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Metabolomics

This is a relatively new field of research that began in the 1970's. Because you may not have heard of it we will begin with definitions:

Definitions:

Metabolomics is the systematic study of the unique chemical fingerprints that specific cellular processes leave behind. More specifically, it is the study of metabolic responses to drugs, environmental changes and diseases. Metabolomics is an extension of genomics (concerned with DNA) and proteomics (concerned with proteins). Following on the heels of genomics and proteomics, metabolomics may lead to more efficient drug discovery and individualized patient treatment with drugs, among other things.

Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. Examples of metabolites are glucose in the metabolism of sugars and starches, amino acids in the biosynthesis of proteins, and squalene in the biosynthesis of cholesterol.

The metabolome refers to the complete set of small-molecule metabolites (such as hormones, sugars, salts, amino acids, nucleotides and other signaling molecules) to be found within a person. The word was coined in analogy with proteomics.

Overview

The metabolome is dynamic, changing from second to second. In January 2007, scientists completed the first draft of the human metabolome. 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. Most often the biological samples used to measure metabolites are urine, saliva, and blood plasma. This is much easier than testing the tissue samples needed in genomics analysis.

While genomic data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling can give an instantaneous snapshot of the physiology of that cell.



 
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Schematic of the 'omic hierarchy: genomics, transcriptomics, proteomics, and metabolomics.

(Yes, the figure leaves out a few others, e.g., epigenomics and phenomics.)

Image courtesy of Royston Goodacre School of Chemistry, The University of Manchester, PO Box 88, Sackville Street, Manchester, M60 1QD, UK

   

Metabolomics is sometimes used to understand how inherited genetic differences among people lead to their metabolizing drugs differently. Sometimes a drug's effectiveness depends upon the availability of a specific end product of metabolism of the cells. However, since individuals sometimes metabolize drugs differently, the active agents may or not be available.

This could, in part, account for why different drugs work differently in different people who appear to have similar diseases.

In genomics, the human genome is now fully sequenced and freely accessible for use by researchers. Proteomics is working hard to catch up but unfortunately metabolomics is not yet nearly as developed.

Implications of Metabolomics for Medical Practice

If metabolomic information could be translated into diagnostic tests, it might have the potential to impact clinical practice, and it might lead to the supplementation of traditional biomarkers.

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.

 
  Metabolomics: What’s Happening Downstream of DNA - Image Courtesy of Brant X Pictures  
The Future for Metabolomics

Metabolomics is in a proof-of-principle phase at the NIH today. Experts agree the field is taking off during a period of "'-omics' fatigue" that has fueled a degree of skepticism among some scientists. Both genomics and proteomics were heavily hyped, and there is some concern over the slow pace of progress in both these fields. Thus, NIH officials are taking a wait-and-see approach to metabolomics, funding small-scale pilot studies designed to produce concrete results.

"We've spent decades studying metabolism, but ironically very little of this has been brought to a diagnostic application. You could say that metabolism is a mature science looking for a game to play in". - Bruce German, University of California, Davis

An Example of the Use of Metabolomic Profiles

A team led by researchers at the Michigan Center for Translational Pathology in Ann Arbor set out to use metabolomics to characterize the progression of benign prostate tissue to prostate cancer. Their work was supported in part by NIH's National Cancer Institute (NCI).

The researchers reported in the February 12, 2009, issue of Nature that the metabolomic profiles enabled them to distinguish between benign prostate tissue, clinically localized prostate cancer and metastatic prostate cancer.

They identified 60 metabolites in prostate tumors that weren't present in benign prostate tissue. The levels of 6 of these metabolites increased with the progression from benign prostate tissue to localized cancer and metastatic disease.

Similar to other strategies currently being investigated to individualize therapy, metabolomic studies are being integrated into preclinical and clinical research and assessed for predictive value. A form of in vivo metabolomics, PET imaging, with the use of radioactive tracers, has already been evaluated as a predictor of drug efficacy in some tumor types. In recurrent GIST, compared with standard computed tomography scanning, [18F]fluordeoxyglucose (FDG) PET was superior in predicting early response to imatinib therapy when evaluated in 56 patients before and after initiating imatinib therapy.

Furthermore, changes on [18F]FDG PET have been predictive of response to standard cytotoxic treatments in patients with breast cancer, locally advanced or metastatic non-small cell lung cancer, ovarian cancer, after high-dose salvage chemotherapy in relapsed germ-cell cancer, and in treatment-na´ve patients with cervical cancer. In hematologic malignancies not amenable to [18F]FDG PET imaging, metabolomic analysis on circulating tumor cells after [13C]glucose administration could be used in assessing treatment effects, thereby providing biological response information noninvasively. This could also be applied to circulating tumor cells from solid tumors.

The principal objectives of early clinical trials are to determine the maximum tolerated dose of new drugs or drug combinations while also collecting information on drug tolerability, pharmacokinetics, and pharmacodynamics. Increasingly, biomarkers are being used preclinically and in early clinical development to identify, validate, and optimize therapeutic targets, to confirm mechanism of drug action, and as pharmacodynamic end points. Additionally, metabolomics can be used as a biomarker of hepatic, renal, and lung toxicity with various metabolites, increasing or decreasing providing a recognizable pattern associated with organ dysfunction.

Much of these data have not been validated and there is some overlap between various toxins but the pattern, rate of change, and extent of change in metabolites can still provide toxicity assessments. Such patterns may be used for preclinical drug screening or as a means of following a patient clinically to monitor target organ effects. (From: Clinical Applications of Metabolomics in Oncology: A Review, Spratlin et al, Clin Cancer Res 2009)

Metabolomic Research Projects

These projects are included as examples of where the science is leading us.

The Human Metabolome Project is a $7.5 million Genome Canadian funded project launched in January 2005.

The purpose of the project is to facilitate metabolomics research through several objectives:

  • Improve disease identification, prognosis and monitoring.
  • Provide insight into drug metabolism and toxicology.
  • Provide a linkage between the human metabolome and the human genome.
  • Develop software tools for metabolomics.

 

CISN Metabolomic Summary

  • "Genomics and proteomics tell you what might happen, but metabolomics tells you what actually did happen". - Bill Lasley, University of California, Davis
  • In the long run, scientists are looking to metabolomics to fill important gaps in systems biology, a research paradigm focused on all the interconnected molecular pathways in cells and organisms.
  • Short-term clinical goals for the field are more concerned with the search for biomarkers, or molecular indicators of pathology.
  • Metabolomics asks, what are the products of cell metabolism and how are they related to disease.
  • Metabolomics tries to determine which genetic differences are related to how drugs are metabolized and hence whether or not they are likely to be effective.
  • Some experts believe metabolomics could provide clinical uses sooner than either genomics or proteomics. Several factors contribute to this view.
    • First, metabolite profiles are comparatively cheap to generate and
    • Second, the functions of most genes and proteins remain unknown, whereas metabolites can often be assigned to particular tissues and disease categories, which allows fairly easy extrapolation of their functions.
    • Finally, metabolomics is noninvasive and allows for repeated sampling over time.

 

 

 

 
   
 
 
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