The Skaggs Institute
for Chemical Biology
is my pleasure to report on another extraordinary year at the Skaggs Institute for
Chemical Biology, which is so vital to The Scripps Research Institute as a whole.
In 2007, scientists at the Skaggs Institute continued to push the boundaries of
discovery, producing innovations at the intersection of chemistry and biology to
advance our shared goal of improving human health.
Investigators at the Skaggs Institutes had many significant accomplishments in 2007, including
hopes of combating the growing scourge of antibiotic-resistant bacteria, in particular,
drug-resistant staphylococci, Professor Kim Janda and colleagues designed a new
type of vaccine that could one day be used in humans to block the onset of infection.
The vaccine would not only work on currently resistant bacterial strains but also
avoid the potential of inducing bacterial resistance. Rather than killing bacterial
cells as antibiotics do, the vaccine blocks the cells' communication system,
preventing the shift from harmless to virulent and allowing the body's natural
defenses to combat the pathogen.
Janda and his group also developed a new monoclonal antibody that destroys the highly
addictive drug methamphetamine. The new antibody, YX1-40H10, converts methamphetamine
to a benign substance, pointing to an entirely new way to treat the global epidemic
of substance abuse. In a separate study, the scientists found that chronic abuse
of methamphetamine may be an unrecognized risk factor for potentially serious cardiovascular
disorders that often occur in methamphetamine abusers.
Sydney Brenner, Tobin J. Dickerson, and other colleagues, I developed a breakthrough
method that can be used to rapidly predict how viruses such as avian influenza H5N1,
a dangerous strain that causes "bird flu," will mutate in response to
attacks by the immune system. The new approach, dubbed "checkmate analysis,"
may also be useful in predicting which antibodies or small-molecule therapeutic
agents will best neutralize these viral mutations before the viruses can result
in global epidemics. Because of its simplicity and low cost, this innovative approach
will be accessible to scientists around the world.
Jeffery Kelly, dean of graduate and postgraduate studies and vice president for
academic affairs, Professor William Balch, and colleagues, came up with a simple
but comprehensive way of probing the biological machinery in humans that controls
folding, packaging, and export of proteins from cells. The new model, called folding
for export (FoldEx), integrates the chemistry and biology of protein folding and
provides a framework for understanding the causes of diseases such as cystic fibrosis
and Alzheimer's disease that arise when the protein homeostasis machinery malfunctions.
FoldEx may also be useful in designing treatment strategies for protein misfolding
Ulrich Müller and coworkers shed light on how vibrations entering the ear are
converted to electrical signals that can be interpreted by the brain. The scientists
showed that 2 key proteins join at the precise location where energy of motion is
turned into electrical impulses. These proteins, cadherin 23 and protocadherin 15,
are part of a complex of proteins called "tip links" on hair cells in
the inner ear.
Julius Rebek, director of the Skaggs Institute, and colleagues described a new chemical
tool that effectively pauses the formation of certain intermediate products never
before seen, allowing the products to be identified and studied. The illumination
of elusive chemical intermediates will improve basic understanding of chemical processes
and may aid in biosynthesis studies, drug development, and detection of pollutants.
Professor Lisa Stowers and colleagues discovered specific pheromone compounds responsible
for eliciting aggressive behavior in mice. The researchers have also identified
the first step in the neurologic pathway that triggers the aggressive response.
These findings further the broad and important goal of elucidating how the neurologic
system can detect and respond to specific cues in of a sea of potential triggers.
Paul Wentworth and coworkers furthered the ongoing search for better treatments
for devastating parasitic diseases such as Chagas' disease and African sleeping
sickness. The group now understands better a critical DNA-protein binding event
that if blocked can kill the parasites that cause the diseases. The researchers
are already working to screen drugs that will block this mechanism.
Wright, chair of Scripps Research Department of Molecular Biology, Professor Jane
Dyson, and colleagues uncovered a process by which disordered or unstructured proteins
become bound to specific cellular sites. The findings offer valuable insights into
how proteins carry out their genetically encoded functions and may provide new targets
for drug development.
In 2007, Skaggs
Institute investigators were again the recipients of numerous awards.
Cravatt, professor and chair of the Department of Chemical Physiology, Scripps Research,
was elected a fellow of the American Association for the Advancement of Science
for the development of innovative chemical proteomic technologies to annotate
enzymatic pathways in mammalian systems. Dr. Cravatt also won the 2007 Young
Investigator Award from the Linda and Jack Gill Center for Biomolecular Science
at Indiana University, Bloomington, in recognition of his work, including the
discovery and structural identification of several biomolecules involved in processes
as diverse as sleep, thermal sensation, and pain, and the identification of a key
enzyme that metabolizes a substance produced by the body that resembles marijuana
in its actions.
Chi-Huey Wong was the recipient of a Humboldt Research Award in recognition
of lifetime achievements in research. The award, conferred by the Alexander von
Humboldt Foundation, honors outstanding scientists and scholars from all disciplines
whose fundamental discoveries, new theories, or insights have had a significant
impact on the scientists' own discipline and who are expected to continue producing
cutting-edge achievements. In addition, in 2007 Dr. Wong received the F.A. Cotton
Medal from Texas A&M, which recognizes excellence in chemistry research; an
honorary degree from Technion-Israel Institute of Technology in recognition of his
original and prolific research in bioorganic chemistry ; and an honorary
fellowship from the Chemical Research Society of India, bestowed every year to eminent
chemists from around the world for outstanding contributions to chemical science.
Dale Boger won the Ernest Guenther Award in the Chemistry of Natural Products from
the American Chemical Society. The award, sponsored by Givaudan, was given in
recognition of contributions to the total synthesis of complex biologically active
natural products and key analogs used to define their mode of action.
Paul Schimmel won the prestigious Stein and Moore Award from the Protein Society
for contributions to the highest level of the study of proteins. The
award, sponsored by the Merck Company Foundation and named for Nobel laureates William
Stein and Stanford Moore, venerates their contribution to understanding the connection
between chemical structure and catalytic activity of the active center of the ribonuclease
June, I received an honorary doctor of science degree from the University of Oxford
for my research on catalytic antibodies. The studies indicate that antibodies can
be used as enzymes and are relevant for such conditions as atherosclerosis and Alzheimer's
I extend my
congratulations to my Skaggs Institute colleagues on another successful year, made
possible by the extraordinary generosity of the Skaggs family and the ALSAM/Skaggs
Institute for Research.