Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany.
Department of Chemical Engineering & Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
Biotechnol J. 2018 Feb;13(2). doi: 10.1002/biot.201700539. Epub 2017 Dec 6.
Apart from product yield and titer, volumetric productivity is a key performance indicator for many biotechnological processes. Due to the inherent trade-off between the production of biomass as catalyst and of the actual target product, yield and volumetric productivity cannot be optimized simultaneously. Therefore, in combination with genetic techniques for dynamic regulation of metabolic fluxes, two-stage fermentations (TSFs) with separated growth and production phase have recently gained much interest because of their potential to improve the productivity of bioprocesses while still allowing high product yields. However, despite some successful case studies, so far it has not been discussed and analyzed systematically whether or under which conditions a TSF guarantees superior productivity compared to one-stage fermentation (OSF). In this study, we use mathematical models to demonstrate that the volumetric productivity of a TSF is not automatically better than of a corresponding OSF. Our analysis reveals that the sharp decrease of the specific substrate uptake rate usually observed in (non-growth) production phases severely impacts the volumetric productivity and thus raises a big challenge for designing competitive TSF processes. We discuss possible approaches such as enforced ATP wasting to improve substrate utilization rates in the production phase by which TSF processes can become superior to OSF. We also analyze additional factors influencing the relative performance of OSF and TSF and show that OSF processes can be more appropriate if a high product yield is an economic constraint. In conclusion, a careful assessment of the trade-offs between substrate uptake rates, yields, and productivity is necessary when deciding for OSF vs. TSF processes.
除了产品产量和效价外，容积产率也是许多生物技术过程的关键性能指标。由于生物量作为催化剂的生产和实际目标产物的生产之间存在固有的权衡关系，因此产量和容积产率不能同时优化。因此，结合用于代谢通量动态调节的遗传技术，两阶段发酵（TSF）具有分离的生长和生产阶段，由于其具有提高生物过程生产率的潜力，同时仍允许高产物产量，因此最近引起了很大的兴趣。然而，尽管有一些成功的案例研究，但迄今为止，尚未系统地讨论和分析 TSF 是否以及在何种条件下保证比单阶段发酵（OSF）具有更高的生产率。在这项研究中，我们使用数学模型证明 TSF 的容积产率不一定优于相应的 OSF。我们的分析表明，在（非生长）生产阶段通常观察到的比特定底物摄取率的急剧下降严重影响容积产率，因此对设计具有竞争力的 TSF 过程提出了巨大挑战。我们讨论了可能的方法，例如强制 ATP 浪费，以提高生产阶段中的底物利用率，从而使 TSF 过程优于 OSF。我们还分析了影响 OSF 和 TSF 相对性能的其他因素，并表明如果高产物产量是经济限制，则 OSF 过程可能更合适。总之，在决定 OSF 与 TSF 工艺时，有必要仔细评估底物摄取率、产率和生产率之间的权衡关系。
