SCRIPPS DISCOVERS
Ac cel e ra tin g D is co ve r i es , S a v i ng L ive s
A Newsletter for Philanthropists Published Quarterly by The Scripps Research Institute
SPRING 2010
|
VOL 6
|
NO 2
California-Florida
I N S T I T U T E U P D AT E
Business Executive and Former U.S. House Leader
Richard A. Gephardt Elected to Lead Scripps Research
Board of Trustees
Richard A. Gephardt
The Scripps Research Institute’s Board of
Trustees has unanimously elected Richard A.
Gephardt, president and CEO of Gephardt
Government Affairs and a former U.S.
Congressman and House Majority and
Minority Leader, as its new Lead Trustee.
Mr. Gephardt served for 28 years in the
United States House of Representatives from
1976 to 2004, representing Missouri’s 3rd
Congressional District, home of his birthplace,
St. Louis. In his role as House Leader, Mr.
Gephardt emerged as one of the leading
strategists of the Democratic Party’s platform
and chief architect of landmark reforms
ranging from healthcare, pensions, and
education, to energy independence and trade
policy. He served as elected House Democratic
Leader for more than 14 years, acting as
House Majority Leader from 1989 to 1995
and Minority Leader from 1995 to 2003.
Inside:
3
4
6
7
7
. . . Scientists Make Advance
Against Melanoma
. . . Fish Story
. . . Scientist Receives Award for Potential
Breast Cancer, Cardiovascular
Disease Treatments
. . . Ding Breakthrough Named Top
Innovation of 2009
. . . Xio Receives Grant for Groundbreaking
Work in Lymphoma
BACK COVER:
As president and CEO of Gephardt
Government Affairs, he provides strategic
advice and direct advocacy services to clients
on issues before the House, Senate, and
Executive Branch in the federal government.
Mr. Gephardt has brought successful
resolution for clients on issues related to
negotiations, crisis management, and strategic
communications. He enjoys strong bipartisan
relationships in the House of Representatives,
serves as a trusted advisor to senior officials
in the Administration and on Capitol Hill,
and has counseled numerous CEOs during
negotiations with labor. He also serves as
public spokesperson for clients on coalitions to
bring about policy solutions to healthcare
reform and climate change.
“The Institute is both honored and
enthusiastic to have Dick as our new Lead
continued on page 2
Businesswoman and Community Leader
Katherine Kennedy to Lead
Scripps Research Institute Council
San Diego businesswoman and community leader Katherine Kennedy, founder
and president of Relocation Coordinates, has been named chair of the newly formed
Scripps Research California Council to heighten awareness of Scripps Research in
the community and to help expand support for the renowned institute.
As chair, she will help to recruit and lead a group of prominent individuals from
various business, nonprofit, and government sectors to assist the biomedical research
Partners, Contact Us
continued on page 2
Richard A. Gephardt,
CONTINUED
Trustee,” said Scripps Research President
Richard A. Lerner, M.D. “His immense
experience as a national and international
leader and his vast knowledge of the
nation’s most pressing issues, coupled
with his skill and energy as a business
executive, will contribute invaluably to
our Board.”
Mr. Gephardt stated: “I am honored
by this opportunity to lead the Scripps
Research Institute Board of Trustees.
Recognized as one of our nation's
largest and well-respected, private,
non-profit research institutes, Scripps
Research has long played a pivotal role
in ensuring America’s competitiveness
globally in medical research. I look
forward to working with the Board’s
Katherine Kennedy,
talented members to continue Scripps
Research’s excellent record of
contributions to medical innovation.”
Widely known for his advocacy for
international human rights, Mr. Gephardt
currently serves as Chairman of the
National Endowment for Democracy,
a private, nonprofit organization that
endeavors to strengthen democratic
institutions around the world through
nongovernmental efforts. He is a member
of The Council on Foreign Relations and
an Advisory Board member to the
International Conservation Caucus
Foundation. He also serves as Advisory
Board chairman at the Richard A.
Gephardt Institute for Public Service at
Washington University in St. Louis. The
Library and Research Center of the
CONTINUED
facility in La Jolla in increasing philanthropic support for its
breakthrough science throughout the state and nation.
“It is crucial that people from our community be introduced
to the science and the innovators at The Scripps Research
Institute,” Kennedy said on accepting the volunteer position.
“Here, in a stunning setting, is a jewel that has
long been contributing to our health and life
enhancement through its discoveries. Now is the
time to shine a very bright and well-deserved
spotlight on The Scripps Research Institute to
increase awareness, recognition, and philanthropy.
She continued, “The California Council has this as its
mission: drawing people to Scripps Research who, when
introduced, are awed by the work and who feel compelled to
promote that work to others.”
“I was delighted when Katherine agreed to lead the
Council,” said Scripps Research President Richard A. Lerner.
“The institution will benefit greatly from her vision and
leadership. Scientific research is expensive and federal funds
so restrictive that we rely on philanthropy to fund our
forward-looking science. Katherine will open doors, make
a strong case to donors, and lend great enthusiasm and
energy to our efforts.”
2 | SCRIPPS DISCOVERS
Missouri History Museum in St. Louis
recently opened The Richard A. Gephardt
Collection to represent his life and
career in Congress.
Born in St. Louis, Missouri, in 1941,
Mr. Gephardt earned a Bachelor of
Science degree from Northwestern
University in 1962 and juris doctorate
from the University of Michigan Law
School in 1965. He has been married to
his wife, Jane, for 38 years and they have
three children, Matt, Chrissy, and Kate.
Mr. Gephardt, who was recently
elected to the Board of Trustees, succeeds
businessman and philanthropist John
J. Moores, who became Lead Trustee in
2006 and who remains on the Scripps
Research board.
SPRING 2010
The Scripps Research
California Council has been
formed to attract volunteer
leaders who will bring valuable
networks of friends and a broad
range of expertise to help
Scripps Research to accelerate
and enhance its results.
“By serving as ambassadors
and advocates for Scripps
Research in various business
and social communities,
Katherine Kennedy
Council members will extend
the reach of staff and members
of our Board of Trustees,” said Wendy Keeney, the institute’s
vice president of philanthropy. “Central to the mission of the
Council is to introduce Scripps Research to people interested
in advancing biomedical research, and to get them involved
in supporting the scientific efforts under way on both our
California and Florida campuses.”
Katherine Kennedy, a graduate of San Diego State
University and former professional opera singer, is founder,
president, and CEO of Relocation Coordinates, a world-class
company with 27 years experience handling domestic and
international relocations for corporations of all sizes. She is
also co-founder and chair of Relocation Information Systems,
a web-based, proprietary, customizable software application
continued on page 5
R E S E A R C H U P D AT E
Scientists Make Advance Against Melanoma
> A team of researchers at The Scripps Research Institute and the Genomics Institute of the Novartis
Research Foundation (GNF) has identified a potential new drug target for malignant melanoma, a deadly
type of skin cancer that kills thousands of people in the United States every year.
his new target is a protein called TYRO3, and its
discovery may lead to new treatments for melanoma.
In a recent issue of the journal Proceedings of the
National Academy of Sciences, the scientists described how the
gene works and show how blocking it affects cancer cells.
“Knocking down this gene [altering it to decrease its
expression] inhibits tumor formation in mice,” explains the
paper’s first author Shoutian Zhu, who conducted the
research with Heiko Wurdak, and their colleagues at Scripps
Research and GNF. The work was led by Peter G. Schultz,
who is the Scripps Family Chair Professor of Chemistry
and director of GNF, and Xu Wu, adjunct assistant professor
at Scripps Research and associate director of biological
chemistry at GNF.
T
Melanoma is by far the most serious type of
skin cancer, accounting for some 75 percent of
all skin-cancer-related deaths. According to
the National Institutes of Health, its occurrence
rate has doubled in the last 30 years.
When diagnosed early, melanoma is very treatable
through routine surgery. Some 80 percent of people whose
melanoma is detected early can be successfully treated by
surgical resection. If the disease progresses undetected,
however, cancerous cells can metastasize and migrate
elsewhere in the body, making the disease harder to address
surgically — especially since melanoma often resists standard
chemotherapy treatments. The five-year survival rate for
people first diagnosed with later-stage melanoma is only
16 percent.
Hoping to find a new way to combat malignant
melanoma, the Scripps Research and GNF team focused on
a protein called MITF, which is a “master regulator” that
controls many different genes necessary for melanoma cell
growth and survival.
MITF has been linked to melanoma in studies of cancer
tissues that have shown it is often found at higher-thannormal concentrations in melanoma cells. Similar studies in
other laboratories have also shown that MITF can help
cancer cells to survive longer and to resist chemotherapy.
However, targeting MITF itself is not feasible, due to the
fact that it is a transcription factor whose function cannot
easily be modulated by drugs.
Aware of this problem, the
scientists at Scripps Research
and GNF went searching for
“druggable” proteins that act
as regulators of MITF itself
— but only in melanoma
cells. The scientists reasoned
that if they could identify
such a protein, they might
have found a potential new
way to fight the cancer.
The researchers screened
Professor Peter Schultz
thousands of genes and
identified 15 candidates that
regulated MITF. When these were subjected to expression
profiling among different types of cells, one gene — called
TYRO3 – showed higher levels in melanoma cells.
Through expression analysis of tissue samples taken from
43 patients with melanoma, the researchers found that the
expression levels of TYRO3 are higher than normal skin tissues
in more than half of the samples tested.
That’s how the researchers identified the potential new
drug target, and could then go on to design experiments to
see what would happen if they reduced the levels of TYRO3
in melanoma cells.
The team found that knocking down the gene’s
expression inhibited the growth of cancer cells in
culture dishes. They also observed that knocking
down TYRO3 prevented the formation of the
tumors in mice with one of the most aggressive
types of melanomas.
Since TYRO3 is a kinase (enzyme that regulates cell
signaling) expressed on the cell surface, the next step, the
researchers say, is to identify compounds or antibodies that
inhibit the action of TYRO3 and to use these compounds or
antibodies as starting points for designing new drugs. Different
types of melanoma have different TYRO3 expression levels,
and it is possible that targeting this protein would be more
effective at combating some types of cancer than others.
continued on page 7
SCRIPPS RESEARCH INSTITUTE
| 3
SCIENTIST PROFILE
Shuji Kishi: Fish Story
> Shuji Kishi, an assistant professor in Scripps Florida’s Department of Metabolism and Aging, brought
approximately 2,500 zebrafish with him (which he expects to eventually grow to more than 30,000
specimens) when he made the move from Harvard Medical School in the spring of last year.
t Harvard, Kishi’s research was aimed at developing
the zebrafish as a model for the study of aging and
age-associated diseases. Zebrafish (Danio rerio)
offer a number of advantages for the study of developmental
biology, not to mention Kishi’s own field of aging.
“Zebrafish embryos are perfect for small molecule
screening for different drug targets in vivo,” he said, “and
their use will help expand our overall understanding of the
physiology of aging as well as early development. With them,
we hope to identify compounds that will protect cells against
oxidative damage, a major issue in aging and an essential risk
factor of many geriatric diseases.”
Over the past decade or so, zebrafish have emerged as a
powerful model system to study the mechanisms underlying
disease, as well as developmental dynamics – and a workable
alternative to the ubiquitous mouse model.
Kishi saw potential in the zebrafish back in the 1990s
when he was working as a research scientist for the Japanese
conglomerate JT Inc. At the time, he had just graduated
from Wakayama University Medical School and was still
working on his doctorate in immunology.
For the company, Kishi was working on chemical
compound screening for the induction or inhibition of
apoptosis—programmed cell death, which has been implicated
in a number of diseases, such as neurodegenerative disease
and cancer.
“I tried to develop zebrafish embryos for our drug
screening efforts,” he said, “but unfortunately the company
really wasn’t interested. That was the start of my thinking
that I wanted to do different kinds of science and research
than what was offered there.”
So, Kishi headed to New York City.
“I was interested in the research environment in the U.S.,”
he said. “I think that many scientists in Japan, South Korea,
and China are often eager to learn about science in the U.S.
because the country has a strong history and background of
doing basic research very well.”
He finished his doctorate in Japan and traveled first to
The Rockefeller University and then to Harvard.
“It was a big gamble,” he said. “The company didn’t want
me to come, so I quit my job and came anyway. I was at
Rockefeller as a guest investigator, but the professor I was
working with left to go back to Japan after only half a year –
which I didn’t want to do. So, I applied as a postdoc with
A
4 | SCRIPPS DISCOVERS
SPRING 2010
another professor. He had just started his own lab at Harvard
Medical School and I joined him.”
It was at Harvard that Kishi got into zebrafish in a
major way.
Zebrafish have been called a nearly perfect model for
vertebrate development because they combine the best
features of all the others – they reproduce like crazy, they can
be genetically manipulated to produce a wide range of
mutations, and their embryos are originally transparent ex
utero (as adults, they typically have stripes like a zebra, with
a line that is transparent throughout life). Moreover, about
90 percent of the genome is conserved between fish and
humans, so they’re remarkably similar to us except that, well,
they’re fish.
“Of course, they have gills instead of lungs and
they have no prostate,” Kishi said, “but they
basically have what we have. It might be difficult
to study lung or prostate cancer but otherwise we
can basically do everything else – the vasculature,
the brain, even the eye structure is the same
as ours.”
As a result of this remarkable (and slightly creepy) similarity,
a number of zebrafish mutants have been produced that are
good models of human diseases, including heart disease, cancer,
and Alzheimer’s – which are all related to aging.
While at Harvard, Kishi worked in the Schepens Eye
Research Institute but that limited his research to one
particular organ.
“The eye is important in aging, for example, with agerelated macular degeneration,” Kishi said. “Actually one of
my fish mutants has a very similar phenotype. But my
research interests are much broader, so being limited to eye
research was difficult.”
Those broader interests eventually led Kishi to Scripps
Florida and the Department of Metabolism and Aging.
He explained it this way: “I moved here because it was much
better for my science. In addition, it’s better for my life.
I love the warm weather and beautiful beach where we can
swim almost anytime.”
“Scripps Florida has the top high-throughput screening
technology in the U.S.,” he continued, "plus the best
chemistry department, and it’s all in one place. At Harvard
there were a lot of different institutes, which had different
areas of expertise but spread out, so I was always jumping
around inefficiently. For instance, we did not have any
high-throughput infrastructure in-house there. But here,
with everything in-house, it’s easy to expand your research.
Of course we don’t have fish people here. At Harvard there
were a lot of fish people.”
So far, Kishi is the only fish person at Scripps Research
on both the Florida and California campuses, but that may
change. For now, he can rely on his family for company.
“Oh, yes,” he said, “my wife knows my fish. Even my kids
know how to take care of the fish. They help me out
with them.”
In the meantime, Kishi is definitely interested in
collaborative possibilities, particularly with Roy Smith, the
head of his department, whose work with ghrelin, a hormone
implicated in aging, dovetails with Kishi’s interests. “Roy
has a very strong background in endocrinology and drug
discovery, to which I would apply my fish aging models and
chemical-genetic approaches,” he said.
Right now, Kishi is focused on the phenomenon of
neurodegeneration in zebrafish. Zebrafish have good
memories—they can memorize different colors, for example
—but just like people, their cognitive memory ability
declines with age.
This is all part of the relationship between stress and
aging, Kishi said.
“With our fish mutant studies, we can combine genetic
Katherine Kennedy,
factors and environmental factors to mimic the human
condition,” he said. “We can expose them to hydrogen
peroxide, gamma irradiation, UV light, and things like colder
or warmer temperatures. After they are exposed to this stress,
they show changes.”
Kishi points out that many chronic diseases are due to
multiple gene mutations and polymorphisms coupled with
various environmental factors. He thinks he has a good
chance of pinpointing which genes and which factors in both
fish and humans—which,
in turn, could lead to ways
to attenuate the process.
You see, fish age in
three distinct ways. Rapidly,
like the salmon; gradually,
like zebrafish; and then,
basically, not at all. The
rockfish, Kishi said, can
live up to 200 years. In
some cases, he said, even
the humble cod can live
100 years.
“I have this dream that
one day I can genetically
engineer zebrafish to keep
Assistant Professor Shuji Kishi
them from growing old,
like carp because zebrafish are
a member of the carp family,” he said. “I don’t know how we
can manipulate human beings, but if we can find ways to stay
healthy until we die and prolong a healthy lifespan, those are
interesting and important goals.”
CONTINUED
that coordinates, manages, and
integrates all areas of the relocation
process. A leader in her industry, she is
also founder of San Diego Relocation
Council, an association dedicated to
educating corporations on trends in
recruiting and relocation.
Kennedy is a passionate advocate of
organizations representing her varied
interests in music, the arts, environment,
politics, and of course health and science.
In addition to her role as chair of the
Scripps Research California Council,
she is currently a member of the Board
of Directors of the La Jolla Music Society,
the Scripps Institute of Oceanography,
and the Lincoln Club, and a member
of the Strategic Advisory Board of
Equinox. She is also involved in
organizations including Patrons of
the Prado, San Diego Rotary Club,
San Diego Yacht Club, San Diego
Zoological Society, Fairbanks Country
Club, San Diego Social Venture
Partners, Pro Kids Golf, American
Red Cross, and Neighborhood
House Association.
She expresses one of her key
beliefs this way, “Every person you
know is a thread of the fabric of a
community, to be woven into the most
colorful and amazing cloth to support,
wrap around, or overlay the needs of
that community.”
Kennedy is married to Robert
Horsman, regional chairman of U.S.
Bank. They have two very large dogs
and two very large cats and reside in
Point Loma.
A key role of the Council will be to
develop specific initiatives designed to
promote Scripps Research in the
philanthropic community. Other roles
include hosting small events for donors
and prospective donors and participating
in an annual flagship event promoting
the institute. The Council will also
advise the administration and Trustees
concerning the impact of program and
policy initiatives upon operations of the
California site. Those interested in
knowing more about the Council’s
activities may contact Wendy Keeney at
(858) 784-7083 or wkeeney@scripps.edu.
SCRIPPS RESEARCH INSTITUTE
| 5
AWARDS AND HONORS
Scripps Research Scientist Awarded More than
$1.2 Million to Identify Potential Treatments for
Breast Cancer and Cardiovascular Disease
> Award Will Be Used to Develop High-Throughput Screening Tests at Scripps Florida
he National Institutes of Health has awarded a
three-year grant of more than $1.2 million to The
Scripps Research Institute to develop a series of
high-throughput screening tests that will help speed the
discovery of potential small molecule therapies for breast
cancer and cardiovascular disease.
Patrick Griffin, chair of the Scripps Research Department
of Molecular Therapeutics and director of the Translational
Research Institute at Scripps Florida, will lead the project
as principal investigator. The grant began in January.
The tests will focus on identifying ligands for the orphan
nuclear receptor liver receptor homolog-1 or LRH-1, which
plays a crucial role in hormone-driven breast cancer through
its regulation of genes involved in hormone biosynthesis as
well as fat and cholesterol metabolism – key risk factors in
cardiovascular disease. Receptors like LRH-1 detect circulating
signaling molecules (known as ligands) such as hormones or
neurotransmitters; the ligand binds to the receptor, creating
a biological response or blocking the receptor.
“Our goal is to uncover small molecules—either agonists
or inverse agonists—that can be used to modulate or alter the
activity of this important receptor,” Griffin said. “Right now,
there are no potent in vivo active LRH-1 agonists and no
reports of any inverse agonists.
T
Griffin has long maintained an interest in nuclear receptors.
“There has been a lot of interest in nuclear receptors like
LRH-1 and the RORs [retinoic acid receptor-related orphan
receptors] because they play separate but overlapping roles in
many important biological processes which make them ideal
targets for the development of therapies for a wide range of
disease,” Griffin said.
“Even though researchers in the field have characterized
all 48 known human nuclear receptors, we’re still looking for
ligands for a number of them and, better still, more potent
and more selective ligands. That’s what our work with
LRH-1 will accomplish.”
Eventually, Griffin said, the development of modulators
for LRH-1 will fall under the Scripps Research Institute
Molecular Screening Center (SRIMSC), part of a collaborative
effort among teams of scientists at the Scripps Research
California and Florida campuses, which includes Griffin as a
co-principal investigator. The center employs assay development
at both campuses, high-throughput robotics to screen large
chemical libraries in Florida, and chemistry at both campuses
to develop high quality chemical probes. The center is one of
only four such large centers nationwide and was awarded
more than $80 million by the National Institutes of Health
in 2008 to expand its work.
“Obviously, we need to better understand the
function of this important receptor and its role
in diseases like breast cancer if we’re going to
develop new treatments. To do that, first we need
to accelerate the identification of chemical probes.”
The functions of agonists and antagonists are well known—
a compound that activates a receptor is an agonist and one that
blocks it is an antagonist. But an inverse agonist, which binds to
the same site as an agonist, induces the opposite action of an
agonist of that receptor.
6 | SCRIPPS DISCOVERS
SPRING 2010
Professor Patrick Griffin
Sheng Ding’s Stem Cell Breakthrough Named
The Scientist’s Top Innovation of 2009
he stem cell work of Sheng Ding, associate professor at The Scripps Research
Institute and founder of Fate Therapeutics, has been named the top innovation
of 2009 by The Scientist, a magazine of the life sciences. The work, published
in Cell Stem Cell in April, found a method to convert adult cells all the way back to the
most primitive embryonic-like cells without using the dangerous genetic manipulations
associated with previous methods. The new technique solved one of the most challenging
safety hurdles associated with personalized stem cell-based medicine, enabling
scientists to make stem cells in the laboratory from adult cells without genetically
altering them.
T
Xiao Receives Recovery Act Grant for Groundbreaking
Work in Lymphoma
cripps Research Assistant Professor Changchun Xiao, Ph.D., was recently
awarded a Challenge Grant under the American Recovery and Reinvestment Act
of 2009 (Recovery Act) to discover microRNAs with diagnostic and prognostic
values for diffuse B cell lymphoma, the most prevalent lymphoma type in the world.
Xiao’s work was cited in a White House press release on recovery act funding for
groundbreaking medical research – “Today, patients receive chemotherapy without
knowledge of each individual’s sensitivity to these powerful drugs. In two years because
of the recovery act, a novel approach to utilizing micro RNAs may be able to predict
which patients have tumors that are likely to spread throughout the body. This
information will allow physicians to identify and aggressively treat high-risk patients
and spare low risk patients from ineffective treatments and their damaging side effects.”
S
Melanoma,
CONTINUED
FOR MORE INFORMATION ON MELANOMA, SEE:
Even if lead drug candidates can be identified, it will
likely take years to develop them into actual formulations,
and their safety and effectiveness will need to be established
in clinical trials before they are approved by the U.S. Food
and Drug Administration.
This work was supported by the Novartis Research
Foundation.
The National Library of Medicine
www.nlm.nih.gov/medlineplus/melanoma.html
The American Academy of Dermatology
www.aad.org/media/background/factsheets/fact_melanoma.html
SCRIPPS RESEARCH INSTITUTE
| 7
Partners
1
Scripps Research continued
its Frontiers in Science lecture
series for donors and friends
in October at the Hyatt Regency
La Jolla at Aventine. At the event,
Scripps Research associate professor
Peter Kuhn, Ph.D. spoke to over 120
Scripps Research contributors and
friends on “Novel Approaches to
Monitoring the Spread of Cancer Cells –
Finding the Needle in the Haystack to
Develop Specialized Treatments.”
Pictured at the event are Scripps
Research trustee Andrew Viterbi,
Ph.D., Peter Kuhn, Ph.D., and
Scripps Research Chief Operating
Officer Doug Bingham. (top left photo)
2
Theresa Esman recently made
a major gift to support research
in the laboratory of Dr. Phil
LoGrasso at Scripps Florida, via the
Saul and Theresa Esman Foundation.
Pictured are Theresa and Phil, with
Theresa holding a Scripps Florida
Alborello, an historic Italian apothecary
jar, which was presented to her in deepest
appreciation of her gift. (top right photo)
3
The Gardens Mall at Palm Beach
Gardens recently helped Scripps
Florida celebrate its one year
anniversary of its official opening, with
a series of special events, culminating
in a day of interactive science exhibits.
The “CELLebrate Science” event was
attended by an estimated 4,000 people.
(bottom right photo)
Contact Us:
• For more information about Scripps Research,
visit our web page at www.supportscrippsresearch.org
• To learn more about supporting Scripps Research’s
cutting-edge research, please contact:
CALIFORNIA
(858) 784.7083 or (800) 788.4931
wkeeney@scripps.edu
FLORIDA
(561) 228.2013
abruner@scripps.edu