FROMLINE: Lauren Quinn
Newswise – URBANA, Ill. – A humble brown bovine from southern Brazil has made history as the first transgenic cow capable of producing human insulin in its milk. The progress, led by researchers from the University of Illinois Urbana-Champaign and that University of Sao Paulocould usher in a new era in insulin production and one day eliminate drug shortages and high costs for people with diabetes.
“Mother Nature designed the mammary gland to be a factory for truly efficient protein production. We can use this system to make a protein that can help hundreds of millions of people worldwide,” he said Matt WheelerProfessor in Department of Animal Sciencespart of College of Agricultural, Consumer and Environmental Sciences (ACES) at the U. of I. He is also a member of the Carle Illinois College of Medicine, The Grainger College of EngineeringThe College of Veterinary MedicineThe Beckman Instituteand that Carl R. Woese Institute for Genome Biology.
Wheeler is lead author of a new book Biotechnology Journal Study describing the development of the insulin-producing cow, a feasibility study that could be expanded upon additional testing and FDA approval.
Wheeler’s colleagues in Brazil inserted a section of human DNA that codes for proinsulin – the protein precursor to the active form of insulin – into cell nuclei from 10 cow embryos. These were implanted into the uterus of normal cows in Brazil and a transgenic calf was born. Modern genetic engineering technology has allowed human DNA to be expressed exclusively in breast tissue – the process by which gene sequences are read and translated into protein products.
“We used to just throw the DNA in and hope it expressed where we wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to breast tissue means that no human insulin circulates in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s ability to produce large amounts of protein.”
When the cow was fully grown, the team tried unsuccessfully to impregnate her using traditional artificial insemination techniques. Instead, they stimulated her first lactation with hormones. Lactation produced milk, although in smaller quantities than after a successful pregnancy. Nevertheless, human proinsulin and, surprisingly, insulin were detectable in the milk.
“Our goal was to make proinsulin, purify it into insulin and go from there. But the cow basically processed it herself. It produces about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”
The insulin and proinsulin, which had to be extracted and purified for use, were present in the milk at a level of a few grams per liter. However, because the lactation was hormonally induced and the milk supply was lower than expected, the team cannot say exactly how much insulin would be produced in a typical lactation.
Conservatively, Wheeler says if a cow could produce 1 gram of insulin per liter and a typical Holstein produces 40 to 50 liters per day, that would be a lot of insulin. Especially since the typical insulin unit is 0.0347 milligrams.
“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just a liter; Holsteins can produce 50 liters per day. You can do the math.”
The team plans to clone the cow again and are optimistic that they will have greater success with pregnancy and full lactation cycles in the next generation. Ultimately, they hope to breed transgenic bulls that mate with the females, creating transgenic offspring that can be used to build a targeted herd. Wheeler says even a small herd could quickly surpass existing methods – transgenic yeasts and bacteria – for insulin production, without having to create high-tech facilities or infrastructure.
“In terms of mass production of insulin in milk, you would need specialized facilities with high levels of cattle health, but for our well-established dairy industry this is not out of the ordinary,” Wheeler said. “We know what we are doing with cows.”
An efficient system for collecting and purifying insulin products, as well as FDA approval, would be required before transgenic cows could provide insulin to diabetics around the world. But Wheeler is confident that day will come.
“I could imagine a future where a 100-head herd, the equivalent of a small dairy in Illinois or Wisconsin, could produce all of the country’s insulin needs,” he said. “And a larger herd? In a year you could meet the needs of the entire world.
The study “Human proinsulin production in the milk of transgenic cattle” is published in Biotechnology Journal [DOI: 10.1002/biot.202300307]. The research was supported by the National Council for Scientific and Technological Development, CNPq [grant no. 245886/2012-5]; the University of North Parana, UNOPAR; and the USDA National Institute of Food and Agriculture Multistate Research Fund [project no. W-4171].