THE BURNHAM INSTITUTE
IN THIS ISSUE:
> Anthrax treatment research
FROM RESEARCH,
> Infectious and Inflammatory Disease Center established
> Taking on tumors
THE POWER TO CURE.
The Burnham Report FALL 2004
Vol. 2, No. 2
Protecting against
biological threats.
New treatment avenues for anthrax were furthered in recent work led by Burnham Professor Robert C. Liddington. In a collaborative study published in the July 4 issue of the journal Nature, Liddington’s laboratory determined—at atomic resolution—how anthrax toxin attaches to one type of receptor in the body. The work may also aid the design of anthrax toxin as an anti-tumor agent.
It is a pleasure to bring you the current issue of The Burnham Report. In it, you’ll read about the establishment of our newest research center, the Infectious and Inflammatory Disease Center (IIDC). Our nation and our world face increasing threats from not only diseases such as arthritis and natural emerging pathogens including SARS and West Nile virus, but also from the threat of engineered agents of terror such as weaponized strains of anthrax or smallpox. Our cover story features a recent breakthrough in understanding of the anthrax toxin. We expect future investigations in the new IIDC will help lay the groundwork toward eliminating this and other threats to our health and security. Progress continues on the cancer front as well. Inside you’ll learn about recent work from Distinguished Professor Erkki Ruoslahti and his team that brings us a step closer to targeting therapies to breast cancer cells. I hope you enjoy reading about our latest research advances. On behalf of everyone at The Burnham Institute, thank you for your support. JOHN C. REED, M.D., PH.D.
President and CEO
Inhalation anthrax, unless diagnosed at
demonstrated by flooding cells with
a very early stage, is fatal—no current
“decoy” receptors that lure PA away
antidotes are effective once the bacte-
from those receptors on the cell surface
ria release toxin into the blood. Three
and prevent the toxin from penetrating.
proteins comprise the toxin: protec-
A second anthrax toxin receptor,
tive antigen (PA), lethal factor (LF),
called TEM8, is mainly found on the
and edema factor (EF). To gain entry
blood vessels that supply tumors with
into host cells, PA must recognize a
the oxygen and nutrients they need to
receptor molecule found on the cell’s
survive. Although the PA-TEM8 com-
surface. “Once attached to the cell
plex is yet to be solved, Liddington
surface,” says Liddington, “PA acts as a
expects the interaction to be similar to
molecular machine to deliver EF and
that of the PA-CMG2 complex. “We
LF into the cell.”
can exploit the differences to design PA
In the Nature study, investigators
PA
molecules that bind better to TEM8
determined the structure at the inter-
than to CMG2,” says Liddington,
face of PA and the receptor known
“which would minimize the side
as CMG2. This receptor is found in
effects of toxin binding to normal tis-
most organs of the body, so drugs that
sues.” Because so many tumors rely on
block PA from attaching to it should
blood vessels, such an agent could be
stop the spread of anthrax poisoning.
used to treat a wide variety of cancers,
The viability of this approach has been
including breast, prostate, and colon.
CMG2
Anthrax toxin enters cells by binding to a specific receptor.
The Burnham Report FROM RESEARCH,
THE POWER TO CURE.
INFECTIOUS AND INFLAMMATORY DISEASE CENTER
New Center
combats disease threats.
The Burnham Institute’s current research strengths,” says John C. Reed, President and CEO. Burnham investigators are leaders in research areas including cell adhesion, relevant to the mechanisms bacteria and viruses use to penetrate human cells; apoptosis and cell death, processes that constitute
On July 4, 2004, The Burnham
made clear the need for an understand-
part of the inflammatory response and
Institute established its newest and
ing of the molecular mechanisms
are manipulated by pathogens to both
third research center, the Infectious
of disease in order to counter threats
kill and resist the immune system;
and Inflammatory Disease Center.
created by terrorists seeking to
genomic instability, in which genetic
Investigators in this new center aim to
weaponize anthrax, smallpox, yersinia,
changes result in drug resistance; and
understand and, eventually, eliminate
SARS, and other biological agents
carbohydrate structures as recognition
the threats from diseases such as
against the United States.
elements for inflammatory cells.
naturally existing and engineered as
I M PA C T O F I N F L A M M A T O R Y
THE PROMISE OF
potential weapons of terror.
DISEASES
B I O I N F O R M AT I C S
The human body is home to
A wide variety of chronic inflammatory
Recent expansion of capabilities in
approximately 100 bacterial cells for
diseases have been linked to dysfunc-
merging mathematics and computer
every one human cell. “Yet, remark-
tional host responses to pathogens,
sciences with biology will allow an
ably little is known about the complex
including rheumatoid arthritis, which
approach to the field that emphasizes
interplay that occurs daily between the
affects more than 40 million Americans;
computational modeling of disease and
genomes of bacteria living in the body
inflammatory bowel diseases, affecting
biological pathways. A strong founda-
and our own genome,” says Professor
more than 55 million Americans; and
tion for exploring such an initiative
Robert Liddington, head of the
multiple sclerosis, a progressive neu-
emerges from work in bioinformatics.
Center’s Infectious Disease program.
rodegenerative disease. Researchers at
“Advances at the interface of biology
The field of host-pathogen interac-
The Burnham Institute are studying
and computer technology offer
tions is one of the bold new frontiers
the cells responsible for inflammatory
great promise to increase efficiency
for applying tools of genomics, pro-
disease and recently discovered a
and reduce costs of drug development,”
teomics, and bioinformatics towards
human gene variant that prompts cells
says Associate Professor Adam Godzik,
elucidating communication between
of the immune system to attack
leader of the Bioinformatics research
the genomes of microorganisms and
insulin-producing cells, causing type 1
program. This improving capability
mammalian genomes.
diabetes. This gene variant also predis-
allows experiments to be conducted
poses to rheumatoid arthritis and
virtually, or “in silico” on computers.
develop treatments for inflammatory
other inflammatory diseases. “These
Scientists in Burnham’s Infectious and
and infectious diseases is great. It is
diseases are extremely debilitating
Inflammatory Disease Center will take
currently estimated that within the
and are becoming increasingly com-
advantage of the tools of computational
next ten years, many antibiotics cur-
mon in our aging population,” says
biology to identify and validate new
rently employed for treating bacterial
Professor Tomas Mustelin, who directs
targets for drug discovery and
infections will no longer be effective
the new Inflammatory
vaccine development.
due to microbial resistance. Drug-
Diseases program.
arthritis and from pathogens, both
“The Burnham Institute is ideally positioned to occupy a unique niche in the study of infectious and inflammatory diseases.” JOHN C. REED, M.D., PH.D.
The need to understand and
resistant strains of pathogens, such as
“The study of infectious
the bacteria that cause tuberculosis,
and inflammatory diseases is
have already appeared. Deadly viral
highly synergistic with
agents are on the rise, threatening increasingly larger numbers of persons worldwide. Recent world events have From left to right: Associate Professor Adam Godzik, Professor Robert Liddington, and Professor Tomas Mustelin
CANCER CENTER
A two-pronged
attack on tumors. Molecular scalpels that can both detect and eliminate cancer cells are under development in the laboratory directed by Distinguished Professor and
Distinguished Professor and
President Emeritus Erkki Ruoslahti,
President Emeritus Erkki
M.D., Ph.D. A team of investigators
Simon, postdoctoral fellow
Ruoslahti and Nicola
headed by Ruoslahti recently showed
“We feel Ly-P-1 has
that a small protein called Ly-P-1 can
of lymph vessels in a tumor is an
of these vessels that distinguishes
excellent potential as the
find and kill breast tumor cells trans-
important determinant in the ability
them from normal lymph vessels. Not
planted into mice, findings published
of a tumor to metastasize.”
only does Ly-P-1 locate and attach
starting point of a new antitumor agent.” ERKKI RUOSLAHTI, M.D., PH.D.
to these vessels, it also destroys them,
in the June 22 issue of the journal
The lymphatic system is critical
Proceedings of the National Academy of
for normal circulation and physiology.
in addition to killing some of the
Sciences. Ruoslahti is a member of the
Its vessels serve as the major highway
tumor cells themselves. It does so in
Academy, a distinguished body of
network for transporting cells of the
isolated and cultured breast carcinoma
scientists founded in 1863 to advise
immune system to sites of infection;
tissue as well as in breast tumors
the federal government on scientific
swollen lymph nodes are a classic sign
transplanted into mice, indicating that
and technical matters.
of a brewing infection. Therefore,
Ly-P-1 has the important ability to
tampering with the system as a whole
find its target in the complex environ-
throughout the body, a process known
could have serious consequences. “We
ment of a living animal.
as metastasis, and much of this spread-
need highly selective agents such as
ing is accomplished by traveling
Ly-P-1 that find and destroy only the
potential as the starting point of a
through a system of branching vessels
lymph vessels being used by cancer
new antitumor agent,” says Ruoslahti.
called the lymphatic system. Like
cells,” explains Ruoslahti.
“We have previously targeted cancers
In many cases, cancer cells spread
blood vessels, lymphatic vessels extend
In earlier work, Ruoslahti’s group
“We feel Ly-P-1 has excellent
through the blood vessels. Now we
throughout the body. For this reason,
had shown that Ly-P-1 can distinguish
can mount a two-pronged attack on a
breast cancer that has migrated to
between normal lymph vessels
tumor through blood and lymphatic
lymph nodes is much more dangerous
and those recruited by certain breast
vessels. As blood vessels and lymphatics
than tumors that have remained as a
cancers. The current work shows
tend to exist in different regions of
single clump of cells. “Recent experi-
that Ly-P-1 destroys the lymph vessels
a tumor, we hope that this one-two
mental and clinical data strongly sug-
used by breast tumors. It does so by
punch will be more effective than
gest,” says Ruoslahti, “that the number
“reading” a code on the exterior walls
what has been available so far.”
B UR N H A M I N T H E N E W S
> Accelerating bench-to-bedside As reported early October in the San Diego Union-Tribune, The Burnham Institute received $18 million in NIH funds to establish a technology center for examination of cellular networks and pathways. The center will be considered a national resource as its mission is to develop and disseminate cutting-edge solutions to the entire research community. The new effort, directed by Associate Professor Jeffrey Smith, Ph.D., will focus on proteins that govern how cells die, differentiate, divide, and move about; aberrations in these fundamental processes underlie diseases ranging from cancer to neurodegenerative
conditions. The technology developed in the center will be of great benefit to the Institute’s Drug Discovery Initiative, which seeks to close the gap between discovery and application of new knowledge.
> Advances in understanding ulcers Professor Minoru Fukuda, Ph.D., and colleagues discovered the enzyme that protects most of us from developing ulcers and stomach cancer due to the bacterium Heliobacter pylori. Their work was covered by U.S. News & World Report, Forbes.com, and the BBC (British Broadcasting Corporation).
> Progress in stroke, neurodegenerative conditions Understanding why cells die and devising strategies for combating cell loss are important goals of Burnham investigators. In October, Nature magazine subsidiary Signaling Gateway reported findings from a study directed by Professors John Reed, M.D., Ph.D. and Stuart Lipton. Originally published in the journal Molecular Cell, the study showed that brain cell death caused by stroke injury is suppressed by a gene, called BI-1, originally isolated by Dr. Reed. The findings suggest a novel approach to protecting brain cells.
> Alzheimer’s contributions noted Professor Stuart Lipton, M.D., Ph.D., director of the Del E. Webb Center for Neuroscience and Aging, was profiled in June issues of the Rancho Santa Fe Review and the Alzheimer’s Association Newsletter. Lipton was a key contributor to memantine, the drug most recently approved by the FDA to treat Alzheimer’s.
THE BURNHAM REPORT JOHN C. REED, M.D., PH.D.
President and CEO KARIN EASTHAM
Executive Vice President and COO TERRY GACH
Vice President Resource Programs SUZANNE CLANCY, PH.D
Editor The Burnham Report LIPMAN HEARNE, INC.
Graphic Design BOB ROSS
Photography www.burnham.org RESEARCH SUPPORT
> Bioinformatics research at Burnham
Nonprofit Organization U.S. Postage PAID The Burnham Institute
received a boost thanks to generous donations by the Viterbi and Nierenberg families totaling $500,000. The funds will be used to establish the laboratories of new investigators who use computational methods based on mathematics and computer science to tackle complex problems in medical research. Andrew Viterbi, co-founder of the San Diego firm QUALCOMM and a Burnham Trustee since 1999, together with his wife, Erna, donated $250,000, a gift matched by Nico and Caroline Nierenberg. Nierenberg, founder and Chairman of the Board of San Francisco-based Actuate, joined the Institute’s Board of Trustees in 2002.
> Nearly $400,000 was raised to support cancer research at The Burnham Institute’s third annual gala, this year themed “Cirque de la Vie.” More than 350 guests enjoyed dinner and entertainment, including a silent auction and acrobatic performances by Cirque du Soleil, at the October 16 event.
> The Stem Cell Biology research program recently received a generous donation from Nu-Aire, Inc. of incubators and tissue culture hoods, initially loaned for an NIH-sponsored course in stem cell biology held at The Burnham Institute in April (see Summer 2004 Burnham Report). “This donation will allow us to proceed with experiments on stem cells for which we can’t use federal funds,” said Burnham Professor Evan Snyder, director of the research program in Stem Cells and Regeneration. The Institute is grateful to Minnesota-based Nu-Aire President Richard Peters and local representative Chris Conrad for supporting this donation.
In October, Snyder co-organized a special satellite session on stem cells during the annual meeting of the Society for Neuroscience, a gathering of approximately 20,000 scientists. Biotechnology firm Invitrogen generously underwrote the symposium, which was co-sponsored by neighboring institutions The Scripps Research Institute, Salk Institute, and University of California, San Diego.
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