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Synthetic Biology: Boon or Bane? Scott C. Mohr Boston University Department of Chemistry & Bioinformatics Program MIT Program on Emerging Technologies (PoET) Synthetic Biology Engineering Research Center (SynBERC). What is “synthetic biology?”.

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What is “synthetic biology?”


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    1. Synthetic Biology:Boon or Bane?Scott C. MohrBoston UniversityDepartment of Chemistry& Bioinformatics ProgramMITProgram on Emerging Technologies (PoET)Synthetic Biology Engineering Research Center (SynBERC)

    2. What is “synthetic biology?” In the broadest sense, synthetic biology is the deliberate, constructive modification of cells, organisms, populations – or their major sub- systems – so as to achieve a human objective. It includes the artificial creation of the natural functional components of living systems as well as non-biological analogs, and ultimately aims to create completely novel organisms, both biomimetic and otherwise. “Why be content with nature’s design, arrived at by sometimes arbitrary and now irrelevant evolutionary pressures, when a little manipulation might yield something more useful?” James D. Watson in DNA:The Secret of Life (2003)

    3. What is “synthetic biology?” • Colonization of molecular biology by engineers and computer scientists? • Genetic engineering on steroids! • “Extreme genetic engineering.” (Etc group) • The logical outgrowth of the scientific examination of the living world – enabled and driven by advances in chemistry and molecular life sciences.

    4. Synthetic Biology, sensu stricto Synthetic Biology is -- “intentional engineering of biological systems...focused on the design of artificial biological systems, rather than on the understanding of natural biology...simplifying some of the complex interactions characteristic of natural biology.” -- Synthetic Biology 1.0 International Conference Massachusetts Institute of Technology (June 10-12, 2004)

    5. Biology’s Millennium Arrives: June 26, 2000 White House news conference announcing the completion of the rough draft of the human genome.

    6. Genome Scorecard First “organism”: fX174 bacteriophage (1977) 5,375 nt First bacterium: Haemophilus influenzae (1995) 1.8 Mb First archaeon: Methanocaldococcus jannische (1996) 1.7 Mb First eukaryote: Saccharomyces cerevisiae (1996) 12 Mb First multicellular organism: Caenorhabditis elegans (1998) 97 Mb First vertebrate: Homo sapiens (2000) 3 Gb Completed Genome Sequences APRIL 2007 Viruses: 2339 Bacteria: 446 Archaea: 37 Eukaryotes: 26 (137 in assembly; 186 in progress) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj

    7. Broad Institute Sequencing Capability April 2007 Annual throughput: 60 Gb ( > all of GenBank as of 1/1/2006 !) ABI 377 sequencers: 117 Monthly sequencing enzyme budget: $2 M Time to sequence a typical virus genome: 4 hours Viral genomes sequenced per week: 120 Dengue virus project: > 3300 genomes Bacterial genomes sequenced per day: 7 Fungal genomes sequenced per day: 0.5 Facility downtime since opening in 2001: 1 day

    8. The Tree of Life Charles Darwin’s notebook entry for July 1837

    9. The Ultimate Archaeology S10 – B/A Alignment Color Scheme: blue – polar green – l hydrophobic red – G, P

    10. Biochemical Unity 20 a-amino acids (all L-stereoisomers) D-glucose ATP RNA based on A, U, G, C and D-ribose Common metabolic pathways etc., etc. All living organisms share the same fundamental molecular “operating system.” We can assume that parts and components from one organism will usually function within the cells of another organism. This opens the door for major projects to re-engineer all types of living systems.

    11. All presently living species/ organisms: Natural Biology

    12. All presently living species/ organisms: Natural Biology Natural Selection (Darwinian) 3.8 x 109 yr

    13. Human Selection (Breeding) 40,000 yr (?) Domesticated Animals, Plants & Fungi All presently living species/ organisms: Natural Biology Natural Selection (Darwinian) 3.8 x 109 yr

    14. “Playing God” Is Nothing New! Domestication has drasti- cally altered more than 40 animal species and innu- merable plants. We are not strangers to altering the biological universe – including the environ- ment. We continue the rampant extermination of vast numbers of species…

    15. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products Domesticated Animals, Plants & Fungi All presently living species/ organisms: Natural Biology Natural Selection (Darwinian) 3.8 x 109 yr

    16. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi All presently living species/ organisms: Natural Biology Natural Selection (Darwinian) 3.8 x 109 yr

    17. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr

    18. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs

    19. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 Synthetic high-Mr Natural Products

    20. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 Synthetic high-Mr Natural Products Polymers (“plastics”)

    21. Origins of Synthetic Biologyin Synthetic Chemistry • Serendipitous synthesis of urea from ammonium cyanate by Friedrich Wöhler in 1828. End of élan vital and beginning of organic chemistry. • Natural products chemistry – isolation of organic compounds from biological sources. • Synthetic organic chemistry – proof of structure by synthesis E. Fischer, R.B. Woodward, Y. Kishi et al. • Rise of polymer chemistry – plastics to biopolymers.

    22. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 Synthetic high-Mr Natural Products Genetically Engineered Cells/Vectors Polymers (“plastics”) 1970’s MOLECULAR BIOLOGY

    23. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 Synthetic high-Mr Natural Products Genetically Engineered Cells/Vectors Polymers (“plastics”) 1970’s Biopharmaceuticals, GM crops Gene therapy MOLECULAR BIOLOGY

    24. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 SYNTHETIC BIOLOGY Synthetic high-Mr Natural Products Genetically Engineered Cells/Vectors ~ 2000 Polymers (“plastics”) 1970’s GENOME ERA Biopharmaceuticals, GM crops Gene therapy MOLECULAR BIOLOGY

    25. >5,000 yr Human Selection (Breeding) 40,000 yr (?) Isolated high-Mr Natural Products ~ 5,000 yr Isolated low-Mr Natural Products Domesticated Animals, Plants & Fungi MODERN CHEMISTRY All presently living species/ organisms: Natural Biology 1828 Synthetic low-Mr Natural Products Natural Selection (Darwinian) 3.8 x 109 yr Drugs ~1900 SYNTHETIC BIOLOGY Synthetic high-Mr Natural Products Genetically Engineered Cells/Vectors ~ 2000 Polymers (“plastics”) Novel gene controls New biosynthetic paths Streamlined organisms Utterly novel life forms? 1970’s GENOME ERA Biopharmaceuticals, GM crops Gene therapy MOLECULAR BIOLOGY

    26. Ever-enhanced Control over Living Cells • Random mutagenesis – followed by selection (1930s) • DNA sequencing & cloning – cells as protein factories (human insulin, 1978) • DNA synthesis & genetic engineering – controlled mutagenesis (1978) • de novo protein engineering (1990s) • Total synthesis of a virus genome – polio (2002), φX174 (2004) • Total synthesis of a bacterial genome (2007…?) • Total synthesis of a eukaryotic genome (2020??)

    27. Landmarks in Synthetic Biology • Genetic Toggle (Gardner, Cantor & Collins, 2000) • Repressilator (Elowitz & Leibler, 2000) • Riboswitches (Breaker, Smolke, 2003) • Tunable Promoters (Mijakovic, 2005) • Artemesinin Pathway (Keasling, 2006)

    28. A Genetic Toggle Switch Inducer 1 relieves the repression of promoter 1, allowing synthesis of repressor 2. This blocks promoter 2 such that no more repressor 1 can be produced. Under these conditions, promoter 2 remains off and the reporter (GFP) does not get synthesized. As the cells grow, the pre- existing repressor 1 gets diluted out and the repressor 2 gene is consti- tuitively on, even in the absence of inducer 1. Adding inducer 2 releases promoter 2, repressor 1 is generated and synthesis of repressor 2 shut off. By the same dilution effect described above, repressor 2 gets re- moved and the system is stably switched to the expression of the pro- moter 2-controlled genes, including the reporter (GFP).

    29. Jim Collins, Tim Gardner Charles Cantor Nature403, 339-342 (2000)

    30. The Repressilator I

    31. The Repressilator II Michael Elowitz Nature403, 335-338 (2000)

    32. The Repressilator III a-c sibling cells with altered phases; d cells from different experiments; e IPTG control; f reporter- only control

    33. Riboswitches Christina Smolke

    34. Complexity Yields Sensitivity E. Andrianantoandro et al. (2006) Molecular Systems Biology 2006.0028

    35. The Key to Conquering Malaria: Artemisinin Moving the biosynthesis path- way from Artemisia annua to yeast and E. coli promises to cut the drug’s cost by > 90%. Jay Keasling

    36. BioBricks BioBricks is a standard for interchangable parts, developed with a view to building biological systems in living cells. The picture to the left shows BioBrick part BBa_B0034 within a plasmid. The brick is flanked by a standard BioBrick prefix (P) and suffix (S). Click the image to find out more or alternatively see: BioBrick Standard Parts Tom Knight etc. http://parts.mit.edu/registry/index.php/Main_Page

    37. Community Conclaves Synthetic Biology 3.0 24th-26th June 2007 Zurich, Switzerland http://www.syntheticbiology3.ethz.ch/ SyntheticBiology2.0 May 20-22, 2006University of California, Berkeley Synthetic Biology 1.0 The First International Meeting on Synthetic Biology June 10-12, 2004 at the Massachusetts Institute of Technology Cambridge, MA

    38. Synthetic Biology Can Be Child’s Play! Nature’s first comic book (published on November 20, 2005) Featuring Bacteria Buddy, Device Dude, and System Sally Downloadable at: http://mit.edu/endy/www/ scraps/comic/AiSB.vol1.pdf

    39. RandyRettberg iGEM - The international Genetically Engineered Machine competition iGEM is an international arena where student teams compete to design and assemble engineered machines using advanced genetic components and technologies. http://parts2.mit.edu/wiki/index.php/Main_Page http://en.wikipedia.org/wiki/IGEM

    40. iGEM Teams Throng MIT’s STATA Center November 2006 The winning team from Ljubljana, Slovenija de- signed a system to inhi- bit over-reaction of the human innate immune system to infection that could lead to sepsis. Their BioBricks function in mammalian cells…

    41. Now for a Glimpse of the Dark Side… Bioterrorism

    42. CDC Select Agents* – Bacteria • Bacillus anthracis (spores) • Brucella abortus • Brucella melitensis • Brucella suis • Burkholderia mallei (aka Pseudomonas mallei) • Burkholderia pseudomallei (aka Pseudomonas pseudomallei) • Clostridium (botulinum- producing species) • Coxiella burnetii • Francisella tularensis • Rickettsia prowazekii • Rickettsia rickettsii • Yersinia pestis n = 12 * Not including agents only on USDA lists.

    43. CDC Select Agents* – Fungi • Coccidiodies immitis • Coccidiodies posadasii n = 2 * Not including agents only on USDA lists.

    44. CDC Select Agents* – Viruses I • Central European Tick-borne encephalitis • Cercopithecine herpesvirus 1 • Crimean-Congo haemorrhagic fever • Eastern Equine encephalitis • Ebola • Far Eastern Tick-borne encephalitis • Flexal South American haemorrhagic fever • Guanarito South American haemorrhagic fever • Hendra • Junin South American haemorrhagic fever • Kyasanur Forest disease • Lassa fever • Marburg * Not including agents only on USDA lists.

    45. CDC Select Agents* – Viruses II • Machupo South American haemorrhagic fever • Monkeypox • Nipah • Omsk haemorrhagic fever • Reconstructed 1918 influenza • Rift Valley fever • Russian Spring and Summer encephalitis • Sabia South American haemorrhagic fever • Variola major (smallpox) • Variola minor (alastrim) • Venezuelan Equine encephalitis n = 24 * Not including agents only on USDA lists.

    46. CDC Select Agents* – Toxins • Abrin • Botulinum neurotoxins • Clostridium perfingens epsilon toxin • Conotoxins • Diacetoxyscirpenol • Ricin • Saxitoxin • Shiga-like ribosome-inactivating proteins • Shigatoxin • Staphylococcal enterotoxins • Tetrodotoxin • T-2 toxin n = 12 * Not including agents only on USDA lists.

    47. CDC Select Agents – Nucleic Acids n = 0 !

    48. Additional Potential Bioterrorism Agents • Chlamydia psittaci • Cryptosporidium parvum • Escherichia coli O157:H7 • hantavirus • Salmonella species • Shigella species • Vibria cholerae