Blindly searching for biomarkers in themetabolome has failed to deliver on early promises – it's time for a new direction.
By Martin Giera, Head of the Metabolomics Group atLeiden University Medical Center, Netherlands.
Numerous research articles have proposed, addressedand promoted metabolomics as one of the key tools for biomarker discovery and personalized medicine. Personally,I am not blessed with a lot of patience, but even those who are might bestarting to wonder, 'Aftermore than a decade of metabolomics-driven research, can anyone actually name asingle resulting biomarker routinely used in the clinic?' I have to admit that, besidestrimethylaminoxide and some markers related to gene defects (for example,7-dehydrocholesterol), nothing comes to mind.
But why? Have we not used the most advancedanalytical and computational approaches available? Have we not invested enoughmoney, manpower and dedication? I don't believe thatlack of effort is the problem; I think we just took the wrong path.
In the beginning, when metabolomics was first used in case–control studies, it all seemed pretty straightforward. Many believedthat with the right equipment and the right bioinformatics approach, we wouldeasily identify somediscriminators between all the moleculeswe can monitor. But the human body contains more than five liters of blood, we eat more than 500 g of(highly diverse) foods and drinks every day and, to make thispicture even more complicated, our molecular fundament depends on genes, sex, weight, race and lifestyle. On top of all these variables, the metabolome isfurther influenced by circadianrhythm, hormones (mood), menstruation and medication. Say you are lookingfor a cancer marker – how are we going to find this one molecule, possiblysecreted by a few million cancer cells somewhere in your brain or lungs, hiddenin a constantly changing five-liter bucket of blood? Frankly, I am not convincedthere is a high chance of success.
I don't want to painttoo dark a view here, but simply illustrate that metabolomics biomarker discovery is a verycomplex endeavor. It's possible that our vision was blurred to the difficulties by thehigh hopes we had. Nevertheless, I am convinced metabolomics will make its way into theclinic, and hopefully fill thepipelines of clinical chemistry with new molecular tools. In life, you have to fall and get up manytimes before you learn to walk, and it's time forclinical metabolomics to take two seminal steps forward.
'I don't want to painttoo dark a view here, but simply illustrate that metabolomics biomarkerdiscovery is a very complex endeavor.'
The first step is to change our mindset –away from traditional biomarker discovery studies and towards understanding the systemseffects of metabolites, asoutlined in a recent article from Gary Siuzdak's lab.
Thesecond step is to define the framework of human metabolism. In other words, what are the actual(true) concentrations of metabolites, what is the range these metabolites areto be expected in vivo, and how are these concentrations affected by circadianrhythm, food intake, tissue distribution and many other factors?
Such steps are increasingly being taken in severalrecently established phenome centers. In my view, these are exactly the rightsteps, in the right direction, at the right time (if not a little too late...). Clinical metabolomicshas learned from its past failures and too few successes, and is ready to starttaking strides into the future.
Reference
Johnson etal., Metabolomics: beyond biomarkers and towards mechanisms, Nat Rev Mol CellBiol, 17, 451–459 (2016).
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