Lk. Nielsen et al., CELL-CYCLE MODEL TO DESCRIBE ANIMAL-CELL SIZE VARIATION AND LAG BETWEEN CELL NUMBER AND BIOMASS DYNAMICS, Biotechnology and bioengineering, 56(4), 1997, pp. 372-379
The use of cell numbers rather than mass to quantify the size of the b
iotic phase in animal cell cultures causes several problems. First, th
e cell size varies with growth conditions, thus yields expressed in te
rms of cell numbers cannot be used in the normal mass balance sense. S
econd, experience from microbial systems shows that cell number dynami
cs lag behind biomass dynamics. This work demonstrates that this lag p
henomenon also occurs in animal cell culture. Both the lag phenomenon
and the variation in cell size are explained using a simple model of t
he cell cycle. The basis for the model is that onset of DNA synthesis
requires accumulation of G1 cyclins to a prescribed level. This requir
ement is translated into a requirement for a cell to reach a critical
size before commencement of DNA synthesis. A slower gl-owing cell will
spend more time in G1 before reaching the critical mass. In contrast,
the period between onset of DNA synthesis and mitosis, tau(B), is fix
ed. The two parameters in the model, the critical size and tau(B), wer
e determined from eight steady-state measurements of mean cell size in
a continuous hybridoma culture. Using these parameters, it was possib
le to predict with reasonable accuracy the transient behavior in a sep
arate shift-up culture, i.e., a culture where cells were transferred f
rom a lean environment to a rich environment. The implications for ana
lyzing experimental data for animal cell culture are discussed. (C) 19
97 John Wiley & Sons, Inc.