Xenobiology: State-of-the-Art, Ethics, and Philosophy of New-to-Nature Organisms

Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 162)


The basic chemical constitution of all living organisms in the context of carbon-based chemistry consists of a limited number of small molecules and polymers. Until the twenty-first century, biology was mainly an analytical science and has now reached a point where it merges with engineering science, paving the way for synthetic biology. One of the objectives of synthetic biology is to try to change the chemical compositions of living cells, that is, to create an artificial biological diversity, which in turn fosters a new sub-field of synthetic biology, xenobiology. In particular, the genetic code in living systems is based on highly standardized chemistry composed of the same “letters” or nucleotides as informational polymers (DNA, RNA) and the 20 amino acids which serve as basic building blocks for proteins. The universality of the genetic code enables not only vertical gene transfer within the same species but also horizontal gene transfer across biological taxa, which require a high degree of standardization and interconnectivity. Although some minor alterations of the standard genetic code are found in nature (e.g., proteins containing non-conical amino acids exist in nature, and some organisms use alternated coding systems), all structurally deep chemistry changes within living systems are generally lethal, making the creation of artificial biological system an extremely difficult challenge.

In this context, one of the great challenges for bioscience is the development of a strategy for expanding the standard basic chemical repertoire of living cells. Attempts to alter the meaning of the genetic information stored in DNA as an informational polymer by changing the chemistry of the polymer (i.e., xeno-nucleic acids) or by changes in the genetic code have already yielded successful results. In the future this should enable the partial or full redirection of the biological information flow to generate “new” version(s) of the genetic code derived from the “old” biological world.

In addition to the scientific challenges, the attempt to increase biochemical diversity also raises important ethical and philosophical issues. Although promotors of this branch of synthetic biology highlight the many potential applications to come (e.g., novel tools for diagnostics and fighting infection diseases), such developments could also bring risks affecting social, political, and other structures of nearly all societies.


Ethics New-to-nature Non-canonical amino acids Philosophy Synthetic biology Xenobiology 



The thoughts and ideas presented here are largely results of our interaction with Philippe Marlière, Sven Panke, Piet Herdewijn, Carlos-Acevedo Rocha, and Dirk Schulze-Makuch. Another very fortunate circumstance was that we worked together in EU-FP7 founded project METACODE (289572) whereby we could start to implement some of our conceptual ideas in the field of xenobiology. MS and NB also acknowledge support form EC FP7 project SYNPEPTIDE (613981) and MS acknowledges EC FP7 project SYNENERGENE (321488).


  1. 1.
    Budisa N (2014) Life at the speed of light. From the double helix to the dawn of digital life. By J. Craig Venter. Angew Chem Int Ed 53(36):9421–9422CrossRefGoogle Scholar
  2. 2.
    Venter JC (2013) Life at the speed of light – from the from the double helix to the dawn of digital life. Viking Penguin, New YorkGoogle Scholar
  3. 3.
    Balter M (2015) Farming was so nice, it was invented at least twice. Science news, from
  4. 4.
    Cameron DE, Bashor CJ, Collins JJ (2014) A brief history of synthetic biology. Nat Rev Microbiol 12(5):381–390CrossRefGoogle Scholar
  5. 5.
    Schmidt M (2010) Xenobiology: a new form of life as the ultimate biosafety tool. BioEssays 32(4):322–331CrossRefGoogle Scholar
  6. 6.
    de Lorenzo V (2010) Environmental biosafety in the age of synthetic biology: do we really need a radical new approach? Environmental fates of microorganisms bearing synthetic genomes could be predicted from previous data on traditionally engineered bacteria for in situ bioremediation. BioEssays 32(11):926–931CrossRefGoogle Scholar
  7. 7.
    Wiltschi B, Budisa N (2007) Natural history and experimental evolution of the genetic code. Appl Microbiol Biotechnol 74(4):739–753CrossRefGoogle Scholar
  8. 8.
    Heinemann M, Panke S (2006) Synthetic biology – putting engineering into biology. Bioinformatics 22(22):2790–2799CrossRefGoogle Scholar
  9. 9.
    Buckling A, Craig Maclean R, Brockhurst MA, Colegrave N (2009) The Beagle in a bottle. Nature 457(7231):824–829CrossRefGoogle Scholar
  10. 10.
    Morowitz HJ, Heinz B, Deamer DW (1988) The chemical logic of a minimum protocell. Orig Life Evol Biosph 18(3):281–287CrossRefGoogle Scholar
  11. 11.
    Budisa N (2004) Prolegomena to future experimental efforts on genetic code engineering by expanding its amino acid repertoire. Angew Chem Int Ed Engl 43(47):6426–6463CrossRefGoogle Scholar
  12. 12.
    Budisa N (2005) Expanding the amino acid repertoire for the design of novel proteins. Willey-VHC, Weinheim/New York/Brisbane/Singapore/TorontoCrossRefGoogle Scholar
  13. 13.
    Church G, Regis E (2012) Regenesis: how synthetic biology will reinvent nature and ourselves. Basic Books, New YorkGoogle Scholar
  14. 14.
    Multhauf RP (1966) The origins of chemistry. Oldbourne, LondonGoogle Scholar
  15. 15.
    Fisher E (1907) Synthetic chemistry in its relation to biology (Faraday Lecture). J Chem Soc Chem Commun 91:1749–1765Google Scholar
  16. 16.
    Acevedo-Rocha CG, Budisa N (2011) On the road towards chemically modified organisms endowed with a genetic firewall. Angew Chem Int Ed Engl 50(31):6960–6962CrossRefGoogle Scholar
  17. 17.
    Mampel J, Buescher JM, Meurer G, Eck J (2013) Coping with complexity in metabolic engineering. Trends Biotechnol 31(1):52–60CrossRefGoogle Scholar
  18. 18.
    Schmidt M, de Lorenzo V (2012) Synthetic constructs in/for the environment: managing the interplay between natural and engineered biology. FEBS Lett 586(15):2199–2206CrossRefGoogle Scholar
  19. 19.
    Acevedo-Rocha CG (2016) The synthetic nature of biology. In: Hagen K, Engelhard M, Toepfer G (eds) Ambivalences of creating life: societal and philosophical dimensions of synthetic biology. Springer, Switzerland, pp 9–53Google Scholar
  20. 20.
    Agapakis CM, Silver PA (2009) Synthetic biology: exploring and exploiting genetic modularity through the design of novel biological networks. Mol Biosyst 5(7):704–713CrossRefGoogle Scholar
  21. 21.
    Budisa N (2014) Xenobiology, new-to-nature synthetic cells and genetic firewall. Curr Org Chem 18(8):936–943CrossRefGoogle Scholar
  22. 22.
    Hutchison CA III, Chuang RY, Noskov VN, Assad-Garcia N, Deerinck TJ, Ellisman MH, Gill J, Kannan K, Karas BJ, Ma L, Pelletier JF, Qi ZQ, Richter RA, Strychalski EA, Sun L, Suzuki Y, Tsvetanova B, Wise KS, Smith HO, Glass JI, Merryman C, Gibson DG, Venter JC (2016) Design and synthesis of a minimal bacterial genome. Science 351(6280):aad6253Google Scholar
  23. 23.
    Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, Benders GA, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi ZQ, Segall-Shapiro TH, Calvey CH, Parmar PP, Hutchison CA 3rd, Smith HO, Venter JC (2010) Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329(5987):52–56CrossRefGoogle Scholar
  24. 24.
    SCHER, SCENIHR, SCCS (2014) Opinion on synthetic biology I definition. Available at
  25. 25.
    Mayer C, Gillingham DG, Ward TR, Hilvert D (2011) An artificial metalloenzyme for olefin metathesis. Chem Commun (Camb) 47(44):12068–12070CrossRefGoogle Scholar
  26. 26.
    Alterovitz G, Muso T, Ramoni MF (2010) The challenges of informatics in synthetic biology: from biomolecular networks to artificial organisms. Brief Bioinform 11:80–95CrossRefGoogle Scholar
  27. 27.
    Danchin A (2009) Information of the chassis and information of the program in synthetic cells. Syst Synth Biol 3(1-4):125–134CrossRefGoogle Scholar
  28. 28.
    Landrain TE, Carrera J, Kirov B, Rodrigo G, Jaramillo A (2009) Modular model-based design for heterologous bioproduction in bacteria. Curr Opin Biotechnol 20(3):272–279CrossRefGoogle Scholar
  29. 29.
    Keasling JD (2008) Synthetic biology for synthetic chemistry. ACS Chem Biol 3(1):64–76CrossRefGoogle Scholar
  30. 30.
    Noirel J, Ow SY, Sanguinetti G, Wright PC (2009) Systems biology meets synthetic biology: a case study of the metabolic effects of synthetic rewiring. Mol Biosyst 5(10):1214–1223CrossRefGoogle Scholar
  31. 31.
    Lajoie MJ, Rovner AJ, Goodman DB, Aerni HR, Haimovich AD, Kuznetsov G, Mercer JA, Wang HH, Carr PA, Mosberg JA, Rohland N, Schultz PG, Jacobson JM, Rinehart J, Church GM, Isaacs FJ (2013) Genomically recoded organisms expand biological functions. Science 342(6156):357–360CrossRefGoogle Scholar
  32. 32.
    Herdewijn P, Marliere P (2009) Toward safe genetically modified organisms through the chemical diversification of nucleic acids. Chem Biodivers 6(6):791–808CrossRefGoogle Scholar
  33. 33.
    Benner SA, Sismour AM (2005) Synthetic biology. Nat Rev Genet 6(7):533–543CrossRefGoogle Scholar
  34. 34.
    Kimoto M, Cox RS 3rd, Hirao I (2011) Unnatural base pair systems for sensing and diagnostic applications. Expert Rev Mol Diagn 11(3):321–331Google Scholar
  35. 35.
    Matsunaga K, Kimoto M, Hanson C, Sanford M, Young HA, Hirao I (2015) Architecture of high-affinity unnatural-base DNA aptamers toward pharmaceutical applications. Sci Rep 5:18478CrossRefGoogle Scholar
  36. 36.
    SCHER, SCENIHR, SCCS (2015) Opinion on synthetic biology II - risk assessment methodologies and safety aspects. Available at
  37. 37.
    Wright O, Delmans M, Stan GB, Ellis T (2015) GeneGuard: a modular plasmid system designed for biosafety. ACS Synth Biol 4(3):307–316CrossRefGoogle Scholar
  38. 38.
    Wright O, Stan GB, Ellis T (2013) Building-in biosafety for synthetic biology. Microbiology 159(Pt 7):1221–1235CrossRefGoogle Scholar
  39. 39.
    Schmidt M (2013) Safeguarding the genetic firewall with xenobiology. 21st century borders/synthetic biology: focus on responsibility and governance, Institute on Science for Global Policy, Tucson, ArizonaGoogle Scholar
  40. 40.
    Brookes P (1959) Studies on the incorporation of an unnatural amino acid, p-di-(2-hydroxy[14C2]ethyl)amino-L-phenylalanine, into proteins. Br J Cancer 13:313–317CrossRefGoogle Scholar
  41. 41.
    Beiboer SH, van den Berg B, Dekker N, Cox RC, Verheij HM (1996) Incorporation of an unnatural amino acid in the active site of porcine pancreatic phospholipase A2. Substitution of histidine by 1,2,4-triazole-3-alanine yields an enzyme with high activity at acidic pH. Protein Eng 9(4):345–352CrossRefGoogle Scholar
  42. 42.
    Budisa N, Minks C, Alefelder S, Wenger W, Dong F, Moroder L, Huber R (1999) Toward the experimental codon reassignment in vivo: protein building with an expanded amino acid repertoire. FASEB J 13(1):41–51Google Scholar
  43. 43.
    Lemeignan B, Sonigo P, Marlière P (1993) Phenotypic suppression by incorporation of an alien amino acid. J Mol Biol 231(2):161–166CrossRefGoogle Scholar
  44. 44.
    Jang MY, Song XP, Froeyen M, Marliere P, Lescrinier E, Rozenski J, Herdewijn P (2013) A synthetic substrate of DNA polymerase deviating from the bases, sugar, and leaving group of canonical deoxynucleoside triphosphates. Chem Biol 20(3):416–423CrossRefGoogle Scholar
  45. 45.
    Mandell DJ, Lajoie MJ, Mee MT, Takeuchi R, Kuznetsov G, Norville JE, Gregg CJ, Stoddard BL, Church GM (2015) Biocontainment of genetically modified organisms by synthetic protein design. Nature 518(7537):55–60CrossRefGoogle Scholar
  46. 46.
    Pinheiro VB, Holliger P (2012) The XNA world: progress towards replication and evolution of synthetic genetic polymers. Curr Opin Chem Biol 16(3-4):245–252CrossRefGoogle Scholar
  47. 47.
    Pinheiro VB, Taylor AI, Cozens C, Abramov M, Renders M, Zhang S, Chaput JC, Wengel J, Peak-Chew SY, McLaughlin SH, Herdewijn P, Holliger P (2012) Synthetic genetic polymers capable of heredity and evolution. Science 336(6079):341–344CrossRefGoogle Scholar
  48. 48.
    Steele FR, Gold L (2012) The sweet allure of XNA. Nat Biotechnol 30(7):624–625CrossRefGoogle Scholar
  49. 49.
    Taylor AI, Pinheiro VB, Smola MJ, Morgunov AS, Peak-Chew S, Cozens C, Weeks KM, Herdewijn P, Holliger P (2015) Catalysts from synthetic genetic polymers. Nature 518:427–430CrossRefGoogle Scholar
  50. 50.
    Marliere P, Patrouix J, Doring V, Herdewijn P, Tricot S, Cruveiller S, Bouzon M, Mutzel R (2011) Chemical evolution of a bacterium’s genome. Angew Chem Int Ed Engl 50(31):7109–7114CrossRefGoogle Scholar
  51. 51.
    Hoesl MG, Oehm S, Durkin P, Darmon E, Peil L, Aerni HR, Rappsilber J, Rinehart J, Leach D, Soll D, Budisa N (2015) Chemical evolution of a bacterial proteome. Angew Chem Int Ed Engl 54(34):10030–10034CrossRefGoogle Scholar
  52. 52.
    Ma Y, Biava H, Contestabile R, Budisa N, di Salvo ML (2014) Coupling bioorthogonal chemistries with artificial metabolism: intracellular biosynthesis of azidohomoalanine and its incorporation into recombinant proteins. Molecules 19(1):1004–1022CrossRefGoogle Scholar
  53. 53.
    Rovner AJ, Haimovich AD, Katz SR, Li Z, Grome MW, Gassaway BM, Amiram M, Patel JR, Gallagher RR, Rinehart J, Isaacs FJ (2015) Recoded organisms engineered to depend on synthetic amino acids. Nature 518:89–93CrossRefGoogle Scholar
  54. 54.
    Dolgin E (2015) Safety boost for GM organisms. Nature 517:423CrossRefGoogle Scholar
  55. 55.
    Nunes-Alves C (2015) GMOs in lockdown. Nat Rev Microbiol 13:3443Google Scholar
  56. 56.
    Schmidt M, de Lorenzo V (2016) Synthetic bugs on the loose: containment options for deeply engineered (micro)organisms. Curr Opin Biotechnol 38:90–96CrossRefGoogle Scholar
  57. 57.
    Bohlke N, Budisa N (2014) Sense codon emancipation for proteome-wide incorporation of noncanonical amino acids: rare isoleucine codon AUA as a target for genetic code expansion. FEMS Microbiol Lett 351(2):133–144CrossRefGoogle Scholar
  58. 58.
    Acevedo-Rocha CG, Schulze-Makuch D (2015) How many biochemistries are available to build a cell? Chembiochem 16(15):2137–2139CrossRefGoogle Scholar
  59. 59.
    Marliere P (2009) The farther, the safer: a manifesto for securely navigating synthetic species away from the old living world. Syst Synth Biol 3(1-4):77–84CrossRefGoogle Scholar
  60. 60.
    Hoesl MG, Budisa N (2012) Recent advances in genetic code engineering in Escherichia coli. Curr Opin Biotechnol 23(5):751–757CrossRefGoogle Scholar
  61. 61.
    Acevedo-Rocha CG, Fang G, Schmidt M, Ussery DW, Danchin A (2013) From essential to persistent genes: a functional approach to constructing synthetic life. Trends Genet 29:273–279CrossRefGoogle Scholar
  62. 62.
    Popa R (2010) Necessity, futility and the possibility of defining life are all embedded in its origin as a punctuated-gradualism. Orig Life Evol Biosph 40(2):183–190CrossRefGoogle Scholar
  63. 63.
    Pezo V, Metzgar D, Hendrickson TL, Waas WF, Hazebrouck S, Doring V, Marliere P, Schimmel P, De Crecy-Lagard V (2004) Artificially ambiguous genetic code confers growth yield advantage. Proc Natl Acad Sci U S A 101(23):8593–8597CrossRefGoogle Scholar
  64. 64.
    Xiao H, Nasertorabi F, Choi SH, Han GW, Reed SA, Stevens RC, Schultz PG (2015) Exploring the potential impact of an expanded genetic code on protein function. Proc Natl Acad Sci U S A 112(22):6961–6966CrossRefGoogle Scholar
  65. 65.
    Konig H, Dorado-Morales P, Porcar M (2015) Responsibility and intellectual property in synthetic biology: a proposal for using Responsible Research and Innovation as a basic framework for intellectual property decisions in synthetic biology. EMBO Rep 16:1055–1059CrossRefGoogle Scholar
  66. 66.
    Owen R, Stilgoe J, Macnaghten P, Gorman M, Fisher E, Guston D (2013) A framework for responsible innovation. In: Owen R, Bessant J, Heintz M (eds) Responsible innovation, vol 1. John Wiley & Sons, London, pp 27–50CrossRefGoogle Scholar
  67. 67.
  68. 68.
    EGE (2009) Ethics of synthetic biology. Available at
  69. 69.
    De Vriend H (2006) Constructing life. Early social reflections on the emerging field of synthetic biology. Available at
  70. 70.
    European Commission (2010) Synthetic biology from science to governance. Workshop organised by the European Commission’s Directorate-General for Health & Consumers, BrusselsGoogle Scholar
  71. 71.
    Schmidt M (2008) Diffusion of synthetic biology: a challenge to biosafety. Syst Synth Biol 2(1–2):1–6CrossRefGoogle Scholar
  72. 72.
    SCHER, SCENIHR, SCCS (2015) Opinion on synthetic biology III: research priorities. Available at
  73. 73.
    Baertschi B (2013) Defeating the argument from hubris. Bioethics 27(8):435–441CrossRefGoogle Scholar
  74. 74.
    Boldt J, Müller O, Maio G (2009) Synthetische Biologie Eine ethisch-philosophische Analyse. Bundesamt für Bauten und Logistik, BernGoogle Scholar
  75. 75.
    Deplazes A (2009) Piecing together a puzzle. An exposition of synthetic biology. EMBO Rep 10(5):428–432CrossRefGoogle Scholar
  76. 76.
    Douglas T, Savulescu J (2010) Synthetic biology and the ethics of knowledge. J Med Ethics 36(11):687–693CrossRefGoogle Scholar
  77. 77.
    Cockell CS (2011) Microbial rights? EMBO J 12:181CrossRefGoogle Scholar
  78. 78.
    Frank D, Heil R, Coenen C, Konig H (2015) Synthetic biology’s self-fulfilling prophecy - dangers of confinement from within and outside. Biotechnol J 10(2):231–235CrossRefGoogle Scholar
  79. 79.
    Heavey P (2013) Synthetic biology ethics: a deontological assessment. Bioethics 27(8):442–452CrossRefGoogle Scholar
  80. 80.
    Minssen T, Rutz B, van Zimmeren E (2015) Synthetic biology and intellectual property rights: six recommendations. Biotechnol J 10(2):236–241CrossRefGoogle Scholar
  81. 81.
    CBD (2012) Nagoya Protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilization to the convention on biological diversity. Available at
  82. 82.
    Trojok RD (2014) Bio-commons whitepaper. Available at
  83. 83.
    Dabrock P (2009) Playing God? Synthetic biology as a theological and ethical challenge. Syst Synth Biol 3(1–4):47–54CrossRefGoogle Scholar
  84. 84.
    van den Belt H (2009) Playing God in Frankenstein’s footsteps: synthetic biology and the meaning of life. Nanoethics 3(3):257–268CrossRefGoogle Scholar
  85. 85.
    Malyshev DA, Dhami K, Lavergne T, Chen T, Dai N, Foster JM, Correa IR Jr, Romesberg FE (2014) A semi-synthetic organism with an expanded genetic alphabet. Nature 509(7500):385–388CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Biofaction KGViennaAustria
  2. 2.AK Biokatalyse, Institut für ChemieTechnische Universität BerlinBerlinGermany

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