SBP Pathways Summer 2016 by Sanford Burnham Prebys

A SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE PUBLICATION | 40TH ANNIVERSARY | SUMMER 2016

THE PATH TO DISCOVERY

ON THEANNIVERSARY COVER: Sed do eiusmod tempor incididunt 40TH ut labore et dolore SUMMER 2016 magna aliqua. Ut enim ad minim

veniam, quis nostrud exercitation ullamco laboris nisi ut aliquip ex ea com. ON THE COVER Pier Lorenzo Puri, M.D., Ph.D., is on a mission to cure muscular dystrophies see page 4

40 Years Celebrating 40 Years of Science with Music The year marks the 40th anniversary of Sanford Burnham Prebys Medical Discovery Institute. The milestone celebration was kicked off with a concert featuring flutists Sir James and Lady Jeanne Galway and pianist Phillip Moll.

10901 North Torrey Pines Road La Jolla, California 92037

SBPdiscovery.org

@SBPdiscovery Sanford Burnham Prebys Medical Discovery Institute is a 501(c)3 nonprofit organization.

Contents 4

Driven to Cure Dystrophies

How to Make Muscle

Along the Road to Discovery

Mentoring Matters

Fighting Deadly Malaria

Celebrating 40 Years of Science with Music

The Inspiration behind the Institute

Art Enthusiasts Support Innovation

Meet Ruth Claire Black, J.D.

Science Benefiting Patients

Discovery Hub

PATHWAYS

Regenerating muscle may help treat muscular dystrophy see page 6

“We are balancing the need to understand disease with the search for new medicines that will advance to the clinic. Our goal is to use our resources— including your generous donations—in ways that will have a profound effect on the health and wellbeing of people everywhere.” Perry Nisen, M.D., Ph.D.

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LETTER

The People, Science and Journeys Behind Our Discoveries Welcome to the first issue of PATHWAYS, our new semiannual publication for friends and family of Sanford Burnham Medical Discovery Institute. This new format replaces Portal magazine and gives you a more intimate insight into the people of Sanford Burnham Prebys Medical Discovery Institute (SBP).

And check out Discovery Hub, a sampling of our latest science—including research to treat HIV, slowing the growth and metastasis of melanoma, the latest in obesity research, and the discovery of a protein that may lead to new Alzheimer’s disease treatment.

PATHWAYS reflects the commitment and inspiration of our people. With this issue, we want you to travel the pathways that scientists like Dr. Pier Lorenzo Puri are taking as they explore diseases. In Driven to Cure Dystrophies, Dr. Puri, an avid soccer player, discusses his motivation to explore the world of muscle regeneration, a clinical trial he has underway in Italy, and how his lab is unravelling the mysteries of muscular dystrophies for patients around the world.

As we celebrate the Institute’s 40th anniversary, we honor the vision of our founders, Dr. William and Lillian Fishman, whose belief in team effort still encourages us “to develop original ideas and create a critical mass of intellects and skills to accelerate progress” in science.

Science is a process of incremental steps that moves discoveries forward. Learning to think, plan and act as a scientist is critical. In Mentoring Matters, Dr. Malene Hansen shares how she helps students in our Graduate School of Biomedical Sciences harness their thoughts, creativity and energy. You’ll also read A Career Making a Difference, which describes our first employee, Dr. José Luis Millán, whose work in soft bone disease research led to the first-ever treatment, asfotase alfa, a therapy that has transformed the lives of patients— including Morgan Fischer.

I want to thank you for your ongoing support and belief in the work we do here— your generosity helps to ensure that our best work continues.

Perry Nisen, M.D., Ph.D. Chief Executive Officer Donald Bren Chief Executive Chair

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FACULTY

Driven to Cure Dystrophies Dr. Pier Lorenzo Puri is advancing research to treat muscular dystrophies

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“I always let life bring me to where I need to be,” says Pier Lorenzo Puri, M.D., Ph.D., professor in the Development, Aging and Regeneration Program. A physician by training, Puri is allowing the momentum of his science to propel him deeper into the biological exploration of disease. “I like to walk—sometimes run—through open doors, taking advantage of opportunities that can change my life, but more importantly, the lives of others.” Puri is dedicating his life to unlocking the body’s mysterious world of muscle regeneration, which seems incredibly fitting for an avid Italian soccer player. Yet Puri is quick to say, “I’m not one of those people who planned to get here.” In between daily surf sessions and weekly soccer matches, he is on a quest to discover treatments for children who are living with muscular dystrophy, a debilitating, often deadly muscle-wasting disease that indiscriminately affects children—mostly boys—of all races, ethnic groups, and social classes. FROM SURGEON TO SCIENTIST Puri is a recognized authority on the promise of drug therapies that promote muscle regeneration. However, his path to the laboratory bench began at the bedside.

“My research efforts are guided by a very simple principle. I just try to do what I would ask a scientist to do if I were a patient or a parent of a dystrophic patient.” Pier Lorenzo Puri, M.D., Ph.D.

As a child, “I was motivated to be a doctor because I found the figure of a physician to be quite intriguing.” After a few years in internal medicine with a specialization in surgery, Puri felt like he was eliminating patients’ problems rather than solving them. “The surgeon is the person who tackles the problem when the problem already exists,” he says. “I want to prevent the whole situation and understand the cause of the underlying disease.” Today, Puri runs two research labs—one in San Diego and another in Rome— simultaneously pursing a promising drug therapy for muscle regeneration that targets muscle stem cells. These drugs, known as histone deacetylase inhibitors (HDACis), make important muscle genes more available to the cell machinery that transcribes their genetic code. Puri’s clinical trial is underway in Italy, and early results are encouraging. Of the 20 boys enrolled in the trial, all are showing signs of improvement after one year. “We are very excited about this—it is fantastic,” he says. He hopes to replicate the study on a larger population in the United States soon. TURNING TO PURI A compassionate and realistic man, Puri never turns people away. He is unofficially “on call” to hundreds of patients and families around the world seeking advice on everything from how to find the right doctor to how to interpret his scientific publications. And, while he jokingly admits that his daily goal is to spend one hour surfing, his ultimate goal is to make a considerable contribution to helping find a cure for muscular dystrophy. “I am just a small part of a large effort. No one can do it alone. All of us involved in this research are part of a huge machine that is trying to cure these children. When that’s done, I’ll rest.”

PATHWAYS

RESEARCH

How to Make Muscle Promoting muscle gene expression may help muscular dystrophy patients

Muscular dystrophies are a group of more than 30 genetic diseases. In all cases, abnormal genes cause progressive muscle weakness and loss that eventually overwhelm the regenerative capacity of muscle tissue. Today, there is no specific treatment to stop or reverse the condition. Puri’s research team is making major advances in our understanding of how muscle genes are turned on and off in satellite cells—adult stem cells found in muscle that mature into skeletal muscle. Activating muscle genes in satellite cells is a promising treatment strategy for dystrophies,

as well as muscle-wasting conditions that can occur with diabetes, rheumatoid arthritis, stroke and other illnesses. Deep down in the nucleus of satellite cells sit chromosomes, three-dimensional structures made of chromatin—the tightly coiled DNAprotein packages that help fit the entire genome in a cell. Chromatin packaging plays a crucial role in gene expression—it is loosely packaged when genes are turned on and tightly packaged when genes are turned off. Like assembling a puzzle, Puri’s team is defining the proteins, mechanics and conditions needed to remodel chromatin and expose muscle genes to help satellite cells build protein.

Human muscle fibers; the muscle contractile protein is stained green and nuclei are purple

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From left to right: Alessandra Dalâ&#x20AC;&#x2122;Agnese, Pier Lorenzo Puri, M.D., Ph.D., Sonia Albini and Paula Toto Coutinho

One encouraging therapy is a class of drugs called histone deacetylase inhibitors (HDACis). HDACis are epigenetic drugs that work by opening up the genome to make muscle genes more accessible to the cell machinery that transcribes the genetic code. In essence, HDACis open the blueprints for protein manufacturing to support muscle regeneration. Several HDACis are already FDA approved for treating certain cancers. If clinical trials show that theyâ&#x20AC;&#x2122;re effective for dystrophies, there is hope that the approval process would be shortened, potentially accelerating a much-needed treatment for these destructive diseases.

MALES

are more likely to be stricken with muscular dystrophy.

90%

of patients will need to use a wheelchair by the age of 24.

Source: Centers for Disease Control

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“Only in America could this happen. The government funded us to do what we loved doing, and we were making headway.” Erkki Ruoslahti, M.D., Ph.D.

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FACULTY

Along the Road to Discovery While driving north from Coronado Island in San Diego, Eva Engvall Ph.D., turned to Erkki Ruoslahti, M.D., Ph.D., and asked a question that would change their lives and impact the success of a then-small cancer research institute in La Jolla. It was 1979, and both scientists were working at the City of Hope National Medical Center in Duarte, California. Engvall said the weather, the sun, and the ocean views “…were so fantastic that I turned to Erkki and said, “Wouldn’t it be great to work in San Diego?”

Erkki Ruoslahti, M.D., Ph.D. and Eva Engvall, Ph.D.

That simple question led to referrals from trusted colleagues to William Fishman, Ph.D., founder of the La Jolla Cancer Research Foundation, who recruited them as senior scientists that same year.

on to use monoclonal antibodies to discover new tissue proteins, some of which we now understand to be key contributors to severe genetic diseases such as muscular dystrophies and Marfan syndrome.

Fast-forward 37 years later, Ruoslahti is a distinguished professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), a member of the National Academy of Sciences, and former president of the Institute (from 1989-2002). Engvall is a professor emeritus at SBP and is collaborating on a book about the Institute with Nina Fishman, the founder’s daughter.

Ruoslahti discovered the molecular basis for cell adhesion, a significant advance in cell biology that earned him the Japan Prize 20 years later, and led to two drugs—Integrelin™ and Aggrastat™—that are now used to treat certain forms of heart disease.

“The environment for scientists was and still is wonderful,” says Ruoslahti. After Engvall’s early discovery of the ELISA test—a laboratory method that uses antibodies to detect proteins—she and Ruoslahti improved the technology, creating a new version that is still the basis for many clinical diagnostic tests, such as the one for HIV. Engvall went

NANOMEDICINE And today, Ruoslahti’s science has taken another road. “I got into nanomedicine about 15 years ago,” he says. “I come from a family of engineers (both his father and brother were engineers) so maybe that’s why nanoparticles and materials science are so fascinating to me. Had I known how interesting it was back then, I would have pursued it earlier,” he adds.

PATHWAYS

Reprinted courtesy of Bob Seidemann

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Erkki Ruoslahti, M.D., Ph.D.

Nanoparticles are considered a promising new approach in medicine because they can carry out many different tasks that a simple drug cannot. One such function—and the one that is Ruoslahti’s specialty—is to direct a drug into tumors in a selective way, increasing the efficacy of the drug, while reducing the collateral damage the drug may cause to normal tissue. He is the founder of three companies that are making progress on this front. A BOOK IN THE WORKS As for Engvall, she took a leave of absence from science when she and Ruoslahti bought a large ranch in the Santa Ynez valley. But ranching was not her passion. “It was a semi-wild Texas longhorn cow that convinced Erkki to sell that ranch!” she says with a smile. “The dogs and I found a newborn calf in the tall

Eva Engvall, Ph.D.

grass, and the mother cow came storming toward me with broad horns and head low. My back was against the barbed wire. Erkki thought the cow was going to kill me for sure, as she came within a foot of me, stopped and stared at me. I could tell in her eyes that she wasn’t going to kill me,” she says. They returned to Rancho Santa Fe, where they live today with their whippets— exceptionally fast, quiet, medium-sized dogs that form very close bonds with their owners. And when not in San Diego, they visit their much smaller ranch in the Santa Ynez valley or vacation with their large family, three sons and six grandsons. “The book I’m working on will share what it was like to work in this incredible place, and hopefully inspire others to pursue paths that ultimately make a difference,” Engvall says.

Image showing how nanoparticles (red) can carry cancer drugs to blood vessels (green) and distribute them directly to cancer cells (blue)

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FACULTY

Mentoring Matters Dr. Malene Hansen guides longevity studies

Associate professor Malene Hansen, Ph.D., and research associate Sara Gelino, Ph.D., are dipping into what some may call “the fountain of youth.” In studying how organisms age at the molecular level, they’re gaining insight into a cellular process called autophagy that is linked with an extended lifespan.

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“We are training the next generation of scientists at a time when research has never been more intellectually exciting and important to the growing population of people suffering from disease.” Malene Hansen, Ph.D.

As associate dean of student affairs and faculty advisor of postdoctoral training, Hansen ensures that young scientists have mentors to advise them in their investigations. “Being a mentor is one of the most gratifying aspects of my job,” she says. “And helping new investigators like Sara focus on a research path and then guiding them to their goal not only helps science, it helps this institution, it helps my lab and it helps people.”

Sara Gelino, Ph.D., (left) and Malene Hansen, Ph.D.

52%

of those earning Ph.D.s in biological science are women

36% 27%

of assistant professors and only

of tenure candidates are women Source: U.S. National Research Council

BALANCE IS KEY The key to good mentoring, she explains, is balance. “You have to help them harness their ideas and energy,” she continues. “As a mentor, you help them think intellectually about a project, calculating how much time is required and the degree of difficulty. I give an informed opinion, but I listen as well. Through communication and compromise, we identify the best course to pursue.” AUTOPHAGY Autophagy, from the Greek auto, meaning “self,” and phagein, “to eat,” is a form of cellular housekeeping. In addition to its impact on aging, it has also been connected with many age-related diseases, such as osteoarthritis, diabetes and cancer. Finding ways to regulate this process may provide novel means to prolong life, and a healthy one at that. In the autophagy process, the subject of Gelino’s research, a cell identifies a component that is dysfunctional or unnecessary, breaks it down and recycles the parts. Of particular interest is that the process can be regulated through calorie restriction.

“When faced with limited nutrients,” Hansen says, “the cell initiates autophagy in order to survive. It breaks down some of its own proteins, for example, into consumable amino acids. Organisms that are really efficient at this process have been found to have an extended lifespan.” A TINY WORM SHEDS LIGHT ON AGING Gelino, Hansen’s former graduate student, is working with a model organism called Caenorhabditis elegans, a microscopic worm that has a sequenced genome and a transparent body. “I’m focusing on how autophagy affects specific tissues in different ways,” she explains. “I’ve found that the intestine, for example, is very reliant on autophagy and that disabling the process makes cells in the tissue malfunction due to a build-up of unwanted material.” It’s tempting to speculate that boosting autophagy in specific tissues might help prevent aging-related disease. But Hansen cautions that there’s more yet to be known. “What Sara has also discovered,” she points out, “is that modulating autophagy in the intestine affects multiple functions of the body. We see that these animals’ ability to move is greatly impaired as well.” So there could be complications in modulating autophagy in one tissue, because it might lead to unwanted effects in another. “So when do you boost autophagy and when do you suppress it? Before we can consider regulating autophagy to

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C. elegans is used for genetic research

“Researchers, including myself, are eager to learn more about autophagy to understand how it works to promote health and longevity.” Sara Gelino, Ph.D.

manage disease, we have to know a lot more about how the process works, both in a single cell as well as in the whole organism,” she says.

as a career. “But being around Dr. Hansen and her enthusiasm for science inspired me to enroll in and complete grad school,” she says.

Gelino, for one, is eager to continue uncovering the answers to these questions. She credits her mentor, Hansen, with providing and nurturing that curiosity. Although hired as Hansen’s first technical assistant, she didn’t intend to pursue science

STEPS FORWARD Now, having been guided by a good mentor and having gained experience herself, Gelino is taking on her own mentoring role. “Sara set up a number of new assays for our lab that we continue to use,” says

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Hansen. “And she’s also mentoring other lab members, including undergrads in the lab. What these young researchers contribute is so important to science.” Famed scientist Isaac Newton once wrote, “If I have seen further, it is by standing upon the shoulders of giants.” His admission emphasizes that scientific progress is carried forward in incremental steps, with

experienced investigators such as Malene Hansen guiding the keen minds of the next generation, such as Sara Gelino. “Great advances in science come with fresh thinking and aspirations to look beyond what you see. Who knows where our next generation of scientists will lead us?” asks Hansen.

From left to right: Linnea Adams, Xing She, Ph.D., Caroline Kumsta, Ph.D., Jose Nieto-Torres, Ph.D., Malene Hansen, Ph.D., Andrew Davis, B.Sc., Sara Gelino, Ph.D.

PATHWAYS

RESEARCH

Fighting Deadly Malaria Reaching across borders to find a cure

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The mosquito-borne Zika virus may be making headlines, but there’s another, deadlier disease transmitted by mosquitoes that puts 3.4 billion people— half the world’s population—at risk: malaria. Each year, nearly 500,000 people die from this disease, most of them children. No vaccine exists yet. Humans have been battling malaria for centuries. A Chinese medical treatise from the second century BCE recommended the qinghao plant (Artemisia annua) as a remedy. Today, artemisinin-based drugs are common antimalarial treatments. In South America, indigenous Indian tribes used bark from the Cinchona tree to cure fevers. The medicine from that bark, quinine, is another effective antimalarial drug. But there is still no cure for the disease, and in the past century, four Nobel Prizes have gone to research on malaria. The malaria parasite is a particularly tricky target. Some species can lie dormant within the body for several years. Its resistance to current drugs is building, and mosquitoes are efficiently transporting it across human populations. And global warming is likely to make matters worse.

Malaria infects red blood cells and causes profound changes that leave them unable to circulate and deliver oxygen to the body

Red blood cell infested with malaria

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MORE THAN 200 MILLION MALARIA CASES AND 440,000 DEATHS EACH YEAR Malaria is the leading cause of death and disease in many developing countries, and young children and pregnant women are most affected Source: World Health Organization

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A NEW BATTLE TACTIC All this calls for a new battle tactic—that’s where Sanford Burnham Prebys Medical Discovery Institute (SBP) scientists are stepping in. Anthony Pinkerton, Ph.D., director of Medicinal Chemistry at SBP, has joined forces with an international cadre that includes Lars Bode, Ph.D., an associate professor in the Department of Pediatrics at UC San Diego, and Katja Becker, Ph.D., chair of Biochemistry and Molecular Biology at the Justus-LiebigUniversity in Gissen, Germany.

The painstaking process, one that “incurs more failures than successes,” according to Pinkerton, is supported by a grant from the National Institutes of Health. He appreciates the grant support, acknowledging that it’s difficult to find funding for early-stage, high-risk research.

The group set out to find a weakness in the parasite’s survival system. In 2012, they became the first to identify a chemical compound that inhibits an enzyme known as G6PD, which is critical to the parasite’s development inside red blood cells. Since their discovery, Pinkerton and his lab have labored tirelessly to optimize that compound.

It’s a calling that suits both Pinkerton’s intellect and his enthusiasm. Though he comes from a long line of medical doctors, Pinkerton has always been attracted to the puzzles of chemistry. Now, instead of treating one patient at a time, he has the opportunity to benefit millions.

Additional support comes from SBP leadership. “We’re encouraged to focus on early-stage drug discovery research here, on doing the high-risk, uncertain-outcome work. We get to be real trailblazers.”

A PROTOTYPE DRUG “We’re working in animals with a prototype drug called ML276,” he says. “It was a great starting point but needed further development before clinical testing. We have actually made and tested over 1,000 derivatives of the compound and are very close to selecting a drug candidate. However, we’re still a couple of years away from testing the candidate in human patients.”

“The odds are always stacked against you in this line of work,” says Pinkerton, “but if you come up with a new drug, you change medicine forever. It has a huge impact on humanity.” Anthony Pinkerton, Ph.D.

Anthony Pinkerton, Ph.D., director of Medicinal Chemistry

PATHWAYS

EVENTS

Celebrating 40 Years of Science with Music To celebrate the 40th anniversary of the Institute, scientists, donors, staff, and friends gathered for a celebratory Tribute Concert featuring renowned flutists Sir James and Lady Jeanne Galway and their longtime accompanist, pianist Phillip Moll. The concert, which took place March 10 at the Museum of Contemporary Art in La Jolla, honored members of the President’s Circle who provide annual contributions of $1,000plus to the Institute, and honorary trustee Conrad Prebys for his philanthropic support of the Institute that bears his name. In his opening remarks, CEO Perry Nisen, M.D., Ph.D., told the capacity audience, “Conrad is a passionate lover of music. What better way to recognize him and the rest of you here today than with a special performance by world-class performers?” The hour-long program of classical compositions for flute and piano was

punctuated by Sir James’ delightful and often humorous commentary. The evening’s emotional highlight came in the encores, when Sir James and Lady Galway, accompanied by Moll, played a flute duet interpretation of Mozart’s “Rondo Alla Turca,” followed by Sir James’ solo rendition of “Danny Boy,” an anthem of his native Ireland. Paying tribute to the legendary “Man with the Golden Flute,” Nisen said, “Our scientists understand how they measure success by their impact. If we measured his contributions to music, Sir James Galway would be a Nobel laureate squared.”

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Lady Jeanne Galway (left), Phillip Moll (center), and Sir James Galway The trio have collaborated and toured together for many years

Music, like science,

uses logic, math and creative thinking to enlighten and inspire.

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LEGACY

The Inspiration behind the Institute How two “retirees” traveled coast to coast to establish their vision At 62, William Fishman, Ph.D., was approaching mandatory retirement age at Tufts University, where he’d served as professor and cancer center director. Lillian, his wife and career partner, was 59. Yet neither was ready to hang up their lab coat. There were still significant scientific questions to ask and answer. Determined to continue their research, they packed their bags, took a $180,000 grant from the National Cancer Institute (NCI) and moved cross-country to the burgeoning scientific community in La Jolla, California. The following year, 1976, the couple leased space in a renovated apartment building and founded the La Jolla Cancer Research Foundation. “We had no budget for new equipment,” Lillian recalled in a 2013 interview with the San Diego Union-Tribune, “so we rolled up our sleeves and started constructing innovative laboratory equipment out of spare parts.” Their plan was to develop an independent research institute where scientists would have the freedom, without bureaucracy or politics, to pursue their investigations. Forty years later, the institute that the couple founded in an apartment building has grown into Sanford Burnham Prebys Medical Discovery Institute (SBP), a worldrenowned research organization with two locations: one on the Torrey Pines Mesa in La Jolla and the other in Orlando, Florida. The original staff of five now exceeds 1,000 employees, including more than 700 scientists. Today, a prestigious monetary award preserves their legacy. Each year, SBP bestows a $10,000 Fishman Fund Award to each of a handful of its brightest postdoctoral scientists. The Fishman Fund was established in 2001 by longtime supporters of the Institute Mary Bradley and Reena Horowitz in honor of the founders’ passion for cultivating early-stage scientific talent.

Bill & Lillian Fishman August 6, 1939

This year, as part of SBP’s 40th anniversary, an additional honor has been created: the Fishman Fund Fellowship. This two-year fellowship will be awarded every two years to one outstanding postdoctoral fellow and will cover that individual’s annual salary. Funds are unrestricted, allowing the recipient to pursue their scientific vision.

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â&#x20AC;&#x153;My parents were amazing people, important role models not just to my family but to many others. My wish is for them to be remembered for their hard work.â&#x20AC;? Nina Fishman

(Top left) The Fishmans secured the current location on Torrey Pines Road. (Top middle) The Fishmans with one of the early faculty recruits, Dr. Erkki Ruoslahti. At a planting ceremony with Malin Burnham and Dr. Ruoslahti. (Top right) Dr. Fishman established and served as the first director of Tufts Cancer Research Center. (Lower left) The Fishmans celebrate the 10th anniversary of the Institute. (Lower right) Lillian Fishman with her daughter, Nina.

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DONORS

Art Enthusiasts Support Innovation Matt and Nancy Browar share their generosity with the STRIVE Program

Matt and Nancy Browar have found meaningful experiences in their charitable gifts. As avid art lovers, their generosity has made San Diego art and art education more accessible to the public. With their recent gift to SBP’s STRIVE Program, they supported six STRIVE awards, including one given to inspired scientist Stan Walls, Ph.D., who will pursue new cancer therapies.

Q. Why did you choose Sanford Burnham Prebys Medical Discovery Institute as a beneficiary of your private giving? And why did you invest in STRIVE? A. We chose Sanford Burnham Prebys Medical Discovery Institute (SBP) because we have watched its progress and development over the years, and have been extremely impressed. We are particularly interested in the STRIVE program because we like the idea of providing funds to creative scientists who may otherwise not have the opportunity—or funding—to pursue their ideas. Q. As a relatively new donor, what are some of your early impressions of the Institute and its scientists? A. The scope and magnitude of the resources that SBP provides are

remarkable. We especially like SBP’s model of collaboration that promotes teamwork between scientists in different areas of research. SBP encourages chemists, cell biologists, geneticists and others to work on projects together. These are the type of “broad strokes” that can only lead to better, deeper insights. Q. Stan Walls, Ph.D., a proud recipient of a “STRIVE Browar Award,” says he looks forward to giving you updates on his research progress. What benefits do you hope to see with your gift? A. I t’s our hope that STRIVE award recipients reach their research goals. It’s also important that their work bring knowledge that will be shared among SBP scientists— and beyond.

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STRIVE: Unleashing Innovation “The value of art is often ‘measured’ by the emotional connection between the artist and the viewer,” says Nancy, a board member of the Museum of Contemporary Art San Diego. “Inspired science can touch people as well—by affecting their health, well-being, and longevity.”

Fast-tracking novel concepts by providing money to incubate and accelerate ideas isn’t new to the high-tech industry, but our scientists are now getting the same opportunity through the STRIVE Program. Part incubator, part accelerator, STRIVE enables faculty, postdoctoral fellows, staff scientists and graduate students to pursue high-risk, highreward research that helps achieve the Institute’s 10-year strategic vision to address unmet clinical needs. The Program solicits elevator-pitch short (one page maximum) proposals to test hypotheses to uncover new information about a disease, applications of new technology, and/or new discoveries in medical science. FUNDS TO EXPLORE Stan Walls, Ph.D., a molecular biologist in the laboratory of Rolf Bodmer, Ph.D., at Sanford Burnham Prebys Medical Discovery Institute, is using his STRIVE Browar Award to study a radically new approach to disease. He is investigating the interactions between lipids and proteins—an emerging area of drug discovery for metabolic disorders and obesity-related cancers, such as

breast, colon and pancreatic cancer. If successful, he will set up a platform to screen for small molecules that can be tested in cell and animal disease models. Since last year, STRIVE has provided grants to more than a dozen scientists like Walls to develop innovative ideas in cancer, Alzheimer’s disease, and heart disease, to name a few—giving each recipient an entrepreneurial lift to impact human health. CREATING A BUZZ Walls presented his concept at the March 2016 meeting of the Board of Trustees. “It was an exciting opportunity to address people who have had such a huge impact on this Institute,” he says. “And support from Matt and Nancy Browar constitutes career-enhancing validation. There’s a lot of buzz about STRIVE here, because it aligns the goals of the scientists with the goals of SBP in a way that’s never been done before.”

“By donating to Dr. Walls’ pioneering work, we may be able to impact the lives of so many people with different types of cancer,” says Matt.

Stan Walls, Ph.D.

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DONOR

“As a cancer patient and now cancer survivor, there is nothing more important to me than improving treatment options for cancer patients.” Ruth Claire Black

Meet Ruth Claire Black, J.D. A passionate donor and advocate for cancer research Ruth Claire Black, J.D., executive director of Cal State Online, the California State University gateway to online education, empowers students by expanding access to postsecondary education and by helping to develop and deliver online degree programs within the California State University system.

As an advisor to the Sanford Burnham Prebys Medical Discovery Institute’s (SBP) NCI-designated Cancer Center, Ruth is bringing a patient and advocate’s perspective to helping scientists advance new knowledge to cure diseases and inspire hope. She speaks here about her service on the Center’s Community Advisory Board (CAB). Q. H ow did you first become involved with the Cancer Center, and what were your early impressions of SBP and its scientists? A. Fellow member Helen Eckmann introduced me to the CAB and encouraged me to join. My first impression of SBP was that it was an institution committed to finding a cure for cancer. As a cancer patient and now cancer survivor, there is nothing more important to me than improving treatment options for cancer patients. Q. How do CAB members contribute to advancing translational research at the Cancer Center?

A. We bring the patient and family member perspective to the scientists. We also help to bridge the communication divide between scientists and the often complex work that they do with the community. While many members of the public are interested in the research, all of the science and jargon can be a little intimidating. Q. W hat are some life lessons you’ve learned as a cancer survivor? How do you share those lessons with patients who have just received a cancer diagnosis and with scientists who are striving to find cures? A. I think patients and survivors need to become passionate and practiced lifelong advocates for better funding of promising research. We also need to support young scientists on the long and difficult path to becoming the researcher that will make the important discovery that helps us to cure cancer.

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President’s Circle Donors – 2015 Sanford Burnham Prebys Medical Discovery Institute honors the following donors who generously supported science benefiting patients with a gift of $1,000 or more in 2015 $50,000 AND ABOVE

$10,000 – $24,999

American Diabetes Association American Heart Association Elaine and Maury Carter Michael R. Cunningham Daniel and Janet Mordecai Foundation The David Whitmire Hearst Jr. Foundation Jeanne and Gary Herberger Hervey Family Fund at The San Diego Foundation International Prostate Cancer Foundation Joseph C. Lewis Douglas F. Manchester Diane and Thomas Might Pedal the Cause Conrad T. Prebys Roche Life Science Diagnostics Corporation Dinah and William* Ruch T. Denny Sanford Takeda Karen and Stuart Tanz The Pew Charitable Trusts ViaCord

Adventist Health System Alexandria Real Estate Equities Rocio and Lorenzo Berho Martin C. Berman Steve Black Susan and James Blair Blair Blum and Jim Sexton Roberta and Malin Burnham Mary and Adam Cherry Chesley G. Magruder Foundation Columbia University Olivia and Peter Farrell Pauline M. Foster Claudia Dunaway and Hudson Freeze Carol and John Gallagher Audrey S. Geisel Hanna and Mark Gleiberman Deana and Morley Golden Kathryn Goria and Arthur Carlson Jeanne Jones and Don Breitenberg Carol Lazier and James A. Merritt Amy and Perry Nisen Milley Mai and Douglas Obenshain Pfizer Robert M. Golden Foundation Linda Robertson and Roger Mills University of California, San Diego Kristiina Vuori Kim and Carl Ware Stephanie and Stephen Williams

$25,000– $49,999 Cassie and Christopher Comins Phyllis and Daniel Epstein Florida Blue Bill Gerhart Marleigh and Alan Gleicher Marilena and Gregory Lucier Julie and Robert Mandell Robin and Hank Nordhoff Science, Technology and Research Support (STARS) W. Henry Weinberg * Deceased

Donors

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$1,000– $9,999

Donors

A. Friends’ Foundation Agios Pharmaceuticals Inc. Elizabeth and Darryl Albertson Alex’s Lemonade Stand Foundation for Childhood Cancer Letizia Amadini-Lane Dode and David Anderson Ardilla Technologies Therese and Robert Armstrong Stephen Aselage Julie and Paul Baker Mindy and Don Barto/Mason’s Hope Molly Jaeger Begent and David Begent Diane and Knox Bell Maggi and Alejandro Berho BioMarin Pharmaceutical Inc. Ruth Claire Black Cindy and Laurence Bloch Bravelets John R. Cashman Sanford Smith and Ellan Cates-Smith Children’s Hospital Los Angeles Deborah and Paul Cleveland Anonymous Bess and Arthur Collias Julie and Gordon Cooke Pamela and Keith Cox Dextra Laboratories Gabrielle and David Dorne Nancy and James Eastman Jee Yeon Shin and Ted Ebel Jennifer and Kurt Eve F. Hoffmann - La Roche Ltd. Michiko and Minoru Fukuda Gatan, Inc. Bannister Hall Fund at The San Diego Foundation Glenn Foundation for Medical Research

Anne-Marie Gordon Gordon Ross Medical Foundation Lynn Gorguze and Scott Peters Grace Wilsey Foundation Kay and William Gurtin Zandra Rhodes and Salah M. Hassanein Lynn and Roger Headrick Kathy and Philip Henry Susan and Paul Hering Harold Hill Dodie and Loren Hinkelman Reena and Samuel Horowitz Debra and Scott Huennekens Margaret and Robert Hulter Human Biomolecular Research Institute HumanZyme, Inc. International Stem Cell Corporation Debby and Hal Jacobs Kactis 4 Kancer Joe Kostiha Barbara and JC Kyrillos Jill and Cheston Larson Carol and George Lattimer Lisa and Gary Levine Sheila and Jeffrey Lipinsky Local Independent Charities of America Kimberly and Ray McKewon Mary and Jack McKinnon Erin and Scott McPherson Silvana and Alberto Michan Lucille A. Miller Barbara and Howard Milstein Marci and Ronald Morgan Bruce A. Morrice Bradley A. Morrice Michael P. Orlando Thomas A. Page Jane and Richard Pickett Patricia and James Poitras

SUMMER 2016

Joan and Ben Pollard Jori H. Potiker Nancy and John Pouk Qualcomm Inc. Sue Raffee Retrophin, Inc. Nicole and Jim Reynolds Ann Riner and John Conyers Melanie and William Roper Marilyn and Michael Rosen Stacy and Donald Rosenberg Mary and Harold Sadler Michael P. Sampson Doreen and Myron Schonbrun Edward R. Schulak Elizabeth Schwarzbach Julie and Costa Sevastopoulos Jean and Gary Shekhter Kathleen Shelton Cynthia and Aaron Shenkman John F. Sheridan Karen and Jeffrey Silberman Mary and Raybourn Smiser Abby Smith Society for Glycobiology Brenda and Roy Steege StemCell Technologies The Neuromuscular Disease Foundation The Simon-Strauss Foundation Ultragenyx Pharmaceuticals Erna* and Andrew Viterbi Jennifer and Douglas Walner Pearl and Kevin Walsh Randi and Charles Wax Judy and Jack* White Maureen and Tom White Mary Jane and James Wiesler Patricia and Mark Wiggins Armi and Albert Williams

* Deceased

Yokohama University Sara Zaknoen Emma and Leo Zuckerman

STAR STRUCK

The Science Technology and Research Support (STARS) made a generous donation to Sanford Burnham Prebys Medical Discovery Institute (SBP) The contribution was presented at the STARS Annual Meeting on June 20 in Sherman Oaks. SBP extends its sincere gratitude to the STARS members for their tremendous support during the past 15 years.

GRAD SCHOOL GATHERS

Sanford Burnham Prebys Medical Discovery Institute (SBP) graduate students retreated to Temecula for three days at the end of May. The 28 students shared research and received constructive feedback from fellow students on their presentations. The retreat also featured talks from SBP graduate program alumna now working at Inhibrx, a San Diego immunotherapeutic company, and a biophysicist at Genentech.

Thank you for supporting us. If you are interested in continuing your support or learning more about us, please go to giving@SBPdiscovery.org or call 1-877-454-5702.

Donors

PATHWAYS

There are nearly 7,000 different rare diseases that impact more than 25 million Americans and their families. National Institutes of Health

SUMMER 2016

Patients join Dr. Hudson Freeze (center) in SBP’s Sanford Children’s Health auditorium

SCIENCE BENEFITING PATIENTS

Lifeline:

Families Unite on Rare Disease Day There’s an African proverb that states, “It takes a whole village to raise a child.” Make that a worldwide village and a child with a truly rare disease and you have the impetus behind the free Rare Disease Day symposium organized annually by Hudson Freeze, Ph.D., director of the Human Genetics Program. Freeze not only spends long hours in his laboratory examining mutations in the genes of afflicted children, he also spends many additional hours communicating with the children’s parents, scientists, pharmaceutical companies and government officials—in countries all around the world— to coordinate research and find answers. Then he brings them all together at our La Jolla campus to talk face to face and share what they know. For many parents, Rare Disease Day is the first time they realize they’re not alone. One parent from

Germany, in an interview with The New Yorker, said, “It feels like we’ve come home, but to a home we didn’t know we had.” NEW TERRITORY Freeze, who received a Fishman Fund Award in its first year, has always been one to investigate the unusual in life. For his doctoral thesis, he studied the soil-living amoeba Dictyostelium discoideum and the enzymes used to make its carbohydrate sheath. That research led him into a new field called glycobiology.

PATHWAYS

Children and parents gathered to learn about their health

Photos courtesy of Victor Goodpasture/ProDigital

Today, Freeze is an acknowledged expert on rare congenital disorders of glycosylation (CDGs) that lead to a myriad of symptoms, including developmental delays and problems with the nervous system, muscles and intestines. “By the time I joined the faculty,” he recalls, “I began to get phone calls from physicians who didn’t know what to do with patients with glycosylation disorders. It’s not taught in medical school, so I became the goto person. I helped fill a gap.”

Little is known about what causes the mutations that give rise to congenital disorders of glycosylation.

CDG were featured at this year’s seventh Rare Disease Day. “It’s an inherited error in metabolism,” Freeze explains, “which affects how sugars are attached to proteins and lipids.” There are numerous CDG subtypes, and each is quite rare, making diagnosis difficult. FREEZE ADVOCATES Besides organizing Rare Disease Day, Freeze regularly travels to Capitol Hill to brief Congress members on biomedical research topics. He advocates changing FDA rules that hinder timely development and testing of novel drugs for rare diseases and urges creating incentives for pharmaceutical companies to develop drugs—even when there are only a dozen prospective patients who will benefit. “As a scientist who won’t be here forever,” Freeze adds, “I’m compelled to advocate now for continued research and pass along what we know.” It’s that sort of determination that perpetuates the legacy of SBP founders William and Lillian Fishman.

SUMMER 2016

SCIENCE BENEFITING PATIENTS

A Career Making a Difference Dr. José Luis Millán, a professor in the Human Genetics Program, is the longest-tenured scientist at Sanford Burnham Prebys Medical Discovery Institute.

A young José Luis Millán sat in a clinical chemistry lab in his native Argentina, itching to know more. “I wanted to know how biology worked,” he said. “In the clinic, I enjoyed interacting with patients, drawing blood and performing tests, but there was no path forward to do research.”

When his mentor advised him to apply for a trainee fellowship, Millán began writing to scientists around the world. One, Dr. William Fishman, wrote back: “Come join me in La Jolla.” “So I arrived to join this organization on August 4, 1977,” Millán says, “one year after it was founded. Back then, we worked out of an old apartment complex in downtown La Jolla, using the rooms as laboratories. One room was converted into a darkroom. We used kitchen sinks to do experiments. It was all very primitive, but it was an exciting time of discovery.” Today, Millán can look back on a near-40-year career at the Institute highlighted by remarkable success. He received the Fishman Fund Award the first year they were bestowed, saw his groundbreaking discoveries presented by NIH to

Congress members to argue the impact of translational research, and watched his research contribute to a unique FDA-approved drug treatment for children with a rare disease. The drug is called asfotase alfa (brand name Strensiq), a bonetargeted version of the enzyme that’s missing in hypophosphatasia. Millán attributes much of his success to the “freedom to research” established by the Fishmans. “This Institute allows me to pursue the avenues that interest me,” he says. After working alongside the Fishmans for three years, Millán accepted an invitation to study in Northern Sweden. There, in only three years, he earned his Ph.D. and published 12 papers. Laughing, he says, “They have almost 24 hours of sunlight in summer, you know, so I worked a lot.”

PATHWAYS

José Luis Millán, Ph.D. and Morgan Fischer

Upon returning to La Jolla, he continued studying alkaline phosphatase, an enzyme that held the key to treating hypophosphatasia—a debilitating condition that causes soft, brittle bones diagnosed in only one in 100,000 births. One of the 100,000 was four-year-old Morgan Fischer— who happened to live in San Diego. Morgan’s mother, Kate, had inquired about the potential new drug that Millán was developing with a pharmaceutical company. She really wanted her daughter to be included in the clinical trials and made that happen, as well as initiating a meeting with Millán.

That interaction added another highlight to his life. While Millán had been thrilled to see research breakthroughs in his laboratory, it paled in comparison to witnessing Morgan’s improvement. She began visiting him regularly. Morgan’s bones were growing; she was gaining strength daily. Millán was charmed by her buoyant personality. “We’re Ph.D.s,” he says, “so meeting the kids and seeing how something that we have contributed to affects their lives is priceless.”

SUMMER 2016

SCIENCE BENEFITING PATIENTS

A Path to Hope Morgan Fischer’s life has changed dramatically thanks to Dr. Millán’s research When she was sixteen weeks pregnant, Kate Fischer’s doctors looked at ultrasound images and informed her and her husband, Michael, that their unborn daughter’s bones weren’t forming correctly. The outlook wasn’t hopeful; if their daughter even survived childbirth, she’d live only a few pain-filled weeks.

A scientist in La Jolla, Dr. José Luis Millán, at Sanford Burnham Prebys Medical Discovery Institute (SBP) was working with a pharmaceutical company to develop a drug to treat this rare disease. It appeared to be effective in laboratory mice. Now it was ready to be tested on humans. Kate, Michael and Morgan eagerly signed up.

Ten years later, Morgan is an energetic little girl who rides a tan-and-black pony, goes camping with the YMCA Adventure Princesses and is packing for a ski trip to Lake Tahoe. “She’s our miracle baby,” Kate says. “And we have Dr. Millán to thank.”

“Within just a week or so of starting on this drug,” recalls Michael, “Morgan, who’d never had much of an appetite, walked into the kitchen and said, ‘I’m hungry.’ Then, in no time at all, she was climbing stairs and playing with her younger brother.”

Though she modestly deflects praise, Kate took a strong hand in Morgan’s care. Upon learning of her daughter’s diagnosis— hypophosphatasia (HPP)—she searched the internet and reached out to experts. There were few of them; one was in St. Louis, and another was in Winnipeg.

The family actively supports continued research into rare diseases. Kate joined the Soft Bones Foundation and serves as an informed and compassionate liaison for others impacted by HPP. Morgan, who communicates with a confidence well beyond her 10 years, speaks at scientific conventions and symposia.

After her daughter survived her first weeks, Kate began taking her to these experts, making round-trip flights as often as once a month. There were surgeries, physical therapies, restrictive diets and, eventually, when Morgan was four years old, a bit of hope.

X-ray of 20-day-old infant with soft bone disease, with visible increase in bone density after 24 weeks of treatment

“They call her a hero, but it’s people like Dr. Millán and the other researchers who are the real heroes.” Kate Fischer

PATHWAYS

DISCOVERY HUB

35 MILLION 0 people live with HIV.

people have been cured despite advances in treatment. Source: World Health Organization

Reawakening Sleeping HIV to Eliminate the Virus Like an inactive volcano, HIV can lie dormant in a person’s cells for decades, evading antiretroviral drugs only to re-emerge as an active, progressive viral explosion. But a new class of drugs identified by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) may be able to purge pockets of the sleeping virus, eliminating it once and for all. “Antiretroviral therapies have made it possible for people to live with AIDS for decades,” says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at SBP. “However, small reservoirs of a patient’s cells hide the virus and go undetected by the immune system. If you take people off antiretroviral therapies, some of these dormant cells reawaken to make more virus. “The key for a cure for HIV is to purge these cells that have dormant HIV.” Reactivating latent HIV-infected cells so that they can be killed off once and for all is called “shock and kill.” The approach has remained elusive so far, because drugs that reawaken the virus could also trigger massive immune system activation, which itself could be deadly.

Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program

Chanda’s research, published in the journal Cell Host & Microbe, shows that a class of drugs called Smac mimetics tap into a cell’s pathway, which wakes up the virus but, based on clinical studies and their data, doesn’t appear to activate the immune system. “Our experiments led us to develop a strategy of using Smac mimetics to reawaken dormant HIV so that we could then kill it with antiviral therapy,” says Chanda. Part of the reason that HIV’s genes stay hidden in its host is that they cover themselves with tightly wound DNA. Chanda and his collaborator at SBP, Nicholas Cosford, Ph.D., reasoned that combining Smac mimetics with a class of drugs called histone deacetylase inhibitors, which unfurl the DNA, may boost the effect of their drug. “When we tested the drug combination, we anticipated that we would see a synergy, because the drugs work along parallel pathways. What we didn’t expect was the level of activation—the potency and efficacy with which we were able to reverse latency in patient samples without triggering immune cell death,” Chanda says. The scientists hope to partner with a pharmaceutical company to develop these molecules for testing in animal models of HIV and then move them into the clinic if they meet safety and efficacy criteria.

SUMMER 2016

DISCOVERY HUB

52 MINS

One person dies of melanoma every 52 minutes, and the rates of melanoma have been rising for at least 30 years.

How a Rare Sugar May Help Prevent Skin Cancer Metastasis

Source: American Cancer Society

Who would have thought that sugar could be good for you? Recent research from the laboratory of Ze’ev Ronai, Ph.D., chief scientific advisor of Sanford Burnham Prebys Medical Discovery Institute (SBP) and professor in its NCI-designated Cancer Center, suggests that a rare sugar found in seaweed, mushrooms, seeds and other foods may be able to slow down the growth and metastasis of melanoma, the most dangerous form of skin cancer. The sugar, called L-fucose, has been linked to a number of pathological conditions including inflammation and cancer. The findings from Ronai’s team suggest that for patients with melanoma, consuming more L-fucose could help fight the disease.

Seaweed contains the sugar L-fucose, which inhibits the spread of melanoma

Sugars, such as glucose and sucrose, come from many different sources and are routinely used by the body. Some sugars, including L-fucose, provide tags on cellsurface proteins that signal inflammation and help direct cell migration. Previous research has shown that changes in the amount of L-fucose on cells are associated with breast and stomach cancers. The study, which was published in Science Signaling, began with an investigation of activating transcription factor 2 (ATF2), a protein that Ronai’s group has studied for over 20 years. ATF2 controls many genes and had been implicated in the development of melanoma. “To our surprise, one of the genes found to be regulated by ATF2 was fucokinase

Ze’ev Ronai, Ph.D., chief scientific advisor

(FUK), which controls the ability of cells to process the dietary sugar L-fucose into a form that is useable for the modification (fucosylation) of proteins, many of which are on the cell surface,” says Ronai. “In human samples, we found that advanced-stage melanomas had more active ATF2 and less FUK compared to early stage-melanoma. We suspect that lower amounts of the sugar on melanoma cells make them less sticky and more likely to break free from the tumor and metastasize,” Ronai explains. Interestingly, in mice with melanoma, the researchers were able to increase fucosylation by adding the modified sugar to their drinking water. “The dietary result was especially gratifying, because it suggests that fucosylation levels could be modified by the simple addition of L-fucose to drinking water,” adds Ronai. Ronai’s lab is continuing to explore how fucosylation and other sugar coatings affect the immune system and impact cancer.

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DISCOVERY HUB More than

33%

of U.S. children and adults are obese. Source: National Health and Nutrition Examination Survey

Generating Good Fat by Pushing the Right Buttons You probably think of fat as a bad thing—unsightly, bulging muffin tops and love handles that store calories that we don’t seem to need. But that’s only true of white fat. There’s another kind, known as brown fat, that actually boosts your metabolism by burning calories to produce heat.

Obesity is a rising epidemic in the U.S. More than onethird of U.S. adults are obese, and obesity has more than quadrupled in adolescents in the past 30 years.

Calorie-burning brown fat comes with health benefits too. For example, people with higherthan-average amounts of brown fat are more likely to maintain a healthy weight and are less likely to develop type 2 diabetes. But today, the only sure way to change white fat to brown—a process called “fat browning”— is chronic exposure to extremely cold temperatures. “Our goal is to change that,” explains Sheila Collins, Ph.D., professor in the Integrative Metabolism Program at Sanford Burnham Prebys Medical Discovery Institute’s (SBP) Lake Nona campus in Florida. “We are part of the effort in obesity research to find drugs to help people burn more calories through fat browning.” Collins’ lab recently made an important advance in understanding the molecular basis of this unique phenomenon. In a paper published in the Journal of Clinical Investigation, they showed that it requires the protein complex mTORC1. “This result came as a surprise, because we knew that mTORC1 is a key player in stimulating growth in many tissues, including white fat,” says Collins. “Since fat browning is

Sheila Collins, Ph.D., professor in the Integrative Metabolism Program

New insight into how white fat (left) becomes brown fat (right)

an opposing process, the fact that it requires the same protein complex is big news.” Collins’ lab found that mTORC1 is directly activated by protein kinase A (PKA), which was already known to play a role in fat browning. However, the way mTORC1 is turned on by PKA is completely different from how it’s activated by growth-promoting signals. “Fat regulation isn’t black and white—our results help put color in the picture. Imagine mTORC1 is a machine with multiple capabilities, like a printer/copier/scanner. Energy-storage signaling pushes one set of buttons and gets one outcome (fat storage), while PKA pushes another set to get a different outcome (an increase in brown fat). “These results add an important detail to our understanding of fat browning, which will help direct the steps that can be targeted for future anti-obesity drugs,” Collins says. Collins, who is a fitness instructor on the side, points out that the significant benefits of exercise—strengthening your heart, toning your muscles and reducing stress—should not be overlooked. So an anti-obesity drug is likely only a part of the solution.

SUMMER 2016

DISCOVERY HUB

Huaxi Xu, Ph.D., professor in the Degenerative Diseases Program

Another Piece in the Alzheimer’s Puzzle Alzheimer’s disease (AD), which slowly, tragically destroys patients’ memory, is common—it affects one in nine people over the age of 65. And it’s affecting more people as the population ages, making the need for effective treatments even more urgent. However, AD involves multiple degenerative processes, so finding therapies that slow its advance requires fitting together innumerable pieces of a highly complicated puzzle.

Alzheimer’s disease is the

leading cause of death in the U.S. Source: Alzheimer’s Association

Histological view of Tau protein tangles within a neuron

Researchers in the lab of Huaxi Xu, Ph.D., professor in the Degenerative Diseases Program at SBP, are on a mission to help solve that puzzle. In a study published in Scientific Reports, the team demonstrated that a previously understudied protein helps block important disease processes in AD.

“Although little is known about the normal function of RPS23RG1, we previously showed that in mice, it regulates betaamyloid and tau, the small proteins that clump together to form the plaques and tangles found in the brains of AD patients.” These plaques and tangles are toxic to neurons.

Xu’s team showed that humans with AD have lower-than-normal levels of a protein called RPS23RG1, and that increasing the amount of RPS23RG1 in mouse models of AD improves spatial learning and preserves neural connections.

“Our next step is to continue to examine how RPS23RG1 levels may be increased to treat AD and to learn more about what it does in normal healthy brains,” says Xu.

“We are excited to have discovered this new contributor to Alzheimer’s pathogenesis. Our new results strongly suggest that increasing levels of RPS23RG1 may be a potential therapeutic approach for treating AD,” says Xu.

PATHWAYS

“Much of our work is made possible through the generous donations of people like you.” Kristiina Vuori, M.D., Ph.D. and President

Trustees

FOUNDERS Dr. William H. and Lillian Fishman HONORARY TRUSTEES

Roberta and Malin Burnham Joseph C. Lewis Conrad T. Prebys T. Denny Sanford TRUSTEES AND OFFICERS

J. Bernard Machen, D.D.S., M.S., Ph.D. CHAIRMAN

James C. Blair, Ph.D. VICE CHAIRMAN

Perry Nisen, M.D., Ph.D. CHIEF EXECUTIVE OFFICER DONALD BREN CHIEF EXECUTIVE CHAIR

Kristiina Vuori, M.D., Ph.D. PRESIDENT PROFESSOR, NCI-DESIGNATED CANCER CENTER PAULINE AND STANLEY FOSTER PRESIDENTIAL CHAIR

Gary Chessum, ACMA, CGMA CHIEF FINANCIAL OFFICER

Knox Bell CORPORATE SECRETARY

Lorenzo M. Berho David W. Down Daniel J. Epstein M. Wainwright Fishburn, Jr. Pauline M. Foster Carol G. Gallagher, Pharm.D. Patrick J. Geraghty William Gerhart Alan A. Gleicher Jeanne L. Herberger, Ph.D. Donald L. Jernigan, Ph.D. Gregory T. Lucier Papa Doug Manchester Henry L. Nordhoff Douglas H. Obenshain Edward R. Schulak Stuart A. Tanz Rasesh Thakkar Luder G. Whitlock Jr.

The research at Sanford Burnham Prebys Medical Discovery Institute is made possible in part by philanthropic support. For more information, please contact giving@SBPdiscovery.org or 1-877-454-5702. 10901 North Torrey Pines Road La Jolla, California 92037

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Our work is made possible through the generous donations of people like you. If you wish to support our research, please email giving@SBPdiscovery.org or call 1-877-454-5702.