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Monitoring Stem Cell Research 
imprinted ^ gene expression represents an important cause of 
embryonic failure. 
In order for cloned embryos to complete development, genes 
normally expressed during embryogenesis but silent in the somatic 
donor cell, must be reactivated. This complex process of epigenetic ^ 
remodeling (i.e., the reconfiguration of the genome by turning on and 
turning off specific genes) that occurs during gametogenesis in 
normal development ensures that the genome of the zygote can 
faithfully activate early embryonic gene expression (Fig la). In a 
cloned embryo, reprogramming, which in normal gametogenesis 
requires months to years to complete, must occur in a cellular 
context radically different from gametogenesis and within the short 
interval (probably within hours) between transfer of the donor 
nucleus into the egg and the time when zygotic transcription 
becomes necessary for further development. Given these radically 
different conditions, one can envisage a spectrum of different 
outcomes to the reprogramming process ranging from (i) no 
reprogramming of the genome, resulting in immediate death of the 
NT embryo; through (ii) partial reprogramming, allowing initial 
survival of the clones, but resulting in an abnormal phenotype and/or 
lethality at various stages of development; to (iii) faithful 
reprogramming producing fully normal animals (Fig lb). The 
phenotypes observed over the past five years in cloned embryos and 
newborns suggest that complete reprogramming is the exception, if 
it occurs at all. 
IV. Development of clones depends on the differentiation-state of 
the donor nucleus 
The majority of cloned embryos fail at an early step of embryonic 
development, soon after implantation in the wall of the uterus, an 
early step of embryonic development (Hochedlinger and Jaenisch, 
2002b; Rideout et al., 2001). Those that live to birth often display 
common abnormalities irrespective of the donor cell type (Table 1). In 
addition to symptoms referred to as “Large Offspring Syndrome”, 
neonate clones often suffer from respiratory distress and kidney, 
liver, heart or brain defects (Cibelli et al., 2002). However, the 
abnormalities characteristic of cloned animals are not inherited by 
their offspring (Tamashiro et al., 2002), indicating that epigenetic 
aberrations (i.e., failure of genome reprogramming) rather than 
genetic aberrations (changes in the sequences within the DNA) are 
the cause. 
PRE-PUBLICATION VERSION 
