Module 4: Production of Neutrophils

Dr Nick Timmins (Lars Nielsen Group, AIBN)

 Module Leader Professor Lars Nielsen
 Host Organisation Australian Institute for Biotechnology and Nanotechnology, University of Queensland

Module description

The overall objective of this Module is to develop bioprocesses suitable for commercial production of mature blood products, in particular neutrophils and red blood cells.

Manufactured neutrophils may be useful for the management of neutropaenia in chemotherapy patients, providing protection against infection by bacteria and fungi. While it is already possible to produce clinically useful quantities of neutrophils from blood stem cells, economic considerations dictate that further improvements in cell yield are required. Due to combinatorial and temporal complexities, classical approaches to optimisation are of limited use. A systems level understanding of the events and mechanisms underpinning growth and differentiation of neutrophils, would provide a rational framework for process optimisation. In parallel to ongoing process development activities, this Module will undertake a detailed investigation of molecular events regulating differentiation and expansion of neutrophils. This data will be used to identify key phenomena amenable to external manipulation in order to maximise cell yields and minimise costs.

Red blood cell products can also be manufactured in large quantities, at least theoretically.  In reality the scale of such operations is simply not feasible at the present time, and new process technologies are required. Utilising an existing high numerical yield process, this Module will undertake initial development of scalable bioreactor based approaches to manufacture of red blood cells.

Aims

  1. Establish bioreactor production of neutrophils as a routine technology that can be used in a pilot clinical trial.
  2. Develop processes for second generation neutrophil products derived from umbilical cord blood.
  3. Generate a high fidelity temporal map of molecular events regulating ex vivo haematopoiesis.
  4. Develop process technology suitable for large scale production of red blood cells.

Module Leader biography

Professor Lars Nielsen is Chair of Biological Engineering and heads the Systems & Synthetic Biotechnology group at the Australian Institute for Bioengineering and Nanotechnology at The University of Queensland. He has worked in cell culture engineering since 1988, and specifically haematopoietic cell culture engineering since 1995. His focus has been on scaling up haematopoietic processes for clinical application and the development of mathematical models to assist the analysis of ex vivo and in vivo haematopoiesis.

At Northwestern University, he was part of the first team successfully cultivating haematopoietic cells in traditional bioreactors and his group’s subsequent work in collaboration with the Australian Red Cross Blood Service and the ASCC has seen the development and patenting of clinical scale bioreactor processes for the production of both neutrophils and red blood cells. Professor Nielsen has published 72 papers and six patents and is associate editor of Biochemical Engineering Journal and on the editorial board of Bioprocess and Biosystems Engineering, Biotechnology and Bioengineering, and Biotechnology Journal.

Contact details

E-mail   lars.nielsen@uq.edu.au
Phone  +61 7 3365 4682 
Web  http://web.aibn.uq.edu.au/cssb/

Selected publications

  1. Timmins NE, Palfreyman E, Marturana F, Dietmair S, Luikenga S, Lopez G, Fung YL, Minchinton R, Nielsen LK (2009) Clinical Scale Ex vivo Manufacture of Neutrophils from Hematopoietic Progenitor Cells. Biotechnol Bioeng., in press.
  2. Timmins NE, Nielsen LK (2009) Blood cell manufacture: current methods and future challenges. TiBTech 27:415-422.
  3. Quek L-E, Nielsen LK (2008) On the reconstruction of the Mus musculus genome-scale metabolic network model. Genome Informatics 21: 89-100.
  4. Hines M, Nielsen LK, Cooper-White J (2008) The hematopoietic stem cell niche: what are we trying to replicate? Journal of Chemical Technology and Biotechnology 83:421-443.
  5. Peng JC, Abu Bakar S, Richardson MM, Jonsson JJ, Frazer IH, Nielsen LK, Morahan G, Thomas R (2006) IL10 and IL12B polymorphisms each influence IL-12p70 secretion by dendritic cells in response to LPS. Immunology and Cell Biology 84: 227-232.
  6. Peng JC, Thomas R, Nielsen LK (2005) Generation and maturation of DC for clinical application under serum-free conditions. Journal of Immunotherapy 28:599-609.
  7. Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK (2003) A method for the generation Of homogeneous multicellular tumor spheroids Applicable to a wide variety of cell types. Biotechnology & Bioengineering 83:173-180.
  8. Nielsen LK (1999) Bioreactors for haematopoietic cell culture. Annual Review of Biomedical Engineering 1:129-152.
  9. Nielsen LK, Bender J, Miller WM and Papoutsakis ET (1998) Population balance model of in vivo neutrophil formation following bone marrow rescue therapy. Cytotechnology 28:157-162.
  10. Collins PC, Nielsen LK, Patel SD, Papoutsakis ET, Miller WM (1998) Characterization of hematopoietic cell expansion, oxygen uptake and glycolysis in a controlled, stirred-tank bioreactor system. Biotechnol. Progr. 14:466-472.