ANYTHING BUT BASIC

By Melinda Smith, PhD
Illustration with science symbols
Illustration with science symbols
From discovery science to clinical studies, research at Children’s Hospital Los Angeles is anything but basic

On the surface, the term basic science isn’t exactly compelling. But investigators at The Saban Research Institute of Children’s Hospital Los Angeles couldn’t be more excited about basic or “discovery” science. Each level of biomedical research—basic, translational and clinical—plays a crucial role in the development of lifesaving treatments. Researchers at CHLA are doing all three types of research, while changing the way scientists think about discovery altogether.

Instead of thinking of science as a one-way street that proceeds from basic to translational to clinical research, investigators at The Saban Research Institute think of it as a loop. The pipeline does not end at the child’s bedside, because each scientific discovery comes with the opportunity to do even better. This close tie between scientific investigation and clinical practice accelerates life-changing discoveries. Ideas for new research studies, even those at the basic level, stem from a clinical need—a need our researchers see every day.

This unique relationship between clinical care and research fosters investigators who are driven to discover and are informed by an intimate understanding of the greatest unmet needs in pediatric medicine. In other words, the kids shape the research.

CHLA investigators are influencing the future of patient care in unexpected ways. Here, meet a medical doctor who learned the importance and beauty of benchwork; a nurse who studies brain scans to give children better lives; an investigator who takes a discovery approach to clinical management of at-risk babies; a laboratory director helping more families get the answers they seek; and a scientist whose drive to understand pediatric cancer is in her bones.

Their paths to discovery are anything but a straight line, and they are most certainly anything but basic.

THE SCIENTIST AND THE 24-HOUR COUNTDOWN

An investigator looks deep inside the infant brain to improve outcomes for babies who have suffered ischemic brain injury.

The phone rings. There was a difficult birth. A critically ill newborn infant is being transported to Children’s Hospital Los Angeles for neuroprotective therapy.

Research investigator Jessica Wisnowski, PhD placing infant into diagnostic machine
“Babies need answers now.” — Jessica Wisnowski, PhD

Jessica Wisnowski, PhD, is an investigator in the Department of Radiology and Division of Neonatology at CHLA. She works to develop therapies for newborns with hypoxic ischemic injury—brain damage caused by lack of oxygen at or around the time of birth. Many babies suffering this injury do not survive, or they develop severe neurological conditions like cerebral palsy. Dr. Wisnowski and her colleagues in the Steven & Alexandra Cohen Foundation Newborn and Infant Critical Care Unit have implemented a hypothermia treatment to prevent brain damage—lowering a baby’s body temperature from 98.6 F to 92.3 F—and it works.

The use of cooling, which is now the standard of care at CHLA, has nearly doubled the chance of a healthy outcome. But there is more work to do. Dr. Wisnowski’s line of research investigates why cooling works and how that knowledge can be used to make it work even better.

“Cooling is just the beginning,” she explains. “There are more than two dozen new therapies for brain injury, and we are working on getting the next generation of therapies into the neonatal intensive care unit.”

But she has to work fast. Her urgency is driven by two needs.

“Brain cells—neurons—don’t die when they’re injured; they die later,” she says. “There’s a 24-hour period after injury before the brain crosses a point of no return. This offers a window of opportunity.”

But then there is her other battle with time. The one that is less immediate but just as critical. The one that she wages to bring treatments to babies more swiftly. As it is now, clinical trials can take almost a decade due to all the planning and analysis they require.

“We need to identify which therapies are working, and we need to identify them earlier and faster,” she says. “Babies need answers now.”

Fortunately, her current research may soon deliver these answers. Using magnetic resonance imaging (MRI), Dr. Wisnowski maps out what biological processes are happening in the brain and precisely when they are happening.

To get answers, scientists need to have an appropriate marker that tracks how brain cells respond to lack of oxygen over time. Using a biomarker like this is common in clinical practice. In a patient who has suffered heart damage, doctors can measure blood levels of a protein that acts as a proxy for how extensive the injury is. Ideally, a marker for brain damage could tell clinicians which brain cells are at risk before they die.

Dr. Wisnowski’s team has identified candidate biomarkers that could do just that. These markers are measured using MRI brain scans during and after hypothermia therapy. This, she hopes, will reduce the time it takes to get critical answers. The National Institutes of Health has awarded Dr. Wisnowski $725,000 to study these biomarkers.

“Working at CHLA affords us an incredible opportunity,” she says. “Here we have the ability to study these questions and immediately implement what works.”

Dr. Wisnowski is not battle-shy. She will keep fighting the clock. “To get to the forefront of medicine,” she says, “we need to ask, ‘Why is this therapy working? What is driving it?’ We want to work out the whys and hows. And soon, those will become the next we can dos.”

THE MICROBIOLOGIST AND THE NEXT GENERATION

This laboratory director is reshaping patient care by revolutionizing diagnostics.

She has never met your child, but she might be able to tell you the genetic makeup of the virus that is making him sick.

Jennifer Dien Bard, PhD, is board-certified in medical microbiology and the Director of the Clinical Microbiology and Virology Laboratory at CHLA. From a patient perspective, she functions behind the scenes. But she leads a team that gets the results clinicians depend upon to make that patient’s diagnosis.

Research investigator Jennifer Dien Bard, PhD in a lab setting
“We want kids getting the right treatments sooner, we want to reduce their length of stay in the hospital, and we want their outcomes to be better.” — Jennifer Dien Bard, PhD

Dr. Dien Bard’s lab in the Department of Pathology and Laboratory Medicine functions 24 hours a day and has dozens of different diagnostic assays. Most clinical testing for CHLA patients can be conducted on-site.

In addition to running this facility, Dr. Dien Bard is interested in understanding the clinical impact of new testing technologies. “We want kids getting the right treatments sooner, we want to reduce their length of stay in the hospital, and we want their outcomes to be better,” she says.

Our understanding of the genome— the entire library of an organism’s genes—has changed the face of research and how clinicians treat patients. Genomes have been decoded for many organisms—not only humans, but also infectious agents such as viruses and bacteria. This gives scientists a template for diagnosing infections.

Recently, Dr. Dien Bard collaborated with colleagues to evaluate the use of metagenomic next-generation sequencing, or mNGS, in clinical settings. This advanced technology was developed for research and was adapted quickly to compare a patient’s sample, which includes genetic information from the infection, to a database of hundreds of known sequences of pathogens.

The ability to quickly test for hundreds of possible infections ultimately translates to faster diagnosis and treatment. In the past, this identification could take weeks, and each round meant more waiting for families to get answers. Today, it is a matter of a few days.

Dr. Dien Bard and her team are currently pursuing the development of new NGS assays at CHLA to detect pathogens that cannot be recovered by conventional methods. Her research findings show that molecular testing is not only quicker, but it can often reveal infections that would otherwise have been missed.

“Findings from these broad-spectrum molecular assays are promising and improving patient diagnosis and management,” she says. “More families are getting answers and they’re getting them faster.”

Clinical laboratories like Dr. Dien Bard’s play a crucial role in health care. They also represent an important bridge between discovery science and clinical research. “These technologies are the product of basic science,” she explains. “My goal is to evaluate them with clinical research trials and determine how they can translate into better care for our patients.”

THE CLINICIAN IMPROVING HEALTH FROM THE LABORATORY BENCH

How one clinician-scientist tackles liver disease from multiple directions

It’s difficult to imagine that Rohit Kohli, MBBS, MS, came into research almost by accident. He went to medical school in India to learn how to help children. But it was in a basic science laboratory where he found the tools to do even more.

After medical school, Dr. Kohli moved to the United States, where he volunteered in a neonatology laboratory before beginning his career in pediatrics. What was supposed to be a brief research experience turned into an epiphany that altered his career trajectory. The work involved basic research into retinopathy of prematurity, a disease that causes blindness in babies—a disease Dr. Kohli had seen in his clinical training.

Research investigator Rohit Kohli, MBBS, MS in his lab
“Here in the lab—this is where it all starts.” — Rohit Kohli, MBBS, MS

“Maybe it wouldn’t have been such a distinct moment of truth if I had been exposed to research first. But I came from the clinic, where I spent time caring for kids with this very disease,” he says. “It really hit me. We can find a fix for these things!”

This was the turning point. Dr. Kohli became invested in research and gained an appreciation for addressing medical concerns from a discovery science perspective.

Flash forward to nearly two decades later, when Dr. Kohli—now CHLA’s Chief of the Division of Gastroenterology, Hepatology and Nutrition and the Associates Chair in Liver and Intestinal Research—has published dozens of peer-reviewed scientific articles. His work integrates multiple levels of research to address pediatric health. “My work comes from a clinical need,” he says, “but it starts in the lab.”

This current clinical need is a condition known as fatty liver disease, a complication of obesity. When the body accumulates too much fat, some of it begins to collect in the liver, resulting in nonalcoholic fatty liver disease (NAFLD). Nearly 1 in 10 children in the United States have this condition, and given the rise of obesity in American youth, the number is likely to increase. The more severe form of fatty liver, called NASH (nonalcoholic steatohepatitis), produces scar tissue and can lead to cirrhosis or liver cancer.

Dr. Kohli researches the mechanisms of fatty liver disease while also working to change outcomes of patients at a clinical level. His research is geared toward understanding cellular mechanisms that result in weight loss. This could lead to treatments or even prevention of NAFLD and NASH.

His research also has shed light on the negative effects sugar has on the liver. “Fructose found in sugary foods can actually cause scarring in the liver,” he says. Not only do findings like these help shape his research, but they also inform his patient interactions.

“It’s not easy to make changes,” he says. “We are wired to eat. I try to start with simple steps, like encouraging patients to reduce sugary drinks.”

Based upon his laboratory findings, Dr. Kohli will soon begin a clinical trial to examine potential benefits of natural sugar substitutes. He will continue to study pediatric disease from many perspectives, but his epiphany about basic research still drives him. “Here in the lab,” he says, “this is where it all starts.”

THE NURSE LOOKING BEYOND THE CURE

After years of caring for patients, this nurse got an advanced degree to do the research that will change their lives.

When your patient’s brain cancer goes into remission, it’s a turning point. But it’s only part of the journey for nurses like Mary Baron Nelson, PhD, RN, CPNP.

A nurse practitioner for much of her career, Dr. Baron Nelson cared for many pediatric patients with neurological disorders and brain tumors. She then worked with many of these children in the clinic as survivors.

Research investigator Mary Baron Nelson, PhD, RN, CPNP
“If we know what is happening neurologically and when, we can start to think about interventions to prevent long-term effects.” — Mary Baron Nelson, PhD, RN, CPNP

After noticing a pattern in the long-term health of these patients, she realized there was more work to do. So she went back to school, earned a PhD and began looking for answers. The cure wasn’t the only objective.

“I was seeing kids who I had known since they were really tiny, who had gone through cancer therapy,” she says. “They were cured of their disease, but they grew up to have lives that were not necessarily of the quality that their parents would have hoped for.”

Dr. Baron Nelson is referring to a wide spectrum of cognitive disabilities that can affect children who have undergone chemotherapy or radiation for the treatment of brain tumors. These children don’t necessarily lose skills that they’ve already gained, but they may have trouble learning new skills. She wanted to know why, but there was little research on the effects of cancer treatments on healthy brain tissue. So, she began the research herself.

She had many questions. Does having a brain tumor itself cause certain delays? Or do chemo and radiation therapies cause different types of irreversible damage? Is there a critical time in development during which children are most vulnerable to these treatments?

“Of course, we can’t change treatment markedly because we don’t want to interfere with their cure,” she explains, “but if we know what is happening neurologically and when, we can start to think about interventions to prevent long-term effects.”

Dr. Baron Nelson examined brain imaging data from patients after treatment. She observed damage to parts of the brain far from the tumor site. Some of these areas—such as the hippocampus and the thalamus—are directly involved in learning new skills and processing information. This could explain some of the deficits Dr. Baron Nelson and others observed in children after cancer treatment.

Her current study examines the effects of cancer treatment on the trajectory of brain growth by comparing brain images from children before and after tumor removal operations, after cancer treatments, and at one-, two- and four-year visits after treatment. This data set will give clinicians an unprecedented look at how therapies affect the developing brain.

“This will help us understand when any cognitive effects start to occur,” she says.

The study’s findings could shape the way patients are treated outside of their cancer therapies. Because children are missing months or even a year of school during critical periods of development, Dr. Baron Nelson suggests that there could be a focus on educational activities between treatments, during times when children feel well.

This hypothesis-driven research is the spirit of outside-of-the-box basic science. It embodies what CHLA is all about—conducting research that not only saves lives but can also alter the trajectory of health, producing benefits that last a lifetime.

THE DOCTOR WHO FIGHTS FOR THE LAST 10%

This investigator is looking to improve outcomes for drug-resistant leukemia using discovery science.

Why would a scientist study a disease that most children beat? If you ask Yong-Mi Kim, MD, PhD, she’ll tell you that it’s because most is not good enough.

Acute lymphoblastic leukemia (ALL) is one of the most treatable childhood cancers. Thanks to advances in science and medicine, most pediatric patients are cancer-free for the long term. Of the roughly 3,000 children who will be diagnosed with ALL this year, nearly 2,700 of them will be cured. What drives Dr. Kim are the remaining 300.

Research investigator Yong-Mi Kim, MD, PhD in her lab
“Without basic science we would not have the tools and knowledge to study, understand and cure diseases.” — Yong-Mi Kim, MD, PhD

This subset of patients with ALL— about 10%—don’t respond to current treatments. Her research is aimed at uncovering potential new treatment targets. She also believes that newer treatments could reduce drug-resistance side effects and toxicity for the majority of children who do respond to therapy.

“With ALL, we have two problems,” says Dr. Kim. “We need to find a way to cure all children. But we also need to help these children survive better.”

She says we are not out of the woods once a child is in remission. Leukemia treatments are highly toxic, and many survivors suffer from late-term side effects.

A clinician-scientist in the Cancer and Blood Disease Institute, Dr. Kim has taken a discovery science approach to ALL. Paradoxically, she studies ALL by not focusing on the cancer. Instead, she studies its microenvironment—the area immediately surrounding the cancer cells. ALL is a type of cancer that affects blood cells, but Dr. Kim’s work is buried deep inside the bones.

“Relapse typically occurs in the bone marrow,” she explains. “Here, the tissue provides a safe environment that shields cancer cells from the chemotherapy.” Research has shown that cells in the bone, called marrow stromal cells, are responsible for shielding the cancer, but scientists still don’t know how they do it.

One major area of study in Dr. Kim’s laboratory involves proteins called integrins. Found on the surfaces of cells, integrins act like glue to fix cells in certain spots. Her laboratory discovered that one of these proteins, integrin alpha 4, anchors leukemia cells in the bone marrow. This allows the cancer to hide in a safe haven and resist treatment.

Dr. Kim’s current research focuses on other adhesion molecules that likely work with integrin alpha 4 to aid cancer cells. The development of newer therapies depends on findings like these that provide critical targets for translational and pharmaceutical research.

Questions begin with basic research that provides initial answers, even long before medications or treatments are developed. “This takes time,” she concedes, “and it may seem far away from clinical research and applications. But the truth is, without basic science we would not have the tools and knowledge to study, understand and cure diseases.” CHLA butterfly icon graphic

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