Using Metabolic Profiling Technology to Advance Cell Culture Development

Through metabolomics, the metabolic underpinnings of cellular changes can be rapidly pinpointed, directing process development scientists to key areas for cell culture optimization.
Jun 02, 2009


Metabolomics, the global, unbiased profiling of biochemicals in a complex system, looks at the widest possible range of pathways in a system to detect changes during cell growth related to the medium, feeding, or temperature shifts. By using metabolomics to understand the action of biochemicals present in a cell system, process development researchers can discover targets for pathway engineering, enhance the development and optimization of growth media, and refine the scale-up process. The technology also can be used to identify the critical quality attributes of a process in a Quality-by-Design approach to process development, or for later application of process analytical technology for ongoing process monitoring.

Metabolon, Inc.
Identifying relevant biochemical markers in cell line selection and growth media development has traditionally been conducted using processes that are largely based on a trial-and-error methodology. Conventional approaches can be very costly, time-consuming, and ultimately frustrating for the researcher. A tool called metabolomics uses global biochemical analysis to gain mechanistic insight into biochemical and metabolite changes in cell systems and media, and greatly increases the speed with which process development researchers can find relevant biomarkers for optimizing their processes for more meaningful results.

Historically, process development researchers have relied on a limited number of metabolites (such as lactate, ammonia, and glucose) to provide insight into the metabolic state of a cell and the performance of the culture in the bioreactor. Improvements in productivity and quality of results have been the target measurements. Even in the era of genomics, metabolites and phenotypic data (e.g., titer) are the principal benchmarks by which cell culture and process development scientists determine the success or failure of an experiment. Although scientists understand the powerful connections between metabolites and phenotype, the inability to study more than a few metabolites at a time has proven a severely limiting factor in advancing research.

Using Metabolomics to Understand Cellular Phenotype

Small-molecule metabolites are the end products of cellular processes, and are considered the most accurate markers of how biological systems respond to genetic or environmental changes. Thus, biochemicals (metabolites) are the key to cellular phenotypes. There are approximately 2,900 biochemicals in the mammalian metabolome. Unlike macromolecules, metabolites represent focused, distilled changes in phenotype.

Scientists developing a recombinant protein process typically look at about five metabolites during an experiment. Whether or not those particular metabolites are significant is not known until the experiment has run its course. The bias shown toward metabolites whose behaviors are chosen for observation during the experiment often excludes potentially relevant markers while generating little useful data. Thus, many iterations of an experiment can be conducted without identifying genuinely significant markers.

Metabolomics, the global, unbiased profiling of biochemicals in a complex system, looks at the widest range of pathways in an experimental system for significant changes that occur during cell growth in a particular medium as well as in response to feeding or temperature shifts. This approach maximizes the chances for determining the relevant pathways associated with a poor product quality or a metabolic switch. In addition, the biochemical markers associated with the pathway can be used for further development and, eventually, in production.

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