Genetically Engineered Livestock
Bringing 21st Century Medicines to the Developing World
The production of biopharmaceuticals in the milk of genetically engineered livestock enables a more than 200-fold increase in productivity over current methods of culturing animal cells in stainless steel bioreactors. This is due to the secretory architecture of the mammary gland and its sophisticated biochemistry for protein modification.
The genetic engineering of livestock began in the 1980s when it was shown that recombinant DNA microinjected into mouse embryos could be integrated into chromosomes by a natural gene repair process. “Transgenes” were then designed to express recombinant proteins in mice and, more productively, in other animals. Some researchers focused particularly on expressing the proteins in the milk of transgenic animals, hoping that they would serve as prodigious, self-replicating “bioreactors”. Other researchers focused on methods for cloning transgenic animals, a notable effort being the production of the sheep "Dolly". Despite many advances, however, achieving low cost transgenic protein production has proven far more difficult than initially anticipated.
Recent advances in genome editing and cloning techniques have overcome some of the obstacles. Transgene "integration" frequencies have been increased from a few per cent to 30% - 100%, simplifying production, reducing cost, and broadening the scope of feasible projects. For example, the pig mammary gland recently has been engineered to better perform the intracellular modifications needed to make very complicated proteins, such as anti-hemophilia Factor IX. Cows have been engineered with a balanced array of three full length gene to make human fibrinogen, which is difficult and expensive to make by conventional methods, especially in the amounts required to manufacture affordable surgical tissue sealants. Only 300 of these cows can produce a metric ton of fibrinogen, enough for large scale commercial production.
Producing proteins in the milk of transgenic livestock can be one tenth as expensive as convention methods for manufacturing biotherapeutics, and he capital investment required to develop transgenic production capacity can be one billion dollars or more below that required for a stainless steel cell culture production facility. The lower capital requirements are particularly important in the developing world where capital often is scarce. Furthermore, the reduced production cost makes it feasible to economically produce large volume biotherapeutics, such as monoclonal antibodies to treat cancer, and fibrinogen to treat exsanguinating trauma, even in developing economies. These advantages and USFDA/ EMEA approval of Atryn, a regulatory coagulation protein made in the milk of transgenic goats, have catalyzed developing countries, such as Brazil and China, to develop biopharmaceutical manufacturing in the milk of transgenic livestock to meet their needs for biopharmaceutical proteins.
This lecture will discuss genetic engineering of livestock animals, particularly for producing biopharmaceutical proteins in milk, and the promise of this technology to provide low cost production of medically important substances in the developing world.
Bill Velander is Distinguished Scholar and Fellow in the Department of Chemical and Biomolecular Engineering at the University of Nebraska - Lincoln. Previously he served as Chair of the Department, and before joining UNL, he was a faculty member at Virginia Tech.
Bill has worked throughout his career on the production of blood plasma-derived medicines, particularly methods for producing them in transgenic animals. His interest in producing safer blood-derived medicines was spurred by the widespread contamination of blood supplies and derivatives by HIV and Hepatitis in the late 1980s. In collaborations with colleagues at the American Red Cross Holland Laboratory he pioneered the production of genetically engineered versions of human Protein C, anti-hemophiliac factors VIII and IX, von Willebrant's factor and fibrinogen in the milk of transgenic animals. And he has also done pioneering work on "humanizing" pig tissues and organs to make them safe for human transplant therapy.
Bill is an author or co-author of many scientific publications and an inventor in many patent applications and issued patents. His work also has been featured in the mass media, including a cover story in National Geographic, articles in Scientific American, Smithsonian and Discover magazine, a broadcast on Discovery Health Channel, and an exhibit at the Chicago Museum of Science and Industry. He also served as consultant to Harrison Ford on “Extraordinary Measures” a film about scientists' contributions to medicine.
Bill was deeply involved in developing the USFDA's regulatory guidelines for human therapeutics derived from transgenic animals and plants. He is an elected fellow of the American Institute of Medical & Biological Engineering, and served as AIMBE's ambassador to Capitol Hill.
Bill earned a BS in Biochemistry at Illinois Benedictine College, an MChE at Illinois Institute of Technology and a PhD in Chemical Engineering at Pennsylvania State University.