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Genetically  engineered  bacteria: Chemical  factories  of  the  future? Image: G. Karp,  Cell and molecular biology Relocation mechanism   Assembly line Central computer Security fence Outer and internal walls
Gregory J. Crowther, Ph.D. Acting Lecturer Mary E. Lidstrom, Ph.D. Frank Jungers Professor of Chemical Engineering
The  chemical  industry  today ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],www.hr/tuzla/slike
Possible  solution: Use  bacteria  as  chemical  factories Starting materials Value-added products ,[object Object],[object Object],[object Object]
Advantages  of  bacteria  vs.  other  cells ,[object Object],[object Object],[object Object],www.milebymile.com/main/United_States/Wyoming/ - thrive in extreme environments - use nutrients unavailable to other organisms
Potential  products •  Fuels •  Natural products (complex synthesis) •  Engineered products www.myhealthshack.net; www.acehardware.com   - hydrogen (H 2 ) - methane (CH 4 ) - methanol (CH 3 OH) - ethanol (CH 3 CH 2 OH) - starting materials for polymers (rubber, plastic, fabrics) - specialty chemicals (chiral) - bulk chemicals (C 4  acids) - vitamins - therapeutic agents - pigments - amino acids - viscosifiers - industrial enzymes - PHAs (biodegradable plastics)
Limitations  of  naturally  occurring  bacteria Bacteria are evolved for survival in competitive natural environments,  not for  production of chemicals  desired by humans! coolgov.com   - are optimized for low nutrient levels - have defense systems - don’t naturally make everything we need
Redesigning  bacteria Goal : optimize industrially valuable parameters. •  Redirect metabolism to specific products •  Remove unwanted products - storage products - excretion products - defense systems pyo.oulu.fi
Metabolic  engineering (a  form  of  genetic  engineering) DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
Deleting  a  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
Deleting  a  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X
Deleting  a  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X X
Deleting  a  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X X X
Adding  a  new  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
Adding  a  new  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4
Adding  a  new  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4 Enzyme 4
Adding  a  new  gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4 Enzyme 4 E
How  are  genetic  changes  made? ,[object Object],[object Object],[object Object],Gene 4 plasmid
How  are  genetic  changes  made? plasmid Gene 4 ,[object Object],[object Object],[object Object]
How  are  genetic  changes  made? plasmid Gene 4 ,[object Object],[object Object],[object Object]
How  are  genetic  changes  made? plasmid ,[object Object],[object Object],[object Object],Gene 4
How  are  genetic  changes  made? DNA Gene 1 Gene 2 Gene 3
How  are  genetic  changes  made? DNA Gene 1 Gene 2 Gene 3 Gene 4
How  are  genetic  changes  made? DNA Gene 1 Gene 2 Gene 3 Gene 4
How  are  genetic  changes  made? DNA Gene 1 Gene 2 Gene 3 X X Gene 4
How  are  genetic  changes  made? DNA Gene 1 Gene 2 Gene 3 Gene 4
Metabolic  engineering  mishaps:  maximizing  ethanol  production PFK ethanol glucose PFK  was thought to be the rate-limiting enzyme of ethanol production, so its levels were increased via genetic engineering. Problem : rates of ethanol production did not increase!
Metabolic  engineering  mishaps:  maximizing  PHA  production CH 2 =H 4 F Serine Cycle CH 2 =H 4 MPT H 4 MPT CH 3 OH HCHO H 4 F CO 2 PHA To maximize PHA production in  M. extorquens , one might try to knock out the right-hand pathway. Problems: •  HCHO builds up and is toxic •  Cells can’t generate enough energy for growth X
Cellular  metabolism  is  very   complicated! •  Lots of molecules •  Highly interconnected •  Mathematical models can help us predict the effects of genetic changes opbs.okstate.edu/~leach/Bioch5853/
Flux  balance  analysis A A B C D E In a steady state, all concentrations are constant.  For each compound, production rate = consumption rate.  To get a solution (flux rate for each step), define an objective function (e.g., production of E) to be maximized. 10 10 10 10 0 0 10
Edwards & Palsson (2000) Reference:  PNAS   97 : 5528-33, 2000. Used flux balance analysis to predict how well  E. coli  cells would grow if various genes were deleted. The graph at left shows their predictions of how fluxes are rerouted in response to gene deletions.
Edwards & Palsson (2000) Fraction of normal growth rate Gene deletions that should  not affect  growth. Gene deletions that should  slow  growth. Gene deletions that should  stop  growth.
Edwards & Palsson (2000) Predictions of whether various  E. coli  mutants should be able to grow were compared with experimental data on these mutants.  In 68 of 79 cases (86%), the prediction agreed with the experimental data.
Ethical  issues •  Is it OK to tamper with the genes of living organisms? •  What are the possible effects on those organisms? •  What are the possible effects on human health? •  What are the possible effects on the environment?
Summary •  Bacteria have great potential as environmentally friendly chemical “factories.” •  Much additional research will be  needed for this potential to be  fulfilled. •  Further progress will require  knowledge of biology, chemistry,  engineering, and mathematics. www.elsevier.com
More  information about  metabolic  engineering depts.washington.edu/mllab web.mit.edu/bamel www.genomatica.com www.metabolix.com Lidstrom lab (UW) Stephanopoulos lab (MIT) Company founded by Palsson (UCSD) Well-written background info and examples

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Genetically engineered bacteria: chemical factories of the future?

  • 1. Genetically engineered bacteria: Chemical factories of the future? Image: G. Karp, Cell and molecular biology Relocation mechanism Assembly line Central computer Security fence Outer and internal walls
  • 2. Gregory J. Crowther, Ph.D. Acting Lecturer Mary E. Lidstrom, Ph.D. Frank Jungers Professor of Chemical Engineering
  • 3.
  • 4.
  • 5.
  • 6. Potential products • Fuels • Natural products (complex synthesis) • Engineered products www.myhealthshack.net; www.acehardware.com - hydrogen (H 2 ) - methane (CH 4 ) - methanol (CH 3 OH) - ethanol (CH 3 CH 2 OH) - starting materials for polymers (rubber, plastic, fabrics) - specialty chemicals (chiral) - bulk chemicals (C 4 acids) - vitamins - therapeutic agents - pigments - amino acids - viscosifiers - industrial enzymes - PHAs (biodegradable plastics)
  • 7. Limitations of naturally occurring bacteria Bacteria are evolved for survival in competitive natural environments, not for production of chemicals desired by humans! coolgov.com - are optimized for low nutrient levels - have defense systems - don’t naturally make everything we need
  • 8. Redesigning bacteria Goal : optimize industrially valuable parameters. • Redirect metabolism to specific products • Remove unwanted products - storage products - excretion products - defense systems pyo.oulu.fi
  • 9. Metabolic engineering (a form of genetic engineering) DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
  • 10. Deleting a gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
  • 11. Deleting a gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X
  • 12. Deleting a gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X X
  • 13. Deleting a gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA X X X
  • 14. Adding a new gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A DNA
  • 15. Adding a new gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4
  • 16. Adding a new gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4 Enzyme 4
  • 17. Adding a new gene DNA Gene 1 Gene 2 Gene 3 Enzyme 1 Enzyme 2 Enzyme 3 A B C D A Gene 4 Enzyme 4 E
  • 18.
  • 19.
  • 20.
  • 21.
  • 22. How are genetic changes made? DNA Gene 1 Gene 2 Gene 3
  • 23. How are genetic changes made? DNA Gene 1 Gene 2 Gene 3 Gene 4
  • 24. How are genetic changes made? DNA Gene 1 Gene 2 Gene 3 Gene 4
  • 25. How are genetic changes made? DNA Gene 1 Gene 2 Gene 3 X X Gene 4
  • 26. How are genetic changes made? DNA Gene 1 Gene 2 Gene 3 Gene 4
  • 27. Metabolic engineering mishaps: maximizing ethanol production PFK ethanol glucose PFK was thought to be the rate-limiting enzyme of ethanol production, so its levels were increased via genetic engineering. Problem : rates of ethanol production did not increase!
  • 28. Metabolic engineering mishaps: maximizing PHA production CH 2 =H 4 F Serine Cycle CH 2 =H 4 MPT H 4 MPT CH 3 OH HCHO H 4 F CO 2 PHA To maximize PHA production in M. extorquens , one might try to knock out the right-hand pathway. Problems: • HCHO builds up and is toxic • Cells can’t generate enough energy for growth X
  • 29. Cellular metabolism is very complicated! • Lots of molecules • Highly interconnected • Mathematical models can help us predict the effects of genetic changes opbs.okstate.edu/~leach/Bioch5853/
  • 30. Flux balance analysis A A B C D E In a steady state, all concentrations are constant. For each compound, production rate = consumption rate. To get a solution (flux rate for each step), define an objective function (e.g., production of E) to be maximized. 10 10 10 10 0 0 10
  • 31. Edwards & Palsson (2000) Reference: PNAS 97 : 5528-33, 2000. Used flux balance analysis to predict how well E. coli cells would grow if various genes were deleted. The graph at left shows their predictions of how fluxes are rerouted in response to gene deletions.
  • 32. Edwards & Palsson (2000) Fraction of normal growth rate Gene deletions that should not affect growth. Gene deletions that should slow growth. Gene deletions that should stop growth.
  • 33. Edwards & Palsson (2000) Predictions of whether various E. coli mutants should be able to grow were compared with experimental data on these mutants. In 68 of 79 cases (86%), the prediction agreed with the experimental data.
  • 34. Ethical issues • Is it OK to tamper with the genes of living organisms? • What are the possible effects on those organisms? • What are the possible effects on human health? • What are the possible effects on the environment?
  • 35. Summary • Bacteria have great potential as environmentally friendly chemical “factories.” • Much additional research will be needed for this potential to be fulfilled. • Further progress will require knowledge of biology, chemistry, engineering, and mathematics. www.elsevier.com
  • 36. More information about metabolic engineering depts.washington.edu/mllab web.mit.edu/bamel www.genomatica.com www.metabolix.com Lidstrom lab (UW) Stephanopoulos lab (MIT) Company founded by Palsson (UCSD) Well-written background info and examples