In the latest issue of FLG magazine, we met a biochemist at the intersection of metabolomics and genomics: Greg Michelotti, Senior Study Director of Global Cohort Studies, Metabolon.
One of the most enduring questions for geneticists is: “what is the significance of these variations that I’m finding?” For many biochemists, a promising path to answering this questions lies in metabolomics, the study of all the small molecules in the body. To understand this rapidly expanding area of research, meet a biochemist from Metabolon, the most prolific company investigating the metabolome today.
In my 25 years as a biochemist, I never saw advancements in my field translate into any appreciable advancements in medicine. This isn’t to say that we didn’t put in a good effort. It’s just that the genomic and transcriptomic methods we were using didn’t provide all the answers we were looking for. Then came the metabolome.
Metabolomics complemented genomics studies by giving us answers that the genome alone could not provide. For example, both phenylketonuria and maple syrup urine disease have been associated with hundreds of mutations, and perhaps thousands more variations yet remain unidentified. Some mutations are penetrant, some aren’t. Each one confers a different level of severity. Predicting the phenylketonuria phenotype by gene sequence, therefore, is a difficult endeavor. In fact, many factors can influence phenotype, including the additive effects of multiple gene networks, the microbiome, and the environment. These elements place pressures on the enzymes and biomolecules that compose the pathways through which the body functions or malfunctions, thereby influencing phenotype. In the end, it is those biomolecules—the metabolome—that reveal what is happening in our bodies at any given moment. For phenylketonuria, maple syrup urine disease, and many other conditions, assessing variance by both genomics and metabolomics can reveal disease etiology faster than following-up on a roster of genetic findings of unknown significance.
As a study director for Metabolon, I manage scientific investigations, which involves designing and analysing studies for client investigators. My mission is to generate actionable information to accelerate scientific discoveries, develop diagnostics, improve agricultural and veterinary science, and advance human health.
Due to the variety of fields these studies cross, my work often makes me feel like the main character in the TV show Quantum Leap who assumes different peoples’ identities in each episode. Every month, I immerse myself in different fields of biology to answer their most pressing questions. One week, I might analyse breath condensate or cerebral spinal fluid to gain insight into debilitating diseases. Next, I might examine whole drosophila to discover the function of a perplexing gene, or fecal matter to make sense of changes in the microbiota contained within. Sometimes, I get to study foods like chocolate to help define what makes them taste the way they do.
Since the metabolome is a fundamental view into any living system, I am tasked with exploring a wide variety of questions. Every day is different for me, but this is one “day in the life” as a study director…
My daughter’s puppy would rather drag me out of bed for her morning walk than let me sleep until my alarm sounds. A long morning walk through a wooded trail with her gives me a chance to review emails on my phone. Since many of my clients are in Europe, my inbox sees a lot of activity while I sleep. This walk allows me to begin to plan and partition my day.
My commute to Metabolon crosses Research Triangle Park, a hub of fastgrowing scientific companies. But with vibrancy comes sacrifice: traffic jams. Morning Edition on NPR provides context and perspective each morning.
At my desk, alert from another red-eye coffee, I tackle the most urgent overnight emails. One investigator sent his study design for evaluation, and I suggest that we include fecal samples from study participants to help identify microbiome-related changes. Another scientist asked how she could augment a planned population genomics study with metabolomic data to accelerate identification of variants of phenotypic significance, and I propose a time next week to examine potential strategies.
PubMed search for new papers in the metabolomics field. Studies— both targeted (a few hundred metabolites) and global (>1,800 metabolites)—have exploded in number in recent years. Keeping up with publications in this space is increasingly part of my job and today, I find a few really interesting papers to read.
I revisit a study that started a few days ago. A cohort of asthmatic children has responded heterogeneously to a steroid treatment, but the underlying biological mechanisms remain unclear. Earlier this month, our mass spectrometrists and biostatisticians analysed plasma samples from those kids for nearly 2,000 human and microbial metabolites, and built a heat map of the relative distribution and changes of those molecules between the responding and nonresponding children. I am assessing the ontology of the significantly affected metabolites, creating a straightforward report on the relevant human and microbial enzymes and pathways. This makes results easier to evaluate for the investigator, who is not a metabolomics expert and hopes to identify new therapeutic targets. It may sound cliché, but this is the rush that makes science worth all its sacrifices. Whether we’re investigating complex human diseases or the cause of colony collapse among bees, the opportunity to change our understanding of the world creates opportunities to make a difference. Before I can finish my report, however, Outlook informs me a teleconference is about to begin.
Be sure to check out the rest of Greg’s day in the latest issue of Front Line Genomics magazine.