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[SANET-MG] synthetic cows

June 12, 2006

Prof. Joe Cummins

Synthetic Cows

(It takes a lot of moola to make a synthetic cow)

Cows with fully synthetic genes may not be far off. However, the first steps in that direction have been taken by creating cows with synthetic transgenes to fight bacterial disease and to produce pharmaceutical drugs. Synthetic genes are used because bacterial genes are not readily translated in animals and plants because of an effect called codon bias. As well, bacterial artificial chromosomes are used as vectors to insert a number of genes (such as genes effecting the immune system) into the animal genome. Building fully synthetic cows may be in reach within a decade.

Synthetic genes are made up an antibacterial gene from Staphylococcus (lyphostatin) joined to a gene from a Streptococcus bacteria phage specifying endolysin that dissolves bacteria. The genes are altered in DNA sequence and truncated. The synthetic gene is used to modify cows so they produce milk that kills bacteria. One problem discussed was allergy of the milk protein. It was pointed out that the cows bearing the synthetic gene were unlikely to be allergic to the toxin because it is a part of their genome thus recognized as self. They failed to mention that children drink the allergenic milk and do not recognize it as self. Efforts were made to alter the DNA sequences specify sugar additions to the protein to avoid human allergy (allergy sites on proteins often have signals for sugar added to the protein) but that approach was only partly effective(1,2,3).. One problem is that USDA regulates the things that they own patents for. The cows with synthetic genes are likely to cause a lot of injury to people if they are rushed to commerce. However, USDA’s synthetic genes may solve one of Monsanto’s greatest problems with its growth hormone which causes mastitis , that is the good news, the bad news is that children who drink the milk may suffer injury or death from allergy.

Artificial chromosomes have been used in microbial genetics for a number of years. They are derived from the sex determining plasmids and they are useful in cloning a number of genes joined together. The artificial chromosomes proved useful in introducing a number of genes born on a single large DNA molecule into the genome of cattle. Human antibody genes specifying polyclonal antibodies for therapy have been introduced into cattle The antibodies are secreted into the transgenic cow’s milk (4,5). The transgenic cattle have been described as “cash cow”(6). When a number of human genes modify the cattle it is desirable to turn off the production of the cow’s genes that produce proteins that are similar to the human protein used in therapy. Recently genes specifying small interfering RNA molecules designed to regulate expression of a gene or a gene family have been introduced into bovine cells destined for cloning. The small interfering RNA is used to turn off cattle genes being replaced by human genes used to produce therapeutics (7). Small interfering RNA genes promise a range of genetic engineering applications well beyond the one described above ,however , there are safety concerns that must be addressed before the transgenic interfering RNA genes are used in commercial releases.

At present the production of cloned transgenic cattle requires a great deal of laboratory work to produce transgenic cells and screen transgenic cells used to produce transgenic cattle and to screen the transgenic cattle. The technique of producing transgenic cattle was enhanced using a technique called cross species ectopic testicular grafting. First bull germ tissue that had been modified with a marker gene, Beta galactosidase, was grafted onto the back of a castrated nude mouse (nude mice have a defective immune system that allows them to tolerate grafts from unrelated mammals called xenografts ). Sperm can be collected from the grafted tissue and used to fertilize embryos in vitro which can be implanted into receptive cows to produce transgenic calves (8). Nude mice, with or without a bull sperm backpack are not likely to survive long in the absence of a germ free environment , so the chances of meeting a bald mouse with a bull sperm back pack in ones daily routine is very slim, indeed. Anyhow, without major changes in tissue plumbing the bull tissue backpack requires the aid of at least one human to complete the sex act. Human testicular tissue has been used to produce sperm when tissue if grafted to the backs of nude mice, this technique is provided so that pre-pubertal boys suffering from cancer can bank frozen sperm prior to whole body radiation treatment (10).

Synthetic genes have been used in crop genetic engineering since its inception. The introduction of synthetic genes , artificial chromosomes and testicular xenografts has begun to provide a whole new era of animal breeding. As indicated above, the technology for making synthetic cattle may also be used to produce synthetic people. There has been a tentative effort to deal with the ethics of transgenesis and animal welfare (11) that kind of effort should be focused as well on people. One looming consequence of the developing technologies may be a general rule: engineering for offspring’s , sex for fun! I wonder where that will leave cattle, pigs, horses , sheep and dogs?


1. Donovan DM, Dong S, Garrett W, Rousseau GM, Moineau S and Pritchard DG. Peptidoglycan hydrolase fusions maintain their parental specificities. Appl Environ Microbiol. 2006 Apr;72(4):2988-96

2. Wall RJ, Powell AM, Paape MJ, Kerr DE, Bannerman DD, Pursel VG, Wells KD, Talbot N and Hawk HW. Genetically enhanced cows resist intramammary Staphylococcus aureus infection. Nat Biotechnol. 2005 Apr;23(4):445-51

3. Donovan DM, Kerr DE and Wall RJ. Engineering disease resistant cattle. Transgenic Res. 2005 Oct;14(5):563-7

4. Robl JM, Kasinathan P, Sullivan E, Kuroiwa Y, Tomizuka K and Ishida I. Artificial chromosome vectors and expression of complex proteins in transgenic animals. Theriogenology. 2003 Jan 1;59(1):107-13

5 Kuroiwa Y, Kasinathan P, Choi YJ, Naeem R, Tomizuka K, Sullivan EJ, Knott JG, Duteau A, Goldsby RA, Osborne BA, Ishida I and Robl JM. Cloned transchromosomic calves producing human immunoglobulin. Nat Biotechnol. 2002 Sep;20(9):889-94

6 Echeland,Y and Meade, H. Toward a new cash cow Nat. Biotechnol 2002 20,8812

7 Wells,K. Use of interfering RNA in the production of transgenic animals United States patent Application 20050266561

8 Oatley JM, de Avila DM, Reeves JJ and McLean DJ. Spermatogenesis and germ cell transgene expression in xenografted bovine testicular tissue. Biol Reprod. 2004 Aug;71(2):494-501

9 Schmidt JA, de Avila JM and McLean DJ. Grafting Period and Donor Age Affect the Potential for Spermatogenesis in Bovine Ectopic Testis Xenografts. Biol Reprod. 2006 May 3; [Epub ahead of print]

10 Geens M, De Block G, Goossens E, Frederickx V, Van Steirteghem A and Tournaye H. Spermatogonial survival after grafting human testicular tissue to immunodeficient mice. Hum Reprod. 2006 Feb;21(2):390-6.

11 Van Reenen CG, Meuwissen TH, Hopster H, Oldenbroek K, Kruip TH and Blokhuis HJ. Transgenesis may affect farm animal welfare: a case for systematic risk assessment. J Anim Sci. 2001 Jul;79(7):1763-79


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