sion increases both synthesis of the gene's messen- 
ger RNA and its stabiUty. They have also prepared 
mutant erythropoietins and sequenced mammalian 
erythropoietins to obtain a better understanding of 
how the hormone acts. Finally, they have developed 
an accurate method for measuring small amounts 
of RNA and DNA. In addition, Associate James M. 
Cunningham, M.D., and his colleagues have identi- 
fied a gene that encodes for a receptor protein that 
permits a leukemogenic murine retrovirus to infect 
mouse cells. 
Mutations resulting from broken and rearranged 
chromosomes frequently produce an unusual mo- 
saic phenotype in which the affected gene or genes 
are expressed in some cells but not others within a 
tissue. This year the studies of Investigator Allan 
Spradling, Ph.D. (The Carnegie Institution of Wash- 
ington) on a small mutant chromosome. Dp 1187, 
constructed from the fruit fly Drosophila, revealed 
that this phenomenon (position-effect variegation) 
is associated with drastic changes in chromosome 
replication near the site of breakage. To understand 
the molecular mechanisms involved. Dr. Spradling 
and his colleagues have localized several elements 
that regulate the replication of a specific chromo- 
some region encoding Drosophila eggshell pro- 
teins. They have also initiated genetic studies of 
early steps in oogenesis, where chromosomes un- 
dergo fascinating processes of replication and re- 
combination during meiosis. 
Assistant Investigator Jeffrey Bonadio, M.D. (Uni- 
versity of Michigan) and his colleagues have charac- 
terized an example of a class of collagen mutation 
that may be more common in the general popula- 
tion than previously suspected. Such mutations 
may be associated with relatively mild manifesta- 
tions of connective tissue dysfunction. They have 
characterized also a mouse model of a form of 
human inherited connective tissue disease, os- 
teogenesis imperfecta. The model provides an op- 
portunity to investigate the effect of a reduced 
amount of type I collagen on the structure and in- 
tegrity of extracellular matrix. This approach may 
provide a system in which therapeutic strategies to 
strengthen connective tissue can be developed. 
Assistant Investigator James M. Wilson, M.D., 
Ph.D. (University of Michigan) and his colleagues 
have been developing new approaches to the treat- 
ment of metabolic diseases based on the transfer of 
genes into somatic cells. A major effort has been di- 
rected toward gene transfer into hepatocytes for 
treatment of inherited diseases associated with 
markedly elevated serum cholesterol levels. A rab- 
bit animal model for an inherited form of 
hypercholesterolemia was used to develop and test 
several new genetic therapies. Expression of a re- 
combinant gene that encodes a receptor capable of 
degrading low-density lipoproteins in hepatocytes 
of hyperlipidemic rabbits led to substantial de- 
creases in total serum cholesterol. Dr. Wilson has 
also introduced recombinant genes into vascular 
endothelial cells that are capable of repopulating 
prosthetic vascular grafts in vivo. This technology 
has potential applications to the treatment of vas- 
cular disease and the design of new drug delivery 
systems. 
The laboratory of Associate Investigator Gary K. 
Schoolnik, M.D. (Stanford University) is engaged in 
studies designed to determine how infectious 
agents cause disease. Microbial molecules that me- 
diate the infectivity and virulence of an organism 
are identified, purified, and chemically character- 
ized, and their corresponding genes are cloned. Im- 
munologically interesting regions of these mole- 
cules are identified, and their efficacy as candidate 
vaccines is studied in animal models of human in- 
fectious syndromes. Those vaccines that exhibit 
protective efficacy are then assessed for their capac- 
ity to stimulate a safe immune response in human 
volunteers. Trials involving many human subjects 
are then conducted to assess the clinical utility of 
the vaccine. In this manner the laboratory seeks to 
prepare a new generation of safe and effective 
chemically defined vaccines. Specific organisms 
under investigation include Neisseria gonorrhoeae, 
Moraxella bovis, and Yersinia enterocolitica. 
Associate Investigator Gerald R. Crabtree, M.D. 
(Stanford University) and his colleagues are study- 
ing the way in which cells of the immune system 
(T lymphocytes) develop the ability to carry out the 
complex functions required to defend the body 
from infection. The T lymphocytes circulating in 
the blood do not have the ability to perform im- 
mune functions until they come into contact with 
foreign antigens carried on invading organisms or 
transplanted tissues. This contact programs the 
T cell to develop an ability to destroy immunologi- 
cally the cells carrying the foreign antigen. Work in 
Dr. Crabtree's laboratory has led to the identifica- 
tion of molecules that are likely to play an essential 
role in programming the T lymphocyte for immune 
function. 
Cachectin or tumor necrosis factor (TNF) is a 
product of macrophages, released after exposure to 
a variety of infectious agents. It is of medical impor- 
tance, since it acts to induce the state of shock that 
Continued 
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