Research Magazine > ARCHIVE > Summer 97 > Article

What is cloning?
Cloning has taken on airs of mystery in popular culture, but it is actually a very simple concept. A clone is simply the progeny of an individual, produced asexually. Biologists generally use the word cloning to refer to the production of multiple genetically identical individuals, but the term is frequently used in a more general sense, i.e., to refer to one or more such offspring.

Before Dolly, the state-of-the-art in cloning - in fact, the ultimate clone in the sense of genetic identity - was identical twins (or triplets, etc.). Identical twin cattle can result from splitting embryos under a microscope and transferring them into recipient cows (usually two different cows) for gestational development. This has been practiced extensively during the past two decades. One of the major questions of developmental biology during the past 50 years has been whether the genes of differentiated cells - such as muscle, brain or mammary cells - can replace the nucleus of a fertilized egg and lead to normal development. (While all differentiated cells contain the entire complement of the organism's genetic code, some genes are suppressed and others expressed during cell differentiation.)

To answer this, scientists have used a method known as "nuclear transplantation" or "nuclear transfer. Because of the relatively large size of frog eggs, early experiments dealt with amphibian cloning. Beginning in 1952, Robert Briggs and Thomas J. King published a series of papers demonstrating that success as defined by cloned frogs depends upon the proper transfer of nuclei obtained from very young embryo donors. Similarly, mature nuclear transplant fish were reported, and by 1981, Karl Illmensee and Peter C. Hoppe had produced live-born mice following nuclear transplantation.

Nuclear transfer has been used in mammals as a valuable tool in embryological studies and as a method for multiplication of "elite" bovine embryos. About a decade ago, at least three biotechnology firms displayed serious interest in offering embryo cloning commercially. This proved to be premature, since procedures were unreliable, cumbersome and costly, and the resulting live calves frequently have been larger than normal. Additionally, since the embryos cloned were products of a dam and a sire, the calves were still a roll of the dice genetically.

Then, in 1996, the now famous Edinburgh team led by K.H.S. Campbell and Ian Wilmut reported the birth of a lamb following nuclear transfer from an established embryonic cell line. Scientists received this report with great excitement since this approach should provide the same powerful opportunities for analyses and modification of gene function in livestock that already were being accomplished in mice. Thus, the stage was set for the ultimate experiment - the use of donor nuclei from an adult for cloning.

Hello, Dolly!
At the annual meeting of the International Embryo Transfer Society in Nice, France, in January, Campbell and Wilmut presented data on embryo-derived cells and nuclear transfer. Although rumors were rampant, they did not openly speak of the lamb "dolly" that had been born several months earlier following transfer of the nucleus from a cell taken from a pregnant ewe's mammary gland. The breakthrough involving the demonstration of cloning of an adult was published in the Feb. 27, 1997, issue of Nature.

Scientists were excited upon hearing the good news of Dolly; the news media and its consumers were overwhelmed. In spite of many obvious advantages for cloning in research and animal production, the big question seemed to be, "When will this be done with human beings?" Human cloning has become a subject of major fascination. Public awareness of the new ewe has sparked creativity around the planet as evidenced by a plethora of jokes, stories and speculations regarding implementation of this new technology. Many countries already have laws against artificial cloning of human beings and it seems likely that ours will follow suit.

Most scientists would argue for maintaining the current system of regulation involving institutional reviews of human experimentation. This system already provides safeguards against abuse, and it also prevents inadvertent elimination of potentially valuable research by excessive
legislation.

Before fear of the new technology leads us to rattle legislative sabers, it's important to understand that efforts to apply cloning technology to humans is presently unthinkable. Remember that in the case of Dolly, 277 eggs were fused with mammary epithelial nuclei and 29 recipient ewes were employed to obtain one live lamb. The technology must be developed and procedures must be improved to make feasible the application of cloning in animals.

Nevertheless, that technology can be - and should be - developed. In fact, I believe that cloning of adult cattle can be anticipated sometime soon. The progress with fetal cells recently announced by American Breeders Service illustrates current efforts directed toward this goal. In this species it requires little imagination to see benefits in elevating efficiency of milk and meat production via transfer of reconstructed embryos known to be capable of expression of the highest production traits.

At the same time, maintenance of genetic diversity, which is the normal result of sexual reproduction, must remain of paramount importance. Without great genetic diversity an entire species could easily be lost to a single devastating disease. Rapid widespread use of cloning in the dairy industry could have severe economic consequences. For instance, milk surpluses already plague the agricultural economy. Through the years, farmers have suffered from successful innovations in agriculture; this new technology holds the potential for exacerbation of this plight.

But these developments also should facilitate "gene targeting" in livestock. This will enable the deletion of specific genes or alteration of genetic traits in a controllable way involving selectivity of responding cells prior to their use in cloning. Cloning now will allow multiplication of animals for large-scale production of a variety of transgenic products, for example, glycoprotein pharmaceuticals from milk, internal organs with altered antigenic components and with complement inhibitor to fill the need for organ donation for human patients.

Techniques of cloning offer an opportunity to study the possible persistence and impact of epigenetic changes, which are external events that influence genes. These include the duplication of genes during somatic cell development, such as replacing skin cells, and the shortening of chromosome ends in aged animals. Contributions of mitochondrial DNA can be better understood and used to advantage. Additional uses and advantages include removal of genetic variation in experiments, rapid production of inbred lines, copying small numbers of animals with outstanding genetic composition for breeding and automatic sex selection. If expense is no obstacle, it should even become possible to duplicate the outward appearance of an aged pet.

Serious discussions of cloning have been initiated by the breakthrough published by Wilmut and his colleagues at the Roslin Institute. With technological developments, cloning should find valuable applications in animal industries and research. Public awareness of developments in this, and other facets of science, is essential for the appropriate handling of new technologies for the betterment of humankind.


For more information, e-mail Benjamin Brackett at brackett@calc.vet.uga.edu.

Benjamin G. Brackett, D.V.M., Ph.D., is a professor of physiology and pharmacology at the UGA College of Veterinary Medicine. After his pioneering efforts with rabbits and rhesus monkeys, Brackett was among the first researchers to work with human in vitro fertilization. Essential to the development of test-tube babies, in vitro fertilization involves removing eggs from a female, fertilizing them in the laboratory, then returning the developed embryo to the female for normal maturation and birth. Brackett's research led to the birth of the first test-tube calf in 1981, and to the first test-tube billy goats, Willy and Nilly, in 1993. This procedure could have major implications for the development of therapeutic drugs and for animal breeding programs.

Possible Uses of Cloning

• increase milk and meat production in cattle
• remove genetic variation in experiments
• copy small numbers of animals with outstanding genetic traits for breeding programs
• produce theraputic drugs to treat cancer and other diseases
• make better formula for premature babies
• engineer animals to produce donor organs that would be less likely to be rejected by human recipients

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