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MOLECULAR HEMATOPOIESIS 
David A. Williams, M.D., Assistant Investigator 
The aim of research performed in Dr. Williams's 
laboratory is an understanding of the basic biology 
of hematopoietic stem cells. Specifically, Dr. Wil- 
liams investigates the relationships between primi- 
tive hematopoietic cells (termed stem cells) and 
other cells located in the blood-forming environ- 
ment. The studies are designed to define more 
clearly the cell-cell interactions, growth stimulatory 
proteins, and other local environmental controls 
that are important in the normal and abnormal pro- 
duction of blood cells. The knowledge gained may 
provide better approaches to growing blood cells in 
the laboratory and may thereby improve bone 
marrow transplantation and gene therapy methods. 
Gene Transfer Into Hematopoietic 
Stem Cells 
The use of retroviral vectors to effect transduction 
of hematopoietic stem cells has been associated 
with several difficulties. Previously, long-lived and 
reconstituting murine hematopoietic stem cells 
could only be targeted for gene transfer infre- 
quently. This is still the case in larger animals, such 
as dogs and monkeys. In addition, the level and sta- 
bility of expression of the inserted gene in primary 
hematopoietic cells (cells derived from infected 
stem cells) in vivo has been problematic. 
Dr. Williams's laboratory and other investigators 
have now demonstrated long-lived expression of sev- 
eral genetic sequences in mice following transplan- 
tation of bone marrow into which these sequences 
have been introduced. Molecular analysis has dem- 
onstrated that the genetic sequences have entered 
very primitive stem cells in the marrow that can give 
rise to blood cells for prolonged periods, probably 
the lifetime of the transplanted mice. 
In an attempt to apply the same technology to 
human diseases. Dr. Tom Moritz in Dr. Williams's 
laboratory has been carrying out studies with both 
monkey and human bone marrow. Along with Drs. 
David Bodine and Arthur Neinhuis at the National 
Institutes of Health, Dr. Moritz has been able to dem- 
onstrate gene transfer of adenosine deaminase 
(ADA) into bone marrow cells that are capable of 
differentiation for prolonged periods in trans- 
planted monkeys. 
The deficiency of ADA causes the fatal, inherited 
disease in children called severe combined immuno- 
deficiency (SCID). Use of retroviral vectors to 
transfer functional ADA into hematopoietic cells is 
one approach to genetic therapy of this disease. Al- 
though these experiments demonstrate that the ADA 
gene has been introduced into only a few primitive 
bone marrow stem cells, the expression of the ADA 
protein is easily detectable in the blood and bone 
marrow of the transplanted monkey. The laboratory 
is continuing these studies in collaboration with the 
NIH investigators. 
In addition. Dr. Moritz has investigated the intro- 
duction of genes into human cells. Human umbili- 
cal cord blood was previously shown to contain 
primitive hematopoietic cells that can give rise to 
all blood cells when transplanted into another hu- 
man. Thus cord blood is a highly available source for 
transplantable blood-forming cells. Dr. Moritz has 
concentrated his studies on determining the effi- 
ciency with which genes can be introduced into 
these cells. 
His studies have demonstrated that genes can be 
introduced into the primitive cells of umbilical 
cord blood easier than into those of the adult bone 
marrow. The reason for the difference is not clear 
and is currently being investigated. This find- 
ing, however, may indicate that umbilical cord 
cells could be used as a source for transplantable 
hematopoietic cells that contain introduced gene 
sequences. 
GENETICS 287 
