Research plan

The eCHO systems biology training and research program will explore the interdisciplinary boundaries that exist across molecular and cell biology, high throughput ’omics technologies, and computational biology methods. This goal will be achieved through a research program for 15 early stage researchers (ESRs) that invokes important systems and synthetic biology approaches divided into three working packages (WPs):

1) CHO Systems Biology: ‘Omics and Genome Scale Models (WP1)
2) CHO Genome Engineering Tool and Chassis Development (WP2)
3) Application of Synthetic Biology Approaches to Reprogram Cellular Networks for Enhanced Growth, Yield and Product Quality (WP3)

These three important topics will be the focus of our work plan and are illustrated in Figure 1.

The ESRs are a part of the research program in terms of each advancing research within one or more of these topics. ESRs in our program are being trained via a cohesive and specialized educational mammalian systems biotechnology program that includes newly developed science, technology, and business courses focused specifically on those interdisciplinary boundaries at the cross section of systems biology and molecular/cell biology. To translate systems biology innovations into the commercial realm and to draw on the tremendous biotechnology capability in industry, our ESRs will interact with a broad range of industrial participants and be hosted by or have secondments with industrial partners. These collaborations will

a) expose industrial partners to the new systems and synthetic biology research paradigm of eCHO Systems
b) facilitate an increase in the critical transfer of technological know-how from industry to academia
c) provide ESRs with experience in a product-focused business environment.

This program will educate a critical mass of researchers that embraces genome scale science and systems biology for the CHO platform and serves to seed these approaches into the European biotechnology industry. The eCHO Systems project represents a rare opportunity to take advantage of the confluence of events including the availability of a published CHO genome, proteome, along with other omics data and advanced computational tools in order to train the next generation of European-based scientists and entrepreneurs to lead the next CHO biotechnology revolution in the 21st century. These goals will be achieved through a multidisciplinary research training programme integrated across 4 universities, 2 company beneficiaries, and 10 affiliated companies.

The ESRs are working on interdisciplinary research topics within advanced mammalian systems biology and biotechnology guided by internationally renowned experts. The ESR´s scientific projects are focusing on combining the resources published in recent years with the first genome-scale metabolic models of CHO to integrate and implement a core set of computational and experimental genome-scale methodologies that will enhance the capability and robustness of the CHO platform.

References:
(1) Gary Walsh. Biopharmaceutical benchmarks 2010: – Nature Biotechnology, 2010; 28:917-924
(2) Bioprocess Technology Consultants
(3) Making a case for a $2700-a-month drug Barbara SibbaldCMAJ – Nov 2, 1999; 161 (9) 1173
(4) Brian Kelley Mabs. 2009 Sep-Oct; 1(5): 443-452. PMCID: PMC2759494: Industrialization of mAB production technology the bioprocessing industry at a crossroads.
(5) J. A. Vernon et al. “Drug Development Costs When Financial Risk is Measured Using the Fama-French Three Factor Model” Health economics letter (2009).
​(6) Lewis et al. Genomic landscapes of Chinese hamster ovary cell lines as revealed by the Cricetulus griseus draft genome. Nat Biotechnol. 2013; 31(8):759-65.
(7) Xu et al. The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line. Nat Biotechnol. 2011; 29(8):735-41.
(8) Brinkrolf et al. Chinese hamster genome sequenced from sorted chromosomes. Nat Biotechnol. 2013; 31(8):694-5.
(9) Feist, A.M., et al., Model-driven evaluation of the production potential for growth-coupled products of Escherichia coli. Metabolic engineering, 2010. 12:173-86.
(10) Harry Yim., et al., Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol, Nature Chemical Biology. 2011; 7:445–452

Figure 1 - The CHO genome will aid in cell line engineering, generate hypotheses for biological discovery, and serve as a context to facilitate sequencing efforts and sequence analysis for additional cell lines, see text for details

About

eCHO Systems

“This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642663”

Background

Since their introduction into the market over 20 years ago, biotherapeutic products have constituted a large and growing percentage of the total pharmaceutical market, as well as app. 25% of the industry’s R&D pipeline. The number of approved products in Europe and the US has steadily increased to 200 in 2010 (1) , of which 27 have “blockbuster“ status, i.e. sales over $1 billion per year (2). In 2011, the annual sales of biopharmaceuticals were estimated at $138 billion worldwide (3), and to grow to over $320 billion by 2020. Most significantly, nearly 50% are produced in a single production host, Chinese hamster ovary (CHO) cells (1).


With their growing importance to heath care, the costs of some biopharmaceuticals serve as a major contributor to the increasing costs in overall health care worldwide (3). Indeed, the cost to develop a biopharmaceutical can range from 2000 to over 20,000 ($ US) per gram (4). Even so, just 2 in 10 approved drugs produce revenues that exceed their research and development costs; thus making the vast majority of drugs unprofitable (5).


One way to address challenges such as this is to make cell line development and manufacturing more efficient. Improvements in manufacturing technology can serve to lower production costs for biopharmaceuticals and address issues associated with product heterogeneity and quality; thus providing significant economic benefits and decreasing healthcare expenditures (6).


Objectives of eCHO Systems

With the release of genome information (6,7,8) and the following explosion of other types of omics data for CHO cells, a unique opportunity presents itself to integrate and leverage this information through a new interdisciplinary effort by leading academic and industrial researchers focused on enhancing CHO Systems Biology (eCHO Systems) graduate education and research. eCHO Systems will employ existing and new omics data to transform the CHO production platform (or chassis) in ways that parallel advances made to other high technology platforms (9,10), employing state-of-the-art cellular modeling to integrate, interpret, and apply omics-knowledge, an ability currently underdeveloped in the field. Further, eCHO Systems will serve to educate much needed industrial scientists and technologists to create the CHO production platforms of the future for next-generation biotherapeutics and biosimilars.


All students in this program work closely with industrial partners to ensure that knowledge of these advanced systems and synthetic biology concepts will be available to the commercial biotechnology industry. The graduates are being prepared through research, business, and entrepreneurship training to become leaders in small and large private companies and academia in the underserved area of CHO biotechnology.