Appendix I. 
289 
The challenges for using human ES cell-derived P-cells for 
transplantation are significant and parallel those that face the entire 
field of ES cell-based transplantation therapies. First, pancreatic 
development is incompletely understood, and it is not yet possible to 
direct ES cells to P-cells efficiently. However, given the pace of 
advances in developmental biology over the last decade, it is likely 
that in the next five to ten years, it will be possible to routinely 
generate clinically useful quantities of P-cells from human ES cells. 
Second, integration into the body in a form that restores function of 
the damaged tissue is essential. This is easier for p-cells than for 
most cell types, as the function that must be restored is secretion of 
insulin into the blood stream in response to high glucose, and this 
function does not require a complex physical connection between the 
transplanted and host tissues. Indeed, the clinical trials using 
cadaver-derived P-cells have transplanted the cells into the liver, and 
the cells function in that site. Third, transplanted P-cells must not be 
rejected by the immune system. Although the transplantation of P- 
cells has been clinically successful, the severe immunosuppressive 
therapy required may make the procedure inappropriate for the 
average diabetic patient. Importantly, P-cells derived from adult 
stem cells from the patient, or even from ES cells derived through 
"therapeutic cloning" using a nucleus from the patient, would not 
solve the immune rejection problem for diabetes. Type 1 diabetes is 
an autoimmune process, and unless that immune response is altered 
the very process that made the patient diabetic in the first place 
would destroy transplanted P-cells genetically identical to the 
patient’s. Finally, neoplastic transformation of the transplanted cells 
is a serious concern for any cell-based therapy in which the cells are 
first cultured extensively. All actively dividing cells accumulate 
mutations over time, and the potential exists that enough mutations 
could accumulate to make some cells tumor cells. 
None of the challenges facing ES cell-based transplantation 
therapies are insurmountable, and indeed, type 1 diabetes is an 
excellent candidate for treatment using this approach. However, the 
challenges do underscore both the importance of careful preclinical 
testing, particularly in non-human primates, and the amount of work 
still to be done before people's lives will be improved by these 
therapies. 
Conclusions 
PRE-PUBLICATION VERSION 
