Sheep to Mice to Cattle: Cloning Leaps Forward

Scientists seek to discover whether their methods will work with other mammals.

First came Dolly, the lamb cloned from an adult Scottish ewe. Now scientists in Hawaii have done the trick with mice. And a Japanese team says it expects to have a small herd of calves, cloned from the ears and rumps of adult cows, by December or January.

Cloning adult animals - a marvel biologists had considered virtually impossible - now is an established experimental practice. These latest reports are likely, once again, to raise concern about the possibility of human cloning. That, in turn, may rekindle public debate about the desirability and morality of pursuing such research. But for the scientists involved, this new work is one small step on a long road toward understanding the basic biology of what they are doing.

Scientists have cloned animals from embryonic material for decades. But many cloning experts were skeptical when Ian Wilmut trotted out Dolly at the Roslin Institute in Roslin, Scotland in February 1997. Did she really spring from genetic material taken from an adult's mature tissue? Or did cells from an embryo sneak in to fool Dr. Wilmut? Alternatively, if Dolly is genuine, is she a merely one-time freak? Or can adult cloning be repeated, especially in other species?

Three reports in the July 23 issue of the journal Nature now lay those doubts to rest. Wilmut and several colleagues, and, separately, Esther Signer of the University of Leicester, England, and colleagues detail analyses proving Dolly is descended directly from a mature cell from the donor sheep.

The scientists settled the issue "by throwing the full panoply of forensic DNA-testing methods at the problem," according to an accompanying commentary by Davor Solter at the Max-Planck Institute for Immunobiology in Freiburg, Germany. Dolly does indeed represent the cloning breakthrough that Wilmut claimed.

The third report, by Ryuzo Yanagimachi and colleagues at the University of Hawaii in Honolulu, tells how they have produced some 22 cloned mice. This is doubly significant. It shows that a technique of adult cloning similar to Wilmut's works in a different species. It also shows that past failures to clone mice by this technique do not mean mice resist the process, as some researchers had worried.

Dr. Solter says "the importance of this report cannot be overemphasized." He notes that mice reproduce rapidly. He adds that it's "much easier" to manipulate their embryos than those of larger animals. Producing mouse embryos by adult cloning techniques opens "the possibility of broad experimental analysis of mammalian cloning and of the factors that determine its outcome."

Japan experiment

Meanwhile, Japan's Nara State Livestock Research Center is "experimenting with cells taken from various parts of adult cows," the institute's Katsuhiko Hata told Associated Press earlier this month. Cells used up to now have come from reproductive organs and mammary glands. The center has five cows pregnant with embryos cloned from tissue such as beef-cow ear and buttock muscles. Calves should arrive in December or January.

What's remarkable about this work is not the cloning of animals but the way this cloning is done. In a review in the journal Science on May 29, Gary Anderson of the University of California at Davis and George Seidel of Colorado State University at Fort Collins explain that cloning by splitting up embryos began in 1970 and now is commercial practice. They note that "many thousands of cloned calves ... are routinely used for cattle breeding."

The new technique, however, differs in two fundamental ways:

First, instead of splitting up an embryo already formed, it creates a new egg cell that will become an embryo. Cells contain a nucleus plus surrounding material. The nucleus holds the DNA that carries an animal's genetic blueprint. Technicians remove the DNA from an egg, then take the DNA-containing nucleus from a cell of the donor animal and put it in the egg. The egg grows into an embryo that is implanted in a surrogate mother of the same species.

Second, the technique uses DNA from adult cells. As an embryo grows, its cells differentiate to form various body parts. Biologists had thought that, once cells specialized, the DNA in their nuclei lost the ability to differentiate. Wilmut and his successors are showing that this adult DNA can be put back into an egg and be reprogrammed to start the embryonic growth process again.

Much more to learn

Drs. Anderson, Seidel, and Solter acknowledge that what is possible in cows, sheep, and mice may one day be possible with humans. But they add that this awesome possibility is a long way off. There are many aspects of cloning and reproduction that scientists don't understand. That includes the mystery of why, despite these recent successes, adult cloning techniques have a very low success rate.

Also, the longer term practical goal of such research is to integrate cloning with genetic-engineering techniques that give animals the ability to produce proteins in milk that are useful as medicines. Commentators note that cloning may make it possible to grow replacement organs using a person's own DNA - organs that the person's immune system would not reject.

The bottom line for the cloning research reported this month is that "the scope of future basic biological research has been increased," Solter says.