Discoveries magazine Fall 2016 by Cedars-Sinai Discoveries magazine

Cedars-Sinai • Fall 2016

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In This Issue

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PRECISION MEDICINE

13 Nano Giant

36 Forecast: Cloudy

18 The Power of Prediction

26 Crossover Rx

What do the Trojan horse of Greek mythology and nanomedicine have in common? They exhibit invasive technology, killer strategy, and more than a modicum of sneakiness.

Renowned ovarian and breast cancer researcher Simon Gayther, PhD, knows geneticists can help save lives by preventing disease. He opens up about the challenges of calculating risk — and his stint as a circus clown.

The science of collecting and analyzing mind-boggling volumes of data is vital to the precision medicine revolution. As scientists take computation to the clouds, the sky is the limit for modern bioinformatics.

By taking a microscopic view of medicine, physicians are drawing a bigger, clearer picture of disease than ever before and opening pipelines that could carry already-proven medications to new patients.

38 Storm Chasers

Predicting the advent of sudden cardiac arrest has been just as perplexing as forecasting the perfect storm. But a landmark study shows that symptoms arise as early as four weeks prior to the deadly event.

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Senior Editor Cedars-Sinai Discoveries 6500 Wilshire Blvd., Ste. 1900 Los Angeles, CA 90048 PHONE: 323-866-8777 EMAIL: groupeditorial@cshs.org To subscribe to Discoveries magazine, visit discoveriesmagazine.org. For more information about Cedars-Sinai, visit cedars-sinai.edu. This publication is for informational purposes only and should not be relied upon as medical advice. It has not been designed to replace a physician’s medical assessment and medical judgment. Always consult first with your physician regarding anything related to your personal health.

ABOUT CEDARS-SINAI

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Cedars-Sinai is a national leader in providing high-quality, patient-centered healthcare encompassing primary care as well as specialized medicine and conducting research that leads to lifesaving discoveries and innovations. Since its beginning in 1902, Cedars-Sinai has evolved to meet the healthcare needs of one of the most diverse regions in the nation, continually setting new standards in quality and innovation in patient care, research, teaching, and community service. Today, Cedars-Sinai is widely known for its national leadership in transforming healthcare for the benefit of patients. Cedars-Sinai impacts the future of healthcare globally by developing new approaches to treatment and educating tomorrow’s physicians and other health professionals. Cedars-Sinai demonstrates a longstanding commitment to strengthening the Los Angeles community through wide-ranging programs that improve the health of its most vulnerable residents.

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• Sustain a program of outstanding biomedical research, healthcare services, and nursing research by fostering basic and clinical investigation in the prevention and causes of medical illnesses, their pathologic mechanisms and diagnoses, and the development of cures for the ailments that afflict our society • Translate research discoveries appropriately to a clinical setting • Provide research training opportunities for graduate students and Cedars-Sinai’s professional teaching programs • Foster the transition of biomedical discoveries to the realms of product development, patient care application, and marketing • Provide cross-fertilization and interdependent synergy between the medical center and the biotechnology industry • Protect the rights of human and animal subjects

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Contents In This Issue

18 The Gene Guru

Al Cuizon

Fueled by the idea that genetics can help save lives by preventing disease, renowned ovarian and breast cancer researcher Simon Gayther, PhD, hunts for a diagnostic breakthrough.

FALL 2016

SAVE OUR STORY Come celebrate the more than 100-year history of Cedars-Sinai by visiting the Historical Conservancy Exhibit, located adjacent to the Medical Library on the Plaza Level. You can help safeguard our proud heritage by donating your keepsake, commemorative items, or any medical treasure to the Historical Conservancy. For more information, contact Leo Gordon, MD, at historicalconservancy@cshs.org or 323-866-2925.

Contents Special Report: Precision Medicine 20 To Be Precise Precision medicine is revealing a path to health as individual as a ﬁngerprint.

22 A Pound of Cure An opportunity to prevent later cardiovascular disease in women who deliver preterm babies

24 To Outsmart Cancer Q&A with genomics expert Monica Mita, MD

26 Crossover Rx Opening pipelines that could carry already-proven medications to new patients

28 Precision Medicine A tour through time

32 The Diversity Question Can precision medicine help solve the problem of inadequate diversity in medical research?

36 Forecast: Cloudy Five reasons why computers should be added to our collective biomedical imagination

Feature 38 Storm Chasers A landmark study reveals that more than half of patients display identiﬁable warning symptoms before suffering sudden cardiac arrest.

SLIDESHOW VIDEO AUDIO LEARN MORE

On the Web Explore the digital version of Discoveries magazine for web exclusives, videos, and interactive features, including the warning symptoms of sudden cardiac arrest and a look at Cedars-Sinai’s virtual reality experience — all at discoveriesmagazine.org

Departments 5 NEWS & NOTES

•Bananas About a Protein•Rewriting the

Genetic Code That Leads to Blindness Regenerative Therapies to Heal Bone Fractures Bacteria to Combat Inﬂammatory Diseases Seeking Higher Ground to Reduce Obesity A Superbug Emboldened by a Certain Antibiotic Reducing Severe Pregnancy Complications Match Game: Medical Lingo Investigational Stem Cell Therapy That Slows Heart Failure New Hope for Duchenne Muscular Dystrophy Patients

•

• •

• • • • •

6 STATS

45 FACULTY NEWS

Inventions and discoveries shepherded by the Cedars-Sinai Technology Transfer Office

Cedars-Sinai’s graduate school is growing by degrees, with the addition of the new Program in Biomedical Science and Translational Medicine; awards and grants

9 WHO’S WHO Following the trail blazed by proteomics expert Jennifer Van Eyk, PhD

10 MY DEVICE

48 TIME CAPSULE A look at how lactation devices have come a long way, baby

Virtual reality’s immersive experiences offer patients a distraction from pain.

13 THIS VS. THAT How nanomedicine’s sneaky strategies correlate to the Trojan horse of legend

COVER ILLUSTRATION Bernard Maisner

FALL 2016 | DISCOVERIES |

From the Dean of Faculty

S We are developing and studying near-patient technologies, health-related outcomes, and diseasespecimen biobanking. These capabilities allow us to accelerate our precision approach to healthcare — from prevention through recovery and beyond.

ince 1816, when the first diagnostic stethoscope was invented, physicians have used technical aids, images, and biochemical and pathologic results to guide therapeutic decisions for broad patient populations. Now we are entering an era of truly wonderful diagnostic potential that incorporates highly specific genetic and clinical information to inform personalized disease treatments. We recently launched Cedars-Sinai Precision Health to efficiently deliver precise and personalized healthcare solutions to patients. Precision medicine requires integration of advanced technology, the latest biomedical discoveries, and rigorous bioinformatics to tailor disease treatments and prevention strategies to each individual. Our medical center is highly conducive to developing precision health solutions. Our nimble institutional environment is facilitating this medical revolution, from our impressive research talent and cutting-edge discovery approaches to our advanced electronic medical record system and wideranging healthcare delivery network. Thanks to these attributes, we are poised to make our mark in this growing field. Precision medicine research and implementation rely on contemporary advancements in genomics and big data processing. We are strongly committed to further developing such pivotal resources. We have constructed a state-of-the-art tissue biobank and recruited world-class specialists, as exemplified in this issue of Discoveries. Cedars-Sinai is exploring precision medicine beyond genetics and informatics. We are developing and studying near-patient technologies, health-related outcomes, and disease-specimen biobanking. These capabilities allow us to accelerate our comprehensive precision approach to healthcare — from prevention through recovery and beyond. Translating promising research from the laboratory to direct patient care is at the heart of Cedars-Sinai. We have human intellectual and technological pipelines in place to transfer novel solutions from discovery to the clinic so we can help more patients, faster. As a profession, we have come a long way in the 200 years since the advent of the stethoscope. In these pages, you will read about many of our precision health projects — and I hope you will be persuaded, as I am, that we are on the threshold of one of the most exciting moments in medical history, and are armed with a great opportunity to transform medical care.

Shlomo Melmed, MD EXECUTIVE VICE PRESIDENT, ACADEMIC AFFAIRS DEAN OF THE MEDICAL FACULTY HELENE A. AND PHILIP E. HIXON DISTINGUISHED CHAIR IN INVESTIGATIVE MEDICINE

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News & Notes Fall 2016

6 STATS | 9 WHO’S WHO | 10 MY DEVICE | 13 THIS VS. THAT | 18 Q&A

Bananas About a Protein

Photograph by CLINT BLOWERS

A tiny molecule discovered by CedarsSinai Heart Institute investigators — and fittingly named the “banana protein” — might hold the key to predicting heart failure. Shaped like the tropical fruit, the protein, BIN1, can be detected in the bloodstream. The investigators found in previous research that, during advanced stages of heart failure, levels of this protein decrease by half. Low levels are also a good predictor of future heart disease. “This little molecule plays a significant role in disease and in the strength of contraction during a heartbeat,” says Robin Shaw, MD, PhD, an expert in heart failure and rhythm abnormalities, and the Wasserman Foundation Chair in Cardiology in honor of S. Rexford Kennamer, MD. Shaw, research scientist TingTing Hong, MD, PhD, and their colleagues studied heart failure in 180 CedarsSinai patients. “A blood test for BIN1 does a beautiful job of detecting the disease,” Shaw says. The team aims to get the blood test approved by the Food and Drug Administration so physicians can use it to help determine heart health and even forecast patient outcomes. The investigators also are studying methods to restore or replace BIN1 in patients with deficiencies as a potential treatment for heart failure. FALL 2016 | DISCOVERIES |

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DNA Cut and Paste

The technique is adapted from a system that bacteria use to defeat invading viruses. The bacteria ﬁrst copy part of the invader’s genetic code into a special sequence of ribonucleic acid (RNA), which acts as a messenger to carry out the code’s instructions. When the virus returns, the RNA binds to a protein called Cas9, guides it to the matching gene in the virus, and thereby disables the gene. By modifying this system, scientists can program the Cas9 protein to turn selected genes on or off, or rewrite a genetic code, giving them the potential to correct the mutations that make cancer cells multiply, defend cells against the AIDS virus, or — in the case of the Cedars-Sinai group — delete the culprit behind retinitis pigmentosa. “We couldn’t be more excited,” Wang says. “Things are moving faster than we ever imagined for patients suffering from this disease.”

STATS : INVENTIONS AND DISCOVERIES The Cedars-Sinai Technology Transfer Office plays a crucial role in helping bring new therapies and medical devices created at the medical center to the marketplace, where they can have the greatest impact on society. The office secures patent protection and licensing agreements for breakthroughs developed by Cedars-Sinai physicians and scientists. The institution reinvests royalties generated by licensing these advances back into research programs to facilitate new discoveries that will eventually join the technology-transfer pipeline.

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300+

The Cedars-Sinai tech-transfer team manages the intellectual property portfolios of more than 300 technologies, including potential new diagnostics and treatments for cancer, cardiovascular conditions, and inﬂammatory bowel disease.

Dan Bejar

Movies, books, and articles all beneﬁt from good editing. So does science: Gene editing may be the answer to treating or hindering many inherited diseases, such as retinitis pigmentosa, a form of blindness. In a study using animal models, Shaomei Wang, MD, PhD, and her team used a revolutionary technique known as CRISPR/Cas9 to remove the genetic mutation that causes the degenerative eye disease. Retinitis pigmentosa currently has no known cure and affects some 100,000 people in the United States alone. “The study was a breakthrough,” says Wang, a research scientist in the Board of Governors Regenerative Medicine Institute’s Eye Program, associate professor of Biomedical Sciences, and the lead author of the study. “It suggests that some forms of retinitis pigmentosa may soon be treatable.” In less than ﬁve years, CRISPR/Cas9 has transformed the science of genome editing by making it easy, cheap, and fast to move genes around in any living organism, from bacteria to people. This is nothing short of a revolution in biomedical research. (CRISPR stands for clustered regularly interspaced short palindromic repeat, the type of DNA sequences involved in this process.)

N&N

Good to the Bone

Clint Blowers

Spinal-compression fractures related to osteoporosis account for more than 750,000 injuries in the United States every year — twice as many as hip fractures. Osteoporosis is a chronic and potentially life-threatening condition characterized by a loss of bone mass that leaves people vulnerable to fractures. Current treatments for the 10 million Americans who suffer from the condition focus on preventing fractures through lifestyle changes, including exercise, and medications to keep bones from shattering after a fall or a simple activity such as sneezing. Unfortunately, no options are available to heal these patients after fractures occur. However, new research suggests that regenerative treatments may be on the horizon. In a landmark study recently published in the journal Molecular Therapy, Cedars-Sinai researchers showed that a combination of adult stem cells and a speciﬁc bone-building hormone may signiﬁcantly speed up the rate at which fractures caused by osteoporosis will mend. During the course of the study, investigators helped repair spinal fractures in animal models by giving them injections of parathyroid

IMAGES The Swan-Ganz Catheter, invented in the early 1970s by two Cedars-Sinai cardiologists, revolutionized the way the medical community understood the physiology of heart failure and heart attacks, and is still a gold standard in cardiac medicine more than 45 years later, helping guide the treatment of critically ill patients throughout the world.

hormone (PTH) for 21 consecutive days, along with ﬁve injections of stem cells. The combination signiﬁcantly enhanced the stem cells’ migration to the bone fracture and increased the formation of new, healthy bone. “We knew that stem cells and PTH each had an effect on the healing process,” says Dan Gazit, DMD, PhD, principal investigator and co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors

Regenerative Medicine Institute. “What we discovered is that stem cells and PTH are much stronger when used in combination than separately.” “It’s as if they have a synergistic effect,” adds co-author Zulma Gazit, PhD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program. “It’s remarkable — like ﬁnding out that one plus one equals three.” The investigators are working toward developing a clinical trial to test the combination therapy in humans.

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99 In FY 2016, CedarsSinai investigators submitted 99 new inventions to the Technology Transfer Office.

Find out more about how the Campaign for Cedars-Sinai will advance precision medicine and targeted therapies at giving.cedars-sinai.edu

The U.S. Patent and Trademark Office issued 24 new patents for Cedars-Sinai technologies in FY 2016.

FALL 2016 | DISCOVERIES |

HELP BY VISITING A DIFFERENT KIND OF BANK. Make a different kind of donation by giving blood. All it takes is one hour to save up to two lives. Schedule an appointment now at donatebloodcedars.org or call 310-423-5346.

WHO’S WHO

her lab: pipeline-ism. Her team takes ideas from basic discovery, tests them, and then produces technology for clinical use.

other cell types and get more effective drugs. That gives you precision medicine.”

ACCESS POINTS

Though much of Van Eyk’s success is in heart disease research, her ideas can be applied to other areas. Her team is collaborating with the CedarsSinai Board of Governors Regenerative Medicine Institute to ﬁnd protein biomarkers generated from induced pluripotent stem cells for treating diseases in motor neurons. In this technology, cells derived from a patient’s skin or blood are manipulated genetically to return to an embryonic state so that they can be transformed into any cell type in the body.

“Ultimately, we want to produce something that a clinician can use and measure, which means you have to be in the clinic, the laboratory, or the pharmacy,” Van Eyk says.

FORGING A PATH

The Trailblazer

UNCONVENTIONAL ROUTE

NAME:

Jennifer Van Eyk, PhD,

John Cuneo

director of Basic Research, Barbra Streisand Women’s Heart Center at the Cedars-Sinai Heart Institute; director, Advanced Clinical Biosystems Research Institute; and the Erika J. Glazer Chair in Women’s Heart Health

[

]

Proteomics expert, avid hiker and painter

Jennifer Van Eyk is a leader in proteomics, which uses molecular biology, biochemistry, and genetics to analyze the structure, functions, and interactions of proteins. Proteomics utilizes large molecules, such as antibodies and enzymes, which are found in every living cell and play a critical role in bodily processes. But, just as she’d prefer bushwhacking to taking a conventional hiking trail, this Canadian-born scientist brings an unusual approach to

N&N

Just as hikers consider their body types, strengths, and weaknesses when selecting personal gear or a trail, medicine is shifting from the one-pill-ﬁtsall mentality to personalized approaches. Van Eyk and her team are leading the pack in this new era: “People are dynamic. You have your own genetic predisposition. You have your own environment. You have the memory of your body’s experience. Medicine should be just as precise.”

CELL INSIDERS Van Eyk’s team is unusually skilled and technologically equipped to quickly conduct millions of tests that suss out what is going on inside a cell. “We can use this process to monitor chemical pathways and determine the impact of a drug in a particular cell type. Then we can do it on

ON THE HORIZON

AIN’T NO MOUNTAIN HIGH ENOUGH Dedicated hikers see a mountain, climb it, look around, and see other challenges to conquer. “Some people get caught in those valleys between the mountains and the ocean because it’s comfortable,” says Van Eyk, who hikes and bikes twice a week, and walks to work every day. “The people in my pipeline, or researchers I like to recruit, will cross that valley. Once they reach the shore and realize it really is an ocean, they have the wherewithal to start swimming.”

FALL 2016 | DISCOVERIES |

N & N MY DEVICE

Hospital Room With a View Virtual reality creates immersive experiences for gaming, training, education — and now even healthcare. Research at Cedars-Sinai demonstrates the technology can offer a therapeutic distraction to hospital patients by transporting them to a different universe. All it takes is specialty goggles and a smartphone or tablet. Brennan Spiegel, MD, Cedars-Sinai’s resident expert in nerdtastic technologies, explains:

VIDEO 10

Take a peek at Cedars-Sinai’s virtual reality experience at discoveriesmagazine.org

| DISCOVERIESMAGAZINE.ORG

address the psychosocial impact of hospitalization. In short, virtual reality could help us better care for the whole patient.” Brennan Spiegel, MD, is director of Health Services Research in Academic Affairs and Clinical Transformation at Cedars-Sinai.

Al Cuizon

“My work is based on existing research showing that virtual reality can shut down pain signals. The spotlight theory posits that we are only able to focus on one narrow matter at once, and our brain shuts down other things to see what’s in the ‘spotlight.’ So if someone is in pain and they play an immersive game, the pain is diminished by virtue of being ignored. “Thanks to recent improvements in virtual reality technologies — and the accompanying reduction in costs — we can bring its benefits to a broad population of patients. My team has completed two studies that offer patients virtual experiences, including an aerial tour of Iceland and an underwater swim with exotic sea life — all in their hospital rooms. We gathered objective, measurable pain scores before and after, along with vital signs like blood pressure. The average pain score dropped from 5.44 to 4.1 after a five-minute virtual reality experience, which is highly statistically significant. “Hospital patients may experience anxiety, uncertainty, and boredom. They are in an unfamiliar environment without their usual freedoms. Virtual reality has the potential to improve patient satisfaction and, possibly, may even help people recover faster and go home sooner. This would not only reduce hospital costs but also

N&N

Inflammation Nation Inflammation is at the root of many diseases, and humans are not the only ones fighting it. Bacteria also face many of the same challenges as patients with inflammatory diseases such as diabetes, rheumatoid arthritis, and pulmonary emphysema. When confronted with inflammation in the human body, bacteria develop strategies on their own tiny scale to combat it and stay alive. These strategies are the subject of a study at Cedars-Sinai to discover new ways to battle inflammation. “The idea is to use bacteria’s own ways of staving off inflammation to help us find new ways to combat inflammatory diseases,” says Stacey Kolar, PhD, a postdoctoral scientist and the study’s first author. The findings are an important step in efforts to develop effective treatments for inflammatory conditions that affect millions worldwide. “Currently, we can help manage symptoms,” Kolar says, “but we can’t always find ways to make the inflammation subside.”

The Hills Are Alive With Weight Loss Looking to lose fat? New research led by the Cedars-Sinai Diabetes and Obesity Research Institute suggests heading for the hills — and staying there. The study, published in the journal Obesity, analyzed data from 31,549 adults in Peru. The prevalence of obesity among men residing at elevations of at least 9,843 feet was 50 percent less than in those living no higher than 1,640 feet. These men also had less abdominal obesity, which is strongly associated with cardiovascular disease. Other risks associated with obesity include diabetes, hypertension, and several types of cancer. The ramiﬁcations reach around the world, according to the study’s primary investigator, Orison Woolcott, MD, a project scientist at the Diabetes and Obesity Research Institute who

previously addressed the relationship between obesity and elevation in the U.S. “Our ﬁndings suggest that the association between geographical elevation and obesity extends to different populations around the world,” he says. Why altitude and obesity may be related also remains a mystery. The researchers speculate that the colder temperatures of high elevations may force the body to burn more calories. Ambient barometric pressure also may be a factor. Another mystery is that women exhibit no correlation between their weight and their altitude of residence. Follow-up studies could reveal more, so perhaps don’t move to a higher elevation just yet.

LEARN MORE

Find out how the Campaign for Cedars-Sinai will advance disease prevention and control at giving.cedars-sinai.edu

FALL 2016 | DISCOVERIES |

BRINGING OUR EXPERTISE TO THE FIELD. THE OFFICIAL HEALTH PARTNER OF THE

THIS VS. THAT

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Nano Giant

Greg Clarke

With its more than 37 trillion cells, the human body can be a challenging — and even hostile — territory for medicines to navigate. However, advances in nanomedicine — which uses materials measured in terms of the nanometer, one-billionth of a meter — are enabling physician-scientists to target and deliver therapy to the precise cells that need it. At Cedars-Sinai, Biomedical Sciences Associate Professor Lali Medina-Kauwe, PhD, and her team are expanding the ﬁeld’s potential by employing molecularlevel treatments to act like Trojan horses of healing, sneaking past the body’s defenses to attack cancer and other diseases. It turns out that nanomedicine shares other characteristics with the Trojan horse legend as well. Here’s a handy chart to help you compare the two.

NANOMEDICINE

TROJAN HORSE

ORIGIN

Hypothesized by Nobel-winner Richard Feynman in 1959 — but a shout-out to the movie Fantastic Voyage and other tales that fed future physician-scientists’ imaginations

Prince Paris’ abduction of Queen Helen of Sparta, later known as “Helen of Troy,” sometime between the 11th and 12th centuries BC

PURPOSE

Combats invading diseases while leaving healthy cells unharmed

Used to invade Troy, harming just about everyone there

APPROACH

Medina-Kauwe adds a peptide sequence to the protein that recognizes tumor cells and unlocks them for medical delivery.

Delivered when the Trojans brought in the giant horse, conned into believing that their enemies had sailed off and left the structure behind as a victory tribute

CONTENTS

Precision nanodrugs that bind to targeted cells

Up to 40 soldiers

MATERIALS

Proteins and other nontoxic, biodegradable substances

Wood, possibly covered in horsehide

RESISTANCE

Can overcome drug resistance built up against other treatments

Overcame Troy’s resistance by attacking while the city’s soldiers slept

TIMING

Drugs stay in place long enough to heal cells, reducing the need for repeated treatments.

The Greek soldiers stayed in place until nightfall, then attacked their sleeping opponents.

ANIMAL MODELS

Employed to test effectiveness compared to standard treatment methods

Instead of a horse, King Arthur’s knights built a giant rabbit in Monty Python and the Holy Grail — but neglected to get inside it before the model was taken in.

RESPONSIBLE FOR

New frontiers in medicine that will save and enhance countless lives

The phrase “beware of Greeks bearing gifts”

FALL 2016 | DISCOVERIES |

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Antibiotics vs. Superbugs Methicillin-resistant Staphylococcus aureus (MRSA) is a mouthful of a name for a particularly virulent and dangerous form of bacteria. The antibiotic-immune superbug causes some 80,000 infections and 11,000 related deaths per year. Researchers have long wondered why MRSA causes more severe disease than other staph infections. Now, in an article published in Cell Host & Microbe, Cedars-Sinai investigators suggest an answer: The main treatment against staph bacteria — beta-lactam antibiotics — not only fails to reverse the disease, but it also actually may make patients sicker. “Normally, beta-lactam antibiotics work by destroying the enzymes that make up the staph bacteria’s cell wall,” explains George Liu, MD, PhD, the study’s senior co-author, a pediatric infectious diseases physician at Cedars-Sinai’s Maxine Dunitz Children’s Health Center, and the F. Widjaja Inﬂammatory Bowel and Immunobiology Research Institute. “But it turns out that one of these enzymes, PBP2A, is not affected by the antibiotics.” Worse, the bacteria’s cell-wall structure changes in a harmful way once it is exposed to beta-lactam antibiotics. “This altered cell wall induces a powerful inﬂammatory response,” says the

Cells inﬂamed by antibiotic-treated MRSA in artwork by Andrea J. Wolf, PhD, a project scientist who contributed to the study

study’s senior co-author, David Underhill, PhD, associate director of the Division of Immunology Research in the Cedars-Sinai Department of Biomedical Sciences, and the Janet and William Wetsman Family Chair in Inﬂammatory Bowel Disease. “In mice infected with MRSA, the PBP2A enzyme, in combination with the antibiotic, increased inﬂammation and made the

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animals sicker.” The study raises the possibility that prescribing beta-lactam antibiotics may worsen MRSA, so why not just stop using these antibiotics? One problem is that culturing MRSA to conﬁrm a diagnosis takes a couple of days, and the effectiveness of betalactam antibiotics often makes them the ﬁrst line of defense for severe infections of unknown origin.

“We don’t always know when we’re dealing with MRSA, and when patients present with serious symptoms of infection, we have to treat them the best way we can,” Liu says. The investigators continue studying the problem because, for some patients, the answer could mean the difference between life and death.

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Spotlight on Maternal Illness morbidity and preterm birth,” Kilpatrick says, “but I did not expect to see 41 percent of these mothers deliver early. This was a surprising result.” Furthermore, the study showed that, of the women who experienced placental hemorrhaging, 63 percent had previously given birth via cesarean and had a higher rate of placental abnormality, suggesting that placental hemorrhage is strongly correlated with early births. “One takeaway from this research is that it is really important to avoid unnecessary cesarean delivery,” Kilpatrick says. “If we can reduce unwarranted C-sections, we may reduce placental abnormality and preterm births.” She adds that, given the association between severe illness during pregnancy and preterm births, hospital care is vital for every symptomatic mother. That way, both her condition and the health of her premature baby can be effectively managed. Results of this study will be used to better manage prenatal care, such as early development of birth plans designed to minimize risks to the mother, and implementation of specialized teams experienced in deliveries with these complications.

LABYRINTHINE LINGO During allergy season, does one sneeze or sternutate? The answer is both, because they mean the same thing. So when you give a hiccupping friend some water, you’re simultaneously helping stop synchronous diaphragmatic ﬂutter and singultus. Can you match the medical nomenclature in the left column to the synonyms in the right column?

THE DATA

67,468

deliveries were studied.

491

experienced severe maternal morbidity.

74% 41%

of these women of such cases experienced preterm involved delivery as a result hemorrhaging of prenatal and/or hypertension. complications.

of women with placental hemorrhage had a prior cesarean.

1. sphenopalatine ganglioneuralgia

A. goosebumps

2. borborygmi

B. nosebleed

3. horripilation

C. stomach growling

4. epistaxis

D. brain freeze Answers: 1–D; 2–C; 3–A; 4–B

Most mothers anticipate the birth of a baby with excitement and joy — and have a safe, problem-free delivery. However, each year approximately 50,000 American women experience pregnancy complications — from hypertension to sepsis to hemorrhaging — that put mother and baby at risk for serious illness and even death. These potentially life-threatening symptoms, known as “severe maternal morbidity,” are on the rise in the U.S. With an eye on reducing the number of women who become severely ill during pregnancy and managing the risks associated with these illnesses, Sarah Kilpatrick, MD, PhD — chair of the Department of Obstetrics and Gynecology at Cedars-Sinai and the Helping Hand of Los Angeles Chair in Obstetrics and Gynecology — led a study to determine the risk factors associated with women suffering from the most severe maternal illnesses, such as hemorrhage or severe hypertension. Her team sought to determine the relationship of this morbidity to preterm births using a more standardized approach than used in prior studies. “Previous research had shown a correlation between severe maternal

FALL 2016 | DISCOVERIES |

Tuck her in. Read her a story. Make sure her heart is beating. That was our daughter Laraâ&#x20AC;&#x2122;s bedtime routine for seven years. She had heart surgery two days after she was born to keep her alive, but we had to wait until she was old enough to get the surgery she needed to live a normal life. Once she was strong enough the team at Cedars-Sinai replaced two valves in her heart. After the procedure, my husband put his head against her chest and heard a normal, stronger heartbeat. I think we all broke down and cried. She still gets to listen to her bedtime stories every night, but my husband and I sleep a lot better. 1-800-CEDARS-1 | cedars-sinai.edu/heartstories

Regina Borda Lara Bordaâ&#x20AC;&#x2122;s Favorite Storyteller

N&N

Heart Strong

Chris Madden

An investigational stem cell therapy derived from patients’ own bone marrow signiﬁcantly improved outcomes in people with severe heart failure, according to a study from the Cedars-Sinai Heart Institute. “This is an important step forward for heart patients in particular and for stem cell medicine in general,” says Timothy D. Henry, MD, director of the Cardiology Division at the Cedars-Sinai Heart Institute, the Lee and Harold Kapelovitz Chair in Research Cardiology, and one of the study’s lead authors. He adds that stem cells could usher in a bright new era in treatments for heart failure. “Our intent is to increase the number of functioning cells in the heart muscle, which, in turn, strengthen the heart and alleviate or slow the advance of severe heart failure,” Henry says.

109

37.9%

patients enrolled in the Phase II study over a 12-month period. All were diagnosed with ischemic cardiomyopathy, a type of heart failure that usually results from a heart attack or coronary artery disease.

patients received the stem cell therapy and showed a 37 percent lower rate of deaths, hospitalizations, and worsening symptoms compared to the 51 patients who received a placebo.

of those who received stem cells were hospitalized with cardiovascular issues during the study. In comparison, 49 percent of patients who received the placebo were hospitalized during the study.

HOPE for Boys’ Hearts Duchenne muscular dystrophy (DMD) is the most common lethal genetic disease in children worldwide. A hereditary disorder characterized by progressive muscle degeneration and weakness, the illness primarily affects boys, robbing them of the ability to walk by the time they reach their 15th birthdays. The average life expectancy remains just 25 years of age. Thanks to research underway at the Cedars-Sinai Heart Institute, this calculus may be changing. In the three decades since the discovery that speciﬁc genetic mutations cause DMD, the mainstays of the disease’s management have remained the same — steroids, which cause many side effects, and supportive care. But a novel therapeutic approach offers the tantalizing possibility of slowing or even reversing the disease process. While most DMD research focuses on skeletal muscle deterioration, the disease’s leading cause

of death is heart failure. Now, with seed funding from Coalition Duchenne — a global partnership created by parents and families whose lives have been touched by DMD — investigators have discovered that mice with muscular dystrophy respond to treatment with cardiac stem cells: They live longer, their hearts beat more strongly, and they can exercise more before becoming fatigued. These ﬁndings form the basis of Halt cardiomyOPathy progrEssion (HOPE)– Duchenne, a clinical trial at the Heart Institute and other centers nationwide. The trial is the ﬁrst to examine whether cardiac stem cell therapy can reverse heart muscle damage in DMD patients by replacing scar tissue with normally functioning cardiac muscle. HOPE–Duchenne may make a critical difference for the 25,000 boys and young men affected by DMD in the U.S. alone.

FALL 2016 | DISCOVERIES |

Q A &

The Power of Prediction By Jeremy Deutchman

Simon Gayther, PhD, is serious about the science of disease prediction and prevention. The renowned ovarian and breast cancer researcher — a new recruit to Cedars-Sinai and a transplant from across the pond — opens up about the challenges of assessing genetic risk factors and the joys of clowning around.

Q: Did you always know you wanted to be a cancer researcher? A: Not at all. I’m from the English countryside and, for a while after ﬁnishing my

undergraduate degree in zoology, not knowing which career to choose, I toured as a clown with a traveling circus. They were looking for someone to come and look after the animals but quickly realized that my tall and clumsy nature was perfect for dressing up to be laughed at by children. Q: What interested you in going into breast and ovarian cancer prevention? A: When I was working on my PhD, I fell in love with the idea that geneticists

could contribute to saving lives by preventing disease. The hot topic at the time was the race to ﬁnd the BRCA1 and BRCA2 genes — it was, in terms of heritable genetics, probably the most exciting story in research. Seeing how discoveries like those could translate into real impact in patients’ lives has pushed me forward and continues to do so today. Q: How has the landscape shifted over the past 20 years in terms of combating these illnesses? A: The answer is simultaneously exhilarating and frustrating. In 1990, ﬁve-year

survival rates in women diagnosed with breast cancer were just 30 percent; today, 70 percent of women with breast cancer will be alive five years in. By contrast, for ovarian cancer, the five-year survival rates have hardly improved in five decades, mainly because it’s a very difficult disease to diagnose at its earliest stages when it is most treatable. We must change that. This interview has been edited and condensed.

| DISCOVERIESMAGAZINE.ORG

Q: How are you approaching the challenge? A: We’re looking at individuals who, based on

family history, are predisposed to getting these cancers. But identifying risk is a tricky business because there are so many factors that inﬂuence it. For instance, if you are taking an oral contraceptive, or if you have given birth, your chances of getting ovarian cancer are cut in half. So conducting studies that yield meaningful results requires an extremely big patient sample size. I’m part of a consortium that comprises more than 50 different centers from around the world, pooling data from tens of thousands of people who do — and don’t — have the disease. Q: What are the potential beneﬁts of predicting genetic risk if there are no cures? A: It’s the promise of precision medicine: tailoring

our approach to healthcare depending on a person’s background and needs. What genetics is doing is allowing us to imagine a future in which, based on individual screening, we can give a woman actionable advice. Perhaps, based on the thousands of genetic variations that contribute to her speciﬁc risk for something like ovarian cancer, we can suggest that she have children early and then elect for a surgical intervention to remove the at-risk organ. For someone who is at lower risk, we can recommend entering her into a screening program so that when she turns, say, 40, we start to monitor her for any signs or symptoms of the disease. Q: Can genetic proﬁles offer clues about why some women won’t develop hormonal cancers? A: When we talk about genetics, we often think of

the risk factors that make us susceptible to disease. But we’ve all heard of people who smoked their whole lives and never got lung cancer. The same way our genes can help dictate what happens to us, they can also offer us a measure of protection from certain illnesses. Part of our work is unlocking the mystery of these safeguards. This has major real-world implications for hormonal cancers because we currently spend huge amounts of time and money on screening the entire population

N&N

SIMON GAYTHER, PhD Director, Molecular Epidemiology, and co-director, Center for Bioinformatics and Functional Genomics, Cedars-Sinai Department of Biomedical Sciences FRUITFUL COLLABORATION

Together with Paul Pharoah, PhD, at the University of Cambridge, and Beth Karlan, MD, at Cedars-Sinai, Gayther has established many international collaborations to identify the genetic causes of ovarian cancer. This developed into the Ovarian Cancer Association Consortium, now the world’s largest population-based ovarian cancer case collection, comprising almost 50,000 subjects. Karlan is director of the Women’s Cancer Program in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, and the Board of Governors Chair in Gynecologic Oncology. EVEN MORE FRUITFUL COLLABORATION

Wife Kate Lawrenson, PhD, is also an ovarian cancer investigator at Cedars-Sinai. The couple had their ﬁrst child this summer.

Al Cuizon

FORMER LIFE

using mammography. If we could pinpoint who isn’t likely to get a disease, we could be investing our resources in screening only the people who are most at risk.

Q: Ever miss the clown business? A: It was an oddly ﬁtting start to my real career

since it taught me that, every time you fall down, you just get right back up again.

Used to be the lead singer in the rock band The Shifting Balance — a name based on an evolutionary theory hypothesizing that the interaction among natural selection, genetic drift, and migration is more important than the action of any single force.

FALL 2016 | DISCOVERIES |

A POUND OF CURE p22 TO OUTSMART CANCER p24

PRECISION MEDICINE

YOU ARE WHAT YOU ATE

TO BE

p25

CROSSOVER RX p26 A TOUR THROUGH TIME p28 MODEL BEHAVIOR p30

UNCLE SAM WANTS YOU(R EXERCISE ROUTINE)

PRECISE

p30

TYPING TEST p31 THE DIVERSITY QUESTION p32 BACK TO THE FUTURE p34

WHAT’S IN A NAME? p34

I’M WITH THE BAND

edicine has never had more power than it does at this very moment: power to detect, diagnose, prevent, and heal. While ancient Greek physicians aimed to defeat diseases (and even bad moods) by adjusting a patient’s unique balance of four humors, today’s clinicians use more sophisticated methods. An ever-deepening understanding of genetics and the molecular function of cells, along with radical advances in computer technology, are heralding a profound transformation in personalized health. Physicians and investigators are developing individualized modes RI WUHDWPHQW 7KH\ DUH UHoQLQJ WKH DUW RI SUHGLFWLRQ $QG WKH\ DUH FOHDULQJ D SDWK WR \RXU KHDOWK WKDW LV DV GLVWLQFWLYH DV \RXU oQJHUSULQW 7KLV LV WKH SURPLVH RI SUHFLVLRQ PHGLFLQH WR RIIHU WKH right treatment to the right patient at the right time — every time. From cancer and back pain, WR )LWELWV DQG PHJDE\WHV ZH EULQJ \RX WR WKH IURQW OLQHV RI D VFLHQWLoF UHYROXWLRQ

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Raul Arias

p36

| DISCOVERIESMAGAZINE.ORG

RISK & PREVENTION

A POUND OF CURE Preterm childbirth correlates with later cardiovascular disease in women, providing an opportunity for prevention.

and cholesterol numbers that might be risk factors in creating a perfect storm of impaired vascular function,â&#x20AC;? Minissian says. To hunt for the biochemical markers, Minissian and her collaborators employ cutting-edge technology that is 1,000 times more sensitive than that used to assess a patient with an active, obvious condition like a heart attack. The study also uses equipment that noninvasively assesses blood-vessel health with extreme acFXUDF\ 7KH GDWD ZLOO KHOS FUHDWH D KHDUW GLVHDVH ULVN VWUDWLoFDWLRQ system for women of childbearing age.

â&#x20AC;&#x153;

In medical school, they emphasized that an ounce of prevention is better than a pound of cure. And it is, especially for chronic conditions like heart disease that must be managed for many years.â&#x20AC;? â&#x20AC;&#x201D; Dermot McGovern, MD, PhD â&#x20AC;&#x153;Women who give birth have put themselves through a ninemonth physiological stress test called â&#x20AC;&#x2DC;pregnancy,â&#x20AC;&#x2122;â&#x20AC;? Minissian says. â&#x20AC;&#x153;We are identifying women who have an adverse response to pregnancy and asking why.â&#x20AC;? Many women are not assessed for cardiovascular problems until they already have symptoms, so clinicians like Minissian end up managing heart attacks and strokes instead of preventing them. â&#x20AC;&#x153;If we can identify these women during their childbearing years, manage their blood pressure and cholesterol, and educate them about nutrition, exercise, and other heart-healthy behaviors, we can deviate them from the track to heart disease,â&#x20AC;? she says.

LEARN MORE

Find out more about how the Campaign for Cedars-Sinai is advancing precision medicine at giving.cedars-sinai.edu Joey Guidone

hronic diseases grab on to the body and are hard to shake. Very few have cures. â&#x20AC;&#x153;In medical school, they emphasized that an ounce of prevention is better than a pound of cure. And it is, especially for chronic conditions like heart disease that must be managed for many years,â&#x20AC;? says Dermot McGovern, MD, PhD, director of Cedars-Sinai Precision Health, DQG WKH -RVKXD / DQG /LVD = *UHHU &KDLU LQ ,QpDPPDWRU\ Bowel Disease Genetics. Besides aiding the sick, precision medicine also can help healthy people stay well. One study at Cedars-Sinai applies its individualized tactics to investigate how adverse pregnancy outcomes can be used to identify women at risk for cardiovascular disease. Once LGHQWLoHG SDWLHQWV DQG SK\VLFLDQV FDQ LQLWLDWH SUHYHQWLRQ VWUDWHJLHV that may limit future heart disease risk. â&#x20AC;&#x153;Preterm delivery is a marker of future heart disease, but many clinicians are unaware of the risk,â&#x20AC;? says Margo Minissian, ACNP, a nurse scientist and cardiology nurse practitioner at the Barbra Streisand Womenâ&#x20AC;&#x2122;s Heart Center at the Cedars-Sinai Heart Institute. In fact, preterm delivery (at 37 weeks or less) doubles a womanâ&#x20AC;&#x2122;s risk for cardiovascular disease. Combine that with other adverse pregnancy outcomes such as preeclampsia, a condition marked by high blood pressure, and a woman is up to eight times more likely to have heart disease later in life. Minissian is investigating the problem in a National Institutes of Health-funded project. When a new mom delivers early, Minissian heads down to the Labor and Delivery Unit within 72 hours to conduct vascular testing and oversee a blood draw in women who consent to participate in the study. More tests are conducted six months later. Minissian is leading the study with maternal-fetal expert Sarah Kilpatrick, MD, PhD (p. 15), and they are collaborating with proteomics specialist Jennifer Van Eyk, PhD (p. 9). k:H DUH ORRNLQJ DW LQpDPPDWRU\ PDUNHUV DV ZHOO DV EORRG SUHVVXUH

| DISCOVERIESMAGAZINE.ORG

SUMMER 2016 | DISCOVERIES |

Q&A

TO OUTSMART CANCER Mysteries surrounding cancer genomics have been stripped away in recent years, exposing the disease as a target for precision medicine. Discoveries asked Monica Mita, MD, co-director of Experimental Therapeutics at Cedars-Sinai, to explain how oncology research stands to gain ground in the near future. Q. What makes cancer genetically interesting? A. Cancer is genetically diverse, even within a single tumor or

among patients with the same type of cancer. Its genetics change over time, and there simply isnâ&#x20AC;&#x2122;t one single treatment for everybody. So we have to outsmart it. Q. How is cancer vulnerable to attack? A. Very simply, cancer cells are abnormal because of gene muta-

tion or variation in how genes are expressed. We have learned that treatments often affect certain targets: If we target the abnormal gene that drives the cancer growth, in some cases, we can kill the disease. Q. Is that precision medicine? A. Yes. Every cancer is different, every mutation is different, and

ZH KDYH WR oQG WKH PXWDWLRQ EHIRUH ZH FDQ WDUJHW LW :H ZDQW to know what is happening inside every personâ&#x20AC;&#x2122;s cancer in order to choose a treatment that is targeted for that individual. That is precision medicine.

LINGO

BASE PAIR

As cells divide to create new ones, base pairing ensures perfect copies. Bases are the letters that spell out our genetic code â&#x20AC;&#x201D; A, T, G, and C, standing for the chemicals adenine, thymine, guanine, and cytosine. Base pairs are the two letters that complement each other: A always matches to T, while G connects to C. If we think of DNA as a curling ladder, each base pair constitutes a rung.

Q. Where are we today with developing targeted treatments for cancer? A. Imatinib (also known as Gleevec) is the classic example of a

targeted treatment that changed cancer research. It was developed to treat chronic myelogenous leukemia [CML]. [Prior to approval of the drug in 2001, less than one in three CML patients VXUYLYHG oYH \HDUV SDVW GLDJQRVLV @ 7RGD\ SHUFHQW RI &0/ patients can achieve remission with Gleevec. Since then, we have developed many other targeted therapies. Still, many more are needed, and we need to learn how to combine them for enhanced anticancer activity. Q. Can precision medicine be used to enhance a patientâ&#x20AC;&#x2122;s own immune system through immunotherapy? A. I think a revolution in immunotherapy is beginning. A patient

might receive antibodies to help the immune system to attack a tumor, but not every personâ&#x20AC;&#x2122;s immune system will respond the same way, and not every tumor will be vulnerable. We are studying why the response varies so we can personalize therapy. Q. How else can precision medicine help outsmart cancer? A. :KHQ ZH FUHDWH JHQHWLF RU PROHFXODU SURoOHV IRU D WXPRU DQG

then try to match the patient with the best treatment, we do it patient by patient. We need a huge database that is of national or international scope so we can correlate many different moOHFXODU SURoOHV ZLWK RXWFRPHV >5HDG PRUH RQ S @ 3UHFLVLRQ medicine also helps us determine who are the best candidates for surgery. Q. What can patients do to help cancer research? A. In the U.S., less than 5 percent of adult patients are enrolled

in clinical trials. If we could increase that to 20 percent, we would achieve results faster and help more people. This interview has been edited and condensed.

| DISCOVERIESMAGAZINE.ORG

CASE STUDY: MICROBIOME

YOU ARE WHAT YOU ATE You are special, and it’s time you started eating like it. A hundred trillion microbes live in and on you, and the population of bacteria in your gut— your microbiome — is as unique as a snowflake. Suzanne Devkota, PhD, a Cedars-Sinai research scientist, parses the relationship of diet, the gut microbiome, and disease. “We know now that medicine is not a one-size-fits-all discipline. Neither is diet,” she says. Everyone is born with certain disease risks baked into their DNA, but environment plays a huge role in whether or not a condition actually develops. Devkota, who studies inflammatory bowel diseases as well as diabetes and obesity, explains that changing the gut microbiome can help some people manage disease or even avoid it altogether. “Bacteria are exquisitely sensitive to the foods we eat,” she says. “I use diet to manipulate the microbiome in research studies and look for links to disease.” She has employed the technique in mice and soon plans to test its advantages in human subjects. Microbiomics is a rapidly expanding field made possible by advances in genetic sequencing. Devkota plans to compile a massive database that combines patients’ genomic data, microbiome profiles, and other health information. “No one — yet — has mechanistic data to provide insights to patients about food beyond, ‘you have a sensitivity,’” Devkota says. “We can do so much better.” The convenient thing about a dietary change is that, unlike a new medication, it carries little risk and does not require Food and Drug Administration approval. “If we discover something in the lab today around diet, we can make a dietary recommendation tomorrow,” Devkota says. Taking that concept even further, investigators envision developing personalized solutions such as proprietary fiber blends or tailored probiotics — so, eventually, each one of us might be consuming a diet that is as specialized as the microbes with whom we share it. ADVANCES

SHARING IS DARING

A large body of medical research goes unpublished and unshared, hampering clinical advances. Project Open Data and other initiatives unlock this treasure trove, enabling information to be pooled and creating larger sample sizes to improve development of evidence-based precision medicine.

FALL 2016 | DISCOVERIES |

DISEASE AGNOSTICISM

CROSSOVER RX

A close-up view of disease opens pipelines that could carry already-proven medications to new patients.

genetics look much more like some people with ankylosing spondylitis than they do like other people with Crohnâ&#x20AC;&#x2122;s, and vice versa,â&#x20AC;? McGovern says. And some patients have both diseases without realizing it. The physicians are discovering treatments that can EHQHoW ERWK JURXSV RI WKHLU SDWLHQWV DQG DOVR LPSRUWDQWO\ VRPH therapies that should be avoided in certain patients. Such crossovers are happening more than ever, according to Daryl Pritchard, PhD, vice president of science policy for the Personalized Medicine Coalition, a Washington, D.C.-based education and advocacy group. He says the Food and Drug Administration

â&#x20AC;&#x153;

,I , oQG D JHQHWLF VLJQDWXUH IRU D JURXS RI SDWLHQWV DQG , oQG D WKHUDS\ WKDW ZRUNV IRU WKHP WKHQ , FDQ ORRN IRU VLPLODU VLJQDWXUHV LQ RWKHU GLVHDVHV Â&#x2039; DQG KHOS PRUH SDWLHQWV y â&#x20AC;&#x201D; Dermot McGovern, MD, PhD is relabeling an unprecedented number of drugs for use in diseases for which they were not originally approved. â&#x20AC;&#x153;Oncology researchers in particular are conducting so-called basket studies,â&#x20AC;? Pritchard says. â&#x20AC;&#x153;Traditionally, a clinical trial focuses on a particular type of cancer, but a basket study targets a gene mutation, regardless of the tissue or organ involved.â&#x20AC;? â&#x20AC;&#x153;This kind of mechanistic approach shortens the process for drug discovery, reducing the time to market, and thereby very VLJQLoFDQWO\ UHGXFLQJ GUXJ FRVWV y 0F*RYHUQ DGGV For him, the approach is more than a novel way of looking beyond WKH FODVVLF RUJDQ V\VWHPV FODVVLoFDWLRQ Â&#x2039; LW V DOVR D SRZHUIXO HQJLQH IRU EURDGHU GLVFRYHU\ k,I , oQG D JHQHWLF VLJQDWXUH IRU D JURXS RI SDWLHQWV DQG , oQG D WKHUDS\ WKDW ZRUNV IRU WKHP WKHQ , ORRN IRU similar signatures in other diseases â&#x20AC;&#x201D; and help more patients.â&#x20AC;? Niel Webb

recision medicine can be thought of as a science of small details. Investigators are examining individual gene mutations, mapping molecular pathways inside cells, and deciphering diseases one subgroup of patients at a time. For instance, the discovery that mutations in the BRCA1 and BRCA2 genes can cause breast cancer was KXJHO\ EHQHoFLDO IRU WKH SHUFHQW RI ZRPHQ who carry those mutations. It might sound like precision medicine is building silos when it should be breaking them down. Actually, by taking the microscopic view, itâ&#x20AC;&#x2122;s helping medicine draw a bigger, clearer picture of disease than ever before. Itâ&#x20AC;&#x2122;s also opening pipelines that could carry already-proven medications to new patients. â&#x20AC;&#x153;If you become agnostic about the organ involved and you become more interested in the underlying causes of diseases, you can start to subtype them by genetic infrastructure,â&#x20AC;? says Dermot McGovern, MD, PhD, who directs Cedars-Sinai Precision Health as well as Translational Medicine at the medical centerâ&#x20AC;&#x2122;s F. Widjaja )RXQGDWLRQ ,QpDPPDWRU\ %RZHO DQG ,PPXQRELRORJ\ 5HVHDUFK Institute. â&#x20AC;&#x153;We are witnessing the emergence of a new molecular taxonomy of diseases instead of the traditional nomenclature based on particular organs and systems.â&#x20AC;? 0F*RYHUQ Â&#x2039; WKH -RVKXD / DQG /LVD = *UHHU &KDLU LQ ,QpDPmatory Bowel Disease Genetics â&#x20AC;&#x201D; is conducting inventive research with colleague Michael Weisman, MD, director of Rheumatology and the Cedars-Sinai Chair in Rheumatology. A decade ago, a gut physician and a joint specialist would not have found common ground in the laboratory. Now they know that many immune-mediated diseases share a genetic architecture, with D SDUWLFXODU FRQQHFWLRQ EHWZHHQ &URKQ V GLVHDVH D IRUP RI LQpDPPDWRU\ ERZHO GLVHDVH ,%' DQG DQN\ORVLQJ VSRQG\OLWLV DQ LQpDPmatory spine disorder. â&#x20AC;&#x153;It turns out that there are people with Crohnâ&#x20AC;&#x2122;s disease whose

| DISCOVERIESMAGAZINE.ORG

SUMMER 2016 | DISCOVERIES |

PRECISION PRECISION MEDICINE: MEDICINE: AATOUR TOURTHROUGH THROUGHTIME TIME

1990

1953

MAP QUEST

Like Like much much inin the the history history ofof medicine, medicine, progress progress often often proceeds proceeds byby tiny tiny baby baby steps steps rather rather than than monumental monumental breakthroughs. breakthroughs. Here Here we we highlight highlight aa few few ofof the the many many millions millions ofof stepping stepping stones stones onon the the road road toto precision precision medicine. medicine.

GENETICS TAKES SHAPE Rosalind Franklin uses X-ray crystallography to discern the shape of DNA, paving the way for James Watson and Francis Crick’s unraveling of DNA’s double-helix structure.

The Human Genome Project begins sequencing the body’s complete set of DNA — the approximately 3 billion letters, or base pairs, that make up the human genome.

1865 BIRTH OF GENETICS Austrian monk Gregor Mendel interbreeds pea plants and explains how traits are inherited, observing 10,000 plants and noting if they are yellow or green, and round or wrinkled.

460– 375 BC

1683

1928

FAVORABLE FUNGUS THE MINUSCULE WORLD OF MICROBES Antony van Leeuwenhoek describes microbes — which he calls “animalcules” — that he sees in plaque from his teeth under a microscope.

THINK DIFFERENT Hippocrates proposes natural rather than mystical theories about what causes disease, and highlights individual differences in the expression of illnesses.

Alexander Fleming accidentally discovers penicillin when a mold kills off bacteria he was cultivating.

2008

1761

2010

NO SENSE OF HUMORS

IT’S A SMALL WORLD

Anatomist Giovanni Battista Morgagni rejects the notion of illness-causing “humors” and publishes a diseasecategorizing tome based on more than 600 postmortem dissections.

After 300 years of mostly ignoring the tiny ecosystems living in and on us, the National Institutes of Health establishes the Human Microbiome Project to understand these potential medical allies.

MODERN DISEASE TAXONOMY

2016

Today, clinicians rely on the World Health Organization’s International Statistical Classiﬁcation of Diseases and Related Health Problems.

BLURRED LINES

2016

Investigators deﬁne the molecular pathways and genetics behind maladies in ways that defy traditional categories and spur the development of drugs that can target multiple conditions.

EXPLORING THE INTERNAL ECOSYSTEM Scientists expand the understanding of molecules in the gut, their relationship to the microbiome and genetics, and how this combination can lead to Crohn’s disease and other disorders.

Cost to sequence a human genome’s worth of DNA:

2003

Outrageous

$90,000,000

2016 $45,000

$1,000

EARLY ARRIVAL An international consortium of scientists develops the reference human genome at a cost of $2.7 billion, two years ahead of schedule.

Time to sequence a human genome’s worth of DNA: Quixotic 3 years 1 month < 2 days

2010

1990

1910

PROTEOMICS PROJECTIONS

2000

2010

MEASURE FOR MEASURE

The international Human Proteome Project is created to examine the palette of proteins in our bodies and may provide clues to abnormal functioning or disease.

BOOT UP

The world’s smallest “scales,” mass spectrometers determine the scope of a molecule. 1964

THE DAWN OF BIG DATA 2016

Today

1920s

Supercomputing and big data trace their beginnings to innovators at IBM and Columbia University.

Seymour Cray designs the ﬁrst supercomputer, a mainframe used in physics experiments at the European Organization for Nuclear Research, known as CERN, in Switzerland.

2016

NANO WEIGHT CLASS

PRESIDENTIAL PRECISION

Today’s highly advanced devices enable scientists to precisely measure proteins and develop new nanoscale drugs.

The president unveils plans for a $215 million investment in the White House’s Precision Medicine Initiative.

1960 2015

1998

PHILADELPHIA CHROMOSOME

TARGETED CANCER DRUGS Herceptin — a drug used for targeted therapy in patients with a speciﬁc genetic makeup — is approved for people with a particularly aggressive form of breast cancer.

Investigators in Philadelphia identify a chromosomal abnormality linked to leukemia, which later becomes the target of one of the ﬁrst precision cancer treatments.

IN THE CLOUDS Cloud computing provides the capacity to cope with big data and is used for the multi-petabyte (1 petabyte = 10 15 bytes) data shared by the International Cancer Genome Consortium.

2016

PRECISION MEDICINE AT CEDARS-SINAI Cedars-Sinai Precision Health is launched to tailor disease treatments and prevention strategies to each individual using the newest technology and best research.

CASE STUDY: BRAIN CANCER

MODEL BEHAVIOR “

ne of these days, prescribing chemotherapy for brain-tumor treatment will be archaic.” These words from Chirag G. Patil, MD — director of the Cedars-Sinai Center for Neurosurgical Outcomes Research — may sound bold, but they are grounded in tangible research and the broader precision medicine revolution. Harnessing the power of big data and virtual modeling, Patil DQG KLV WHDP FUHDWH D FRPSUHKHQVLYH SURoOH RI HDFK SDWLHQW V cancer. Their work furthers the quest to personalize treatment for a pernicious disease. k7UDGLWLRQDO FKHPRWKHUDS\ DQG UDGLDWLRQ FDQ W UHDGLO\ GLIferentiate between healthy and unhealthy tissue, and therein lies the problem with our conventional approaches,” Patil says. 7KH SURoOH DSSURDFK VWDUWV ZLWK FHOOV IURP WKH SDWLHQW V EUDLQ tumor. The cancerous tissue is grown in the laboratory, and Patil — in collaboration with an outside biotech company* — then builds an identical, mathematical model of the tumor. By running the virtual tumor through genomic sequencing, researchers can test for millions of genetic mutations. Once the culprits are discovered, the team devises treatments that target only the abnormal proteins that are the building blocks of cancer. Historically, the prognosis for a glioblastoma multiforme — the most aggressive type of brain tumor — has been bleak, with a survival rate of 14–15 months after diagnosis. Patil and his team believe this kind of research and technology heralds a new era in cancer treatment. Patil participated in the White House Precision Medicine Summit in February, which brought together top medical researchers, clinicians, community advocates, and others from around the country. The technology Patil is studying also has applications beyond brain cancer. Similar modeling is being used in lung cancer — and precision medicine holds great promise for breakthroughs against a multitude of other deadly malignancies (see p. 24). — Jasmine Aimaq *Disclosure: Patil receives payment from the outside biotech ﬁrm for providing consulting services.

| DISCOVERIESMAGAZINE.ORG

UNCLE SAM WANTS YOU(R EXERCISE ROUTINE) One million U.S. residents will soon volunteer their personal medical information to science. President Barack Obama announced the Precision Medicine Initiative in 2015 to, as he said, “bring us closer to curing diseases like cancer and diabetes.” Some $215 million was allocated to the project, with $130 million earmarked for the National Institutes of Health to build a largescale research participant group. Volunteers will donate their medical records, genetic data, and environmental and lifestyle information as part of the initiative, which promises to accelerate biomedical discovery. President Obama touted the beneﬁts of the effort when he spoke about it in January last year. “If we’re born with a particular disease or a particular genetic makeup that makes us more vulnerable to something … that’s not our destiny, that’s not our fate. … We can remake it. That’s who we are as Americans. And that’s the power of scientiﬁc discovery.” ADVANCES

DNA ANALYSIS, AMPLIFIED

Next-generation sequencing has revolutionized DNA analysis, making it exponentially faster and less expensive, while often unveiling valuable information about the genetic makeup of the disease to be treated. In battling cancer, for example, pathologists can scan a tumorous tissue sample for more than 2,800 cancer-related mutations in some 50 cancer genes to elucidate the most powerful treatment options for each patient. Because of its incredible speed and capacity, this technology is also known as high-throughput sequencing.

CASE STUDY: BLOOD MATCHING

TYPING TEST

he promise of precision medicine includes understanding each person’s body on such a minute level that physicians can make even common procedures, such as blood transfusions, safer than ever before. For a successful blood transfusion, donor and patient blood types must be matched accurately. Otherwise, the immune system attacks donor cells as invaders, causing shock, kidney failure, and even death. At Cedars-Sinai, a new technique called extended blood matching goes beyond the standard typing of A, B, O, and AB, and positive or negative Rh factor. “We are one of very few hospital blood banks that uses genetics for blood typing and matching,” says Ellen Klapper, MD, director of Transfusion Medicine at Cedars-Sinai. Matching a blood donor to a recipient comes down to antigens, which are encoded in our DNA. Blood types A and B, and the Rh factor, refer to antigens: proteins and sugars that sit on the surface of blood cells — which is all most hospital transfusion services test for. However, dozens of other antigens reside

QUOTE

on red blood cells that, while harmless in the donor, can cause an immune reaction in the recipient. As a result, up to 60 percent of transfusion recipients may experience an unintended immune response, depending on their health status and other factors. Patients receiving multiple transfusions, or who have conditions such as sickle cell disease, are at highest risk. In addition to the immediate health problems, antibody formation can complicate future transfusion therapy and increase the cost of treatment. Klapper’s studies have been instrumental in demonstrating that a hospital transfusion service can test for genetically based variations in antigens. Previously, such molecular testing was restricted to specialized labs. “We also showed that, in a hospital setting, it is quite possible to select more highly matched blood for transfusion, thereby reducing the risk of antibody formation — the immune response,” Klapper says. The Cedars-Sinai blood bank has genetically typed 15,000 donors since 2008 and can now identify 32 antigens with a single blood test. Klapper next plans a study to test Rh-negative blood donors because she believes some actually may be Rh-positive but carry an atypical protein. “This is precision medicine,” Klapper says of the increasingly nuanced categories for typing patients. “We can’t put people in two large buckets of Rh-positive or Rh-negative anymore. The buckets are more like a variety of teacups.”

TOLSTOY STORY

The prescient Russian writer Leo Tolstoy, in his 1869 epic War and Peace, identiﬁed the gap that would be ﬁlled by precision medicine. “No disease suffered by a live man [or woman] can be known,” he wrote, “for every living person has his own peculiarities and always has his own peculiar, personal, novel, complicated disease, unknown to medicine.” FALL 2016 | DISCOVERIES |

| DISCOVERIESMAGAZINE.ORG

RESEARCH SUBJECT

The DIVERSITY QUESTION Can precision medicine help solve the problem of inadequate diversity in medical research? The

PROMISE

By conquering mountains of medical data â&#x20AC;&#x201D; particularly regarding genetic differences â&#x20AC;&#x201D; scientists can reach new heights in understanding every individualâ&#x20AC;&#x2122;s health. That is the big, basic idea behind precision medicine.

The

CHALLENGE

Differences in health sometimes are encoded in DNA â&#x20AC;&#x201D; and variations in the human genome can cluster by ethnicity or geographical origin. Sickle cell disease is more likely to affect African-Americans, for example, while a subtype of breast cancer is more common in those of Ashkenazi Jewish descent than in the rest of the population. <HW WKH VFLHQWLoF FRPPXQLW\ UDUHO\ KDV PDGH GLYHUVLW\ D SULRULW\ IRU medical research. Racial and ethnic minorities make up nearly 40 percent of the U.S. population, but clinical trials have historically enrolled Caucasian men more than any other group. Since 1993, less than 2 percent of studies funded by the National Cancer Institute LQFOXGHG VXIoFLHQW PLQRULWLHV DFFRUGLQJ WR 1DWLRQDO ,QVWLWXWHV RI Health (NIH) criteria. The NIH and others are starting to address the problem, but, in the meantime, much of the clinical research that informs treatments does not necessarily apply to female or minority patients.

Davide Bonazzi

The

ANSWER

Trans-ethnic studies encompassing the full sweep of the human population simply equal good medicine â&#x20AC;&#x201D; and this is truer than ever in the age of precision medicine. One of precision medicineâ&#x20AC;&#x2122;s greatest tools is the powerful data analysis that captures and sifts through millions of health details, seeking connections. In this way, the practice of precision medicine may contain its own solution: Technology has made it easier than ever to tap into the complexity of all humankind.

LINGO

BIOMARKER

Short for â&#x20AC;&#x153;biological marker,â&#x20AC;? biomarkers are molecules found in the body that can be used as measures for detecting, tracking, and predicting disease progression. They also can show how patients respond to treatments.

FALL 2016 | DISCOVERIES |

CASE STUDY: BACK PAIN

BACK TO THE FUTURE

ne of the biggest hurdles in diagnosing back disorders has long been how to pinpoint the disc causing a patientâ&#x20AC;&#x2122;s pain. Now an advanced imaging technique and the power of precision medicine are giving doctors a detailed roadmap to problems in the spine. â&#x20AC;&#x153;When people experience lower back pain, which is up to 85 percent of the population, they often cannot tell us exactly where it is,â&#x20AC;? says Debiao Li, PhD, director of the Cedars-Sinai Biomedical Imaging Research Institute. â&#x20AC;&#x153;Our approach is to use a detailed image map that allows you to visualize each part of the spinal cord and the disc.â&#x20AC;? 7KH LPDJH PDS WKDW /L GHVFULEHV LGHQWLoHV D ELRPDUNHU Â&#x2039; LQ WKLV FDVH DQ DUHD RI ORZ S+ Â&#x2039; ZKLFK FDQ RIWHQ EH DQ LQGLFDWRU RI GLVF GHJHQHUDWLRQ DQG SDLQ 7KLV ELRPDUNHU LV located via a sophisticated form of magnetic resonance imaging. While traditional methods can be painful and invasive, the new, painless imaging technique yields crucial GLDJQRVWLF LQIRUPDWLRQ E\ oQGLQJ VPDOO FKHPLFDO FKDQJHV WKDW LQGLFDWH LQMXU\ â&#x20AC;&#x153;This approach of pH measurement has many other potential roles,â&#x20AC;? Li says. â&#x20AC;&#x153;Changes in the bodyâ&#x20AC;&#x2122;s metabolic process always precede disease, and lactate accumulation [which causes a decrease in pH] indicates that something is wrong.â&#x20AC;? Li and an interdisciplinary team, which includes Dan Gazit, DMD, PhD, co-director of the Skeletal Program in the Board of Governors Regenerative Medicine Institute and the 'HSDUWPHQW RI 6XUJHU\ UHFHLYHG D MRLQW JUDQW IURP WKH 1DWLRQDO ,QVWLWXWHV RI +HDOWK WR develop the technique. With the new imaging technique as a platform, Gazit and his colleagues are taking precision medicine a step further. By using adult stem cells known as induced pluripotent stem cells (iPSCs), they have been able to engineer the repair of skeletal tissue. â&#x20AC;&#x153;We have developed several novel stem cell therapies for skeletal diseases,â&#x20AC;? Gazit says. â&#x20AC;&#x153;For instance, in complex fractures that are so severe they would never heal and could lead to amputation, we have developed a technique that causes stem cells to DFFXPXODWH DW WKH IUDFWXUH VLWH DQG WKHQ WR DFWLYDWH DQG KHDO WKH LQMXU\ y 7KH L36&V GHULYHG IURP D SDWLHQW V RZQ VNLQ DUH PRGLoHG WR EHKDYH OLNH HPEU\RQLF VWHP FHOOV k%\ DSSO\LQJ D YHU\ VSHFLoF WUHDWPHQW WR WKH VNLQ FHOOV LW LV SRVVLEOH to bring this cell back into something of an embryonic state, which then allows the cell to be directed into a targeted differentiation,â&#x20AC;? says Zulma Gazit, PhD, co-director of the Skeletal Program at Cedars-Sinai. â&#x20AC;&#x153;The results so far have been extremely encouraging. We have been able to repair complex fractures using iPSCs and we are now looking into using the same cells as a therapy for back pain.â&#x20AC;? Even more exciting to researchers is the wider promise of this approach. â&#x20AC;&#x153;This information can be integrated into the bigger picture of a patientâ&#x20AC;&#x2122;s disease, and that means individualized treatment strategies can be developed,â&#x20AC;? Zulma Gazit says. â&#x20AC;&#x153;The more you can learn about each patient, the more able you are to treat WKHP 7KDW V WKH WUXH QDWXUH RI SUHFLVLRQ PHGLFLQH y Â&#x2039;9HURQLTXH GH 7XUHQQH

| DISCOVERIESMAGAZINE.ORG

WHATâ&#x20AC;&#x2122;S IN A NAME? â&#x20AC;&#x153;That which we call a rose by any other name would smell as sweet.â&#x20AC;? With this line, William Shakespeare took a sarcastic jab at the Rose Theatre, a competitor to his beloved Globe Theatre. The Roseâ&#x20AC;&#x2122;s lavatory facilities were sorely lacking, and hence it was known for a decidedly unsweet odor â&#x20AC;&#x201D; or so the tour guides say. What has this to do with the newly launched Cedars-Sinai Precision Health effort? Well, you may have heard the phrase â&#x20AC;&#x153;precision healthâ&#x20AC;? or â&#x20AC;&#x153;precision medicineâ&#x20AC;? a lot lately, including from President Barack Obama. Or perhaps youâ&#x20AC;&#x2122;ve heard the term â&#x20AC;&#x153;personalized medicineâ&#x20AC;? bandied about by lawmakers and news media. From other sources, such as the Mayo Clinic, you may hear â&#x20AC;&#x153;individualized medicine.â&#x20AC;? What, the concerned reader may wonder, is the difference among these names? Whatever the phrasing, all describe tailored diagnostic and treatment systems that provide customized care to every patient, every time. And that really is sweet.

WEARABLE TECHNOLOGY

Iâ&#x20AC;&#x2122;M WITH THE BAND :HDUDEOH WHFKQRORJLHV VXFK DV VPDUW ZDWFKHV DQG oWQHVV WUDFN LQJ EDQGV DUH XELTXLWRXV LQ WKH HUD RI WKH kTXDQWLoHG VHOI y 0HD VXULQJ SHUVRQDO UHDO WLPH GDWD OLNH VWHSV KHDUW UDWH DQG VOHHS HIoFLHQF\ KDV RSHQHG GRRUV WR KHOSLQJ XV TXLW VPRNLQJ PRQLWRU KHDUW KHDOWK DQG HYHQ GLDJQRVH FDQFHU ,W DOVR KDV DGGHG D VHW RI KDQG\ WRROV IRU SUHFLVLRQ PHGLFLQH k1LQHW\ SHUFHQW RI D GLDJQRVLV FRPHV IURP KHDULQJ SDWLHQWV VWRULHV WKHLU H[SHULHQFH DQG ZKDW WKHLU ERGLHV DUH WHOOLQJ XV y

Tummy Tuner A sensor listens to the guts of individuals recovering from abdominal surgery, while a computer constantly monitors the sensorâ&#x20AC;&#x2122;s signal and helps determine when a patient is able to eat.

Apple Integration Patients link Appleâ&#x20AC;&#x2122;s free Health app to their CedarsSinai electronic medical record to personalize the healthtracking experience and, if they choose, contribute data to research projects.

Arthritis Gyroscope A biosensor measures motion in those treated with a particular arthritis medication. The ankle-mounted apparatus provides real-time data on steps taken, velocity, and total active time to help assess the drugâ&#x20AC;&#x2122;s effectiveness.

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Fit for Chemo Potential chemotherapy patients strap on Fitbits, which may help physicians determine whether their bodies are strong enough to handle the treatment, with the devices offering objective data on patient functionality.

Movement Monitor The Personal KinetiGraph tracks the movements of Parkinsonâ&#x20AC;&#x2122;s patients, showing how their symptoms ďŹ&#x201A;uctuate and respond to medication throughout the day, and in the future may allow physicians and patients to reďŹ ne treatment plans.

Walk the Walk Patients wear Fitbits after one of seven types of major surgery to quantify ambulation and to see whether the measurements correlate to length of hospital stay or a need for additional rehabilitation, since the ability to walk after surgery is key to determining when a patient can leave the hospital.

Transplant Readiness A new study tests whether information from a Fitbit can predict frailty in those with liver cirrhosis who are on the transplant list. If successful, the information could be used to assist physicians in determining the readiness for organ transplant by how frail or hardy a patient is.

Top, Andre da Loba; Bottom, Getty

INNOVATION DRIVER

Serbian-born American inventor Nikola Tesla left many gifts to the future, including the idea of combining computation and telephony â&#x20AC;&#x201D; the source of todayâ&#x20AC;&#x2122;s mobile and wearable devices. His ideas were put forward as early as 1893 and were considered the ramblings of a â&#x20AC;&#x153;mad scientist,â&#x20AC;? but wearables are rapidly becoming integrated into daily 21st century life.

FALL 2016 | DISCOVERIES |

| DISCOVERIESMAGAZINE.ORG

BIOINFORMATICS MATTERS

FORECAST: CLOUDY Mention medical research and images of lab coats, microscopes, and test tubes spring to mind. Yet one vital tool fueling advances in precision medicine may escape our thoughts: the computer. Ben Berman, PhD, co-director of Cedars-Sinaiâ&#x20AC;&#x2122;s Center for Bioinformatics and Functional Genomics, gives ďŹ ve reasons why computers should be added to our collective biomedical imagination.

THE CLOUDâ&#x20AC;&#x2122;S THE LIMIT.

Geneticists rely on bioinformatics specialists like Berman because of the vast volumes of information through which they wade. DNA molecules are made up of chemical units in pairs, and every human genome has about 3 billion base pairs. Plus, new genomic technologies allow researchers to investigate changes between thousands of cells within a tissue, or across thousands of individuals. â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s rapidly become information you cannot analyze on your desktop computer,â&#x20AC;? says Berman, who speeds up the process by running different sections of the genome across hundreds of computer servers at once. His programmers are experimenting with using commoditized cloud-based services. â&#x20AC;&#x153;Instead of spreading computations across 120 servers at Cedars-Sinai, by using a cloud, we could spread it across thousands of servers,â&#x20AC;? he explains.

2 THE PUZZLE HAS MANY PIECES. *HQHV DUH QRW WKH oQDO DUELWHUV RI RXU PHGLFDO IDWHV /LIHVW\OH exposure to toxins, nutrition, and treatments all matter. Many health factors are summed up in the clinical data of our medical records. Combining that data with genomic information is key to unlocking a new era of precision medicine. â&#x20AC;&#x153;Going forward, genomic studies will be increasingly linked to clinical trials so we can see how the genome determines responses to certain drugs,â&#x20AC;? Berman says.

â&#x20AC;&#x153;JUNKâ&#x20AC;? DNA IS LITTERED WITH GEMS.

4 SOFTWARE IS KING. The challenge to bioinformatics is binding together an exponentially expanding universe of data to make it usable. Innovative software programs are starting to strategically connect clinical and genomic data. â&#x20AC;&#x153;In the research community, there is an emphasis on open software standards, and this paradigm should be embraced to link up medical organizations around the country,â&#x20AC;? Berman notes. â&#x20AC;&#x153;For precision medicine, this is a major task that involves technical, ethical, and regulatory hurdles. It has to bring together data scientists who work in diverse areas, including clinical information systems, mobile devices, and social media.â&#x20AC;?

GENETIC ANALYSIS HAS GONE GLOBAL.

Berman is involved in the biggest effort ever to systematically analyze cancerous tumors. The International Cancer Genome Consortium is examining complete tumor genomes, including the non-protein coding regions, from 2,800 patients. This massive effort includes patients and data from more than a dozen countries, being analyzed by a consortium of more than 700 scientists (Berman co-leads the group evaluating epigenetic data). â&#x20AC;&#x153;Instead of moving patientsâ&#x20AC;&#x2122; genetic data to our hardware, we move our software to the cloud,â&#x20AC;? Berman says. The move protects patient privacy â&#x20AC;&#x201D; a Parisian patientâ&#x20AC;&#x2122;s information will never be downloaded to a computer at Cedars-Sinai, for example Â&#x2039; EXW HQDEOHV H[SHUWV IURP /RV $QJHOHV 6LQJDSRUH DQG )UDQFH WR MRLQWO\ DFFHVV LQIRUPDWLRQ DQG ZRUN WRJHWKHU WR oJXUH RXW what makes cancer tick.

James Steinberg

)RU GHFDGHV DIWHU WKH\ oUVW WUDFHG '1$ V GRXEOH KHOL[ PDQ\ genetic scientists estimated that only the 2 percent of the genome that codes for proteins was worth a look. The rest was â&#x20AC;&#x153;dark matterâ&#x20AC;? at best, and â&#x20AC;&#x153;junk DNAâ&#x20AC;? at worst. After the human genome was sequenced â&#x20AC;&#x201D; a colossal effort to which Berman contributed â&#x20AC;&#x201D; systematic comparisons of different individualsâ&#x20AC;&#x2122;

genetic makeups revealed that this supposed detritus actually held many regions that act as switches, turning genes on and off. â&#x20AC;&#x153;Genomic regions that used to be considered junk encompass more than half the regions implicated in increased cancer risk,â&#x20AC;? %HUPDQ VD\V k7KLV ZKROH oHOG RI JHQH UHJXODWLRQ Â&#x2039; HSLJHQHWLFV â&#x20AC;&#x201D; is very important.â&#x20AC;?

FALL 2016 | DISCOVERIES |

Sudden cardiac arrest is a rapid electrical short circuit of the heart, which can be reversed by a life-giving electric shock. However, life ebbs within minutes, and most victims cannot be reached in time. Predicting which heart is destined for electrical failure is one of the hottest areas in heart research today.

| DISCOVERIESMAGAZINE.ORG

STORM CHASERS It’s the only known condition that kills 90 percent of its victims within 10 minutes. And predicting it is just as perplexing to cardiologists as forecasting the perfect storm is to meteorologists. But what if we could identify symptoms of sudden cardiac arrest as early as four weeks prior to the deadly event? Would it make a difference in saving lives? Investigators at the Cedars-Sinai Heart Institute say “yes,” and they can prove it.

By ANNETTE WELLS-SAUR

Photography by SEBASTIAN GRAY

FALL 2016 | DISCOVERIES |

Pacing and rhythm-control devices, including pacemakers and implantable cardioverter deﬁbrillators, are used to treat arrhythmias and other disturbances of the heart’s rhythm. These devices send and receive electrical signals to and from the heart to regulate heartbeat. They are lifesaving in many situations. Pictured here, the leadless pacemaker is the size of a vitamin capsule and completely self-contained within the heart — no wires required.

| DISCOVERIESMAGAZINE.ORG

In a landmark discovery, published in January 2016 in the Annals of Internal Medicine, investigators showed that more than 50 percent of patients experience warning symptoms up to a month before suffering a sudden cardiac arrest â&#x20AC;&#x201D; a deadly condition that, until now, seemed to strike without warning. Unfortunately, most of those affected will ignore those symptoms and essentially lose any chance at lifesaving medical intervention. â&#x20AC;&#x153;This is a major paradigm shift in cardiology,â&#x20AC;? says Sumeet S. Chugh, MD, medical director of the Heart Rhythm Center in the Cedars-Sinai Heart Institute and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research. â&#x20AC;&#x153;Earlier on, our focus was only on the immediate time preceding cardiac arrest, and on people known to have heart disease. Now we can focus on targeted symptoms as predictors of sudden cardiac arrest, and we can potentially save many lives through earlier preventive care.â&#x20AC;&#x2122;â&#x20AC;&#x2122;

The study, which followed 839 patients between the ages of 35 and 65, outlines the most common symptoms of sudden cardiac arrest. These include intermittent chest pain and presVXUH VKRUWQHVV RI EUHDWK SDOSLWDWLRQV DQG RQJRLQJ LQpXHQ]D like indicators such as nausea and abdominal and back pain. â&#x20AC;&#x153;This is pretty exciting research, given that we are that much closer to solving the riddle of predicting cardiac arrest in people, especially those who are of middle age,â&#x20AC;&#x2122;â&#x20AC;&#x2122; says Eduardo MarbĂĄn, MD, PhD, director of the Cedars-Sinai Heart Institute. â&#x20AC;&#x153;The societal burden is greatest among this age group because they often leave behind widows and descendants, and if, by some miracle, they survive, they are less likely to be self-supporting.â&#x20AC;? 7KHVH QHZ oQGLQJV DOVR JLYH JRRG UHDVRQ QRW WR LJQRUH XQusual sensations and to seek medical attention early. Although â&#x20AC;&#x153;heart attackâ&#x20AC;? and â&#x20AC;&#x153;sudden cardiac arrestâ&#x20AC;? often are used interchangeably, the terms are not synonymous. A heart attack â&#x20AC;&#x201D; myocardial infarction â&#x20AC;&#x201D; is typically caused by clogged

STUDY HIGHLIGHTS 51 percent of patients experienced warning symptoms, predominately chest pain, prior to the cardiac arrest. In the group that experienced symptoms, 93 percent experienced them again in the 24 hours preceding the cardiac arrest. Only 19 percent of those who experienced symptoms called emergency medical services. Patients who experienced symptoms and sought medical help had a survival rate of 32 percent. Those who did not seek medical treatment for symptoms had a survival rate of 6 percent.

FALL 2016 | DISCOVERIES |

The surgically implantable deďŹ brillator can function as a personal paramedic. This electrical device provides a shock that restores life within seconds, but new discoveries must identify who will beneďŹ t the most. Ongoing research at the Cedars-Sinai Heart Institute has made major contributions in this area of clinical science.

VIDEO

What are the warning symptoms for sudden cardiac arrest? Chugh explains at discoveriesmagazine.org

| DISCOVERIESMAGAZINE.ORG

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FALL 2016 | DISCOVERIES |

WITH YOUR HELP, WEâ&#x20AC;&#x2122;LL BE HERE FOR THEIR GRANDCHILDREN, TOO.

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Fall 2016

Faculty News Yesol Sapozhnikov, RN, is the ﬁrst master’s student in Cedars-Sinai’s Graduate Program in Biomedical Science and Translational Medicine.

Al Cuizon

Graduate School Is Growing by Degrees Cedars-Sinai’s dynamic graduate school, which trains young scientists to pursue discoveries in the laboratory that shed light on diseases and inspire new therapies, has added a master’s degree program. Seven years after opening its doors to PhD candidates, the Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine welcomed its ﬁrst master’s student: Yesol Sapozhnikov, RN, who began the program in fall 2015. Among other features, the two-year curriculum

makes it possible for participants to hold down jobs while pursuing their studies. “It’s perfect for me,” says Sapozhnikov, an educator in the Medical Surgical Rehabilitation Division of Nursing at Cedars-Sinai. “I can continue working, and it’s a way for me to assess how much I like the research world before I jump into a full-time PhD program.” “Having a vibrant, broad-based graduate program is extremely important for efforts to increase the breadth and (continued on page 47)

Robert H. Baloh, MD, PhD, director of Neuromuscular Medicine, associate professor of Neurology, and the Ben Winters Chair in Regenerative Medicine, was elected to the American Society for Clinical Investigation, one of the nation’s oldest and most respected medical honor societies. The organization includes more than 3,000 physician-scientists from all specialties who are selected for their outstanding records of scholarly achievement in biomedical research. Cedars-Sinai now has 16 active members in the society. He also received Cedars-Sinai’s 2016 Prize for Research in Scientiﬁc Medicine for a series of discoveries involving an inherited form of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, a type of brain dementia that can accompany ALS. Matthew Bloom, MD, associate director of Trauma Services and assistant professor of Surgery, received the Peter C. Canizaro Award from the American Association for the Surgery of Trauma (AAST). The award was established by AAST in 1991 to recognize the best paper by a young member.

FALL 2016 | DISCOVERIES |

Faculty News

Linda Burnes Bolton, DrPH, RN, FAAN, chief nursing officer and vice president for Nursing at Cedars-Sinai, received the 2016 TRUST Award from the Health Research & Educational Trust of the American Hospital Association. The TRUST Award honors individuals who exhibit visionary leadership in healthcare and who use research and education to improve healthcare quality in the United States. Burnes Bolton is one of the nation’s most visible and respected ﬁgures in nursing. Under her leadership, CedarsSinai founded the Geri and Richard Brawerman Nursing Institute in 2002 to help expand the supply of skilled nurses in the Los Angeles region. Sumeet S. Chugh, MD, associate director of the Cedars-Sinai Heart Institute, medical director of the Heart Rhythm Center, and the Pauline and Harold Price Chair in Cardiac Electrophysiology Research, received a $2.5 million grant from the National Heart, Lung, and Blood Institute to develop a risk-assessment tool that could identify patients susceptible to sudden cardiac arrest, a usually fatal heart rhythm malfunction.

David Engman, MD, PhD, a molecular genetic pathologist renowned for his groundbreaking research into parasitic diseases, has joined Cedars-Sinai as chair of the Department of Pathology and Laboratory Medicine. He was previously professor of Pathology and MicrobiologyImmunology at the Northwestern University Feinberg School of Medicine and medical director of the Molecular Genetics Laboratory and the Diagnostic Molecular Biology Laboratory at Northwestern Memorial Hospital, as well as head of the hospital’s Division of Diagnostic Molecular Biology in the Department of Pathology. Benedick A. Fraass, PhD, vice chair for Research and director of Medical Physics, received the Gold Medal from the American Society for Radiation Oncology for outstanding lifetime contributions to the ﬁeld. Joel M. Geiderman, MD, professor of Emergency Medicine and co-chair of the Ruth and Harry Roman Emergency Department, received the Howard I. Wilner, MD, Alumnus of the Year Award from the CedarsSinai Alumni Association and medical staff

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to honor his accomplishments and contributions to medicine. TingTing Hong, MD, PhD, a research scientist at the Cedars-Sinai Heart Institute, received two grants from the American Heart Association to study the role of BIN1, a gene that codes for proteins in the heart. The ﬁrst, an Innovative Research Grant of $150,000, will fund a project to develop BIN1 as a blood-based biomarker for arrhythmia and heart failure. The other, a Beginning Grant-inAid of $140,000, will fund an investigation into how calcium is regulated in cardiac structures that are organized by BIN1 and help determine the strength of beat-tobeat heart contraction. John Jenrette, MD, has been named executive vice president of the Cedars-Sinai Medical Network. A respected physician-executive known for developing new delivery models to meet consumer desires for accessible, high-quality care, he was previously senior vice president of San Diego–based Sharp HealthCare and CEO of Sharp Community Medical Group. Stanley Jordan, MD, director of Nephrology and Transplant

Immunology and medical director of Cedars-Sinai’s Kidney Transplant Program, received the Award for Outstanding Achievement in Transplantation (Clinical) from The Transplantation Society. A Cedars-Sinai group led by Beth Y. Karlan, MD, has been awarded a grant from the Ovarian Cancer Research Fund to support research into the relationship between the evolution of ovarian carcinoma and the microenvironment. Karlan is director of the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, director of the Division of Gynecologic Oncology, director of the Gilda Radner Hereditary Cancer Program, the Board of Governors Chair in Gynecologic Oncology, and a professor of Obstetrics and Gynecology. The project team also includes Sandra Orsulic, PhD, associate professor of Obstetrics and Gynecology and director of Women’s Cancer Biology; W. Ruprecht Wiedemeyer, PhD, research scientist with the Women’s Cancer Program; and Paul-Joseph Aspuria, PhD, a postdoctoral researcher in Karlan’s lab.

Beth Y. Karlan, MD, and Linda Burnes Bolton, DrPH, RN, FAAN, have been elected to the National Academy of Medicine, one of healthcare’s highest honors. Julia Ljubimova, MD, PhD, director of the Nanomedicine Research Center in the Department of Neurosurgery and the Nanomedicine Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, has received a career award from the Proteomass Scientiﬁc Society for achievements in translational medicine. She also has garnered a ﬁve-year, $2.8 million grant from the National Cancer Institute to advance her research of tumor nanoimmunology to treat cancers of the brain, breast, and lung. C. Noel Bairey Merz, MD, received the 2016 Bernadine Healy Leadership in Women’s Cardiovascular Disease Award from the American College of Cardiology for her contributions to the profession. Bairey Merz is director of the Barbra Streisand Women’s Heart Center at the Cedars-Sinai Heart Institute. She is a pioneer in investigating sex and gender differences in cardiovascular disease. The annual award is

(continued from page 45) depth of science at Cedars-Sinai,” says Marilyn Ader, PhD, an associate professor of Biomedical Sciences who directs the master’s program. “To be able to train the next generation of graduate students makes Cedars-Sinai a premier institution in both patient care and basic research.” In their ﬁrst year, master’s and doctoral students take the same courses. They learn the fundamentals of biomedical research and how to translate that work into tangible therapeutics for healthcare settings. For hands-on experience, they rotate among three Cedars-Sinai laboratories. During the second year, working with mentors, both groups of students choose research projects to satisfy degree require-

bestowed upon a fellow of the American College of Cardiology who has demonstrated leadership and accomplishment in the ﬁeld of cardiovascular disease in women, exempliﬁed by research, teaching, practice, or service. Rekha Murthy, MD, has been named vice president for Medical Affairs and associate chief medical officer. She succeeds Neil Romanoff, MD, who retired June 30 after 25 years at Cedars-Sinai. Murthy has served as medical director of the Department of Hospital Epidemiology for 21

ments. But while PhD candidates have several years to complete these endeavors, master’s students have just one, so their projects are more modest in scope while remaining rigorous. “With the two-year degree option, the graduate school can embrace talented applicants who don’t ﬁt into the traditional PhD track,” Ader says. “These may include budding scientists, such as Sapozhnikov, who are not ready to commit to four or ﬁve years of training, as well as future physicians looking to burnish their research credentials for medical school.” Hired by Cedars-Sinai in 2012, Sapozhnikov initially worked in an oncology inpatient unit, specializing in bone marrow transplant nursing. “It was

years. She received the Ritz E. Heerman Memorial Award from the California Hospital Association for leadership in enhancing infection prevention and treatment statewide. She served as chair of the Hospital Acquired Infection Workgroup of the association’s Hospital Quality Institute and has led initiatives in hand-hygiene compliance, vaccination, and response to evolving Ebola-related regulations. Ueli Rutishauser, PhD, assistant professor of Neurosurgery and director of Human

Neurophysiology Research, received the 2016 Memory and Cognitive Disorders Award from the McKnight Endowment Fund for Neuroscience. The award, which supports innovative efforts to solve the problems of neurological and psychiatric diseases, will provide $300,000 over three years to fund Rutishauser’s research into mechanisms of memory disorders. Mark Vrahas, MD, has been named founding chair of the CedarsSinai Department of Orthopaedics. An expert in orthopedic

a very special experience — heartbreaking, challenging, and inspiring,” she says. “Patients go through extreme situations.” The experience spurred Sapozhnikov to expand her knowledge of transplant medicine and then become an educator in the medical surgical rehabilitation division of Nursing. “As one nurse at bedside, I can only inﬂuence those around me,” she explains. “As a nurse educator, I can bring more change to more nurses.” Enrolling in Cedars-Sinai’s master’s program was the logical next step. “Learning the science is extremely satisfying,” she says. “And the translational aspect of the curriculum makes it relevant to my job because we learn about diseases that nurses help manage in the hospital every day.”

trauma and pelvic surgery, he previously served as a professor of Orthopaedic Surgery at Harvard Medical School and vice chair for Population Health and OR Operations at Massachusetts General Hospital’s Department of Orthopaedic Surgery. He founded the Harvard Orthopedic Trauma Initiative to foster collaboration among services at Harvardaffiliated teaching hospitals. Vrahas completed medical school and residency at the University of Pittsburgh.

Daniel Wallace, MD, professor of Medicine and associate director of the Rheumatology Fellowship Program, has been named a master of the American College of Rheumatology, among the organization’s highest honors.

FALL 2016 | DISCOVERIES |

Time Capsule

Feeling Pumped Although inexpensive, the earliest manual breast pumps were no bargain. The small devices, which were operated by repeatedly squeezing a rubber suction bulb, failed to sufﬁciently stimulate or empty the breast, and could damage breast tissue, harbor bacteria, and fatigue the user. Wisely, physicians recommended them only for infrequent use. Today, lactating women have many options for extracting breast milk. While bicycle horn-style pumps are still on the market, they remain difﬁcult to clean and dry. More advanced manual pumps also are available, along with electric and battery-powered pumps. Cedars-Sinai is continuing a study of breast milk composition to enhance the nourishment these pumps help extract. To date, researchers have performed hundreds of analyses with a device that evaluates the percentages of fat, protein, and carbohydrates in breast milk. The resulting information enables individually optimized nutrition and should ultimately lead to healthier weight gain, better outcomes, and shorter hospital stays for babies in the Neonatal Intensive Care Unit at the Cedars-Sinai Maxine Dunitz Children’s Health Center. Cedars-Sinai’s Historical Conservancy maintains an extensive collection of donated artifacts such as Ingram’s bicycle horn-style breast pump, along with documents and memorabilia relevant to the evolution of medicine and the development of the medical center since the early 1900s.

VIDEO 48

Find out more about Cedars-Sinai’s Historical Conservancy at discoveriesmagazine.org

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Lisa Hollis

Bicycle horn-style breast pump, Ingram’s, London Date of manufacture: circa 1920s

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