=21 November 2012|volume=491|issue=7425|pages=516–518|doi=10.1038/491516a|pmid=23172197|bibcode=2012Natur.491..516K|doi-access=free}} 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.

By 1996{{cite journal|last1=Benner|first1=Steven A.|title=Non-Standard Base Pairs as Biomedical Research Tools|url=http://grantome.com/grant/NIH/R01-GM054048-01|journal=Grantome|access-date=1 July 2016}} 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.{{cite web|title=Participants|url=http://humbleapproach.templeton.org/exploring_exoplanets/participants.html|website=The Humble Approach Initiative|access-date=1 July 2016}}

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.

Benner founded EraGen Biosciences in 1999. The company was acquired by Luminex in 2011.{{cite news|last1=Wyzan|first1=Andrew| title=Former Gainesville biotech sold for $34 million| url=http://www.gainesville.com/news/20110712/former-gainesville-biotech-sold-for-34-million|access-date=1 July 2016|work=The Gainesville Sun|date=July 12, 2011}}{{cite web|last1=Carroll|first1=John|title=Luminex snaps up EraGen Biosciences in $34M deal|url=http://www.fiercebiotech.com/biotech/luminex-snaps-up-eragen-biosciences-34m-deal|website=Fierce Biotech|access-date=June 22, 2011}} He founded Firebird BioMolecular Sciences LLC in 2005.{{cite news|last1=Clark|first1=Anthony|title=Local team to head $5.4 million quest to study origins of life on Earth|url=http://www.gainesville.com/news/20160324/local-team-to-head-54-million-quest-to-study-origins-of-life-on-earth|access-date=30 June 2016|work=The Gainesville Sun|date=March 24, 2016}}{{cite journal|last1=Howgego|first1=Josh|title=On stranger nucleotides|journal=Chemistry World|date=25 February 2014|url=http://www.rsc.org/chemistryworld/2014/02/unnatural-dna-base-pairs|access-date=1 July 2016}}{{cite web|url=http://www.firebirdbio.com/|title=Firebird BioMolecular Sciences LLC}}

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{{cite web|title=President's Dream Colloquium|url=https://www.sfu.ca/colloquium/speaker-biographies/steven-benner.html|website=Simon Fraser University|access-date=1 July 2016}}

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.

In 1984, Benner's laboratory at Harvard was the first to report the chemical synthesis of a gene encoding an enzyme,{{cite journal

|last1=Gross|first1=Michael

|title=What exactly is synthetic biology?

|journal=Current Biology|date=August 2011|volume=21|issue=16|pages=R611–R614

|doi=10.1016/j.cub.2011.08.002

|doi-access=free|bibcode=2011CBio...21.R611G

}}{{cite journal

|last1=Nambiar|first1=K.|last2=Stackhouse|first2=J|last3=Stauffer|first3=D.|last4=Kennedy|first4=W.|last5=Eldredge|first5=J.|last6=Benner|first6=S.

|title=Total synthesis and cloning of a gene coding for the ribonuclease S protein

|journal=Science|date=23 March 1984|volume=223|issue=4642 |pages=1299–1301

|doi=10.1126/science.6322300

|pmid=6322300|url=http://www.baseballhall.ffame.org/pubs/Total%20synthesis%20and%20cloning%20of%20a%20gene%20coding%20for%20the%20ribonuclease-s%20protein.pdf|access-date=5 July 2016|bibcode=1984Sci...223.1299N}}{{cite book

|last1=D'Alessio|first1=Giuseppe|last2=Riordan|first2=James F.

|title=Ribonucleases structures and functions|date=1997

|publisher=Academic Press|location=San Diego|isbn=9780125889452

|url=https://books.google.com/books?id=sj21cDNJGtIC&pg=PA214|page=214|access-date=5 July 2016}} following Khorana's synthesis of a shorter gene for tRNA in 1970.{{cite journal

|last1=Khorana|first1=H.G.|last2=Agarwal|first2=K.L.|last3=Büchi|first3=H.|last4=Caruthers|first4=M.H.|last5=Gupta|first5=N.K.|last6=Klbppe|first6=K.|last7=Kumar|first7=A.|last8=Ohtsuka|first8=E.|last9=RajBhandary|first9=U.L.|last10=van de Sande |first10=J.H.|last11=Sgaramella |first11=V.|last12=Tebao |first12=T.|last13=Weber|first13=H.|last14=Yamada|first14=T.

|title=CIII. Total synthesis of the structural gene for an alanine transfer ribonucleic acid from yeast|journal=Journal of Molecular Biology

|date=December 1972|volume=72|issue=2|pages=209–217

|doi=10.1016/0022-2836(72)90146-5

|pmid=4571075}} This was the first designed gene of any kind, a pioneering achievement that laid the groundwork for protein engineering.{{cite journal|last1=Gramling|first1=Carolyn|title=For Chemistry Professor Steven Benner, Life As We Know It May Not Be The Only Alternative|url=http://www.research.ufl.edu/publications/explore/v10n1/story1.html|access-date=9 July 2016|journal=Amazing Science|volume=10|issue=1|date=2005}} The design strategies introduced in this synthesis are now widely used to support protein engineering.{{cite book|editor-last1=Köhrer|editor-first1=Caroline|editor-last2=RajBhandary|editor-first2=Uttam L.|title=Protein engineering|date=2009|publisher=Springer|location=Berlin|isbn=978-3-540-70941-1|pages=274–281, 297|url=https://books.google.com/books?id=Udk_AAAAQBAJ&pg=PA297|access-date=5 July 2016}}

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.{{cite news

|url=http://www.utsandiego.com/news/2014/may/08/tp-life-engineered-with-expanded-genetic-code/

|title=Life engineered with expanded genetic code|last=Fikes|first=Bradley J.|date=May 8, 2014

|work=San Diego Union Tribune|access-date=5 July 2016}}{{cite journal

|last1=Switzer|first1=Christopher|last2=Moroney|first2=Simon E.|last3=Benner|first3=Steven A.

|title=Enzymatic incorporation of a new base pair into DNA and RNA

|journal=Journal of the American Chemical Society|date=October 1989 |volume=111 |issue=21 |pages=8322–8323 |doi=10.1021/ja00203a067

|bibcode=1989JAChS.111.8322S }}{{cite journal

|last1=Piccirilli|first1=Joseph A.|last2=Benner|first2=Steven A.|last3=Krauch|first3=Tilman |last4=Moroney|first4=SimonE.|last5=Benner|first5=Steven A.

|title=Enzymatic incorporation of a new base pair into DNA and RNA extends the genetic alphabet

|journal=Nature|date=4 January 1990|volume=343|issue=6253|pages=33–37

|doi=10.1038/343033a0|pmid=1688644|bibcode=1990Natur.343...33P|s2cid=4363955}} 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).{{cite journal|last1=Benner|first1=SA|last2=Hutter|first2=D|last3=Sismour|first3=AM

|title=Synthetic biology with artificially expanded genetic information systems. From personalized medicine to extraterrestrial life.

|journal=Nucleic Acids Research. Supplement|volume=3|date=2003|issue=3|pages=125–6|pmid=14510412

|doi=10.1093/nass/3.1.125}}{{cite journal

|last1=Yang|first1=Z|last2=Hutter|first2=D|last3=Sheng|first3=P|last4=Sismour|first4=AM|last5=Benner|first5=SA

|title=Artificially expanded genetic information system: a new base pair with an alternative hydrogen bonding pattern

|journal=Nucleic Acids Research|date=2006|volume=34|pages=6095–101

|url= |doi=10.1093/nar/gkl633|pmid=17074747|issue=21|pmc=1635279}}{{cite journal|last1=Yang|first1=Zunyi|last2=Chen|first2=Fei|last3=Alvarado|first3=J. Brian|last4=Benner|first4=Steven A.

|title=Amplification, Mutation, and Sequencing of a Six-Letter Synthetic Genetic System

|journal=Journal of the American Chemical Society|date=28 September 2011|volume=133|issue=38|pages=15105–15112|doi=10.1021/ja204910n

|pmid=21842904|pmc=3427765|bibcode=2011JAChS.13315105Y }}{{cite journal|last1=Merritt|first1=Kristen K|last2=Bradley|first2=Kevin M|last3=Hutter|first3=Daniel|last4=Matsuura|first4=Mariko F|last5=Rowold|first5=Diane J|last6=Benner|first6=Steven A

|title=Autonomous assembly of synthetic oligonucleotides built from an expanded DNA alphabet. Total synthesis of a gene encoding kanamycin resistance

|journal=Beilstein Journal of Organic Chemistry|date=9 October 2014|volume=10|pages=2348–2360

|doi=10.3762/bjoc.10.245

|pmid=25383105|pmc=4222377|url=}} AEGIS has its own supporting molecular biology. 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,{{cite journal|last1=Laos|first1=Roberto|last2=Thomson|first2=J. Michael|last3=Benner|first3=Steven A.|title=DNA polymerases engineered by directed evolution to incorporate non-standard nucleotides|journal=Frontiers in Microbiology|date=31 October 2014|volume=5|pages=565|doi=10.3389/fmicb.2014.00565|pmid=25400626|pmc=4215692|doi-access=free }} and how alternative genetic systems might appear in non-terran life.{{cite book|author=Committee on the Limits of Organic Life in Planetary Systems, Committee on the Origins and Evolution of Life ; Space Studies Board, Division on Engineering and Physical Sciences ; Board on Life Sciences, Division on Earth and Life Sciences ; National Research Council of the National Academies|chapter=4. Alternatives to Terran Biochemistry in Water|title=The limits of organic life in planetary systems|date=2007|publisher=National Academies Press|location=Washington, D.C.|isbn=978-0-309-10484-5|chapter-url=https://books.google.com/books?id=-8POSN8AkJ8C&pg=PA20}}

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.{{cite journal|last1=Matsuda|first1=Shigeo|last2=Fillo|first2=Jeremiah D.|last3=Henry|first3=Allison A.|last4=Rai|first4=Priyamrada|last5=Wilkens|first5=Steven J.|last6=Dwyer|first6=Tammy J.|last7=Geierstanger|first7=Bernhard H.|last8=Wemmer|first8=David E.|last9=Schultz|first9=Peter G.|last10=Spraggon|first10=Glen|last11=Romesberg|first11=Floyd E.|title=Efforts toward Expansion of the Genetic Alphabet: Structure and Replication of Unnatural Base Pairs|journal=Journal of the American Chemical Society|date=August 2007|volume=129|issue=34|pages=10466–10473|doi=10.1021/ja072276d|pmc=2536688|pmid=17685517|bibcode=2007JAChS.12910466M }}{{cite news|last1=Pollack|first1=Andrew|title=Scientists Are Starting to Add Letters to Life's Alphabet|url=https://www.nytimes.com/2001/07/24/health/genetics/24DNA.html|access-date=30 June 2016|work=The New York Times|date=July 24, 2001}}{{cite news|last1=Singer|first1=Emily|title=New Letters Added to the Genetic Alphabet|url=https://www.quantamagazine.org/20150710-genetic-alphabet/|access-date=30 June 2016|work=Quanta Magazine|date=July 10, 2015}}{{cite journal|last1=Switzer|first1=CY|last2=Moroney|first2=SE|last3=Benner|first3=SA|title=Enzymatic recognition of the base pair between isocytidine and isoguanosine.|journal=Biochemistry|date=5 October 1993|volume=32|issue=39|pages=10489–96|pmid=7691174|doi=10.1021/bi00090a027|citeseerx=10.1.1.690.1426}}{{cite journal|last1=Takezawa|first1=Yusuke|last2=Shionoya|first2=Mitsuhiko|title=Metal-Mediated DNA Base Pairing: Alternatives to Hydrogen-Bonded Watson–Crick Base Pairs|journal=Accounts of Chemical Research|date=18 December 2012|volume=45|issue=12|pages=2066–2076|doi=10.1021/ar200313h|pmid=22452649}}{{cite book|last1=Simon|first1=Matthew|title=Emergent computation emphasizing bioinformatics|date=2005|publisher=AIP Press/Springer Science+Business Media|location=New York|isbn=978-0-387-27270-2}}{{rp|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).{{rp|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. According to the double-helix model, DNA is composed of two complementary strands of nucleotides coiled around each other.{{cite journal | vauthors = Watson JD, Crick FH | title = The structure of DNA | journal = Cold Spring Harb. Symp. Quant. Biol. | volume = 18 | pages = 123–31 | year = 1953 | pmid = 13168976 | doi = 10.1101/SQB.1953.018.01.020 }} 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.{{cite book|author=Committee on the Limits of Organic Life in Planetary Systems, Committee on the Origins and Evolution of Life ; Space Studies Board, Division on Engineering and Physical Sciences ; Board on Life Sciences, Division on Earth and Life Sciences ; National Research Council of the National Academies|chapter=4. Alternatives to Terran Biochemistry in Water|title=The limits of organic life in planetary systems|date=2007|publisher=National Academies Press|location=Washington, D.C.|isbn=978-0-309-10484-5|chapter-url=http://www.nap.edu/read/11919/chapter/4#23}}{{cite book|editor-last1=Westhof|editor-first1=E.|editor-last2=Hardy|editor-first2=N.|last=Benner|first=Steven|chapter=Evolution-based genome analysis: An alternative to analyze folding and function in proteins|title=Folding and Self-assembly of Biological and Macromolecules : proceedings of the deuxièmes Entretiens de Bures, Bures-sur-Yvette, France, 27 November - 1 December 2001|date=2004|publisher=World Scientific|location=Singapore|isbn=978-981-238-500-0|pages=1–42|chapter-url=https://books.google.com/books?id=7BjJCgAAQBAJ&pg=PA12|access-date=6 July 2016}}{{cite journal|last1=Benner|first1=Steven A.|last2=Hutter|first2=Daniel|title=Phosphates, DNA, and the Search for Nonterrean Life: A Second Generation Model for Genetic Molecules|journal=Bioorganic Chemistry|date=February 2002|volume=30|issue=1|pages=62–80|doi=10.1006/bioo.2001.1232|pmid=11955003|url=http://www.ffame.org/pubs/Phosphates,%20DNA,%20and%20the%20search%20for%20nonterrean%20life%3A%20A%20second%20generation%20model%20for%20genetic%20molecules.pdf|access-date=6 July 2016}}

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

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.{{cite web|title=Prof. Gaston Gonnet: when technology holds the key to evolution|url=https://www.inf.ethz.ch/news-and-events/spotlights/gonnet-farewell.html|access-date=9 July 2016|website=ETH Zurich}}{{cite journal|last1=Gonnet|first1=GH|last2=Cohen|first2=MA|last3=Benner|first3=SA|title=Exhaustive matching of the entire protein sequence database.|journal=Science|date=5 June 1992|volume=256|issue=5062|pages=1443–5|pmid=1604319|url=http://www.ffame.org/pubs/Exhaustive%20matching%20of%20the%20entire%20protein%20sequence%20database.pdf|access-date=9 July 2016|doi=10.1126/science.1604319|bibcode=1992Sci...256.1443G}} 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.{{cite news| title=Genomics Meets Geology| url=http://www.astrobio.net/news-exclusive/genomics-meets-geology/| access-date=1 July 2016|work=AstroBiology Magazine|date=September 10, 2001}} 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.

The use of multiple sequence information to predict secondary structure of proteins became popular as a result of the work of Benner and Gerloff.{{cite journal|last1=Jones|first1=David T.|title=Protein Secondary Structure Prediction Based on Position-specific Scoring Matrices|journal=Journal of Molecular Biology|date=1999|volume=292|issue=2|pages=195–202|url=http://csb.stanford.edu/class/public/readings/Structure_Prediction_I_Lecture8/Jones_JMB_99_PSIPRED_Secondary_structure.pdf|archive-url=https://web.archive.org/web/20160818154501/http://csb.stanford.edu/class/public/readings/Structure_Prediction_I_Lecture8/Jones_JMB_99_PSIPRED_Secondary_structure.pdf|url-status=dead|archive-date=2016-08-18|access-date=6 July 2016|doi=10.1006/jmbi.1999.3091|pmid=10493868}}{{cite journal|last1=Benner|first1=SA|last2=Gerloff|first2=D|title=Patterns of divergence in homologous proteins as indicators of secondary and tertiary structure: a prediction of the structure of the catalytic domain of protein kinases|journal=Advances in Enzyme Regulation|date=1991|volume=31|pages=121–81|pmid=1877385|doi=10.1016/0065-2571(91)90012-b}}{{cite journal|last1=Gonnet|first1=Gaston H.|last2=Korostensky|first2=Chantal|last3=Benner|first3=Steve|title=Evaluation Measures of Multiple Sequence Alignments|journal=Journal of Computational Biology|date=February 2000|volume=7|issue=1–2|pages=261–276|doi=10.1089/10665270050081513|pmid=10890401|citeseerx=10.1.1.48.4250}} Predictions of protein secondary structure by Benner and colleagues achieved high accuracy.{{cite journal|last1=Russell|first1=R.B.|last2=Sternberg|first2=M.J.E.|title=Structure Prediction: How good are we?|journal=Current Biology|date=May 1995|volume=5|issue=5|pages=488–490|doi=10.1016/S0960-9822(95)00099-6|pmid=7583096|doi-access=free|bibcode=1995CBio....5..488R }} 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.

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.{{cite book|editor-last1=Spoto|editor-first1=Giuseppe|editor-last2=Corradini|editor-first2=Roberto|title=Detection of non-amplified genomic DNA|date=2012|publisher=Springer|location=Dordrecht|isbn=978-94-007-1226-3|page=104|url=https://books.google.com/books?id=Crnul35RNXYC&pg=PA104|access-date=6 July 2016}} AEGIS has been the basis of the development of tools for multiplexed detection of genetic markers such as cancer cells{{cite news|last1=Dambrot|first1=Stuart Mason|title=The ties that bind: Recreating Darwinian ligand evolution in vitro|url=http://phys.org/news/2014-01-ties-recreating-darwinian-ligand-evolution.html|access-date=6 July 2016|work=Phys.org|date=January 24, 2014}} and single nucleotide polymorphisms in patient samples. These tools will allow personalized medicine using "point-of-care" genetic analysis,{{cite journal|last1=Jannetto|first1=Paul J.|last2=Laleli-Sahin|first2=Elvan|last3=Wong|first3=Steven H.|title=Pharmacogenomic genotyping methodologies|journal=Clinical Chemistry and Laboratory Medicine|date=1 January 2004|volume=42|issue=11|pages=1256–64|doi=10.1515/CCLM.2004.246|pmid=15576288|s2cid=34338787}} as well as research tools that measure the level of individual mRNA molecules within single processes of single living neurons.{{cite web|title=Award Abstract #0304569 Nanoscale Arrays for Direct RNA Profiling in Single Cells and their Compartments|url=https://www.nsf.gov/awardsearch/showAward?AWD_ID=0304569|website=National Science Foundation|access-date=6 July 2016}}

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.{{cite book|last1=Plaxco|first1=Kevin W.|last2=Gross|first2=Michael|title=Astrobiology : a brief introduction|date=2006|publisher=Johns Hopkins University Press|location=Baltimore|isbn=978-0801883675|pages=165–170|url=https://books.google.com/books?id=x83omgI5pGQC&pg=PA165|access-date=6 July 2016}}{{cite journal|last1=Benner|first1=Steven A.|title=Interpretive proteomics—finding biological meaning in genome and proteome databases|journal=Advances in Enzyme Regulation|date=June 2003|volume=43|issue=1|pages=271–359|doi=10.1016/S0065-2571(02)00024-9|pmid=12791396|url=http://www.ffame.org/pubs/Interpretive%20proteomics%20-%20finding%20biological%20meaning%20in%20genome%20and%20proteome%20databases.pdf|access-date=6 July 2016|citeseerx=10.1.1.104.7549}}

{{Further|Ancestral gene resurrection}}

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.{{cite journal|last1=Jermann|first1=TM|last2=Opitz|first2=JG|last3=Stackhouse|first3=J|last4=Benner|first4=SA|title=Reconstructing the evolutionary history of the artiodactyl ribonuclease superfamily.|journal=Nature|date=2 March 1995|volume=374|issue=6517|pages=57–9|pmid=7532788|url=http://www.ffame.org/pubs/Reconstructing%20the%20evolutionary%20history%20of%20the%20artiodactyl%20ribonuclease%20superfamily.pdf|access-date=6 July 2016|doi=10.1038/374057a0|bibcode=1995Natur.374...57J|s2cid=4315312}} Experimental work on ancient proteins has tested hypotheses about the evolution of complex biological functions, including the biochemistry of ruminant digestion,{{cite journal|last1=Benner|first1=SA|last2=Caraco|first2=MD|last3=Thomson|first3=JM|last4=Gaucher|first4=EA|title=Planetary biology--paleontological, geological, and molecular histories of life.|journal=Science|date=3 May 2002|volume=296|issue=5569|pages=864–8|pmid=11988562|doi=10.1126/science.1069863|bibcode = 2002Sci...296..864B |s2cid=2316101}}{{rp|209}} the thermophily of ancient bacteria, and the interaction between plants, fruits, and fungi at the time of the Cretaceous extinction.{{rp|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.{{cite book|last1=Liberles|first1=David A.|title=Ancestral sequence reconstruction|date=2007|publisher=Oxford University Press|location=Oxford|isbn=9780199299188|page=221|url=https://books.google.com/books?id=G3YTDAAAQBAJ&pg=PA221}}{{rp|221}}

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.{{cite book|last1=Ward|first1=Peter|last2=Kirschvink|first2=Joe|title=A New History of Life: The Radical New Discoveries About the Origins and Evolution of Life on Earth.|date=2014|publisher=Bloomsbury|location=USA|isbn=978-1608199075|pages=55–60|url=https://books.google.com/books?id=DA8bBQAAQBAJ&pg=PA363|access-date=6 July 2016}} He suggested that the planet Mars may have had more desirable conditions than Earth for the initial production of RNA,{{cite journal |last=Zimmer |first=Carl |author-link=Carl Zimmer |date=26 June 2004 |title=What Came Before DNA? |url=http://discovermagazine.com/2004/jun/cover |journal=Discover |issn=0274-7529}}{{cite news|last1=Zimmer|first1=Carl|title=A Far-Flung Possibility for the Origin of Life|url=https://www.nytimes.com/2013/09/12/science/space/a-far-flung-possibility-for-the-origin-of-life.html?_r=0|access-date=1 July 2016|work=The New York Times|date=September 12, 2013}} 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.

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.{{cite news|last1=Boyd|first1=Robert S.|title=ANY BEING OUT THERE? Extreme Earth environments test astrobiology ideas|url=http://articles.philly.com/2002-11-11/news/25353747_1_earthlike-extraterrestrial-life-john-baross|archive-url=https://web.archive.org/web/20160817001914/http://articles.philly.com/2002-11-11/news/25353747_1_earthlike-extraterrestrial-life-john-baross|url-status=dead|archive-date=August 17, 2016|access-date=6 July 2016|work=Philadelphia Inquirer|date=November 11, 2002}}{{cite journal|last1=Greenwood|first1=Veronique|title=What Life Leaves Behind What We Know: The search for life beyond our pale blue dot is fraught with dashed hopes. Will the chemical and mineral fingerprints of Earthly organisms apply on other worlds?|journal=Seed Magazine|date=November 9, 2009|url=http://seedmagazine.com/content/article/what_life_leaves_behind/|archive-url=https://web.archive.org/web/20091115134105/http://seedmagazine.com/content/article/what_life_leaves_behind|url-status=unfit|archive-date=November 15, 2009|access-date=6 July 2016}}

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.{{Cite journal |last1=Benner |first1=Steven A. |last2=Hutter |first2=Daniel |date=2002-02-01 |title=Phosphates, DNA, and the Search for Nonterrean Life: A Second Generation Model for Genetic Molecules |url=https://linkinghub.elsevier.com/retrieve/pii/S0045206801912325 |journal=Bioorganic Chemistry |language=en |volume=30 |issue=1 |pages=62–80 |doi=10.1006/bioo.2001.1232|pmid=11955003 |url-access=subscription }} 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.{{Cite journal |last=Benner |first=Steven A. |date=2023-02-27 |title=Rethinking nucleic acids from their origins to their applications |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |language=en |volume=378 |issue=1871 |doi=10.1098/rstb.2022.0027 |pmid=36633284 |issn=0962-8436|pmc=9835595 }} This idea has been suggested as a framework by which scientists may look for life on other solar bodies besides Earth.{{Cite journal |last1=Špaček |first1=Jan |last2=Benner |first2=Steven A. |date=2022-10-01 |title=Agnostic Life Finder (ALF) for Large-Scale Screening of Martian Life During In Situ Refueling |url=https://www.liebertpub.com/doi/10.1089/ast.2021.0070 |journal=Astrobiology |language=en |volume=22 |issue=10 |pages=1255–1263 |doi=10.1089/ast.2021.0070 |pmid=35796703 |bibcode=2022AsBio..22.1255S |issn=1531-1074|url-access=subscription }}

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{{DEFAULTSORT:Benner, Steven A.}}

Category:University of Florida faculty

Category:21st-century American chemists

Category:American molecular biologists

Category:Living people

Category:1954 births

Category:Harvard University alumni

Category:American astrobiologists

Category:Synthetic biologists

Category:Searle Scholars Program recipients

Category:Yale University alumni