Summer 2004

THE BURNHAM INSTITUTE

IN THIS ISSUE:

> Anti-obesity

> Genetic

drug inhibits prostate cancer growth

FROM RESEARCH,

research may improve heart function

> NIH-sponsored stem cell course held at Burnham

THE POWER TO CURE.

The Burnham Report SUMMER 2004

Vol. 2, No. 1

new treatments underway for prostate cancer.

Potential

Prostate cancer growth can be slowed by a commonly prescribed anti-obesity drug, according to recent work by Burnham Associate Professor Jeffrey Smith and his research team.

The investigators showed that the drug, orlistat (marketed by Roche as XENICAL™), inhibits prostate tumor growth in mice without any apparent side effects.

Welcome to the third issue of The Burnham Report. In this issue, you’ll read about the discovery that a commonly prescribed obesity drug may have efficacy against prostate cancer, a finding that opens the door to identifying new drugs with even more potency. You’ll learn about a growing research area at Burnham—investigations relevant to heart disease.Two of our newest faculty members round out our research team in this field.

The issue of stem cell research is heating up, as Californians prepare to vote this fall on an initiative to provide state funds to support research not eligible for federal funds under current guidelines.The Burnham Institute has come forward in support of this initiative. Inside you’ll also read about our involvement in one of only five NIH-sponsored courses in human embryonic stem cell biology, held recently at Burnham and co-sponsored by Children’s Hospital Orange County. All of us at The Burnham Institute are grateful for your interest and support of our research.

“This is a big advance in the sense that

Additional screening of breast cancer

we have an approved drug—approved

and colon cancer cells revealed that

for one indication—that has another

fatty acid synthase activity is highly

target and another potential disease

active in these tumors as well, indicat-

indication, prostate cancer,” says Smith.

ing they may also be susceptible to

Tumor cells require enormous

orlistat or a similar drug. Orlistat was

amounts of energy to fuel their unbri-

originally developed to inhibit an

dled growth and division. Orlistat

enzyme that processes fats in the

works to cut off this energy supply by

digestive tract, thereby preventing

disabling an enzyme that plays a key

absorption of dietary fat.

role in metabolism, the production of

The screening method developed

energy from food. Smith and his col-

and used by Smith in this study repre-

leagues developed a chemical screen

sents a quantum leap in drug discovery.

that showed that prostate cancer cells

It allows investigators to compile

have unusually high levels of the

a comprehensive profile of a drug or

enzyme fatty acid synthase, which con-

potential drug’s activities, revealing

verts dietary carbohydrate to fat. The

unintended functions. Smith now

same screen also identified orlistat’s

plans to work on synthesis and testing

ability to block the enzyme. The results

of derivatives of orlistat to increase

were published in the March 15th edi-

the effectiveness of the drug’s action

tion of the journal Cancer Research.

toward tumors.

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

President and CEO

Jeffrey Smith, Ph.D. Associate Professor, Cancer Center

The Burnham Report FROM RESEARCH,

THE POWER TO CURE.

THE DEL E. WEBB CENTER FOR NEUROSCIENCE AND AGING

“Young at heart”genes may mean longer lives.

A diminutive mutant fly with the

humans, raising the possibility of

embryonic stem cells to become car-

colorful name of Tinman is telling

therapeutically improving the function

diac muscle cells (cardiomyocytes). For

investigators how the heart ages.

of an aging heart.

instance, a dish of cultured embryonic

These flies contain a mutation that

Bodmer and Oldham hope that drugs or genetic therapies can be devised, based on their work, that will help to delay or treat heart failure in humans.

New faculty members,

cells will form heart muscle cells that

causes them to have no heart and

A G E - R E S I S TA N T G E N E S

beat in unison, much like the rhyth-

were discovered by Rolf Bodmer, a

Like Bodmer, Assistant Professor Sean

mic beating displayed by a functioning

professor who joined The Burnham

Oldham makes use of the excellent

heart. Their work indicates that it

Institute in fall 2003. A gene like

genetics available for the fruit fly,

should be possible to develop protocols

Tinman was later found in humans as

scientifically known as Drosophila, to

to induce stem cells to differentiate

well, and mutations in this and many

examine biological pathways that

into functioning cardiac cells.

other “heart-forming” genes with

impinge on heart development and

relatives in flies are associated with

function. Oldham is studying mutants

embryonic stem cells can be cultured

congenital heart diseases. Bodmer

in a biological pathway that includes

in the same dish with genuine cardiac

also identified mutant flies that possess

a gene called Tor, which is known to

muscle cells, and in fact, some will

hearts that age more or less quickly

regulate many aspects of growth but

“pair up” with the more mature cells

than normal. That is, some elderly

had not previously been implicated in

and take on heart-like appearance and

flies about five weeks old possess a

heart function.

function. Problems develop, however.

heart equivalent of a young fly, and

Bodmer and Oldham hope that

Cardiomyocytes derived from

The cells appear normal for a time,

vice versa. These results suggest that

drugs or genetic therapies can be

but then undergo hypertrophy, similar

it may be possible to “uncouple”

devised, based on their work, that will

to the enlarged heart cells seen in

heart disease from the aging process

help to delay or treat heart failure in

people with heart failure. In collabora-

and prolong the condition of a heart

humans. They join a team of Burnham

tion with Assistant Professor Vincent

through later life. “Flies do not actually

investigators whose work is relevant to

Chen, Mercola’s group is examining

have hearts like we do,” says Bodmer,

understanding and treating heart dis-

how the stem cells in these cultures

“but they do have a small organ that

ease. Assistant Professor Giovanni

are communicating with their mature

pumps essential fluid, comparable to

Paternostro also uses the fruit fly as a

cardiomyocyte neighbors. Cardiac cells

blood, through their bodies.” As with

model. In flies, just as in humans, aged

are “electrically coupled,” exchanging

Tinman many of the “young at heart”

hearts do not withstand stress as well as

signals that allow them to beat in

genes he studies are also found in

younger hearts. Paternostro has found

harmony. Mercola and Chen hope

mutant flies whose hearts appear

to develop methods to normalize

perennially robust and is working to

electrical activity in differentiated stem

identify the molecular mechanisms that

cells. Mercola’s laboratory is also

cause this resistance to aging.

collaborating with a team of chemists

Rolf Bodmer, Ph.D., and Sean Oldham, Ph.D., discuss mutations that affect heart function.

to develop candidate drugs to combat C U LT I V A T I N G C A R D I A C C E L L S

the hypertrophy and induce more

Professor Mark Mercola has identified

stem cells to become heart muscle.

a number of genes that guide initial

“We really have a broad-based

formation of the heart in developing

effort now in heart disease research,”

embryos. His laboratory is now

says Mercola. “It’s very exciting to

applying this knowledge to induce

see it grow.”

NEWS AND NOTES

> Professor Stuart Lipton received the 2004 Ernst Jung Prize for Medicine in recognition of his “trailblazing research in the field of neuroscience and its diagnostic and therapeutic consequences.” In a May 2004 ceremony in Hamburg, Germany, Lipton received 125,000 (approximately $140,000) from

the Jung Foundation for Science and Research. German industrialist Ernst Jung endowed this award in 1976 to recognize outstanding scientific discoveries that have had a major impact in experimental medicine. The prize has been awarded to 56 scientists since its founding.

> Several large federal grants have been awarded recently to Burnham investigators working in the area of infectious diseases.

Approximately $19 million in funding will support a multi-disciplinary team, headed by Professor Robert Liddington, in studies aimed at deciphering how virulence factors

cause cell death. Almost $10 million was awarded to support an effort, directed by Professor Alex Strongin, to design therapies for smallpox, and $1.5 million will fund a project, headed by Associate Professor Adam Godzik, to study the virus responsible for the emerging disease SARS.

BURNHAM

Burnham hosts an international workshop on stem cells.

Satellite view

Participants spent a good deal of their

Thirteen graduate students, postdoc-

time working “hands on,” learning

toral fellows and technicians served as

methods for culturing stem cells, as

instructors for the laboratories, and all

well as analyzing them and transplanting

of the Burnham faculty in the stem

Scientists from around the world

cells into laboratory animals. Many

cell program participated in the course.

converged recently at The Burnham

scientists think stem cells have the

Almost all of the equipment and

Institute to attend one of only five

potential to replace cells lost to disease

supplies was donated by companies;

courses on human embryonic stem

in conditions such as Alzheimer’s,

Invitrogen and Chemicon provided

cell biology sponsored by the National

diabetes and heart disease.

chemicals, NuAire and Brinkman lent

Institutes of Health. The course,

“There is a long way to go, how-

equipment, and Corning and VWR

co-sponsored by Children’s Hospital

ever, until we can reliably prompt stem

supplied tissue culture materials.

of Orange County and Burnham, was

cells to turn into the type of special-

Olympus Instruments made nearly

held during two weeks in April and

ized cells we want for any particular

$100,000 worth of sophisticated

offered participants an opportunity to

purpose,” says Jeanne Frances Loring,

microscopes available.

immerse themselves in the field.

Ph.D., a Burnham adjunct associate

Students traveled from within the

professor and course co-director. “The

that this is an extremely important

United States, as well as South Korea,

techniques for growing these cells and

area and generously contributed to

Singapore and India.

encouraging them to thrive are still

the course’s success,” says Snyder.

“We were busy from about eight

being worked out. The purpose of this

“The scientific vendors believe

“We’re training the pioneers in

each morning until almost ten in the

course was to expose investigators to

this field,” adds Loring, “and expect

evening for ten days,” says Evan Snyder,

the best techniques available, so they

our first group of students to make

M.D., Ph.D., a Burnham professor and

can go back to their home institutions

their own important advances in

course co-director. “It was intensive.”

and share what they’ve learned.”

stem cell biology.”

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 MARTIN MANN

Photography www.burnham.org

RESEARCH HIGHLIGHTS

Center Advisory Boards Further Research Mission.

Investigators in The Burnham Institute’s two major research centers— the Del E. Webb Center for

Neuroscience and Aging Council of

CANCER CENTER

Advisors, Executive Committee.

ADVISORY BOARD

Both these groups are composed

For more information on the Cancer Center Advisory Board, please contact: Mr. Chris Lee, 858.713.9932, chrislee@burnham.org

Linden Blue Mary Beth Burnham Judge Robert Coates Dani Grady Charlie Jones Robert Kyle Helen Eckmann, Ph.D.

Neuroscience and Aging and the

of people who share an enthusiasm

National Cancer Institute-designated

for scientific research and a dedication

Center—conduct research leading to

to supporting the centers through

significant improvements in the treat-

their leadership roles in the community.

ment and prevention of disease, includ-

Members act as “ambassadors,” help-

ing many types of cancer, neurological

ing to raise public awareness of the

DEL E. WEBB CENTER FOR

conditions such as Alzheimer’s and

exciting work being conducted in the

N E UR O S C I E N C E S A N D A G I N G

other disorders associated with aging.

centers and stimulating greater com-

C O UN C I L O F A D V I S O R S ,

They are supported in this effort

munity involvement and philanthropic

by two special groups of friends—

support. The Burnham Institute is

the Cancer Center Advisory Board

very grateful for their support.

Nonprofit Organization U.S. Postage PAID The Burnham Institute

and the Del E. Webb Center for

For more information on the Del E. Webb Center for Neuroscience and Aging Council of Advisors, Executive Committee, please contact: Ms. Judy Cottrell, 858.713.9913, cottrell@burnham.org

EXECUTIVE COMMITTEE

Howard and Toby Cohen Bill and Susan Evans Lowell and Julie Potiker Bernie and Carey Simkin Bobbi and Bill Warren

The Burnham Report

THE POWER T O C U R E. La Jolla, CA 92037

10901 North Torrey Pines Road

T H E B UR N H A M I N S T I T U T E

FROM RESEARCH,