June 15, 2023
Illuminating unknowns in the dynamic interplay of genetics, environment, and disease
Sapient, a San Diego company specializing in biomarker discovery, explains how their next-generation rapid liquid chromatography-mass spectrometry technology is helping to rapidly map out the metabolome to support the development of new targeted therapies. Photo courtesy of Sapient.
By Sapient Bioanalytics
The field of genetics has been at the forefront of biopharmaceutical research and attention over the last two decades, with the promise that decoding our DNA would unlock the secrets and subsequently targets for optimizing health and eliminating disease. Spurred by the advent of massively parallel, next-generation sequencing, our ability to interrogate the genome at scale across large populations has now identified hundreds to thousands of genetic variants associated with virtually every disease. These insights have enabled significant advancements in the development of precision therapies to target specific mutations (genetic biomarkers) and have led to improved drug efficacy and patient outcomes, particularly in genetically driven disease areas including cancer.
As these discoveries have emerged, it has also become clear that genetics represents only a fraction of the total story, in essence serving as a “probabilistic” barometer for disease, rather than a ‘deterministic’ indicator of disease risk. Complementing genetic risk are the thousands of key modulators and exposures that occur over a person’s lifetime. Central to these modulators are the dynamic measures of pathway activation, cellular function, and organ-level physiology that serve as indicators of real-time health status. Indeed, during an annual physical at the doctor’s office, two tubes of blood are drawn and from that biological sample, a dozen to several dozen dynamic markers are assayed—from metabolites to proteins to inorganic ions—and used to drive disease diagnoses, implement therapeutic strategies, and monitor overall health. While they are a mainstay of modern medicine, these several dozen dynamic markers represent less than 0.1 percent of the total molecules circulating in human blood. The next stage of drug discovery and development will largely depend on our ability to move beyond the genome to capture, measure, and make sense of the 99.9 percent of dynamic biomarkers that to date have remained unexplored.
Exploring biology beyond the genome: where do we go next?
Metabolomics and lipidomics, which examine the small molecules produced by human cells and organs, have emerged as powerful tools for gaining insight into the complex interplay between genetics, environment, and disease. Small molecule biomarkers represent dynamic measures that integrate information on an individual’s pathobiology with readouts of external factors—what they eat, drink, smell, smoke, etc.—and how they may drive biological changes. They can reveal how such exposures interact with and influence genetics and identify additional factors contributing to disease.
Small molecules are continually produced within living cells and release into the blood where they influence distal tissue biology. Measuring these tens of thousands of circulating small molecules may provide unparalleled insight into not just what could happen, but rather what is happening and what will happen in near time. In terms of application, these insights can enable earlier disease detection, better prediction of disease progression, and better understanding of who in fact may respond to a given drug.
Small molecule biomarkers: a trove for discovery
It is clear that small molecule biomarkers have enormous potential to advance our understanding of disease mechanisms and aid in development of better therapies and diagnostics. However, the benefits of small molecule biomarkers—their dynamic nature and diversity—also present an analytical challenge. There are tens of thousands of metabolites and lipids circulating in humans, some at very low concentrations, and capturing these molecules with varied sizes, chemical characteristics, and abundance in a single bioanalytical modality and biosample presents analytical challenges. Importantly, technical advances in mass spectrometry and analytical chemistry now provide the tools required to interrogate this veritable treasure trove of information. When coupled to computational tools and advanced AI approaches, we can finally begin to make sense of and derive knowledge from these dynamic and complex measures, and ultimately accelerate their translation to patient care.
Discovery mass spectrometry: the catalyst to uncover new dynamic biomarkers
The team behind Sapient, a biomarker discovery as a service organization, saw the discovery opportunity in small molecule biomarkers and founded the company to lead the post-genomics revolution. After nearly a decade of development within leading academic labs, our next-generation rapid liquid chromatography-mass spectrometry (rLC-MS) systems are now capable of assaying tens of thousands of dynamic circulating biomarkers in tens of thousands of biosamples at a time. Our services are enabling biopharma, academic, and nonprofit research institutions to discover new, robust small molecule biomarkers of biological processes, disease mechanisms, and drug response across broad disease areas.
With these technologies and approaches, the opportunity for discovery has been unleashed: instead of focusing on the dozen or so known molecules that are routinely assayed as part of medicine, rLC-MS can be used to rapidly probe thousands of markers simultaneously from across the breadth of human chemistry, and rapidly hone in on the most biologically relevant biomarkers—even those yet to be characterized. To date, these emerging approaches have been applied to understand and validate new targets for disease intervention, uncover early diagnostic markers of disease, identify companion diagnostics that predict response to particular drugs, and to understand who may be at risk for an adverse drug event.
Leading the post-genomics revolution by deciphering dynamics of disease at scale
Given the dynamic complexity of small molecule biomarkers, it is critical that discovery occurs at scale, across diverse populations representing different lifestyles, geographies, disease states, and time. By greatly accelerating sample analysis to under 1 minute, Sapient’s technologies provide a means for population-scale profiling across a broad and diverse range of human complexity. This rapid data generation is key to enabling discovery beyond genomics, paired with better data interpretation to ensure those discoveries can be applied in a way that improves drug development and impacts human health.
Already, Sapient has amassed data from more than 100,000 individuals and biosamples from around the world, leveraging our rLC-MS systems to measure over 50,000 different circulating small molecule biomarkers. By linking these measures to deep longitudinal clinical data on each patient, including demographic features, lifestyle factors, clinical outcomes, genetics, microbiome, and drug response over time, discovery, validation, and generalization of findings has been greatly accelerated. We make this in-house database and our biocomputational framework available to our customers as part of each discovery project, to ensure they can derive actionable insights from the data we generate to apply within their programs.
Achieving such “specificity at scale” will enable the biopharma industry to more fully leverage small molecule biomarkers in drug discovery, development, and deployment, identifying new measures of dynamic disease processes that can be used to align patients and precision therapies for better outcomes.