News and Publications
TSRI Scientific Report 2003
Richard A. Lerner, M.D.
Like many things in life, science is a serendipitous enterprise. Although
we conduct experiments according to well-prescribed methods, the surprises that
come to the diligent and the prepared are often those moments that yield the
most unexpected and exceptional insights. And so it is this year in the life
of The Scripps Research Institute that we find ourselves, somewhat serendipitously,
in collaborations with 2 unique partners in what will be truly exciting and profoundly
After months of discussions with Florida Governor Jeb Bush, TSRI recently began
negotiations that will lead to the establishment of a new Scripps research science
center in Palm Beach County, with an emphasis on biomedical research, advanced
technology, and drug discovery. I fully expect that the extension of TSRIs
activities in this new scientific arena will increase the scope and depth of
scientific inquiry in the biomedical sciences; the synergy between the 2 research
centers most likely will lead to major new developments to improve human health.
This enterprise is expected to serve as a stimulus to Floridas economic
development in biotechnology, because TSRI and other academic institutions have
been the engine driving the burgeoning biosciences industry in San Diego County.
Further, TSRI will be involved with the business community, the university system,
and school districts in the Palm Beach area.
We are particularly grateful to Governor Bush for his foresight, his confidence
in TSRI, and this unprecedented opportunity to play an important part in creating
and transforming the scientific landscape in South Florida. I have every hope
that this initiative will contribute not only to economic development, job creation,
and educational enrichment but also to the overall growth of biomedical knowledge.
In another development that simultaneously acknowledges the reputation of TSRI
in the international scientific community and elevates it to the next level,
TSRI and the University of Oxford Department of Biochemistry have announced the
establishment of a joint graduate program to train young doctoral candidates
at both acclaimed institutions. Named for supermarket and drugstore magnate L.S.
Skaggs and his wife Aline, the Skaggs Oxford Scholarships Program will support
the enrollment of 10 graduate students during the next 5 years. This collaboration
is the first time in Oxfords 800-year history that the university has offered
a degree jointly with another academic institution, and the new program is the
first such venture for TSRI. Indeed, it is a distinct honor to be associated
with Oxford University and to share a commonality in the pursuit of education
at the highest level for the chemical biologists of the future.
Changes in Board of Trustees
A change in board leadership in any organization is a double-edged sword. Although
the change brings with it the opportunity for new ideas, a new perspective, and
innovative thinking, it also acknowledges the closing of a chapter in the history
of an institution. And so it is that we welcome the Honorable Alice D. Sullivan,
a former Alameda County superior court judge, as chair of the TSRI Board of Trustees
and thank John Diekman, former chairman of the board of Affymetrix and Bay City
Capital, for his many years of extraordinary leadership. Judge Sullivan has served
with distinction as a member of our board for the past several years and for
the past decade has worked in private practice in the resolution of business
disputes, particularly in the life sciences and technology fields.
In addition, this year we welcomed the following new members to the Board of
Trustees: Rod Dammeyer, president of CAC, L.L.C., a private company offering
capital investment and management advisory services; Thomas Insley, former managing
partner of the San Diego office of PricewaterhouseCoopers L.L.P., and current
vice president and chief financial officer of SkinMedica, Inc., a privately held
health specialty pharmaceutical company; Richard J. Elkus, Jr., an executive
and entrepreneur whose career has been closely connected with the development
and evolution of Silicon Valley; Warren Beatty, Academy Award-winning film actor,
director, screenwriter, and producer; and Mervin Morris, founder of Mervyns
chain of retail stores.
Major Research Grants
TSRI continues to attract large-scale consortia grants from the National Institutes
of Health, an accomplishment that reflects its leadership position in numerous
fields of study in the biomedical sciences and its collaborative relationships
with centers of scientific excellence throughout the United States. Early in
2003, the National Institute of Allergy and Infectious Diseases awarded a multiyear,
$24 million grant to a group of researchers at TSRI, the Institute for Systems
Biology in Seattle, and Rockefeller University in New York City. The groups
charge is to create an encyclopedia of innate immunity, a comprehensive
picture of this ancient, essential first line of defense against bacterial and
fungal diseases that is mustered by all living creatures. The knowledge generated
could help scientists develop treatments for septic shock, certain autoimmune
disorders, and diseases caused by potential agents of bioterrorism.
Later in 2003, the National Institute of Allergy and Infectious Diseases awarded
a $9.2 million, multicenter program project grant to a team of scientists at
TSRI, Harvard Medical School, and the Salk Institute for Biological Studies to
discover and develop novel anthrax antitoxins and ways of delivering them. The
overall goal of the program is to design antianthrax nanosponges, antitoxin particles
that could be administered to someone who has been exposed to anthrax. In addition,
another government agency, the U.S. Centers for Disease Control and Prevention,
awarded a group of TSRI investigators a multiyear, $11.4 million grant to study
the interaction of the human immune system with toxins of the microorganism that
causes anthrax. The goal is to understand how these toxins suppress immune responses
in humans, circumventing the usual mechanisms by which the body would destroy
Significant Scientific Discoveries
As is the norm, TSRI researchers this year contributed a prodigious volume of
work to the body of scientific knowledge in a broad range of disciplines, work
that changes the way we think about biological mechanisms and the course of human
disease. The following merely skims the surface of knowledge they created and
the importance of their discoveries.
Work in the laboratory of Peter Schultz, professor of chemistry and Scripps Family
Chair of The Skaggs Institute for Chemical Biology, effectively removed a billion-year
constraint on the ability to manipulate the structure and function of proteins.
Dr. Schultz and his research group completed the synthesis of a form of the bacterium
Escherichia coli with a genetic code that uses 21 basic amino acid building blocks
to synthesize proteins, instead of the 20 found in Nature. This creation was
the first one of an autonomous organism that uses 21 amino acids and has the
metabolic machinery to build those amino acids. Further, the group introduced
revolutionary changes into the genetic code of organisms such as yeast that allow
the mass production of proteins with unnatural amino acids. By so doing, Dr.
Schultz and his team set the stage for an entirely new approach to applying the
same technology to other eukaryotic cells, and even to multicellular organisms.
Simply stated, these scientiests have opened up the whole pathway to higher organisms.
Researchers in the laboratory of Stephen Mayfield and in my laboratory used algae
to express an antibody that targets herpesvirus. The usefulness of the anitbody
lies not only in the potential production of an antiherpes topical cream or treatment
but also in the development of technology that could facilitate the production
of multiple human antibodies and other proteins on a massive scale. This technology
enables the generation of antibodies, soluble receptors, and other proteins so
much more cheaply than previous technology that an entire new class of therapeutic
agents may become available.
Jeffery Kelly and his colleagues in the Department of Chemistry and The Skaggs
Institute for Chemical Biology, discovered a new approach for treating amyloid
diseases, particularly transthyretin amyloid diseases, which are similar to Parkinsons
and Alzheimers diseases. Amyloid diseases are caused by misfolding of proteins
into a structure that leads the proteins to cluster, forming microscopic fibril
plaques that are deposited in internal organs and interfere with normal function.
Dr. Kelly and his team showed the efficacy of using small molecules to stabilize
the normal fold of transthyretin, preventing this protein from misfolding. By
so doing, they were able to inhibit the formation of fibrils by a mechanism that
can ameliorate disease.
In what was a first for biology, researchers in my laboratory, including Paul
Wentworth in collaboration with Bernard Babior, reported that the human body
makes ozone. Ozone appears to be produced in a process involving human immune
cells known as neutrophils and human antibodies. The presence of ozone in the
body may be linked to inflammation, and the reserach may have important ramifications
for treating inflammatory diseases. In addition to killing bacteria, the neutrophils
feed singlet oxygen to the antibodies, which convert it into ozone.
Carlos Barbas, Janet and W. Keith Kellogg II Chair in Molecular Biology, designed
a hybrid anticancer compound that combines the efficacy of a cancer cell-targeting
agent with the long-lasting dose of an antibody. This potent combination has
a profound effect on the size of tumors in animal models, shrinking both Kaposi
sarcomas and colon cancers in preclinical studies. The approach is general enough
to be used to design hybrids against numerous different cancers; a single antibody
can be mixed with multiple small molecules, resulting in a multiplicity of therapeutic
A group of researchers led by immunology professor Bruce Beutler discovered rare
genetic mutations in a subset of patients who have a severe form of sepsis, an
acute and often deadly disease. These mutations, in gene called Tlr4, predispose
persons to susceptibility to meningococcal sepsis, which strikes more than 2500
persons each year in the United States and has an overall fatality rate of 12%.
Besides indicating the increased risk of severe sepsis in patients with these
mutations, the results suggest that protection of patients at risk may be possible.
Eventually, persons with these mutations might be given prophylactic treatment,
for example, before undergoing surgery or traveling to a location where exposure
to meningococcal bacteria is likely.
Scientists led by Kim D. Janda, Ely Callaway, Jr., Chair in Chemistry and an
investigator in the Skaggs Institute, designed a new way to make a vaccine against
nicotine that could become a valuable tool for treating addiction by helping
the body clear the drug from the bloodstream. The vaccine, which eventually would
be given to persons in smoking cessation programs, greatly suppresses the reinforcing
aspect of nicotine. The researchers used an immunopharmacotherapy approach,
by designing a drug that stimulates the immune system to clear the nicotine from
In a related research study, Dr. Janda and his group discovered that a chemical
called nornicotine, a major metabolite of nicotine, modifies proteins that misfold
and form the fibril plaques found in abundance in the brains of patients who
have Alzheimers disease. Simply stated, this process physically inhibits
the formation of the fibrils. The research is promising--not because nornicotine
most likely would be an effective therapeutic agent, but because it shows how
a single molecule can cause a chemical interaction that may alter a mechanism
important in Alzheimers disease. This research could lead to the development
of small molecules similar to nornicotine that are not toxic but could interact
in a similar fashion, preventing the aggregation of amyloid-b protein and perhaps
A group of scientists including John Tainer, Lisa Craig, Mark Yeager, and Mike
Pique solved 2 key structures of a bacterial protein called pilin, which is required
for infection by pathogens that cause diseases such as meningitis, gonorrhea,
pneumonia, and cholera. The members of the group think that the research provides
essential knowledge to help scientists develop novel antibiotics and vaccines
against these deadly and emerging bacterial diseases. Because the structures
are too large and flexible to be solved by using the traditional techniques of
structural biology, the team used both x-ray crystallography and electron microscopy
to build a model of the pili that would have otherwise been impossible at that
level of molecular detail.
In another structural achievement, a multi-institutional group of researchers
led by Ian Wilson and Dennis Burton solved the structure of an antibody that
effectively neutralizes HIV, an important step toward the goal of designing an
effective vaccine against HIV and a new means by which scientists may design
antibodies in general. The structure of the antibody has never been seen before,
prompting the scientists to speculate on whether they can use this knowledge
to engineer antibodies with higher affinity against other antigens.
In a development that could improve the prospects for designing new ways to fight
malaria, a group of researchers led by Elizabeth Winzeler described a comprehensive
global profile of genes in the parasite that causes malaria, associating the
function of a few such known genes with the thousands that have no known function.
The researchers think that these data will accelerate our understanding of the
malaria parasite and its interaction with humans and should provide new avenues
for more effective drugs and vaccines. In collaboration with researchers at the
Genomics Institute of the Novartis Research Foundation, Dr. Winzeler created
a malaria-specific gene chip with probes specific for the entire genome of the
malaria parasite, enabling her to examine the expression of genes at each stage
of the parasites life cycle. This accomplishment should accelerate the
pace of research on the parasite by categorizing uncharacterized genes in functional
Using a new technique known as subtractive proteomics, Larry Gerace and John
Yates recently identified more than 50 previously unknown proteins, several of
which are associated with rare human muscle and nerve degenerative diseases.
Recognizing the proteins that may cause or contribute to diseases such as congenital
muscular dystrophy and spinal muscular dystrophy is a first step in the long
process of looking for ways to detect, prevent, or treat diseases. The study
may clarify a significant number of the more than 300 human dystrophies for which
a causative gene has not been identified. The researchers think understanding
how these diseases occur requires understanding more about the network of interlinked
Faculty Honors and Awards
Many TSRI scientists, at various stages of their careers, were honored by their
peers this year with awards for achievement in numerous areas of scientific endeavor.
Dale L. Boger and Bernard Babior were elected to membership in the American Association
for the Advancement of Science, Francis Chisari and Peter Vogt were elected to
the Institute of Medicine of the National Academies, and Michael B.A. Oldstone
won the Pioneer in NeuroVirology Award of the International Society for NeuroVirology.
Ernest Beutler was awarded the E. Donnall Thomas Lecture and Prize of the American
Society of Hematology, Tamas Bartfai received a Distinguished Investigator Award
from the National Alliance for Research on Schizophrenia and Depression, Eng
Tan was selected for the Japan Rheumatism Foundation/Wyeth Lederle Japan International
RA Award, and Ben Cravatt won the Eli Lilly Award in Biological Chemistry from
the American Chemical Society. Clare Waterman-Storer was awarded a Keith Porter
Fellowship of the Porter Endowment for Cell Biologyy and Erica Ollman Saphire
won the Burroughs Wellcome Fund Career Award in the Biomedical Sciences.
The events of this year have been nothing short of extraordinary, with profound
and far-reaching implications for the future of TSRI. In an organization that
often exceeds expectations on multiple levels and whose faculty and Staff remain
at the leading edge of science in an era in which the pace of discovery accelerates
on a continual basis, these new developments will provide greater impetus for
TSRI to play an even larger role on the international stage of scientific discovery.
I could not be more proud of our faculty, employees, trustees, donors, and friends,
all of whom make me grateful to have the opportunity to work with them every