UTSA researcher collaborates on NIH grant to study cloned mice

(June 20, 2002)--UTSA biology professor John McCarrey and Ryuzo Yanagimachi of the University of Hawaii were recently awarded an NIH grant to investigate genetic reprogramming in cloned mice. The 5-year award totals $2,225,000. Yanagimachi, a member of the National Academy of Sciences, is a leader in the fields of cloning and assisted reproductive techniques, such as in vitro fertilization. His laboratory has the expertise in cloning that will be required by this project.

McCarrey's laboratory will focus on epigenetics -- mechanisms that affect genetic programming without changing DNA structure -- and particularly on the programming of germ cells (the cells that develop into ova or sperm). McCarrey, who has significant experience analyzing genetic and epigenetic programming in germ cells in normal mice, will analyze similar characteristics in the germ cells of cloned mice.

McCarrey and his collaborators suspect that for a cloned embryo to develop normally, the donor nucleus must undergo rapid preprogramming of epigenetic mechanisms with a low frequency of mutations. The project will try to identify relationships between various epigenetic factors and/or mutation rates and survival rates in cloned embryos. These studies will also investigate the extent to which genetic or epigenetic programming abnormalities in cloned mice can be corrected when these animals are naturally mated and produce offspring.

Cloning -- replicating a living organism -- depends on the successful transfer of genetic information from the donor to the host, and the successful reprogramming of that genetic information so that it can direct the development of an entire embryo. In a typical cloning process called the nuclear transfer method, the nucleus of a somatic cell – any kind of cell other than a germ cell – is implanted into an egg cell which has had its own nucleus removed. The implanted cell must somehow be reprogrammed so that it can switch from its originally specialized differentiation pathway into the much broader program required to direct the growth of a complete new organism.

Most non-germ cells, collectively known as somatic cells, have singular and determined functions. An arm cell becomes an arm; an eye cell develops into an eye. But while germ cells differentiate and develop into ova or sperm, the gametes of reproduction, they are also responsible for directing the growth and development of the next generation.

McCarrey notes, somewhat facetiously, that "Since, from an evolutionary standpoint reproduction is one of the most important things an individual can do, germ cells can be viewed as the most important cell type in the body and all the rest of the cells serve to carry these cells around."

McCarrey's research will focus on what is involved in the reprogramming process. Since the DNA sequences are equivalent between the donor and host cells and between somatic and germ cells, the answer can't lie in DNA structural differences. But, there are changes that affect gene functioning -- such as whether or not a gene is turned on -- that don't rely on actual changes in DNA structure. These epigenetic mechanisms are required for successful embryonic development.

One epigenetic mechanism is DNA methylation or chemically modified DNA, a process that affects whether or not a gene gets turned on and expresses its message. Many of the genes that can be methylated belong to a category known as imprinted genes. Imprinted genes are often directly involved in growth and development, so they are good candidates to investigate for their roles in the reprogramming process that takes place in cloning.

Only a small proportion of cloned mice embryos, usually less than two percent, develop to term and only a subset of those become fertile adults. McCarrey is most interested in looking at the offspring of successful clones. Do the successful clones -- those that are fertile -- somehow fix any problems related to gametogenesis in order to produce offspring? And, if so, where and how does that occur?

Looking at the genomic imprinting patterns, the chromatin structure, and other germ cell-related characteristics in the offspring of clones may provide some of the answers. The study as a whole hopes to produce new insight into the efficacy and safety of cloning.