Molecular Biology
Chairman's Overview
Peter E. Wright, Ph.D.
Research in the Department of Molecular Biology encompasses a wide range
of disciplines, extending from structural biology at one extreme to molecular
genetics at the other. During the past year, our scientists have continued to
make exciting progress toward understanding the fundamental molecular events
that underlie the processes of life. These accomplishments have been reported
on the pages of the most influential journals and have been rewarded by a higher
than ever level of grant support. The faculty members of this department have
every reason to be proud of these achievements, as do the exceptionally talented
postdoctoral fellows, graduate students, technologists, and support personnel,
who are absolutely vital to the success of each and every research program.
Within the confines of this brief overview, I cannot do justice to the many
exciting research programs within the department. These are described in detail
on the following pages, and a few of the highlights are mentioned briefly here.
A collaboration between Joel Gottesfeld of this department and Peter Dervan
at the California Institute of Technology led to the development of small synthetic
molecules that bind in the minor groove of DNA and can regulate gene expression.
Gottesfeld, Dervan, and their colleagues showed that these compounds, pyrrole-imidazole
polyamides, can be designed to target specific DNA sequences and interfere with
the transcription of specific genes. Polyamides directed against DNA target sequences
within the HIV enhancer and promoter are highly effective inhibitors of viral
replication in isolated human blood peripheral lymphocytes. These compounds offer
the potential for design of small molecules that can regulate the transcriptional
activity of selected target genes in living cells. These results are extremely
exciting and could eventually lead to a new class of therapeutic agents directed
against a broad spectrum of viral and other diseases.
A different approach to targeted gene regulation is being pursued by Carlos
Barbas and his colleagues. Proteins containing multiple zinc-finger domains are
being engineered to recognize specific binding sites containing as many as 18
nucleotides. Such proteins can target a unique locus in the human genome and
have considerable potential as genetic regulators in a variety of human diseases.
In the area of structural biology, a number of spectacular new advances were
made during the past year. Ian Wilson and his coworkers determined the three-dimensional
structure of murine CD1, a protein that is distantly related to MHC molecules
and that presents antigens to T cells. The overall structure is similar to that
of an MHC class I molecule, but CD1 contains a deep, almost entirely hydrophobic,
binding cavity. The structure reinforces the view that the role of CD1 is to
display lipid and glycolipid antigens.
In another major advance, Elizabeth Getzoff and coworkers determined the
atomic resolution structure of a signaling intermediate in the light cycle of
a photoreceptor protein by using millisecond time-resolved x-ray crystallography.
This achievement is impressive, because the lifetime of the photocycle intermediate
is less than 1 second, and the findings provide the first detailed insights into
the structure of a light-activated intermediate. The structural changes observed,
relative to the ground state, suggest a mechanism for signal transduction and
provide a general framework for understanding the structural mechanisms of protein
photocycles.
Other important structures determined during the past year include catalytic
antibodies; animal and plant viruses; calcium signal transduction proteins; the
first structure of a complex between a transcriptional activation sequence and
a domain of the coactivator CREB-binding protein; and the structure of a human
DNA-repair enzyme, uracil-DNA glycolase. This last structure is of interest for
the insights it provides into the mechanism of recognition of damaged bases,
which are flipped out from the double helix and into the active site of the enzyme,
where they are excised.
Gerald Joyce and Martin Wright developed a new method to evolve catalytic
RNA molecules continuously in vitro. This method is a major advance in the evolution
of novel RNA catalysts. In addition, continuous in vitro evolution provides a
more realistic model of biological evolution and should provide new insights
into evolutionary mechanisms. Other work in the Joyce laboratory led to the development
of a small and highly efficient DNA enzyme that can be tailored to recognize
and cleave different RNA target sequences. Such DNA enzymes have potential applications
both as laboratory reagents and in medicine.
In the area of cell-cycle regulation, Curt Wittenberg and his colleagues
published several key articles describing the phosphorylation-dependent degradation
of cyclins. Cyclins regulate cell-cycle transitions in eukaryotes through association
with cyclin-dependent protein kinases. Wittenberg and coworkers showed that phosphorylation
of a G1 cyclin, by the kinase that the cyclin activates, provides
a signal that promotes rapid degradation of the cyclin by a ubiquitin-dependent
pathway and thereby makes activation self-limiting. This work is providing important
new insights into the complex molecular mechanisms that govern the major cell-cycle
transitions.
Finally, I am delighted to report that we have recruited several outstanding
scientists to full or joint appointments in the department. Gary Siuzdak, director
of the Mass Spectrometry Facility, joined our faculty during the past year, and
Paul Schimmel, Jamie Williamson, and Martha Fedor will soon bring new strengths
to our programs in the molecular and structural biology of RNA. In addition,
Jonathan Hirst, Chris Garcia, Robyn Stanfield, and Luis de Lecea have recently
joined us and strengthen our research in the areas of theory, x-ray crystallography,
and molecular neurobiology.
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