Streamlining the Bio-Production of Fuels, Chemicals, and Pharmaceuticals

This article is adapted from an article published on Al Fin Energy blog

The team's method can be compared to understanding both the chemical reactions and the machinery that are required to refine crude oil into petrol in a large, industrial factory. Modeling metabolism tells you what biochemical reactions need to take place. Modeling the organism's gene expression tells you what kind of machinery you need. The team's method specifically accounts for the expression of enzymes, which are the molecular machines responsible for the biochemical processes of life. With this knowledge, it is possible to explore how an organism distributes its resources to promote growth and how genetic manipulation of these organisms alters this distribution. _SD

This new approach devised by UCSD researchers is likely to expedite the creation of biological organisms capable of producing high volumes of fuels, chemicals, pharmaceuticals, etc. in a fast and profitable manner.

A biochemically accurate model of molecular biology and metabolism will facilitate comprehensive and quantitative computations of an organism's molecular constitution as a function of genetic and environmental parameters. Here we formulate a model of metabolism and macromolecular expression. Prototyping it using the simple microorganism Thermotoga maritima, we show our model accurately simulates variations in cellular composition and gene expression.

Moreover, through in silico comparative transcriptomics, the model allows the discovery of new regulons and improving the genome and transcription unit annotations. Our method presents a framework for investigating molecular biology and cellular physiology in silico and may allow quantitative interpretation of multi-omics data sets in the context of an integrated biochemical description of an organism. _NatureCommunications

Nature Communications 3, Article number: 929 doi:10.1038/ncomms1928

UCSD researchers have taken an important step toward the general ability to custom design the genome of organisms, in order to produce synthetic fuels, chemicals, pharmaceuticals, on a commercial scale.

"What you could hypothetically do with our model is simulate the total cost of producing a value-added product, such as a biofuel. That includes all the operating and maintenance costs," said Daniel Hyduke, a project scientist in Palsson's lab. Hyduke said the method has the potential to help streamline industrial metabolic engineering efforts by providing a near complete accounting of the minimal material and energy costs associated with novel strain designs for biofuel, commodity chemicals, and recombinant protein production.

Hyduke and Lerman prototyped the method on the minimal, yet metabolically versatile, hyperthermophile Thermotoga maritima. Because T. maritima is not currently ready for use in industrial applications, Hyduke and Lerman are working as part of a larger team to produce similar models for industrially relevant microorganisms, such as E. coli.

"We've built a virtual reality simulator of metabolism and gene expression for Thermotoga maritima, and shown that it much better approximates phenotypes of cells than modeling metabolism in isolation," said Lerman.

...Their method accounts, in molecular detail, for the material and energy required to keep a cell growing, the research team reported in the journal Nature Communications.

"This is a major advance in genome-scale analysis that accounts for the fundamental biological process of gene expression and notably expands the number of cellular phenotypes that we can compute," said Bernhard Palsson, Galetti Professor of Bioengineering, at the UC San Diego Jacobs School of Engineering.

"With this new method, it is now possible to perform computer simulations of systems-level molecular biology to formulate questions about fundamental life processes, the cellular impacts of genetic manipulation or to quantitatively analyze gene expression data," said Joshua Lerman, a Ph.D. candidate in Palsson's Systems Biology Research Group. _SD

This approach provides more useful information in advance, to researchers considering various approaches to the design of custom chemicals-producing organisms -- particularly microbes, but eventually plants and animals as well.

In summary, the development of this tool should streamline the design and development of organisms capable of producing commercially valuable chemicals and fuels in an economical and timely manner. It should also prevent much wasted energy on the part of researchers, by pointing out dead-end research approaches in advance.

Full article in Nature Communications

Tools such as this will take us closer to the world where fast-growing weeds can be transformed into complete nutrient food crops capable of growing virtually anywhere, or life saving pharmaceuticals grown in one's own garden or window sill. High value "inks" for 3D printing will likely be produced from organisms designed by this or similar methods. And you can count on clever criminals learning to create tomato plants that produce cocaine, or squash that produce opium.

These tools will not stay in laboratories. They will migrate into garage biohacking facilities in short order. And then we will see disruptive change. Slowly at first, and then more rapidly.

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.

Gene Expression Instantiated: The Metabolome

Metabolomics is a newborn cousin to genomics and proteomics. Specifically, metabolomics involves the rapid, high throughput characterization of the small molecule metabolites found in an organism. Since the metabolome is closely tied to the genotype of an organism, its physiology and its environment (what the organism eats or breathes), metabolomics offers a unique opportunity to look at genotype-phenotype as well as genotype-envirotype relationships. Metabolomics is increasingly being used in a variety of health applications including pharmacology, pre-clinical drug trials, toxicology, transplant monitoring, newborn screening and clinical chemistry. However, a key limitation to metabolomics is the fact that the human metabolome is not at all well characterized.

Unlike the situation in genomics, where the human genome is now fully sequenced and freely accessible, metabolomics is not nearly as developed. There are approximately 2900 endogenous or common metabolites that are detectable in the human body. Not all of these metabolites can be found in any given tissue or biofluid. This is because different tissues/biofluids serve different functions or have different metabolic roles. To date, the HMP has identified and quantified (i.e. determined the normal concentration ranges for) 309 metabolites in CSF, 1122 metabolites in serum, 458 metabolites in urine and approximately 300 metabolites in other tissues and biofluids. Clearly more concentration data would be desirable and this is one of the long term goals of the HMP and other affiliated metabolomic projects around the world. _Metabolomics

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The power to watch the changes in the products of metabolism in the body does not come easily. But it is incredibly important in developing an understanding of gene expression in response to everyday events -- normal and pathological. It is one of the dreams of biomedical scientists and diagnosticians that is coming true. The following is a report on the comprehensive metabolic effects of smoking, as an example:

"Our analysis uncovered hallmarks of liver, heart, and kidney toxicity in otherwise healthy patients," says the study's lead investigator, Ping-Ching Hsu, a doctoral student who works in the laboratory of oncology researcher Peter Shields, MD, who specializes in tobacco carcinogenesis. Shields is the senior author....

...In their pilot study, they analyzed the blood of 10 smokers before and after they smoked a cigarette, and then measured the effects again after a second cigarette smoked one hour later in a smoking laboratory. Because frequent tobacco users may metabolize smoking-related toxins differently, the study enrolled 5 light smokers (fewer than 12 cigarettes a day) and 5 heavy smokers (23 or more cigarettes smoked a day).

The researchers then analyzed the global metabolomic profile of about 3,000 chemicals in the blood of each smoker. A metabolite is produced when anything taken into the body – such as food, tobacco smoke, alcohol, medicine – is metabolized, or broken down into chemicals that produce a biological function via metabolic pathways. The global metabolome is the network of metabolic reactions, and metabolomics is analysis of the metabolome at any given time.

Using complicated tools, researchers can trace the metabolites in the context of relevant pathways that are affected by cigarette smoke including cell death, cell-cell interactions (a marker of inflammation), lipid metabolism, and gene expression In heavy smokers, they then traced metabolites that were being produced after smoking back to damage in multiple organs and to a breakdown in the phospholipids that make up a cell's membrane, and a change in production of bile acids. _Source

The tools being developed to study metabolic responses to various events and stimuli, are incredibly advanced, involving the cutting edge of analytic and computational machines and methods.

Here is a study from Howard Hughes Medical Institute looking at the plasma metabolic profile of human mitochondrial disease -- an incredibly important area of study in connection with aging, degenerative diseases, resilience to injury, and normal body function and performance.

An e-briefing on the metabolome from the New York Academy of Sciences Click on "media" for 3 flash lectures and slide shows displaying detailed descriptions of research.

More presentations from NYAS on biomedicine

Metabolomics looks at the dynamic phenotype of gene expression. The tools seem advanced to us, yet they are still only rudimentary compared to the challenge. Still, it is easy to be optimistic about the long term prospects for this endeavour.