07 November 2010

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

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.


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