News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 2001-2002
Julius Rebek, Jr., Ph.D.
Each year it is my pleasant duty to report the highlights of the scientific
accomplishments in The Skaggs Institute for Chemical Biology. The Institute was
established in 1996 by a remarkable gift from the Skaggs family. Their generosity
has enabled the recruitment of 31 members as principal investigators. More than
103 postdoctoral fellows and more than 62 graduate students received direct fellowship
support from the Skaggs Foundation last year. It is increasingly difficult to
choose between those research accomplishments that capture the thrill of discovery
in biology and the ingenuity of invention in chemistry. More than 300 publications
were generated by the researchers in the past year, but which of these accomplishments
will lead to cures for diseases-the ultimate mission of the Institute-will be
determined only in the future. For the present, I have selected only a few of
the discoveries of the principal investigators, our most valuable asset; the
details are available in the individual reports that follow.
The most prominent distinctions, and there were plenty of contenders, were
the awards of the Nobel Prizes in chemistry. Professor K. Barry Sharpless shared
the prize in 2001 for work in catalytic asymmetric synthesis, and Professor Kurt
Wüthrich, our most recently appointed investigator, shared the 2002 prize
for the determination of protein structures in solution. These prizes, the numerous
other awards, the elections to learned societies, and the endowed lectureships
brought a collective distinction to our faculty; our graduate program in organic
chemistry is now rated second in the United States by U.S. News & World
Report. This program is still a fledgling, little more than a dozen years
old, and we have every reason to believe that the resources made available by
the Skaggs Institute will maintain this widely acknowledged status in the years
Synthesis lies at the heart of organic chemistry, and the synthesis of natural
products drives the discoveries of chemical biology. The flow of synthetic molecules
from the team at TSRI-K.C. Nicolaou, chairman of the Department of Chemistry,
Dale Boger, Erik Sorensen, and Barry Sharpless-has resulted in some remarkably
active agents. During the past year, antibiotic agents targeting cancer were
the focus of research: duocarmycins that strike at cancerous DNA, designed agents
that inhibit growth of blood vessels to tumors, synthetic structures that stabilize microtubules reversibly, and synthetic
agents that target proteins and nucleic acids irreversibly. Modified epothilones
with reduced toxicity were synthesized, and an inhibitor of acetylcholinesterase
with unprecedented affinity was created by a process in which the enzyme itself
assembles the agent by selecting its components in the active site. The reagents "click" together
in the space provided by the enzyme.
The discovery by Richard Lerner and his colleagues that antibodies can destroy
antigens by chemical methods is a profound one and most likely will have its
greatest impact in future years. The finding speaks for the versatility of the
immune system and indicates that radical new departures can be found in basic
science. Current research is directed at identifying which of the activated forms
of oxygen, for example, ozone or the hydroxyl radical, is responsible for the
chemistry that protects the system from toxic agents.
A third discovery, which has deep significance for biology, emerged from
the work of Paul Schimmel and Peter Schultz. They have been manipulating the
genetic code with the aim of engineering organisms that use a 21st amino acid.
This research resulted in the discovery of a molecule that inhibits angiogenesis
and may also be able to target tumors. This discovery shows such promise that
a scientific consortium was able to obtain long-term support from the National
Institutes of Health to pursue the findings. Again, the Skaggs gift enables amplification
of future research.
Another recent development in Jeff Kelly's research group promises to bring
medicinal chemistry at TSRI one step closer to clinical trials. This project
involves the misfolding of proteins implicated in debilitating diseases such
as Alzheimer's disease and other amyloidoses. Dr. Kelly and his colleagues found
that a nonsteroidal, anti-inflammatory drug approved for other indications is
effective at preventing this misfolding. The drug is orally available, and the
results of human clinical studies have been so impressive that it, or a second-generation
analog, will be effective in a larger population of patients.
All of us in the Institute keep an inner eye on the mission: to relieve human
suffering by moving basic research to applications in medicine. We are grateful
for and relying on the continued support of The Skaggs Institute for Research.