Appendix N. 
391 
The efficiency of creating cloned animals is strongly influenced by 
the differentiation-state of the donor nucleus (Table 1). In the mouse, 
for example, only 1-3% of cloned blastocysts derived from somatic 
donor nuclei, e.g., those prepared from-fibroblasts or cumulus cells, 
will develop to adult cloned animals (Hochedlinger and Jaenisch, 
2002b). In certain cases, such as those using terminally 
differentiated B or T cell donor nuclei, the efficiency of cloning is so 
low as to preclude the direct derivation of cloned animals. In stark 
contrast to these examples, cloning using donor nuclei prepared from 
embryonic stem (ES) cells is significantly more efficient (between 15 
and 30 %, Table 1). This correlation "with differentiation-state 
suggests that embryonic nuclei require less reprogramming of their 
genome, ostensibly because the genes essential for embryonic 
development are already active and need not be reprogrammed. In 
fact, the nucleus of an embryonic cell such as an ES cell may well 
have the same high efficiency to generate postnatal mice after 
nuclear transfer as the nucleus prepared from a recently fertilized 
egg (Table 1, compare Fig. 4). Nonetheless, most if not all mice that 
have been cloned from ES cell donor nuclei, in contrast to mice 
derived through natural fertilization from the zygote, eire abnormal, 
indicating that the processes of gametogenesis (development of 
sperm and of egg) and fertilization endows the zygote nucleus with 
the ability to direct normal development. In summary, these data 
indicate that the potential of a nucleus to generate a normal embryo 
is lost progressively v\hth development. 
V. Adult cloned animals: how normal are they? 
The observation that apparently healthy adult cloned animals have 
been produced in seven mammalian species (albeit at low efficiency) 
is being used by some as a justification for attempting to clone 
humans. In fact, even those that survive to adulthood, such as Dolly, 
may succumb relatively early in adulthood because of numerous 
health problems. Insights into the mechanisms responsible for clone 
failure before and after birth have come from molecular and biological 
analyses of mouse clones that have reached (i) the blastocyst stage, 
(ii) the perinatal period and (iii) adulthood. 
fi) Most clones fall short of activatinQ key embry onic prenes and fail 
early . 
As stated above in order for clones to develop, the genes that are 
normally expressed during embryogenesis, but are silent in the 
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