Following the Life History of Lymphocytes 
Irving L. Weissman, M.D. — Investigator 
Dr. Weissman is also the Karel and Avice Beekhuis Professor of Cancer Biology and Professor of Pathology, 
Developmental Biology, and (by courtesy) Biology at Stanford University School of Medicine. He directs 
the Program for Molecular and Genetic Medicine and the Immunology Program. He received his M.D. 
degree from Stanford and remained to do postdoctoral studies in the Department of Radiology. He also 
studied at Oxford with Jim Gowans in 1964 and returned in 1975 for part of a sabbatical year, which he 
then completed with Melvin Cohn at the Salk Institute. Dr. Weissman is a member of the National 
Academy of Sciences and the American Academy of Arts and Sciences. 
LIKE all other blood cells, lymphocytes — the 
principal players in immune recognition of 
self from nonself — are derived ultimately from 
stem cells in the bone marrow. It is both biologi- 
cally and clinically important to delineate the de- 
cisions these bone marrow precursors make as 
they pass through microenvironments that define 
the type of lymphocyte (or other blood cell) they 
shall become. We have focused on identifying the 
earliest cells in mouse and human bone marrow 
that have multipotent capacity, the so-called he- 
matopoietic (blood-forming) stem cells. 
Several years ago we were able to isolate the 
hematopoietic stem cell of the mouse. This year 
we showed that no other cell type in the bone 
marrow has stem cell activity or potential. We 
have also demonstrated its full developmental 
potential by transferring a single stem cell from 
one mouse strain mixed with 1 00 stem cells from 
another strain into lethally irradiated mice of the 
second strain. Progeny from the single marked 
stem cell regularly gave rise to over 100 million 
blood cells of all types, including hundreds to 
thousands of stem cells. 
These thousands of stem cells, derived from the 
initially injected single cell, could be retrieved 
and transferred to a second generation of irra- 
diated animals, all of whom were fully reconsti- 
tuted. Thus this stem cell has a remarkable pro- 
file of activities, including that of massive 
self-renewal. 
In the past year we also found that stem cells in 
mouse fetuses have the capability of giving rise to 
a broader variety of T cells than do stem cells in 
the adult bone marrow.* The additional types of 
T cells derived from fetal stem cells are those 
cells that move from the fetal thymus to the skin 
and other epithelial coverings of the body, pre- 
sumably to act as sentinels to protect against in- 
coming infectious microorganisms. 
Most remarkably, in preparation for this added 
capacity in fetal life, stem cells apparently start a 
T cell developmental "clock" on one T cell re- 
ceptor chromosome. We propose that after sev- 
eral stem cell divisions, the clock moves past that 
part of the chromosome that will be expressed as 
receptors for antigens expressed on epithelial T 
cells, and concentrates only on other T cell re- 
ceptors to fight off infection in other sites of the 
body. We believe that the genetic events that set 
developmental clocks and then shut them down 
at the level of hematopoietic stem cells lie at the 
heart of understanding the determination of 
choices that cells can make in general, and hope 
to develop in the next few years new methods to 
investigate the regulators that set the clock and 
how they do so in the developmental history of 
the mouse embryo. 
Several years ago our laboratory developed a 
mouse model of human organ function, wherein 
human hematopoietic and lymphoid organs, such 
as fetal liver, thymus, and bone marrow, could be 
implanted in the immunodeficient SCID mouse.* 
We found that the human lymphoid microenvi- 
ronments implanted in the SCID mouse could 
provide the right soil for human T cell lymphoma 
growth, while the same primary tumors from pa- 
tients will not grow in the SCID mouse in any 
other microenvironment. This presents the op- 
portunity to study the earliest stages of growth 
and malignant progression of human cancers, 
lymphomas, and leukemias, if the general princi- 
ple holds that their early growth is dependent on 
the organ in which they find themselves. This im- 
plies that there might exist factors within human 
organs that are responsible for the early neoplas- 
tic grov^h of cancer cells, some of which may be 
tissue specific. 
In the past year, we also identified the genes 
that encode a Peyer's patch homing receptor — 
the molecule that is involved in the traffic of lym- 
phocytes from the bloodstream to intestinal lym- 
phoid organs such as Peyer's patches, appendix, 
and mesenteric lymph nodes. The molecule is a 
member of the integrin family of adhesion pro- 
teins and uses the combination a^^-j. Lymphomas 
that express a^^^ were found to metastasize to 
* This work is supported by a grant from the National Insti- 
tutes of Health. 
457 
