researchA PublicAtion of The ReseaRch InsTITuTe aT naTIonwIde chIldRen’s hospITal

listening to the heart’s smallest messengerHow this devicegets cells to tell

features

4 wanted: a Generation of Quitters brady Reynolds, PhD, has never smoked a cigarette in his life. Yet most of his day is spent trying to find ways to quit.

8 The Importance of studying adolescents What if in addition to the normal awkwardness of adolescence, you are diagnosed with an illness that will last a lifetime? findings suggest that adolescents shouldn’t be treated like adults, but they shouldn’t be treated like children either.

12 listening to the heart Down at the cellular level lives the cardiac myocyte, the heart’s smallest messenger. Although it is simply a microscopic cell extracted from the heart muscle, it has a story to tell. that is, if you’re listening.

extras

7 noteworthy news about the Research institute and its faculty.

16 Into the Future the look of Research in 2012.

on tHe coveR Loren E. Wold, PhD, examines a device used to study the function of heart muscle cells, a tool that could change the way science understands heart disease.

leadeRshIp The Research Institute at nationwide children’s hospital

John a. Barnard, MdPresident

lauren o. Bakaletz, phdVice President, Basic Sciences Research

Kelly Kelleher, Md, MphVice President, Health Services Research

Grant Morrow III, MdMedical Director

daniel R. MannVice President, Research Administration and Operations

Katherine s. MilemVice President, Research Business Services

researchWriter and editorMelissa hamilton

DesignerTanya Bender

PhotographersBrad smithdan smith

Manager, Research communicationsJan arthur

contact us at ResearchMagazine@nationwidechildrens.org

research is dedicated to the

mission of informing and inspiring

readers by highlighting scientific

performance at the Research

institute at nationwide children’s

Hospital. this publication is

produced biannually by the

Marketing and Public Relations

Department at nationwide

children’s Hospital.

table of contents

Dear Friends and Colleagues:

One of the prevailing joys of being a scientist is the knowledge that each day could

be a day of fascination and revelation. The intellectual pursuit of a life-altering

discovery, particularly one that could improve the life of a child, drives us to

continue our years of research.

Our excitement and fascination shouldn’t stay within our walls. We want to share

these experiences with you. So welcome to our first issue of reSearch.

Within these pages, you will discover how impulsive thought processes affect a teen’s

ability to quit smoking; be privy to the way heart cells “communicate” and what they

say about heart disease; and be revealed to the world of an adolescent facing a chronic

GI illness, and how we are searching for the ideal ways to treat this condition.

Join us in our enthusiasm for the future of pediatric research and in the milestones

– sometimes incremental and sometimes monumental – we reach each day in our

pursuit of discovery.

John Barnard, MdPresidentthe Research institute at nationwide children’s Hospital

Professor of Pediatricsthe ohio State university college of Medicine

a message from the president

research | 3

research | 54 | research

Brady Reynolds, phd, has never smoked a cigarette in his life. Yet most of his day is spent trying to find ways to quit.

You won’t see him crunching on a piece of nicotine gum or slapping on nicotine patches. instead, you’ll find him crunching numbers and trying to patch holes in research about what motivates adolescents to quit smoking.

that’s because as a principal investi-gator in the center for biobehavioral Health at the Research institute at nationwide children’s Hospital Dr. Reynolds is using research techniques to learn how to help adolescents become quitters.

“Adolescence is a sensitive period to begin smoking,” said Dr. Reynolds.

According to surveillance by the Morbidity and Mortality Weekly Report, approximately 2,000 adolescents initiate smoking each day. that means that every minute, an adolescent is trying a cigarette for the first time.

And that first time may not be the last. Studies show that the majority of adolescents who smoke daily continue

to smoke into adulthood, practically guaranteeing increased health risks, since approximately half of people who smoke are expected to die from smoking-related illnesses, according to the World Health organization.

Although adolescent smokers often continue their habit into adulthood, it may not always be clearly by choice. Sixty-one percent of adoles-cents report wanting to quit smoking cigarettes and 59 percent report a quit attempt in the past year.

So why can’t they just quit? that’s what Dr. Reynolds wants to find out.

As a behavioral psychologist, Dr. Reynolds has spent his career trying to understand what motivates people to certain behaviors. Although some motivators tied to cigarette smoking have already been identified, such as impulsivity, there is still a lot to learn.

“impulsivity is not described by one type of behavior. it is multifaceted,” said Dr. Reynolds.

A recently studied aspect of impulsivity is delay discounting. Delay discount-ing describes an individual’s preference for a smaller, immediate reward over

a larger reward that is delayed for a period of time. Delay discounting has been shown to play an important role in cigarette smoking behavior.

to further understand this relation-ship, Dr. Reynolds has developed a delay discounting task that he believes overcomes some of the shortcomings of previously developed methods.

Most delay discounting tasks ask participants to choose between hypothetical situations, such as, would you prefer $10 now or $100 one year from now. but according to Dr. Reynolds, this hypothetical method can be tricky for adolescents.

“because adolescents, particularly younger adolescents, aren’t as psycho-logically developed in many ways as adults; they perceive information differ-ently,” said Dr. Reynolds. “for example, they don’t seem to understand the con-cept of time (like a year) as adults do.”

that’s why Dr. Reynolds developed the experiential Discounting task (eDt), a computer-based program that measures delay discounting by requiring participants to choose between moment-in-time situations as opposed to hypothetical situations.

to complete the eDt, the participant views a computer screen that displays two monetary amounts, one that offers a smaller immediate reward and another that offers the possibility of a larger reward at a delayed time. for example, do you want 15 cents now or the possibility of 30 cents 28 seconds from now? if the participant clicks the computer to choose 15 cents now, coins come clinking out of a specialized change machine that is connected to the computer.

“that’s why it’s called the experiential Discounting task. Participants actually experience the choice they make at that moment,” said Dr. Reynolds.

if the participant instead chooses 30 cents, they have to wait a set period of time to see if they will actually receive the money, since the delayed option may not actually pay out each time. this time delay can vary from zero seconds, 7 seconds, 14 seconds, to 28 seconds. After the time delay, the selected money amount appears in the computer’s “bank account” that will be cashed out once the par-ticipant has completed the entire task.

every time the participant chooses the smaller, immediate amount, that quantity goes down for the next choice (the next option may give you 10 cents). this calculation helps provide a clearer measure of delay discounting. those who chose the smaller, immedi-ate reward more often than the larger, delayed option are described as being more impulsive discounters.

to determine how delay discounting relates to cigarette smoking behavior, the eDt is being evaluated with an adolescent smoking cessation program called not-on-tobacco (n-o-t), the official teen smoking cessation program of the American lung Association. Dr. Reynolds initiated

the program at nationwide children’s in January of 2006, one of the first-and-only smoking cessation programs for adolescents in central ohio.

Adolescents who enroll in this pro-gram attend a smoking cessation class held at nationwide children’s main campus once a week for 10 weeks. During the first half of the program, participants are taught health and smoking education

including the common myths of smoking. class five is the required “smoking quit date” for participants and the remaining sessions are used as a support group to help deal with withdrawal and lifestyle changes associated with quitting smoking.

Participants of the n-o-t program at nationwide children’s Hospital can choose whether or not they want to perform the delay discounting task along with their participation in the 10-week program. Dr. Reynolds’ delay discounting studies with this adolescent smoking population have shown that the adolescents who discount more often are those who are less likely to quit smoking, even after participating in the n-o-t program.

these findings have implications for designing effective smoking cessation programs. “A person who discounts most by delay is someone whose behavior is led by more immediate consequences. to reach an adoles-cent smoker who discounts a great deal, you need to make the benefits of quitting smoking more immediate. Programs that stress the long-term effects of smoking are going to be less

effective for these adolescents,” said Dr. Reynolds.

Although Dr. Reynolds is quick to suggest his

findings could be applied to current smoking cessation programs, he says that even the best of research needs to be strengthened by further evidence. that’s why he has made the eDt available via the web for behavioral laboratories throughout the world. other investigators can access the software, purchase the appropriate coin machine and conduct their own experiential delay discounting studies. Dr. Reynolds will then analyze their findings from the eDt, in hopes that they can also help shape smoking cessation and education programs for adolescents.

More Smoke Signalsthe eDt is not the only method Dr. Reynolds is using to understand

Wanted: a Generation of Quitters HoW ReSeARcH iS finDing neW WAYS to HelP ADoleScentS Quit SMoking

“That’s why it’s called the experiential discounting Task. participants actually experience the choice they make at that moment,” said dr. Reynolds.

Brady Reynolds, PhD, demonstrates the Experiential Discounting Task.

Circulatory System Could Provide New Strategy for Mus-cular Dystrophy Gene Therapy Future Study to Monitor Medication Usage and Effects Technique Helps Diagnose Asthma Attacks Circulatory System Could Provide New Strategy for Muscular Dystrophy Gene Therapy Future Study to Monitor Medication Usage and Effects Tech-nique Helps Diagnose Asthma Attacks Circulatory Sys-

research | 76 | research

smoking behavior. Working with collaborators, he is collecting data from a web-based contingency management program. Participants of this program are asked to record “video diaries” of themselves three times a day using web cameras. At the time of each “diary entry” they blow into a picometer, a device used to measure carbon monoxide levels, a distinct marker of how much tobacco someone has smoked in the past three to six hours. Participants are given money for continued abstinence during the treatment phases.

Preliminary results have shown that the participants significantly maintained abstinence from smoking when they were being paid, even during a period at the end of the program when it didn’t matter how much they smoked.

With continued funding, Dr. Reynolds hopes to maintain this method of research with the hopes of one day combining the contingency manage-ment model with the n-o-t program model, for a more comprehensive smoking cessation course.

“by reinforcing positive behavior, the contingency management portion could help kids get through the withdrawal stage that is common with the early days of smoking cessation. then combining the n-o-t

program style would encourage maintenance by providing the needed peer support group,” said Dr. Reynolds.

until then, the n-o-t program continues to make an impact. of the more than 60 adolescents who have participated in the n-o-t program at nationwide children’s, 25 percent made a significant decrease in smoking frequency and many of the others report at least some decrease.

Genetic Contributions beyond his current research methods, Dr. Reynolds would like to further the understanding of adolescent smoking cessation by investigating how genetics contribute to smoking habits. He and chris bartlett, PhD, principal investiga-tor in the center for Quantitative and computational biology at the Research institute, are already collecting pilot data that involves isolating genes associated with different neural systems in the brain (many of which are associated with addiction) to search for genetic markers of delay discounting.

other hopeful genetic studies include investigating recent research in the field that suggests the relationship between smoking behavior in parents and their children can most likely be accounted for by their genetic relatedness, not just by a child mimicking parental behavior.

Although Dr. Reynolds would like to delve into these new areas of research, he is not abandoning the eDt. in fact, fellow principal investigators at the Research institute have plans to use it to determine the role delay discounting plays in behaviors beyond smoking cessation. Planned studies include measuring suicidal impulsivity and studying what makes people likely to use safety equipment, such as sports safety equipment or parent use of infant car seats and home smoke alarms.

even though Dr. Reynolds’ original plans for the eDt were focused on adolescents, his findings may have implications for adult smokers. “the research would have to be explored, but there are indications that these findings may apply to the adult population since research has already shown that adult smokers discount more than adult non-smokers,” he said.

for now, however, Dr. Reynolds plans to focus his research on ways to help adolescents specifically. “if we can change smoking habits during adolescence, we’ll be able to greatly reduce the long-term effects of smoking,” said Dr. Reynolds.

For more information about the not-on-Tobacco program at nationwide children’s hospital, call (614) 355-3445, or click on “education classes” at nationwidechildrens.org.

Further Reading: Reynolds, b.; Patak, M.; Shroff, P. “Adolescent smokers rate delayed rewards as less certain than adolescent nonsmokers.” Drug and Alcohol Dependence, v. 90 issue 2-3, 2007, p. 301-3.

preliminary results have shown that the participants significantly maintained abstinence from smoking when they were being paid, even during a period at the end of the program when it didn’t matter how much they smoked.

noteworthy | tHe ReSeARcH inStitute At nAtionWiDe cHilDRen’S HoSPitAl

Circulatory System Could Provide New Strategy for Muscular Dystrophy Gene Therapy investigators at the Research institute have received an $8.1 million grant from the national institutes of Health to learn more

about strategies to treat muscular dystrophy, potentially leading to two new gene therapy approaches. the primary research strategy will use the circulatory system for gene delivery of the dystrophin gene, as opposed to direct injections into individual muscles. this vascular delivery strategy provides a more favorable opportunity for correction of lost function throughout the body reaching many muscles, as well as the heart.

Two Centers of Emphasis Obtain Leadership Bill smoyer, Md, Robert c. kelsch chair of Pediatric nephrology at the university of Michigan, has been appointed director of the center for clinical and translational

Research at the Research institute. Dr. Smoyer will work to orchestrate further development of clinical and translational research across the organization.

After serving in an interim position, leif nelin, Md, has been appointed director of the center for Perinatal Research at the Research institute. Dr. nelin plans to continue to improve the integration between the center for

Perinatal Research and the Division of neonatology, an ability he demonstrated during his interim position.

Future Study to Monitor Medication Usage and Effects A research study is planned to trial a new technology that helps monitor how medications, specifically anti-depressants, are used in children and teens.

the project, named “PhaSt”, or Pharmaceutical Safety tracking: Managing Medications for Patient Safety, involves an interactive voice response telephone system to contact parents or teenage patients. the system requires simple yes or no answers to questions about the medications and their side effects. When a parent or patient indicates a problem,

the system alerts a trained psychiatric nurse to contact the patient or parent and when necessary, contact the patient’s physician or hospital emergency services.

the PhaSt project could provide medication monitoring in instances when families or the overstretched child mental health systems do not have the resources to follow the recommended–often weekly–physician visits.

the study is expected to begin in early 2008 and continue through 2010. initial funding for the study was made possible by a collaborative grant between nationwide children’s and the ohio State university.

Study Helps Differentiate Between Asthma and Vocal Chord DysfunctionDoctors at nationwide children’s Hospital performed a clinical study using spirometry in the emergency Department to identify adolescents who had findings suggestive

of vocal chord dysfunction (vcD) compared to an acute asthma attack. the manuscript was published in the July issue of Pediatric Pulmonology.

According to the study, 12 of the 17 adolescents who presented to the emergency Department with difficulty breathing, but with high normal oxygen levels, were found to have evidence of vcD on spirometry. this led to a change in the therapy for these patients. Spirometry used in the acute setting of difficulty breathing can help differentiate vcD from asthma attacks.

the study suggests that if more emergency departments made use of the spirometry test, it could cut down on the number of children who are misdiagnosed and potentially hospitalized.

Learn about more research news and highlights at NationwideChildrens.org/research.

research | 98 | research

children’s Hospital, are studying adolescents to better understand how this patient population adjusts to chronic illness.

Although their research might not be poetic, what their findings suggest seems to be worth writing home about: adolescents shouldn’t be treated like adults, but they shouldn’t be treated like children either.

The Uniqueness of Adolescence Adolescence involves more changes than any developmental period other than infancy.

these years are wrought with extreme biological changes including raging hormones, acne, and increased body odor and body hair.

on top of the stressors normally associated with adoles-cence, imagine having an incurable condition in which your main symptoms include diarrhea, rectal bleeding, abdominal pain and delayed puberty.

inflammatory bowel diseases (ibDs) such as crohn’s disease and ulcerative colitis are chronic conditions in which inflammation in the intestines can result in these sometimes embarrassing symptoms. Although ibD has typically been viewed in the medical community as an adult disease, about 25 percent of ibD cases occur in the pediatric population, with the majority beginning their onset in adolescence. Adjusting to the normal changes adolescence brings is tough enough; adolescents with ibD are given even more to adjust to.

“ibD is an ideal disease for investigating adolescent adjustment to chronic illness, given its adolescent onset, and embarrassing, socially limiting, and appearance-changing symptoms,” said Dr. Mackner.

So how has research into this condition shed light on how adolescents adjust to chronic illness? therein we find the issue.

“When we first started investigating this area of research about five years ago, there was little research focusing on the psychosocial aspects of ibD. there hasn’t been much

research on adolescent adjustment to other conditions, either,” said Dr. Mackner.

overall, a comprehensive adolescent perspective is lacking. “the research on psychosocial adjustment to pediatric chronic illness has focused primarily on children. if adoles-cents are included in this research, they are often included in the same sample with younger children. even when adolescents are the focus, development issues are often not taken into account,” said Dr. Mackner.

When Drs. Mackner and crandall refer to adolescents, they mean those age 11 through 18, since this is the period when most changes in psychosocial adjustment appear. So, why should an 11-year-old be categorized separately from an 8-year-old? When it comes to psychosocial development, adolescence and childhood are worlds apart. Adolescents spend significantly more time with their peers than children do. close friends begin to surpass parents as a primary source of social support and acceptance by peers plays an important part of adolescent self-identity. involvement in extracurricular activities contributes not only to acceptance by peers, but also takes on an important role for those planning to apply to college. in addition, the development of romantic relationships becomes a significant focus.

When Illness Adds Insult to InjuryWith so many aspects of psychosocial development how do you study whether or not an adolescent is adjusting well to this new stage of life?

“there are two main aspects of studying psychosocial functioning,” said Dr. Mackner. “one is psychological functioning: Are they depressed? Do they have anxiety? Do they have other types of behavioral problems? the other is social functioning: How are they getting along with friends? Do they have friends? Are they able to participate in social activities at an age appropriate level? Are they able to attend school and do well?”

Drs. Mackner and crandall studied the psychological and social aspects of adolescents with ibD in order to

The Importance of Studying Adolescents

Researchers work to understand chronic Illness in a neglected Field of study

Apoet once remarked, “You don’t have to suffer to be a poet. Adolescence is enough suffering for anyone.” but what if in addition to the normal awkwardness of adolescence, you are diagnosed with an illness that actually will last a lifetime?

laura Mackner, phd, an investigator in the center for biobehavioral Health at the Research institute at nationwide children’s Hospital, and wallace crandall, Md, Director of the center for Pediatric and Adolescent inflammatory bowel Disease at nationwide

“IBD is an ideal disease for investigating adolescent adjustment to chronic illness, given its adolescent onset, and embarrassing, socially limiting, and appearance-changing symptoms.”

Wallace Crandall, MD and Laura Mackner, PhD

understand whether having the condition might affect psychosocial func-tioning. What they found was that adolescents with ibD have significantly fewer close friends than healthy adolescents and participate in fewer organized activi-ties. these results suggest that ibD has an adverse impact on adolescent social functioning. this finding is important because research has shown social function-ing among children is an important predictor of difficulties later in life.

Drs. Mackner and crandall believe that these differ-ences in social functioning may be attributed to the fact that ibD is more of a stigmatized disease. “A lot of diseases, for lack of better words, are socially acceptable,” said Dr. crandall. “everybody understands asthma, everybody understands cancer. if a kid with asthma or cancer goes to school, kids rally around them; they don’t think they’re going to catch it. kids with ibD have a stigmatizing disease. they don’t want to talk about the symptoms because they can be very embarrassing. it is a condition that can be quite isolating.”

Although they have identified the fact that social functioning may be impaired in patients with this condition, that’s just half the battle. “the extent of the difficulties is unknown,” said Dr. Mackner.

learning more about the extent of the difficulties may help identify risk factors for this patient population. “once we identify risk factors, we’ll be able to identify which adolescents are likely to have problems in adjustment,” said Dr. Mackner.

“if there is a way to know up front who is going to have difficulties down the line, we could involve the appropriate

people sooner, like psycholo-gists and social workers to try to help patients with that ad-justment process as opposed to waiting until there is some crisis,” said Dr. crandall.

identifying risk factors could also help identify appropriate treatment methods, such as emphasizing coping strate-gies during therapy or group intervention situations.

So Much More to Learn More studies need to be completed before the re-search field is robust enough to start drawing conclusions about adolescent adjustment to chronic illness, especially adolescent adjustment in ibD.

“there are very few researchers who focus on psychosocial issues in pedi-atric ibD,” said Dr. Mackner, who believes there are only a few researchers in the nation doing so.

With continued funding, Drs. crandall and Mackner want not only to tackle the unanswered questions that their previous research has raised, but also focus on the bi-directional nature of ibD, the relationship between mind and body.

“Disease affects psychosocial factors and psychosocial factors affect disease,” said Dr. crandall. “When you’re treating one of these things, you’re potentially treating both sides of the equation. We need to continue research to tease out how much of it is a psychological effect and how much of it is a disease effect.”

To do so, they’d like to focus research on the following role players: • The role of stress: “there is some thought that stress may affect the disease activity, rather than just the way that patients deal with it. Stress does cause a physiologic response, but may cause one that actually increases

the inflammation of the intestine,” said Dr. crandall. “better control of stress could help with the psycho-social aspect, but could potentially help with disease control issues as well.”

Drs. crandall and Mackner would utilize behavioral measures to study patient stress levels, as well as markers of inflammation at the bowel level to see if stressors predict flares in disease.

Dr. crandall would also like to investigate the genetic components of stress as it relates to ibD. there are normal variations within a gene known as polymor-phisms that result in different effects. these gene variations may influence the effect of stress on ibD.

• The role of depression: “there is research that exists that shows that children with ibD have higher rates of depression than healthy kids,” said Dr. Mackner. “in the past, we always thought that it was a reaction to having this disease since it is a disease that is often embarrassing to have.” However, new evidence suggests that there may be aspects of the inflammatory process that actually contribute to the development of depression.

future studies would involve looking specifically at the role of pro-inflammatory cytokines in ibD. these proteins that are released by white blood cells have been found to be byproducts of both inflammation and depression.

“there is a substance known as tumor necrosis factor alpha that is known to be an important contributor to the inflammatory process in crohn’s disease,” said Dr. crandall. “Another one of its effects is causing a poor appetite. So if a patient comes in and says ‘i’m tired; i’ve been having trouble sleeping; i don’t want to eat,’ are they depressed or is it a symptom of the crohn’s disease?” Questions like these are of special importance to an adolescent population since Drs. Mackner and crandall think that kids with ibD who are more depressed are going to have more problems with social functioning.

• The role of the adjustment process: Drs. crandall and Mackner would like to develop a web-based program in which adolescents with ibD would fill out questionnaires quarterly regarding stress, coping skills, social support and disease activity during their first year of diagnosis. this would help create a data entry system that could

be used to help identify risk factors, especially during the first year of diagnosis, when the majority of disease adjustment is expected to occur.

• The role of social functioning: Although preliminary results show that ibD has an adverse impact on adolescent social functioning, more research needs to be done to clearly identify the extent of disease impact. Dr. Mackner identifies this as a vital need considering social functioning is so important during adolescence. “Adolescents’ social lives are very complex and we don’t yet know how ibD affects them or how to best help adolescents in this area,” said Dr. Mackner.

• The role of medication: “one of the medications used to treat ibD is steroids and steroids have been associated with depression and emotional liability,” said Dr. Mackner. “they also are associated with aspects of adolescence that can be additionally stressful like weight gain and increased acne.”

• The role of age at disease onset: “A lot of the chronic health conditions that have been studied from the psychosocial research are ones that children are born

with or acquire early in life,” said Dr. Mackner. “coping mechanisms involved in this situation are vastly different compared to being 13 and suddenly being diagnosed with a chronic gastrointestinal disorder.” future research would investigate how age at disease onset affects psychosocial functioning in adolescence.

even though Drs. Mackner and crandall have earmarked these as areas that need further research, they probably won’t stop there. “Just being in the clinic and interacting with ibD patients helps spark new research ideas,” said Dr. Mackner.

What a good problem to have. More data would bring the health care field a little closer to providing new answers to the question that Dr. crandall says is of utmost importance.

“How do adolescents adjust to chronic illness? the answer is we don’t know, but we need to find out.”

Further Reading: Mackner, lM.; crandall, Wv. “Psychological factors affecting pediatric inflammatory bowel disease.” Current Opinion in Pediatrics, v. 19 issue 5, 2007, p. 548-52.

“Kids with IBD have a stigmatizing disease. They don’t want to talk about the symptoms because they can be very embarrassing. It is a condition that can be quite isolating.”

“If there is a way to know up front who is going to have difficulties down the line, we could involve the appropriate people sooner…”

research | 1110 | research

When’s the last time you talked to yourself? the truth is you’re doing it right now.

cells in the human body are living gossip mills. Sending and receiving chemical messages along neural pathways, firing synapses, exchang-ing gasses and elements, regulating temperature and cellular growth, your body is in constant conversation with itself.

of all of the body’s conversationalists, the heart is one of the biggest. this

fist-sized organ is responsible for one of the most vital life functions, pumping oxygen-rich blood through blood vessels to reach the rest of the body. Although we are most used to listening to this big communicator with a stethoscope, research is showing that it’s worth getting another perspective when it comes to studying heart disease.

Down at the cellular level lives the cardiac myocyte, the heart’s smallest messenger. Although it is simply a microscopic cell extracted from the

heart muscle, it has a story to tell. that is, if you’re listening.

loren e. wold, phd, is listening. As a principal investigator in the center for cardiovascular Medicine at the Research institute at nationwide children’s Hospital, Dr. Wold is studying heart function by taking a big look at the smallest of parts.

“in order to understand cardiology, you need to understand what is happening at the cell level,” said Dr. Wold.

Getting Cells to TellHow do you get cells to tell you what is happening? first, you have to make them feel at home.

When an organ is housed inside the human body, it is exposed to blood, which serves as the major source of energy. to extract cells from an organ outside of the body, you must supply an energy source. So the organ is “per-fused” by being placed in a solution that is chemically representative of blood. “We try to trick them into think-ing they’re still in the body and still healthy, but they’re actually in a dish in an incubator in artificial fluid,” said Dr. Wold. this artificial fluid also contains an enzyme that breaks apart all of the scaffolding around the cells. once the cells are exposed at their rawest level, they are “suspended,” a process that leaves them unattached and floating in a special liquid bath.

now the real, nitty gritty investigation can begin.

“cardiac myocytes actually beat when stimulated, just like the heart does. that’s what makes up the mechanics of the heart,” said Dr. Wold.

to get the cells to beat, more coaxing is required. “We use a device that stimulates the cell in the same way that the nervous system would stimulate the heart to contract,” said Dr. Wold. While this superfusion/stimulation chamber, which looks like a shallow, cylindrical dish with horizontal, metallic prongs pointing inward, makes the cell beat, investigators view the cell through a specialized microscope that captures images of the beating in real time. A program then analyzes the cell’s

motion and performs mathematical conversions to represent the beat graphically, similar to the graph of a heart monitor. investigators can then analyze the slopes on the graph to determine whether or not the beating cell is functioning properly.

if the graphical results reveal that the cell is not functioning properly, it is time to find out why. one way is by looking at molecules involved in cell signaling. “cell signaling is the way a cell communicates within itself and with other cells,” said Dr. Wold. one of the cell signaling molecules of most

interest to Dr. Wold is the calcium ion because it regulates contraction and relaxation of the cell.

Just like when the heart beats, there are two phases involved when the cell beats. the cell squeezes together during a contraction phase and then returns to resting state (relaxation phase) before it can contract again. When the cell contracts, calcium ions

are released, but these ions have to return to their “stor-age facility” before the cell can contract again. When the cell isn’t functioning properly, it takes longer for the calcium ions to return, slowing the beating process, which is represented by a flattened out slope on the graph.

When Cells Tell of Heartbreaking News the ability to show exactly what is going wrong within a cell is proving to be an important part of disease diagnosis. “What we’ve found is that the cells

respond similarly to the whole organ and the whole organism,” said Dr. Wold. once you get cells in the mood to communicate, they have plenty to say about heart harming disease, including type 2 diabetes.

As opposed to type 1 diabetes, in which a malfunctioning immune system doesn’t allow the pancreas to produce insulin, the pancreas of a type 2 diabetic creates plenty of insulin, but the body stops reacting to it properly. this malfunction can lead to serious impacts on many systems of the body,

including the heart.

“the main killer of diabetics is heart disease. Most people think that if diabetics take their medicine, they’ll be fine, but that’s

not the case,” said Dr. Wold.

When type 2 diabetes is investigated at the cellular level, the slope representing the relaxation phase of the heart beat is flattened out more than it would be in a healthy cell. this means that the heart muscle is weakened for some reason, which impacts the functioning of the whole heart.

Listening to the HeartinSigHt fRoM tHe HeARt’S SMAlleSt MeSSengeRS ReveAlS eARlY WARningS of HeARt DiSeASe

research | 13

These graphs show the shortening and the relength-ening of a cardiac myocyte, a representation of its “heartbeat.”

studying disease at the cellular level doesn’t only help identify what doesn’t work for the

heart, but also what does work, including therapeutic interventions like medication.

12 | research

but according to Dr. Wold’s studies, a subject doesn’t have to be living with diabetes for these heart conditions to be present. it can happen when lipid levels are heightened but glucose levels are normal (a condition known clinically as pre-diabetes).

these findings could have important implications for the pediatric population. Although type 2 diabetes is sometimes referred to as adult-onset diabetes, it is no longer just an adult-hood disease. According to the centers for Disease control, type 2 diabetes, although still rare, is being diagnosed more frequently in children and adolescents, a striking phenomenon considering the prevalence of childhood obesity is on the rise.

Telling During TherapyStudying disease at the cellular level doesn’t only help iden-tify what doesn’t work for the heart, but also what does work, including therapeutic interventions like medication.

Many medications prescribed to treat heart conditions, like those associated with type 2 diabetes, inhibit the cell signaling process. by dissemi-nating the drug directly at the cell level and monitoring the effects, investigators can see exactly how the cell reacts (and how the drug would affect the entire heart). “We need to understand the mechanisms of heart cells in order to understand where we can involve drug therapy to adequately reverse this condition,” said Wold.

the benefits of cellular investigation don’t stop at drug investigation. other health treatment methods, such as an increase in exercise and improvement in diet, can be viewed at the cellular level.

When Dr. Wold looked at the heart cells of pre-diabetic rats once they were put on an exercise regime or fiber was added to their diet, all signs of heart complications had disappeared. When the same diet and exercise routine was applied to cells in a diabetic state, a significant decrease in heart complications were shown.

Such investigation isn’t beneficial only to diabetic-related heart diseases. the same methods can be applied to look at heart functioning, drug and treat-ment performance in hypertension, and heart conditions associated with children who were born with fetal alcohol syndrome.

Communicating with Human Cells Most of Dr. Wold’s findings have come from investigating cells from animal models. As striking as the results may be, are they directly applicable to humans, specifically children? to help understand just how translational the cellular findings are, Dr. Wold is collaborating with alistair phillips, Md, a cardiothoracic surgeon at nationwide children’s Hospital.

“translational research needs to be a communication between scientists and clinicians, in order to take findings from the bedside to the bench top and vice versa. Presently there is a lot of focus on mouse models of a specific disease and equating what is happening in the mouse to the human,” said Dr. Phillips. “if we can understand how individual cells of the heart work by examining human tissue, we can equate that to animal models of heart disease and clinical outcomes, with the result of developing new strategies.”

to go beyond the animal model, Dr. Phillips has received institutional Review board permission to extract tiny pieces of heart tissue that are removed normally and discarded during surgical correction of congenital defects. these “explants” are then made available to Dr. Wold to use for isolating individual human cells. With both specialists working at nationwide children’s, the handoff of the heart tissue typically takes about 10 minutes (as opposed to the time it takes to transport such a sample from one institution to another, across town or even across country).

Although such collaboration may seem commonsensical, it is a rarity, according to Dr. Wold. “We are one of the only pediatric institutes with this kind of access. using human samples and applying basic science concepts, that’s translational research,” he said.

14 | research

As one of the only places in the world doing this, the learning curve is steep. “We’re just getting started on isolating cells from these human samples. no one has published how to do this in pediatric samples, so we’re charting the water and figuring out how to do it,” said Dr. Wold. isolating pediatric cells is so unique because they are functionally different than adult cells; they respond to stress differently, so the isolation technique is much more sensitive.

the time is worth the effort, in Dr. Phillips’ opinion. “We’re going to be able to take what we do in the clinical realm and see what its benefit is on the cellular level. With the ability to culture individual cells, we’re going to be able to look into the microscope and say ‘this cell responds differently than this cell because we did this procedure.’”

this also has applications for the future design of clinical trials. “being able to understand how the cell responds at the cellular level and understanding the signaling mechanisms at each step along the way is the best way for drug develop-ment and testing,” said Dr. Wold.

Sharing their “Stem Cell” Secrets “in some of the pediatric samples, we’ve found progenitor cells,” said Dr. Wold. “Some people use the words ‘stem cells,’ but we call them progeni-tor cells because we’re not exactly sure what role they play,” said Dr. Wold.

As he explains it, these progenitor cells are particularly common in pediatric heart samples because children’s hearts are still growing. no one knows exactly what they do, but the theory is that they’re like the heart’s military, waiting for a sign of injury

so they can move to where they’re needed and grow into heart cells. Right now, this theory is just a theory, since it has never been proven.

Dr. Wold would like to find a way to isolate these progenitor cells to determine if they can indeed transform into heart cells. After finding a way to isolate them, he plans to inject progenitor cells into an animal model of hypoplastic left heart syndrome, a condition in which the left ventricle is either very small or missing. He hopes that by putting the cells in an environ-ment where they are needed, they will grow to rebuild the damaged heart. this research is of particular interest to Dr. Phillips since hypoplastic left heart syndrome is one if his clinical specialties.

continued investigation into progenitor cells could provide remarkable new insights into overall heart functioning. “if we can show how the heart regener-ates, it has incredible implications across the board,” said Dr. Phillips.

but before they look at the big picture, they have to continue to look at the small one.

“the key is breaking down cardiology to the functional unit, which is the myocyte,” said Dr. Wold. “the only way we’re going to understand the whole heart and how it responds is to understand it at the cellular level.”

Further Reading: Wold, le., et al. “impaired SeRcA function contributes to cardiomyocyte dysfunction in insulin resistant rats.” Journal of Molecular and Cellular Cardiology, v. 39 issue 2, 2005, p. 297-307.

“The only way we’re going to understand the whole heart and how it responds is to understand it at the cellular level.”

Loren Wold, PhD

Alistair Phillips, MD

research | 15

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PeRMit no. 777700 children’s Drivecolumbus, ohio 43205-2696

New Research Building Included in Campus Expansion Plans

the Research institute at nationwide children’s Hospital continues to experience tremendous

growth and success. it is one of the fastest growing pediatric research centers in the united

States in recent years, ranking in the top ten nationally in funding from the national institutes

of Health. to accommodate the need for additional space, a third research building will be

added to the nationwide children’s campus. this vital space will enable nationwide children’s

to continue recruitment of leading investigators and make possible scientific discoveries that

may change the course of medicine and the lives of patients and families we serve.

the additional research building is part of nationwide children’s Hospital’s campus expansion

plan. by 2012, the campus will have added more than 1 million square feet, including a new

main hospital, making nationwide children’s Hospital one of the largest pediatric facilities in

the country.

While details are

not finalized yet,

this graphic shows

a glimpse of what

is on the drawing

board for Nationwide

Children’s Hospital

in 2012.

into the future | t H e l o o k o f R e S e A R c H i n 2 0 1 2