How an Obscure Asian Rodent Took Over Biotechnology

The earliest domestic rodents were cavies (“Guinea pigs”) kept as food animals in the Andes since 5000 BC (as shown by mummified cavies) and carried to Europe in the 16th century (Elizabeth I had one as a pet). Although rats weren’t domesticated until the mid-19th century (a byproduct of the blood sport of rat-baiting), mouse selection and breeding began many centuries earlier. Selection of unusually colored mice was first documented ~1100 BC in China, and breeding such “fancy” mice as pets was an established hobby in Asia by the 17th century, from whence the practice (and the mice) migrated to Europe and the New World.

Mice might have been the first model organism in genetics but for an uptight Austrian Bishop who disapproved of monks keeping copulating animals in their quarters (1). So Gregor Mendel was forced out to his garden and sweet peas. Even so, 50 years later, the availability of established fancy mouse colonies with documented pedigrees gave the first wave of genetics researchers in the early 20th century a ready animal model with which to confirm their rediscovery of Mendelian inheritance (1).

Inbred mice, being prone to various cancers, sparked early oncology research. Ironically, those tumor transplant studies “had no significant impact on our understanding of cancer,” but through “discovery of the major histocompatibility complex,” they greatly advanced cellular immunology (1). The Wistar Institute bred the first standardized laboratory rat in 1906, and Clarence Cook Little developed standardized laboratory mice at Cold Spring Harbor in 1909, leading to today’s industrial-scale rodent breeding for research. In addition to their use in genetic and medical R&D, rodents and rabbits were used to produce the first generation of monoclonal antibodies (in ascites). Meanwhile, several other rodent species (chinchillas, gerbils, and hamsters) proved amenable to domestication as both laboratory animals and pets.

Chinese hamsters (Cricetulus griseus) are nocturnal rodents native to the deserts of Mongolia and northern China. They first appeared in research in 1919 as wild specimens used for typing Pneumococci. Because of contemporaneous work on mouse and rat genetics, early researchers such as George Yerganian were alert to the emergence of hereditary diseases as they established the first inbred populations of domestic Chinese hamsters. As carriers of the deadly Leishmania parasite, the rodents also became valuable epidemiological research models. After World War II, several laboratory hamsters were smuggled to the United States in defiance of a Chinese export ban (China feared the release of infected rodents as agents of biological warfare — the dark side of being known vectors). However, in one of history’s kinder ironies, the immortal ovary cells of Chinese hamsters have instead saved many human lives (2).

The hamsters are not likely to replace rats or mice in most research; they are better for certain specialty applications. It was noticed early that Chinese hamsters have fewer chromosomes (22) than do rats (42) and mice (40). That made them useful for radiation cytogenetics and tissue culture studies. In 1957, the University of Colorado’s Theodore Puck isolated an ovary from a Chinese hamster and from it established a robust and resilient tissue culture, the grandmother of most CHO cell lines in use today. Adaptable and easy to maintain, these cells rapidly became the mammalian counterpart of Escherichia coli as a laboratory model. They have contributed greatly to our understanding of cell signaling and DNA damage/repair and served as useful tools in cancer biology, high-throughput screening, pharmacology, and toxicology.

Puck and others using mutagenesis to produce auxotrophic cells in the 1960s did not have a manufacturing future in mind. But the nutritional finickiness of their auxotrophic lines made those especially suited for selection of specific protein-expressors. Establishment of multiple mutant CHO cell lines for research purposes (especially the DHFR-deficient cell lines DXB11 and DG44) was a fortuitous prerequisite to expressing heterologous proteins at industrial scale. So CHO cells moved into factories.

The first CHO-expressed therapeutic was a tissue plasminogen activator for treating myocardial infarctions (launched in 1987). Since then, dozens of CHO-produced proteins (mostly antibodies) have reached the market, many for previously untreatable diseases. And having begun with embarrassingly modest productivity compared with bacterial systems, CHO cells have achieved continually improving expression titers despite limited genomic knowledge. To address that lack, the CHO Genome Project was initiated in 2002, with multiple parallel efforts to sequence individual CHO lines as well as the species genome. Two CHO cell line genomes were published in 2011 (3, 4), and researchers have established a public, open-source database at www.CHOgenome.org.

A final note: Demonstrating their adaptiveness, feral Chinese hamsters are now an official pest species in New Jersey and California, locations that suggest populations founded by escapees from research labs.

About the Author

Author Details
Ellen M. Martin is a consultant with the Haddon Hill Group Inc., 650 Kenwyn Road, Oakland, CA 94610; 1-510-832-2044, fax 1- 510-832-0837; [email protected].

REFERENCES

1.) Paigen, K. 2003.One Hundred Years of Mouse Genetics: An Intellectual History: I — The Classical Period (1902–1980), Genetics Society of America, Bethesda.

2.) Jayapal, KP, and MGS. Yap. 2007. Recombinant Protein Therapeutics from CHO Cells: 20 Years and Counting (CHO Consortium). Chem. Eng. Prog. 103:40-47.3.) Hammond, S. 2011. Genomic Sequencing and Analysis of a Chinese Hamster Ovary Cell Line Using Illumina Sequencing Technology. BMC Genomics 12.4.) Xu, X. 2011. The Genomic Sequence of the Chinese Hamster Ovary (CHO)-K1 Cell Line. Nat. Biotechnol. 29:735-741.