Cow Eggs Accommodate, Reprogram Other Species' Genes

The finding, reported here today (Jan. 19) at a meeting of the International Embryo Transfer Society by a team of University of Wisconsin-Madison scientists, not only lends important experimental support to the technology that created Dolly, the world's first animal cloned from an adult cell, but adds an important new twist to the unfolding story of mammalian cloning: It suggests that the molecular machinery responsible for programming genes within the cytoplasm of the egg may be similar or identical in all mammals.

It illustrates, the scientists said, the possibility of using the eggs of one species as a "universal recipient" for genes from other species. If perfected, such a technology would have broad applications, from the development of customized tissue cell lines for transplants in humans to new ways to propagate valuable farm animals, or rare and endangered species.

While no successful pregnancies have been achieved using the technique developed in the laboratory of cloning pioneer Neal L. First, the eggs with the foreign genes developed into viable preimplantation-stage embryos.

"We've shown that the genome of different species can undergo some reprogramming in bovine oocytes" or eggs, said Maisam M. Mitalipova, one of the authors of a pair of studies that profile the results of work undertaken since Dolly was revealed to the world nearly a year ago.

The expression of stage-specific genes in intraspecies clones is now under investigation by the same team. Initiating the current studies was Tanja Dominko, formerly of First's lab and now at the Oregon Regional Primate Research Center.

Using cells obtained from the ears of five different species of mammals, all fully grown, and eggs gleaned from cows, the Wisconsin team applied the same technique that scientists at Scotland's Roslin Institute used to create Dolly, a sheep whose genes came from a mammary cell of an adult sheep.

The ear cells, which contain all the genes needed to make an animal, were fused with cow eggs that had been denucleated or stripped of their genetic material. Once fused, it seems that the eggs incorporate the genes from the ear cells and reset them to drive early stages of development.

Because cells develop and divide after fertilization and subsequently differentiate into muscles, organs, bones and other types of tissue, the ability to produce an animal from the genetic material from an adult cell nucleus, as is apparently the case with Dolly, was surprising evidence that gene expression can be reprogrammed, said First.

"That was the real breakthrough," according to First who, a decade ago, was the first to make mammal clones using undifferentiated embryonic cells from cattle.

In any adult differentiated cell, there exist all the genes necessary to make an animal, but only the genes that make proteins for those specific tissues are activated. Before Dolly, most scientists did not believe that the genetic material from differentiated cells could be reset to produce clones of adult animals.

The objective of the new Wisconsin study was to determine the ability of a cow's egg, and specifically its cytoplasm, to reprogram the genetic material of differentiated cells from an array of mammals. The cytoplasm consists of the contents of the egg cell, exclusive of its nucleus of genetic material.

That it was able to do so with the genes of several different animals suggests that the molecular mechanism within the cytoplasm responsible for embryonic reprogramming has been conserved in mammals from a distant common ancestor. Precisely how the cytoplasm reprograms old genes is still a mystery, said Mitalipova.

The practical upshot of the Wisconsin study is that cow eggs may serve as a convenient, universal recipient for the genetic material of other animals, including those animals where eggs may be difficult or impossible to obtain, such as endangered species or prize farm animals.

If perfected, the technology could also lead to the development of cell lines for the development of tissue for human transplants. By taking tissue from a transplant candidate and growing genetically identical tissue, problems of organ or graft rejection could potentially be eliminated.

In addition to First and Mitalipova, scientists contributing to the work reported today include Dominko, Brad Haley, Zeki Beyhan, Erdogan Memili, Hanna Segev, Arthur Chen and Esther Ofulue.