Over the last 20 years, the yields for bioprocesses performed in single-cell suspension cultures of mammalian cells have increased
dramatically. It remains to be seen whether the physical properties of secreted proteins, in terms of solubility or in interactions
with other cell-derived components, may eventually limit the rise in product concentrations in cell culture media. Undoubtedly,
the overall cell densities in reactors will rise further and provide the most promising approach for further improvements
in final product concentrations. Even at the highest reported cell densities of 10–15 x 106 cells/ mL, the total biomass represents less than 5% of the culture volume. The other 95% of the volume is composed of
the liquid medium and the soluble components therein. Higher cell densities will depend on better basic and feed media. This
vast area of research has not obtained the visibility and recognition of novel vector systems and productivity-enhancing DNA
elements. Whether specific productivities of 50–100 pg/cell/day can, in the future, be reached routinely for the majority
of recombinant proteins is to be found out, but surely this goal depends on careful screening and better and more efficient
tools to identify such superproducers that also have the multitude of characteristics necessary to survive under scale-up
and production conditions.
David L. Hacker, PhD, is a senior scientist, Sophie Nallet is a doctoral student, and Florian M. Wurm, PhD, is a professor, all at the Laboratory of Cellular Biotechnology, Lausanne, Switzerland. Wurm is also the founder and chief
scientific officer of ExcellGene SA, Lausanne, Switzerland, +41.21.693.6141, firstname.lastname@example.org
1. Walsh G. Biopharmaceutical benchmarks 2006. Nat Biotechnol. 2006 Jul;24(7):769–76.
2. Wurm FM. Production of recombinant protein therapeutics in cultivated mammalian cells. 2004 Nov;22(11):1393–8.
3. Barnes LM, Bentley CM, Dickson AJ. Advances in animal cell recombinant protein production: GS-NS0 expression system. Cytotechnol.
4. Kwaks TH, Otte AP. Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells. Trends
Biotechnol. 2006 Mar;24(3):137–42.
5. Baer A, Bode J. Coping with kinetic and thermodynamic barriers: RMCE, an efficient strategy for the targeted integration
of transgenes. Curr Opin Biotechnol. 2001 Oct;12(5):473–80.
6. Browne SM, Al-Rubeai M. Selection methods for high-producing mammalian cell lines. Trends Biotechnol. 2007 Sep;25(9):425–32.
7. Majors BS, Betenbaugh MJ, Chiang GG. Links between metabolism and apoptosis in mammalian cells: applications for anti-apoptosis
engineering. Metab Eng. 2007 Jul;9(4):317–26.
8. Gottschalk U. The renaissance of protein purification. BioPharm Int. 2007 Oct supp;41–2.