II. PROGRAM IN GENETICS 
In recent years genetics has come to occupy a 
critical position in all biomedical research. It is not 
surprising, therefore, that it should be the largest of 
the Institute's research programs. Much of the 
work being carried out in the Institute's other pro- 
grams also depends to a greater or lesser extent on 
the techniques and conceptual underpinnings of 
genetics in general and molecular genetics in par- 
ticular. Investigators who are specifically associated 
with the Program in Genetics are located at the Uni- 
versity of Michigan, The Johns Hopkins University, 
The Carnegie Institution of Washington at Balti- 
more, Harvard Medical School, Children's Hospital 
in Boston, the University of Colorado at Boulder, 
The University of Chicago, the University of Texas 
Southwestern Medical Center at Dallas, Duke Uni- 
versity, Baylor College of Medicine, the University of 
Iowa, Yale University, The Rockefeller University, 
Stanford University, the California Institute of Tech- 
nology, the University of Pennsylvania, Princeton 
University, the University of Utah, the University of 
Washington, Brandeis University, and the University 
of California at Berkeley, at Los Angeles, and at San 
Francisco. Collectively their work includes studies 
of human genetic diseases and various animal mod- 
els of these diseases, analysis of developmental and 
differentiation processes, experimental studies of 
the regulation of gene expression, and the mapping 
of identified genes within the human genome and 
in the genomes of other animals. Their work ranges 
from basic studies at the molecular and cellular 
level through clinical studies of the human genetic 
disorders to the development of potential thera- 
peutic approaches. 
Understanding the processes that govern the 
development of a complex organism from a single 
fertilized egg is one of the central problems in mod- 
ern biology. From the fertilized egg must arise many 
thousands of cell types, each with its unique prop- 
erties and functions. Those functions are de- 
termined to a large extent by the subset of genes 
that the cell chooses to express, and it is the basis 
for those choices that concerns the laboratory of 
Investigator Shirley M. Tilghman, Ph.D. (Princeton 
University). Considerable progress has been made 
in the past several years in identifying the signals 
encoded by the DNA surrounding specific genes 
that determine in which cells those genes will be 
expressed. These genetic signals are complex, often 
present in multiple copies, and are presumed to 
be sites at which proteins interact with the DNA 
to either enhance or diminish the expression of 
the genes in question. In the case of the a-fetopro- 
tein gene (a gene that is activated in three cell types 
in the developing mouse embryo), at least five dif- 
ferent DNA signals have been identified that are 
necessary to activate the gene appropriately and re- 
press its expression later in development. Dr. 
Tilghman's laboratory is currently focusing on the 
identification of the proteins that interact with the 
DNA signals, anticipating that these proteins and 
the genes that encode them are critical compo- 
nents in determining cell type-specific expression 
of genes. 
The interest of Senior Investigator Philip Leder, 
M.D. (Harvard Medical School) is in understanding 
some of the genes that control cell growth and de- 
velopment. The research of his laboratory, which is 
particularly relevant to the cancer problem, is 
largely focused on genes that modify an organism's 
susceptibility to the development of malignancy. 
Recently Dr. Leder and his colleagues have shown 
how genes that perturb the maturation of certain 
types of cells can protect the organism from the de- 
velopment of cancer and that certain other gene 
products, lymphokines, can act as potent antitumor 
agents, mobilizing the organism's defenses against 
the establishment of malignant tumors. Still other 
studies in Dr. Leder's laboratory have identified 
genes that perturb embryonic development and 
can lead to serious birth defects. 
Recently developed techniques of gene targeting 
(which involves homologous recombination be- 
tween DNA sequences residing in the chromosome 
and newly introduced, cloned DNA sequences) 
have made it possible, in principle, to generate 
mice with any desired genotype. This technology, 
which was perfected by Investigator Mario R. 
Capecchi, Ph.D. (University of Utah) is now being 
used to dissect genetically the developmental pro- 
gram responsible for specifying organogenesis and 
morphogenesis of the mouse. 
Investigator Richard D. Palmiter, Ph.D. (Univer- 
sity of Washington) and his colleagues, in collabora- 
tion with Dr. Ralph Brinster (University of Pennsyl- 
vania), use a different technique that involves the 
transfer of selected genes into the germline of mice 
to study various aspects of development and dis- 
ease. The genes of interest are microinjected into 
the pronuclei of fertilized eggs, where they often 
integrate into one of the endogenous chromo- 
somes and are later expressed as new genetic traits. 
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