Fall 2004

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.

The Burnham Report

FROM RESEARCH,

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