Worms as model for personalized medicine
Using four unrelated strains of the microscopic nematode C. elegans originating from different parts of the world, a group of worm biologists have developed a model system to study individual differences in metabolism. The use of C. elegans, a widely studied model organism, allowed the team to study the unique and complex interplay between genetics, diet, microbiota and other environmental factors that can affect fundamental metabolic processes in different individuals. This advancement represents a potentially important step toward “personalized” or “precision” medicine, a relatively new discipline that tailors dietary advice and disease treatment to an individual’s own genome sequence.
The research, by Marian Walhout, PhD, the Maroun Semaan Chair in Biomedical Research and chair and professor of systems biology at UMass Chan Medical School and collaborators Erik Andersen, PhD, from Northwestern University and Frank Schroeder, PhD, from Cornell University, published in Nature, identifies a novel metabolic condition linked to variation in the hphd-1 gene of a strain of C. elegans found on the Big Island in Hawaii. The strain, known as DL238, has an abnormal accumulation and secretion of the metabolite 3-hydroxypropionate (3HP). Moreover, this strain was found to generate a set of novel metabolites that have 3HP conjugated to several amino acids. These novel metabolites are not found in the laboratory strain that has been used for decades to make seminal biological discoveries. By conjugating 3HP to amino acids, DL238 is removing 3HP, which is toxic at high concentrations.
“This work provides an important step toward the development of metabolic network models that capture individual-specific differences of metabolism and more closely represent the diversity that is found over entire species,” said Walhout. “Employing this system, we can begin studying interindividual metabolism and the unique interplay of metabolites, diets and environments on an individual level.”
When the human genome was sequenced, clinical researchers envisioned an era when our personal genomic information could be used to tailor medical treatments to fit the needs of each individual, explained Walhout. Despite the completion of the Human Genome Project in 2003, and advancements in genomics and deep sequencing technologies, personalized medicine remains more promise than reality.
Part of the challenge in developing personalized medicine is that our DNA makes up only a portion of human health; an individual’s diet and environment both profoundly impact metabolic processes. And because no two individuals have the same exact diet, unraveling the complex interplay of genetics, diet and environment and connecting these to variations in metabolism is cumbersome. In addition to sequencing individual genomes, scientists would need to replicate metabolic measurements in people of the same age and gender, who ideally would also consume the same exact diet and experience identical environments.
To address this challenge, Walhout, a leader in metabolism and gene expression research, teamed up with Dr. Andersen, an expert in quantitative genetics, and Dr. Schroeder, a chemist, to develop a comparative system for studying interindividual variations in metabolism.
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