NEWS & NOTES

DNADriven Ups and Downs

Women’s and men’s risk factors for high blood pressure may need different medical approaches. Research at Cedars-Sinai recently revealed that the potential for high blood pressure—also known as hypertension—is more driven by genetics in women.

“A woman with low genetic risk is less likely to develop hypertension than a man with low genetic risk,” says Susan Cheng, MD, MPH, MMSc, director of the Institute for Research on Healthy Aging at the Smidt Heart Institute and the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science. “Conversely, a woman with high genetic risk is more likely to develop hypertension than a man with high genetic risk.”

For the study, Cheng and her team analyzed five decades of blood pressure and genotype data from more than 200,000 people. The results confirmed that sexspecific genetic risk traits are more associated with hypertension risk in women than in men—especially for the type of hypertension that starts early in life.

3 QUESTIONS WITH

Ophir Klein

A pediatrics leader looks ahead

Ophir Klein, MD, PhD, is the inaugural executive director of Cedars-Sinai Guerin Children’s, a new initiative that will offer the full spectrum of pediatric specialties as well as a robust research program and training for future pediatricians. Guerin Children’s has been made possible by the generosity of the Shapell Guerin Family Foundation and its president, Vera Guerin, a longtime Cedars-Sinai supporter who currently serves as board chair of Cedars-Sinai Health System®. We asked Klein, the David and Meredith Kaplan Distinguished Chair in Children’s Health, what the future of pediatric care might look like.

Is there an area of pediatrics that particularly requires the attention of the medical community in

the next 10 years? One of the most important areas for us to think about is the childhood roots of adult disease. Whether they’re infectious, environmental or societal, many of the impacts that children experience are important in determining the course of their future health. There is intriguing evidence that early childhood events are at the root of several different adult illnesses. What we do is important not just for children but also for the adults they will become.

How do you think innovations in vaccine development and delivery will impact

childhood diseases? Hopefully, one long-term result of the pandemic is that it will give a boost to vaccine development. This will not only help us deal with emerging diseases that can impact us locally but also address diseases in underdeveloped regions of the world. There are many parts of the world where infectious disease plays a huge role in childhood illness and mortality. Part of our mission as clinician-scientists is to think globally; it’s an important part of medical research.

What research avenues are

you pursuing? My laboratory is interested in figuring out how organs form in the embryo and how they renew and regenerate in the adult. We call this field developmental and stem cell biology. We focus on craniofacial development and intestinal biology. These days, we’re interested in questions of cell identity and fate: How does a cell determine who it is and what it does? How is this identity malleable in the face of damage and regeneration? For example, in inflammatory bowel disease, we study the stem cells in the gut and try to understand how they sense there’s been an inflammatory flare and how their neighbors respond to these insults. If you understand how cells sense what’s going on around them and how they react to differences, then it enables you to think about how you could evoke different or better responses from them under conditions of damage. When you have inflammation, a neighboring cell’s response might be to further rev up, but it would be more helpful if it calmed the inflammation.

Bladder Cancer Breakthroughs

Cedars-Sinai is attacking bladder cancer through innovations in both the operating room and the laboratory.

Patients with early-stage disease now have the option of a procedure called en bloc resection, which allows surgeons to remove the tumor in one piece. The technique involves looking inside the bladder with a tiny camera and then removing the tumor by encircling it with a thin laser. The intact tissue makes it easier for pathologists to check whether the cancer is confined to the bladder lining or has invaded deeper into the organ, and it allows surgeons to determine whether any cancer has been left behind.

Meanwhile, for the 25% of patients whose malignancies invade bladder-wall muscle— increasing the danger of metastasis—Cedars-Sinai investigators have developed a means of predicting how bladder cancers respond to certain therapies.

“My hypothesis was that if we looked at the expres-

Patients with early-stage disease now have the option of a procedure called en bloc resection, which allows surgeons to remove the tumor in one piece.

sion of individual cells within the bladder tumor, we could develop more effective tools to guide treatment and perhaps even find novel targets for future therapies,” says Dan Theodorescu, MD, PhD, the PHASE ONE Foundation Distinguished Chair and director at the Samuel Oschin Comprehensive Cancer Institute and Cedars-Sinai Cancer.

His team used singlenucleus RNA sequencing— which relies on isolated cell nuclei instead of whole tissue— to profile the genes expressed by each individual cell in aggressive muscle-invasive bladder cancers in 25 patients, map each cell’s position and study the cells’ interactions.

RNA sequencing also enabled the study team to discover a previously unclassified type of cell in the bladder lining that expresses high levels of a protein associated with poor surgical outcomes.

Assessing Immunity

Individuals may respond differently to COVID-19 vaccines

People should feel confident that their COVID-19 shots will keep them safe from serious illness. But overall, individual immunity is still a bit of a mystery: Who produces the strongest immune response? Who stays protected the longest—and what can this reveal about a person’s current and future health?

Cedars-Sinai investigators are leading an ambitious five-year study that seeks to better define how and why people respond differently to COVID-19 vaccines. Ultimately, they hope to understand how factors such as age, sex and preexisting conditions influence immune response. Results could inform public health efforts to curb the spread of the virus and its variants—and improve long-term health across the population.

The EMBARC study tracks immune measures, including antibody levels, in tens of thousands of Cedars-Sinai patients who have been vaccinated against COVID-19. Study leaders are working with community partners to recruit from schools, churches and neighborhood associations, and they are developing special outreach programs to ensure that the most vulnerable patients—such as those with immune-altering diseases—are represented.

“We’re on a mission to expand our understanding as broadly as possible,” says Susan Cheng, MD, MPH, MMSc, director of Public Health Research at the Smidt Heart Institute and the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science. “This data will help us understand how we can build dynamic, long-lasting immunity as individuals and as communities. We aim to understand how we get out of the pandemic and how we survive and thrive beyond it.”

Once published, the research will expand on insights gained from previous studies focused on healthcare workers, which found variations in immune response based on whether people had been infected with SARS-CoV-2, the virus that causes COVID-19, or had been previously inoculated for other infectious diseases.

Study participants will have access to their own antibody-level measures as well as a database that could predict the strength of their immunity at different times following vaccination.

“We’re taking the science back to our patients and our communities and developing tools to help with questions like: What is the outlook for myself and my family?” Cheng says.

Vaccine Response in IBD Patients

When vaccines first became available for COVID-19, 70% of surveyed people with inflammatory bowel disease (IBD) expressed concerns about side effects.

Crohn’s disease, ulcerative colitis and other forms of IBD are chronic conditions that occur when the intestinal immune system becomes overreactive, causing chronic diarrhea and other digestive symptoms. Because immune system malfunction is one possible cause of IBD— and patients are often treated with immune-modifying medications— patients also worried that vaccines might not produce a sufficient immune response to protect them against COVID-19. But recent Cedars-Sinai research should ease their minds and digestive systems.

The study revealed that IBD patients receiving immune-modifying therapies were not at risk of increased side effects from the Pfizer-BioNTech or Moderna COVID19 vaccines. More than 90% of IBD patients produced antibodies in response to COVID-19 vaccines, regardless of vaccine type and whether they were taking immunemodifying medications, according to Gil Melmed, MD, director of Inflammatory Bowel Disease Clinical Research. However, IBD patients receiving the Johnson & Johnson vaccine developed significantly lower antibody levels than those receiving the two other vaccines.

“The mRNA vaccines may have a more potent mechanism for inducing antibody response,” Melmed says of the Pfizer and Moderna vaccines. “And because they are delivered in two doses, rather than one dose like the Johnson & Johnson vaccine, they provide two immunological hits.”

COVID-19 IN KIDS

A rare condition in pediatric COVID-19 patients can trigger an attack on vital organs weeks after infection. But an investigation led by Cedars-Sinai has uncovered potential predictors of the condition, called multisystem inflammatory syndrome in children (MIS-C), and could open avenues to better therapies.

The scientists identified an array of pathways leading to MIS-C—along with proteins in the blood that could act as biomarkers to forecast the severity of the syndrome and help drive treatment decisions.

Another recent study by CedarsSinai unmasked potential culprits contributing to MIS-C. The investigators found that children with the condition were unique because of differences in their T cells—immune cells that help the body fight infection. While most people have a diversity of T cell receptors, the study revealed that children with MIS-C likely have limited types of receptors or even just one type, suggesting an immune response to a special type of virus molecule called a “superantigen.”

The findings shed new light on the mysteries of MIS-C.

COVID-19 RESEARCH N & N

“We’re taking the science ... and developing tools to help with questions like: What is the outlook for myself and my family?”

Susan Cheng, MD, MPH, MMSc

The Wide World of Cells

There are more cells in the human body than stars in the Milky Way, each with a unique role in vital functions—from breathing to growing and eating.

While the roughly 200 cell types work together, they follow different playbooks and routinely change casts. This cellular diversity is underappreciated, says Lali Medina-Kauwe, PhD, co-director of the Cancer Biology Program.

“Structures are organized very intricately in and around cells, supporting all of the travel and various processes underway,” she says.

Here are a few of the most fascinating cellular factoids.

While the roughly 200 cell types work together, they follow different playbooks and routinely change casts.

CLEANUP CREW

Macrophages

LONG-DISTANCE RUNNERS

Neurons

RENEWABLE RESOURCE

Skin Cells

FREQUENT FLYERS

Red Blood Cells

TALENT DEVELOPMENT

Stem Cells

Macrophages are the body’s biggest eaters. They overwhelm and kill off bacteria and then clear dead cells and tissue debris. If overactivated, though, macrophages can trigger inflammatory disease and cancer growth. “They can be heroes or villains,” says Cedars-Sinai immunologist Helen Goodridge, PhD, who notes that macrophages are one of her favorite cells.

Neurons are the longest cells, with the lengthiest stretching nearly 5 feet down the spinal cord. Aided by motor proteins, these nerve cells transmit electrochemical messages that create movement, thought and sensations, including pain. They go the distance in age, too: Brain neurons can last an entire human lifespan and, theoretically, even longer. Compare that to the lifespan of heavily worked gut epithelial cells (three to five days) or pancreatic cells (one year).

Skin is constantly shedding and being replenished. The human body sloughs off 200 million dead cells from the skin’s outer layer every hour (almost 5 billion a day), replacing the skin entirely every 40 to 56 days.

About 70% of the human body’s cells—25 trillion—are red blood cells, or erythrocytes, making them the most common. That vast supply is critical to life: Tiny erythrocytes continuously ferry oxygen from the lungs throughout the whole body. The hemoglobin protein inside these cells is what paints blood its trademark red.

Found in embryonic and certain adult tissues, stem cells have not yet specialized. These prolific cells are at the heart of regenerative medicine, with their potential to be manipulated into immune, bone, skin, nerve or muscle cells. There is evidence that, in certain circumstances, just one hematopoietic stem cell in the bone marrow could regenerate and sustain an individual’s entire blood supply, including red blood cells and more than a dozen types of immune cells, Goodridge notes.

Caroline Carbajal, a community health worker with Cedars-Sinai’s Community Connect Program, makes weekly house calls to patients.

Beyond the Exam Room

For more than three months, Caroline Carbajal made weekly house calls to one of her patients: a retired 76-yearold man who had been experiencing panic attacks and increased blood pressure. Her visits revealed that he was also straining to manage mounting bills and facing eviction from his L.A. apartment.

Carbajal isn’t a doctor. She is a community health worker employed by CedarsSinai as part of its Community Connect Program. The effort is an innovative response to a growing body of research demonstrating that fundamental life challenges—such as struggles related to housing, food, finances, transportation, substance use or mental illness—have an enormous impact on an individual’s health.

Identifying and addressing social determinants of health is the cornerstone of the Community Connect Program, which aims to screen every Cedars-Sinai patient for 13 social risk factors, says Katie Hren, LCSW, MPH, the program’s manager.

When screenings uncover health-related social needs, social workers and nurse care coordinators consult an electronic referral platform powered by findhelp.org to match patients with support services.

“It’s important for treatment teams to be aware of health-related social needs that patients are experiencing because these factors play a pivotal role in one’s health,” Hren says. “Armed with this information, caregivers can provide comprehensive, whole-person care.”

Carbajal’s work is part of a Community Connect Program pilot initiative evaluating the effectiveness of assigning community health workers like herself to vulnerable patients to connect them with long-term assistance.

Ultimately, Carbajal helped establish a relationship between her patient and two local nonprofits that provide ongoing food assistance as well as mental health and financial services. As a result, he avoided eviction and paid his bills, and his panic attacks subsided and blood pressure stabilized.

As a thank you, the man gave Carbajal a bow-accented houseplant. She pointed out an even better gift for them both: “He learned how to advocate for himself.”

Heartfelt Support

Heart assist devices underused in older patients

For patients with heart failure who are unable to undergo heart transplantation, cardiac surgeons sometimes turn to mechanical left ventricular assist devices (LVADs) to get the blood flowing properly. Patients over age 75 who are otherwise healthy should be provided the option more often than they are, according to a Smidt Heart Institute study.

The research, conducted through the Interagency Registry for Mechanically Assisted Circulatory Support, reviewed national data from more than 24,000 patients who had LVADs implanted to treat advanced heart failure.

“I’ve treated some patients in their late 70s who had previously been very active and, after getting their LVAD, sent me pictures of themselves resuming activities they once loved—like travel and sports,” says Dominic Emerson, MD, associate surgical director of Heart Transplant and Mechanical Circulatory Support in the Smidt Heart Institute. Emerson served as lead author of the research.

Fear of complications such as stroke, bleeding and infection has made some physicians wary of suggesting LVADs for elderly patients. But it’s time to reevaluate who might benefit from the devices, notes Joanna Chikwe, MD, founding chair of the institute’s Department of Cardiac Surgery and the Irina and George Schaeffer Distinguished Chair in Cardiac Surgery in honor of Alfredo Trento, MD. “For many patients with advanced heart failure, newer-generation LVADs are transformational,” she says.

These LVADs are smaller than older models—half the size of a fist, rather than the previous dinner-plate dimensions—and use new technology to reduce blood clots and infection.

The researchers found that patients receiving these newer LVADs experienced fewer device failures, less blood clotting within the device, and lower rates of infection and stroke than patients with previous-generation devices.

Patients older than 75 even experienced fewer complications than their younger counterparts.

GENDER CLINIC OPEN

A new clinic for youth who are questioning their gender or experiencing gender dysphoria—the distress caused when a person’s biological sex does not align with their true gender identity— has opened at Cedars-Sinai. The Pediatric and Adolescent Gender Wellness Clinic is overseen by pediatrician Paria Hassouri, MD, a specialist in the field.

The clinic helps youth and their parents by providing resources and support to navigate options such as medical transition or blocking puberty. This includes social support—especially for younger patients who have not reached puberty but feel gender fluid.

“My advice to parents is to not hesitate or be scared about making that first appointment with someone who specializes in genderdiverse youth,” Hassouri says. “That first conversation is just about gathering information, which makes all the difference for families.”

Once a patient turns 18, their care is transferred to physicians at Cedars-Sinai who specialize in adult gender wellness, including, if appropriate, therapeutic transitions.

Cancer Prognosticator

Scientists aim to predict ovarian cancer risk

“What if we could predict how serious the cancer would be—or if it will develop at all?”

Clive Svendsen, PhD

Everyone has BRCA genes. They typically protect against cancer, but some people inherit mutated versions of the genes that increase their cancer risk. Women with these genetic changes are at greater risk of breast and ovarian cancer.

Some women who discover they have BRCA mutations choose to have riskreducing surgery, removing their breast tissue or ovaries and fallopian tubes. They can’t know for certain whether they will get cancer, so they must weigh their risk and make the best decisions they can.

“But what if we could predict how serious the cancer would be—or if it will develop at all?” says Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.

The seeds of ovarian cancer sprout in the fallopian tubes. Svendsen is using stem cell technology to take blood cells from women with BRCA mutations and reprogram them to make fallopian tubes in a culture dish. This process uses induced pluripotent stem cells (iPSCs). Human iPSCs are created by taking adult body cells “back in time” to create stem cells that can develop into any kind of human body cell.

Because fallopian tube cells that are created from the iPSCs contain the DNA of the donor patient, they may develop cancer in the dish that is identical to what the woman would experience years or decades down the road.

“We aim to use this model to predict individuals’ cancer development,” Svendsen says. “We also can test drugs on the cancerous tissue and determine which ones work.”

The methodology could help monitor, prevent and treat a woman’s cancer— even determining drugs that could be taken prophylactically.

Rock-a-Bye MRI

Studying an infant’s brain can help predict the first few years of a child’s development—and the ripple effect this starting point will have on their adult life.

“The brain grows the fastest during these years,” says Wei Gao, PhD, director of Neuroimaging Research at the Biomedical Imaging Research Institute at Cedars-Sinai. “Subtle deviations from a child’s normal developmental trajectory can have a butterfly effect down the road, potentially leading to various adult-onset or child-onset developmental disorders and disease.”

The best way to map an infant’s brain in the first two years of development is by performing an MRI. But scanning babies’ brains in a research setting presents a major hurdle: To get a clear and accurate MRI scan, infants must be sleeping naturally and lying very still while on the scanner bed.

“Even if we can get a baby to sleep naturally before the MRI, they often wake up, especially during the transition from the mother’s arms to the scanner bed,” Gao says. “Because this movement is disturbing for the baby, I thought, ‘Why not design an MRIcompatible crib?’”

“The earlier we can identify any risk in a child’s development, the earlier we can intervene to achieve better outcomes.”

Wei Gao, PhD Making MRI Scans a Dream for Babies

Designed by Gao and his research team, the MRI-compatible crib resembles a bassinet attached to a rollable gurney.

Gao’s main goal was to minimize the risk of disturbing a sleeping baby during transfer, thereby increasing the chances of a successful infant brain scan. The scanner bed of the MRI is raised up to the level of the crib prior to the scan. Made of a mesh-like fabric, the bassinet can be detached from its base using a series of clasps. The rest of the bassinet and the gurney are then rolled away from the MRI machine, leaving the baby on the scanner bed without experiencing any vertical or horizontal movement.

“The prototype worked with the first baby we tested it on,” Gao says. “I was very happy.”

Identifying Risk Factors in Infancy

Gao’s MRI-compatible crib, which is only available for research use, will be instrumental to the HEALthy Brain and Child Development Study. Following a large cohort of pregnant women and their children for at least 10 years, the National Institutes of Healthfunded study aims to map typical earlychildhood brain development and how risk factors such as parental substance use, impoverished environments and other social determinants of health may affect young brains. Gao sees a lot of potential in early intervention.

“The first two years of a child’s development lay the foundation for their entire life,” Gao says. “The earlier we can identify any risk in a child’s development, the earlier we can intervene to achieve better outcomes.”

BILL POLLARD

Dr. Wei Gao and his research team designed this MRIcompatible crib. NEW DISORDER DISCOVERED

A rare disorder that disrupts the motor skills of infants and teenagers has been discovered thanks to a research collaboration involving a Cedars-Sinai pediatric neurologist. Tyler Mark Pierson, MD, PhD, joined scientists from nearly 50 institutions worldwide to report on 31 children with this condition, known as HPDL deficiency.

The genetic disorder occurs in two forms. The more severe form consists of lowerextremity spasticity associated with significant cognitive delays and frequent seizures. The milder type has a later onset and produces weakness and muscle stiffness in the legs of otherwise healthy teens. Both forms stem from abnormal activity in the cerebral cortex, which is responsible for functions such as thought, muscle tone and voluntary physical action.

Pierson and his colleagues found that the study’s subjects had abnormalities in both copies of their human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene, which previously was not associated with any disease. Affected children inherit one mutation from each of their unaffected parents. The combined mutations decrease levels and activity of HPDL proteins, which are important for neurons’ cellular functioning.

Scientific Stunt Doubles

Big data gets harnessed for personalized cancer treatments

Cedars-Sinai Cancer has joined with precision-medicine firm Tempus to design personalized cancer treatments. The partnership harnesses artificial intelligence and big data to create virtual replicas of patients’ DNA, RNA, proteins and other molecular information to help identify the most effective approach to overcoming each individual’s disease.

By creating these “molecular twins,” scientists genetically classify cancer genes and proteins of particular tumors obtained from thousands of Cedars-Sinai patients to build a database that will advance research and treatments everywhere.

“Molecular twins serve as scientific stunt doubles that are always in the lab, ready to identify the best current therapies and, perhaps, reveal important details of how a cancer will affect the patient,” says Dan Theodorescu, MD, PhD, the PHASE ONE Foundation Distinguished Chair and director at the Samuel Oschin Comprehensive Cancer Institute and Cedars-Sinai Cancer.

The data—stripped of personal details to protect privacy— will offer insights into why some patients are resistant to certain therapies and also provide potential avenues to new treatments. Another aim is to remedy disparities in care.

“While there are success stories with targeted, precision treatments for cancer, they are limited today to only a few cancer types,” Theodorescu says. “Additionally, the research that leads to lifesaving breakthroughs often falls short among certain racial and ethnic groups. I hope that the molecular-twin platform will change that since it has the potential to analyze cancer disparities in vulnerable populations and possibly find solutions to closing the cancer health-equity gap by streamlining and reducing the complexity and cost of these tests.”

“Molecular twins serve as scientific stunt doubles that are always in the lab, ready to identify the best current therapies and, perhaps, reveal important details of how a cancer will affect the patient.”

Dan Theodorescu, MD, PhD

ID on Idiopathic Fibrosis

Mechanisms behind idiopathic pulmonary fibrosis (IPF), a dangerous disease that scars the lungs and impairs breathing, are being demystified by Cedars- Sinai investigators. The condition affects more than 100,000 people in the U.S., with most patients dying within five years of diagnosis unless they receive a transplant.

In normal lungs, type 2 alveolar epithelial cells (ATII) function as progenitor or stem cells, regenerating to support lung renewal and health. Meanwhile, other stem cells support their ATII kin by secreting growth factors. But in IPF, these mechanisms are lost, leading to progressive scarring that disrupts the flow of oxygen into the bloodstream.

To understand why, investigators created a mouse model of pulmonary fibrosis in which they eliminated the growth hormone receptor. The results showed that mice without these receptors were more prone to developing fibrosis.

These findings suggest that treatment with growth hormone receptors using a nanosize delivery mechanism may improve lung function.

A Better Read on Blood Pressure in Pregnancy

When the American Heart Association and American College of Cardiology updated their guidelines on blood pressure treatment and management in 2017, they left out a considerable swath of the population: pregnant women.

“It’s because there wasn’t enough data on pregnancy to provide evidenceinformed recommendations,” says Natalie Bello, MD, MPH, director of Hypertension Research at the Smidt Heart Institute at Cedars-Sinai. “I’ve taken that to heart, and I’m trying to build a better knowledge base of the best protocols to follow for high blood pressure during pregnancy.”

The United States has the highest rates of maternal morbidity and mortality compared to similarly wealthy countries. Cardiovascular disease is now the leading cause of death during pregnancy.

Bello co-chairs a work group for the American College of Cardiology that focuses on cardio-obstetrics. The group seeks to expand scientific knowledge in the field, inform both cardiologists and obstetricians of the heart health needs of pregnant patients, and advocate for policy changes to help this population.

A recent study she led, published in the Journal of the American Medical Association Network Open, found that applying a lower blood pressure threshold for hypertension allowed clinicians to better predict risk of preeclampsia (high blood pressure in pregnancy) and other adverse pregnancy outcomes. The study used electronic medical record data of women who delivered infants between 2009 and 2014 at a large regional health system.

Blood pressure is measured as two values. The first measures pressure on blood vessels when the heart beats, and the second measures pressure when the heart is relaxed. When applying a 130/80 mmHg threshold to diagnose hypertension—rather than the 140/90 mmHg traditionally used to define high blood pressure in pregnancy—the investigators found they could more accurately identify which women were likely to develop preeclampsia.

Hypertension treatment during pregnancy is approached with caution, as an adequate blood supply must flow to the placenta to nourish the developing fetus.

“In pregnancy, we have to look out for both patients—the mom and the baby,” Bello says. “This warrants more testing, but our findings are a real signal that we can identify maternal risks without creating greater risk for babies.”

This is one example, Bello says, of the need to expand the data about pregnancy to match what we know about adults who are not pregnant.