SBP Pathways Summer 2018

A SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE PUBLICATION | THE AGING RESEARCH ISSUE | SUMMER 2018

BIOHACKERS Cracking the Aging Code

THE AGING CODE Researchers at Sanford Burnham Prebys Medical Discovery Institute are exploring the science behind living longer and stronger.

THE AGING RESEARCH ISSUE SUMMER 2018 ON THE COVER Malene Hansen, Ph.D., is investigating the link between autophagy and aging.

See page 4.

Contents 4

Digging Deep

8 12

A Race Against Time

16 20 23 24 27 28

The Heart Matters

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Fishman Fund Awards for Young Scientists

30 32 34

Scouting Sparks a Scientist

35 36

A Dream to Be Free

Renewed Strength

Bring It! Meet the Co-chairs President’s Circle Donors SBP Insights SBP Brings Science to STEM Expo Day

We Can’t Do It Alone Compassion Drives Lifelong Research

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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Maintaining muscle mass and strength can stave off sarcopenia.

See page 12.

“Understanding the biological connection between aging and age-related diseases will lead to new approaches to prevent, diagnose, treat and potentially cure the most common health problems in our society.�

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

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LETTER

Cracking the Aging Code Is aging an inevitable part of life or a disease? There’s a lot of debate on this question. In this issue of PATHWAYS, you will learn about SBP scientists who are immersed in answering this question, and in cracking the aging code to find ways to help us live longer and stronger.

Getting older is the leading risk factor for common diseases such as heart disease, cancer, arthritis, Alzheimer’s disease and many more. Our goal is to understand how our biology changes over time to put us at greater risk of disease. The answers—sometimes unexpected—may lead to new ways to prevent, diagnose, treat and possibly cure many health conditions.

In Digging Deep you will read about Dr. Malene Hansen’s work unearthing new links between cellular recycling and longevity. Dr. Peter Adams in A Race Against Time discusses his pursuit to understand why cancer is mostly a disease of aging.

Dr. Alessandra Sacco in Renewed Strength shares her work on stem cells that may help us maintain healthy muscle. And Drs. Karen Ocorr and Rolf Bodmer in The Heart Matters discuss what it’s like to be a wife-husband team who studies the heart. By focusing on the biology of aging, our scientists hope to uncover new ways to maintain health throughout a person’s life.

A special thank you to those who attended 2018 Bring It!—the fundraiser that supports biomedical research at our Institute. We hope you enjoy the photos.

Your continued support and generosity helps our work in aging and other important areas of research. If you enjoy this issue or have comments on the topic, I’d like to hear from you.

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

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

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Digging Deep

Malene Hansen, Ph.D., is a professor in the Development, Aging and Regeneration Program

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Dr. Malene Hansen is unearthing new links between cellular recycling and a long-lived life A few months ago, Malene Hansen, Ph.D., was going through some old childhood papers when she came across an essay she’d written back in eighth grade. The topic? Her desire to become a scientist.

That dream came true—but the picture the young Hansen had drawn with the assignment was not quite so prophetic.

“It was an older man with a bald head in a lab coat, poking a mouse with one hand and holding a beaker with some chemicals bubbling in the other,” she says, laughing. “That was my own bias as to what a scientist would look like.”

It would have been more accurate, of course, to draw a woman at a microscope, blonde highlights in her short hair, a volleyball in one hand and a tiny worm in the other.

After work, Hansen pursues beach volleyball; however, the worm takes center stage daily in her lab at Sanford Burnham Prebys Medical Discovery Institute (SBP), where she’s a professor in the Development, Aging and Regeneration Program and associate dean of Student Affairs.

Called C. elegans, the worm lives just two weeks. But Hansen is using it to study a fundamental cellular process that may hold the key to a long and healthy life for all organisms— including humans.

Hansen’s eighthgrade essay on biochemistry

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CELLULAR TRASH Growing up in Denmark, Hansen’s interest in science stemmed from a penchant for exploring the inner makeup of things. She eagerly cut open a fruit fly, for example, just to see how it worked.

Studying C. elegans has benefits. Because it’s transparent, researchers can see inside its organs while it’s alive. That trait and its short life span make the nematode an ideal model for studying the process at the center of Hansen’s research: autophagy (pronounced ah-TOF-a-gee).

“With a little bit of genetic tinkering, we can improve the autophagy process and help extend the life span of these worms.”

Malene Hansen, Ph.D.

Autophagy is the way that cells remove old or broken cellular materials, and then recycle them into new molecules or energy.

Essentially, the cell builds a “trash bag” from pieces of membrane and puts damaged parts in the bag. Tiny vesicles—now fluidfilled sacs of trash—are then transported to a “recycle plant,” a sealed-off compartment in the cell where powerful enzymes degrade the unneeded material.

It’s a remarkable process that’s gaining increasing scientific attention. (It was the subject of the 2016 Nobel Prize.) One reason: Several age-related diseases, including Alzheimer’s, Parkinson’s and cancer, have been linked to defective autophagy.

“In diseases like Alzheimer’s, proteins start to clump up and aggregate and become toxic,” Hansen explains. “Normally, autophagy clears those out. So does autophagy fail because you accumulate too many of these aggregates, and the system gets constipated? Or do the proteins clump up because autophagy fails? We really don’t know.”

GUT REACTION One thing researchers have found—and Hansen helped establish—is that restricting food intake (without malnutrition) speeds up autophagy.

She first made that direct link as a postdoc at UC San Francisco. Since coming to SBP in 2007, her lab has examined multiple longevity paradigms and shown that foodrestricted C. elegans seem to have higherthan-normal rates of autophagy, and longer life spans.

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Her team is now studying how dietary restriction boosts autophagy, as well as how the process weakens with age.

Because, like most things, autophagy declines over time.

“Maybe there’s too little membrane to build the trash bag,” Hansen says. “Or the roads they travel on—and there are all kind of roads inside cells, believe it or not—start to have potholes. Or maybe the trash reaches the plant, but the plant can’t degrade the components.”

She cautions against just blindly boosting autophagy to increase longevity: “If you boost it at the wrong time or the wrong place, you may eat up something that normally should not be eaten.”

One other caveat? Even the long-lived worms die. “I don’t see this as a fountain of youth,” she adds. “It’s about understanding the fundamental mechanisms that underlie many age-related diseases, which could have huge implications for treating those diseases.”

EMPOWERING OTHERS As much as Hansen enjoys peering inside a cell—“It’s a huge room; it’s amazing what’s in there”—science is not her only love. At least three times a week, she heads to the beach to play volleyball.

“I’ve played competitive team sports my whole life,” she says. “It’s really taught me how team members play different roles— and that applies in the lab as well.”

She’s particularly passionate about mentoring other researchers, and she received the 2017 Mentor of the Year Award from the National Postdoc Association.

Indeed, that’s another element that was missing from her childhood drawing: a team.

“Science is a very collaborative event,” Hansen says. “I work with a great group of people that I also have the good fortune to mentor. I find it very rewarding to empower others and to build strong teams.”

Hansen oversees a lab exploring life extension

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Peter Adams, Ph.D., is a professor in the Tumor Initiation and Maintenance Program

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A Race Against Time Dr. Peter Adams is on a mission to beat the clock—and slow the aging process in our cells Peter Adams, Ph.D., is an avid cyclist, and he loves to compete. But while he’s done his share of road races in the past, he much prefers squaring off against a different opponent: the clock.

“I’ve always gotten a lot of pleasure out of time-trialing, which is basically you against the clock,” says Adams. “It’s a huge mental and physical challenge.”

But his bike isn’t the only place where he goes head-to-head against the hands of time. A professor in the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), Adams is leading research into how our cells age—and how we can potentially slow that process to live longer and healthier lives.

And yes, he insists, we can slow the aging process.

“The evidence that life span and healthy aging can be controlled is overwhelming,” Adams explains. “Take the example of mice, which live two to three years, and naked mole rats, which live 25 years. That tells us that evolution has figured out a way to massively manipulate life spans.

“Beyond that, we can introduce genetic interventions in flies, worms and mice and make them live longer,” he continues. “And

there are interventions such as calorie restriction that promote longevity; and exercise, which supports healthy aging.”

THE CANCER–AGING LINK As excited as Adams is about the science of aging, there was a time when it wasn’t even on his radar as a researcher.

Originally from Coventry, England, Adams started off his career studying cancer. He earned his Ph.D. at what is now Cancer Research UK, did postdoc work at Dana-Farber Cancer Institute in Boston, and spent nearly two decades at other cancer institutes, joining the Beatson Institute for Cancer Research in Glasgow, Scotland, in 2008.

But while investigating a particular gene’s role in “senescent” cells—cells that have stopped dividing—he found himself increasingly intrigued with the mechanisms of aging. Senescence is thought to prevent cancer because it stops cells from dividing uncontrollably, but there’s a downside: Senescent cells, which are inflammatory, promote aging.

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“Cancer is mostly a disease of aging.

It’s not that younger people don’t develop cancer, just that they are less likely to.”

Peter Adams, Ph.D.

At the same time, Adams was delving deeper into the epigenome—the pattern of chemical tags that turn genes “on” or “off.” But the more he studied the epigenome, the more he saw that—like senescence—the epigenome’s impact is broader than cancer. It plays a critical role in aging, too.

“It wasn’t a new discovery, but it was my own realization that there is this relationship between aging and cancer that is fascinating and poorly understood,” he explains. “Because in most cases cancer is a disease of aging. And yet we really don’t know why.”

DAMAGE CONTROL Eager to pursue his broader aging research in greater depth, Adams came to SBP in December 2016, leaving his position as head of the Epigenetics Unit at Beatson and moving to San Diego with his wife, Helen, and their two daughters.

Today, his lab combines his research interests in both cancer and aging. It

What is epigenetics?

Epigenetics literally means “above” or “on top of “ genetics.

focuses on how chromatin (the molecular substance of a chromosome) and the epigenome change over time in ways that promote cancer and age-associated diseases.

One of his recent studies—a collaboration with Trey Ideker, Ph.D., at UC San Diego— found that interventions that extend life span made the epigenome of an old mouse look like that of a much younger one. Adams is now investigating whether epigenetic changes actually drive aging and what cellular processes cause those changes, providing possible targets for anti-aging medicines. His team is also examining how inflammation is activated in senescent cells.

“The epigenome can change with age and become damaged, and these inflammatory senescent cells can be damaging,” he explains. “In a way, healthy aging is a case of damage control, through such things as proper energy utilization, food, diet and exercise.”

CELL

with 23 pairs of chromosomes

CHROMOSOME

Why is epigenetics important?

Whether your genes are turned “on” or “off” depends on how accessible they are. Your genes are made of DNA that coils around proteins called histones—similar to thread around a spool. Epigenetic tags on DNA and histones wrap DNA tightly or loosely, altering gene accessibility.

made up of genes

Epigenetic Tag Gene

“Closed DNA”

“Open DNA”

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BOTH SIDES Adams certainly has the exercise part of that equation covered. Each day, he cycles eight miles into work and eight miles home, often doubling the route and adding “repeats” up the Torrey Pines hill.

Cycling has been a passion since his teen years—encouraged by his dad, who gave him a red Mercian road bike for time trials for his 21st birthday. He still has that bike, and he’s passed on his love for an active lifestyle to his daughters, who are both involved in sports.

The San Diego weather is perfect for sports and for Adams’ daily rides. But that’s not the reason he loves SBP. “Here, I have both sides of what I’m interested in,” Adams says. “It’s a great cancer institute, but there’s also this whole community of people who are really interested in the biology of aging.

Everybody is very collaborative. It’s absolutely fantastic.”

Adams leads a team of scientists exploring how cells age

Diet Psychological State

Social Interactions

Sleep

G

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C MODU ETI LA

ON

Therapeutic Drugs

Disease Exposure

TI

Exposure to pharmaceutical and toxic chemicals, diet, stress, exercise and other environmental factors create positive or negative epigenetic modifications with lasting effects on development, metabolism and health.

EP I

Your epigenetic life

HEALTH AND LONGEVITY

Toxic Chemicals

Drugs of Abuse

Microbiome Exercise

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FACULTY

Renewed Strength Dr. Alessandra Sacco is probing the regenerative powers of muscle stem cells to find the key to maintaining muscle mass as we age During her scientific training, Alessandra Sacco, Ph.D., watched enthralled as each muscle stem cell in a petri dish made a life-altering choice: to stay the same, or to transform into something new.

“At each cell division, a stem cell has to decide: Is it going to make more copies of itself, or is it going to mature into a committed cell type?” explains Sacco, associate professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), and associate dean of Curriculum for the SBP Graduate School. “That was fascinating to me. How does it choose what it wants to become?”

That fundamental question has been at the heart of her research ever since. As a postdoc at Stanford University, she found ways to isolate adult skeletal muscle stem cells and provided the first definitive evidence that they can self-renew in a living organism.

skeletal muscle—something that has potential implications not only for devastating disorders like Duchenne muscular dystrophy, but also for a condition we all face: aging.

“During aging, our muscles become less strong, and we’re less efficient in regenerating muscle if there is an injury,” notes Sacco, who joined SBP in 2010. “What we’re trying to understand is, how is that happening? And how can we improve the function of our muscle stem cells so we can maintain our strength and quality of life?”

Today, her lab investigates exactly how muscle stem cells repair and regenerate Alessandra Sacco, Ph.D., is an associate professor in the Development, Aging and Regeneration Program

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When you do biomedical research, you are trying to find answers that aren’t there yet, but may be important to advancing human health. I really enjoy that challenge.�

Alessandra Sacco, Ph.D.

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FACTS ABOUT Sarcopenia (Muscle Loss with Aging) • T he name sarcopenia is derived from the Greek sarx (flesh) and penia (loss).

• M ost people begin losing modest amounts of muscle mass after age 30.

• A sedentary lifestyle puts people at increased risk of developing sarcopenia.

• A 10% reduction in sarcopenia would result in a savings of more than $1 billion per year in U.S. healthcare costs.

STAVING OFF DECLINE Throughout our lives, adult muscle stem cells have an important job: Maintain and repair our skeletal muscle tissue, such as leg, arm and back muscles.

“It’s been thought that muscle regeneration during aging or during injury is essentially the same process and involves the same players,” Sacco says. “We found this is not the case at all.”

The cells, which live on the outskirts of muscle fibers, do this in two ways.

Some decide to differentiate into muscle cells, which then form new fibers to replace damaged ones.

But other stem cells simply make copies of themselves, ensuring an adequate stem cell supply for the next injury.

Using a genetic labeling tool called in vivo multi-lineage tracing, the team tracked the fate of individual stem cells in living mice. They found that, in an aging mouse, the diversity of the stem cell population stayed the same—but the cells did not function as well. With injury, the opposite happened: Stem cell diversity declined, but cell function improved.

The process works beautifully. But by our 40s, muscle mass begins a slow decline. Called sarcopenia, this age-related loss of muscle size and function accelerates in seniors and can lead to disability and loss of independence.

To find potential therapeutic targets that could prevent or reverse this decline, Sacco and her team are examining how muscle stem cells interact with an aging environment.

For example, they found that a molecule called STAT3, which is more active in aging, inhibits skeletal muscle regeneration in older mice.

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Nearly of 65+ year-olds are affected by sarcopenia

Another key aspect: the cells themselves. “Stem cells are not all identical; they each have different abilities,” she notes. “There’s a lot of diversity.”

60%

of 80+ yearolds are affected by sarcopenia

Source: Journal of the American Geriatrics Society

AGE vs. INJURY Related to that diversity, her team has uncovered surprising findings about how stem cells respond to age versus injury.

The takeaway? Therapies for regenerating muscle will likely need to be different for seniors than for patients with injuries or chronic disease. “There probably isn’t a one-size-fits-all approach,” she says.

CHOOSING HER PATH Like the stem cells she studies, Sacco herself once faced a lifedefining decision between two distinctly different paths.

Born and raised in Rome, she was the first in her family to go to college. But she soon found herself torn between staying in Italy, near her parents and two brothers, and pursuing greater scientific opportunities abroad.

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She chose the latter path, taking a postdoc position at Stanford University. It was her first time living away from home. “It took a few months of adjustment!” she says, letting out a long, deep laugh. “But it made me grow.”

Today, she feels like “both an Italian and a Californian.” Most of all, she is a scientist and a dedicated mentor to other researchers at SBP. (Two of her postdocs won SBP’s prestigious Fishman Award last year.)

what attracts me is the process of working with the team to get there,” she says. “When you do research, you’re at the forefront of science. You’re trying to find answers that are not there yet. I really enjoy that challenge.”

“The potential impact of what we discover is exciting, but day to day

Muscle stem cells sit along a muscle fiber

THE LIFE OF A MUSCLE STEM CELL When muscle stem cells need to divide due to injury or aging, they have options: They can self-renew, give rise to muscle cells or do both—known as asymmetric cell division.

Muscle Stem Cell

Self-renewal

Asymmetric cell division

Immature Muscle Cell

Commitment to muscle cell

Mature Muscle Cell

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Karen Ocorr, Ph.D., assistant professor; and Rolf Bodmer, Ph.D., professor—both in the Development, Aging and Regeneration Program

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The Heart Matters How SBP’s super-couple balance research, family and marriage

Trying to balance the demands of high-stress careers, publishing and traveling internationally while simultaneously raising a family and having a successful marriage... isn’t easy. When the stars are aligned, most dual-career couples would say it’s, at best, doable.

But Karen Ocorr, Ph.D., assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute (SBP); and Rolf Bodmer, Ph.D., professor and director of the Development, Aging and Regeneration Program at SBP, take it in stride.

“I wanted a family and I wanted to work in science,” says Ocorr.

“I wanted a balanced life,” says Bodmer.

They were postdocs when they met. She was at Stanford University School of Medicine; and he was at the UC San Francisco School of Medicine working for a high-powered couple, both of whom were members of the National Academy of Sciences.

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“Even though we have separate careers, our research paths cross, and we learn a tremendous amount from one another.”

Rolf Bodmer, Ph.D. Ocorr speaks at the Kennedy Space Center

NAVIGATING CAREERS It takes mutual respect and cooperation to navigate separate scientific careers. The Bodmer-Ocorrs have found a way to maintain separate careers with shared goals, and to integrate their work and home lives by helping and supporting each other.

FLIES IN SPACE “When I was a kid, I wanted to be an astronaut,” says Karen Ocorr, Ph.D. “So this is really cool for me.”

Ocorr is talking about teaming up with NASA to send fruit fly eggs on SpaceX to the International Space Station, where they will hatch and live up there for a month, which is about half the life span of a fruit fly.

“Given the increasing interest in commercial space exploration, it’s really important to know how gravity—or lack of gravity—affects human physiology.”

By the time Bodmer was offered a position at the University of Michigan, they’d had their first child. Ocorr took a teaching position at the University of Michigan and co-wrote a textbook, The Absolute Ultimate Guide to Principles of Biochemistry, with Marcy Osgood, which is still in use today.

After 12 years, they took a sabbatical to work in Marseille, France. “When we returned, I knew I didn’t want to teach,” says Ocorr. “I was very good at it, but I craved something new. However, it’s tough to re-enter research once you leave it.”

Bodmer took a research position at SBP to continue his work using the fruit fly Drosophila as a genetic model to study cardiac development, and Ocorr began a teaching position at UC San Diego.

“That’s when I decided I really needed to get back into research,” she says. “A lot of women in science have just one kid; they put in 80-hour weeks, and that’s all they have time for. We had three children by then, but I still wanted to pursue science.”

A self-described jack of all trades who learned how to design and program her own website in the ‘90s, Ocorr, who was trained as a physiologist, came up with a fruit fly dissection technique and started to monitor heart function with movies of actively beating hearts. “Rolf gave me the chance to bring it all together,” she says. “It was good for his lab, too—now he could look at cardiac development genes in the adult heart as well as embryos.”

WHEN SCIENCE HAS WINGS Both Ocorr and Bodmer work with Drosophila to unravel complex biological processes. Fruit flies have common features with humans to a remarkable degree; 75 percent of the genes that cause disease in humans, are also found in the fly. This means that we can apply what we learn from studying flies to medicine.

The Bodmer-Ocorr couple studies Drosophila hearts as a way to assess genes and mechanisms involved in heart development, congenital heart disease, cardiomyopathies and the effects of aging on the human heart.

Ocorr is collaborating with NASA to uncover the basis of cardiac and muscle atrophy in astronauts exposed to extended periods of microgravity.

Her team launched flies aboard SpaceX-3 and 11 for monthlong journeys to see how well the insects’ hearts function and which genes are expressed in a weightless environment.

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Recently, the Bodmer lab used Drosophila as a model to show that elevated levels of ceramide (a type of fat or lipid) play a crucial role in lipotoxic cardiomyopathy (LCM), a heart condition that occurs in patients with diabetes and obesity. The research may lead to new treatments and preventions for LCM and end-stage heart failure.

FLY AWAY “Almost all of our vacations are working vacations,” says Ocorr. “We try to tag vacations onto scientific meetings, but we always have grants and papers to discuss. Sometimes it’s hard to find other things to talk about—but that’s okay. We love our work.”

“When we do take time off, we hike, bike, swim and scuba dive (off Thailand recently), and of course we ski—after all, I’m Swiss!” says Bodmer. “One of our favorite vacations is skiing with our kids at Mammoth Mountain.

“Karen has really helped bring balance to our family. She has always been that way, and it’s great.”

SMALL FLIES: BIG DISCOVERIES 6 NOBEL PRIZES have been awarded to scientists who have used Drosophila as the basis for groundbreaking research

1933 Thomas Hunt Morgan used Drosophila to uncover the role played by chromosomes in heredity

1946 Hermann Joseph Muller discovered that X-ray irradiation caused mutations in fruit flies

1995 Edward B. Lewis, Christiane Nüsslein-Volhard and Eric Wieschaus used Drosophila to understand genetic control of early embryonic development

2004 Richard Axel concentrated on odor receptors and the organization of the olfactory system

2011 Jules A. Hoffman was given the award for his research on the activation of innate immunity

2017 Jeffrey C. Hall, Michael Rosbash and Michael W. Young won the prize for their studies of circadian rhythms

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EVENTS EVENTS

2018 Bring It! Fundraiser Rocks It for Research Medical Discoveries and Beyond was the spaceage theme of this year’s Bring It! fundraising event held on April 19 at the Del Mar Fairgrounds.

More than 300 Sanford Burnham Prebys Medical Discovery Institute (SBP) supporters and guests donned Star Trek uniforms, Star Wars costumes, Conehead and cosmic Athena warrior outfits and dressed as aliens—all to raise money for biomedical research.

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Co-chairs Juli Oh, Matt Browne, and Sarah and David Szekeres were pleased that the event attracted so many people. “This event makes raising money fun and helps SBP reach a broad group of prospective supporters,” said Sarah.

In keeping with the cosmic theme, guests were served liquid nitrogen space popcorn, spuds in space and moon pies by waiters wearing lab coats.

$15,000 SPONSOR

SBP Board Chairman Hank Nordhoff enthusiastically welcomed “the next generation of philanthropists” and reinforced SBP’s position as a global leader in science.

Nordhoff attended with his wife, Robin. Board member Alan Gleicher and his wife, Marleigh, also attended the event.

The uniquely SBP event had four rounds of space-themed trivia and six out-of-this-world stage challenges including spooning Reese’s Pieces into an empty bowl without hands while wearing an E.T. headband; throwing cheese curls onto a team member’s shower-capped head covered in shaving cream; and launching space shuttle gliders into luminescent hula hoops.

There was also a raffle for an Honorary Padres for a Day package, courtesy of SBP board member and Padres coowner Peter Seidler; a wine toss featuring exclusive wines donated by award-winning HALL Wines in Napa Valley; and the Fund-A-Need paddle raising.

“It’s through basic research that we will be able to prevent, treat and cure diseases that are devastating to families,” said David Szekeres. “A great cause and a great event!”

John Weisbarth, host of Tiny House Nation, emceed the event for the second year in a row.

$10,000 SPONSOR

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Meet the Co-chairs For the second year in a row, Matt Browne (partner at Cooley LLP); his wife, Juli Oh (attorney); Sarah Szekeres (educator); and David Szekeres (executive at Heron Therapeutics) agreed to co-chair the Bring It! Gala—SBP’s fast-paced fundraiser.

Why chair the Bring It! fundraiser again?

David: There was never a question in my mind as to whether I would continue to support SBP. And the Institute was kind enough to ask that I cochair the Bring It! event again. It is an honor and a privilege to be able to help, even in this small manner.

What makes SBP worth your time?

Matt: The way SBP pursues its mission—giving scientists the freedom to explore a wide range of diseases and emphasizing collaboration—is unique and creates a culture of innovation that really permeates throughout the campus. Although SBP is a local, long-standing San Diego institution, I appreciate that its research influences the work of scientists around the world.

Are there personal reasons that drive you to support biomedical research?

Juli: I’m not a biologist, but I’m passionate about the power of basic research. Our dear friends’ daughter was diagnosed with spinal muscular atrophy (SMA) when she was just 18 months old, in 2001. At the time, there had been little research done on SMA, but our friends made incredible efforts to fund scientists and encourage collaborations. Today, there are treatments that dramatically improve SMA patient outcomes, and a cure seems to be within reach.

Sarah: I have the BRCA 2 gene mutation—one of the best known mutations to breast cancer risk.

Going through genetic counseling, and learning the results and the statistics of my future cancer risk was a very overwhelming and frightening experience for me. I’m grateful that research is being done to help prevent, diagnose and treat cancers that could affect me, my family members and others who face similar experiences.

How do you want to improve human health?

David: I work at a for-profit biopharma in San Diego, and I have pledged my career to try and make a difference for patients. Getting drugs through the development stage is a long and arduous endeavor, but once that drug gets approved, there is no better feeling than knowing you had a small part in giving a patient the best options to improve his/her health. I am hopeful that research will lead to life-saving cures for diseases, including cancer, which would affect millions of folks now and in years to come. I think about my children during my workday and hope that biomedical research can create a future world that’s not afraid of cancer.

David and Sarah Szekeres, Juli Oh, and Matt Browne

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President’s Circle Donors – 2017 Sanford Burnham Prebys Medical Discovery Institute honors the following donors who believe in the power of medical research and have generously supported SBP science with a gift of $1,000 or more.

$50,000 AND ABOVE

$10,000 – $24,999

Susan and James Blair

Rocio and Lorenzo Berho Allison Blackwell Blair Blum and Jim Sexton Nancy and Matthew Browar Roberta and Malin Burnham Mary and Adam Cherry Cooley, LLP Natalie and David Dragotto Claudia Dunaway and Hudson Freeze FEI Company Debby and M. Wainwright Fishburn, Jr. Melissa Seipel and William Gerhart Hanna and Mark Gleiberman Deana and Morley Golden Susan and Paul Hering Heron Therapeutics Tammy and Lawrence Hershfield Susan and Bill Hoehn Christine Infante and Robert L. Cushman Robin and Hank Nordhoff Milley Mai and Douglas Obenshain Pfizer Marilyn and Michael Rosen Liberty Ross and Jimmy Iovine Evan Snyder Science, Technology and Research Support (STARS) Tevy Tith and Yun Yung University of California, San Diego Dr. Andrew Viterbi Kristiina Vuori Mary Jane and James Wiesler

Bruce Ford and Anne Smith Bundy Foundation David Whitmire Hearst, Jr. Foundation Epstein Family Foundation Gilbert J. Martin Foundation Jeanne Herberger, Ph.D. Hervey Family Fund at the San Diego Foundation Jean Perkins Foundation Marilena and Gregory Lucier Victoria and Thomas McDowell Diane and Thomas Might Pedal the Cause Dinah Ruch T. Denny Sanford Shaffer Family Foundation

Donors

Sky Foundation, Inc. Richard P. Woltman

$25,000– $49,999 Alexandria Real Estate Equities Cindy and Stephen Aselage Marleigh and Alan Gleicher Illumina NuVasive, Inc. Retrophin, Inc. Debbie Turner

* Deceased

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$1,000– $9,999

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Patti and Dave Down Barbara and Jim Dudl

Alagille Syndrome Alliance

Nancy and James Eastman

Karen L. Alexander

Rebecca and Edward Etess

Alex’s Lemonade Stand Foundation for Childhood Cancer

Jennifer and Kurt Eve

Laura and John Alioto

Michiko and Minoru Fukuda

Lisa and Steven Altman Letizia Amadini-Lane Arcturus Therapeutics, Inc. Arena Pharmaceuticals, Inc. Carolyn Armstrong Arnerich Massena, Inc. Julie and Paul Baker Bank of America Barney & Barney, LLC BDO Molly Jaeger Begent and David Begent Diane and Knox Bell Eve Benton and Malcolm Bund Bioelectron Technology Corporation BioLegend BioMarin Pharmaceutical Inc. Ruth Claire Black Steve Black Tatiana Kisseleva and David A. Brenner Kathy and Ed Brown Juli Oh and Matthew Browne Sue and Howard Busby Pamela J. Carter David Cason CBRE CGS3 Law Firm Tracey and Gary Chessum Bess and Arthur Collias Liz and Michael Copley Rebecca and Nick Cosford Gigi Cramer Patrick Crutcher Danaher Corporation Jennifer and Thomas DeLonge Carol and Thomas Dillon DLA Piper

* Deceased

Amanda and Sean Freeman Joyce and James Furby Audrey S. Geisel Gene DX, Inc. Ed Gillenwaters Glycomine, Inc. Gordon Ross Medical Foundation Anne-Marie Gordon Lynn Gorguze and Scott Peters Lola and Walter Green Vivian and Samuel Hardage Lynn and Roger Headrick Hercules Capital, Inc. Dodie and Loren Hinkelman Clarice and Neil Hokanson Reena and Samuel Horowitz Douglas Horton Debra and Scott Huennekens Margaret and Robert Hulter Ichorion Therapeutics, Inc. Debby and Hal Jacobs Ashley and Ted Jacobs JEOL USA, Inc. Jeanne Jones and Don Breitenberg Terry and Stath Karras Lord Killearn Amy and Bill Koman KPMG Krystal Productions Kristin and Thierry Lancino Jenna and James Langley Victory and Richard Lareau Larry Hillblom Foundation Carol and George Lattimer Lisa and Gary Levine Sara and Kevin Lind Shirley and Gene Littler

Donors

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Donors

Debra and Michael Lobatz

Dawn Saunders

Vicki and Larry London

Meredith and Richard Schoebel

Lytx, Inc.

Doreen and Myron Schonbrun

Kimberly and Michael Manhard

Marie G. Schrup

Tara Marathe and Lawrence Lum

The Schultz Family

Dawn and James Mason

Julie and Costa Sevastopoulos

Karen and Neil McFarlane

Christine J. Shamborsky

Mary and Jack McKinnon

Cynthia and Aaron Shenkman

Bruce W. McRoy

Shire Human Genetic Therapies, Inc.

Silvana and Alberto Michan

The Simon-Strauss Foundation

Lucille A. Miller

Square 1 Bank

Dr. Howard and Barbara Milstein

StemCell Technologies

Bradley A. Morrice

Street Swings

Bruce A. Morrice

Dong Sun

Murfey Construction

Sarah and David Szekeres

Melissa and Scott Murfey

Teachers Federal Credit Union

Josie and James Myers

The San Diego Foundation

Amy and Perry Nisen

Stephen B. Thomas

Michael P. Orlando

Molly McCormick Thornton

Oxford Finance

Jonelle and Gregory Tibbitts

Thomas Page

Julie and Court Turner

Charles Patton

Zuhre and Ahmet Tutuncu

David A. Pearce

Sandy and Bob Uslander

Pegasus Building Services Co., Inc.

Nancy Vaughan

Joan Pollard

Lina and Christian Waage

D. Nielsen Pollock

Peggy Walker-Conner

Isaac Pollock

Robert D. Wallace

Jori H. Potiker

Jennifer and Douglas Walner

Peggy and Peter Preuss

Jean Y. Wang

Qualcomm, Inc.

Randi and Charles Wax

Sue Raffee

Ellen G. Weinstein

Resident Brewing Co.

Eric Weitzen

Ann Riner and John Conyers

WekaIO, Inc.

Shereen and Isa Rizk

Wells Fargo Bank

Pamela and Jerome Robinson

Judy White

Alia and Dave Rodman

Armi and Albert Williams

Stacy and Donald Rosenberg

Stephanie and Stephen Williams

Kathy and Bill Rote

Willis Towers Watson

Joyleen S. Rottenstein

Dong-Er Zhang

Victoria W. Sack

Weining Zhen

Beth and Norman Saks

Bebe L. Zigman

San Diego Padres Baseball Club

Emma and Leo Zuckerman

Rupert M. Sanders

SUMMER 2018

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COMMUNITY

SBP Insights: Perspectives on Prostate Cancer New speaker series brings together a scientist, doctor and patient In March, Sanford Burnham Prebys Medical Discovery Institute (SBP) launched a unique speaker series called “SBP Insights,” which featured a scientist, clinician and patient and focused on prostate cancer, a disease that impacts one in nine men. The intent of this exciting quarterly series is to educate and interact with the community on the latest advances in medical research, treatments and potential cures for a wide range of diseases.

low-grade prostate cancer. About age and surgical treatments, he said, “You should only have surgery if you can still bring your dad to see me.”

The panelists included Nicholas Cosford, Ph.D., professor and deputy director of SBP’s NCI-designated Cancer Center; Hank Nordhoff, SBP Board Chairman and prostate cancer survivor; and Christopher Kane, M.D., senior deputy director of Moores Cancer Center and professor and chair of urology at UC San Diego. FOX5 morning weather anchor Brad Wills, who shared his father’s battle with prostate cancer 10 years ago, served as moderator.

Cosford discussed how his research is leading to new treatments for advanced prostate cancer by harnessing autophagy, the normal physiological process that deals with the destruction of cells in the body. He also emphasized the importance of collaborative partnerships with UCSD Moores Cancer Center and the Salk Institute.

Kane updated the audience on the latest methods of diagnosis and treatment and described how each patient has individual risks that should be assessed to achieve the best possible clinical outcome. He shared how if examined closely, nearly half of all 70-year-old men will have low-volume,

First diagnosed with prostate cancer more than 20 years ago, Nordhoff shared stories of his personal experience, how far treatment has progressed since then, and discussed the Institute’s goal of translating bench discoveries to viable early pipeline projects for the pharmaceutical industry.

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

The event attracted nearly 90 participants— more than half of whom visited SBP for the first time.

For more information, go to SBPdiscovery. org/insights.

WHAT’S NEXT? The next issue of Pathways will recap the June SBP Insights event focused on Alzheimer’s disease, featuring Jerold Chun, M.D., Ph.D., professor and senior vice president of neuroscience drug discovery; Michael Lobatz, M.D., director of the rehabilitation center at Scripps Memorial Hospital; Serena Reid, a caregiver for her mother and grandmother, both of whom suffered from Alzheimer’s disease; and Kristen Cusato, associate director of communications at the Alzheimer’s Assocation. In October SBP Insights will focus on breast cancer.

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COMMUNITY

SBP Brings Science to STEM Expo Day About 40 Sanford Burnham Prebys Medical Discovery Institute (SBP) faculty, postdocs, staff and graduate students volunteered on a rainy March 3, 2018, at the 10th annual San Diego Festival of Science and Engineering Expo Day—one of the largest STEM (Science, Technology, Engineering and Math) festivals in the U.S. The group worked in shifts throughout the day to talk with students in kindergarten through 12th grade and guide them through hands-on activities to ignite their passion for STEM education.

“STEM Expo is a great way to get our future researchers excited about science, and I believe that’s why SBP’s involvement continues to expand,” says Karen Ocorr, Ph.D., an SBP faculty member who organized a research demonstration for the exhibit booth.

Ocorr set up a station where children received paper lab coats with personalized name tags to explore the food preferences of fruit flies and how diet impacts heart health. Visitors used microscopes and high-powered LED magnifying glasses to look at fly abdomens to see if they had eaten sugar (dyed red) or fat (dyed blue). Not surprisingly, the fruit flies prefer a highsugar diet. Videos of beating fly hearts showed that compared to a normal diet, both high-sugar and high-fat are bad for heart function.

A second station gave visitors an opportunity to interact with models of drugs and human proteins made by a 3D printer, courtesy of Adam Godzik, Ph.D., director of the Bioinformatics and Structural Biology Program at SBP. Godzik’s lab also brought glasses for viewing a virtual reality program showing how protein-folding configurations are used to design drugs.

The free event, held at Petco Park, featured more than 130 interactive exhibits and attracted an estimated 25,000 people.

SUMMER 2018

EDUCATION

Fishman Fund Awards for Young Scientists The generosity of SBP donors keeps the tradition alive For the 16th consecutive year, exceptional postdoctoral researchers at Sanford Burnham Prebys Discovery Institute (SPB) were recognized at the annual Fishman Fund Award ceremony, held at the Sanford Consortium in La Jolla.

David Sala Cano, Ph.D., a postdoc in the laboratory of Alessandra Sacco, Ph.D., is working on muscle stem cells. He focuses on muscle wasting, a major health problem that leads to poor quality of life; and is associated with diseases such as diabetes, chronic kidney disease, cancer and aging. He is working on identifying new targets for drugs that may prevent skeletal muscle degeneration.

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.

Jose Luis Nieto Torres, Ph.D., a postdoc in the laboratory of Malene Hansen, Ph.D., is conducting research on autophagy—a process our bodies use to eliminate cell waste by recycling debris into usable sources of energy. Autophagy declines with aging, and is associated with many age-related diseases.

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 have planned a career path to achieve their goals. The competition is open to all SBP postdoctoral researchers.

Malin Burnham, SBP’s Honorary Board Trustee, along with SBP supporters Reena Horowitz and Jeanne Jones, led the recent award ceremony. Greg Lucier, former SBP Chairman of the Board and CEO of NuVasive, Inc., spoke on the topic of “we versus me,” emphasizing the importance of teamwork.

Burnham, along with Dr. Andrew Viterbi, co-founder of Qualcomm and former SBP Trustee; and Armi Williams, Fishman Fund Advisory Board Member and former SBP Trustee, presented the awards.

From left to right: David Sala Cano, Ph.D.; Jose Luis Nieto Torres, Ph.D., and Michael J. Stec, Ph.D.

Michael J. Stec, Ph.D., focuses on understanding the mechanisms regulating stem cell function and skeletal muscle regeneration. He is also a postdoc in the laboratory of Alessandra Sacco, Ph.D. His goal is to develop novel therapies for improving muscle function in aged and diseased individuals.

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EDUCATION

Scouting Sparks a Scientist Graduate student Karina Barbosa is inspired to take on big healthcare challenges

“I’m committed to finding new medical avenues for patients— it’s why I’m here and what I’m going to do.”

Karina Barbosa

SUMMER 2018

Karina during Girl Guide community service activities in Tijuana, 2010

At the age of 10, Karina Barbosa joined the World Association of Girl Guides and Girl Scouts at the suggestion of her mother, once a scout herself. Little did she know how the experience would lead her to a career in biomedical research.

Today, Barbosa is a first-year Ph.D. student studying epigenetics—the modifications to DNA that control gene activity. She is studying how this fascinating field of biology impacts cancer under the guidance of Ani Deshpande, Ph.D., assistant professor in the Tumor Initiation and Maintenance Program at Sanford Burnham Prebys (SBP).

Growing up in Mexico, Barbosa became a Girl Guide, the country’s equivalent to U.S. Girl Scouts. Before becoming a Girl Guide, she had seen scientists on television but had never met one in person. As part of her program, she visited a lab for the first time. Suddenly she could see herself as a scientist: “If it wasn’t for that experience, I might not have pursued research.”

Barbosa is researching acute myeloid leukemia (AML), an extremely deadly cancer, with only a quarter of patients living five years past diagnosis. Understanding epigenetics could create better treatments for AML and beyond: Scientists are linking epigenetic processes with many types of cancer, autoimmune disorders and neurological conditions.

INSPIRING FUTURE SCIENTISTS While currently focused on completing her Ph.D., she aspires to serve as a role model for other girls.

One day she hopes to plan a field trip to SBP for her former troop. “Many young people don’t grow up thinking of science as a career because they don’t know a scientist,” she says. “I feel a responsibility to help others understand what scientists do, and how we work to solve many of the health issues facing society today.”

Barbosa is pleased she landed at SBP, noting, “Here, scientists not only share supplies, but we share ideas, and there are tremendous opportunities to collaborate.”

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SCIENCE BENEFITING PATIENTS

We Can’t Do It Alone SBP’s Rare Disease Day strengthens the global network of families, physicians and researchers to better understand and fight rare diseases in children

With more than 175 attendees and 22 noted scientists and clinicians from around the world, Sanford Burnham Prebys Medical Discovery Institute (SBP) hosted the ninth annual Rare Disease Day Symposium, a global forum for those interested in congenital disorders of glycosylation (CDG)—rare inherited disorders that affect only 1,200 patients worldwide.

Malin Burnham and T. Denny Sanford, honorary trustees of SBP, kicked off the three-day event in February, noting that advances in medicine require the participation of, and exchange among, all stakeholders—scientists, physicians, affected patients and their families, support groups, granting agencies, industry and philanthropists.

Hudson Freeze, Ph.D., director of Human Genetics Program at SBP, an acknowledged expert in CDG and the symposium chair, said, “This event brings together stakeholders from around the world to share in each other’s successes and challenges and discuss the future of CDG research.”

Children with CDG have varying levels of difficulty with speech and language, balance, motor control, vision, hearing and seizures.

Because the condition is so rare, many patients bounce between doctors and clinics for years before they receive an accurate diagnosis.

An innovative session called “Doctor-is-in” connects families with medical researchers and clinicians in small groups. For medical researchers, the session is often their first opportunity to observe and interact with patients in person.

The symposium, the largest in the history of the event, was organized and run by SBP, members of CDG CARE (Community Alliance and Resource Exchange) and the nonprofit corporation NGLY.1. It was funded by donations, grants, and corporate and industry sponsorships, including support from Retrophin, a biopharmaceutical company focused on the discovery and development of drugs for the treatment of catastrophic diseases that are debilitating and often lifethreatening, and for which there are currently limited patient options.

SUMMER 2018

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From left to right: Malin Burnham, T. Denny Sanford and Hudson Freeze, Ph.D.

“Being the parent of a child with an undiagnosed rare disease can be a lonely place,” said Darlene Schopman, mother of Nolin, a 6-year-old boy diagnosed with CDG. “We thought we were the only people in the world affected by Nolin’s type of CDG. We’ve since learned that there are nine more children with his specific condition. And now at this conference, I’m meeting other families that have had similar experiences— there is an immediate connection—a common bond.”

Nolin Jutten with his parents, Darlene and Frank

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SCIENCE BENEFITING PATIENTS

Compassion Drives Lifelong Research

Making life easier for children with rare metabolic disorders compels this influential scientist to search for a cure

Freeze with his sister Jackie Hudson Freeze, Ph.D., director of the Human Genetics Program, seeks answers for children with rare metabolic conditions

For more than 20 years, Hudson Freeze, Ph.D., has worked with children with CDG and created an international network of families, scientists and physicians. The walls of his office and lab are filled with photos of the children he has met. “Not a day goes by when I don’t think of them and their struggles—but mostly their smiles,” he says.

“It’s the reason we won’t give up on a cure.”

CDG—which stands for congenital disorders of glycosylation—are rare inherited disorders that can cause serious, sometimes fatal, malfunctions of different organs and systems in the body.

Freeze understands firsthand about watching a family member struggle with physical and neurological challenges.

His younger sister, Jackie, is severely disabled. “When I’m with my CDG families, I’m at home with her,” says Freeze. “It feels like I’m in my own living room when I was a kid.”

He visits his sister every year in Indiana, where she lives in a residential home setting with other disabled housemates.

She’s been tested for CDG, which she

does not have. Freeze also tested himself to see if he has the PMM2 mutation, which is shared by many CDG patients. “I was surprised to discover that I carry the most common PMM2 mutation, bringing me even closer to my CDG family,” says Freeze.

Families reach out to Freeze almost weekly seeking help. He says: “If someone asks for help, I say, ‘Let me try.’ Any glimmer of hope is a path worth pursuing, anything to make life easier for children with CDG.”

SUMMER 2018

SCIENCE BENEFITING PATIENTS

A Dream to Be Free Morgan Webb Liddle’s dream to be coached by Olympic equestrian Steffen Peters came true, thanks to Dr. Hudson Freeze Morgan Webb Liddle, 26, has poor peripheral vision, no sense of balance and uses a wheelchair. Yet the equestrian champion, who was diagnosed with a congenital disorder of glycosylation (CDG) at age 14, says, “I was born to ride; it’s the one time I feel free.”

Morgan Webb Liddle

Liddle hasn’t let her disease deter her from pursuing her passion. She competes on the international circuit, where she won the Australian National Championship for Para-Dressage multiple times and is currently on the short list for Para-Reining at the World Equestrian Games in South Carolina in September.

“As a child, Morgan attended public school with her siblings until her physical and neurological condition worsened rapidly,” says her mother, Merrell Liddle. “We had her tested and retested until we finally got a diagnosis. Just knowing the diagnosis was a relief and made it possible to search for resources to help her.”

The Liddles met Hudson Freeze, Ph.D., professor and director of the Human Genetics Program at Sanford Burnham Prebys Medical Institute (SBP) and an acknowledged expert on CDG, at conferences in Brussels and Chicago. When Freeze learned that Liddle and her mother were flying from Australia to attend SBP’s Rare Disease Day Symposium and Family Conference in February 2018, he set a plan in motion to fulfill Liddle’s lifetime dream.

Morgan rides with Steffan Peters

Each year, SBP hosts a conference for families battling rare childhood diseases.

Freeze organized the recent event, where scientific experts shared their insights and discoveries with families and physicians.

During the Liddles’ visit, Freeze arranged a riding session with one of her heroes, Olympic bronze medalist Steffan Peters, at Arroyo Del Mar Stables in San Diego.

“Morgan, what you do is so much more amazing than what I do,” said Peters.

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DISCOVERY HUB

Left: Maria Diaz-Meco, Ph.D., professor in the Cancer Metabolism and Signaling Networks Program Right: Jorge Moscat, Ph.D., professor and director, of the Cancer Metabolism and Signaling Networks Program, and director of Metabolism Initiative at SBP There are more than

New Insights on the Addictions of Tumors

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types of cancer Source: National Cancer Institute

Most cancers require large amounts of glutamine for rapid growth, and there are numerous studies indicating that they cannot survive without it—a phenomenon termed “glutamine addiction.”

A study by Maria Diaz-Meco, Ph.D., and Jorge Moscat, Ph.D., professors in Sanford Burnham Prebys Medical Discovery Institute’s NCI-designated Cancer Center, reveals how tumors ensure a reliable glutamine supply by eliminating the p62 protein in surrounding stromal tissue. Specifically, p62 deficiency helps tumors and stroma (supportive tissue outside the tumor) survive and grow, despite being deprived of the essential amino acid.

The findings, published in Cell Metabolism, suggest the p62 pathway in tumor stroma could be a potential anti-cancer target.

Tumors demand significant nutrients to support their growth

“Cancer has traditionally been treated with chemotherapies that target oncogene addictions—the oncogenic signals that tumors use to survive,” says Diaz-Meco. “We are looking at the non-oncogenic addictions that also contribute to the survival of many cancers.”

Tumors must develop unique mechanisms to ensure adequate nutrient supplies. To do this, they rewire surrounding tissue, particularly cancer-associated fibroblasts in the stroma, which are hijacked to do the tumor’s bidding.

Essentially, the cancer remodels its nest.

The new research shows that reducing p62 increased ATF4, an essential transcription factor protein that instructs cells to adapt to situations in which nutrients are at a premium in the tumor microenvironment. ATF4 levels only changed in stroma, remaining constant in epithelial cells, regardless of p62 levels.

Ultimately, losing p62 and gaining ATF4 activates a complex pathway that generates the amino acid asparagine, which allows stromal cells, and ultimately tumor cells, to survive and grow despite the nutrient-poor conditions. From a therapeutic angle, this forces the tumor to become reliant on this pathway, making ATF4 a potential vulnerability to be exploited to undermine cancer growth.

“The role of the stroma is understudied,” says Diaz-Meco. “There have been very few studies on how stromal metabolism affects tumor growth. We really need to understand more about this basic rewiring to develop more efficacious and less toxic therapeutic approaches for cancer.”

SUMMER 2018

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DISCOVERY HUB

Huaxi Xu, Ph.D., Jeanne and Gary Herberger Leadership Chair in Neuroscience Research, and professor and director of SBP’s Neuroscience Initiative

The Brain’s Immune System May Be Key to New Alzheimer’s Treatments Research from the laboratory of Huaxi Xu, Ph.D., professor in Sanford Burnham Prebys Medical Discovery Institute’s Degenerative Diseases Program, shows how TREM2, a receptor found on immune cells in the brain, interacts with toxic amyloid beta proteins to restore neurological function. The research, published in Neuron, was performed on mouse models of Alzheimer’s disease, and suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders including Alzheimer’s disease.

EVERY 65 SECONDS someone in the United States develops Alzheimer’s disease Source: The Alzheimer’s Association

“Our studies, performed in collaboration with X. William Yang, M.D., Ph.D., professor at the David Geffen School of Medicine at UCLA, identify how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer’s disease pathogenesis,” says Xu. “Importantly, we also demonstrated that added TREM2 signaling stopped disease progression and even restored cognitive function.”

Alzheimer’s disease affects more than 47 million people worldwide, a number expected to grow as the population ages.

One of the hallmarks of the disease is the accumulation of amyloid plaques that form between neurons and interfere with brain function. Many drug companies have been working for years to reduce amyloid beta production to thwart Alzheimer’s—but with minimal success.

Amyloid plaques are a pathological hallmark of Alzheimer’s disease

“TREM2 offers a potential new strategy,” says Xu. “Researchers have known that mutations in TREM2 significantly increase Alzheimer’s risk, indicating a fundamental role for this particular receptor in protecting the brain. This new research reveals specific details about how TREM2 works, and supports future therapeutic strategies to strengthen the link between amyloid beta and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease.

“These studies are important because they show that in addition to rescuing the pathology associated with Alzheimer’s disease, we are able to reduce the behavioral deficits with TREM2,” says Xu. “To our knowledge, this provides convincing evidence that minimizing amyloid beta levels alleviates Alzheimer’s disease symptoms.”

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DISCOVERY HUB

Jing Crystal Zhao, Ph.D., assistant professor in the Tumor Initiation and Maintenance Program at SBP

Discovery May Advance Neural Stem Cell Treatments for Brain Disorders

Parkinson’s disease affects about

As neural stem cells (NSCs) are increasingly explored as a cell replacement therapy for neurological diseases and injuries, understanding how they self-renew and differentiate into neurons, astrocytes and other brain cells is essential.

Research from the lab of Jing Crystal Zhao, Ph.D., assistant professor in Sanford Burnham Prebys Medical Discovery Institute’s NCIdesignated Cancer Center, is among the first to describe how an mRNA modification impacts the life of NSCs, and may advance stem cell therapies and gene-targeting treatments for neurological diseases such as Alzheimer’s disease, Parkinson’s disease and mental health disorders that affect cognitive abilities.

Neural stem cells give rise to new neurons, astrocytes and oligodendrocytes.

The study, published in Nature Neuroscience, used knockout mice (KO) for an enzyme that catalyzes an mRNA modification, known as m6A. Zhao’s team found that m6A modification maintains a NSC pool by promoting proliferation and preventing premature differentiation of NSCs. Importantly, the researchers found that m6A modification regulates this by regulating histone modifications.

Histones—the proteins in cells that bind and package DNA—and their modifications play an important role in whether genes are turned “on” or “off.” Some histone modifications compact the DNA to hide a gene from the cell’s protein-making machinery and consequently

1 MILLION people in the United States Source: Parkinson’s Foundation

turn the gene “off.” On the other hand, histone modifications can also loosen up DNA to turn genes “on.”

“Our findings are the first to illustrate cross-talk between mRNA and histone modifications, and may lead to new ways to target genes in the brain,” says Zhao. “Conceptually, we could use the modification, which is the methylation of adenosine residues, as a special code in mRNA to target histone modifications to control gene activity.”

Drugs that alter histones have a long history of use in psychiatry and neurology, and increasingly in cancer. But current drugs that modify histones are often times non-specific; they work across the entire genome.

“Our study addressed the interaction between mRNA and histone modification in a genomewide scale. In the future, we plan to study such interactions on a gene-by-gene basis.

Ultimately, by modulating mRNA modification and its interacting histone modifications at a specific genomic region, we hope to correct aberrant gene expression in brain disorders with precision,” explains Zhao.

SUMMER 2018

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DISCOVERY HUB

Jamey Marth, Ph.D., professor at SBP’s NCI-designated Cancer Center, and director of the UC Santa Barbara Center for Nanomedicine

Gut Reaction: Repeated Food Poisoning Triggers Chronic Disease A startling discovery published in the journal Science reveals how your past history of minor bacterial infections can add up to cause a severe inflammatory disease. Small bacterial infections that may go unnoticed and that the body easily clears without treatment, which occurs during mild food poisoning, nevertheless can start a chain of events that leads to chronic inflammation and potentially life-threatening colitis. These findings may also help identify the long-mysterious origins of inflammatory bowel disease (IBD).

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Each year,

million people get sick from a foodborne illness Source: Centers for Disease Control

Jamey Marth, Ph.D., who holds a joint appointment at Sanford Burnham Prebys Medical Discovery Institute and UC Santa Barbara’s Center for Nanomedicine (CNM), led a team of researchers who developed a model of mild human food poisoning using healthy mice that were administered very low doses of Salmonella Typhimurium, a leading cause of human foodborne illness.

“We observed the onset of a progressive and irreversible inflammatory disease caused by previous infections. That was quite surprising because the pathogen had been easily cleared by the host,” says Marth.

The disease mechanism was linked to an acquired deficiency of intestinal alkaline phosphatase (IAP), an enzyme produced in the duodenum of the small intestine. Salmonella infection elevated neuraminidase activity in the small intestine, which in turn accelerated the molecular aging and turnover of IAP, resulting in IAP deficiency in the colon.

Salmonella food poisoning is one of the most common types of food poisoning

“These findings are of potential great concern to the human population,” says Marth. “Food contamination at these low bacterial levels is likely to be more common than we recognize, while symptoms could be nonexistent or mild and disappear in a day or two without treatment.”

The good news is that ways to boost IAP levels and inhibit neuraminidase activity exist.

IAP augmentation can be as simple as adding the enzyme to drinking water. Neuraminidase inhibition can be achieved using a currently marketed antiviral neuraminidase inhibitor, a drug that is used to prevent influenza viral infections.

Marth says, “We found that both treatment approaches were similarly effective at preventing the onset of colitis. In fact, published studies by others have recently reported IAP deficiencies and high neuraminidase levels in IBD patients.”

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SBP is a preeminent, independent biomedical research institute dedicated to understanding basic human biology and disease, and advancing scientific discoveries to profoundly impact human health.

“Our work is only made possible with the

Our track record of pioneering research, anchored by our NCIdesignated Cancer Center, spans more than 40 years, and has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases.

generous donations of

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

people like you.”

• SBP consistently ranks among the top 3 percent of research organizations worldwide in total number of publication citations, which attests to the quality and impact of its science.

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

• SBP ranks among the top three independent research institutes in the amount of NIH funding it receives, and in 2017 alone, increased NIH grant revenue 15 percent over the previous year.

Driven by an entrepreneurial spirit and one of the most advanced nonprofit drug discovery centers in the world, we harness breakthrough discoveries to develop prototype therapies with the potential to improve human health and save lives.

Supported by a deep culture of collaboration, generous benefactors and a global network of partners, we’re also committed to educating and training the next generation of scientific leaders to ensure our legacy continues.

Check out our website at SBPdiscovery.org

SBP conducts biomedical research funded primarily by grants from agencies of the federal government and private philanthropic support.

SBP is a California not-for-profit 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 Joseph C. Lewis Conrad Prebys* T. Denny Sanford TRUSTEES AND OFFICERS

Henry L. Nordhoff CHAIRMAN

James C. Blair, Ph.D. VICE CHAIRMAN

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

David W. Down Daniel J. Epstein William Gerhart Alan A. Gleicher James M. Myers Jeanne Herberger, Ph.D. James E. Jardon II Douglas H. Obenshain Donald J. Rosenberg, J.D. Peter Seidler Kazumi Shiosaki, Ph.D. 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.