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TITLE:  Designer milk from transgenic clones
SOURCE: Nature Biotechnology, Vol 21(2): 138-139, by Costas N. Karatzas
        doi:10.1038/nbt0203-138
DATE:   February 2003

------------------ archive: http://www.gene.ch/genet.html ------------------


Designer milk from transgenic clones 

Costas N. Karatzas is senior vice president of R & D, Nexia
Biotechnologies, 1000 Avenue St-Charles, Vaudreuil-Dorion, Quebec, Canada
J7V 8P5 e-mail: ckaratzas@nexiabiotech.com

Biotechnology gets a step closer in the pre-harvest production of "new
milks" by generating cows that overexpress casein proteins in their milk.
Transgenic dairy animals producing milks with altered composition, other
than pharmaceutical proteins, are becoming a reality. Designer milks,
specialty milks, or humanized milks may be competing in the next ten
years to capture part of the global dairy product market worth $400
billion annually. The concept of modifying milk composition (Table 1) by
augmenting the protein content of milk through increased casein gene
dosage in the cow genome has been postulated for years(1-3). Now, Brophy
et al.(4) have reduced this concept to practice, generating eight
transgenic cows - through a combination of genetic engineering and
nuclear transfer techniques(4, 5) - that produce in their milk elevated
levels of [beta] - and [kappa] -casein proteins. The use of the nuclear
transfer procedure allowed selection of gender and elite genetic
background(4, 5). DNA transgene integration was random, similar to
pronuclear microinjection gene transfer experiments, and therefore the
authors produced a few transgenic lines in order to select the best-
expressing animals(4).

Milk, a "nearly perfect food" because of its balanced protein, fat,
carbohydrate, and mineral content, represents a fundamental dietary
ingredient of many societies. Intensive cross-breeding strategies,
nutritional management, and quantitative genetics have resulted in a
steady improvement in milk yield, but have not produced major changes in
milk protein composition. The world production of fluid milk in 2001 was
474 gigaliters!

A glass of milk contains 8.0 grams of protein, with caseins comprising
78-80% of this amount(1-3). Together with fat, the casein proteins are
responsible for the characteristic white chalky children's milk
"mustache". There are four casein proteins in cow's milk(1, 2): [alpha]
S1- and [beta] -casein (10 g/l each), [alpha] S2-casein (3.7 g/l), and
[kappa] -casein (3.5 g/l). One of the properties of caseins is to bind
and sequester calcium phosphate and magnesium within spherical particles
named casein micelles(1, 2). The outer surface of these is enriched with
[kappa] -casein, which is cleaved by chymosin used in cheese-making to
destabilize micelles and form the curd(1, 2).

But why alter the casein concentration of milk? The percentage of casein
in milk determines cheese yield; therefore, a clear incentive for
changing milk composition has been the increase in cheese yield(1, 2)
(see Table 1 [not attached]). An increase of 20% in the content of
[alpha] S1-casein content of milk would result in an increase of $200
million per year(6). The milks with increased casein content could also
be exploited in the manufacturing of milk protein concentrates (MPC) and
casein forms. Edible casein is used in vitamin tablets, instant drinks,
and infant formulas. Technical acid caseins are used for paper coatings,
cosmetics, button-making, paints, and textile fabrics. In 2000, the
United States imported a combined 381.4 million pounds of MPC and casein
for a total value of approximately $650 million(7). High-casein milks, if
and when they become available, may influence national milk supply
management and international trade standards and regulations(7).

In the present paper, Brophy et al.(4) overexpress casein variants,
resulting in a 30% increase in the total milk casein or a 13% increase in
total milk protein(4). Although milk was collected from induced lactation
during which the mammary gland may not be functioning at maximum
capacity, it appeared that the transgenic proteins were produced
partially at the expense of the endogenous milk proteins. This
competition has also been observed at the mRNA level in transgenic mice
overexpressing ovine [beta] - lactoglobulin in their milk(8). These
compensatory events may occur at a post-transcriptional or translational
stage or during the passage of proteins through the secretory pathway of
the mammary cell(8).

Interestingly, a measurable variation was observed in the concentration
of the [beta] - and [kappa] -caseins among the eight transgenic genetic
clones(4). The transgenics generated(4) contain, in addition to embryonic
cell-derived nuclear DNA, oocyte-derived mitochondrial DNA and probably
also donor cell-derived mitochondrial DNA(9). As mitochondria are the
sites of many metabolic reactions that are an integral part of lactation,
it is possible that differences in the genetic bloodline origin of the
mitochondria in these transgenic animals may account for differences in
milk production and lactation physiology.

Considerable effort and time is required to propagate the new genetics
into commercial dairy herds. Rapid dissemination of the genetics of the
parental animals by nuclear transfer could result in the generation of
mini-herds in two to three years. However, the existing inefficiencies in
nuclear transfer make this a huge undertaking(4, 5). It is noteworthy
that the genetic merit of the "cloned" animals will be fixed while
continuous genetic improvements will be introduced in commercial herds by
using artificial insemination breeding programs(10, 11).

In an alternative scenario of herd expansion, homozygous semen may be
available in four to five years. Extensive breeding programs will be
critical in studying the interaction and co-adaptation of the
transgene(s), with the background polygenes controlling milk production
and composition(10). Controlling inbreeding and confirming the absence of
deleterious traits so that the immediate genetic variability introduced
by transgenesis is transformed into the greatest possible genetic
progress is equally critical(10, 11).

The innovative results reported by Brophy et al . clearly demonstrate
that it is possible to generate transgenic cattle producing "novel"
milks. Future studies with the new genetics will likely investigate
(among others) the effects of casein overexpression in mammary gland
biology, casein micelle structure and composition, cheese-making
processes, and nutritional value of milk in addition to animals'
physiology and nutritional requirements.

If these new milks are destined for human consumption, it is imperative
that the public is aware and engaged in a substantive dialog about animal
welfare, environmental impact, regulatory processes, and food safety and
labeling. At the same time, the research necessary for these developments
should not be impeded, but should remain transparent and open to debate.
The US Food & Drug Administration (Rockville, MD) has recently advised
companies developing somatic cell nuclear transfer clones for
agricultural use that food from cloned animals or their progeny may not
be entered into the human or animal food supply until evaluation of the
issue is completed(12).

With the current policies and cost of accessing the "novel" genetics
(Table 1), changes in the pricing system and quotas for milk will be
required to facilitate the introduction and adaptation of novel milks
produced from specialized transgenic breeding programs. The major
economic incentive for genetic changes in milk composition will be the
prices that the consumer is willing to pay for "novel" products and the
price that the farmer receives for the milk components(10). It is
encouraging that despite the uncertainties surrounding the acceptance of
these "new milks" and the razor-thin margins well known in the dairy
industry, organizations in Australia and New Zealand are funding such
long-term and pioneering research programs.


REFERENCES

 1. Jimenez-Flores, R. & Richardson, T. Dairy Sci. 71, 2640-2654 (1988).
 2. Martin, P. & Grosclaude, F. Livestock Production Sci. 35, 95-115 (1993).
 3. Yom, HC & Richardson, T. Am. J. Clin. Nutr. 58, 299S-306S (1993).
 4. Brophy, B. et al., Nat. Biotechnol. 21, 157-162 (2003).
 5. Colman, A. Cloning 1, 185-200 (2000).
 6. Hennighausen, L., Ruiz, L., & Wall, R. Curr. Opin. Biotechnol. 1, 74
(1990).
 7. http://dairyoutlook.aers.psu.edu
 8. McClenaghan, M., Springbett, A., Wallace, R.M., Wilde, C.J. & Clark,
A.J Biochem. J. 310, 637-641 (1995).
 9. John, J.C. Theriogenology 57, 109-123 (2002). 10. Hoeschele, I. J.
Dairy Sci. 73, 2601-2618 (1990).
11. Seidel, G.E. Jr. J. Anim. Sci. 71, (Suppl. 3) 26-33 (1993).
12. http://www.fda.gov/cvm/index/updates/clones.html