Pathways Summer 2019

A SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE PUBLICATION | IMMUNE RESEARCH ISSUE | SUMMER 2019

MASTERS OF

IMMUNITY Scientists are seizing control of your body’s first line of defense

THE IMMUNE RESEARCH ISSUE SUMMER 2019

ON THE COVER Carl Ware, Ph.D., uses herpes virus “tricks” to control the immune system. See page 4.

DIALING UP DEFENSE Researchers at Sanford Burnham Prebys are learning new ways to manipulate immune cells to fight disease.

Contents 4

Waves of Discovery

8 12

Shaping Immunity

16 17 18 20 23 24 27

The A-TEAM

28

Seeking Answers in the Molecular Maze of Heart Disease

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Inspiring Future Scientists at the STEM EXPO

32 36

Opening a World of Hope

Going for the Goal

Insights into the Heart A Patient Meets Heart Pioneers Bring It! What’s It All About?

President’s Circle Donors Fishman Fund Award Ceremony Celebrates Early-Career Scientists

Discovery Hub

10901 North Torrey Pines Road La Jolla, California 92037

SBPdiscovery.org

FOLLOW US ON:

@SBPdiscovery

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

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HIV seeks refuge in immune cells to avoid elimination.

See page 12.

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Letter from the President

DIALING UP DEFENSE The journal Nature recently reported that the biomedical sciences have helped global average life expectancy rise by 20 years since 1960. Advances in the field of immunology, among others, have certainly been a contributing factor. Today, thanks to a better understanding of the immune system, we have vaccines that provide long-term immunity against many deadly diseases, and we have effective immunotherapies to treat debilitating autoimmune conditions and certain cancers.

But there is still so much to learn. Immunotherapies don’t work for everyone—and we don’t know why. HIV continues to devastate resource-poor communities.

And we desperately need new approaches to fight deadly battles against drugresistant pathogens that are constantly evolving.

Kristiina Vuori, M.D., Ph.D.

At Sanford Burnham Prebys, we are dedicated to uncovering the origins of disease and launching bold new strategies that lay the foundation for achieving cures. Our researchers continue to make meaningful discoveries and translate those findings into innovative therapies that improve human health.

In this issue of Pathways, you’ll read Waves of Discovery, which describes Dr. Carl Ware’s immunology research and his collaboration with Eli Lilly, which led to a new clinical trial for autoimmune disease. Shaping Immunity discusses Dr. Francesca Marassi’s advances leading to better treatments for antibiotic-resistant infections— one of the biggest public health challenges of our time. In Going for the Goal, we share how Dr. Sumit Chanda’s work toward eliminating HIV has opened new paths to boost the immune system to fight cancer.

Within these pages we also keep you up to date on some of our community activities and events, including Bring It!—a fundraiser that supports biomedical research at our Institute.

Great discoveries require equally great resources. Your continued support helps us make discoveries that lead to better ways to prevent, treat and cure disease, and we thank you for your generosity.

Kristiina Vuori, M.D., Ph.D. President Pauline and Stanley Foster Presidential Chair Professor, NCI-designated Cancer Center

“Breakthroughs in immunology are leading to better treatments for diseases that are caused—and cured— by the immune system.”

Kristiina Vuori, M.D., Ph.D.

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FACULTY

Waves

As a surfer, Dr. Carl Ware rides on the surface of the sea. In the lab, he does a deeper dive—into the ebb and flow of the immune system.

The ocean, every surfer knows, can be both friend and foe. Time a wave just right, and you can take a joy ride along the crest of paradise.

One wrong move, though, and that beautiful breaker will toss you into a tumbling, humbling wipeout.

A lifelong surfer, Carl Ware, Ph.D., experiences those two sides of the ocean on a near-daily basis. And as a full-time scientist, he sees that same dualistic power in the entity he’s spent his life studying: the immune system.

“The immune system is a friend; without it, we couldn’t live on Earth,” says Ware, director of the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys. “It helps protect us from all sorts of pathogens, and even cancer. But when the immune system sees an individual’s normal tissue as foe, autoimmune disease develops.”

Learning how to navigate that delicate friend-foe line has been the focus of Ware’s 40-year research career. To do so, he and his research team take their cues from some of the planet’s foremost immune system experts: viruses.

“No one knows the immune system better than viruses,” Ware explains. “They’re our teachers. By studying them, we can understand how the immune system functions, and then design therapies to either turn on the immune system, or turn it off.”

BALANCING ACT One type of those immune system “teachers” are the herpes viruses. Best known for causing cold sores or chickenpox, this group of viruses can stay with a person for life, despite a strong immune system attack.

“The viruses have evolved techniques—tricks, if you will—that allow them to establish latency, where they hide out in certain cells,” Ware says.

Carl Ware, Ph.D., is director of the Infectious and Inflammatory Diseases Center

of

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Discovery

“We’ve made tremendous strides in advancing the science for conditions such as rheumatoid arthritis, lupus and psoriasis.”

Carl Ware, Ph.D.

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ABOUT AUTOIMMUNE DISEASES An autoimmune disease is a condition in which your immune system mistakenly attacks your body.

More than 23 million Americans have an autoimmune disease— nearly 8 percent of the U.S. population.

Studies suggest almost 75% of those affected by autoimmune disorders are women.

Autoimmune diseases represent: • The fourth-largest cause of disability among women.

• The eighth-leading cause of death of women between the ages of 15 and 64.

Credit: American Autoimmune Related Diseases Association, Inc.

Immune Therapy Enters Clinical Trial An investigational immune therapy that came out of a collaboration between Sanford Burnham Prebys and Eli Lilly has now entered a Phase 1 clinical trial.

The compound, called LY3361237, is being developed as a potential treatment for autoimmune diseases such as lupus, psoriasis and rheumatoid arthritis. In autoimmune diseases, the immune system attacks healthy tissue, causing inflammation and damage. The compound is designed to inhibit this inflammation by activating an immune checkpoint receptor called BTLA, short for “B and T lymphocyte attenuator.”

Carl Ware, Ph.D., led the foundational research into the role of BTLA and formed the collaboration with Eli Lilly in 2015.

“In a little more than three years, we’ve put this candidate in clinical trials. That’s exciting,” Ware says. “It illustrates how the fundamental understanding of a biological process—in this case, the role of checkpoint receptors in immune function—can translate to the development of new medicines.”

One way they evade the immune system is by usurping molecules called cytokines— proteins secreted by immune cells that normally act as communication signals. Some proteins are pro-inflammatory—signaling the immune system to attack. Others, often called checkpoints, order the immune system to “put the brakes on” and leave tissue alone.

Understanding this signaling system is at the heart of Ware’s research; and it has profound implications for treating autoimmune diseases, cancer and infectious diseases.

In fact, therapies based on manipulating immune signals already exist—including some cancer immunotherapy drugs known as “checkpoint inhibitors,” and drugs for autoimmune diseases.

Ware wants to add to that list. His work has led to the discovery of several tumor necrosis factor (TNF) cytokines and their signaling circuitry. Some of that work laid the foundation for an investigational autoimmune therapy that recently entered a Phase 1 clinical trial through a partnership with Eli Lilly [see box on left].

Currently, Ware and his team are working on another molecule they hope will lead to a potential autoimmune therapy. That project resulted from close observations of cytomegalovirus, a herpes virus that causes a mono-like illness. The virus has a gene that mimics a “checkpoint” cytokine, suppressing an immune response. The team developed a drug based on that gene.

On the flip side, the lab is working on a molecule that activates the immune system— directing it to tumors the immune cells were previously unaware of.

“Cancer and autoimmunity are two sides of the same coin,” Ware says. “In cancer, oftentimes the brakes are on the immune cells, and they can’t go after the tumor. In autoimmunity, the brakes have been taken off. We’re working to address both sides.”

FATEFUL ENCOUNTER Growing up in Fullerton, Calif., Ware was not thinking about viruses—or even a career in science.

“I was surfing!” he says with a laugh.

But as an undergrad at the University of California, Irvine, he fell in love with biology.

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Ware’s research team delves into the complex world of the immune system

Then, one fateful day during his junior year, he ran into a postdoc in the biochemistry department. The researcher let Ware look in the microscope while he added cytokines to a culture dish of cancer cells.

The cancer cells died. “They were all shriveled up, just basically floating there,” Ware remembers. “I thought, this is fantastic!

I want to study this!”

He ended up getting his Ph.D. in that lab, working on TNF cytokines, and launched a career in immunology research that gives him as much joy today as it did that first day in the lab.

THE IMMUNE SYSTEM CAN FIGHT CANCER Checkpoint inhibitors are treatments that release the natural brakes of your immune system so that T cells can recognize and attack cancer cells.

The other thing that gives him joy, of course, is surfing. One of his sons spent 12 years as a professional surfer, and Ware always participates in the Luau & Legends of Surfing Invitational in La Jolla, a cancer fundraiser.

His other son shares the same passion for science, pursuing a Ph.D. in immunology.

But mostly, it is the excitement of venturing into the unknown—to catch that next wave of discovery—that draws him, day after day, to both science and surfing.

“When you paddle out into the ocean, you paddle out into the wilderness,” Ware says.

“That is what I love most.”

Colored scanning electron micrograph of T lymphocytes attaching to a cancer cell

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Francesca Marassi, Ph.D., is a professor in the Cancer Metabolism and Signaling Networks Program

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FACULTY

Shaping Immunity With a scientific mind and an artistic eye, Dr. Francesca Marassi is uncovering the form—and function—of infection and immunity.

“It looks like a little spaceship, almost,” says Francesca Marassi, Ph.D. “It’s really cool.”

Marassi is contemplating the 3-D, multicolored image she’s just pulled up on her computer screen. The intersecting strands of red, blue, green and gold—with a purple, pearl-sized ball in the center—look a bit like a spider’s web. Or even, when viewed from another angle, like an alien, jellyfish-like creature.

What it really is, though, is a protein called vitronectin—and it’s Marassi’s pride and joy.

Earlier this year, she and her team were the first to discover what that protein looks like, mapping out how its 459 amino acids fold together in intricate molecular detail to form the image now on her screen.

That’s important because vitronectin, found in abundance in blood, plays a key role in the innate immune system—your body’s first line of defense against invading pathogens. In fact, one of the deadliest pathogens in history— the bacterium that causes plague—attacks vitronectin as soon as it invades.

“It hijacks it and then degrades it,” explains Marassi, a professor in the NCI-designated Cancer Center at Sanford Burnham Prebys.

“And that takes away this key component of the innate immune system, so it can’t fight the infection.”

A LOCK AND KEY The bacterium that causes plague—which killed up to 60 percent of Europe’s population in the 1300s—is called Yersinia pestis (Y. pestis), and it takes center stage in Marassi’s lab.

Y. pestis is highly virulent, and while it can be treated with antibiotics, the U.S. government has classified it as a Category A bioterrorism agent—something that could be used to threaten public health or national security.

That’s reason enough to study it, but Marassi is most interested in it as a model for how pathogens interact with the human immune system. Numerous bacteria, for example, hijack vitronectin. Studying the pathways Y. pestis uses can open up novel ways of treating other bacteria, too—a critical task in an era of growing antibiotic resistance.

To do that, though, scientists first have to understand what these proteins look like at a molecular level.

“Proteins are not just strings of amino acids; they also fold together into different shapes,” Marassi explains. “And those shapes are really important for their function.”

To determine those structures, she and her

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Vitronectin is a major blood protein that controls immunity, coagulation and many diseases including cancer

“The emerging threat of bacterial drug resistance makes our work particularly important.”

Francesca Marassi, Ph.D.

team use nuclear magnetic resonance (NMR) spectroscopy, an MRI-like technology that helps them peer inside proteins. Recently, they’ve identified not only the structure of vitronectin but also the structure of a Y. pestis protein that attacks vitronectin.

Now, the team is mapping the interaction that occurs between those two proteins, as well as other interactions in the immune system.

“If you can see the molecular picture of what’s happening, in detail, then you can design a drug that targets that,” she says.

“It’s like a lock and key.”

BETWEEN TWO WORLDS Originally from the small city of Mantua, Italy, Marassi moved to Toronto, Canada, with her family when she was 12.

“I loved to draw and paint, but I also loved math and chemistry and physics,” she says of her childhood. “I was always in between the two worlds.”

Structural biology—with its emphasis on shapes, patterns and symmetries—turned out to be a perfect fit. After earning her Ph.D. in chemistry from the University of Toronto, she did a postdoc at the University of Pennsylvania and then joined the structural biology division at the Wistar Institute in Philadelphia, part of the Penn campus. She came to Sanford Burnham Prebys in 2000.

“Having the freedom to pursue your ideas is the most important thing, and that’s what I have here,” she says.

Outside of her lab, she likes to hike and spend time with her husband (a biochemist) and their dog. And, of course, draw.

Recently, she’s shared some of her artistic side with her colleagues—sketching a pencil drawing for some campus posters, and creating computer-generated, stylized images of various scientific discoveries at the Institute. The images were made into a mural just around the corner from her office.

And while Marassi doesn’t call herself an artist, she notes that the two worlds share some commonalities.

“There’s something to this process of just getting lost in a project that you can experience with science, with art, with writing, with any sort of activity that engages your imaginative side,” she says.

“That’s what attracts me to what I do.”

That, and the joy of discovering both form and function in a beautiful, symmetrical protein.

“The rewarding part is being able to make a contribution to biology,” she notes, then smiles. “The really fun part is doing it.”

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Marassi oversees a lab exploring the structure and function of membrane proteins

Deaths from drug-resistant infections and other causes in 2050 Antimicrobialresistant infections

10.0m 8.2m

Cancer Diabetes

1.5m

Diarrheal disease

1.4m

Road traffic accidents

1.2m

Measles

130,000

Cholera

1200,000

Tetanus

60,000

Source: Review on Antimicrobial Resistance

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Going for the Goal Dr. Sumit Chanda takes a high-risk approach to science with an ambitious endgame: everything from cancer therapies to a cure for HIV. On Sunday mornings, Sumit Chanda, Ph.D., can usually be found on the soccer field, playing an informal pickup game with friends.

“We just have fun,” he insists. He adds with a laugh, “My goal is not to get injured! If I don’t get injured, it’s a successful day.”

That play-it-safe strategy, though, only applies on the soccer field. In his lab at Sanford Burnham Prebys, his approach is completely the opposite: Go big or go home.

“In academic research, we should be more high risk, try to disrupt things,” says Chanda, a professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys. “You should be failing 95 percent of the time because you should be doing something that innovative and that risky.”

Innovation is the hallmark of Chanda’s lab, and his goals are definitely big. Like a cure for HIV. An HIV vaccine. New, breakthrough cancer therapies. And they’re not just pipe dreams, either; he’s getting results.

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“The future of HIV/AIDS treatment lies in curing the disease.”

Sumit Chanda, Ph.D.

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

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Sumit Chanda, Ph.D., leads a team of scientists working toward the next generation of antiviral medicines

DID YOU KNOW? 36.9 million

people worldwide are currently living with HIV/AIDS. Source: HIV.gov

In the U.S.,

1 in 7

living with HIV

unaware

is of their infection

“WAKING UP” HIV Take the idea of an HIV cure. Although antiretroviral drugs—which prevent the virus from replicating—have been hugely successful in turning HIV into a chronic, manageable disease, patients must take them for life.

The reason is that HIV essentially “goes to sleep” in a tiny number of the body’s cells—a process called latency, where the virus doesn’t make proteins or replicate. It can live like this for decades, hidden from the immune system like a hibernating bear protected from the winter cold.

The only way to cure HIV, then, is to purge this small reservoir of infected cells. That means you have to wake up those viruses—smoke ’em out, essentially—and then kill them.

That’s easier said than done. “It’s been kind of this Goldilocks problem, where some agents wake up HIV too much, and the immune system goes haywire,” Chanda explains. “Others don’t wake up the virus robustly enough.”

In 2016, though, the team discovered a molecule that wakes up HIV “just right”—enough to bring it into the open, but not enough to cause a potentially harmful immune response.

“We’re super excited,” Chanda says. “We’re now studying this in combination with immunotherapies to see if we can get rid of the infected cells and essentially clear the body of HIV, once and for all.”

UNEXPECTED JOURNEYS The thing that fascinates Chanda about viruses is that they offer a window into so many biological pathways.

“We study how a virus uses our cell machinery to replicate and escape immune surveillance,” he says. “That has implications for developing antiviral drugs, but it also illuminates pathways in autoimmune diseases and cancer.”

As a result, the lab’s work sometimes goes in unexpected directions. For example, the team identified a protein,

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known as PQBP1, that enables the immune system to detect active (not latent) HIV. The group is now using that knowledge to create an HIV vaccine adjuvant—a substance that could increase the effectiveness of a potential HIV vaccine.

That’s exciting enough on its own.

But the team took a chance and investigated a second possibility: Could the same molecule boost the immune system against cancer?

The answer was yes. The team now hopes to partner with a biotech company that could take the molecule to a potential clinical trial in cancer.

“We had no idea this was going to be important for cancer,” Chanda says. “But viruses tend to illuminate pathways that are critical in a lot of different diseases.”

MAKING AN IMPACT The son of two biochemists who came to the U.S. from India, Chanda grew up in Rochester, New York, and considered careers in computers, medicine and science. Science won out.

“I’m kind of a geek about technology, but it was the ability to impact human health on a global level that made me choose science,” he explains.

He earned his Ph.D. in molecular pharmacology at Stanford University (where he met his wife, also a scientist—they now have two children) and did a postdoc at the Genomics Institute of the Novartis Research Foundation (GNF). He went on to lead a cellular genomics research group at GNF. He thought he would spend his career on the pharmaceutical side. But in 2007, he came to Sanford Burnham Prebys.

“What I missed was the ability to work on something much more high risk than a pharmaceutical company typically has the appetite for,” Chanda explains.

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He stresses that his group’s projects are made possible through collaborations with labs nationwide— and the supportive environment of Sanford Burnham Prebys.

“Here, we’re encouraged to go out on those limbs and say, ‘What if?’” he adds. “At the same time, this Institute also has the capacity to move discoveries to a stage where they can translate into a practical impact on human health. It’s a really special place.”

Colored scanning electron micrograph of HIV viruses budding from T cell

HIV plays hide-and-seek HIV “hides” in a dormant state in reservoirs throughout the body. Latent viruses periodically become activated to produce new viruses and infect new cells.

1. Initial infection CD4+ T cell HIV

2. Establishment of latency

3. HIV lies dormant in T cell genome

CD4+ T cell

CD4+ T cell

OR

3. HIV activates, causing virus production CD4+ T cell

Infection of other CD4+ T cells

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From left: Rolf Bodmer, Ph.D., Chris Larson, Ph.D., Karen Ocorr, Ph.D., Evan Muse, M.D., Ph.D., Alexandre Colas, Ph.D.

STORIES FROM THE HEART

The A-TEAM

Your heart skips a beat, races, then flutters. You think to yourself: Is this something serious? Perhaps you instinctively feel for your pulse, which is weak and erratic. These heart palpitations could be atrial fibrillation (AFib), one of the most common types of arrhythmia.

At least six million people in the U.S. alone are living with some variation of AFib. For some, the symptoms are worrisome. For others, it’s very serious and can increase a person’s risk of stroke and more severe heart problems.

Current treatment options for AFib are limited. Some include serious side effects—and are rarely curative.

Our vision at Sanford Burnham Prebys is very ambitious: to emerge as the world’s leader in AFib drug discovery and development by 2025. Beyond this, our vision is to change the course of care for all people with AFib.

“In recent years we have learned that there are many—actually over a hundred—genetic variations linked to AFib,” says Evan Muse, M.D., Ph.D., a cardiologist at Scripps Clinic and investigator at Scripps Research Translational Institute, who will be collaborating with Sanford Burnham Prebys. “In other words, not all AFib is alike. This opens the door to developing more personalized treatments, tailored for each patient, based on genetics, heart rhythm characteristics and clinical risk factors.”

“Now is the time for innovation,

discovery and improvement in AFib health outcomes,” says Rolf Bodmer, Ph.D., director of Sanford Burnham Prebys’ Development, Aging and Regeneration Program. “As scientists, we are focused on the goal—helping patients with AFib—and we are collaborating toward that goal.”

We have assembled a team of our talented experts in fundamental biology and drug discovery and clinical researchers from Scripps Clinic to develop personalized, lowrisk treatments for AFib. Our plans include developing essential industry and philanthropic partnerships with those who understand the impact of collaborative science and are passionate about better solutions for patients with AFib. We invite you to make an impact. sbpdiscovery.org/donate

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STORIES FROM THE HEART

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Insights into the Heart Insights speaker series invites a scientist, a doctor and a patient to share their perspectives on heart disease.

To help educate the public about heart health and share the latest scientific advances, Sanford Burnham Prebys invited the San Diego community to Insights: Heart Disease—a free panel discussion focused on matters of the heart.

More than 70 people attended the event to hear featured speakers: • A nthony N. DeMaria, M.D., founding director of UC San Diego’s Sulpizio Cardiovascular Center • K aren Ocorr, Ph.D., assistant professor at Sanford Burnham Prebys • D onna Marie Robinson, an individual living with heart failure In his remarks, DeMaria shared that the biggest breakthrough in heart disease is a new class of drugs for atherosclerosis called PCSK9 inhibitors. He said that these drugs, delivered by injection, are so effective “that with continued research, it’s possible that the next generation may not know the ravages of atherosclerosis.”

Heart disease research is paramount to improving the health of Americans.

It’s the leading cause of death—killing one in four adults every year.

Ocorr explained how fruit flies are helping her study the genes that cause atrial fibrillation (AFib), a condition in which the heart’s rhythm is thrown off. AFib itself is usually not life threatening, but can lead to blood clots, strokes and heart failure.

“Fruit flies are ideal to study the genes that affect the heart,” said Ocorr. “The proteins called ion channels that make the heart contract are the same as [in] humans, so we can observe which genes cause an aberrant heartbeat and find ways to fix them.”

Robinson, a former banking executive, described how her life changed

in October 2015 when she was diagnosed with heart failure. Prior to that, she ate healthfully and engaged in physical fitness—high-intensity spinning, weight training and Pilates.

Today, she wears a defibrillator/ pacemaker and is an advocate for the American Heart Association.

Following the presentations, the panelists engaged in a lively questionand-answer session with the audience.

DeMaria advised: “We should all move to Italy for a lot of reasons. The best data in the world supports a Mediterranean diet and exercise.”

But for challenging conditions that occur independent of lifestyle—we need more research to improve heart health.

From left: Anthony N. DeMaria, M.D., Donna Marie Robinson, and Karen Ocorr, Ph.D.

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STORIES FROM THE HEART

A Patient Meets Heart Pioneers

Donna Marie Robinson visits Sanford Burnham Prebys to meet four early-career scientists—all recipients of American Heart Association fellowships.

From left: Katja Birker, Clara Guida, Ph.D., Donna Marie Robinson, Chiara Nicoletti, Ph.D., and Ee Phie Tan, Ph.D.

“I may have heart failure, but heart failure doesn’t have me,” says Donna Marie Robinson.

“I’m here today because of advances in biomedical research that led to excellent medical care and medicines that saved—and continue to save—my life.”

Robinson, a former Bank of America executive, was in peak fitness when she passed out on vacation in the south of France. When she returned to the U.S., she was diagnosed with heart failure, a condition that affects about five million Americans every year. Although genetics can influence the risk for heart conditions in many ways, Robinson was unsuspecting.

“It came as quite a shock to hear the diagnosis ‘heart failure,’ but I’m learning to live with it,” says Robinson.

“Instead of high-intensity spinning

classes, I now practice yoga to keep my body and mind in shape.”

On a recent visit to our campus, Robinson met with Katja Birker, Clara Guida, Ph.D., Chiara Nicoletti, Ph.D., and Ee Phie Tan, Ph.D., all recipients of American Heart Association fellowships for early-career scientists.

Over a lunch of healthy salads, they described how their research might one day improve the care of patients with heart disease.

Birker, a graduate student, is studying

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genes that could contribute to hypoplastic left heart syndrome—a condition that affects roughly two to four of every 10,000 babies. Guida, a postdoc, is studying the inheritance of epigenetic marks in fruit flies fed a high-fat diet that causes heart problems in offspring. Nicoletti, a postdoc, is studying the genetics of metabolic changes in skeletal muscle that lead to heart disease. And Tan, also a postdoc, is looking at the cell networks that govern lipophagy—a process that can contribute to toxic fat deposits and heart disease when gone awry.

“It was so interesting to see how they use worms and fruit flies as research tools to study the genes that affect heart function and how the heart ages over time,” says Robinson. “It’s an eye-opener to see firsthand how scientists work, and then realize this is where medical breakthroughs begin.

“But the best part was seeing how passionate these women are about their research. It’s women like these who will create the paths that lead to better medicine for heart patients—like me.”

The American Heart Association (AHA) supports early-career scientists with passion, commitment and focus. Fellowships help finance projects that will help people live healthier lives, free of cardiovascular disease and stroke.

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EVENTS

2019 Bring It! Discovery at the Disco Tech From the moment guests stepped into the disco-lit room, it was clear that Bring It! was not your typical fundraiser.

Donned in bell-bottoms, sequined bodysuits and platform heels, this year’s guests sampled hors d’oeuvres supplied by roller skating servers and grooved to classics such as “Stayin’ Alive” and “Dancing Queen.”

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The 70s-themed event, held on May 2, 2019, at the Del Mar Fairgrounds, drew a crowd of more than 400 attendees—the largest yet—a testament to the hard work and dedication of co-chairs Juli Oh and Matt Browne, and Sarah and David Szekeres. John Weisbarth, host of Tiny House Nation and a San Diego native, emceed the event for the third year in a row.

While fun was had by all, the night’s mission was never far from anyone’s mind: fundraising for our Institute’s work to find cures for diseases such as Alzheimer’s, cancer, heart disease, diabetes and more.

Co-chair Sarah Szekeres shared her personal story about why research is important to her: “Learning I have the BRCA2 gene mutation, which puts me at a greater risk of breast and ovarian cancer, has been an overwhelming and frightening experience for me and my family. It’s through basic research that we will develop effective medicines or tests that prevent, diagnose or treat disease—and hopefully create a future where my daughter, and her children and grandchildren, aren’t afraid of cancer or Alzheimer’s or the many serious diseases our society faces today.”

Guests vied for an opportunity to participate in onstage competitions— spots so coveted that they were raffled off to the highest bidders. Topscoring teams partook in absurdly hilarious games, such as “Hungry Hungry Human,” where guests attempted to collect plastic balls from an inflated pool while wheeled on a dolly; and “Rocky,” where participants furiously boxed and ran in place to reach the most steps on a pedometer. Despite wearing wigs and hats, contestants even braved a bobbing-for-apples-style competition involving candy encased in a Jello mold.

Altogether, Bring It! certainly put the “fun” in fundraising. We hope to see you next year—stay tuned for more details about the date and theme of the event.

Building for Breakthroughs We’re proud to partner with the innovators at Sanford Burnham Prebys.

$25,000 Sponsor

$15,000 Sponsor Marleigh & Alan Gleicher

$10,000 Sponsor

Marilena & Greg Lucier

$5,000 Sponsor

Jeanne Herberger, Ph.D.

Robin & Hank Nordhoff

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What’s It All About?

For Phyllis and Dan Epstein, it’s all about helping others live life to the fullest.

Phyllis and Dan Epstein grew up in families that believed in giving back—if not with money then at least with time. Their recent gifts to Sanford Burnham Prebys support finding solutions to the most pressing issues confronting cancer patients.

Q. Why is Sanford Burnham Prebys a good philanthropic investment?

Phyllis and Dan: We chose Sanford Burnham Prebys because basic science is often where breakthroughs occur that create innovative healthcare advances. We are particularly impressed that the scientists understand the need to partner with clinicians and pharma to take their discoveries from “bench to bedside.” Our goal is to see research advances introduced to the clinic in practical ways that benefit patients.

Q. What are your hopes for the future?

Phyllis and Dan: We would like to leave a legacy that makes a difference in people’s lives. We are both cancer survivors, so we are especially eager to see progress made in preventing, diagnosing and treating the disease. We all know someone who has suffered from cancer and its effects—family members, friends or colleagues. Our hopes are that one way or another, the disease will be minimized—stopped in its tracks so that people can live rich, full lives. That’s what it’s all about.

Phyllis and Dan Epstein

Q. What are you most proud of?

Dan: I’ve spent my career building ConAm Management Corporation, and I’m very proud that since 1975 we have successfully developed and managed housing—including affordable housing— throughout the U.S. Now, as a couple, Phyllis and I have a “side career” investing in opportunities that can solve problems—homelessness, healthcare and education, as well as music and art—causes that enrich people’s lives and help those who need assistance. We are also very proud of our two children and five grandchildren, and very pleased that they live close by in San Diego.

“Our charitable giving is centered on the building blocks for a good life: education, health and the arts.”

Phyllis Epstein

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President’s Circle Donors – 2018 Sanford Burnham Prebys Medical Discovery Institute honors the following donors who generously supported our Institute with a gift of $1,000 or more in 2018.

$50,000 AND ABOVE

$10,000 – $24,999

Nicole and Robert Barth

Alagille Syndrome Alliance Alexandria Real Estate Equities Vivian and Jon Barfield Rocio and Lorenzo Berho Roberta and Malin Burnham Mary and Adam Cherry Columbia University Cooley, LLP Daiichi Sankyo Claudia Dunaway and Hudson Freeze Nancy and James Eastman The David Geffen Foundation Hanna and Mark Gleiberman Connie K. Golden Deana and Morley Golden Heron Therapeutics, Inc. Tammy and Lawrence Hershfield NuVasive, Inc. Pfizer Rady Children’s Hospital Retrophin, Inc. Marilyn and Michael Rosen The Schultz Family Science, Technology and Research Support (STARS) Christine J. Shamborsky Cynthia and Aaron Shenkman Tobacco-Related Disease Research Program University of California, San Diego Kristiina Vuori Mary Walshok Randi and Charles Wax William’s Warriors, Inc.

Susan and James Blair Nancy and Matthew Browar Bruce Ford and Anne Smith Bundy Foundation Epstein Family Foundation Gilbert J. Martin Foundation Jeanne Herberger, Ph.D. Hervey Family Fund at the San Diego Foundation Jean Perkins Foundation Diane and Thomas Might Pedal the Cause Dinah Ruch Shaffer Family Foundation Debbie Turner Dr. Andrew Viterbi

Donors

Danna and Ben Weiss Richard P. Woltman

$25,000– $49,999 Marleigh and Alan Gleicher Illumina Robin and Hank Nordhoff Trish and Daniel Ryan Karen and Stuart Tanz Melissa Seipel and William Gerhart

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$1,000– $9,999

Creative Fusion, Inc.

Gilda and Jeffery Adler

Cushman & Wakefield

Karen L. Alexander

Patrick Crutcher

Jodie and David Alonso

The Carole & Robert Daly Charitable Foundation

Lisa and Steven Altman

Danaher Corporation

Amour Fund

Elaine and Dave Darwin

Dode and David Anderson

Andrea and Doug Davidson

Karen and Jeremy Anderson

The Diller-von Furstenberg Family Foundation

Shelli and Irving Azoff Florence Azria BDO Diane and Knox Bell Bradford C. Benter Eve Benton and Malcolm Bund Maggie and Alejandro Berho Gillian and David Berman Fernanda Bertotti BioAlta, LLC Dawn and Ralph Birchmeier Blachford-Cooper Foundation, Inc. Julie and Les Blake Ronne and Linden Blue Diane Birnie Bock Steven K. Brauer Irma and Robert Brewer Julie and George Bronstein Kathy and Ed Brown Juli Oh and Matthew Browne Jill Brzozowski and William A. LeMasters Julie and Kenneth Buechler Sue and Howard Busby Carsey Living Trust Pamela J. Carter CBRE Linda Chester and Kenneth Rind CiBots Inc. Kathy and Louie Coffman David Cohen Lisa Cohen and Michael Step Jackie and Brian Collesano Heather and Matt Conneran Julie and Gordon Cooke Liz and Michael Copley Robin and Daniel Crabtree Gigi Cramer

* Deceased

25

Carol and Thomas Dillon Direct Electron, LP Patti and Dave Down Alexia and Ladd El Wardani Jennifer and Kurt Eve Beryl and Edward Flom Michiko and Minoru Fukuda Larry Gagosian Gatan, Inc. Audrey S. Geisel* Tabby and Barry Gerber Ann and Jim Gianopulos Ed Gillenwaters Gordon Ross Medical Foundation Brian Grazer Lynn and Roger Headrick Dodie and Loren Hinkelman Jane Holzer Douglas Horton Linda Howard Robyn Hudgens Arianna Huffington Candace and Kent Humber Sharon Hunt Ashley and Ted Jacobs Joan and Brent Jacobs Catriona Jamieson and Sheldon Morris Kathryn and Douglas Kanaan Ana Khouri KPMG LLP Carol and George Lattimer Susan Lee Waggener and Steven McCracken Milley Mai and Douglas Obenshain Kimberly and Michael Manhard Dawn and James Mason Margret and J. Nevins McBride

Donors

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Donors

Karen and Neil McFarlane

Sascha S. Siegel

Diane McKernan and Steve Lyman

The Simon-Strauss Foundation

Kimberly and Ray McKewon

Single Particle, LLC

Mary and Jack McKinnon

Society for Glycobiology

Silvana and Alberto Michan

Square 1 Bank

Amy and Vincent Monteparte

Brenda and Roy Steege

Moon Valley Nurseries

StemCell Technologies

Marci and Ronald Morgan

Kari L. Stoever

Bradley A. Morrice

Gayle Sullivan

Bruce A. Morrice

Alex Syed

Peter Morton

Sarah and David Szekeres

Murfey Construction

10x Genomics

Melissa and Scott Murfey

The San Diego Foundation

Josie and James Myers

Molly McCormick Thornton

Neurocrine Biosciences, Inc.

Jonell and Greg Tibbitts

Elizabeth and Carlos Nunez

Julie and Court Turner

Oxford Finance

Zuhre and Ahmet Tutuncu

Charles Patton

Rebecca and Chris Twomey

Pegasus Building Services Co., Inc.

Union Bank

Becky Petitt

Sandy and Bob Uslander

Jori H. Potiker

Nancy Vaughan

Sue Raffee

Leigh Vosseller

Reflow Medical, Inc.

Lina and Christian Waage

Resnick Family Foundation, Inc.

Wachter Family Foundation

Nicole and Jim Reynolds

Peggy Walker-Conner

Ann Riner and John Conyers

Jennifer and Douglas Walner

Shereen and Isa Rizk

Kim and Carl Ware

Linda Robertson and Roger Mills

Joan Weaver

Liberty Ross and Jimmy Iovine

Ellen G. Weinstein

Joyleen S. Rottenstein

Wells Fargo Bank

Lawrence Rudolph

Ruth and Stanley Westreich

Saint John Regional Hospital Foundation

Judy White

Beth and Norman Saks

Helen and Clynn Wilker

Sheryl Sandberg and Bobby Kotick

Armi and Albert Williams

San Diego Padres Baseball Club

Helen and Pharrell Williams

Meredith and Richard Schoebel

Stephanie and Stephen Williams

Barbara Scholz and Giovanni Paternostro

Willis Towers Watson

Doreen and Myron Schonbrun

Molly and Burnet Wohlford

Marie G. Schrup

Beverly Wolgast

Sheel and Peter Seidler

Martha and Gerard Wyrsch

Julie and Costa Sevastopoulos

Dong-Er Zhang

Carolyn and Jay Short

Emma and Leo Zuckerman

SUMMER 2019

27

EDUCATION

Fishman Fund Award Ceremony Celebrates Early-Career Scientists The generosity of our donors keeps the tradition alive For the 17th consecutive year, exceptional postdoctoral researchers at Sanford Burnham Prebys were recognized at the annual Fishman Fund Award ceremony, held at the Sanford Consortium in La Jolla.

The $10,000 award is given to promising young scientists to advance their careers by attending scientific workshops and international conferences to learn the latest about developments in their research field. A Fishman Fund Fellowship, which provides salary support for two years in addition to benefits and a career-development stipend, was awarded at the event for the second time in our history.

Established in 2001 by Reena Horowitz and Mary Bradley in honor of Institute founders Dr. William and Lillian Fishman, the award recognizes young scientists who have chosen a field of research and planned a career path to achieve their goals. The competition is open to all Sanford Burnham Prebys postdoctoral researchers.

Co-founder Horowitz, Fishman Fund Board member Armi Williams and former Institute trustee Andrew Viterbi, presented the awards.

Co-founder designee Jeanne Jones shared that since the fund’s inception, 64 recipients have been awarded. “These awards honor Dr. William and Lillian Fishman—the founders of Sanford Burnham Prebys—who believed in helping young postdoctoral researchers become great scientists.”

Ee Phie Tan, Ph.D., is studying autophagy—a cellular recycling process that helps maintain health.

Koen Galenkamp, Ph.D., specializes in seeking ways to starve pancreatic cancer tumors of the food they need to survive and grow.

Usue Etxaniz Irigoien, Ph.D. (Fishman Fund Fellowship), is studying communication signals between nerves and muscles to advance neuromuscular disease research.

Laura Martin-Sancho, Ph.D., is working to develop antiviral medicines that will combat infectious diseases such as influenza, dengue, and West Nile and Zika viruses.

From left to right: Ee Phie Tan, Ph.D., Koen Galenkamp, Ph.D., Usue Etxaniz, Ph.D., and Laura Martin-Sancho, Ph.D.

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EDUCATION

Seeking Answers in the Molecular Maze of Heart Disease Graduate student Katja Birker’s research doesn’t miss a beat

Growing up in the picturesque Canadian town of Kelowna, where she spent summers alternating between lakeside hikes and working in her parents’ restaurant and clothing stores, Katja Birker’s initial career path didn’t include research.

“I thought that I would become a surgeon. I’m fascinated by the human body, and I knew my mission in life was to help others, so it seemed like a natural fit,” she says. “But once I stepped foot in a lab, everything clicked. I liked that I could ask questions and find answers that had the power to help people in need.”

Today, Birker’s research, conducted under the guidance of Rolf Bodmer, Ph.D., director and professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys, could help some of the world’s most vulnerable patients.

Working with Mayo Clinic, Birker aims to identify genes and molecular pathways that may contribute to hypoplastic left heart syndrome (HLHS), a heart defect that affects roughly one out of every 4,000 babies in the U.S. Infants with HLHS must undergo multiple heart surgeries that start within the first two weeks of life.

“I absolutely love my project,” says Birker.

“Motivation is never a problem.”

While her project focuses on HLHS, the work’s fundamental nature could also reveal how the heart develops. Using fruit flies, a surprisingly good model of the human heart, Birker removes candidate genes—identified through whole-genome sequencing of infants with HLHS at Mayo Clinic—and observes the effect on the organ’s development and function. Downstream changes can range from a missing heart to irregular heartbeats to an enlarged heart.

“Many congenital heart defects share the same molecular pathways,” says Birker. “Our hope is that our findings will apply to other, more common heart conditions, such as malfunctioning valves or holes in the heart chambers.”

Birker is delighted that she is able to pursue this important work in San Diego, a city she has long admired.

“San Diego is a biologist’s dream: There are incredible research institutions and thousands of biotech companies. Nearly every day multiple, fascinating scientific seminars take place at our Institute or nearby,” says Birker.

“I tell people, ‘If you are a country singer, you head to Nashville. If you are a scientist, you go to San Diego.’”

SUMMER 2019

“There is no magic wand to cure congenital heart conditions— we have to do the research.”

Katja Birker

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COMMUNITY

Inspiring Future Scientists at the STEM EXPO Armed with wiggly worms and striped zebrafish, on Saturday, March 2, more than 20 volunteers from Sanford Burnham Prebys helped kids and their families learn about the power of DNA at the San Diego Festival of Science & Engineering’s EXPO Day. One of the largest STEM (Science, Technology, Engineering and Math) festivals in the U.S., this year’s event featured more than 130 interactive exhibits designed to ignite a passion for science in K–12 students. Despite an uncharacteristically rainy morning, an estimated 17,000 people attended.

For Joseph Lancman, Ph.D., a postdoctoral researcher who was the first in his family to graduate from college, the festival was an opportunity to provide children with the experience he wished he’d had as a kid.

SUMMER 2019

“Growing up, I knew I was interested in human health, but I had no idea that research was an option,” Lancman says. “Like many kids, I thought I wanted to be a doctor. But in college, I quickly learned that I wanted to know more. I wanted to know what causes disease and how scientists go about finding cures.”

At our booth, postdoctoral researchers, graduate students and staff helped children don paper lab coats and explore DNA-themed activities.

Children were able to see live worms with DNA mutations that affect their movement, courtesy of the lab of Malene Hansen, Ph.D., professor in the Development, Aging and Regeneration Program. Compared to normal worms, some mutant worms moved mindlessly in circles, and others remained relatively immobile— illustrating how changes in a DNA sequence can dramatically affect life.

At the adjacent station, provided by the lab of Duc Dong, Ph.D., assistant professor in the Human Genetics Program, children squinted through microscopes and peered into fish tanks to observe how DNA changes can dramatically affect the heartbeat of zebrafish—one of the most powerful model organisms used to study vertebrate biology.

Lancman, who works in the Dong lab, made sure he explained the exhibit in child-friendly language (he credits his 4-year-old son for this skill).

“I want kids to know that science is like a puzzle,” he explains. “It takes time to put all the pieces together, but when you’re done, you can see the big picture—and that big picture can lead to improving human health.”

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FROM RESEARCH, THE POWER TO CURE

Opening a World of Hope Sanford Burnham Prebys’ 10th annual Rare Disease Day strengthens the global network of families, physicians and researchers to advance research for rare diseases This year marked Sanford Burnham Prebys’ 10th annual Rare Disease Day—an event that brings families living with uncommon disorders together and gives them an opportunity to meet with researchers and clinicians. The topic was rare bone disorders and bone cancers, with a special emphasis on a condition called multiple hereditary exostoses (MHE) that causes numerous bone tumors in children. Surgery and pain management are currently the only treatment options for MHE patients.

95% of rare diseases do not have FDA-approved drug treatments

Now, palovarotene, the first medicine that may be able to slow or halt this bone growth, is being tested in a clinical trial— potentially saving children with MHE from a lifetime of surgeries. Yu Yamaguchi, M.D., Ph.D., symposium chair and professor in Sanford Burnham Prebys’ Human Genetics Program, participated in key laboratory studies needed in order for the clinical trial to begin.

“For the first time, a diagnosis doesn’t feel like a life sentence,” says Greta Falkner, who attended the symposium with her 8-year-old son, Jackson. He has MHE and has undergone 13 surgeries to date.

“Today we have hope for a cure.”

The launch of a study evaluating

palovarotene as an MHE treatment is the result of decades of hard work and collaboration among scientists, clinicians, Clementia Pharmaceuticals (now Ipsen) and the MHE Research Foundation—a patient advocacy and support group.

The symposium featured an all-star lineup of distinguished speakers in the field of skeletal biology and MHE research, including keynote speaker Henry Kronenberg, M.D., of Massachusetts General Hospital and Maurizio Pacifici, Ph.D., of Children’s Hospital of Philadelphia, whose research formed the scientific rationale for the use of the drug in MHE. The event was sponsored by the MHE Research Foundation and Clementia Pharmaceuticals.

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“We are so grateful that Sanford Burnham Prebys holds this Rare Disease Day symposium to bring together all the important players in rare disease drug discovery: scientists, doctors, families and drug companies. It is literally ‘bench to bedside’ at one event,” says Sarah Ziegler, who co-founded the MHE Research Foundation with Craig and Susan Eaton after Sarah’s son was diagnosed with MHE in 1993.

Multiple parents and children with MHE, some of whom are enrolled in the clinical trial, attended the event. For most of these children, this was the first time they’d met another person with their condition.

The study has also provided a unique opportunity for the children to see science in action.

“Amanda was reading Little House in the Big Woods, so we came up with the idea that she is a ‘medical pioneer,’” says Alicia Walker, whose 8-year-old daughter, Amanda, is enrolled in the clinical trial.

“We are typically tech-free at home, but we got her a digital camera, printer and scrapbook, which has made this journey even more special for her. When we go home, she’ll present to her class about visiting Sanford Burnham Prebys and meeting her ‘heroes.’”

The condition is typically diagnosed when bumps appear on a child’s body.

These bumps are benign (not cancerous) and can range from mild nuisances that are alleviated with lifestyle changes to

severe and life altering [read one boy’s MHE story on page 34].

“Even if the drug just freezes the progression of MHE, that would be everything to us,” says Alicia. “We are telling everyone to stay positive and send good thoughts that the medicine is working.”

“I am truly humbled to see firsthand what the initiation of this clinical trial means to so many children and their families,” says Yamaguchi. “It is a true testament to the power of foundational research—and the power of many helping hands—that the MHE community has arrived at this milestone today, nearly 25 years after the gene that causes MHE was identified.”

Greta adds, “Until Jackson’s diagnosis, I never understood the importance of research and how influential it is in the treatment of disease. We are so grateful to Dr. Yamaguchi and others for doing the underground work that led to this day. Our hope lies in this research. It’s all we’ve got.”

At least 350 million people worldwide suffer from rare diseases, defined in the U.S. as those affecting fewer than 200,000 Americans at any given time.

Source: World Health Organization

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FROM RESEARCH, THE POWER TO CURE

Jackson’s Story As a mother of triplets, Greta Falkner knew something was off when one of her sons, 6-month-old Jackson, had a hard lump on his rib. But getting an answer proved a tougher proposition: Her well-meaning pediatrician thought it might have been a kick from one of his siblings while in the womb and told her not to worry.

Jackson underwent his first surgery at 18 months old to remove bone tumors caused by MHE

But when another bump appeared on his back six months later, she immediately rushed him to the emergency room. As the doctor completed a full-body skeletal scan, she pleaded, “Please just tell me it’s not cancer.”

“They said it’s not cancer, but it’s very serious,” says Greta. “And we walked to a room with four or five computer screens with all of these images shown. Those two little spots were devastating to me, but I instantly saw that it was only the tip of the iceberg. Jackson had hundreds of those bumps inside of his body.”

Jackson’s left forearm is now mostly metal after the removal of a complex tumor that intertwined his radius and ulna

It was then that she learned he had a rare genetic condition called multiple hereditary exostoses (MHE) that causes numerous bone tumors in children.

While most people inherit the condition, Jackson’s mutation arose spontaneously and has been particularly aggressive. He underwent his first surgery when he was 18 months old, and he’s had 13 surgeries since then.

“The first emotion he could convey was pain,” says Greta. “It has been really, really heartbreaking.”

“It has been truly so amazing to see this research come to life. What Dr. Yamaguchi and others have been working on for so long might be able to help my son, and others like him,” says Greta Falkner. “For the first time, we have hope.”

Shortly after Jackson’s diagnosis, Greta was connected to Sarah Ziegler, cofounder of the patient support and advocacy group, the MHE Research Foundation. For the first time, Greta was able to speak with someone who knew about MHE firsthand—Sarah’s now-28year-old son has the condition—and she had some answers.

Sarah became a close friend and mentor throughout Jackson’s journey. In fact, she was the first person who notified Greta about the clinical trial for palovarotene, the first potential treatment for MHE. “I will never forget the moment she called,” says Greta. “She said, ‘The cure is ready.’”

Jackson became one of the youngest patients to enroll in the study.

FROM RESEARCH, THE POWER TO CURE

Bone Buddies Two girls with MHE take a VIP tour of Dr. Yu Yamaguchi’s lab and become fast friends after meeting at the Rare Disease Day symposium.

Despite living at opposite ends of the West Coast—8-year-old Amanda resides in Los Angeles, and 10-yearold Linnea lives in Alaska—these two girls have a lot in common. They’re both cat lovers, they’re both excited to perform in their schools’ upcoming talent shows and science is their favorite subject.

Both of them also happen to have a rare bone condition called multiple hereditary exostoses, or MHE. Only one in 50,000 people has the disorder.

The two girls met at Sanford Burnham Prebys’ Rare Disease Day symposium in San Diego after Amanda spotted Linnea playing cards and introduced herself (“Making friends is my superpower,” Amanda explains). They soon became inseparable.

We caught up with Amanda and Linnea after a special tour of Dr. Yamaguchi’s lab to learn more about who they are and what it’s like being a kid living with MHE. Linnea, I know you traveled really far to be here. Could you tell me more about your home?

Linnea: Right now it’s snowing—we live in Anchorage, Alaska. And once I heal from my surgery, I can sled!

From left: Linnea, Amanda, and Yu Yamaguchi, M.D.

Amanda: I read about that in Little House in the Big Woods! The snow comes, and then they can get syrup out of the trees.

Linnea: That she has MHE. Since I’m the only kid in the whole school who has MHE, it’s nice to know someone who is more like me.

Amanda, what do you like to do for fun?

Amanda: Same!

Amanda: I like to dance! I go to ballet after school, and I’m practicing for the talent show.

What would it mean to you to have a medicine that could help your bones?

Let’s talk a little bit about your bones. How do you tell your friends about them?

Linnea: I usually just tell them the full name of the condition: multiple hereditary exostoses.

Amanda: Me, too!

What do they usually say after that?

Amanda: They say, “Whatta, whatta, whatta?!”

Linnea: Then I usually explain that I grow bones where I’m not supposed to.

Linnea, what’s the most awesome thing about Amanda? And Amanda, what’s the most awesome thing about Linnea?

Amanda: I think about the other kids it could help. Sometimes I don’t like taking the medicine, but I tell myself that I’m doing this because it could help me and other kids in the future.

Whenever I have to miss school [because of the clinical trial], I always tell my friends, “I’m not ditching! I’m doing this to help other kids with MHE.” Linnea: That would be really cool.

I wouldn’t take away having MHE, because that’s what makes me who I am. But the surgeries I need are really scary. It would be incredible to never have to worry about getting surgery again.

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DISCOVERY HUB

Jerold Chun, M.D., Ph.D., senior vice president of Neuroscience Drug Discovery

Morphing Brain DNA Hints at Whole New Way to Treat Alzheimer’s A study in Nature reveals that gene recombination in neurons produces thousands of new gene variants within Alzheimer’s disease brains. The research shows for the first time how the Alzheimer’s-linked gene, APP, is reshuffled by using the same type of enzyme found in HIV.

“We used new approaches to study the APP gene, which gives rise to amyloid plaques, a pathological hallmark of the disease,” says Jerold Chun, M.D., Ph.D., senior author of the paper and professor and senior vice president of Neuroscience Drug Discovery at Sanford Burnham Prebys. “Gene recombination—a type of genetic reshuffling—was discovered as both a normal process for the brain and one that goes wrong in Alzheimer’s disease.”

Amyloid plaques on a nerve cell

The scientists found that the gene recombination process required an enzyme called reverse transcriptase, the same type of enzyme HIV uses to infect cells. Although there is no medical evidence that HIV or AIDS cause Alzheimer’s disease, existing FDA-approved antiretroviral therapies for HIV that block reverse transcriptase might also be able to halt the creation of APP variants—and could be explored as a new treatment for Alzheimer’s disease.

The thousands of APP gene variants observed in Alzheimer’s disease provide an explanation for the failures of more than

Alzheimer’s disease is the

6TH

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

400 clinical trials targeting single forms of amyloid or involved enzymes,” says Chun.

“APP gene recombination may be producing many disease-related proteins that were therapeutically missed in prior clinical trials.

“Our findings provide a scientific rationale for immediate clinical evaluation of HIV antiretroviral therapies in people with Alzheimer’s disease. Such studies may also be valuable for high-risk populations, such as people with rare genetic forms of Alzheimer’s disease.

“Today’s discovery is a step forward—but there is so much that we still don’t know,” says Chun. “We hope to evaluate gene recombination in more brains, in different parts of the brain and involving other recombined genes—in Alzheimer’s disease as well as other neurodegenerative and neurological diseases—and use this knowledge to design effective therapies targeting gene recombination.”

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DISCOVERY HUB

Left: Jorge Moscat, Ph.D., professor and director of the Cancer Metabolism and Signaling Networks Program and director of Metabolism Initiatives Right: Maria Diaz-Meco Ph.D., professor in the Cancer Metabolism and Signaling Networks Program

Research May Identify a Deadly Form of Colorectal Cancer Colorectal cancers arise from earlier growths, called polyps, found on the inner surface of the colon. Scientists are now learning that polyps use two distinct molecular pathways as they progress to cancer, called the “conventional” and “alternative” pathways. The latter leads to an often treatment-resistant tumor, called serrated colorectal cancer; thus, distinguishing between these two cancer types holds implications for patient care.

20% TO 30% of colon cancers arise from serrated polyps Source: Cleveland Clinic

Serrated colon cancer biopsy removed during a colonoscopy

Now, scientists from Sanford Burnham Prebys, in collaboration with clinicians from Scripps Clinic, have identified that the loss of two genes drives the formation of serrated colorectal cancer—yielding potential biomarkers. The research has also identified a combination treatment that has treated the cancer in mice. The study was published in Immunity.

kinase C zeta. Mice lacking these genes spontaneously developed serrated colorectal cancer, and expression of these proteins was reduced in human samples of serrated colorectal cancer.

“Serrated adenocarcinomas pose difficult diagnostic and therapeutic challenges to clinical medicine,” says Darren Sigal, M.D., a study author and program director of gastrointestinal oncology at Scripps MD Anderson Cancer Center. “This study identified two genetic markers that may clearly identify this colon cancer subgroup and offer an effective precision medicine treatment option.”

“Our findings identify both a promising combination treatment for serrated colorectal cancer and potential biomarkers that can identify this cancer subtype—both of which are urgently needed,” says Jorge Moscat, Ph.D., senior author of the paper and director and professor in the Cancer Metabolism and Signaling Networks Program. “Additionally, the mouse model we created more closely mirrors the human disease, an important step that could help reveal more insights into this deadly cancer.”

In the study, the scientists identified that the loss of two genes drove the formation of serrated colorectal cancer: protein kinase C lambda/iota and protein

Combined treatment with two compounds— a TGF-beta receptor inhibitor and an antiPD-L1—reduced the number and size of tumors in mice.

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DISCOVERY HUB

Erkki Ruoslahti, M.D., Ph.D., distinguished professor in the Tumor Microenvironment and Cancer Immunology Program

Compound Advances to Phase 1 Trial for Pancreatic Cancer Solid tumors, such as pancreatic cancer, are difficult to treat. The tumor cells are often surrounded by thick fibrotic walls, making it hard for treatments to get access to the tumor cells. As a result, many solid tumors are also some of the deadliest cancers, including brain, ovarian and pancreatic cancer. Fewer than 10 percent of people with pancreatic cancer live more than five years.

A compound discovered at Sanford Burnham Prebys has advanced into a Phase 1 trial for metastatic pancreatic cancer. Called CEND-1 (scientifically known as iRGD), the compound has been exclusively licensed to a private company, DrugCendR Inc. The drug candidate was discovered in the laboratory of Erkki Ruoslahti, M.D., Ph.D., distinguished professor at Sanford Burnham Prebys and founder, president and CEO of DrugCendR. Pancreatic mass showing malignant cells

CEND-1 overcomes barriers to allow cancer treatments to penetrate farther into tumors.

The compound harnesses a transport pathway that appears to be designed to ferry nutrients to a tissue that is nutrient deficient.

Ruoslahti’s research team named it the CendR pathway.

“Cancer cells hijack processes they can use to fuel tumor growth, and the CendR pathway is one such route,” says Ruoslahti.

“CEND-1 activates the CendR pathway only

150

Every day, more than

adults

are diagnosed with pancreatic cancer in the United States

in tumors and not elsewhere in the body, and that allows us to sneak a drug into the activated pathway.”

Research in mouse models of cancer shows that if a drug is given at the same time as CEND-1, it is swept into the transport pathway and eventually engulfed by the tumor cells.

As a result, the drug is able to bypass the tumor’s barrier, travel deep into the tumor and poison it—leaving healthy tissues unaffected.

“While this initial study focuses on pancreatic cancer, mouse experiments show that it works for many different kinds of solid tumors—including breast, brain, lung and ovarian cancers and melanoma,” says Ruoslahti. “We expect that CEND-1 will be used with the anti-cancer drugs patients already receive. CEND-1 doesn’t modify drugs—but it can streamline their deep penetration into tumors.”

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DISCOVERY HUB

Jamey Marth, Ph.D., professor at Sanford Burnham Prebys and director of the UC Santa Barbara Center for Nanomedicine

A Smartphone App for One-Hour Identification of Bacteria

Urinary tract infections (UTIs) are extremely common—nearly one in two women will experience a UTI during her lifetime. For women who are pregnant, UTIs are especially dangerous, as they increase the risk of miscarriage. Thus, there is a need for fast, low-cost tests—particularly for resource-limited settings.

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Women get urinary tract infections up to

times

more often than men Source: U.S. Department of Health & Human Services

Scientists at Sanford Burnham Prebys have contributed to the development of a smartphone app that identifies UTI-causing bacteria in only one hour—a fraction of the 18 to 28 hours current clinical tests require.

Rapid identification of disease-causing bacteria is essential for doctors to make faster diagnoses—and proceed to an effective treatment more quickly.

Jamey Marth, Ph.D., professor in the NCIdesignated Cancer Center, and professor and director of UC Santa Barbara’s Center for Nanomedicine, collaborated with scientists at UC Santa Barbara, including senior author Michael Mahan, Ph.D., and his laboratory, as well as scientists at Stanford and Santa Barbara Cottage Hospital to help create the technology.

The findings were published in the journal EBioMedicine.

Using a smartphone’s camera, the app measures a chemical reaction taking place in a diagnostic kit. Less than half a teaspoon of urine—1.5 mL—is required for bacterial identification. The only

E. coli is one of the most common pathogens found in urinary tract infections

materials required are relatively easy to find in a low-resource environment—including a hot plate, LED lights, a mini centrifuge and a cardboard box. The app is free, designed for Android devices and available via the Google Play Store.

The diagnostic kit can be produced for as little as $100.

In addition to UTI-causing bacteria, the test can be configured to identify different bacteria—and thus could potentially expand to new areas, including sepsis, a dangerous condition that occurs when bacteria enter the bloodstream.

It can work with a variety of patient samples, including blood, urine and feces—which could help its expansion.

“This technological advance has the potential to identify the pathogen quickly in order to tailor treatments effectively. Currently, generic treatments are provided in the absence of pathogen detection, and this ‘one size fits all’ approach we know is inadequate. Sepsis, for example, still claims millions of lives each year,” says Marth.

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“Our work is only made possible with the generous donations of people like you.”

Kristiina Vuori, M.D., Ph.D., President

Sanford Burnham Prebys Medical Discovery Institute conducts worldclass collaborative research dedicated to finding cures for human disease, improving quality of life, and educating and training the next generation of scientists, thus creating a legacy for its employees, partners, donors and community.

Our track record of pioneering research spans more than 40 years, and has produced breakthrough discoveries in cancer, neuroscience, immunology and children’s diseases.

• Our scientists are prolific in their pursuits, publishing nearly one peer-reviewed research article per day.

• Sanford Burnham Prebys scientific discoveries are widely recognized by scientists worldwide; in fact, we consistently rank among the top 2 percent of research organizations in number of publication citations.

• Sanford Burnham Prebys ranks among the top three independent research institutes ranked by the amount of NIH funding it receives.

Sanford Burnham Prebys operates one of the most advanced drug discovery centers in the nonprofit world that leverages biomedical discoveries to develop prototype drugs with the potential to improve human health.

Our deep culture of collaboration has attracted a global network of passionate partners.

Check out our website at SBPdiscovery.org

Sanford Burnham Prebys conducts biomedical research funded primarily by grants from agencies of the federal government and private philanthropic support. Sanford Burnham Prebys is a California not-forprofit public benefit corporation under Section 501(c)3 of the Internal Revenue Code.

Trustees

FOUNDERS Dr. William H. and Lillian Fishman* HONORARY TRUSTEES

Malin Burnham Conrad Prebys* T. Denny Sanford

TRUSTEES AND OFFICERS

James C. Blair, Ph.D. CHAIRMAN

William Gerhart VICE CHAIRMAN

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

Louis Coffman CHIEF ADMINISTRATIVE AND FINANCIAL OFFICER

Knox Bell CORPORATE SECRETARY

Anna D. Barker, Ph.D. Matthew Browne David W. Down Daniel J. Epstein Jeanne Herberger, Ph.D. James E. Jardon II James M. Myers Henry L. Nordhoff Douglas H. Obenshain Peter Seidler Kazumi Shiosaki, Ph.D. David L. Szekeres Stuart A. Tanz

*Deceased

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

SBPdiscovery.org

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SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE

10901 North Torrey Pines Road La Jolla, California 92037 SBPdiscovery.org

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.