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