It's not easy being the new kid on the block, but metabonomics is quickly finding its way into the world of Big Pharma. The term, coined by a research group at the Imperial College of Science (London), is defined as "the systemic profiling of metabolites and metabolic pathways in whole organisms through the study of biofluids and tissues."
Some of its potential applications include: preclinical evaluation of drug safety studies, patient stratification for drug treatment, and information on disease processes. Metabonomics also has several advantages over other measurements (genomics, proteomics), such as noninvasive samples (urine, plasma) and identification of individual molecules in complex samples using methods that allow for quantitative interpretation.
However, the major advantage of metabonomics is that the human metabolome contains only about 2,500 unique molecules. "What we're talking about are the small, non-proteinaceous, monomeric molecules made by humans, endogenously synthesized, like glucose and ATP," explains John Ryals, Ph.D., president and CEO, Metabolon (www.metabolon. com).
In order to analyze and identify these molecules, the company has developed a high throughput platform combining high-end LC/MS, GC/MS with proprietary software. Once identified, the molecules are related back to biochemical pathways.
"One of the benefits of this technology is we know the context with how these molecules are synthesized and degraded. So when the amount of a compound increases or decreases, we can understand that change as it relates to biochemical processes."
Dr. Ryals says that many companies are looking for "off-targeted" effects, or unanticipated side effects of drugs prior to clinical trials. "There are a lot of drugs that have many side effects that aren't related at all to their site of action. We can test panels of drugs and find out whether they are off- or on-target."
He adds that companies are also using metabonomics for preclinical work with animals and in early-stage clinical trials. "Many diseases are probably more like syndromes rather than singular molecular problems. We can sub-set patient populations based on how they show up biochemically."
This capability was recently well illustrated through a collaboration with Massachusetts General Hospital, where Metabolon used its platform to identify four unique groups of ALS patients. Sera samples of controls and patients with motor neuron disease were analyzed for total biochemical constituents.
The surprising result was that the analysis was able to differentiate patients with lower motor neuron disease from those with ALS. Further research has identified key biomarkers generic to motor neuron disorders in general, and specific biomarkers unique for ALS and other diseases.
What makes Metabolon's approach unique, says Dr. Ryals, is the ability to identify chemical structure and quantitate molecules, then cast that information against biochemistry. "Other companies are just fingerprinting.' We don't think that is the best way of doing it because you lose a lot of the value of having this type of information."