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Animal Cell Technology: Becoming more and more important

By definition animal cell technology is that part of biotechnology which is based on the use of animal (including human) cells, propagated in vitro, for the manufacture of biopharmaceuticals and as toolbox in the discovery and testing of medicines. The main field of application of animal cell technology is the medical and pharmaceutical arena. The members of ACTIP, the Animal Cell Technology Industrial Platform, want to support and reinforce further development of animal cell technology which will lead to increased utilization of animal and human cells to be propagated in vitro. As early as the 19th century, animal cell technology already formed the basis for providing vaccines against small pox and rabies, although these vaccines were actually produced in living animals. In the 20th century, knowledge in many areas of the life sciences increased tremendously. In the early 1950s this led to the Salk and Sabin processes of in vitro cultivation of cells for the production of highly effective vaccines against polio virus. Other vaccines against a wide variety of human and animal viral diseases like rubella, measles, foot and mouth disease etc. followed soon after. In addition, novel animal cell technologies made it possible to develop high throughput assays for the screening of new candidate pharmaceuticals and as diagnostic tools.

Breakthroughs in the 1970s and 1980s

A major breakthrough in the field of animal cell technology came in the late 1970s/early 1980s with the development of hybridoma and recombinant DNA technology. The hybridoma technology makes it possible to elicit, select and produce, in vitro, so called monoclonal antibodies of consistent quality, high specificity and unlimited quantities, whereas previously antibodies could only be produced in life animals with a varying degree of quality. Antibodies are nowadays widely used for passive immunization of patients against infectious diseases, for diagnostic purposes like blood group typing and disease testing, and for therapeutic intervention. The development of recombinant DNA technology or heterogenous gene expression allows for e.g. the production of human proteins in animal cells at a relatively efficient production scale. Previously, many of these human proteins could not be produced or isolated at all.

Need for animal cells

The recombinant DNA technology - also called genetic engineering - makes it possible to transfer a gene from one species into cells of another, and to let these transformed cells produce the encoded gene product. For example, the encoding gene for human insulin has been successfully transfected into the easy to grow bacterium Escherichia coli. However, with more complex and larger gene products than insulin, it is no longer possible to use bacteria like E. coli as host cells for the production. The reason is that these bacteria can not perform the complicated posttranslational processing steps such as glycosylation, folding and trimming, which is often a prerequisite to exert biological functions. Alternatively, such proteins can be expressed successfully and correctly in cultured animal cells. For example, the bioactivity of erythropoietin, tissue plasminogen activator or factor VIII is strongly dependent on a correct posttranslational processing. Development of novel cell lines has resulted in an increased frequency in which animal cells are being used. In the early eighties the majority of biopharmaceuticals was produced in E. coli (86%), whereas in the early nineties this figure had been dropped to around 40%, the other 50-60% was produced in animal cells such as Chinese Hamster Ovary (CHO) cells and Baby Hamster Kidney (BHK) cells. Nevertheless, using animal cells as production factories, however, has the disadvantage that the production costs are relatively high in comparison with production in cultivated bacteria or yeast cells, and related to this, the relatively small production scale. Therefore, many research programs have been and are being started to develop robust and high-producing animal host cell lines.

Therapeutics: demand for large scale manufacturing facilities

At present, the majority of therapeutic biopharmaceuticals has been produced using animal cell technology and include proteins used for the treatment of cardiovascular diseases (tissue plasminogen activator: tPA, reteplase), cystic fibrosis (DNases), anemia (erythropoietin: EPO), haemophilia (coagulation factors VIII and IX), cancer and viral infections (interferons and interleukins), multiple sclerosis (interferon-beta2) and dwarfism (human growth hormone: hGH). Monoclonal antibodies are used for the treatment of a rapidly expanding list of diseases, e.g. to reduce the rejection of transplanted organs by the recipient (e.g. Simulect and Zenapax), to treat metastasized breast cancer (Herceptin), to treat non-Hodgkin lymphoma's (Rituxan), to inhibit allergic asthma (Xolair), and many others (see monograph on monoclonal antibodies). These different antibody indications have in common that effective patient dosing requires relatively large amounts of antibody-protein, which translates into a huge demand for large scale manufacturing capacity. Although only 10% of all biopharmaceuticals relate to monoclonal antibodies, more than 75% of the world wide manufacturing capacity is dedicated to its production. Therefore, improvement of production processes remains imperative.

Gene therapy

Culturing of animal cells forms also an important basis for the new area of gene therapy. In contrast to direct treatment of patients with recombinant biopharmaceuticals, gene therapy is based on the delivery of the corresponding gene to a patient, in such a way that the patient may produce the functional gene product (i.e. the protein) intracellularly. In principle, such an approach is considered to result in long-lasting treatment or cure. For the delivery of relevant genes into specific tissues in patients recombinant viruses are being used. These viruses are genetically modified and produced in vitro in animal cells. Gene therapy is very promising since it may yield a number of advantages. When we consider for example patients suffering from a bleeding disorder such as Haemophilia A, these patients have a deficient gene encoding for clotting Factor VIII. Current treatment is based on the life long treatment with the recombinant protein Factor VIII. Gene therapy might make it possible to administer the gene encoding Factor VIII into the liver cells of these patients. These cells are the natural producer cells of Factor VIII and, thus, may behave naturally after transfection with the functional gene encoding Factor VIII.

Drug discovery

The evolution of the drug discovery and development process has been revolutionized by the implementation of high-throughput technologies, combinatorial chemistry and genomics-based target identification and validation. Animal and human cells have become an essential part of the cell-based assays and models, which form the basis of target identification and validation experiments, HT-screening of chemical libraries for lead finding and optimization purposes and HT-testing for ADME/tox of candidate drugs. Given the fact that these areas are still in rapid development, it will be obvious that improvement of cell culture procedures remains a prerequisite. In this respect, multidisciplinary R&D programmes remain crucial to feed further progress in the tool box needed for efficient drug discovery.

How are animal cells propagated?

Animal cells are cultivated in vitro by mimicking the same conditions as they have in their natural environment, the body. They need complex and balanced culture media which contain substrates such as glucose, amino acids, vitamins, salts, trace elements and others. Small scale cultures are performed in tissue culture flasks or roller bottles in a 37°C incubator. Large scale cultivation for industrial purposes is mainly performed in bioreactors which are large stainless steel tanks with gentle agitation and aeration to supply oxygen. In these systems, cells grow, multiply and, in the case of recombinant cells, release human proteins into the culture medium from which the protein product can be purified, formulated and packaged. Currently, a major development is to design large scale cultivation procedures utilizing media free of serum additives or protein growth factors. Resulting protein free media or procedures are considered to be far more safe as to the transfer of biological contamination. Particularly, potential contamination of biopharmaceutical end products with agents that may transfer Bovine Spongiform Encephalitis (BSE) has been the major driver to develop such protein/serum free media and related cell culturing processes.

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