The Skaggs Institute
for Chemical Biology
Director's Overview
The Skaggs Institute
for Chemical Biology was established in 1996 by a spectacular gift from L.S. "Sam"
Skaggs. During the past 12 years, more than 100 million dollars has been awarded
in research support for members of the Skaggs Institute. Currently, the funding
supports 31 principal investigators, 99 postdoctoral fellows, and 61 graduate students.
The mission of the institute is to conduct science that leads to new medicinal agents
to relieve suffering. Here I describe some of the progress made by members toward
these goals. More details can be found in the individual reports.
Stephen
Mayfield has used his genetically modified algae to produce carbon-neutral liquid
biofuels, a splendid result at a time when fossil fuels reserves are dwindling.
Algae can produce biomass at a rate higher than terrestrial plants do and can be
used to synthesize therapeutic proteins. In short, algae are a versatile and renewable
energy source.
M. Reza Ghadiri has developed new cyclic
peptide mimetics as scaffolds to present amino acid side chains involved in protein-protein
interactions. Using the triazole as a peptide bond surrogate, he has developed useful
bioactive probe molecules that imitate the 3-dimensional pharmacophore of naturally
occurring tetrapeptides.
M.G. Finn continues to modify the surfaces
of intact viral capsids by using, among other methods, click chemistry. These modifications
have been used to display carbohydrates on the exterior capsid surface as well as
polycations that efficiently inhibit the action of heparin.
Jeff Kelly, the new chairman of the Department
of Molecular and Experimental Medicine, is studying the role of amyloidosis in diabetes.
Deposits of amylin in the pancreas are related to the compromised function of these
secretory cells that characterize the disease.
Jamie Williamson has developed a powerful
enzymatic synthesis of nucleotides such as adenosine triphosphate. The process involves
28 enzymes but can be carried out in 60% yield starting from glucose, carbon dioxide,
ammonia, and serine. The synthesis is ideal for isotopically labeled products for
use in nuclear magnetic resonance analysis of the structure of proteins and nucleic
acids.
Ullrich Müller is studying the hair
cells of the inner ear that are the principal mechanosensors for the detection of
sound and head movement. He is unraveling the molecular composition of the mechanotransduction
machinery in these cells by identifying the genes that control their functions.
Ehud Keinan has proposed a general synthetic
strategy of using a simple pentagonal core to produce chemical capsids that are
approximately the size of spherical viruses. He has modeled the assembly and dissociation
of these systems under controlled environmental conditions and has made progress
in synthesizing the molecules that have the proper shapes and recognition surfaces.
Dale Boger and his group work on inhibiting
enzymes that control natural painkillers such as anandamide. They have developed
synthetic molecules that are more efficient than ibuprofen and are similar to morphine
in potency as analgesics in neuropathic pain.
Carlos Barbas used a reductionist approach
on catalytic antibodies to identify the key features of their catalytic abilities.
He has shown that simple chiral amines can be nearly as effective in asymmetric
catalysis for many reactions that make complex carbon-carbon bond arrays.
Geoffrey Chang has developed x-ray crystallography
to characterize molecules involved in multidrug resistance. These molecules transport
small drug molecules from inside the cell to outside and are involved in the efflux
of antibiotic compounds. The goal is to develop inhibitors of the process that can
be used in the treatment of infections.
Gerald Joyce, dean of the Scripps Research
faculty, has developed "evolution on a chip." This method combines a large
population of RNA molecules and computer controlled microfluidic chips that allow
adaptation to occur through hundreds of cycles in a few days. He has also developed
small molecules that can trigger RNA enzymes to catalyze their own formation: molecular
replication.
Kim Janda is working to manipulate the
chemical biology of cell-to-cell signaling known as quorum sensing. His findings
have applications in controlling virulence and infectivity of bacterial and other
microbial agents.
Peter Schultz continues to add more amino
acids to the repertoire of synthetic biology. Proteins made from amino acids with
an expanded genetic code can confer an evolutionary advantage and improved pharmacologic
properties. These proteins are directed to applications in biomedical technology.
Ian Wilson continues to study those few potent
but broadly neutralizing antibodies that recognize HIV type 1. The elusive goal
is still to develop the structural information in these complexes for use in a vaccine.
Lisa Stowers studies neural circuits
that underlie innate behavior. She uses olfactory stimulus in rodents to identify
the neurons involved. Her studies suggest that maternal-infant behavior in rodents
is also triggered by olfactory mechanisms.
In prebiotic chemistry, a debate continues
on the relative importance of replication vs metabolism in the origins of life.
Albert Eschenmoser is making progress on both of these fronts. He and his group
make use of ever-simplified backbones derived from glyceric acid for replication
and explore the chemistry of glyoxylate for metabolism.
Chi-Huey Wong has invented a new method
for the ligation of peptides in which attached sugars are used as delivery vehicles.
The intent is to optimize the methods to achieve the total synthesis of therapeutic
glycoproteins as single isomers.
In my own research group, we continue
to explore the behavior of molecules in small spaces. These arrangements, known
as encapsulation complexes, isolate molecules from the medium and expose unusual
behaviors, shapes, and reaction intermediates that cannot be seen in solution.
Among the honors bestowed on the Skaggs
investigators, 2 were particularly noteworthy. Peter Wright, chairman of the Department
of Molecular Biology, was elected to the National Academy of Science, and Tamas
Bartfai, Chairman of the Molecular and Integrative Neurosciences Department, was
elected to the Swedish Academy of Sciences. Members of the Skaggs Institute won
numerous national and international prizes and earned many honorary degrees in the
past year.
My colleagues and I are grateful for
the continued support of the Skaggs Institute for Research. They provide generous
funding for basic science at the interface of chemistry and biology.
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