Direct observation (and prediction) of cell line instability driven by heterogeneities that arise within clonal populations
Seminar | April 2 | 12-1 p.m. | 321 Stanley Hall
Troy Lionberger, Senior Manager of Technology Development, Berkeley Lights
Stable cell lines are critical to the production of all antibody therapies used to treat human disease. Instability in cell lines (e.g., the gradually reduced secretion of a genetically-encoded antibody) has been attributed to genomic instability (i.e., the heavy and light chain of the antibody is gradually lost through genetic recombination, silencing, etc.). Currently, cell line instability can only be observed empirically over 8-10-week periods of continuous culturing and sampling. This process requires enormous amounts of time, effort, and resources, much is which is ultimately wasted on cell lines that will be determined to be unusable. This wasted effort translates to increased costs to pharmaceutical companies, which in turn drives up the price of desperately needed next-generation biologic therapies.
Here, I will discuss a high-throughput, single-cell culturing apparatus we are using to rapidly measure with high precision the phenotypic heterogeneities that exist within clonal populations. I will also explain how these observed heterogeneities can be used to quantitatively describe the eventual fate of the measured cell line. Data from 6 cell lines will demonstrate that this approach is able to correctly predict instability in clonal cell lines within 1 week (at least 7 weeks faster than using conventional methods). Emerging from this work is a new model for the origin of cell line instability, wherein a faster-growing (undesired) subpopulation simply overwhelms a slower-growing (desired) fraction. This underlying mechanism complements the long-held assumption of genetic instability, but suggests that such events are rare in frequency.
Troy Lionberger is the Senior Manager of Technology Development at Berkeley Lights, an Emeryville startup that has invented the Beacon microscope platform, a fully automated system that uses light to move single cells and leverages the unique properties of a microfluidic device produced by Berkeley Lights to perform high-precision, quantitative assays from cultured cell populations. As an inventor of much of this technology, Dr. Lionberger initially applied it to biopharmaceutical applications to make antibody therapies more effective, safer, cheaper, and developed in a fraction of current timescales. Now, he is now applying Beacon technology to accelerate research and development in other areas of cell biology, ranging from synthetic biology to agriculture. Dr. Lionberger received postdoctoral training in biophysics under Prof. Carlos Bustamante at UC Berkeley, prior to which he earned a Ph.D. in Cellular and Molecular Biology and Masters in Mechanical Engineering from the University of Michigan.