Winter 2003

The Burnham Report

THE BURNHAM INSTITUTE

IN THIS ISSUE:

the pace of drug discovery

FROM RESEARCH,

FROM RESEARCH,

THE POWER

THE POWER

> Accelerating

> A new way to combat cancer, thanks to Burnham researchers

> Why brain cells die—and what that could mean for treating disease

> Announcing the President's Council

TO CURE.

TO CURE.

The Burnham Report WINTER 2003

Vol. 1, No. 1

GIVING OPPORTUNITIES

Announcing the President’s Council.

This pin is worn by people who share a passion for eliminating human suffering from disease.

THE PRESIDENT’S COUNCIL OF THE BURNHAM INSTITUTE

The Burnham Institute has established

$1000 or more to The Burnham

the President’s Council in recognition

Institute. At the annual President’s

of a simple fact: extraordinary generos-

Council reception, members will

ity makes for extraordinary science.

hear how their generosity supports

Private philanthropy is essential in the Institute’s progress, making possi-

mysteries of cells to improve human life.

President’s Council, you’ll ensure that The Burnham

researchers’ latest breakthroughs.

By joining the President’s Council,

ble new therapies and potential cures

you make a strong statement about

for cancer, stroke, heart disease,

the importance of The Burnham

Parkinson’s, Alzheimer’s and other

Institute’s mission—and can take

diseases. Private support ensures that

pride in knowing that you have

scientists have access to the latest tech-

played a role in the discovery of

nological advances, helps young scien-

tomorrow’s cures.

tists launch their careers, and nurtures

For more information about

pilot projects that forge new frontiers.

the President’s Council, please call

The President’s Council honors

Unlocking the

“By joining the

Institute will be at the vanguard of lifesaving treatments and diagnostic discoveries.”

JOHN C. REED, M.D., PH.D.

President and CEO, The Burnham Institute

858.713.6277.

donors who make annual gifts of

T H E B UR N H A M I N S T I T U T E 10901 North Torrey Pines Road La Jolla, CA 92037

A new trigger to brain cell death uncovered recently by Burnham Institute scientists may point

Nonprofit Organization U.S. Postage PAID The Burnham Institute

toward new treatments for conditions such as Alzheimer’s disease, multiple sclerosis and stroke.

WELCOME TO THE B UR N H A M R E P O R T It is a pleasure to welcome you to The Burnham Report, designed to bring you news of happenings at the Institute on a regular basis. The current issue describes several research programs with important implications for human health. You’ll read about advances ranging from an exciting new program to find cancer drugs to new developments in neuroscience, which may lead to treatments for Alzheimer’s disease, Parkinson’s and stroke.

We hope you enjoy reading about this work and the other Institute news you’ll find inside. We appreciate your support.

JOHN C. REED, MD., PH.D.

President and CEO

The trigger, a common gas known as

between cells that allow activities

nitric oxide, flips a switch on proteins

such as learning and memory forma-

called MMPs (for matrix metallopro-

tion to take place. MMPs are found

teinases) that are known to spark

outside brain cells, where they appear

nerve cell death.

to help maintain a proper environ-

“The new work uncovers the

ment for the cells. But evidence

mechanism of activation of an enzy-

suggests that excessive or mistimed

matic pathway that leads to nerve

activation of either system could

cell death,” says Professor Stuart A.

lead to wholesale destruction

Lipton, a practicing neurologist and

of nerve cells, resulting in a host

director of Burnham’s Center for

of neurological disorders.

Neuroscience and Aging Research.

Lipton and his colleagues hope

“Now that we know about this new pathway causing nerve cell

that learning more about nitric oxide,

death, we can design drugs to inter-

MMPs and the interactions between

rupt it,” says Lipton. He and his team

them will allow the development of

are starting to test potential drugs in

strategies to counteract their lethal

experimental models of stroke and

effects on brain cells.

neurodegenerative diseases.

Both nitric oxide and MMPs

“The work gives us a new way

are needed for normal functions in

to think about preventing excessive

the body. Nitric oxide plays a vital

activity of MMP enzymes and as

role in regulating blood pressure

such it could lead to new therapies

and, in the brain, carries messages

for a wide variety of brain disorders.”

Stuart A. Lipton, M.D., Ph.D. Director Del E. Webb Center for Neuroscience and Aging Research

The Burnham Report FROM RESEARCH,

NEWS AND NOTES

THE POWER

> Distinguished Professor Erkki Ruoslahti,

TO CURE.

has been elected to the Institute of Medicine of the National Academy of Sciences, an independent advisory organization to Congress and the government that exists “to advance and disseminate scientific knowledge to improve human health.” Ruoslahti is known internationally for his cancer research.

> In June, Professor John Reed, President and CEO, was presented with the Bill Otterson Cancer Fighter Award by Cancer Survivorship: San Diego, an umbrella organization of cancer survivors, hospitals, researchers and support organizations in San Diego County.

> Professor Evan Snyder, director of the Institute's program in Stem Cells and Regeneration, was interviewed by the San Francisco Chronicle in January. Learn about his vision for stem cell research by linking through the Burnham news site www.burnham.org/NewsAndInformation/ News.asp.

> To receive Burnham Institute news via email, please register at www.burnham.org/news_listserv/ emailsubscribe.asp

NEW CANCER CENTER INITIATIVE:

Focus on

drug discovery.

Since the Institute’s inception in 1976,

at their immediate bottom line,” says

“Retinoids, like hormones, work

its scientists have contributed to

Abraham. “But we can be much

by directing genes to turn on and

approximately ten potential new drugs

more flexible.”

off,” says Dawson. “And if you

for treatment of cancer, heart disease and Alzheimer’s. A newly launched

COMBINING BIOLOGY

effort, the Cancer Drug Discovery

WITH CHEMISTRY

The promise of cancer research.

In Professor Robert Abraham's laboratory,

Initiative, seeks to accelerate the drug

To help Burnham investigators find

the functions of cancer proteins, and

development process—perhaps by as

and validate new drug targets, the

chemists who generate compounds

much as tenfold.

Institute is seeking to expand its capa-

that interact with those protein targets.

“Investigators at Burnham have a

bilities in the area of chemistry.

Chemical compounds that bind to

Abraham’s own work identified the

collaboration,” says Professor Robert

disease-causing proteins represent the

target for a drug, Rapamycin, now in

Abraham, director of the Cancer

starting points for new drugs. Proteins

clinical trials for breast and prostate

Center. “They can mobilize to focus

are encoded by genes, and they repre-

cancers, lymphomas and brain tumors.

on new drug targets much more

sent the workhorses of our cells,

quickly than large pharmaceutical

carrying out functions that instruct

clinical trials include a drug that blocks

companies.”

cancer cells when to live or die, when

new blood supplies from reaching

to divide or rest. Burnham scientists

tumors, based on work in Professor

causes disease and can be altered or

have traditionally excelled in identify-

Erkki Ruoslahti’s laboratory. A novel

disabled by interacting with a drug.

ing those proteins in cancer cells that

DNA-based therapy based on the

For example, the AIDS drug AZT

cause their aberrant growth.

work of Professor John Reed, presi-

targets—disarms—a key viral enzyme called reverse transcriptase.

To validate proteins as potential

cancer cells.

Employing this approach,

great track record of multi-disciplinary

A drug target is a molecule that

investigators seek new means of killing

throughout the body, you’re going to cause problems. What we needed were selective retinoids that would affect small numbers of genes— particularly the ones involved in cancer—and leave other important genes alone.”

So Dawson and her colleagues set out to build just that. They broke

In the hands of Burnham Professor

class known as retinoids, which

and refashioned chemical bonds,

Marcia Dawson, molecules are care-

includes vitamin A and its set of

relocated “accessory” groups and

fully molded, their parts rearranged

chemical cousins. Retinoids have long

linked on stabilizing chemical “com-

and fine-tuned to her liking. And

been known to orchestrate many

panion” groups.

can mobilize to focus

at least one result of Dawson’s

physiological activities including

crafting is being applied to a critical

embryonic growth and development.

Bexarotene has been found to have

on new drug targets

purpose—combating cancer.

They have also been observed to

efficacy against one type of lym-

reverse signs of cancerous growth.

phoma. It is also showing promise in

Other treatments in advanced

dent and CEO of the Institute, is

manipulate large numbers of genes

“Investigators at Burnham

In 1999, the Food and Drug

much more quickly than

clinical trials for lung cancer, in

Administration approved a new drug,

large pharmaceutical

Thus far, the modified retinoid

TA R G E T E D T H E R A P I E S

combination with two chemotherapy

T cell lymphoma. Bexarotene, the

“It was known as early as 1925,” says

drugs, and in animal models of breast

drug’s generic name, was created by

Dawson, “that tissues from vitamin A-

cancer, when used in combination

Dawson and her colleagues, including

deficient animals often resembled tissues

with anti-estrogen therapy.

Targretin™,

drug targets, however, investigators

showing efficacy in trials for leukemia

need to isolate large quantities of pro-

and melanoma and breast, prostate,

entities excel at late stages of drug

teins in the lab and then find chemicals

colon and lung cancers.

development, moving drugs to market,

that affect their functions. If blocking

but they are slow to seek out new,

a protein from doing its job suppresses

to see one of our own discoveries lead

Associate Professor Xiao-Kun Zhang,

treated with carcinogens. Later studies

unproven targets. They are also reluc-

the cancerous properties of a cell,

to something that helps real people

by consistently modifying a series

showed that application of retinoids

chemistry, but I’ve also been interested

tant to take on diseases that afflict

then that may be a good target for a

with the disease,” Abraham says. “And

of chemicals in a process of molecular

could restore their normal appearance.”

in medicine for a long time,” says

only small numbers of people.

cancer therapeutic. This goal requires

I think we have a lot of untapped

sculpting.

a close working relationship between

potential at Burnham for moving

According to Abraham, commercial

“They’re obligated to be marketdriven and profit-oriented—to look

biologists who discover and delineate

companies.”

“It’s been tremendously satisfying

more findings toward the clinic.”

Professor Marcia Dawson and her colleagues use chemistry to optimize novel cancer-fighting agents.

IN REMEMBRANCE W A LT E R F I T C H ( 1 9 1 6 – 2 0 0 2 )

Walter Fitch III served on The Burnham Institute’s Board of Trustees from 1989 through 1997. During this time, and in the years that followed, Walter helped to lay the foundation for the Institute’s success. His involvement supported the Institute as it more than doubled in size,

as the Cancer Center gained national prominence, and as the Neuroscience and Aging Center was established.

Walter contributed resources and leadership that launched the careers of a number of young scientists, provided laboratory facilities and equipment and

helped to ensure the Institute’s future.

The naming of the Walter Fitch III Research Building recognizes the support of this outstanding individual. Walter will be greatly missed.

for treatment of cutaneous

The starting point for their venture was a compound in the general

But typical retinoids are too toxic to be used for treating most cancers in humans.

“I have always been fascinated by

Dawson. “It’s exciting to see them come together.”

The Burnham Report FROM RESEARCH,

NEWS AND NOTES

THE POWER

> Distinguished Professor Erkki Ruoslahti,

TO CURE.

has been elected to the Institute of Medicine of the National Academy of Sciences, an independent advisory organization to Congress and the government that exists “to advance and disseminate scientific knowledge to improve human health.” Ruoslahti is known internationally for his cancer research.

> In June, Professor John Reed, President and CEO, was presented with the Bill Otterson Cancer Fighter Award by Cancer Survivorship: San Diego, an umbrella organization of cancer survivors, hospitals, researchers and support organizations in San Diego County.

> Professor Evan Snyder, director of the Institute's program in Stem Cells and Regeneration, was interviewed by the San Francisco Chronicle in January. Learn about his vision for stem cell research by linking through the Burnham news site www.burnham.org/NewsAndInformation/ News.asp.

> To receive Burnham Institute news via email, please register at www.burnham.org/news_listserv/ emailsubscribe.asp

NEW CANCER CENTER INITIATIVE:

Focus on

drug discovery.

Since the Institute’s inception in 1976,

at their immediate bottom line,” says

“Retinoids, like hormones, work

its scientists have contributed to

Abraham. “But we can be much

by directing genes to turn on and

approximately ten potential new drugs

more flexible.”

off,” says Dawson. “And if you

for treatment of cancer, heart disease and Alzheimer’s. A newly launched

COMBINING BIOLOGY

effort, the Cancer Drug Discovery

WITH CHEMISTRY

The promise of cancer research.

In Professor Robert Abraham's laboratory,

Initiative, seeks to accelerate the drug

To help Burnham investigators find

the functions of cancer proteins, and

development process—perhaps by as

and validate new drug targets, the

chemists who generate compounds

much as tenfold.

Institute is seeking to expand its capa-

that interact with those protein targets.

“Investigators at Burnham have a

bilities in the area of chemistry.

Chemical compounds that bind to

Abraham’s own work identified the

collaboration,” says Professor Robert

disease-causing proteins represent the

target for a drug, Rapamycin, now in

Abraham, director of the Cancer

starting points for new drugs. Proteins

clinical trials for breast and prostate

Center. “They can mobilize to focus

are encoded by genes, and they repre-

cancers, lymphomas and brain tumors.

on new drug targets much more

sent the workhorses of our cells,

quickly than large pharmaceutical

carrying out functions that instruct

clinical trials include a drug that blocks

companies.”

cancer cells when to live or die, when

new blood supplies from reaching

to divide or rest. Burnham scientists

tumors, based on work in Professor

causes disease and can be altered or

have traditionally excelled in identify-

Erkki Ruoslahti’s laboratory. A novel

disabled by interacting with a drug.

ing those proteins in cancer cells that

DNA-based therapy based on the

For example, the AIDS drug AZT

cause their aberrant growth.

work of Professor John Reed, presi-

targets—disarms—a key viral enzyme called reverse transcriptase.

To validate proteins as potential

cancer cells.

Employing this approach,

great track record of multi-disciplinary

A drug target is a molecule that

investigators seek new means of killing

throughout the body, you’re going to cause problems. What we needed were selective retinoids that would affect small numbers of genes— particularly the ones involved in cancer—and leave other important genes alone.”

So Dawson and her colleagues set out to build just that. They broke

In the hands of Burnham Professor

class known as retinoids, which

and refashioned chemical bonds,

Marcia Dawson, molecules are care-

includes vitamin A and its set of

relocated “accessory” groups and

fully molded, their parts rearranged

chemical cousins. Retinoids have long

linked on stabilizing chemical “com-

and fine-tuned to her liking. And

been known to orchestrate many

panion” groups.

can mobilize to focus

at least one result of Dawson’s

physiological activities including

crafting is being applied to a critical

embryonic growth and development.

Bexarotene has been found to have

on new drug targets

purpose—combating cancer.

They have also been observed to

efficacy against one type of lym-

reverse signs of cancerous growth.

phoma. It is also showing promise in

Other treatments in advanced

dent and CEO of the Institute, is

manipulate large numbers of genes

“Investigators at Burnham

In 1999, the Food and Drug

much more quickly than

clinical trials for lung cancer, in

Administration approved a new drug,

large pharmaceutical

Thus far, the modified retinoid

TA R G E T E D T H E R A P I E S

combination with two chemotherapy

T cell lymphoma. Bexarotene, the

“It was known as early as 1925,” says

drugs, and in animal models of breast

drug’s generic name, was created by

Dawson, “that tissues from vitamin A-

cancer, when used in combination

Dawson and her colleagues, including

deficient animals often resembled tissues

with anti-estrogen therapy.

Targretin™,

drug targets, however, investigators

showing efficacy in trials for leukemia

need to isolate large quantities of pro-

and melanoma and breast, prostate,

entities excel at late stages of drug

teins in the lab and then find chemicals

colon and lung cancers.

development, moving drugs to market,

that affect their functions. If blocking

but they are slow to seek out new,

a protein from doing its job suppresses

to see one of our own discoveries lead

Associate Professor Xiao-Kun Zhang,

treated with carcinogens. Later studies

unproven targets. They are also reluc-

the cancerous properties of a cell,

to something that helps real people

by consistently modifying a series

showed that application of retinoids

chemistry, but I’ve also been interested

tant to take on diseases that afflict

then that may be a good target for a

with the disease,” Abraham says. “And

of chemicals in a process of molecular

could restore their normal appearance.”

in medicine for a long time,” says

only small numbers of people.

cancer therapeutic. This goal requires

I think we have a lot of untapped

sculpting.

a close working relationship between

potential at Burnham for moving

According to Abraham, commercial

“They’re obligated to be marketdriven and profit-oriented—to look

biologists who discover and delineate

companies.”

“It’s been tremendously satisfying

more findings toward the clinic.”

Professor Marcia Dawson and her colleagues use chemistry to optimize novel cancer-fighting agents.

IN REMEMBRANCE W A LT E R F I T C H ( 1 9 1 6 – 2 0 0 2 )

Walter Fitch III served on The Burnham Institute’s Board of Trustees from 1989 through 1997. During this time, and in the years that followed, Walter helped to lay the foundation for the Institute’s success. His involvement supported the Institute as it more than doubled in size,

as the Cancer Center gained national prominence, and as the Neuroscience and Aging Center was established.

Walter contributed resources and leadership that launched the careers of a number of young scientists, provided laboratory facilities and equipment and

helped to ensure the Institute’s future.

The naming of the Walter Fitch III Research Building recognizes the support of this outstanding individual. Walter will be greatly missed.

for treatment of cutaneous

The starting point for their venture was a compound in the general

But typical retinoids are too toxic to be used for treating most cancers in humans.

“I have always been fascinated by

Dawson. “It’s exciting to see them come together.”

The Burnham Report

THE BURNHAM INSTITUTE

IN THIS ISSUE:

the pace of drug discovery

FROM RESEARCH,

FROM RESEARCH,

THE POWER

THE POWER

> Accelerating

> A new way to combat cancer, thanks to Burnham researchers

> Why brain cells die—and what that could mean for treating disease

> Announcing the President's Council

TO CURE.

TO CURE.

The Burnham Report WINTER 2003

Vol. 1, No. 1

GIVING OPPORTUNITIES

Announcing the President’s Council.

This pin is worn by people who share a passion for eliminating human suffering from disease.

THE PRESIDENT’S COUNCIL OF THE BURNHAM INSTITUTE

The Burnham Institute has established

$1000 or more to The Burnham

the President’s Council in recognition

Institute. At the annual President’s

of a simple fact: extraordinary generos-

Council reception, members will

ity makes for extraordinary science.

hear how their generosity supports

Private philanthropy is essential in the Institute’s progress, making possi-

mysteries of cells to improve human life.

President’s Council, you’ll ensure that The Burnham

researchers’ latest breakthroughs.

By joining the President’s Council,

ble new therapies and potential cures

you make a strong statement about

for cancer, stroke, heart disease,

the importance of The Burnham

Parkinson’s, Alzheimer’s and other

Institute’s mission—and can take

diseases. Private support ensures that

pride in knowing that you have

scientists have access to the latest tech-

played a role in the discovery of

nological advances, helps young scien-

tomorrow’s cures.

tists launch their careers, and nurtures

For more information about

pilot projects that forge new frontiers.

the President’s Council, please call

The President’s Council honors

Unlocking the

“By joining the

Institute will be at the vanguard of lifesaving treatments and diagnostic discoveries.”

JOHN C. REED, M.D., PH.D.

President and CEO, The Burnham Institute

858.713.6277.

donors who make annual gifts of

T H E B UR N H A M I N S T I T U T E 10901 North Torrey Pines Road La Jolla, CA 92037

A new trigger to brain cell death uncovered recently by Burnham Institute scientists may point

Nonprofit Organization U.S. Postage PAID The Burnham Institute

toward new treatments for conditions such as Alzheimer’s disease, multiple sclerosis and stroke.

WELCOME TO THE B UR N H A M R E P O R T It is a pleasure to welcome you to The Burnham Report, designed to bring you news of happenings at the Institute on a regular basis. The current issue describes several research programs with important implications for human health. You’ll read about advances ranging from an exciting new program to find cancer drugs to new developments in neuroscience, which may lead to treatments for Alzheimer’s disease, Parkinson’s and stroke.

We hope you enjoy reading about this work and the other Institute news you’ll find inside. We appreciate your support.

JOHN C. REED, MD., PH.D.

President and CEO

The trigger, a common gas known as

between cells that allow activities

nitric oxide, flips a switch on proteins

such as learning and memory forma-

called MMPs (for matrix metallopro-

tion to take place. MMPs are found

teinases) that are known to spark

outside brain cells, where they appear

nerve cell death.

to help maintain a proper environ-

“The new work uncovers the

ment for the cells. But evidence

mechanism of activation of an enzy-

suggests that excessive or mistimed

matic pathway that leads to nerve

activation of either system could

cell death,” says Professor Stuart A.

lead to wholesale destruction

Lipton, a practicing neurologist and

of nerve cells, resulting in a host

director of Burnham’s Center for

of neurological disorders.

Neuroscience and Aging Research.

Lipton and his colleagues hope

“Now that we know about this new pathway causing nerve cell

that learning more about nitric oxide,

death, we can design drugs to inter-

MMPs and the interactions between

rupt it,” says Lipton. He and his team

them will allow the development of

are starting to test potential drugs in

strategies to counteract their lethal

experimental models of stroke and

effects on brain cells.

neurodegenerative diseases.

Both nitric oxide and MMPs

“The work gives us a new way

are needed for normal functions in

to think about preventing excessive

the body. Nitric oxide plays a vital

activity of MMP enzymes and as

role in regulating blood pressure

such it could lead to new therapies

and, in the brain, carries messages

for a wide variety of brain disorders.”

Stuart A. Lipton, M.D., Ph.D. Director Del E. Webb Center for Neuroscience and Aging Research