The Scripps Research Institute (TSRI) serves humanity by creating basic knowledge in the biosciences, applying breakthroughs
in research to the advancement of medicine and drug discovery,
and educating and training the next generation of scientists.
As we begin 2015, it is my pleasure to share my reflections
about our accomplishments of the past year and my optimism
for the future of The Scripps Research Institute (TSRI).
This year, TSRI continued to be recognized around the
world for its research. As highlighted in these pages, highprofile findings ranged from inventing a breakthrough
method to disrupt a gene involved in a majority of cancers to
developing new chemical transformations with profound implications for drug development. Wide public exposure also
came from TSRI discoveries that addressed unmet medical
needs—from the Ebola crisis to autoimmune diseases including multiple sclerosis and ulcerative colitis.
The high quality of TSRI’s faculty was acknowledged this
year with numerous awards, honors, federal grants and
rankings that bring recognition to TSRI. To name only a
few of these, Dale Boger and Benjamin Cravatt were elected
to the National Academy of Sciences and Gerald Joyce was
elected to the National Academies Institute of Medicine.
Chi-Huey Wong won the Wolf Prize in Chemistry. Erica
Ollmann Saphire was elected to both the American Association for the Advancement of Science and American Academy
of Microbiology. In addition, based on citations per paper
Thomson-Reuters listed 11 TSRI faculty members as among
the “World’s Most Influential Scientific Minds.”
Also this year, U.S. News & World Report reaffirmed that
TSRI’s Kellogg School of Science and Technology is among
the nation’s best in the biological and chemical sciences. The
program is now ranked second in the specialty of biochemistry, sixth in the specialty of organic chemistry, seventh
overall in chemistry and ninth overall in the biological
sciences. We applaud the faculty, students, alumni and
donors who have built the Kellogg School’s well-deserved
reputation for excellence.
Notable among this year’s philanthropic supporters are the
late Jean and Keith Kellogg, committed friends of higher
education who provided more than $5 million in support
to TSRI over time through outright and planned gifts. Jean
passed away earlier this year and has further enriched the
Kellogg family legacy at TSRI by providing a bequest that
will be used to support first-year graduate students and
Alzheimer’s disease research. Another significant unrestricted bequest to TSRI was made by the estate of Allan and
Beverly Gale of San Diego.
This year we also renewed our collaboration with the
International AIDS Vaccine Initiative (IAVI) to extend our
joint work at the Neutralizing Antibody Center for the next
five years, supported by $6.5 million in funding in 2014,
which includes approximately $4.4 million from the Bill &
Melinda Gates Foundation. The Gates Foundation also
provided TSRI with up to $3 million in direct support for
operations and equipment, including the powerful new Titan
cryo-electron microscope. A federal grant of $13 million was
also awarded to support HIV research at the institute.
The National Institutes of Health also awarded a significant grant to establish a center for excellence at TSRI to
fight Ebola. This effort was buoyed by a crowdfunding
campaign that raised more than $200,000 from more than
800 contributors to purchase two badly needed machines
to speed work to find new therapies for the disease. As
part of the campaign, an anonymous family foundation
provided a $25,000 matching gift, and the Shaffer Family
Foundation gave a gift of $100,000, matching its support
for postdoctoral and graduate students in the laboratory of
Dr. Jerold Chun.
While grants and contracts provide funding for a significant portion of the institute’s research activities, gifts from individuals
and private foundations provide a critical source of funding for
high-risk, high-return research, advancing emerging fields and
speeding the application of research to patients in need.
Thank you for helping us reach $ 16.9 million in philanthropy revenue in FY 2014!
Your gifts help support TSRI’s life-saving research.
TSRI REVENUES, FISCAL YEAR 2014
In Florida, to name just a few of our supporters, the Klorfine
Foundation made gifts totaling $200,000 for two postdoctoral
training fellowships under the direction of Patrick Griffin,
whose laboratory is laying the groundwork for new treatments for immune disorders, diabetes and osteoporosis. The
Men’s Golf Association at the BallenIsles Country Club provided more than $160,000 to fund a prostate cancer research
fellowship and the Frenchman’s Creek Women for Cancer
Research group surpassed $1 million in cumulative giving
in support of women’s cancer research. Peter and Janice
Brock made a $100,000 pledge to fund blood cancer research.
Also, Abby Jablin made a $100,000 gift to fund cardiovascular
research in memory of her father, Dr. Paul A. Hurwitz, who
practiced pulmonary medicine.
84%
FEDERAL AND OTHER GRANTS
8%
INVESTMENT INCOME
5%
PHILANTHROPY
3%
OTHER
TSRI EXPENSES, FISCAL YEAR 2014
88%
As we conclude celebrations of Scripps Florida’s 10th anniversary, it is notable that our Florida campus has attracted a
total of more than $412 million in grants from federal sources—including a $5.7 million grant from the U.S. Department
of Defense in 2014 to create an artificial immune system—as
well as generous gifts from foundations and donors. As a testament to the quality of research, the Florida campus has
generated more than 100 domestic and foreign patent applications and 40 technology licenses. We take pride in these
accomplishments and look forward to our next 10 years as
part of the Florida community.
BIOMEDICAL RESEARCH
6%
GRADUATE SCHOOL
4%
MANAGEMENT/GENERAL
2%
FUNDRAISING/OTHER
PHILANTHROPY REVENUE SOURCES
FISCAL YEAR 2014
On a personal note, I am proud to be a member of this institute and want to thank all of you for your support in this
time of transition. Currently, the Board of Trustees and faculty are united in the goal to chart a future for TSRI as a
vibrant independent research institute. The search for a permanent president and CEO is ongoing.
68%
FOUNDATIONS
20%
INDIVIDUALS
9%
PLANNED GIVING/ESTATES
3%
CORPORATIONS
It is my privilege to acknowledge your role in making this
year’s scientific achievements possible and to ask for your
continued commitment to work together to advance critical
biomedical discoveries in the new year.
Warm regards,
www.scripps.edu
philanthropy@scripps.edu
Jim Paulson
Acting President and CEO
(561) 228-2017
(800) 788-4931
BIOMEDICAL
ADVANCES
FROM 2014
Scientists at The Scripps Research
Institute (TSRI) continue to make
strides in the quest to understand
the fundamental processes of life
and advance human health. Here is
a small sampling of highlights
from 2014.
NEW STRATEGY TAKES AIM AT ALS,
FRONTOTEMPORAL DEMENTIA
A team led by researchers from Scripps Florida and the Mayo
Clinic successfully designed a therapeutic strategy targeting
a specific genetic mutation causing a common form of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s
disease) as well a type of frontotemporal dementia (FTD).
“Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic
protein translation—and establish that it could be possible to
treat a large number of these patients,” said TSRI Professor
Matthew Disney (above), whose research was funded in part by the
federal government and Target ALS.
In other discoveries relating to ALS, TSRI Professors Elizabeth
Getzoff and John A. Tainer (also of Lawrence Berkeley National
Laboratory) led research showing that proteins linked to more
severe forms of the disease are less structurally stable and more
prone to form clusters. Stabilizing these proteins, called superoxide dismutase, could offer another approach to treating or
preventing some forms of the disease.
DRUG FOR MULTIPLE SCLEROSIS AND
ULCERATIVE COLITIS ADVANCES
MIMIC OF ‘GOOD’ CHOLESTEROL COULD FIGHT
HEART DISEASE AND STROKE
CHEMICAL BIOLOGISTS TACKLE
‘UNDRUGGABLE’ TARGET TO BLOCK TUMOR GROWTH
Positive new data were released in two separate clinical trials
of a drug candidate first discovered and synthesized at TSRI,
advancing potential new treatments for both multiple sclerosis
and ulcerative colitis.
Scientists created a synthetic molecule that mimics “good”
cholesterol and showed it can reduce plaque buildup in the arteries of animal models. The molecule, taken orally, improved
cholesterol in just two weeks.
TSRI chemical biologists invented a new method to disrupt the
function of MYC, a regulator involved in a majority of cancers
that had been thought to be “undruggable.”
RPC1063 was first discovered by a “hit” from an NIH molecular
library at Scripps Florida’s Molecular Screening Center. It was
then synthesized and further developed in the laboratories of
Scripps California Professors Ed Roberts and Hugh Rosen (above).
This research, funded by the National Institutes of Health
(NIH) and the American Heart Association Western States
Affiliate, points scientists toward a new method for treating
atherosclerosis, a condition where plaque buildup in the arteries can cause heart attacks and strokes.
San Diego biotechnology company Receptos, Inc. has licensed
the compound. After Phase 2 results suggesting the drug is safe
and effective, the company is now conducting late-stage clinical
trials with patients suffering from the two autoimmune conditions.
“We are delighted that RPC1063 is showing promise,” said Rosen.
“The unique multidisciplinary environment in chemistry and
biology at TSRI allowed this progression to clinical trials.”
HIV SHOWS NEW VULNERABILITY FOR VACCINE DEVELOPMENT
In good news for the effort to develop a vaccine against AIDS, a
team has uncovered a new vulnerable site on the HIV virus.
“HIV has very few known sites of vulnerability, but in this work
we’ve described a new one, and we expect it will be very useful in
vaccine research,” said Professor Dennis R. Burton (above, right)
of TSRI’s Department of Immunology and Microbial Science, who
leads the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and the NIH Center for HIV/AIDS Vaccine
Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.
“It’s very exciting that we’re still finding new vulnerable sites on
this virus,” added Professor Ian A. Wilson (above, left), Hansen
Professor of Structural Biology, member of the Skaggs Institute
for Chemical Biology and Chair of the Department of Integrative Structural and Computational Biology at TSRI.
In another study related to vaccine design, Professor William
R. Schief, Department of Immunology and Microbial Science,
and his team successfully made key ingredients for a candidate
vaccine against respiratory syncytial virus (RSV), a dangerous
and fast-mutating virus that lacks a licensed vaccine. This work
serves as a proof-of-principle demonstration of a technology that
could also be useful against many highly variable viruses.
“Atherosclerosis is the number-one killer in the developed
world,” said TSRI Professor M. Reza Ghadiri (above), senior
author of the new study with TSRI Assistant Professor of
Chemistry Luke Leman. “This research clears a big step toward
clinical implementation of new therapies.”
The researchers found that a molecule they developed moves
in and disrupts the critical interactions between MYC and its
binding partner MAX. They also showed the drug candidate
can stop tumor growth in animal models.
“We finally hit a home run with this—maybe a grand slam,”
said Kim Janda (above), co-author of the new study and Ely
R. Callaway, Jr. Professor of Chemistry, director of the Worm
Institute for Research and Medicine, and Skaggs Scholar and
member of the Skaggs Institute for Chemical Biology at TSRI.
In other work this year, the Janda laboratory corrected one of the
most talked about errors in the drug industry, an inaccurate structure of a drug known as TIC10 that had reached Phase 1 clinical
trials. The highly promising anticancer compound—now with the
amended structure—is in clinical trials for cancer patients.
DISCOVERY MAY LEAD TO IMPROVED
BREAST CANCER TREATMENTS
NEW TECHNIQUE HAS PROFOUND IMPLICATIONS
FOR DRUG DEVELOPMENT
Scripps Florida scientists found new targets for potential intervention in breast cancer that could eventually increase effectiveness and reduce the undesirable side effects associated with
current treatments.
An increasingly important avenue for drug development is breaking carbon-hydrogen (C-H) bonds to alter existing molecules to
create new ones. Of particular interest is mirror-image or “onehanded” compounds, but C-H breaking methods for making pure
batches of these molecules have worked with only a limited range
of starting materials.
Approximately two out of three breast cancers are driven by
receptors that bind the hormones estrogen and progesterone—
when the hormones bind to these receptors in cancer cells, they
signal the cancer cells to grow. The progesterone receptor has
two activation domains—AF1 and AF2—and both are normally
needed for full activation of the receptor. The new study reveals
how AF2 communicates with AF1, providing the first evidence
of their long-range interaction.
“These findings support further research to look for promising
small molecules that block that interaction,” said Patrick R.
Griffin, chair of the Department of Molecular Therapeutics and
director of the Translational Research Institute.
In addition to exploring potential new drugs for breast cancer,
the researchers also hope to investigate the implications for
prostate cancer, another hormone-driven disease.
Now a team led by Jin-Quan Yu (above), who is Frank and
Bertha Hupp Professor of Chemistry at TSRI, has established
a new technique that opens the door to creating a broader range of
pure molecules of one-handedness or “chirality,” eliminating previous starting-material limitations. “The potential may be huge,”
said Yu, whose innovative chemistry resulted in four Science or
Nature papers in 2014.
In other groundbreaking work, a team led by Nobel laureate K. Barry Sharpless, who is W.M. Keck Professor of Chemistry and member of the Skaggs Institute for Chemical Biology
at TSRI, used his “click chemistry” to uncover unprecedented, powerful reactivity for making new drugs, diagnostics,
plastics and other products. These “Sulfur Fluoride Exchange”
(SuFEx) reactions provide easy access to an entire, unexplored
galaxy within the chemical universe.
SURPRISE FINDINGS SUGGEST ANTI-ALZHEIMER’S APPROACH
REVEALED: WEAK SPOTS IN EBOLA’S DEFENSES
In surprising findings, transthyretin, a protein with a propensity
to form harmful aggregates (clumps) in the body when produced
in the liver, may protect against Alzheimer’s disease aggregates
when produced in the brain. Nerve cells appear to make more of
the molecule to protect themselves against the harmful effects
of the Alzheimer’s protein.
A team identified weak spots on the surface of Ebola virus that
are targeted by the antibodies in ZMapp, the experimental drug
cocktail administered to several patients during the recent Ebola
outbreak. The study, led by TSRI structural biologists Erica
Ollmann Saphire and Andrew Ward (above), provides a revealing
3-D picture of how the ZMapp antibodies bind to Ebola virus.
The new study suggests that drugs that can boost the production specifically in the neurons of older people (whose brains’
manufacture of transthyretin decreases with age) could one day
help ward off Alzheimer’s disease. “This result was completely
unexpected when we started this research,” said TSRI Professor
Joel N. Buxbaum. “But now we realize that it could indicate a
new approach for Alzheimer’s prevention and therapy.”
“The structural images of Ebola virus are like enemy reconnaissance,” said Saphire. “They tell us exactly where to target antibodies
or drugs.”
Ward added, “Now that we know how ZMapp targets Ebola, we can
compare all newly discovered anti-Ebola antibodies as we try to
formulate an even better immunotherapeutic cocktail.”
In other work, a team led by Srinivasa Subramaniam, funded
by an O’Keeffe Neuroscience Scholar Award and the State of
Florida, identified new elements of a pathway deeply involved
in Alzheimer’s progression. Another study led by Professor
William E. Balch suggested “protein misfolding” diseases such as
Alzheimer’s and cystic fibrosis can be seriously exacerbated by
the body’s response to that misfolding, providing fundamental
insights that will immediately affect design of new therapies.
FOUND: CALORIE-BURNING SWITCH IN BROWN FAT
SCIENTISTS GIVE LIFE BIGGER GENETIC ALPHABET
Most fat cells in our bodies are “white fat” cells that store fat
as a reserve energy supply. But we and other mammals also
have depots of “brown fat” cells. These apparently evolved not
to store but to burn energy—quickly, as a way of generating
heat and keeping the body warm in cold conditions, as well as
possibly to get rid of excess caloric intake.
Voted People’s Choice for science breakthrough of the year in an
online competition sponsored by the journal Science, a study described how TSRI scientists created the first living organism that
transmits added letters in the DNA “alphabet.”
Now TSRI biologists have identified a signaling pathway that
switches on this powerful calorie-burning process in brown fat
cells—of great interest to medical researchers because it naturally
stimulates weight loss and may also protect against diabetes.
“This finding offers new possibilities for the therapeutic activation of ‘brown fat thermogenesis,’” said team leader TSRI
Associate Professor Anastasia Kralli (above).
The cells of this unique bacterium can replicate the unnatural DNA
bases—which the team dubbed X and Y—more or less normally,
for as long as the molecular building blocks are supplied.
“Life on Earth in all its diversity is encoded by only two pairs
of DNA bases, A-T and C-G, and what we’ve made is an organism that stably contains those two plus a third, unnatural
pair of bases,” said TSRI Associate Professor Floyd E. Romesberg, who led the research team. “This shows that other solutions to storing information are possible and, of course, takes
us closer to an expanded-DNA biology that will have many
exciting applications—from new medicines to new kinds
of nanotechnology.”