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Biological Chemistry

Harvesting therapeutic proteins from animal slobber

Scientists genetically engineered mice to secrete human nerve growth factor in their saliva, a first step toward using critter spit to crank out drugs

by Ryan Cross
February 21, 2017

Credit: Shutterstock
Researchers hope to engineer pigs to secrete human therapeutic proteins in their saliva.
A photograph of a drooling barnyard pig.
Credit: Shutterstock
Researchers hope to engineer pigs to secrete human therapeutic proteins in their saliva.

Anyone who has ever been to a farm knows there’s no shortage of drool dangling from the mouths of barnyard animals. Those super-active salivary glands could someday be put to good use, according to a new study.

Zhenfang Wu and colleagues at the South China Agricultural University transformed the salivary glands of mice into miniature bioreactors for producing human nerve growth factor (NGF) proteins in their spit (Sci. Rep. 2017, DOI: 10.1038/srep41270). “This is the first paper that reports production of therapeutic protein from transgenic animals’ saliva,” Wu says.

Protein drugs, such as blood clotting factors and insulin, are often produced in large vats of genetically engineered cells. Sometimes yields are low, and if bacterial or yeast cells are used, the protein drugs may lack the appropriate chemical modifications that occur in mammalian cells, such as glycosylation.

To get around that limitation, some scientists have turned to harvesting the proteins from transgenic animals. Two therapeutic proteins produced in in the milk of genetically modified animals, ATryn and Ruconest, have been approved for use in Europe and the U.S.

In the new study, Wu’s team looked to produce NGF. Scientists have studied human NGF because of its therapeutic implications in a number of neurological diseases, including Alzheimer’s, Parkinson’s, spinal cord injury, and glaucoma. Surprisingly, NGF is produced in both mouse and human saliva, but Wu and colleagues engineered mice to produce human NGF protein in their salivary glands instead of the mouse version.

To collect the NGF protein, the researchers anesthetized the mice and administered pilocarpine hydrochloride, a known salivary stimulant. After purifying NGF from the saliva, the team showed that the protein was functional, triggering rat adrenal gland cells to become neuronlike.

“Currently we are working on using this process in pigs,” Wu says, adding that his team has already developed methods for “repeated, long-term and large-volume collection of saliva from pigs.”

“The production of pharmaceutical proteins from transgenic animals is developing slowly. This is the case even for the production from milk, which is likely the best system,” says Louis-Marie Houdebine, an expert on producing drugs in transgenic animals at the French National Institute for Agricultural Research.

Enqi Liu of the Laboratory Animal Center at Xi’an Jiaotong University School of Medicine says that compared with milk, saliva would be especially “susceptible to microbial contamination,” posing a further complication for purifying the proteins.

But could scientists produce a high enough concentration of a protein and collect a large enough volume of saliva to make spit a viable option? “In theory, I think it could work,” says Karen Beauchemin, a ruminant nutrition scientist at Agriculture & Agri-Food Canada. Beauchemin says that dairy cows produce more than 200 L of saliva in a single day to buffer fermentation in the rumen, the cow’s first of four stomachs.

Like humans, pigs have only one stomach. Wu says that swine produce about 15 L of saliva per day, and his team has been able to collect 3 L of spit per day from pigs, for 40 days straight, without any apparent harm to the animals.

Houbedine points out that salivary glands are not the first unusual tissue researchers have attempted to tap for protein production. Other researchers have proposed to engineer bladder epithelium and male epididymis tissues for collecting therapeutic proteins in animal urine and semen, respectively. “These two systems were soon abandoned,” he says, perhaps because of low yield, and also the foreseeable difficultly in marketing such a product.


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