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Relocation mechanism. Assembly line. Central computer. Outer and internal walls. Security fence. Genetically engineered bacteria: Chemical factories of the future?. Image: G. Karp, Cell and molecular biology. Gregory J. Crowther, Ph.D. Acting Lecturer. Mary E. Lidstrom, Ph.D.

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genetically engineered bacteria chemical factories of the future

Relocation mechanism

Assembly line

Central computer

Outer and internal walls

Security fence

Genetically engineered bacteria:Chemical factories of the future?

Image: G. Karp, Cell and molecular biology

slide2

Gregory J. Crowther, Ph.D.

Acting Lecturer

Mary E. Lidstrom, Ph.D.

Frank Jungers Professor of Chemical Engineering

the chemical industry today
The chemical industry today
  • • supplies chemicals for many manufactured goods
  • • employs many scientists and engineers
  • • based on chemicals derived from petroleum
    • not a renewable resource
    • supplied by volatile areas of the world
    • - many produce hazardous wastes

www.hr/tuzla/slike

possible solution use bacteria as chemical factories
Possible solution:Use bacteria as chemical factories

Value-added products

Starting materials

  • Self-replicating multistage catalysts
  • Environmentally benign
  • Use renewable starting materials (feedstocks)
advantages of bacteria vs other cells
Advantages of bacteria vs. other cells
  • • Relatively small and simple
  • • Reproduce quickly
  • Tremendous metabolic / catalytic diversity
  • - thrive in extreme environments
  • - use nutrients unavailable to other organisms

www.milebymile.com/main/United_States/Wyoming/

potential products
Potential products

• Fuels

• Engineered products

- hydrogen (H2)

- methane (CH4)

- methanol (CH3OH)

- ethanol (CH3CH2OH)

- starting materials for polymers (rubber, plastic, fabrics)

- specialty chemicals (chiral)

- bulk chemicals (C4 acids)

• Natural products (complex synthesis)

- vitamins

- therapeutic agents

- pigments

- amino acids

- viscosifiers

- industrial enzymes

- PHAs (biodegradable plastics)

www.myhealthshack.net; www.acehardware.com

limitations of naturally occurring bacteria
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
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

Gene 1

Gene 2

Gene 3

DNA

DNA

Enzyme 1

Enzyme 2

Enzyme 3

A

B

C

D

A

Metabolic engineering(a form of genetic engineering)
deleting a gene
Deleting a gene

X

Gene 1

Gene 2

Gene 3

DNA

DNA

X

X

Enzyme 1

Enzyme 2

Enzyme 3

A

B

C

D

A

adding a new gene
Adding a new gene

Gene 1

Gene 2

Gene 3

DNA

DNA

Enzyme 1

Enzyme 2

Enzyme 3

A

B

C

D

A

adding a new gene12
Adding a new gene

Gene 1

Gene 2

Gene 3

Gene 4

DNA

Enzyme 1

Enzyme 2

Enzyme 3

A

B

C

D

Enzyme 4

A

E

how are genetic changes made
How are genetic changes made?
  • Most common approach:
  • Put a gene of interest into a stable carrier (vector), a circle of DNA called a plasmid.
  • 2. Put the plasmid into a new cell.

Gene 4

plasmid

how are genetic changes made14

Gene 4

How are genetic changes made?
  • Most common approach:
  • Put a gene of interest into a stable carrier (vector), a circle of DNA called a plasmid.
  • 2. Put the plasmid into a new cell.

plasmid

how are genetic changes made15

Gene 4

How are genetic changes made?
  • Most common approach:
  • Put a gene of interest into a stable carrier (vector), a circle of DNA called a plasmid.
  • 2. Put the plasmid into a new cell.

Gene 4

plasmid

how are genetic changes made16

Gene 4

How are genetic changes made?
  • Most common approach:
  • Put a gene of interest into a stable carrier (vector), a circle of DNA called a plasmid.
  • 2. Put the plasmid into a new cell.

plasmid

how are genetic changes made19
How are genetic changes made?

Gene 1

Gene 2

Gene 3

Gene 4

DNA

metabolic engineering mishaps maximizing ethanol production
Metabolic engineering mishaps: maximizing ethanol production

glucose

ethanol

PFK

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
Metabolic engineering mishaps: maximizing PHA production

CH3OH

To maximize PHA production in M. extorquens, one might try to knock out the right-hand pathway.

H4MPT

H4F

HCHO

X

CH2=H4F

CH2=H4MPT

Serine Cycle

CO2

PHA

Problems:

• HCHO builds up and is toxic

• Cells can’t generate enough energy for growth

cellular metabolism is very complicated
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
Flux balance analysis

0

C

A

10

0

10

A

B

10

D

10

10

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.

edwards palsson 2000
Edwards & Palsson (2000)

Reference: PNAS97: 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 200025

Gene deletions that should not affect growth.

Gene deletions that should slow growth.

Gene deletions that should stop growth.

Edwards & Palsson (2000)

Fraction of normal growth rate

edwards palsson 200026
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
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
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
More informationabout 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

contacts for theme interviews
Contacts for theme interviews

Xiaofeng Guo (4th-year grad student)

[email protected]

Project: studying metabolic shifts of methanol-consuming bacteria by quantifying enzyme activities and metabolite concentrations under various conditions.

Alex Holland (4th-year grad student)

[email protected]

Project: manipulating polyphosphate metabolism in radiation-resistant bacteria to generate an organism that can precipitate heavy metals.

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