The work carried out by Investigator Bernardo 
Nadal-Ginard, M.D., Ph.D. (Children's Hospital, 
Boston) and his colleagues is oriented toward the 
elucidation of the genetic mechanisms responsible 
for the production of muscle cells. The main com- 
ponent of these cells is the contractile apparatus 
that confers the functional properties of skeletal 
and cardiac muscle. The genes that encode for the 
contractile proteins are being analyzed by the labo- 
ratory. Once these genes are activated, they pro- 
duce several different versions of the relevant con- 
tractile proteins, each of which is functionally 
different and may change in response to different 
physiological and pathological demands. The gen- 
eration of different contractile systems is possible, 
because several genes produce different versions of 
the same protein and, in many cases, the same gene 
can produce a large number of variants by the pro- 
cess of alternative mRNA splicing. The molecular 
mechanisms responsible for these two modes of 
regulation are under investigation. 
Assistant Investigator Jeremy Nathans, M.D., 
Ph.D. (The Johns Hopkins University) and his co- 
workers are studying the molecular mechanisms 
underlying our sense of sight and the genetic alter- 
ations that cause inherited variations in that sense. 
They have concentrated on the visual pigments, the 
hght-sensitive proteins in the eye that mediate vi- 
sion, and have recently determined the nature of 
the alterations that cause blue cone monochrom- 
acy, a rare defect characterized by a complete ab- 
sence of color sense, low acuity, nystagmus (invol- 
untary eye movements), photophobia, and in some 
cases a progressive scarring of the central retina. In 
most affected individuals, sequences adjacent to 
the genes encoding the red- and green-sensitive 
pigments are deleted. Most likely, the deleted re- 
gion contains DNA sequences that control expres- 
sion of these genes in the retina. 
The human immunodeficiency virus type 1 (HTV-l) 
encodes a regulatory protein. Rev, that is essential 
for viral replication. The laboratory of Assistant In- 
vestigator Bryan R. CuUen, Ph.D. (Duke University) 
has shown that the role of Rev is to activate viral 
structural protein expression by facilitating the nu- 
clear export of viral mRNA molecules within the in- 
fected cell. Mutational analysis of the rev gene sug- 
gests the existence of two functional protein 
domains— one that binds directly to a viral mRNA 
target sequence and a second that interacts with 
the cellular RNA transport machinery. Defective Rev 
proteins that lack this second domain but continue 
to bind viral mRNAs have now been shown to in- 
hibit Rev function and hence to prevent HIV-1 rep- 
lication. These trans-dominant repressors of Rev 
function may prove useful in strategies for gene 
therapy as an approach to the treatment of AIDS 
(acquired immune deficiency syndrome). 
The laboratory of Assistant Investigator Patrick O. 
Brown, M.D., Ph.D. (Stanford University) is examin- 
ing the mechanism by which a retrovirus can inte- 
grate its genes into a chromosome of its host cell. 
Integration is an essential step in retroviral repro- 
duction and may provide a tool for the therapeutic 
introduction of genes into human cells. Dr. Brown 
and his colleagues have determined the structure 
of two key intermediates in integration and have 
identified a specific biochemical step carried out by 
a viral protein. Extending their previous studies on 
a murine retrovirus, this group has developed a 
test-tube method for studying the integration of 
HIY 
The laboratory of Assistant Investigator John W 
Belmont, M.D., Ph.D. (Baylor College of Medicine) 
has focused on the investigation of retroviral gene 
transfer into hematopoietic stem cells. The primary 
application of these studies is in the development 
of a clinically useful method for gene transfer ther- 
apy. Retroviral vectors are being utilized because of 
their potential for efficient gene transfer. These 
studies are also aimed at defining some of the bio- 
logical properties of hematopoietic stem cells and 
their lymphoid progeny. 
Chemical reactions necessary for life are typically 
catalyzed by enzymes. These large molecules are 
usually proteins, but recently it has been found 
that RNA, which was previously thought to be only 
an information-carrying molecule, can act as an en- 
zyme. In the past year a more detailed view of the 
mechanism of one example of RNA catalysis has 
been obtained by Investigator Thomas R. Cech, 
Ph.D. (University of Colorado at Boulder) and his 
colleagues. For example, the release of the product 
from the active site was found to limit the speed of 
the reaction, and the reverse direction of the reac- 
tion was observed for the first time. A new method 
was also developed to determine which parts of the 
RNA molecule are on its surface and which are bur- 
ied in the interior. The result is a clearer picture of 
the overall molecular structure. 
The laboratory of Associate Investigator Jeffry 
L. Corden, Ph.D. (The Johns Hopkins University) 
has been studying RNA polymerase, the enzyme 
that synthesizes mRNA copies of activated genes. 
RNA polymerase contains an unusual repeated 
amino acid sequence that is modified by the enzy- 
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