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The Science

BioPharm International


E. coli has been studied in microbiology laboratories for many years and was the first organism to have its entire genome mapped. It is common — certain strains live in our lower intestine all the time without causing a problem. It is cheap to cultivate, it replicates quickly, and it serves as a good model organism — that is, it provides an example of how other similar life forms will behave — how they grow and reproduce, what makes them deteriorate or die, and so on. When molecular biologists needed an organism to help them study genetics, they naturally turned to E. coli. Once safe strains had been engineered — most of which cannot even survive outside the optimal conditions of the lab — it only made sense to use them for further, more involved, experiments. When some researchers left academia to become biotech entrepreneurs, they took their knowledge of E. coli with them, and the bacterium became the workhorse of the biotechnology industry.

Yeasts. When yeasts were considered as a means of producing biopharmaceuticals, Saccharomyces cerevisiae was naturally the first candidate. Also known as brewer's yeast, it has been studied, characterized, and cultured over thousands of years. It and its similarly employed cousin Schizosaccharomyces pombe are our best understood species of yeast. The full genome of Saccharomyces cerevisiae was mapped and sequenced by molecular biologists in 1996.

Another species of yeast used in biotechnology is Pichia pastoris, which offers an interesting advantage for production. Some organisms tend to hold the protein they have produced inside their cell walls, which can make it more difficult to recover the protein. P. pastoris is one of the best of the yeasts at secreting protein into the liquid it grows in, which makes the product easier to purify. P. pastoris also is capable of posttranslational modifications that resemble those of human beings.

Animal cells. If historical precedent was important in the choice of E. coli and S. cerevisiae as tools for biotechnology, the same could be said of the choice of the most widely used animal cell: Chinese hamster ovaries (CHO).

Certain kinds of cells, particularly epithelial cells, are more robust than others and thus are easier to grow in culture. CHO cells are epithelial cells that were introduced to science in the 1950s. They multiply quickly, are relatively hardy, and grow well in culture.

In the 1960s, cancer researchers in Seattle discovered an interesting mutation in a particular line of CHO cells they were studying. It enabled the cells to grow in the presence of methotrexate, a chemical that kills cancer cells. That made them useful for later genetic engineering: When scientists add genes to a batch of cells, not every cell is modified. The trick is to separate cells that have taken on the new DNA from those that haven't. By adding the gene for methotrexate resistance to the new DNA package, scientists had a simple tool for distinguishing: If methotrexate was added to the culture, cells without the resistance gene would die off, and only the recombinant cells would survive. (A similar process is used in working with bacteria, but using a gene for resistance to antibiotics.)

By the 1980s, many molecular biologists were using CHO cells in their work, studying viruses among other things. So when those people went into the biotechnology industry, they took with them the knowledge of that particular cell line.

CHO cells are not the only cell line used for production of recombinant proteins by mammalian cell culture. Other commonly employed epithelial cell lines include human cervix (HeLa), African green monkey kidney (COS and CV-1), and baby hamster kidney (BHK) cells. In the realm of gene therapy, Per.C6, a cell engineered from certain cells from the human eye, is common. The abnormal cells created in cancers have also proven useful in biotechnology; hybridomas — "immortalized" cell lines from cancerous lymphocytes—are frequently used in the production of antibodies.


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