Enhancing CHO by Systems Biotechnology
Nicole Borth and Wei-Shou Hu
Twoandahalf years ago,in2015,Biotechnology Journalreleased a
on Mammalian Production Systems with an
Editorial entitled “On the cusp of rational cell engineering.” This
title was chosen to express the expectancy, arising from recent
biochemicalmechanismsatworkin mammalian cell lines used for
the production of biopharmaceutics. Since then, we have seen the
publication of genome sequences for several more cell lines, of a
plethora of transcriptome and proteome datasets and the ﬁrst
exploration of the impact of epigenetics on cellular behavior in
bioprocessing,alongwiththeadventofhighlyefﬁcient and targeted
genome editing tools such as CRISPR/Cas9, which have
considerably enhancedthescopeandspeedof cell line engineering.
Due to the importance of biopharmaceutics for research, medicine
and industry, the European Union realized the urgency of having
appropriatelytrainedindividualsintheir workforce, able to handle the
associated multi-disciplinary challenges. Therefore, an International
Training Network on “enhancing CHO by systems biology,” in short
eCHO, was established within the EU Marie-Curie Actions Program,
to train 15 PhD students in the diverse ﬁelds of computational biology
and modeling, cell culture technology and cell line engineering
within the period of 2015 to 2018 (www.echo-systems.eu). Part of the
training includes entrepreneurial training and a secondment to one
of the numerous industrial partnerstoensurethatgraduatesofthis
program are exposed to and familiar with both the academic (more
exploratory, and oriented toward generation of understanding and of
algorithms and rules) and industrial realities (in part as adventurous
and aiming toward understanding, but more restricted by the
necessity to follow regulatory and safety considerations).
In this special issue we wanted to capture the advances made
since 2015 and to evaluate whether the expectancy was indeed met
in reality. A brief call for paper submissions to the players in the
ﬁeld was met with such success that the number of proposed
contributions was soon outside the scope of a single issue. It was
therefore decided that Biotechnology Journal would in 2018 see two
issues on the topic of “enhancing CHO by systems biotechnology”
including several contributions from industrial authors, demon-
strating that this is not a merely academic playground, but has in
the meantime reached industrial relevance and reality. These two
issues will also contain 11 manuscripts written by the ESRs (Early
Stage Researchers) of the eCHO Training Network, to present a
brief glimpse into the diverse work and data generated by this
program (these are marked with an asterisk below).
In this ﬁrst issue, several reviews summarize the state of the art:
Stolfa et al.
give a comprehensive overview over the impact of
the available resources and databases for CHO. Kyriakopoulos
present the advances made in kinetic modeling of
bioprocesses and how these help to advance biomanufacturing by
improving prediction of cell behaviour. Pereira et al.
our knowledge of toxic metabolites and nutrients and their impact
on culture performance, while Tejwani et al.
contribution of systems biology and modelling to glyco-engineer-
ing strategies that target to control the level of sialylation or
fucosylation,the heterogeneityofglycan structures on the product,
the presence of bi-secting glycans and the degree of branching. As
these are all parameters that impact the bio-activity of the product,
it becomes clear how important these approaches will be in
generating more efﬁcacious therapies with fewer side effects.
Romanova and Noll
ﬁnally open the ﬁeld of synthetic biology by
exploringbothnaturalandengineeredpromoters for generationof
high producing and stable recombinant cell lines.
Animportantaspectinthecontext of genomic stability and
homogeneity, which authorities are aiming to ensure by proof of
clonality, are the frequent chromosomal rearrangements that are
known to occur in immortalized cell lines that grow rapidly. Baik and
show a correlation between such a rearrangement and growth
rate, while Vcelar et al.
demonstrate the large degree of karyotype
variation present in general in CHO cells, irrespective of whether the
population is derived from a pool, a recombinant, and sorted cell line
or subclones. Switching from genome to transcriptome, Chen
present a workﬂow for standardized analysis of gene
expression while Orellana et al.
again come back to the issue of
clonal variation by demonstrating the large number of differentially
expressed genes between two subclones of the same parent.
In the context of a cell
s ability to handle difﬁcult to express
proteins and the stress of high productivity in general, Maldonado-
Agurto and Dickson
present results on the Unfolded Protein
Response, highlighting new targets for cell engineering and for
following stress-sensitivity in production cell lines. Wang et al.
show how the initial bioinformatics analysis of likely chaperones
required for the complex butyrylcholinesterase was able to guide
engineering efforts to improve its production.
sek et al.
provide a new approach to efﬁciently
select for highest yield in bioprocesses from early stages of clone
selection by combining measurements for growth and titer,
Biotechnol. J. 2018, 13, 1800077 © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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