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Article| Volume 80, ISSUE 9, P2225-2232, September 1997

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Toward Altering Milk Composition by Genetic Manipulation: Current Status and Challenges

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      Abstract

      The implementation of large-scale genome mapping and sequencing has improved the understanding of animal genetics. A large number of gene sequences are now available to serve as regulatory elements or genes of interest. Although the central thrust of this work is focused on understanding disease states, the manipulation of normal metabolic processes is feasible. To date, the genetic manipulation of livestock has been limited to the permanent addition of genes of clinical interest. This study explores the utility of genetically engineered cattle as a means of altering milk composition to improve the functional properties of milk, increasing marketability. Improvements would include increasing the concentration of valuable components in milk (e.g., casein), removing undesirable components (e.g., lactose), or altering composition to resemble that of human milk as a means of improving human neonatal nutrition. The protracted time lines of genetically modifying dairy cattle has prompted the development of animal models. A model for dwarf goats is discussed in terms of circumventing the lengthy time lines involved in generating transgenic cattle and allowing for an accelerated expansion of research in molecular genetics of dairy animals. Thus, the genetic manipulation of dairy cattle is feasible and could have significant impacts on milk quality, attributes of novel dairy products, and human health.

      Key words

      Abbreviation Key:

      BELE (breed early, lactate early), ES (embryonic stem), hLF (human lactoferrin)

      References

        • Bawden W.S.
        • Passey R.J.
        • MacKinlay A.G.
        The genes encoding the major milk-specific proteins and their use in transgenic studies and protein engineering.
        Biotechnol. Genet. Eng. Rev. 1994; 12: 89
        • Blackburn D.G.
        Lactation: historical pattern and potential for manipulation.
        J. Dairy Sci. 1993; 76: 3195
        • Bremel R.D.
        Potential role of transgenesis in dairy production and related areas.
        Theriogenology. 1996; 45: 51
        • Bremel R.D.
        • Yom H.C.
        • Bleck G.T.
        Alteration of milk composition using molecular genetics.
        J. Dairy Sci. 1989; 72: 2826
        • Clark A.J.
        Genetic modification of milk proteins.
        Am. J. Clin. Nutr. 1996; 63: 633S
        • Clark A.J.
        • Bissinger P.
        • Bullock D.W.
        • Damak S.
        • Wallace R.
        • Whitelaw C.B.A.
        • Yull F.
        Chromosomal position effects and the modulation of transgene expression.
        Reprod. Fertil. Dev. 1994; 6: 589
        • Colman A.
        Production of proteins in the milk of transgenic livestock: problems, solutions and successes.
        Am. J. Clin. Nutr. 1996; 63: 639S
      1. Colman, A., G. Wright, L. Sawyer, and D. J. Rigden, inventors. 1995. Modified alpha-lactalbumin. Pharmaceutical Proteins Ltd., assignee. WO 95/02692.

        • Dahlqvist A.
        Digestion of lactose.
        in: Delmont J. Milk intolerances and rejection. Karger, Basel, Switzerland1983: 11
        • Dalgleish D.G.
        Bovine milk protein properties and the manufacturing quality of milk.
        Livest. Prod. Sci. 1993; 35: 75
        • Datar R.V.
        • Cartwright T.
        • Rosen C.G.
        Process economics of animal cell and bacterial fermentations: a case study analysis of tissue plasminogen activator.
        Biol. Technol. 1993; 11: 349
        • Ebert K.M.
        • Schindler J.E.S.
        Transgenic farm animals: progress report.
        Theriogenology. 1993; 39: 121
        • Eyestone W.H.
        Challenges and progress in the production of transgenic cattle.
        Reprod. Fertil. Dev. 1994; 6: 647
        • First N.L.
        New animal breeding techniques and their application.
        J. Reprod. Fertil. 1990; 41: 3
      2. Food and Drug Administration. 1995. Points to consider in the manufacture and testing of therapeutic products for human use derived from transgenic animals. FDA Ctr. Biologics Eval. Res., Rockville, MD.

        • Furth P.A.
        • Shamay A.
        • Wall R.J.
        • Henninghausen L.
        Gene transfer into somatic tissues by jet injection.
        Analyt. Biochem. 1992; 205: 365
        • Gekas V.
        • Lopez-Leiva M.
        Hydrolysis of lactose: a literature review.
        Process Biochem. 1985; 20: 2
        • Gibson J.P.
        Altering milk composition through genetic selection.
        J. Dairy Sci. 1989; 72: 2815
        • Gordon J.W.
        • Scangos G.A.
        • Plotkin D.J.
        • Barbosa J.A.
        • Ruddle F.H.
        Genetic transformation of mouse embryos by microinjection of purified DNA.
        Proc. Natl. Acad. Sci. USA. 1980; 77: 7380
        • Hennighausen L.
        • Ruiz L.
        • Wall R.
        Transgenic animals—production of foreign proteins in milk.
        Curr. Opin. Biotechnol. 1990; 1: 74
        • Hettinga D.H.
        Why alter milk composition? J.
        Dairy Sci. 1989; 72: 2790
        • Hoban IV, J.T.
        Anticipating public reaction to the use of genetic engineering in infant formula.
        Am. J. Clin. Nutr. 1996; 63: 657S
        • Hoeschele I.
        Potential gain from insertion of major genes into dairy cattle.
        J. Dairy Sci. 1990; 73: 2601
        • Houdebine L.M.
        The production of pharmaceutical proteins from the milk of transgenic animals.
        Reprod. Nutr. Dev. 1995; 35: 609
        • International Dairy Federation
        The world dairy situation.
        Int. Dairy Fed., Brussels, Belgium.1995 (Page 2 IDF Bull. 303)
        • International Dairy Federation
        Milk payment systems for ex-farm milk.
        Int. Dairy Fed., Brussels, Belgium1995 (IDF Bull. 305)
        • International Dairy Federation
        The world market for cheese.
        Int. Dairy Fed., Brussels, Belgium1995 (IDF Bull. 307)
        • Jaenisch R.
        Transgenic animals.
        Science. 1988; 240: 1468
        • Jimenez-Flores R.
        • Richardson T.
        Genetic engineering of the caseins to modify the behaviour of milk during processing: a review.
        J. Dairy Sci. 1988; 71: 2640
      3. Karatzas, C. N., F. R. Pieper, I. De Wit, G. Platenburg, and R. Berg, inventors. 1996. Production of collagen in the milk of transgenic mammals. Gene Pharming Europe B.V., assignee. WO 96/03051.

        • Krimpenfort P.
        • Rademakers A.
        • Eyestone W.
        • van der Schans A.
        • van den Broek S.
        • Kooiman P.
        • Kootwijk E.
        • Platenburg G.
        • Pieper F.
        • Strijker R.
        • De Boer. H.
        Generation of transgenic dairy cattle using “in vitro” embryo production.
        Biotechnology. 1991; 9: 844
        • Kumar S.
        • Clarke A.R.
        • Hooper M.L.
        • Horne D.S.
        • Law A.J.R.
        • Leaver J.
        • Springbett A.
        • Stevenson E.
        • Simons J.P.
        Milk composition and lactation of β-casein-deficient mice.
        Proc. Natl. Acad. Sci. USA. 1994; 91: 6138
        • L’Huillier P.J.
        • Soulier S.
        • Stinnakre M.G.
        • Lepourry L.
        • Davis S.R.
        • Mercier J.C.
        • Vilotte J.L.
        Efficient and specific ribozyme-mediated reduction of bovine α-lactalbumin expression in double transgenic mice.
        Proc. Natl. Acad. Sci. USA. 1996; 93: 6698
        • Lonnerdal B.
        Recombinant human milk proteins—an opportunity and a challenge.
        Am. J. Clin. Nutr. 1996; 63: 622S
        • Lonnerdal B.
        • Iyer S.
        Lactoferrin: molecular structure and biological function.
        Annu. Rev. Nutr. 1995; 15: 93
        • Maga E.A.
        • Anderson G.B.
        The effect of mammary gland expression of human lysozyme on the properties of milk from transgenic mice.
        J. Dairy Sci. 1995; 78: 2645
        • Martin P.
        • Groslaude F.
        Improvement of milk protein quality by gene technology.
        Livest. Prod. Sci. 1993; 35: 95
        • Massey J.M.
        Animal production industry in the year 2000 A.D.
        J. Reprod. Fertil. 1990; 41: 199
        • McClenaghan M.
        • Springbett A.
        • Wallace R.M.
        • Wilde C.J.
        • Clark A.J.
        Secretory proteins compete for production in the mammary gland of transgenic mice.
        Biochem. J. 1995; 310: 637
        • McMahon D.J.
        • Brown R.J.
        Composition, structure, and integrity of casein micelles: a review.
        J. Dairy Sci. 1984; 67: 499
        • Mercier J.C.
        • Vilotte J.L.
        Structure and function of milk protein genes.
        J. Dairy Sci. 1993; 76: 3079
        • Morr C.V.
        Functionality of heated milk proteins in dairy and related foods.
        J. Dairy Sci. 1985; 68: 2773
        • National Dairy Council
        Nutritional implications of lactose and lactase activity.
        Dairy Counc. Dig. 1985; 56: 25
        • Platenburg G.J.
        • Kootwijk E.P.A.
        • Kooiman P.M.
        • Woloshuk S.L.
        • Nuijens J.H.
        • Krimpenfort P.J.A.
        • Pieper F.R.
        • De Boer H.A.
        • Strijker R.
        Expression of human lactoferrin in milk of transgenic mice.
        Transgenic Res. 1994; 3: 99
        • Pursel V.G.
        • Rexroad Jr, C.E.
        Status of research with transgenic farm animals.
        J. Anim. Sci. 1993; 71: 10
        • Rijnkels M.
        • Kooiman P.M.
        • Krimpenfort P.J.A.
        • de Boer H.A.
        • Pieper F.R.
        Expression of the individual bovine β-, αs2- and κ-casein genes in transgenic mice.
        Biochem. J. 1995; 311: 929
        • Rosen J.M.
        • Li S.
        • Raught B.
        • Hadsell D.
        The mammary gland as a bioreactor: factors regulating the efficient expression of milk protein-based transgenes.
        Am. J. Clin. Nutr. 1996; 63: 627S
        • Saavedra J.M.
        • Perman J.A.
        Current concepts in lactose malabsorption and intolerance.
        Annu. Rev. Nutr. 1989; 14: 475
        • Schedl A.
        • Larin Z.
        • Montoliu L.
        • Thies E.
        • Kelsey G.
        • Lehrach H.
        • Schutz G.
        A method for the generation of YAC transgenic mice by pronuclear microinjection.
        Nucleic Acids Res. 1993; 21: 4783
        • Seidel Jr, G.E.
        Resource requirements for transgenic livestock research.
        J. Anim. Sci. 1993; 71: 26
        • Simons J.P.
        • McClenaghan M.
        • Clark A.J.
        Alteration of the quality of milk by expression of sheep β-lactoglobulin in transgenic mice.
        Nature (Lond.). 1987; 328: 530
        • Stacey A.
        • Schnieke A.
        • Kerr M.
        • Scott A.
        • McKee C.
        • Cottingham I.
        • Binas B.
        • Wilde C.
        • Colman A.
        Lactation is disrupted by α-lactalbumin gene replacement in mice.
        Proc. Natl. Acad. Sci. USA. 1995; 92: 2835
        • Stacey A.
        • Schnieke A.
        • McWhir J.
        • Cooper J.
        • Colman A.
        • Melton D.W.
        Use of a double-replacement gene targeting to replace the murine α-lactalbumin gene with its human counterpart in embryonic stem cells and mice.
        Mol. Cel. Biol. 1994; 14: 1009
        • Strelchenko N.
        Bovine pluripotent stem cells.
        Theriogenology. 1996; 45: 131
        • Van Slyke L.L.
        • Price W.V.
        Cheese.
        Ridgeview Publ. Co., Atascadero, CA1979 (Page 65)
        • Wall R.J.
        Transgenic livestock: progress and prospects for the future.
        Theriogenology. 1996; 45: 57
        • Wall R.J.
        • Seidel Jr, G.
        Transgenic farm animals—a critical analysis.
        Theriogenology. 1992; 38: 337
        • Ward K.D.
        • Nancarrow C.D.
        The genetic engineering of production traits in domestic animals.
        Experientia. 1991; 47: 913
        • Wigley P.
        • Becker C.
        • Beltrame J.
        • Blake T.
        • Crocker L.
        • Harrison S.
        • Lyons I.
        • McKenzie Z.
        • Tearle R.
        • Crawford R.
        • Robins A.
        Site-specific transgene insertion: an approach.
        Reprod. Fertil. Dev. 1994; 6: 585
        • Wilkins T.D.
        • Velander W.
        Isolation of recombinant proteins from milk.
        J. Cell. Biochem. 1992; 49: 333
        • Wilmut I.
        • Whitelaw C.B.A.
        Strategies for production of pharmaceutical proteins in milk.
        Reprod. Fertil. Dev. 1994; 6: 625