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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?

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Genetically engineered bacteria chemical factories of the future l.jpg

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 l.jpg

Gregory J. Crowther, Ph.D.

Acting Lecturer

Mary E. Lidstrom, Ph.D.

Frank Jungers Professor of Chemical Engineering


The chemical industry today l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 made17 l.jpg

Gene 4

How are genetic changes made?

Gene 1

Gene 2

Gene 3

DNA


How are genetic changes made18 l.jpg

Gene 4

How are genetic changes made?

Gene 1

Gene 2

Gene 3

X

X

DNA


How are genetic changes made19 l.jpg

How are genetic changes made?

Gene 1

Gene 2

Gene 3

Gene 4

DNA


Metabolic engineering mishaps maximizing ethanol production l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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.


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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 l.jpg

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 l.jpg

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.


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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 l.jpg

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 l.jpg

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


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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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