Editor’s note (10/9/2012): We are making the text of this article freely available for 30 days because the author, Sir John B. Gurdon, is one of the winners of the 2012 Nobel Prize in Physiology or Medicine. The full article with images, which was published in the December 1968 issue, is available for institutional users only at this time (pdf).

The means by which cells first come to differ from one another during animal development has interested humans for nearly 2,000 years, and it still constitutes one of the major unsolved problems of biology. Much of the experimental work designed to investigate the problem has been done with amphibians such as frogs and salamanders because their eggs and embryos are comparatively large and are remarkably resistant to microsurgery. As with most animal eggs, the early events of amphibian development are largely independent of the environment, and the processes leading to cell differentiation must involve a redistribution and interaction of constituents already present in the fertilized egg.

Several different kinds of experiment have revealed the dependence of cell differentiation on the activity of the genes in the cell's nucleus. This is clearly shown by the nonsurvival of hybrid embryos produced by fertilizing the egg of one species (after removal of the egg's nucleus) with the sperm of another species. Such hybrids typically die before they reach the gastrula stage, the point in embryonic development at which major cell differences first become obvious. Yet the hybrids differ from nonhybrid embryos only by the substitution of some of the nuclear genes. If gene activity were not required for gastrulation and further development, the hybrids should survive as well as nonhybrids. The importance of the egg's non-nuclear material—the cytoplasm—in early development is apparent in the consistent relation that is seen to exist between certain regions in the cytoplasm of a fertilized egg and certain kinds or directions of cell differentiation. It is also evident in the effect of egg cytoplasm on the behavior of chromosomes [see "How Cells Specialize," by Michail Fischberg and Antonie \V. Blackler; SCIENTIFIC AMERICAN, September, 1961]. Such facts have justified the belief that the early events in cell differentiation depend on an interaction between the nucleus and the cytoplasm.

Nuclear transplantation is a technique that has enormously facilitated the analysis of these interactions between nucleus and cytoplasm. It allows the nucleus from one of several different cell types to be combined with egg cytoplasm in such a way that normal embryonic development can take place. Until this technique was developed the only kind of nucleus that could be made to penetrate an egg was the nucleus of a sperm cell, and this was obviously of limited use for an analysis of those interactions between nucleus and cytoplasm that lead to the majority of cell differences in an individual.

The technique was first applied to the question primarily responsible for its development. The question is whether or not the progressive specialization of cells during development is accompanied by the loss of genes no longer required in each cell type. For example, does an intestine-cell nucleus retain the genes needed for the synthesis of hemoglobin, the protein characteristic of red blood cells, and a nerve-cell nucleus the genes needed for making myosin, a protein characteristic of muscle cells? If unwanted genes are lost, the possibility exists that it is the progressive loss of different genes that itself determines the specialization of cells, as August Weismann originally proposed in 1892. The clearest alternative is that all genes are retained in all cells and that the genes are inactive in those cells in which they are not required. Before describing the nuclear-transplant experiments that distinguish between these two possibilities, we must outline the methods used to transplant living cell nuclei into eggs.

Comments