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survival, it may not prevent maladies to become manifest at later 
ages. Therefore, most if not all clones are expected to have at least 
subtle abnormalities that may not be so severe as to result in an 
obvious phenotype at birth but will cause serious problems later as 
seen in aged mice. Clones may just differ in the extent of abnormal 
gene expression: if the key “Oct-4 like" genes are not activated, 
clones die immediately after implantation. If those genes are 
activated, the clone may survive to birth and beyond. 
As schematically shown in Fig. 2, the two stages when the 
majority of clones fail are immediately after implantation and at birth. 
These are two critical stages of development that may be particularly 
vulnerable to faulty gene expression. Once cloned newborns have 
progressed through the critical perinatal period, various 
compensatory mechanisms may counterbalance abnormal expression 
of other genes that are not essential for the subsequent postnatal 
survival. However, the stochastic occurrence of disease and other 
defects at later age in many or most adult clones implies that such 
compensatory mechanisms do not guarantee “normalcy" of cloned 
animals. Rather, the phenotypes of surviving cloned animals may be 
distributed over a vNhde spectrum from abnormalities causing sudden 
demise at later postnatal age or more subtle abnormalities allowing 
survival to advanced age (Fig. 2). These considerations illustrate the 
complexity of defining subtle gene expression defects and emphasize 
the need for more sophisticated test criteria such as environmental 
stress or behavior tests. However, the available evidence suggests 
that truly normal clones may be the exception. 
It should be emphasized that “abnormality" or “normalcy" is 
defined here by molecular and biological criteria that distinguish 
cloned embryos or animals from control animals produced by sexual 
reproduction. The most informative data for the arguments presented 
above come from the mouse. There is, however, every reason to 
believe that these difficulties associated with producing mice and a 
variety of other mammalian embryos by nuclear transplantation will 
also afflict the process of human reproductive cloning (Jaenisch and 
Wilmut, 2001). 
fv) Is it possible to overcome the problems inherent in reproductive 
cloning? 
It is often argued that the “technical" problems in producing normal 
cloned mammals will be solved by scientific progress that will be 
made in the foreseeable future. The following considerations argue 
that this may not be so. 
PRE-PUBLICATION VERSION 
