What Is Metabolic Engineering and Why Should We Care?

LBLNewsMetabolic Engineering is one of those bastard terms which is often spawned by science-savvy folks in academia who are functionally illiterate. For example, MIT has a lab department of Bioinformatics and Metabolic Engineering. Rice has studies in Biological Chemistry and Metabolic Engineering. Harvard teaches Systems Metabolic Engineering. Cornell has a lab for Biomolecular and Metabolic Engineering. At Berkeley, the subject falls under the Department of Chemical and Biomolecular Engineering... and so on. When will we be given entire departments of Respiratory Engineering, Mitochondrial Engineering, Liposome Engineering, or Cholesterol Membrane Engineering? There truly is no end to the number of departmental classifications that could be spawned by the postmodern twits of academia who have acquired a little bit of specialised scientific training.

Forgive me, I got a bit sidetracked. Chemical engineer Jay Keasling has published an article in Science discussing the "Future of Metabolic Engineering," in which he looks at the possibilities of creating designer molecules, cells, and micro-organisms.

In a paper published in the journal Science titled “Manufacturing molecules through metabolic engineering,” Keasling discusses the potential of metabolic engineering – one of the principal techniques of modern biotechnology – for the microbial production of many of the chemicals that are currently derived from non-renewable resources or limited natural resources. Examples include, among a great many other possibilities, the replacement of gasoline and other transportation fuels with clean, green and renewable biofuels.

“Continued development of the tools of metabolic engineering will be necessary to expand the range of products that can be produced using biological systems, Keasling says. “However, when more of these tools are available, metabolic engineering should be just as powerful as synthetic organic chemistry, and together the two disciplines can greatly expand the number of chemical products available from renewable resources.”

...Metabolic engineering is the practice of altering genes and metabolic pathways within a cell or microorganism to increase its production of a specific substance. Keasling led one of the most successful efforts to date in the application of metabolic engineering, when he combined it with synthetic organic chemistry techniques to develop a microbial-based means of producing artemisinin, the most potent of all anti-malaria drugs. He and his research group at JBEI are now applying that same combination to the synthesis of liquid transportation fuels from lignocellulosic biomass. In all cases, the goal is to engineer microbes to perform as much of the chemistry required to produce a desired final product as possible.

“To date, microbial production of natural chemical products has been achieved by transferring product-specific enzymes or entire metabolic pathways from rare or genetically intractable organisms to those that can be readily engineered,” Keasling says. “Production of non-natural specialty chemicals, bulk chemicals, and fuels has been enabled by combining enzymes or pathways from different hosts into a single microorganism, and by engineering enzymes to have new function.”

These efforts have utilized well-known, industrial microorganisms, but future efforts, he says, may include designer molecules and cells that are tailor-made for the desired chemical and production process. _LBLNews_via_BrianWang

Sound familiar, this metabolic engineering? Like a contrived illegitimate offspring of genetic engineering, synthetic biology, and metabolomics? It's bad enough to have a proliferation of -omics, such as genomics, proteinomics, metabolomics, glycomics, lipomics . . . It is almost enough to turn a person homicidalomic.

Psychiatry with its DSM is almost as insane. But these irrational and cumbersome systems of classification tend to evolve by the method of poorly punctuated disequilibrium, leaving those downstream to deal with the offalness of it all.

Does Keasling simply want to excel in a field that another researcher -- Craig Venter -- has already staked out -- synthetic biology? Venter has long since founded a company called Synthetic Genomics. Is it possible that Keasling is unwilling to share the same field with a person such as Venter, who is already hot on the trail of the very things that Keasling claims to be pursuing in the name of Metabolic Engineering? Fine. Do the same thing, but call it something different. No one will ever know.

Microbes Rule the World, The Least They Could Do is Give Us All the Energy We Want

...historically, the study of microbes has focused on single species in pure culture, so understanding of these complex communities lags behind understanding of their individual members. NAS_New_Science_of_Metagenomics

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It is fortuitous that humans are finally learning the reality behind the community of microbes that rules the world, just at the time that we could use their help. Craig Venter and competitors are trying to create the perfect energy-making microbe. But growing single strains of microbes to make energy from sunlight, waste nutrients, and CO2 may not be the right approach. A community of microbes working together might do a better job. In fact, you might even say it takes a village of microbes to make a fuel.

Unlike the E. coli situation, using just one species may not work well for bioenergy, since, in nature, bacteria do not grow in isolation. In other words, no bacterium is an island. The very biodiversity that fills the Earth with bacteria and offers great bioenergy potential also presents a challenge for engineers. Even if one picks the ideal "bug," growing, maintaining, and optimizing conditions for its use in bioenergy applications remains a daunting challenge in terms of scalability and reliability.

"Microbial communities that are used to harvest energy must be resilient to fluctuations in environmental conditions, variations in nutrient and energy inputs and intrusion by microbial invaders that might consume the desired energy product," say the authors. The key to large-scale success in microbial bioenergy is managing the microbial community so that that the community delivers the desired bioenergy product reliably and at high rate.

In the absence of these molecular techniques, the authors state, our understanding of methanogenic communities progressed through slow, incremental advances over several decades. Today, society cannot wait decades for new bioenergy sources. Fortunately, an array of pre-genomic, genomic, and post-genomic tools is available to understand microorganisms involved in bioenergy production. Taking full advantage of these tools will greatly speed up scientific and technological advances, which is what society most needs.

Genomics provides the base sequence of the entire DNA in an organism, and the complete genome reveals all the possible biological reactions that a microorganism can carry out. In the past, complete genomes were only obtained for those microorganisms that could be isolated into pure culture, but it is now possible to sequence the genomes of uncultivated microorganisms using metagenomics.

To date, approximately 75 genomes are available from microorganisms that have a role in bioenergy production. These include 21 genomes from methane producing archaea, 24 genomes from bacteria that can produce hydrogen or electricity, and 30 genomes from cyanobacteria that are potential biodiesel producers. At least half of the completed microbial genomes that are relevant to bioenergy were released in the past 2 years, and more than 80 bioenergy-related genomes are currently being sequenced. __ScienceDaily_via_NextBigFuture

If you are not familiar with "metagenomics" you are not alone. It is less than a decade old, and like its siblings "synthetic biology" and "systems biology" it is still developing the new tools it will need to take off like a rocket.

The "community microbe" approach to bioenergy makes a lot of sense. One microbe can only carry so many tools to work with, and a robust approach to high-yield bioenergy will require several tools working simultaneously.

I once suggested using multiple microbes for biofuels production, grown individually in a series of bioreactors. I suspect that a combination of the two ideas may be most successful--a series of bioreactors, each containing specialised communities of microbes rather than single cultures. Working out the best ways of separating the desired product from each stage--for transfer to the next bioreactor -- may take some time.

Also, see Brian Wang's excellent overview of microbial approaches to bioenergy.