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Renewable production of natural product pharmaceuticals: In vitro engineering advances


Plants are a tremendous source of natural diversity in the multitude of compounds that they synthesize, many of which are useful therapeutics for treating a variety of human illnesses and maladies. In fact, it has been estimated that approximately two-thirds of the active ingredients in anticancer drugs and drugs for infectious diseases are plant-derived. However, commercial production of many of these biologically active phytochemicals represents an enormous challenge due to the slow growing nature of many plants and the extremely low yields of the chemicals of interest. A sustainable production alternative to natural harvest is in vitro suspension culture, in which plant material is induced to de-differentiate, resulting in cultures of undifferentiated cells or plant “stem cells,” which can be grown in liquid medium and scaled up to bioreactors in an industrial setting.

The Roberts laboratory at the University of Massachusetts Amherst has studied the use of plant cell culture technology to produce the vital cancer therapeutic paclitaxel for over 10 years. Recent advances made by Martin Kolewe, an IGERT trainee, in conjunction with the Henson computational laboratory, will help facilitate the commercialization of this technology for paclitaxel production as well as other natural products. Unlike cell cultures such as yeast and bacteria which are commonly used in industrial fermentations, plant cells do not grow as single cell suspensions, but as aggregates of up to several hundred cells. These aggregates can reach sizes of several millimeters, and have profound effects on culture properties such as bulk productivity and growth. While the aggregated nature of undifferentiated plant cells has been recognized as one of the key characteristics and significant hurdles to large scale production, little is known about the dynamics of aggregation, as there had previously been no way to rapidly and reliably measure the size distribution of the aggregates.

Kolewe et al. developed a novel method to measure plant cell aggregates utilizing a Coulter Counter, which is commonly used for counting single cell particles in other cell culture systems. Using IGERT funds delegated to establishment of cutting edge cellular engineering facilities, Kolewe was able to secure a state of the art Coulter Counter to advance his research. The method he developed was shown to be rapid and precise, and could be easily correlated to other time-consuming techniques which had been previously used to measure plant cell aggregates, such as filtration and image analysis. This work was published in Plant Cell Reports, and has enabled advanced engineering and process control studies aimed at understanding the phenomenological basis of aggregation dynamics as well as optimizing aggregate profiles to increase paclitaxel production.

Address Goals

One of the most significant obstacles to widespread commercialization of plant cell culture technology, which could potentially be a renewable supply option for many natural products which are currently inaccessible via standard production methods such as natural harvest or chemical synthesis, is a general lack of advanced process characterization and engineering strategies. Most process engineering work has focused on applying the same strategies used for other types of cell cultures (such as optimization of nutrients and operating conditions), neglecting some of the fundamental characteristics of plant cells.

The process monitoring approach developed is sufficiently general to be applied to any type of in vitro plant species, and allows for a much more detailed understanding of process dynamics which were previously unavailable. This technology will enable research into a range of both fundamental processes inherent to plant cell culture as well as applied engineering strategies. In particular, the interdisciplinary team from the Roberts and Henson laboratories are applying computational approaches commonly used in food science and chemical processing industries to describe plant cell aggregation. The population balance equation model being developed will provide insight into the fundamental cellular processes underlying the aggregation phenomena, and provide a quantitative framework to develop process control strategies which can be readily implemented in an industrial setting. Industrial partnerships are being pursued where these approaches can be used to increase commercial production output.