"Which cow gives chocolate milk?" So goes the child's naivequestion. Little did anyone suspect how close to reality that questionwould some day come. Only, today, the actual question that maybecome common is, "Which biopharmaceutical does that cowproduce?" If scientists developing transgenic animals asbiomanufacturing options have their way, these will be the questionsasked in the near future.

Alan Colman, research director at PPL Therapeutics Ltd. inEdinburgh, Scotland, is one of the major players in the efforts toderive high-value, biopharmaceutical proteins from the milk ofdomestic animals. In the most recent issue of the Proceedings of theNational Academy of Sciences, dated March 28, his group publishedtheir newest work in an article titled, "Lactation is disrupted by a-lactalbumin deficiency and can be restored by human a-lactalbumingene replacement in mice." He describes experiments that show genetargeting which replaces the mouse version of this major milk proteinwith that of the human still allows normal lactation in the mouse.

Mice whose a-lactalbumin genes were knocked out produced reducedamounts of thickened milk that contained little or none of the milksugar lactose. Mouse pups that suckled on lactating females from thisknockout strain died, yet these same pups survived when they wereremoved to suckle on normal lactating females. This deficiency in a-lactalbumin expression had no effect in these knockout mice otherthan during lactation.

Replacement of the knocked out mouse a-lactalbumin gene with thehuman version of this gene restored normal lactation. Mothers withthis inserted human gene lactated normally and could successfullyrear their offspring.

Human Genes Work In Mice

As Alan Colman told BioWorld Today, "We established this programto show that we could perform gene knockouts and replacements. Wechose to study the a-lactalbumin protein because of its importantphysiological role in lactose synthesis and milk volume production."He added, "These experiments served as `proof of concept' for ourknockout program and contributed to answering basic sciencequestions at the same time."

"An interesting, but unexpected, result was that introducing thehuman a-lactalbumin gene into the mice caused there to be increasedlevels of this protein in the mouse milk," continued Colman. "Inessence, we got a bovine somatotropin-like effect on milk yieldwithout using hormone injections."

Genzyme Transgenics Inc., of Framingham, Mass., is one of PPL'smajor competitors. As Harry Meade, their research director, said,"This work confirms the importance of a-lactalbumin and its role inmilk volume production. The production of essentially normal mousemilk with human a-lactalbumin clearly shows the universal nature ofmilk."AColman reported, "What we now need are embryonic stem [ES] celllines for livestock, like the ones we have for mice." Meade agreed."Eventually everyone wants to move into cows because this is one ofthe production systems of choice. But our ability to manipulate cowsand sheep is much more limited than it is for mice," he said. "Wedefinitely need ES cell lines in these species for further developmentof their biomanufacturing capabilities." n

-- Chester Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.