bST is a naturally-occurring protein hormone produced in the pituitary gland of cattle and is a major regulator of milk production and growth in lactating dairy cows. Since the 1920s, administering pituitary extracts to lactating animals was known to increase milk production. During World War II, efforts to use bST to enhance milk production were unsuccessful because of the difficulty in harvesting the pituitaries and purifying sufficient quantities of bST from slaughtered cattle.¹ (It takes the pituitaries of 25 cows to get enough bST to supplement one cow for one day.)

In 1979, Monsanto coordinated a research program with Genentech, Inc., a biotechnology company working on human protein production (insulin, somatotropin and tissue plasminogen activator) in San Francisco, California. From this program Monsanto obtained the rights to develop fully and commercialize Genentech's recombinant bST manufacturing process.

The process developed by Genentech is the basic process used to produce several products other than bST, such as human insulin, interferons, and human and animal somatotropins. This technology enables new strains of bacteria to produce products that could otherwise only be produced in the host or target animal. To manufacture POSILAC, the gene that produces bST in the pituitary gland of the cow is spliced into the genetic information of an E. coli K-12 bacterium. This organism is a well-studied laboratory strain, which is modified so it cannot survive outside a carefully controlled laboratory environment and is commonly used to produce other drugs (eg, insulin). E. coli K-12 possesses a small circular piece of DNA (plasmid) into which the bovine DNA is inserted. After the vector DNA carrying the bST gene is introduced into the E. coli cells, the cells make the protein coded for by the bST gene using their own protein synthesis machinery (Figure 1).

During the manufacturing process, the genetically engineered organism is then grown under classical fermentation conditions and bST is produced within the organism.² The E. coli bacteria are killed and ruptured. Bacterial constituents, such as membranes, DNA, and proteins, are separated from the bST. Highly-purified bST is incorporated into an injectable slow-release formulation (POSILAC) via specialized pharmaceutical procedures.

Figure 1
Bovine somatotropin Production

The majority of functions of a cell and a whole organism are carried out by proteins, which are strings of the 20 amino acids found in nature. The particular function of any given protein is determined by the sequence of amino acids composing the protein and its three-dimensional structure. Four different versions of bST are made in the pituitary gland of the cow.2 They differ from one another by one or two amino acids, and are made up of 190 or 191 amino acids. POSILAC bovine somatotropin has the identical sequence for 190 of the 191 amino acids found in one of the pituitary forms. The only difference is that the amino acid methionine, which is already found in pituitary bST, has been substituted for alanine at the NH2 end of the chain. Based on extensive analysis, POSILAC and the pituitary bST forms have essentially the same chemical structure and biological activity.

bST is an important control in the coordination of nutrients to support higher milk production.3 Initially, changes in the partitioning and oxidation of key precursors such as glucose, amino acids, and free fatty acids provide additional substrate for milk synthesis. In the next weeks, feed intake adjusts upward to provide a new equilibrium for nutrient input into the cow and outflow in the milk. Overall basal metabolic rate is not increased, so cows will not disproportionately increase feed intake or lose excessive body weight.

How POSILAC Works

• Blood flow through the mammary gland is increased during the administration of POSILAC bovine somatotropin. This enhanced flow provides critical precursors for the synthesis of milk fat, protein, and lactose in the mammary gland.
  
  
• POSILAC may increase either the number of mammary cells or the synthetic activity of existing cells. The mechanism for this is not known but the somatomedins (eg, insulin-like growth factor IGF-1) may have a role, for somatomedin receptors have been identified on the surface of mammary cells.
  
  
• Increases in milk production can occur only if the rate of lactose synthesis from available glucose is increased. Administration of POSILAC results in the reduction in the uptake of glucose by body tissues, such as muscle and fat; an increase in glucose production in the liver from propionate; and additional glucose from glycerol released during lipolysis. More glucose is therefore available at the mammary gland for lactose synthesis.
  
  
• Lipogenesis in body tissues is also reduced. This allows more free fatty acids either to be oxidized as an energy source by most tissues, or to be used directly in milk fat production in the mammary gland.
  
  
• One of the classic physiologic actions of bST is to conserve nitrogen. bST reduces protein turnover in the muscle and the oxidation of amino acids for energy production, so that more amino acids are available for milk protein synthesis. This results in a lowering of plasma urea nitrogen and creatinine.
  
  
• In the long run, the adaptations observed during administration of POSILAC are natural and are to be expected from a cow transferring to higher milk production .

References

1. Young FG: Experimental stimulation (galactopoiesis) of lactation. Br Med Bull 1947;5:155.
2. Hammond BG, Collier RJ, Miller MA, McGrath M, Hartzell DL, Kotts C, Vandaele W: Food safety and pharmacokinetic studies which support a zero (0) meat and milk withdrawal time for use of sometribove in dairy cows. Ann Rech Vet 1990;21(Suppl. 1):107s.
3. Peel CJ, Bauman DE: Somatotropin and lactation. J. Dairy Sci 1987;70:474