This work is done in yeast, because of its genetic 
tractability. Their second interest concerns the bio- 
chemical nature of the biological clock that drives 
daily changes in behavior and physiology. The Dro- 
sophila is their model system, because the fruit flies 
manifest circadian rhythms, and mutant strains are 
available that have aberrant or absent rhythms. 
The laboratory of Investigator Michael W. Young, 
Ph.D. (Rockefeller University) also employs Dro- 
sophila as a model system to study mechanisms of 
circadian rhythms and developmental pathways. 
Mutations of the period {per) gene influence the 
fly's circadian rhythms. In vitro mutagenesis reveals 
a region of ~20 amino acids where substitutions 
predominantly generate short period phenotypes. 
Possibly, this region of the protein suppresses activ- 
ity of the per protein — and therefore plays a regula- 
tory role — in wild-type flies. A second chromosome 
being studied is timeless (tim), which produces ar- 
rhythmia for both eclosion and locomotor activity 
like per. It also affects expression of per, altering its 
circadian cycling. In other work, neurogenic genes 
essential for correct patterns of mesodermal devel- 
opment are under scrutiny. Seven genes may work 
together to influence cell fate choices undertaken 
independently in mesoderm and ectoderm. Investi- 
gation of the molecular details underlying genetic 
interactions between the Notch and Delta genes has 
shown that single-amino acid substitutions measur- 
ably alter interactions between their proteins, 
which may change intracellular signaling by the 
Notch protein. 
The main research interest of Investigator Robert 
Tjian, Ph.D. (University of California, Berkeley) and 
his colleagues concerns the means by which the ge- 
netic information stored in DNA is retrieved in a 
controlled and orderly fashion during the biochemi- 
cal process of transcription, which subsequently 
leads to the expression of specific genes in animal 
cells. The laboratory has taken a biochemical ap- 
proach to the problem of gene control and has de- 
vised various means of isolating the individual cel- 
lular components responsible for transcription and 
of reconstructing this complex reaction in the test 
tube. In this way, they can study how specific genes 
are turned on and off" during cell growth and devel- 
opment of eukaryotic organisms. The mechanisms 
that govern the switching on and off of genes are of 
fundamental importance in understanding the nor- 
mal metabolic processes that maintain and perpetu- 
ate living cells, as well as in deciphering the basis of 
disease and other cellular or genetic disorders. 
The alteration of cellular phenotype, as might oc- 
cur during oncogenesis or cell differentiation, is 
largely a function of alterations in the control of 
gene expression. The basis for such control has been 
investigated by the laboratory of Investigator Joseph 
R. Nevins, Ph.D. (Duke University) in systems that 
focus on transcriptional regulatory mechanisms, par- 
ticularly as they relate to oncogenic transformation 
by the products of DNA tumor viruses. These studies 
have elucidated basic mechanisms for the control of 
transcription factor activity and have provided a uni- 
fication of the manner in which viral oncoproteins 
disrupt the action of the retinoblastoma tumor sup- 
pressor protein Rb. Finally, similar strategies have 
focused on the underlying mechanisms for gene 
control via the processing of mRNA precursors 
to create polyadenylated 3' termini. This work 
has identified factors that control the processing 
of a pre-mRNA that are likely involved in the con- 
trol of gene expression during differentiation of 
lymphocytes. 
In a mouse fibroblast cell line, immediate-early 
transcription factors are induced within minutes 
after nonproliferating cells are exposed to growth 
factors. Within two or three hours, a set of delayed- 
early genes is activated, presumably by the induced 
transcription factors. A number of delayed-early 
genes have been identified by cDNA cloning and se- 
quencing by the laboratory of Senior Investigator 
Daniel Nathans, M.D. (Johns Hopkins University). 
Such genes include those that encode a protein af- 
fecting the mobility of macrophages, a membrane 
protein involved in water transport, a DNA polymer- 
ase, an enzyme involved in purine nucleotide syn- 
thesis, nonhistone chromosomal proteins, and cy- 
clin CYLl , which is thought to regulate an early step 
of the cell division cycle. Upstream of some of the 
genes are binding sites for immediate-early tran- 
scription factors. Studies are in progress to deter- 
mine whether these genes are activated by the tran- 
scription factors. 
New experiments on translational phenomena in 
the laboratory of Investigator Raymond F. Geste- 
land, Ph.D. (University of Utah) have revealed com- 
plexities that more and more point toward the 
crucial involvement of an intricate folding of mes- 
senger RNA molecules in regulating translation. Ge- 
netic experiments are beginning to define elements 
of the ribosome that recognize structural features in 
the folded mRNA. An unusual example is in the 
mRNA for gene 60 that has a 50-nucleotide region 
over which ribosomes hop very efficiently. Detailed 
features in the mRNA of retroviruses are sensed by 
ribosomes in order to circumvent a stop codon and 
to make the crucial reverse transcriptase. The ines- 
capable conclusion from these experiments is that a 
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