Studies of Blood Cell Formation 
formation begins in the yolk sac. Little is known 
about the interaction between supporting cells in 
this environment and the earliest primitive stem 
cells, a very few of which are thought to give rise 
to all blood cells in the adult. Our laboratory has 
derived cell lines from each part of the yolk sac, 
and Merv Yoder, a visiting scientist, is character- 
izing the interactions of supporting cells from the 
yolk sac with blood stem cells derived from 
mouse adult bone marrow, yolk sac, and the em- 
bryonic liver. 
In addition, Pamela Kooh, an HHMI associate, 
is examining the effects of expression of various 
growth proteins during fetal development. She is 
utilizing embryonic stem cell technology to ex- 
amine mouse fetal blood development in vivo 
and in vitro. 
Gene Transfer and Somatic Gene Therapy 
A long-standing focus of research in our labora- 
tory has been the use of viral vehicles, or vectors, 
to introduce new genetic material into bone 
marrow stem cells. These manipulated cells can 
then be introduced into a recipient by bone 
marrow transplantation, so that the daughter 
blood cells contain the new gene. In the future 
these methods, called somatic gene therapy, may 
provide a means of curing severe genetic 
diseases. 
Our work has utilized information we have 
gained about blood formation to improve the de- 
livery of genes into mouse stem cells. Barry Lus- 
key, an HHMI associate in our laboratory, has 
shown that use of the Steel factor ensures that 
100 percent of mice transplanted with manipu- 
lated bone marrow can be made to express hu- 
man protein. We hope to apply this knowledge 
clinically. Children with adenosine deaminase 
(ADA) deficiency, a genetic disease involving 
bone marrow-derived cells, exhibit severe com- 
bined immunodeficiency (SCID) . With a view to 
treating this fatal condition, we are collaborating 
with David Bodine and Arthur Nienhuis at the Na- 
tional Institutes of Health in testing the ap- 
proaches outlined above in monkeys, but so far 
without success. 
Tom Moritz, a postdoctoral fellow in our labo- 
ratory, is collaborating with Ronald Hoffman at 
Indiana University in investigating the transfer of 
the ADA gene in human bone marrow cells that 
have been highly enriched for stem cells. At this 
point it is unclear whether the use of such stem 
cell enrichment will improve the efficiency of 
gene transfer into blood stem cells. Gene transfer 
efficiency is a critical issue in the successful ex- 
tension to humans of gene transfer methods devel- 
oped in mice by this and other laboratories. 
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