Child research

UMCUTRECHT

ChiLD

research


Colophon

Child Health magazine, edition 2019

Publisher

This magazine is published by UMC Utrecht,

Strategic Program Child Health

Editors

Celine Uit de Weerd-Bakker, Anneke van der Brug

Magazine concept, design and art direction

UMC Utrecht Design & productions;

Barbara Hagoort, Laura Langenbach

Contributors

Kors van der Ent, Anneke van der Brug, Berent Prakken,

Mireille Bekker, Kitty Bloemenkamp, Jeroen Dudink,

Floris Groenendaal, Manon Benders, Helen Torrance,

Frank Broekmans, Gijs van Haaften, Hans Kristian Ploos

van Amstel, Albertien van Eerde, Marc Lilien, Hans Breur,

Peter van Tintelen, Sabine Fuchs, Peter van Hasselt,

Judith Jans, Nanda Verhoeven, Jeffrey Beekman,

Saskia van Mil, Bas Vastert, Jorg van Loosdregt,

Femke van Wijk, Louis Bont, Patricia Bruijning,

Marry van den Heuvel-Eibrink, Roelie Wösten-van Asperen,

Hanneke van Santen, Jaap van Laar, Nico Wulffraat,

Harry Heijerman, Kathelijn Fisscher, Roger Schutgens,

Elise van de Putte, Tim Takken, Janjaap van der Net,

Marianne Boes, Marjolijn Ketelaar, Sanne Nijhof,

Martha Grootenhuis, René Eijkemans, Niels Eijkelkamp,

Freek Hoebeek, Joost Frenkel, Cyrus Park.

colofon

Copy editors

Sarah Opitz, Cyrus Park

Coordination photography

UMC Utrecht Design & Productions; Jelle Westerhoff

Photography / contributing photographers

UMC Utrecht Design & Productions;

Rudi Hovig, Ed van Rijswijk, Thomas Dobber, Ivar Pel

Getty Images, Unsplash

Illustrations

Barbara Hagoort, Laura Langenbach

Print

Revon

Contact

Anneke van der Brug

Program manager Child Health

abrug@umcutrecht.nl

0031 6 16 36 11 51

www.umcutrecht.nl/childhealth

childhealth@umcutrecht.nl

2 UMC Utrecht - Child research

The photographs on the

coverpage and this page

show microscopic pictures

of intestinal organoids used

by several research groups

of the Child Health Program


UMC UTRECHT I WILHELMINA CHILDREN’S HOSPITAL


Child Health

in Utrecht


In the 17th and 18th centuries, medical care for children was in the hands of general

physicians and surgeons. It was not until the second half of the 19th century that

doctors began to focus on caring for sick children and formed the basis for current

pediatric medicine.

The Wilhelmina Children’s Hospital was founded in 1888 and

is one of the oldest children’s hospitals in the world. From the

very beginning, excellent medical care and new medical

developments went hand-in-hand, working closely with the

Utrecht University. In 1997, the children’s hospital merged

with the Academic Hospital Utrecht and the medical faculty

of Utrecht University to form the University Medical Center

Utrecht (UMC Utrecht).

Today, the UMC Utrecht is one of the largest academic

centers in the Netherlands. Patient care and biomedical

research are closely linked, which creates an environment

where scientific advancements quickly move from bench to

bedside. The UMC Utrecht finds itself in the middle of a

vibrant biomedical research community: Utrecht Life

Sciences. This represents a strategic alliance in education,

research and entrepreneurship in the domain of the life

sciences in the Utrecht area, located in the very heart of

the Netherlands.

The UMC Utrecht’s strategy ‘Connecting U’ concentrates

research into six programs, each with a focused number of

disease targets and patient care is integrated into these

programs. Care and research for sick children are still at the

heart of the organization, and one of the six research

programs is ‘Child Health’. This Program is an integrated

framework for child-centered interdisciplinary research,

aligning patients, clinicians, investigators and resources, so

that it can lead by filling significant gaps to improve the lives

of children during childhood and thereafter.

This magazine gives you an insight into the program and

introduces you to our researchers and their subjects.

We invite you to contact them and work together -

because children are our future!

I believe the children are our


future

Teach them well and let them lead the way

Show them all the beauty they possess inside

Give them a sense of pride to make it easier.

- Whitney Houston, 1985

Kors van der Ent Chair of Child Health

Program UMC Utrecht.

Care for chronic diseases in the future

asks for rigorous changes in our

old-fashioned health care systems.

- Kors van der Ent

UMC Utrecht - Child research 3


06Contents

The Child Health Program

Ante- and

perinatal

damage

Congenital

and hereditary

disorders

Severe

inflammatory

disorders

Postoncology

When you

save the

mother,

you save

the family.

- Kitty Bloemenkamp

Your DNA

at the

center

of care.

- Hans Kristian and

Ploos van Amstel

Prevention is

better than

treatment.

- Patricia Bruijning


Our mission in

pediatric oncology

research is to

improve cure rates

for all children and

to enhance quality

of survival.

- Marry van den Heuvel-Eibrink

10 16 22

30

32

Strategic Themes

40 Unique Resources

32

36

38

Lifecycle

Interdisciplinarity

Mental & Physical Health

40 Patients cohorts

41

45

Facilities & Expert Knowledge

Clinical Trials

46 Education and Talent

4 UMC Utrecht - Child research


CHILD HEALTH PROGRAM UMC UTRECHT

Collaborations

& networks

Visualization network of collaboration partners of Child Health - based

on co-authorship of 1324 articles and reviews in Web of Science

published in 2016-2018. The graph shows the 100 organizations that

Child Health most frequently collaborates with. Bubble size is

proportional to number of publications, line thickness to the number

of papers co-authored by researchers from the respective organizations.

connections are only shown between organizations that co-published

10 or more papers.

UMC Utrecht - Child research 5


The Child Health Program

of the UMC Utrecht

UMC Utrecht is one of the top-ranked academic medical centers

in Europe in which patient care and biomedical research are

closely linked. Partners, for example the Hubrecht Institute, can

be found at a close distance, and collaboration with the Faculties

of Veterinary Medicine and Science at Utrecht University

reinforces the relationship between animal and human health

and the environment. The UMC Utrecht has been awarded

international accreditation on quality of care, research and

education by the Joint Commission International (JCI).

Our program, Child Health, is one of six

hospital-wide strategic research programs.

The diseases we focus on are characterized

by their influence on an individual’s entire

lifespan as they often start at the

beginning of life, or even before birth, and

can have consequences far into adulthood.

Within our Child Health program, we

ensure that our ‘Cycle of Life’ approach is

strongly intertwined with innovation.

Goals

We focus on healthy development of a

child, from pre-conception to adulthood.

We’ve established an interdisciplinary

child-centered research community that

aligns with the European Commission’s

philosophy of Responsible Research and

Innovation (RRI) and aims to:

Anneke van der Brug, MSc is the Child Health Program

manager. She enjoys stimulating (clinical) researchers working

together in multidisciplinary research and is eager to continuously

think up opportunities to promote excellent scientific results.

abrug@umcutrecht.nl

Kors van der Ent, MD PhD is chair of the Child Health

Program. He is an experienced pediatric pulmonologist with

special interest for chronic diseases, like cystic fibrosis. Besides

top-notch science he is mainly focused on what really matters for

patients and their families.

cent@umcutrecht.nl

• Improve pediatric disease outcomes

within a lifespan context.

• Cure congenital and hereditary diseases

by unravelling pathogenesis; by developing

diagnostic and prognostic markers

and tools; and by developing and implementing

novel therapeutics and lifestyle

interventions.

• Improve resilience and quality of life for

children and their relatives during childhood

and thereafter.

6 UMC Utrecht - Child research


CHILD HEALTH PROGRAM UMC UTRECHT

By collaborating

we can multiply

our


success.

- Anneke van der Brug

Societal impact

In the past few decades, the field of

pediatrics has been successful in

combating disease and the life expectancy

of many disorders has significantly

improved. Unfortunately, although children

may survive their disease, they’re

burdened with long-term physical and

mental consequences. This requires drastic

changes for future healthcare: Pediatrics

should focus on the development of children

towards healthy and balanced adults.

Our Child Health Program is dedicated to

developing disease prevention strategies,

as well as safe treatment options for

children, which requires intensive

collaboration and cross-fertilization

between our basic and clinical scientists.

But most importantly, our program is

constantly interacting with children

themselves and with the environment in

which they grow up, including their family,

school, sports clubs and broader living

environment. Our program is an active

participant in the midst of a child’s society.


Research

Areas

The Child Health Program of the University

Medical Center links top referent care for

pediatric patient groups to interdisciplinary

research. This ranges from fundamental to

translational to longitudinal applied medical

research. All chronic diseases within the focus of

our program are similar in that they emerge

early, in the beginning of life and can have

consequences far into adulthood. Our research

areas high lighted in this magazine are:

Ante- and perinatal damage

This program has a life-cycle character hosting several

Centers of Excellence. It provides high quality care and

research through the periconceptional, antenatal and

perinatal phases up to neonatal intensive care, aiming for

the best long-term outcome of child health. Women,

babies and their families are the center of our service as

we strive for excellence and innovation.

Congenital and hereditary disorders

Many disorders of genetic origin are rare and require

academic specialist care. The Child Health Program

focuses in particular on congenital diseases of the heart,

liver and kidney and plays a key role in respective

European Reference Networks.

Severe inflammatory disorders

We host several Centers of Excellence for children with

sustained severe inflammatory disorders, such as Juvenile

Idiopathic Arthritis, Cystic Fibrosis, Inflammatory Bowel

Disease and Recurrent Respiratory Tract Infections.

Post-oncology

Treatment of cancer in children can result in severe

physical and psychosocial consequences later in life. The

Child Health Program closely collaborates with the

Princes Máxima Center to improve long term outcomes of

cancer treatment.

Let’s collaborate on a culture

of trust and innovation.

- Kors van der Ent

UMC Utrecht - Child research 7


Berent Prakken,

Acting Dean:

}What I most appreciate about

the Child Health program is that

it thrives to deliver top notch

science and translate it into

societal impact.~

Partnering with society

Today, scientific discovery and societal needs

go hand-in-hand. One does not preclude the

other. Because of this, there’s a great deal of

cooperation between the Child Health Program

with external social partners such as the

municipality of Utrecht, the Trimbos Institute

for Mental Health, the Jantje Beton Charity and

a large number of patient organizations.

Together, we ensure that basic science and

clinical science harmonize to revolutionize

patient care, and we’re motivated by both

acquiring and applying knowledge.

Team sport

There’s a reason why we do what we do. We’re

curious, we’re motivated, we’re passionate. We

push our research beyond conventional

questions. If we discover an important new

gene, we don’t stop with a beautiful genetics

paper. Instead, we continue hunting for the

protein it encodes, and for its function. This

feeds our passion for healing patients and we

cannot do this alone. Fortunately, we don’t have

to. From the molecular biologist discovering a

molecule to the translational scientist

investigating methods of delivery, to the

physician making a diagnosis, to the

psychologist encouraging adherence, to a

treatment regimen, to the patient foundation

focused on patient experiences. We’re all in this

together. It’s no longer just a handful of

researchers, but really a team sport.

Berent Prakken

Professor , Pediatric Immunology, Acting Dean,

Education, Director, Biomedical Education Center

3 Strategic Themes

The research areas within the Child Health

Program are cross-linked by three Strategic

Themes that are represented in all research areas.

1. Life-cycle research

Prognosis of pediatric diseases have improved dramatically

over the past few decades. For example, the life expectancy

of children with cystic fibrosis has increased from about 10

years in the 1950s to almost 50 years in current times. The

first heart surgery in children was performed in at the end

of the 1940s, when the lifespan was very short. Today, heart

surgery is routine and most children with congenital heart

disease are operated on and therefore have a normal life

expectancy. Advances in cancer research and care are also

providing a better and longer quality of life for children

with cancer.

The advancements in survival rates and success of

combating acute complications have, in turn, changed care

requirements of pediatric patients. New long-term

complications of diseases are emerging, for example,

cardiac arrhythmias can develop in adults after pediatric

heart surgery and 40% of children with cystic fibrosis

develop diabetes in adulthood. In addition, the effects of

drug treatment in children with, for example, juvenile

rheumatoid arthritis on the function of the liver, kidneys

and lungs in adulthood are unknown. Research in

chronically ill children demands parallel focus on longterm

health for adults.

bprakken@umcutrecht.nl

8 UMC Utrecht - Child research


CHILD HEALTH PROGRAM UMC UTRECHT

2. Interdisciplinary innovation loops

Our Child Health Program has created a scientific infrastructure

that integrates various fields of biomedical research connected

to groups of children with chronic diseases and their parents/

relatives. Advancing research for the benefit of these children

requires an interdisciplinary approach including basic,

translational and applied medical research.

Patient problems, new technologies and societal developments

continuously raise new research questions. Our

coherent, interdisciplinary research strategy enables us to

answer these research questions and discover meaningful

outcomes for patients, their families and society. Therefore, all

of our scientists and professionals who are involved in the care

of our sick children, collaborate closely and share the same

ambition to find the best solutions for our young patients. In

addition, we’re dedicated to communicating our findings to

our patients, relatives and the public; there is clear value in

collecting feedback and properly evaluating our research as

these will inevitably lead to new research questions. It is

through this innovation loop that societal issues are considered

when defining research directions, and where we can

accelerate scientific results quickly from bench to bedside.

I am daily impressed


by

the talent of the people

who already work and

study at these

organizations. We must

ensure that they can

thrive and contribute to

solving the social

problems that our

world faces.

- Professor Anton Pijpers,

President Utrecht University

3. Physical – mental interaction

Physical restrictions in childhood can have profound

influence on the psychosocial development and identity

formation in adulthood. Pain and discomfort in early life

can affect basic trust in children. Deprivation from

parents, families and friends during early life might

influence social adaptations. Absence from school and

inability to participate in sports might have a negative

impact on the development of resilience in adolescence.

It’s not enough to only pay attention to the physical

health of children. On the other hand, psychological

problems during childhood can have major adverse

effects on medical treatment and the course of a disease.

For example, denial of symptoms and poor adherence to

therapy can highly influence outcome of chronic diseases.

Therefore, we pay particular attention to the development

of children with chronic diseases and study determinants

of, for example, pain and fatigue at both the basic science

and clinical care levels. This can help to develop and

evaluate intervention programs. Our ultimate goal in this

strategic theme is to empower and to engage children

and their relatives to be fit for their future.

Health and happiness are broad concepts. Chronically

ill children indicate that they feel happy too though

they are ill. By support from the environment and the feeling

just to be able to participate, at school and at


home.

- Jan van Zanen, mayor of Utrecht

UMC Utrecht - Child research 9


ANTE- AND PERINATAL DAMAGE

Reproductive care

before, during and after birth

kbloemen@umcutrecht.nl mbekker3@umcutrecht.nl

Mireille Bekker, MD, PhD

is a maternal fetal medicine

specialist with an interest in

fetal medicine, counseling,

patient empowerment and

eHealth in obstetric care. She’s

a member of the board of the

national NIPT consortium that

performs nationwide implementation

studies (Trials by

Dutch laboratories for

Evaluation of Non-Invasive

Prenatal Testing). Mireille is the

project leader of several

research projects regarding

home telemonitoring and

other eHealth strategies in

obstetric health care.

Kitty Bloemenkamp. MD,

PhD is and has been a PI of

several randomized controlled

trials, observational studies

and experimental studies in

the field of maternal health.

She is the Chairman of Nethoss

(Netherlands Obstetric Survey

Study), National Enquiry of

Maternal Death Review,

Netherlands and of INOSS

(International Network of

Obstetric Survey Systems).

Improving the health of women and

children is a global public health issue.

This mission was adopted by all United

Nations Member States in 2015 and

addresses sustainable development to

ensure healthy lives and promote wellbeing

at all ages.

In this research area of Child Health, we focus on reproductive,

maternal, newborn and child health. More specifically, we develop

novel clinical strategies to innovate and improve the quality of care for

the mother, fetus and child by integrating research with clinical care.

This includes translational research, advanced imaging technologies,

creating and integrating patient registries, diagnosis accompanied by

genetic testing, eHealth, auditing to evaluate impact and value-based

health care approaches. This is done in close collaboration with our

colleagues in the fields of fertility, gynaecology and neonatology.

In this way we investigate the entire lifecycle from preconception and

complicated pregnancy to delivery, postpartum and consequences of

these complications later in life.

eHealth and high-risk pregnancy

eHealth converges healthcare and technology, and is allowing our

patients to actively participate in their own healthcare regimens. It also

provides our physicians up-to-date information about our patients, in

real-time, making diagnosis and treatment more efficient and

accurate. And with the availability of mobile phones and internetbased

applications, we can reach women and their babies in

improverished areas.

We often use eHealth methods in our research and care, and to share

our findings. For example, women with high-risk pregnancies need to

visit the hospital frequently, which may become burdensome on both

the mother and unborn child. We’re currently running two studies,

Safe@home and HOTEL, using smart telemonitoring systems. In the

SAFE@home study, we monitor pregnant women at home for high-risk

factors, for example high blood pressure and diabetes, reducing the

number of visits they need to make to the doctor. In the HOTEL study,

the fetal condition is monitored at home by a fetal cardiotocography

device instead of hospital admission or daily visits.

10 UMC Utrecht - Child research


ANTE- AND PERINATAL DAMAGE

Life

starts

in the

uterus.

- Mireille Bekker


Empowering women and their doctors

Through previous eHealth studies on maternal health, we’ve

discovered a need for reliable registration methods and audit

processes for maternal and neonatal mortality. In addition, morbidity

must be recorded in order to assess strategies on improving health

conditions for women and their babies. Our goal is to translate our

findings, as well as eHealth technologies, to help women, and their

doctors monitor their pregnancies outside of the hospital in low to

middle income countries. We aim to improve the quality of care for

women and their families, and empower them through novel

healthcare systems.


When you save

the mother, you

save the family.

- Kitty Bloemenkamp

UMC Utrecht - Child research 11


Building better brains

Improvements in fetal and neonatal care

have significantly reduced mortality in

preterm infants and critically ill term infants.

Unfortunately, half of the infants admitted to

the neonatal intensive care unit (NICU)

experience long-term neurodevelopmental

problems, including cognitive deficits, motor

disabilities and psychiatric diseases. This

creates a lifelong burden, both socially and

financially, for the affected individuals and

their families.

We’re on a mission to “build better brains”

for vulnerable infants. Adverse early life events

such as preterm birth, neonatal cardiac and

non-cardiac surgery and hypoxic-ischemic

encephalopathy can have a profound effect on

brain development. Our neonatal neurology

research group studies these events in relation to

the developing infant brain by combining

routine clinical neuroimaging (ultrasound and

MRI), neuromonitoring (aEEG and NIRS) and

neurodevelopmental follow-up.

Babies get stressed too

Premature infants are suddenly thrust into the

bleak and sterile environment of the NICU and

expected to thrive. During this period, exposure

to stressful stimuli causes significant

neurobiological changes affecting brain volume,

DNA methylation and the hypothalamicpituitary-adrenal-axis.

We’re investigating the

effects of early stress on brain development and

are optimizing neonatal care by enriching the

extra-uterine environment and increasing

parental involvement. Together with our national

(Hippo-trial) and international research partners

(University of Leuven, Kings College London,

SickKids Toronto), we’re investigating how stress,

such as painful procedures, and stress relievers,

such as skin-to-skin care and sleep, can influence

brain connectivity in order alleviate the

harshness of premature birth and to further

improve our care.

Good sleep, healthy brains

When babies sleep, their brains are actively

developing. A preterm newborn spends most of

his or her time in ‘active sleep’ (REM sleep),

which coincides with heightened synaptogenesis

and brain plasticity. It’s difficult to

visually recognize sleep stages in preterm

infants. However, to optimize sleep (and to set

up intervention studies) we’re studying ways to

automatically detect sleep stages. To do this,

we’re using deep learning algorithms to

recognize neonatal sleep stages based on

monitor values. And together with two technical

Universities (Delft and Eindhoven) we’re developing

advanced wireless biomedical sensors

(e.g. low frequency radar devices) to record

sleep stages.

Personalizing treatment

Within our team, we’ve improved current

neuroprotective treatments. One example is

therapeutic hypothermia for infants with

hypoxic-ischemic encephalopathy, and we’re

optimizing patient selection for this treatment

by studying pharmacokinetics of neurotropic

medication. Additional therapies are also

explored (Benders).

The foundation for optimal brain development

starts peri-conceptionally and lasts well beyond

the teenage years. This calls for an interdisciplinary

approach and together with our

national and international colleagues, we’re

improving the long-term neurodevelopmental

outcome for infants with challenges in longterm

brain development. We’re proud that our

investigations can contribute to new European

standards of care (e.g. ENCFI standards) and we

benchmark our outcome using the International

Consortium for Health Outcomes Measurements

(ICHOM) standards.


Floris Groenendaal,

MD, PhD is a neonatologist

whose goal is to improve

diagnostics of early brain

injury, using MRI/MRS and

aEEG. In collaboration with

the Laboratory of

Neuro-immunology and

Develop-mental Origins of

Disease, UMC Utrecht, he’s

explored novel neuroprotective

strategies. Floris

introduced therapeutic

hypothermia in The

Netherlands, and performed

pharmacokinetics during

cooling.

Jeroen Dudink, MD, PhD

is a neonatologist with

expertise in neonatal

neuroimaging. He studies

the relation between

neonatal sleep and early

brain development. Together

with technical Universities

and commercial partners, he

develops new devices to

automatically recognize

sleep stages. Furthermore,

Jeroen studies the relation

between neonatal cerebellar

injury and long-term

outcome.

Better baby brains -

the challenge goes on.

- Floris Groenendaal

fgroenen@umcutrecht.nl

jdudink@umcutrecht.nl

12 UMC Utrecht - Child research


ANTE- AND PERINATAL DAMAGE

A brighter future for

high-risk neonates

mbenders@umcutrecht.nl

Manon Benders, MD,

PhD focuses on neonatal

imaging of brain

development and predicting

outcome. She also

investigates neuroprotective

and neuro-regenerative

strategies to reduce

brain injury.

The early years – starting from prebirth

– is a critical period in a child’s

development, as they form bonds with

their parents, develop language skills

and other cognitive functions, and

establish behavioral patterns. Given the

strong link between perinatal

complications and adverse adolescent

outcomes, we focus on developing

interventions that may prevent, or at

least reduce, perinatal life adversities.

We have an outstanding Neonatal

Neurology team that specializes in the

development of objective biological

measures in the developing brain in

relation to long-term outcome (lifespan

approach). We’ve established an

integrated approach to study this, and

by combining basic and translational

developmental neuroscience, neuromonitoring

and MRI analysis, we’ve

developed perinatal neuro-protective

and neural rescue strategies for the

human fetus and infants. Because of our

strong collaborative approach, we’ve

became an internationally recognized

center of expertise by the Committee of

Rare Diseases of the National Federation

of University Hospitals in the Netherlands

and are part of the EpiCARE, a European

Research Network for rare and complex

epilepsies.

CRUCIAL clinical trial

There is an urgent need for

neuroprotective strategies for infants

with congenital heart disease (CHD) as

they often experience long-term

neurodevelopmental impairments.

Perinatal

improvement

is multiplying

health gain

later on.

- Manon Benders

To investigate this, we recently launched a

multicenter CRUCIAL-trial (CeRebrUm and

Cardiac protection with Allopurinol) in

neonates with CHD who require cardiac

surgery with cardiopulmonary bypass.

We’re investigating the effects of postnatal

and perioperative allopurinol

administration on postoperative brain

injury in CHD neonates. Patients will be

screened using fetal MRI and included

before birth, requiring extensive

collaboration with obstetricians,

neonatologists, cardiologists, pediatric

intensivists and pediatric thoracic

surgeons. Our primary outcome is based

on fetal, postnatal and post-operative MRI

analysis in close collaboration with

quantitative MRI analysts at the Image

Sciences Institute, UMC Utrecht. Longterm

outcome is a secondary objective of

this study, evaluated by psychologists and

occupational therapists, for which we

collaborate with pediatric rehabilitation

and psychiatry. Additional therapies are

also explored within our team

(Dudink and Groenendaal).

In addition to our goals of improving

long-term outcome in high-risk neonates,

we subscribe to the philosophy of open

science. Through the YOUth study

(uu.nl/youthcohort), a large longitudinal

cohort study that collects information

about brain and behavioral development,

we’re able to broadly share anonymous

information about our healthy and highrisk

neonates.

Big Data for small Babies

Premature babies admitted to the

neonatology intensive care unit are closely

monitored as they are susceptible to

infection. Over the past decade, we’ve

collected a vast amount of data and a

group led by Daniel Vijlbrief, PhD, uses

machine learning on this data in order to

improve diagnosis and treatment options

regarding sepsis for preterm babies.

Preparing our future talent

Within our team, we have a culture of

collaboration and this extends to young

clinicians and researchers with high

potential. They have opportunities to learn

and train through our educational

programs and to contribute to our overall

societal impact through our outreach

activities. Our multidisciplinary approach

will lead to earlier diagnosis, tailored

treatments and enable us to create new

and better interventions to transform

children’s lives.

UMC Utrecht - Child research 13


Protecting

fertilityFor many,

parent is one of the happiest

days in life. Unfortunately,

1 in 6 couples who want to

conceive, fail to do so. This

infertility has many different

causes and we focus on

reduced ovarian reserve

and late effects of childhood

cancer treatment.

becoming a


Helen Torrance and Frank Broekmans

work at the Center for Reproductive

Medicine which is an international

and national expert center and global

leader in the field of reproduction.

Both care and research are aimed at

optimizing the chances of a healthy

conception and thereby the chances

of a healthy child.

14 UMC Utrecht - Child research


ANTE- AND PERINATAL DAMAGE

Helen Torrance MD,

PhD specializes in

reproductive medicine.

She combines clinical

and scientific research

related to fertility.

Her current interests

include future fertility

for children with

chronic disease and

optimizing successful

implantation.

htorranc@umcutrecht.nl

Changing IVF protocols

Ovarian ageing and reduced ovarian reserve have been a main topic of

research at the Center for Reproductive Medicine for more than 20 years,

and we’ve answered many diagnostic, prognostic, etiologic and therapeutic

questions. One of our most recent multicenter randomized controlled trials

studied the efficacy of individual hormonal treatment for IVF. We

demonstrated that high doses of hormones in women with a reduced

ovarian reserve actually do not increase her chances of having a baby.

Our findings have helped change long-standing IVF practice in which

high-dose hormones were prescribed for infertility. This is especially

important as there are concerns that IVF impacts the long-term health of the

children conceived through this technique. Although still unclear,

high hormone doses may be a causal factor.

Caring for the entire reproductive life cycle

Ovarian ageing can have a clear cause, be idiopathically or be iatrogenically

caused by, for example, cancer treatment. We collaborate with the Princess

Maxima Center to provide both care and research for children with cancer,

focusing on early fertility counselling and fertility preservation.

can be devastating.

We’re Infertility

improving care for these

patients so more people can enjoy

the exceptional path of parenthood.

- Helen Torrance

This type of lifecycle medicine and care is also important for children with

other childhood diseases that used to be lethal but are now considered

chronic diseases. These children need follow-up care directly related to their

condition and sadly, disease progression and exposure to medication during

childhood and adolescence may affect their reproductive system.

More research into current and future fertility of these patients is needed.

Mapping out infertility

If patients have concerns about future fertility, then fertility counselling and

fertility preservation should be offered to all individuals at risk as becoming

a parent may significantly contribute to a long-term improved quality of life.

From 2019 onwards, we expect to complement existing long-term child

health follow-up databases with fertility parameters so that early

determinants can be connected to late fertility outcome. Our team will start

by including girls with chronic hematologic conditions (for example,

Diamond Blackfan anemia, sickle cell anemia or thalassemia; in collaboration

with the department of haematology (Bartels) and will then extend this

concept to other childhood diseases.

Frank Broekmans

MD, PhD is devoted to

the mysteries behind

ageing ovaries. He

focuses on assessing

fertility in childhood

disease survivors with

the goal of preventing

early life onset genetic

disease. His group

conducts Preimplantation

Genetic Diagnostic

testing of embryos

created by Assisted

Reproductive

Technology.

fbroekma@umcutrecht.nl

time to be proactive - to provide

preventative It’s

care for infertility and

to avoid reproductive consequences

of childhood disease. - Frank Broekmans

UMC Utrecht - Child research 15


CONGENITAL AND HEREDITARY DISORDERS

ghaaften@umcutrecht.nl

Finding genetic

variations


Your DNA

at the

center of

care.

- Hans Kristian

Ploos van Amstel

Gijs van Haaften,

PhD focuses on

understanding

the genetics and

biology of monogenic

disorders, with

a focus on metabolic,

craniofacial and

cardiac disorders.

Genetic testing can identify

aberrations and changes in our

genetic information. This can

help confirm or rule out

suspected genetic diseases, it

can identify hereditary genetic

conditions and determine

whether an unborn infant has

a certain disorder. With the

event of advanced genome

sequencing technologies,

genetic testing is becoming

more routine in medical care.

The Department of Genetics within the

Child Health Program focuses on

developing technologies for genetic

diseases, in particular, on genome-wide

detection of genetic variations. We aim to

establish the relationship between

clinical presentation, gene expression

and protein function of both morbid

genes (genes that are causally linked to

disease) and candidate morbid genes.

To address this, two national cooperative

studies have been initiated and Hans

Kristiaan Ploos van Amstel leads the

diagnostic lab.

WGS-based approach to

understanding genetic diseases

Whole genome sequencing (WGS)

can identify almost all disease-causing

mutations and has broad applicability in

diagnostics, treatment and drug response.

It has been therefore hypothesized

whether a “one-test-fits-all” could be

implemented to diagnose rare genetic

disorders. This would increase diagnostic

yield in a shortened time frame, reduce

complexity and costs, result in early access

to personalized patient care and reduce

co-morbidity and mortality. We’re

currently performing a study with patients

from the neonatal intensive care unit and

with neurodevelopmental disorders.

A new blood test for prenatal

genetic diagnosis

Our second study is in collaboration with

Wouter de Laat, PhD at the Hubrecht

Institute. Together, we’ve developed

a Monogenic Non-Invasive Prenatal

Diagnosis (MG-NIPD), a new highly

sensitive blood test, to detect

monogenetic disorders during the early

stages (8-10 weeks) of pregnancy.

MG-NIPD can detect genetic diseases

that have a small genetic variation, and

may replace traditional, more invasive

methods such as amniocentesis and

chronic villus sampling. We’re currently

validating and optimizing the MG-NIPD

in at-risk families as a safe and reliable

alternative for prenatal diagnosis.

Understanding the biology of

genetic disease

For many genetic diseases, the precise

genetic cause is not understood, and by

studying genes and their functions in

human health and disease, we gain

insights into patient care and novel

biological processes. We focus on the

biology and genetics of rare diseases,

with a particular interest in metabolic,

craniofacial and cardiac anomalies;

this area of investigation is led by

Gijs van Haaften.

A recent example is the discovery that

germline mutations in histone H4 cause

a developmental syndrome by altering

DNA damage response and cell cycle

control. We model patient mutations to

study effects on gene and protein

function, and use several approaches

including patient cells, cell lines in

which we introduce the patient-specific

mutated allele and the zebrafish

developmental model.

We recently described a method to

engineer the zebrafish genome at the

single nucleotide level, using the geneediting

technology CRISPR/Cas9 in

combination with homology-directed

repair. This allows us to generate precise

models for human genetic disorders.

We’re currently investigating whether

certain therapies can reverse

cardiovascular defects with the goal of

translating our findings to patients

in the future.

jploos@umcutrecht.nl

Hans Kristian

Ploos van Amstel,

PhD focuses his

research on impro -

ving detection and

interpretation of

genomic variations

and on identifying

disease genes.

He strives to

diagnosis, prognosis

and treatment. He is

chair of the Dutch

Society for Clinical

Genetic Laboratory

Diagnostics (VKGL).

16 UMC Utrecht - Child research


CONGENITAL AND HEREDITARY DISORDERS

truly connected

interdisciplinary

Our

network

enables swift transition

from bedside to bench

and back, directly

supporting improvement

of care for vulnerable

patients.

- Marc Lilien

Kidney

and Urinary tract

An end stage renal disease patient is

referred to the outpatient clinic for

hereditary renal disease: The patient is

diagnosed with an autosomal dominant

renal disease. Recently, his first child was

born with an autosomal dominant renal

disease. This does not recur in a kidney

graft. His eldest (at 50% risk) was

subsequently evaluated at the pediatric

hereditary renal disease outpatient clinic.

Wishing to further establish their family,

the couple was informed about their

options and chose to try to conceive using

preimplantation genetic diagnosis.

aeerde@umcutrecht.nl

mlilien@umcutrecht.nl

Albertien van Eerde

MD, PhD is clinical

geneticist at the UMC

Utrecht who specializes

in nephrogenetics. She’s

the coordinator of the

Expert Center for

Hereditary and Congenital

Renal and Urinary

Tract Disorders, which is

accredited both

nationally and by the EU

(through ERKNET).

Marc Lilien MD,

PhD is a pediatric

nephrologist at the

Wilhelmina Children’s

Hospital and has

expertise in renal

ciliopathies and renal

tuberous sclerosis

phenotypes.

Our research in the kidney and urinary tract

focuses on clinical expertise in the nationally

accredited Center of Expertise for Hereditary and

Congenital Nephrologic and Urologic Disorders.

The Expert Center ensures optimal care and

research for families with renal disease and spans

infancy to adulthood, including preconception

and prenatal care. It encompasses (pediatric)

nephrology, (pediatric) urology, clinical and

laboratory genetics, obstetrics, nephropathology,

radiology, and we participate in ERKnet:

the European Reference Network for Rare

Kidney Disease.

The case above is a good clinical example of the

interdisciplinary nature of our work. When a

diagnosis is challenging or undetermined, we

incorporate genetic testing and functional follow

up. This has proven effective for the ITGA3 gene.

For insights into cystinosis-related phenotypes,

we collaborate with Roos Masereeuw, PhD at

Utrecht University who is an expert on how

pharmacologics affect molecular pathways, and

to further investigations into new candidate

genes we collaborate with the Antignac’s group

in Paris.

We also perform cohort-based research. Albertien

has shown that NPHP1 gene deletions can cause

adult renal disease, which comprises about 0.5%

of adult end stage renal disease at all ages. This

challenges the paradigm that nephronophthisis is

primarily a pediatric renal disease, and has

consequences for follow up into adulthood and

kidney donation, especially by siblings. We both

actively participate in the AGORA cohort (for

example, patients with congenital anomalies of

the kidney and urinary tract and renal ciliopathies).

Marc has recently published a detailed overview

of renal ciliopathy phenotypes, and steps towards

early biomarkers.

With a recently acquired Dutch Kidney Foundation

grant, Albertien will further establish a registry of

patients with rare renal diseases, and will build a

Kidney Gene Regulatory Network. We both also

want to further the understanding of “renal

sensitivity”: What drives the variability in severity

in patients with similar genetic predisposition or

toxic exposure.

Genetic diagnoses have an effect in the full circle

of life. And they are too often missed, especially in

adult nephrology. Together, our research activities

create synergy and we’re able to create impact for

instance, by developing informational material

(like online movies) for patients, by conceiving a

national guideline for genetic testing in (pediatric)

nephrology and by teaching pediatricians,

nephrologists and geneticists, nationally and

internationally. We often work together with the

Dutch Kidney Patient Association.

UMC Utrecht - Child research 17


Congenital and genetic

heart disorders

Roughly 1 in 100 children

have a congenital cardiac

abnormality and about 1

in 200 individuals have a

gene mutation predisposing

him or her to an inherited

cardiac disorder including

a cardiomyopathy or

arrhythmia syndrome.

More and more genes and

mutations underlying these

different cardiac disorders

have been identified. Our

departments of Genetics

and Pediatric Cardiology

are focused on elucidating

these genetic defects and

our discoveries advance

both patient and family

care, as well as research.

Congenital heart

defects have the

highest prevalence

of all congenital

defects.

- Hans Breur


hbreur@umcutrecht.nl

Hans Breur MD, PhD

Pediatric cardiologist is

one of the founders of

the Congenital Heart

Disease LifeSpan

Program in which all

patients with severe

congenital heart disease

undergo extensive and

lifelong cardiac and

neurocognitive

follow-up, and where

interventions are

developed to improve

outcome.

In patient and family care, the results of a

genetic test can be used for genetic

counseling as it provides important

information on inheritance patterns and

aids with determining recurrence risk

with a potential for prenatal diagnostics.

In cases of a late onset autosomal

dominantly inherited disease,

presymptomatic genetic testing

(where a genetic mutation may be

detected before an individual presents

with clinical symptoms) in family

members can be facilitated with these

genetic discoveries. Given the autosomal

inheritance, this may lead to 50% fewer

family members who require follow-up

by a cardiologist.

Unfortunately, clinical variability is still

poorly understood: Individuals with an

identical mutation can be symptomless

for decades while close family members

may encounter signs of the disease at an

early age. And we still don’t know which

factors contribute to disease

development at what phase in life. Our

researchers and clinicians collaborate

with several patient organizations and

together, we’re identifying factors that

influence the development and

progression of these disorders. From this,

we can better determine risk and develop

personalized treatments. In our

diagnostic and therapeutic work-up we

use cutting edge imaging techniques like

3-D rotational angiography.

Organizing our data

In the Netherlands we closely collaborate

with all other centers involved in

Congenital and Cardiogenetic Disease

within the Dutch National Working Group

on cardiogenetic diseases.

Within this multidisciplinary network of

clinical and molecular geneticists,

cardiologists, pediatric cardiologists and

pathologists, we aim to improve

diagnostics and care for these patients.

We’ve initiated several large-scale patient

registries, including the national

18 UMC Utrecht - Child research


CONGENITAL AND HEREDITARY DISORDERS

jtintel3@umcutrecht.nl

Peter van Tintelen,

MD, PhD

Chair, Department of

Genetics

is a clinical geneticist

who set up cardiogenetics

research at

the UMC Groningen. In

2018, he returned to

Utrecht to become

Chair of the Department

of Genetics. The

main focus of his

research is understanding

clinical variability

in inherited cardiac

disease.

The worldwide impact

of congenital heart disease is

greater than cancer when

looking at years lost to disability.

Arrhythmogenic Cardiomyopathy Registry

(www.acmregistry.nl) which contains data

from over 1000 patients and family

members, and the PLN Cardiomyopathy

Registry, which has enrolled over 800

patients who carry an identical mutation.

Using these data, we’re able to improve

risk prediction for patients and

their families.

Lifelong care for our patients

All patients with a severe congenital

heart defect enroll in our Congenital

Heart Disease Life Span Program. In this

program, life-long structured cardiac

and neurocognitive follow-up starting

from pre-natal diagnosis onwards, is

combined with an extensive research

program including blood and tissue

biobanking for all patients. A stateof-the-art

pipeline including whole

One in 250 children have a

mutation predisposing for

an inherited cardiomyopathy

or arrhythmia syndrome.

- Peter van Tintelen

genome sequencing and zebrafish

modeling (together with the Hubrecht

institute) allows us to study the origin of

congenital heart disease. Patients with

inherited cardiomyopathies and

arrhythmias enroll in our multidisciplinary

life cycle follow-up, where families are

counselled and treated by both the adult

and pediatric cardiologists as well as a

clinical geneticist.

With current excellent survival rates,

our focus needs to shift from mortality

to quality of life.

- Hans Breur

UMC Utrecht - Child research 19


Better care for the rare

Gastroenterology - Hepatology - Metabolic Diseases

Metabolic diseases comprise a group of more than 1000 rare genetic diseases in which

a metabolic pathway is perturbed. These conditions often have devastating

consequences for patients and their families, and may involve a diagnostic odyssey,

prognostic uncertainty and absence of treatment options. Our multidisciplinary

research, in which laboratory and clinical scientists closely collaborate, aims to increase

knowledge on these diseases in a number of ways.


Let’s make use of

the unprecedented

technological possibilities

to improve

patient care in

terms of diagnostics

and (personalized)

therapies.

- Sabine Fuchs

Disease discovery

In undiagnosed patients with a

metabolic phenotype, whole exome

sequencing, metabolomics and deep

phenotyping are combined to elucidate

existing and new defects. When we find

a candidate gene with related changes in

the metabolome or phenotype of a

patient, we perform functional studies in

cells or organoids from the patient or

after CRISPR-Cas9 gene-editing or in

animal models like the zebrafish to

identify and characterize new genetic

metabolic diseases. In recent years, we

have collaboratively described two new

defects in the malate aspartate shuttle,

two defects in glutamate metabolism

and a defect in ketone utilization.

This approach has also elucidated 8

inborn errors outside the classical

boundaries of metabolism (STX3,

NSMCE3, UNC13A, ANKZF1, PET117

(complex iv), KIAA1109, TRAPPC2L,

SMARCC2). In all families involved, these

discoveries have led to long-awaited

diagnoses and prenatal screening

possibilities, and in some, to successful

treatment of affected children.

Pathogenesis of disease

We focus on defects in vitamin B6 and

amino acid metabolism. To pave the way

for better treatments, our team

investigates pathogenic mechanisms in

these defects making use of deep

phenotyping, metabolomics and model

systems. We’ve published a zebrafish

model of pyridoxine dependent epilepsy,

a mouse model of pyridoxal phosphatase

deficiency and a new cause of vitamin

B6-dependent epilepsy: pyridoxal

phosphate binding protein deficiency.

Similarly, these strategies have

contributed to the discernment and

publishing of a common clinical

phenotype for amino acid tRNAsynthetase

deficiencies, putatively based

on a common disease mechanism.

Follow-up of treatment

Patients with lysosomal storage disease

can be treated with stem cell therapy.

Although this can be successful, residual

disease is substantial. To address this, we

make use of a unique standardized

multidisciplinary follow-up facility

(Sylvia Toth Center; also used for deepphenotyping)

to investigate the natural

history of these diseases, and clinical and

biochemical follow-up of patients who

have been transplanted. Examples of

novel biochemical markers include the

analysis of iduronidase in blood spots

and saliva, analysis of glycosaminoglycans

in tear drops by mass spectrometry and

analysis of vacuoles in lymphocytes as a

marker for neuronal ceroid lipofuscinosis.

Organoid research

In close collaboration with groups at the

Hubrecht Institute, we generate liver and

intestinal organoids from patient-derived

adult stem cells. These organoids

represent a unique patient-specific in

vitro model that we use to elucidate

disease mechanisms, develop novel

therapeutic strategies (including

organoid transplantations) and test these

strategies in a personalized manner.

This led to the identification of novel

causes of secretory diarrhea (due to

deficiencies of STX3 and DGAT1).

Furthermore, we’re in the process of

evaluating small molecule therapy for

genetic cholestatic diseases, such as

progressive familial intrahepatic cholestasis.

20 UMC Utrecht - Child research


CONGENITAL AND HEREDITARY DISORDERS

nverhoev@umcutrecht.nl

Nanda Verhoeven

PhD has a special

interest in disorders

of vitamin B6 and amino

acid metabolism and

the discovery of new

diseases in this area.

Nanda is Head Laboratory

Metabolic Diseases.

sfuchs@umcutrecht.nl

Sabine Fuchs MD,

PhD is a pediatrician in

metabolic diseases,

pharmacist and basic

scientist with a lab in

the Hubrecht institute,

with the aim to improve

care for patients with

metabolic/liver diseases

by unraveling disease

mechanisms (in patient

derived organoids) to

develop and test novel

treatment strategies,

including liver stem cell

transplantations.

phassel2@umcutrecht.nl

Peter van Hasselt MD,

PhD focuses on translational

research aimed at

creating 'better care for

the rare' by 1) elucidating

the genetic cause; 2)

describing effects of

treatment on the natural

disease course; 3)

improving early recognition

and/or preventive

measures; and 4)

creating novel diseaseseverity

markers.

jjans@umcutrecht.nl

Judith Jans PhD

focuses on the development

and introduction of

untargeted metabolomics

in diagnostics to

elucidate novel genetic

metabolic diseases and

improve current

diagnostic practice. She

aspires to fully integrate

genomics and metabolomics

data to advance

patient care.


Ask yourself how the present

situation compares to your ideal

situation, and how it helps you

see how to decrease the gap.

- Peter van Hasselt


A solid diagnosis

is the foundation

on which care and

treatment can

be built.

- Nanda Verhoeven

In our labs, technology development is a

driving force for the above-mentioned

projects. We’ve developed a direct

infusion high-resolution mass spectrometric

pipeline for untargeted metabolomics.

We’ve validated this approach

in blood spots and plasma from a number

of patients with known genetic metabolic

diseases and demonstrated that this

method is capable of correctly

establishing diagnoses. This approach is

promising for disease discovery,

identification of biomarkers and for

research on pathogenic processes. In

addition, we employ frontline geneediting,

organoid technologies and

animal models for in vitro modeling. The

strong clinical embedding, with an

interest in patients with novel genetic

metabolic defects, deep phenotyping

and use of the human phenotype

ontology informs our research on the

clinical presentation and natural course

of known and novel disease entities.

In the Netherlands, we collaborate with

the five other University Medical Centers

in a national initiative, United for

Metabolic Diseases. This multidisciplinary

consortium consists of pediatricians,

internists, clinical geneticists, laboratory

specialists and scientists in the field of

genetic metabolic disease and patient

organizations. We aim to improve

registration, education, technology and

e-health and to find a diagnosis for 500

undiagnosed patients, both children and

adults, by combining multi-omics

technologies and bioinformatics. The

first patients were included in

March/May 2019.


Significant

advances in

diagnostics can

be made when

we successfully

combine the

diverse strengths

of metabolomics

and genomics.

- Judith Jans

UMC Utrecht - Child research 21


SEVERE INFLAMMATORY DISORDERS

Cystic Fibrosis:

personalized treatment

for all patients


We are honored to be

selected to participate in the

HIT-CF Europe consortium and

join forces with key thought

leaders to explore the potential of

a personalized medicine

approach as a possible new

frontier for CF therapy.

- Meenu Chhabra, President and Chief

Executive Officer of Proteostasis

22 UMC Utrecht - Child research


SEVERE INFLAMMATORY DISORDERS

The UMC Utrecht hosts the largest

expertise center for Cystic Fibrosis (CF) in

the Netherlands, giving care to about onethird

of more than 1500 Dutch CF

patients. Our multidisciplinary team, led

by Kors van der Ent, MD (pediatric

pulmonologist) and Harry Heijerman, MD,

PhD (adult pulmonologist) covers the

entire spectrum of care from heel prick

screening to lung transplantation. In

addition, we have our own clinical research

team, which supports investigator-driven

and pharmaceutical-driven clinical trials.

These trials have focused on treatment of

pulmonary inflammation and infection

(microbiome studies) and on the effects

of CFTR-modulators.

Chloride Concentration and intestinal current

measurements.

Organoids in drug discovery

Preclinically, organoids are used to identify and

develop CFTR-modulating drugs and to explore

mechanisms associated with differences in CFTR

function. Pharmaceutical companies use intestinal

organoids in their drug development pipeline

and initial high-throughput-screening has

resulted in the discovery of different chemical

structures as potential CFTR-modulating drugs.

Organoids are used to test both the potency of

single drugs and to compare the efficacy of

combination treatments. Our group also

highlighted the translational potential of

organoids, demonstrating that genotype-specific

effects of CFTR-modulators correlate with clinical

trial data at group level.

Our CF Center leads the cystic fibrosis core

network of the European Reference Network

LUNG (ERN-LUNG), a network of European

healthcare providers dedicated to ensuring and

promoting excellence in care and research for the

benefit of patients affected by rare respiratory

diseases. We’re also a member of the Clinical Trial

Network of the European CF Society, and have

participated in the European CF Patient Registry

for more than 10 years, enabling quality control

and studying long-term patient outcomes.

A formal collaboration agreement between the

UMC Utrecht and the Dutch CF Patient

organization was signed in 2016 and joint

initiatives between patients and caregivers have

been developed.

Organoid technology

Our CF Center Utrecht has its own research lab

headed by Jeffrey Beekman, PhD, and the close

collaboration between basic science and clinical

care in Utrecht has led to a highly translational

research profile. His research group developed an

adult stem cell-based culture and assay

technology (organoids) to model human

pulmonary disease and in particular, CF.

Organoids are three-dimensional, multi-cellular

structures that recapitulate tissue features of the

parental organ and are usually grown from donor

tissue fragments. As organoids are functional

expressions of individual genomes, they’re

particularly useful for understanding how genetic

factors contribute to individual disease. Intestinal

organoids have been at the forefront of these

developments as culture methodology was first

developed for this tissue source. For CF, human

intestinal organoids can be grown from intestinal

crypt fragments isolated from rectal biopsies.

We’ve shown that organoid measurements reflect

residual CFTR function and correlate with

predicted severity of the CF genotype and other

biomarkers of CFTR function, including Sweat

Promising drug treatments for CF

Recent proof-of-concept in two patients with

ultra-rare mutations showed clear in vitro-in vivo

correlation in response to treatment with the drug

ivacaftor. A subsequent study found that intestinal

organoid measurements with the drugs curcumin,

genistein, ivacaftor and lumacaftor/ivacaftor

correlated with in vivo responses in pulmonary

function and sweat chloride concentrations on the

individual level. These techniques have

revolutionized CF care, especially in patients with

ultra-rare mutations. New mutation class-specific

drugs are currently only being tested in patients

with well-described, very common mutations.

As a result, market authorization and

reimbursement of these drugs is only granted in

these specific subsets of patients. Nevertheless,

other patients with less common mutations might

also benefit from them.

Using organoids to predict

treatment response

In our group, Kors coordinates an EU-funded

consortium study (www.HITCF.org) which aims to

develop a path for access to therapies for

individual patients or patient groups who show

positive response to the therapy in an organoid

test, and to pave the way for organoid-based

personalized medicine. Our organoid studies in

CF focus on pre-treatment selection of patients

with ultra-rare CFTR-variants and biopsies of

patients with ultra-rare CFTR mutations are

collected all over Europe and bio-banked in

Utrecht. Currently four pharmaceutical companies

deliver their lead CFTR-modulating compounds

for screening and ultimately clinical trials in

pre-selected patient groups are foreseen, in close

collaboration with the European Medical Agency

and MoCA (Mechanisms of Coordinated Access

to Orphan Medicinal Products).

cent@umcutrecht.nl

jbeekman@umcutrecht.nl

Kors van der Ent,

MD, PhD initiated the

CF-Center Utrecht in

1997. He is a co-developer

of the Utrecht

organoid model for CF.

Kors is coordinator of

the H2020 HIT-CF

program and core

network leader for CF

in the European

Reference Network

(ERN-LUNG).

Jeffrey Beekman,

PhD heads a research

program focused on

development of

personalized medicine

for CF. His work aims

to develop new

diagnostics and

therapeutics to enable

individually optimized

treatments.

UMC Utrecht - Child research 23


We are extremely excited to be

participating in the HIT-CF research

project, which has the potential to

lead to treatment options for many

CF patients, based on their


functional responses in the lab.

- Dr. Gregory Williams, Chief Operating Officer, Eloxx Pharmaceuticals

The patient not only

thinks along, but

decides. The patient

perspective must be

considered for care

and research.

What is important

for CF patients and

what research is

needed?

- Jacquelien Noordhoek, Director,

Dutch CF Foundation

Ethics

and innovation

are natural partners,

In fact, you would like

doctors and researchers to

always think about the ethical

and social impact of their

innovation at an early stage.


Patients can think along about the design

of the technology and become

co-designers.

- Annelien Bredenoord, Professor,

Ethics of Biomedical Innovation

My experience gave me new insights. For example, how important it is for doctors to express

their confidence in me as a parent. As a mother you are defeated and powerless, you dare not

attach yourself for fear of loss. It is also very supportive if the doctor fulfills the role of a mental

coach and encourages you. Parents must play a central role; parental love is the best medicine.

Benjamin is now eight years old. He is healthy and goes to school. I often drive past the

Wilhelmina Children's Hospital - and I always have a deep sense of gratitude.

- Anne Marie Louwerse, mother of Benjamin, who was born at barely 25 weeks.


~

24 UMC Utrecht - Child research


SEVERE INFLAMMATORY DISORDERS

Inflammatory

Bowel Disease

Inflammatory bowel disease (IBD) is a complex disorder associated with a

dysregulated immune response to environmental triggers in a genetically

susceptible host. The incidence of IBD is increasing around the world:

Approximately 25% of patients with IBD present before the age of 20, with an

annual pediatric incidence of 0.5 to 23/100,000 person-years in Northern and

Western Europe. The cause of this increase is poorly understood, but proposed to

include increased antibiotic use, changes in diet and the adoption of prepared

foods that include emulsifiers and surfactants, all of which contribute to

alterations in the gut microbiome.

Saskia van Mil,

PhD Associate

Professor

studies the roles

of microbiota, bile

acids and their

receptors in health

and chronic

infla-mmatory

diseases, e.g.

Inflammatory

Bowel Disease

and non- alcoholic

steatohepatitis.

smil2@umcutrecht.nl

Small bugs can make a big difference

In children with Crohn’s disease, exclusive

enteral nutrition is the therapy of choice for

remission induction with remission rates

comparable to steroids, indicating that nutrition

plays an important role in IBD activity. Even

though several dietary factors have been

implicated in the pathogenesis of IBD, their

relative importance and exact role is unknown.

Current research on the interactions between

food, microbiome and IBD are based on crosssectional

cohort studies, which do not catch the

changes in diet and microbiome prior to the

development of an IBD flare. In addition,

microbiome research has focused on the

difference in the microbial species between IBD

patients and controls, and in IBD patients in and

out of an inflammatory episode. The most

imminent questions that we are currently

investigating are: what are the metabolic

functions of these differentially present

microbes, how do those functions affect host

metabolism and IBD activity and what are the

effects of dietary changes?

Our research contributes to the cycle of life

theme of Child Health, by gaining a better

understanding of the nutrition-microbiome-bile

acid-host health axis, and pursuing development

of non-invasive biomarkers and novel therapies

for IBD.

acids act as

hormones Bile

and dictate

microbiome composition

and host metabolism.

- Saskia van Mil

25% IBD cases

diagnosed during

Childhood

A potential therapeutic target

In addition, our previous work has contributed

to our current knowledge on bile acids as a

treatment target for IBD. Bile acids activate the

bile acid receptor FXR, which regulates the fate

of dietary components; it also counteracts

inflammation and controls the composition and

abundance of gut bacteria. In IBD patients, the

expression and function of FXR is suppressed.

In collaboration with TES Pharma, we’re

developing tissue and gene-selective FXR

ligands for the treatment of IBD.

Up to 1 in 4 cases of IBD are

diagnosed during childhealth

6x

To develop

More

likely

Colorectal

cancer

IBD patients are six times

more likely to develop

colorectal cancer.

UMC Utrecht - Child research 25


RSV & Rotavirus:

so much in common

Translational

research is

needed to

improve the

health of

children.

- Louis Bont


lbont@umcutrecht.nl

Louis Bont, MD, PhD

has an interest in understanding,

preventing and treating

respiratory syncytial virus

(RSV) bronchiolitis. He was

one of the founders of the

TULIPS program, which

furthers the career of

multidisciplinary early stage

researchers in the field of

child health.

Infant mortality is a major global health threat and the most

prevalent clinical syndromes are diarrhea and respiratory

infection. According to a Global Burden of Diseases study

conducted by the Institute for Health Metrics and Evaluation

at Washington University, rotavirus and respiratory syncytial

virus (RSV) are the primary causes of infant diarrhea and

infection, respectively.

In a retrospective case series, we’ve demonstrated that indeed, most children

dying from an RSV infection are younger than 6 months of age. The World Health

Organization has prioritized vaccine development for rotavirus and RSV infections;

rotavirus vaccines have now been introduced and it’s expected that RSV vaccines will

soon follow.

RSV is the

second

cause of

death

during

infancy

worldwide

Within the Child Health Program, we also prioritize rotavirus and RSV, which have

much in common. Both are RNA viruses with exclusive tropism for the epithelium.

Although each virus itself is genetically diverse, it appears that, while genetic diversity

is needed to escape the immune system, it doesn’t contribute to disease severity.

Children with co-morbidities, such as preterm birth, have the highest risk of a severe

course of disease, including death.

Developing a vaccine is complicated

Viruses are excellent at evading our immune system, which makes developing an

effective vaccine challenging. An early formalin-inactivated RSV vaccine developed

the 1960s was a disappointment. Rather than prevent infection, it augmented RSV

disease in vaccine recipients upon natural infection in the community; two immunized

infants died upon infection and the clinical trial was abruptly ended. Several decades

later, the first rotavirus vaccine Rotashield® was approved for infant gastroenteritis.

Unfortunately, it increased susceptibility to intussuception, a rare form of bowel

obstruction where the bowel folds upon itself. Upon investigation, it was concluded

that Rotashield® did contribute to or increased the risk of intussuception and the

vaccine was withdrawn from the market.

26 UMC Utrecht - Child research


SEVERE INFLAMMATORY DISORDERS

Viruses also infect older patients

RSV and rotavirus infections also cause severe disease throughout life.

An RSV infection during infancy is associated with recurrent wheeze and asthma.

We conducted a multicenter, double-blind, randomized placebo-controlled MAKI

clinical trial and showed that RSV is causally-related to infant wheeze. In older

adults, RSV is associated with similar incidence and severity compared with

influenza. Rotavirus can cause acute gastroenteritis throughout life, but is especially

severe in immunocompromised adults and frail elderly. In general, increased

awareness of severe RSV and rotavirus infection in adults is needed.

pbruijni@umcutrecht.nl

Patricia Bruijning, MD,

PhD focuses on vaccinepreventable

diseases, which is a

central theme in epidemiological

research. She aims to

optimize vaccination strategies

for infants and children with a

special focus on medicallyvulnerable

pediatric

populations.

It takes a village

Our aim in Child Health is to contribute to the development and implementation of

vaccines against RSV and rotavirus. We conduct our research as part of large

national and international consortia, including RIVAR, RESCEU, ReSViNET and RSV

GOLD. The RIVAR-program (Risk-Group Infant Vaccination against Rotavirus) aims to

implement a hospital-based rotavirus vaccination program for high-risk infants;

the IMI-funded RESCEU project informs the European Union of the RSV burden in

Europe before future introduction of RSV vaccines; Louis Bont is the founding

chairman of the ReSViNET Foundation, which brings together a global network of

stakeholders in order to decrease the vurden of RSV infection; and The Bill and

Melinda Gates Foundation-funded RSV GOLD project studies clinical characteristics

of children dying from RSV infection. By defining age distribution of RSV-related

deaths we can guide impact analysis of future maternal RSV vaccines.

Together with our collaborators in other areas, including Linde Meyaard, PhD

(immune dysfunction in HIV), Jeanette Leusen, PhD (therapeutic antibodies) and

Jose Borghans, PhD (leukocyte dynamics), we’re characterizing virus transmission

dynamics and conducting health economic evaluations of vaccination strategies.

We’re gaining a better understanding of disease pathogenesis, and developing

effective and affordable preventive interventions and immunodiagnostic tools.


Prevention is better than treatment.

- Patricia Bruijning

UMC Utrecht - Child research 27


Pediatric Rheumatology:

Collaboration is essential

The Pediatric Rheumatology Department, Wilhelmina Children’s

Hospital is comprised of both basic science and clinical research groups.

These include a joint pediatric rheumatology research group, led by

Bas Vastert, MD, PhD and Jorg van Loosdregt-Vastert, PhD; a translational

immunology lab headed by Femke van Wijk, PhD; and research by several

clinical pediatric rheumatology groups, including Joost Swart, MD, PhD,

Nico Wulffraat, MD, PhD and Sytze de Roock, PhD (Juvenile Idiopathic

Arthritis, JIA) and Annet van Royen, MD, PhD (Juvenile Dermatomyositis).

Together, we have a longstanding track record of studying

chronic inflammatory disorders in children.

bvastert@umcutrecht

Bas Vastert, MD,

PhD is a pediatric

rheuma-tologist with

expertise in translational

immunology. He’s

passionate about

developing novel,

biologically informed

therapeutic strategies

to personalize the

treatment for juvenile

idiopathic arthritis.

This truly translational research collaboration, where basic immunological scientists and clinician

scientists work together, lies at the heart of the acknowledgement of our department as a EULAR

Center of Excellence in pediatric rheumatology – we’re only the 2nd pediatric rheumatology

center worldwide. And thanks to the efforts of Nico, who has led several European Union funded

collaborations including Pharmachild (European Pharmacovigilance register) and SHARE

(developing evidence and consensus based guidelines on rare pediatric rheumatic diseases),

our ability to have a real impact on patient care is excellent.

Juvenile Idiopathic Arthritis (JIA)

We cover a broad spectrum of chronic inflammatory diseases in children, with a particular interest

in JIA, a chronic autoimmune disease characterized by arthritis and clinical presentation of

systemic inflammation. In addition, we’re focused on finding off-label uses for existing drugs or

alternative combinations of drugs in order to improve treatment strategies, and we perform

clinical trials based on the fundamental research we perform in our labs.

In 2014, we reported the first prospective cohort study of a first-line therapy with recombinant

IL-1Ra in children with new-onset JIA; the majority of patients responded quickly and could stop

treatment within one year. Based on research in our department, we postulate that timing of

recombinant IL-1Ra administration could be change disease progression. Since then, we’ve

initiated a the Early Stop of targeted Treatment in Systemic JIA (ESTIS), a ZonMw Rational

Pharmacotherapy-sponsored clinical trial, where we’re testing IL-18 as a therapy response

biomarker in systemic JIA in a multicenter clinical trial in the Netherlands.

Another example of off-label use is nicotinamide, also known as vitamin B3, which is used as a

dietary supplement and to treat acne and skin cancers. Most recently, we’ve planned a study to test

whether nicotinamide can act as a regulatory T-cell-inducing compound in a stop strategy of

biologicals and/or methotrexate (a chemotherapeutic agent and immune system suppressant),

which are used as maintenance treatments in non-systemic JIA.

From an immunology perspective

We’re also understanding epigenetic and epitranscriptomic regulatory mechanisms that modulate

immune homeostasis and might be dysregulated in chronic inflammatory (autoimmune) diseases

like JIA. We’re using JIA as a model to study fundamental immune-regulatory mechanisms, and

by combining our findings and observations from both the lab and the clinic, we can gain

insight into the complex interplay between the molecules and pathways involved in

pediatric inflammatory conditions.

We also focus on juvenile dermatomyositis (JDM) from an immunological point of view, where we’re

identifying distinctive and overlapping molecular mechanisms in order to develop early precision

treatment approaches. Together Annet and Femke, have discovered and validated a novel robust

jloosdre@umcutrecht.nl

Jorg van Loosdregt,

PhD is a fundamental

immunologist who

aims to translate

fundamental discoveries

into novel

therapeutic strategies.

He loves collaborating

with experts in other

fields of research.

28 UMC Utrecht - Child research


SEVERE INFLAMMATORY DISORDERS


Here in the city of Utrecht, we work together with all

kinds of organizations to ensure that children who

want to exercise within their means enjoy sports.

And that children coming from the hospital can work

out at a sports club nearby. We do this with partner

organizations in the ‘Sport op Maat’-network and the

Wilhelmina Children's Hospital.

- Victor Everhardt, counciler of Utrecht


Translational immunology

is much

more than a linear

process; it’s based

on perpetuating

circles of knowledge

and implementation,

fueled by different

disciplines.

- Femke van Wijk

fwijk@umcutrecht.nl

Femke van Wijk,

MD, PhD focuses on

the role of T cells in

(tissue) homeostasis

and chronic inflammation.

She enjoys

training and mentoring

young scientists.

marker for disease activity in JDM that can guide precision treatment; this is now being tested

in a large international multicenter setting. In other studies. Femke has also contributed to the

understanding of immune regulation in JIA, by proposing the paradigm of human T-cell

resistance to regulation. Together with the pediatric rheumatology research group, she’s

recently described a role for regulatory T-cell programming in JIA joint inflammation.

Surprisingly, this regulatory T-cell signature is not only present in JIA and rheumatoid arthritis,

but also in tumors, demonstrating conservation of developmental pathways across different

diseases.

The close-knit interaction of our team members, together with our breadth of expertise, allows

us to expand our current understanding of the intricate mechanisms that facilitate inflammation

in the joints of JIA patients. As translational scientists, we rely on both clinical and lab

observations to ask the right questions and design smart experimental and clinical studies.

Our ultimate aim is to identify novel therapeutic targets for the treatment of this disease.

UMC Utrecht - Child research 29


POST-ONCOLOGY

Improving care for

oncology PICU patients

Marry van den

Heuvel-Eibrink MD,

PhD Pediatric Oncologist

focuses on renal

tumors and (genetic)

variation of toxicity in

childhood cancer.

Roelie Wösten-van

Asperen MD, PhD is

a pediatric intensivist

whose research focuses

on pediatric cancer

patients admitted to

PICU. She is the chair of

the PICU Oncology Kids

in Europe Research

group (POKER)

rasperen@umcutrecht.nl m.m.vandenheuvel-eibrink@prinsesmaximacentrum.nl

Survival rates for children with

cancer have improved over the past

20 years; however, intensified

concomitant treatment has resulted

in the fact that 40% of patients

require at least one pediatric

intensive care unit (PICU) admission

throughout their disease course,

and PICU mortality rates are higher

(around 30%) compared to those of

other PICU subcohorts. In addition,

PICU mortality has remained

relatively unchanged over the past

decades, in contrast to the researchled

improvements observed in

adults with cancer admitted to

intensive care unit.

Identifying critically ill pediatric cancer

patients. It’s crucial to timely identify critically

ill hospitalized cancer patients in order to

prevent further clinical deterioration by

providing early-required treatment. In this

high-risk population, we need tools that

differentiate early between ‘relatively well’

and ‘critically ill’ patients (requiring PICU

admission). We’ve launched an interdisciplinary

research project between the PICU,

Wilhelmina Children’s Hospital and the

Princess Máxima Center, which aims to

determine the predictive value of the

Bedside Pediatric Early Warning Score

(BedsidePEWS) for the identification of


PICU mortality rates of

pediatric cancer patients

are far higher when

compared to current

mortality rates of the

general PICU population.

- Roelie Wösten-van Asperen

critically ill pediatric cancer patients and, if

necessary, to optimize the score for its use in

this specific patient population. This will

facilitate timely identification, referral to and

treatment at the PICU and result in improved

survival and reduced morbidity.

PICU Oncology Kids in Europe Research

group (POKER) There is little to no data on

changes in clinical conditions in pediatric

cancer patients preceding PICU admission;

there is also no outcome data available. More

research is needed to improve our ability to

timely recognize clinical deterioration and to

appropriately treat our patients. Recognizing

the need for international collaboration on

this issue, we established the PICU Oncology

Kids in Europe Research group (POKER),

comprising of 10 PICUs which belong to large

pediatric oncological centers in seven

different countries (the Netherlands,

Belgium, Denmark, Germany, Switzerland,

United Kingdom and France), and is endorsed

by the European Society for Pediatric and

Neonatal Intensive Care. As a first step,

POKER aims to obtain consensus in

determining the top research and core

outcome priorities for pediatric cancer

patients in a PICU for the next 10 years.

Our mission in

pediatric oncology

research is to

improve cure rates

for all children and

to enhance quality

of survival.

- Marry van den Heuvel-Eibrink

30 UMC Utrecht - Child research


POST-ONCOLOGY

The endocrine

system and cancer

Hanneke van

Santen, MD PhD

is a pediatric endocrinologist

with a focus on

damaged endocrine

systems in children.

Endocrine effects of

cancer treatment in

childhood, thyroid

tumors and craniopharyngioma.

In 2013, she moved to

Utrecht to support the

new Princes Máxima

initiative and coordinate

endocrine care for

children with cancer.

hsanten@umcutrecht.nl

It’s estimated that about 80% of pediatric

cancer survivors reach the 5-year mark;

however, about 50% of all patients

experience an endocrine adverse event.

Endocrine disorders in children with cancer

can be caused by the tumor itself or by

treatment. Children need an intact endocrine

system for normal growth and to recover

from their treatment. With early detection,

endocrine disorders can be treated, and the

balance or deficiency restored.

Unfortunately, these disorders aren’t always

diagnosed in time because they aren’t

recognized or understood and ultimately, we

must also find ways to prevent endocrine

damage.

I focus on early and late endocrine effects of

childhood cancer treatment with a special

interest in the thyroid and pituitary gland,

and at improving care for children with

thyroid cancer and craniopharyngioma.

Rare tumors and hormonal changes

Located in the brain, the hypothalamus and

the pituitary gland are the main regulators of

the endocrine system. If damaged, children

present with a variety of clinical signs caused

by hormonal deficiencies, including small

stature, delay of puberty, tiredness, disturbed

day-night rhythm, temperature instability

and hypothalamic obesity.

Tumors in this area during childhood are rare,

necessitating centralization of care and an

experienced multi-disciplinary team to

ensure optimal treatment and outcome.

I also study hormonal disorders during

cancer treatment, which is challenging

because hormones may be altered because

of drug toxicity or because a child is ill

(adaptive regulatory mechanism). The first

requires hormone replacement therapy,

while the second does not. To date, no

prospective studies have been performed in

children with cancer to differentiate between

hormonal changes during childhood cancer

and adaptive hormonal changes.

THYRO-Dynamics Study

We’re supported by the Foundation KIKA

(Children Cancer-free Foundation, for The

THYRO-Dynamics study, where we will

prospectively measure thyroid hormones in

children treated at the Princess Máxima

Center (PMC). We will gain insight into the

prevalence and causes of true thyroid

dysfunction versus changes regarded as

adaptation. Our findings will lead to better

diagnostics, earlier treatment and better

outcome for children during and after

treatment. This new study illustrates the

unique collaboration between the

Wilhelmina Children’s Hospital and the

Prinses Máxima Center.


All children with (chronic)

diseases, deserve screening and

timely treatment of endocrine

deficiencies, so they can grow

and develop just as their peers.

- Hanneke van Santen

UMC Utrecht - Child research 31


STRATEGIC THEMES: LIFECYCLE

The life-course approach

eputte@umcutrecht.nl

Elise van de Putte,

MD, PhD is a pediatrician

specialized in

social pediatrics and a

Professor of Lifecycle

Pediatrics. Her

research is focused on

well-being, participation

and social inclusion

in chronically ill

children.

The Child Health Program can be characterized by a unique life-course approach for our

different patient groups. Our aim is to enable chronically ill children to develop and realize

their potential. We support them in adaptation and self-management to meet the social,

physical and emotional challenges they may encounter. A child with a chronic disease

experiences the cumulative impact of all these challenges over time, with direct effect on

his or her health and development. We operationalize this approach within Social Pediatrics

Department in the PROactive life-course cohort study.

PROactive life-course cohort study

In this study, we collect data from young chronic patients (2-25 years old) and their parents using a

comprehensive set of questionnaires. The aim of this research project is to study the relationship

between chronic disease and fatigue, pain, societal participation and wellbeing – assessed from both a

child’s and parent’s perspective. Specifically, the project aims to unravel the complex interplay of

protective and risk factors that affect the development of these chronic patients, their societal

participation and their wellbeing. Modern digital tools enable us to report these factors on both the

individual and group level.

Most pediatric patient groups participate in this life-course cohort study: patients with severe

inflammatory disorders (juvenile idiopathic arthritis, cystic fibrosis, irritable bowel disease), children

after oncology treatment and patients with congenital diseases (kidney, heart). A particular strength of

this study is the integration of biological, psychological, social and behavioral data with a focus on

well-being, including health, social inclusion and participation, and with fatigue and chronic pain as

important proxies for these outcome measures. Clinical data are collected from the electronic patient

file in the research data platform and are combined with the data from questionnaires that are filled

out using a web-portal (www.hetklikt.nu). Since 2017, we’ve already included 1000 children and we

expect to double this number by the end of 2019.


The availability and cross-linking with large scale cohort studies outside the hospital, such as the

Whistler, Piama and Youth cohorts, enable us to further understand the cumulative impact of the

challenges that chronically ill children encounter.

Investing in the child creates a

threefold gain: in their present, in

their future as adults and in their

children, our next generation.

- Elise van de Putte

32 UMC Utrecht - Child research


STRATEGIC THEMES: LIFECYCLE

Let’s try to

help patients

manage their

own disease.

- Jaap van Laar


Jaap van Laar, MD, PhD is an

academic rheumatologist, and his

professional goal has always been to

explore new roads to improve patient

care. He was PI of the landmark ASTIStrial

and currently runs a productive

research program that focuses on

developing innovative therapies for

systemic sclerosis and rheumatoid

arthritis.

jlaar@umcutrecht.nl

Nico Wulffraat, MD, PhD is a

pediatric immunologist and

rheumatologist who works on JIA

and stem cell transplantation. He leads

studies on autologous stem cell

transplant in JIA, vaccination

development and drug treatment trials.

nwulffra@umcutrecht.nl

Pediatric and adult

rheumatology:

2 sides of the same coin

Whilst the outcomes of young adults with rheumatic diseases such as juvenile idiopathic arthritis (JIA) has

markedly improved since the introduction of biologicals and more intensive treatment regimens, they still face

multiple challenges in daily life. Not only do they need to develop strategies to cope with pain, fatigue and

disability, they also need to prepare for an uncertain future in terms of jobs, relationships and long-term

outcome of their condition. Surprisingly few studies have addressed long-term multidomain outcomes in JIA

and there is a pressing need for new observational studies of JIA patients, even those with optimally controlled

disease. There is even less data available for patients with connective tissue diseases and immunodeficiencies.

Basic fundamental questions remain unanswered. How is the immune system shaped by recurrent bouts of

rheumatic disease and infections and what are the long-term clinical sequelae?

Reuma2Go: managing disease smartly

The successful conduct of long-term studies on

pharmacovigilance and immune health not only requires

smooth transitional care from pediatric rheumatology to adult

rheumatology, but also harmonisation of data collection,

integration of electronic patient records and development of

tailor-made solutions (such as the use of smart mobile apps).

We are currently setting up a prolonged transition of care plan

supported by an E-Health tool called Reuma2Go. It is our

ambition to promote self-management. With adequate selfassessment,

patients can, for instance, reduce the number of

outpatient visits when in remission.

Predicting treatment response

Even more relevant is the search for biomarkers predicting

response to medication and long-term prognosis. For this we

have set up a multicenter program (a multi “omics” approach)

in which all Canadian and Dutch academic pediatric

rheumatology centers participate. Patient engagement is

critical for the successful implementation of such ambitious

projects. Ultimately new digital technologies and advances in

disease monitoring should help put patients in the driver’s seat

with respect to managing their own disease.

UMC Utrecht - Child research 33


Transitioning care as

child becomes adult

Cystic Fibrosis (CF) is the most prevalent hereditary disease in

Western countries. CF was first described just before World War

II. At that time, all patients died during early childhood because

of severe lung damage as a result of untreatable airway

infections. Until the 1970s, CF was mainly a pediatric disease

which required intensive treatment with antibiotics, chest

physiotherapy and food supplements. With improvement of

prognosis, new complications emerged: About one third of

patients developed CF-related liver disease during late childhood

and more than half acquired CF-related diabetes in early

adulthood. Of those born in the 1980s, about 75% survived into

adulthood. In addition to the increasing complexity of patient

care, CF was no longer only a pediatric disease, as it permeated

into the fields of adult lung specialists, gastro-enterologists and

endocrinologists. Current mean life expectancy has risen up to

almost 50 years of age and thus, care issues like male infertility,

child birth and labor participation are reality for most patients.

With the recent introduction of modulators of the CF

Transmembrane Conductance Regulator (CFTR) protein, survival

will further improve for many patients.

Care needs to include the transition from child to adulthood

The transition from a monodisciplinary deadly disease in children

to a multidisciplinary complex chronic disease in older adults

requires far-reaching changes in health care systems. For many

years, ‘transition programs’ were developed to bridge the gaps

between pediatric and adult knowledge and culture of care, but

they were hampered by logistical and financial barriers. Such

programs have never been successful and evaluations show that

patients are dissatisfied and lost in follow-up. Transition

programs focus on adapting the patient to the existing health

care system, without considering changing care needs and

prognosis. In addition, the current system impedes further

knowledge development and innovation because ‘early

determinants’ in childhood are disconnected from ‘late

outcomes’ in adulthood.

Our solution

This is why, for years, the CF Center Utrecht has been using the

concept of life-course care. Children and adults are followed and

treated within a single team working with one continuous

patient file and database, and where research focuses on

improving the entire life-course perspective. This concept is

accomplishing what the transition programs failed to do.

cent@umcutrecht.nl

hheijer2@umcutrecht.nl

Kors van der Ent, MD,

PhD initiated the Cystic

Fibrosis Center Utrecht in

1997 and is a co-developer

of the Utrecht organoid

model for CF. Kors is the

coordinator of the European

Union Horizon 2020 HIT-CF

Program and the core-network

leader for CF in the

European Reference

Network (ERN-LUNG)

Harry Heijerman, MD,

PhD is adult chest physician

who founded (1989) and

chaired the adult CF Center

in The Hague and is also

founding editor of The

Journal of Cystic Fibrosis

and CF Research News, of

which he is currently

Editor-in-Chief.

34 UMC Utrecht - Child research


STRATEGIC THEMES: LIFECYCLE

Living better with a

clotting disorder

In 1964, Simon van Creveld founded a special clinic for children with hemophilia, a rare

congenital disease. Patients with hemophilia lack clotting factors VIII or IX,

characterized by bleeding in the joints, which leads to crippling joint arthropathy in

adulthood. During the 1960s, these patients were admitted to the hospital for months

and received multidisciplinary care with a physiotherapist, nurse, psychologist and

teacher. Since then, treatment has improved and the Van Creveldkliniek has evolved

into an outpatient clinic for patients of all ages with congenital clotting disorders. It’s

now part of the UMC Utrecht, but maintains its unique concept of multidisciplinary care

provided by a designated team. We provide care for approximately 50% of all patients

with congenital clotting disorders in the Netherlands.

rschutge@umcutrecht.nl

kfische2@umcutrecht.nl

Roger Schutgens, MD, PhD is an adult

hematologist and epidemiologist. He is

Head of the Van Creveldkliniek, Center for

Benign Hematology, Thrombosis and

Hemostasis. He is Chair of the

Anticoagulation Committee at the

UMC Utrecht, Secretary of the Dutch

Society of Hemophilia Treaters and

Secretary of the Dutch Society for

Thrombosis and Hemostasis.

Kathelijn Fischer, MD, PhD is a

pediatric hematologist and clinical

epidemiologist. At the Van Creveldkliniek

(part of the UMC Utrecht), she combines

clinical care for children with clotting

disorders with multidisciplinary research.

Concomitantly, she is the epidemiologist

for two European Hemophilia Registries

(EUHASS and PedNet) and section editor

for ‘Thrombosis and Haemostasis’.

Collecting interdisciplinary data

Our research focuses on patients with hemophilia, where care and research

are combined: All patients with severe hemophilia are seen annually within

our multidisciplinary clinic, and their medical file includes documen tation

of treatment and bleeds, laboratory tests, physical assess ment,

questionnaires about physical activities and quality of life, and consultation

with a hemophilia nurse and social worker. Provision of lifelong care

provides the opportunity to see the effects of pediatric treatment through

to adulthood and provides crosstalk between adult and pediatric specialists.

Data from patient medical files, available since the 1970s, combined with

annual multi disciplinary assessment, have established a longitudinal cohort

study with repeated outcome assessments.

Over the years, we’ve used these data to research effective replacement

therapy, to understand the natural history of hepatitis C infections, to

conduct a prospective study on cardiovascular disease and to investigate

the value of various imaging techniques.

Can patients with clotting disorders do sports?

One current research project is a prospective study on sports participation

and injuries. We started this because many patients are discouraged from

participating in sports, because of perceived bleeding risk. At baseline, we

test strength, endurance and coordination. Then sports participation and

injuries are assessed for a year. The rate of injuries will be compared to

general population data and we will use results of baseline tests to counsel

patients on injury risk in a sports outpatient clinic.

Our research projects strive to improve lifelong multidisciplinary care

for patients with hemophilia and other clotting disorders.

UMC Utrecht - Child research 35


STRATEGIC THEMES: INTERDISCIPLINARITY

Janjaap

van der Net,

PhD is a pediatric

physiotherapist and

clinical health scientist,

whose special interest is

motor-proficiency and

physical literacy in

childhood chronic

conditions.

Tim Takken, PhD is

medical physiologist

and a special interest in

clinical pediatric

exercise physiology.

t.takken@umcutrecht.nl

jnet@umcutrecht.nl

Become competent now,

to be confident later

A family-centered and interdisciplinary showcase for Child Health research

At the Center for Child Development, Exercise and Physical

Literacy, we study Activity & Health in Childhood Chronic

Conditions. This is done in close collaboration with the

Psychosocial Depart ment of the Wilhelmina Children’s Hospital,

which focuses on Empowerment and Resilience in Childhood

Chronic Conditions. Embedded within the Child Health

Program is this complementary, interdisciplinary approach to

studying health in childhood chronic conditions from a social,

behavioral and physical activity perspective.

Studying health within the context of disease

An inspiring example is the Congenital Heart Disease-Lifespan

study (CHD-Ls), a program in which health, rather than disease

alone, in children with a congenital heart disease (CHD) and

their families is longitudinally studied from as early as 20 weeks

of gestation into their 40s. we focus on a family-centered and

patient-centered perspective and on the physical, cognitive

and emotional development and health in children with CHD

and their family members.

Nested within the CHD-Ls study is the CRUCIAL TRIAL, a

collaboration between obstetrics, pediatric cardiology and

cardiosurgery, neonatal and pediatric intensive care medicine,

as well as pediatric physiotherapy, exercise physiology and

pediatric psychology. This trial aims to minimize cerebral

damage and increase cardiac health during pregnancy,

perinatally and in early childhood to improve neuro-cognitive

and motor-development as well as long-term health-related

fitness in children with a congenital heart disease.

Promoting physical activity in children with

a chronic condition

With survival rates increasing in childhood conditions (e.g.

cystic fibrosis, childhood cancer and more recently, spinal

muscular atrophy), as well as more efficient disease control (e.g.

pediatric rheumatic conditions and hemophilia), there is an

increasing desire from children and their families to be able to

fully participate in an active healthy lifestyle. We therefore

joined the Active Healthy Kids Global Alliance, together with

Mark Tremblay, PhD, and expert in exercise science at the

University of Ottawa, Canada, and produced the Dutch Physical

Activity Report Card for Children and Youth. In this

interdisciplinary and societal project, we collaborated with

many national societal organizations and mapped health

policies on local, municipal, provincial and national levels to

improve active healthy living in children with a chronic

condition. Together with the Department of Preventive

Medicine and Youth from the municipality of Utrecht, we’re

currently implementing a program “WKZsportief” to improve

physical literacy, and to enhance participation in sports and

active recreation in children with chronic conditions. Our motto

for this approach is: become competent now, to be confident

later.

36 UMC Utrecht - Child research


STRATEGIC THEMES: INTERDISCIPLINARITY

Empowering the entire family

Center of Excellence for Rehabilitation Medicine

(De Hoogstraat Rehabilitation)

Advances in medical technology, diagnosis and treatment have increased the life expectancy

of various childhood disorders. Pediatric rehabilitation aims to optimize autonomy, selfmanagement

and participation of children with developmental disabilities and their families.

Our interdisciplinary program focuses on developmental trajectories, identification of children

at risk for physical and mental health problems and interventions to mitigate those risks.

Because families are central in the lives and development of children, we also focus on family

empowerment.

Patients and families are involved throughout our research process, from idea to

implementation, and we have a strong collaboration with patient organizations, including

Cerebral Palsy Netherlands (CP Nederland; formerly known as BOSK). A good example is our

study on sleep, nutrition and physical activity of children with Brain Based Developmental

Disabilities. Together with Neonatology, we’ve developed clinical care pathways to guide

clinicians with assessment and early identification of problems in these areas, based on

systematic data collection. We seek to understand the quantity and quality of sleep and its

relationship with development. In partnership with parents, we’re developing a support

program, including an instructional video and online knowledge translation resources, to

educate and empower families so they can support the development and health of their child.

mketela2@umcutrecht.nl

We collaborate with

patients and families in all

stages of research.

- Marjolijn Ketelaar


Marjolijn Ketelaar,

PhD focuses on the

development of children

with developmental

disabilities, and

empowerment of

families to optimize

autonomy and

participation.

Novel insights into cancer immunotherapy

mboes@umcutrecht.nl

Marianne Boes,

PhD focuses on

immunodeficiencies

and immune activation

with a special

interest in immune

checkpoints and

developing immunotherapy

for cancer

patients.

Immunotherapy based on checkpoint blocking antibodies (anti CTLA4, anti PD-1) has

revolutionized treatment for patients suffering from well-responding cancers such as

melanoma and non-small cell lung cancer, which are tumors with acquired mutational loads.

Neuroblastoma accounts for 15% of childhood cancer mortality, yet susceptibility to

checkpoint blockade-based immunotherapy is not evident. Because the level of expression

of major histocompatibility (MHC) Class-I molecules is low, neuroblastoma tumors evade a

major immune defense strategy based on MHC-restricted cytotoxic T cells. In our opinion,

induction of MHC-I membrane expression is prerequisite for optimal efficacy of T-cell therapy

in neuroblastoma and should be incorporated into treatment regimens.

My team initiated an interdisciplinary collaboration with colleagues at the Netherlands

Cancer institute to screen for targets that upregulate MHC-I display at the neuroblastoma cell

surface, yielding TNIP1 and N4BP1. Validation experiments in neuroblastoma revealed

increased MHC-I antigen presentation capacity and induced recognition by neuroblastoma

tumor-antigen specific T-cells. Supporting our findings, patients expressing high levels of

TNIP1 and N4BP1 in neuroblastoma have lowered MHC-I tumor surface display and have

worse survival probability. Use of these targets in therapy has the potential to augment

current treatments in innovative ways that will improve clinical outcomes for neuroblastoma

cancer patients.

UMC Utrecht - Child research 37


STRATEGIC THEMES: MENTAL & PHYSICAL HEALTH


mgroote5@umcutrecht.nl

Healthy play, better coping

the importance of monitoring and acting on psychosocial development

A child living with a chronic disease carries this burden, whether

he or she is ill or well at any given time. It affects his or her everyday

life. Chronic disease extends beyond the actual illness itself and

has a negative impact on a child’s physical, social, emotional and

cognitive development. Lower psychological well-being of and

decreased social participation by chronically ill patients is

demonstrated in conditions such as cystic fibrosis, autoimmune

disorders, cardiac disorders, cancer and premature birth. We study

play and focus on innovative gaming approaches as coping and

healthy developmental tools for children with chronic conditions.

For children, play is essential

Play behavior is essential for the healthy development of an individual and

hospitalization, pain, fatigue and social isolation limit opportunities to engage in

social play. Play allows children to experiment with their behavioral and social

repertoire and to practice physical and communication skills; it facilitates the

development of social competence, emotional capacities, resilience, creativity and

of problem-solving skills. Therefore, impaired play may have long-lasting

consequences for these children as they grow up, in addition to the direct physical

effects of their disease. Unfortunately, direct empirical evidence demonstrating

the importance of play is lacking.

Patient reported outcomes like fatigue and pain represent the

struggles patients experience on a day-to-day basis.

Martha Grootenhuis,

PhD studied

psychology and

worked at the Emma

Children’s Hospital

from 1992-2015.

Thereafter, she moved

to Utrecht to become

Principal Investigator

in the Princess Máxima

Center. Martha is

founder of the

Pediatric Psycho-

Oncology Committee

of the International

Society of Pediatric

Oncology (SIOP).

- Sanne Nijhof

Healthy Play, Better Coping

We participate in a new multidisciplinary research project focused on play and

applied games in children with chronic or life-threatening conditions: Healthy Play,

Better Coping. In this consortium we investigate various ways to stimulate or

modify play behavior and how to assess its effects on patient-reported outcomes.

We hypothesize that helping children better adapt to the stress of their chronic

condition will promote their short-and long-term cognitive, social, emotional and

psychomotor development. To do this, we focus on preventative programs,

applied games (games created with a specific purpose other than pure

entertainment) and other interactive technologies, such as video games and

virtual reality. Our network combines expertise from various collaborators,

including several partners within Utrecht University (Dynamics of Youth theme,

Game Research Graduate Program, Behavioral Neuroscience Department, Faculty

of Veterinary Medicine); the Princes Máxima Center; and the Trimbos Institute for

Mental Health. Our integrated systematic approach will help young patients better

cope with the consequences of their illness by stimulating healthy social play and

an overall healthy development.

Social and emotional development of teenagers

We investigate social and emotional development based on lifespan studies in

young patients and their families. Sanne was involved in a randomized clinical trial

FITNET (Fatigue In Teenagers on the interNET), which demonstrated the

effectiveness of internet-based cognitive behavioral treatment for adolescents

with chronic fatigue syndrome. Based on outcomes of the trial, Sanne has extended

her experience with severe fatigue to new somatic domains, including

snijhof@umcutrecht.nl

Sanne Nijhof, MD, PhD

is a pediatrician and

clinical researcher with

focus on social

pediatrics and

patient-reported

outcomes, like fatigue

and pain. She is driven

by the hypothesis that

(chronic) childhood

diseases influence all

aspects of a child’s life

- not only the physical,

but also the social, emotional,

educational and

economical. Sanne

co-developed personalized

digital tools to

assess and treat the

associated psychosocial

consequences of

chronic disease.

38 UMC Utrecht - Child research


STRATEGIC THEMES: MENTAL & PHYSICAL HEALTH

Childhood

cancer affects the

whole family.

Screening


and

monitoring help to

prevent traumatic stress

and provide timely

interventions.

- Martha Grootenhuis

rheumatology, pulmonology and oncology. Together with Elise

van de Putte, MD, PhD, she’s translated insights into tailored

e-health interventions: FitNet-plus, a web-based portal for

cognitive behavioral therapy; and PROfeel, a smartphone app

where children can log their complaints in real-time.

Martha’s group has longitudinally studied several pediatric

populations. Her studies demonstrate, for example, that young

adults who grow up with a childhood chronic disease achieve

fewer milestones, or achieve them later than their peers across

different domains (i.e. autonomy, psychosexual and social). A

delayed social development, including limited participation in

sports, was related to a lower quality of life in adulthood. This

underlines the urgent need to address social development

earlier in life.

Together with Elise van Putte, MD, PhD, we collaborate in the

PROactive study (Patient Reported Outcomes in Adolescents

with Chronic/life-threatening disease and Tailored

InterVentions in a digital Environment). PROactive enables the

early detection of a disturbed psychosocial development and

prompts subsequent interventions, that considers the

perspective of both the child and his or her family, and aims to

improve self-management and growth towards independency

in adulthood. In particular, we have a special focus on fatigue

and social/sports activities.

Early interventions will empower our chronically ill patients

and help them cope with the psychosocial effects of their

physical condition. We expect that, through health play and

game interventions, our patients will develop into healthy

resilient adults.

UMC Utrecht - Child research 39


UNIQUE RESOURCES

Patients cohorts

in the child health program

The Child Health program focusses on the longterm outcomes of patients with chronic diseases.

Within the program an extensive number of longitudinal patient cohorts are being studied, many of

them covering birth, pediatric and adult care. We invite you to collaborate with us and to add or use

these cohort data for your own research. For full description of the cohorts we refer to our website:

www.umcutrecht.nl/childhealth

Congenital

heart

diseases

Wilson

diseases

Progressive

familiar

intrahepatic

cholestasis

Mixed

endocrine

diseases

Post cancer

treatment

Mixed

metabolic

diseases

Pregnant

women

with fetal

abnormality

Congenital

kidney

diseases

Extremely

preterm

infants

Cystic Fibrosis

Perinatal

brain

damage

Juvenile

rheumatic

arthritis

Syncytial

40 UMC Utrecht - Child research


UNIQUE RESOURCES

Facilities

& Expert Knowledge

You can find some examples of our facilities & expert knowledge on the next

pages. Lease check our website for lots more! www.umcutrecht.nl/childhealth

Metabolic diagnostics

We use an in-house developed direct infusion mass spectrometry pipeline to

investigate the metabolome in patients’ body fluids and cells and to

characterize model systems like cell lines, knock out mice and zebrafish.

Validation of interesting findings is performed by targeted mass spectrometry

by a range of dedicated platforms. This approach greatly contributes to

diagnostics, disease-discovery and elucidation of pathogenic mechanisms.

For more information please contact Judith Jans, jjans@umcutrecht.nl

or Nanda Verhoeven, nverhoev@umcutrecht.nl

Cardiac 3D imaging

We are world leading in 3D imaging of the heart in young children. We have

a state of the art catheterization laboratory with 3 dimensional rotational

angiography that is able to obtain high resolution 3D images in small

infants. Also fetal and neonatal MRI scanning of heart and brain is being

performed. Furthermore we have a 3D printer that is able to convert any 3D

dataset into a 3D model within 24 hours. 3D datasets and 3D prints can be

further analyzed using our (MRI compatible) computational fluid dynamics

lab and software.

For more information please contact Hans Breur, hbreur@umcutrecht.nl

Organoids

We work with organoids from different disciplines. Sabine Fuchs’

laboratory participates in the RMCU (Regenerative Medicine Center

Utrecht) in the Hubrecht Institute. Her main facility involves liver and

intestinal organoid research, including functional assays and frontline

gene-editing technologies. Clinically, we have a unique multidisciplinary

standardized diagnostic/follow-up facility (Sylvia Toth Center) in the

Wilhelmina Children’s Hospital for evaluation of diseases of unknown

origin, or for the follow-up of novel treatment strategies.

Jeffrey Beekmans’ laboratory focuses on

translational research with stem cells in cystic

fibrosis. He leads a research group that

develops stem cell based culture and assay

technology to model human pulmonary

disease, and currently mostly focusses on

(personalized) treatment of cystic fibrosis.

For more information please contact

Jeffrey Beekman, jbeekman@umcutrecht.nl

UMC Utrecht - Child research 41


Facilities

& Expert Knowledge

Zebrafish model

Creation of a zebrafish

model, including gene

knockout and knockin

of variants. Zebra fish

modeling

(Hubrecht Institute,

prof. Jeroen Bakkers)

For information, please contact

Gijs van Haaften,

ghaaften@umcutrecht.nl

meijkema@umcutrecht.nl

René Eijkemans,

MD, PhD focuses on

clinical prediction

models and machine

learning in high

dimensional data. He

has worked in many

clinical areas, in

particular, in reproductive

medicine.

Applied big data analysis &

machine learning

In infants, Respiratory syncytial virus (RSV) is the

leading cause of lower respiratory tract infections

and is responsible for up to 80% of acute

bronchiolitis cases. Several risk factors for

developing severe RSV disease in infants have

been identified. Nevertheless, this knowledge

only allows us to predict approximately 50% of all

severe RSV infections in young children. Currently,

we cannot predict whether an infant will progress

to severe disease, or clear the virus without

extensive medical care. Consequently, many

infants are hospitalized for observation, and a

significant number do not progress to a severe

disease condition. Thus, medical care for infants

with an RSV infection could be more efficient and

patient-tailored with accurate prediction. We

investigated whether a genomic prognostic

signature exists that can predict the course of

RSV infection with high accuracy. We used early

onset blood transcriptome profiles from 39

hospitalized infants who were followed until

recovery and whose level of disease severity was

determined retrospectively. Applying support

vector machine learning on age by sex

standardized transcription data, an 84-gene

signature was identified that discriminated

hospitalized infants with eventually mild or

moderate RSV infection from infants suffering

from severe RSV disease with a validated AUC of

0.971 on the experimental data. We conclude that

this 84-gene signature may serve as the basis to

develop a prognostic test to support clinical

management of RSV patients, making the care for

these patients more patient-tailored.

We are drowning

in information

and starving for

knowledge.

- Rutherford D. Roger


42 UMC Utrecht - Child research


UNIQUE RESOURCES

Understanding and

treating chronic pain:

Neuro-Immunology of pain

Chronic pain affects more than 20% of the

population and is a huge clinical and

societal problem. Current therapies often

fail because of their limited effectiveness,

or because of severe side effects such as

addition (opioids). We aim to understand

how chronic pain develops in children and

adults and identify potential differences

between these groups. Our goal is to

translate novel insights into ways to predict

who will develop chronic pain to enable

earlier pain treatment to prevent the

development of chronic pain and to

develop novel treatments. Based on

recently identified neuro-immune

interactions in chronic pain we have

developed an interleukin-4 and

interleukin-10 fusion protein of that shows

remarkable effects in resolving pain; this is

being further developed for clinical use.

Why does pain persist?

Pain normally serves as a warning sign of

inflammation and damage that disappears

when these conditions are resolved.

However, pain persists even after cessation

of inflammation or damage in many

patients with inflammatory diseases, for

example, children with rheumatic disease.

The mechanisms for persisting pain are

poorly understood. We hypothese that this

persisting pain results from failing pain

resolution programs caused by aberrant

immune and nervous system interactions.

For example, we’ve identified macrophages

as key regulators of the resolution

of inflammatory pain through interactions

with sensory neurons. However, sensory

neurons are also able to change

macrophage function, such that

macrophages switch to maintenance of

chronic pain, independent of the original

inflammation or damage. We study how

these systems interact and contribute to

pain. We’ve determined that various antiinflammatory

cytokines signal to sensory

neurons and glia cells to prevent

development of long-lasting pain and also

identified new pain genes such as

FAM173b.

Using a multidisciplinary approach

to pain

Pain is a multidisciplinary problem and

therefore we work together with scientist

from different disciplines (e.g. neuroscientists

and immunologists) and

clinicians (e.g. pediatric rheumatologists

and anesthesiologists) within and outside

(for the UMC Utrecht (as an example, see

www.bonepain.eu). We use various

preclinical chronic pain models including

inflammatory, neuropathic, chemotherapy,

visceral, diabetes, and osteoarthritis pain

models. Moreover, we perform studies in

relevant patient populations such as

juvenile idiopathic arthritis and

osteoarthritis. With our efforts, we’re

taking the next step in outsmarting

chronic pain.

neijkelk@umcutrecht.nl

Niels Eijkelkamp,

PhD is an expert in the

field of neuroimmunology.

His research topics

include understanding

chronic pain and the

development of novel

therapeutic approaches.

pain, a

neglected Chronic

global

health problem, is

not a symptom of

disease but a

pathologic entity

that requires

mechanism-based

new and specific

therapies.

- Niels Eijkelkamp

Pediatric exercise and muscle lab

Special equipped to measure al relevant parameters of health related

fitness, including Bio Impedance measures and nutritional status.

Including a platform to measure real-time –Spectrometry (7T) of

exercise metabolism and Near Infrared Spectography (NIRS) in

muscles.

For more information please contact Janjaap van der Net, jnet@umcutrecht.nl

or Tim Takken, ttakken@umcutrecht.nl

UMC Utrecht - Child research 43


Facilities

& Expert Knowledge

Functional brain measurements

1. State-of-the-art neonatal and infant MRI scanning

(3 tesla and recently 7 tesla) including advanced

postprocessing (e.g. DTI, MRS, Segmentations

(volumetric measurements)).

2. State-of-the-art cerebral ultrasound.

3. State-of-the-art neuromonitoring (aEEG, NIRS,

sleep assessments).

4. A dedicted highly specialized

neurodevelopmental follow up group

For more information please contact

Jeroen Dudink, jdudink@umcutrecht.nl

Translational research

for early stages of life

What happens early in life can have detrimental effects

later on. The Department for Developmental Origins of

Disease provides unique resources to the Child Health

Program and we focuse on causes, consequences of and

cures for adverse events that occur during early life stages.

We collaborate with patient organizations and clinical

investigators in the Neonatology, Obstetrics and Pediatric

Departments, UMC Utrecht to ensure that we develop

interventions that truly matter to our patients and families.

Using cutting edge techniques and biotechnological

innovations, in collaboration with technical universities in

Eindhoven and Delft, we combine molecular, anatomical,

physiological and behavioral expertise and investigate

intra-uterine processes and interventions to prevent

cardiovascular and neurodevelopmental disorders later in

life (led by Titia Lely, MD, PhD); the developing connectivity

of neuronal networks that enable social play, motor

learning and cognition (led by Freek Hoebeek, PhD); and

novel neuroprotective and neuroregenerative

interventions including stem cells, nutrition and growth

factors for perinatal brain injury (led by Cora Nijboer, PhD).


Translational

research not

only spans

fundamental to

clinical science,

but also forms

the bridge

allowing Child

Health experts

to innovate

therapies.

- Freek Hoebeek

fhoebeek@umcutrecht.nl

Freek Hoebeek,

PhD focuses on

neuroscience and

building multidisciplinary

research teams.

He is the UMC Utrecht

Chair of Translational

Research of Early Life

Events in 2018.

44 UMC Utrecht - Child research


UNIQUE RESOURCES

Clinical Trials

Changing lives through trials

An important aspect of research in

pregnant women and children is the

design and performance of clinical studies

and trials. To do this in the best way, we’ve

taken an approach which translates basic,

fundamental science into clinical

application, by developing innovative,

patient-centric biomarkers and

therapeutics. We also collaborate with

public and private sectors to bring a

spectrum of innovative treatments, not

easily or readily available, to children in

need. By working with scientists, clinicians,

institutes, and industry, the sum of its parts

is truly greater than what could be

achieved alone.

The UMC Utrecht U-TRIAL initiative helps

researchers within this strategic theme

bring their research ideas to the forefront.

Together with patient organizations,

health authorities, industry partners and

Julius Clinical (the academic research

organization spin-off of the UMC Utrecht),

investigators are stimulated to develop

new and impactful clinical hypotheses

which can be tested within a bold, highquality

framework. In doing so, we deliver

essential clinical results and thereby

treatments to quickly and effectively

improve the health of pregnant women

and children.

cpark@umcutrecht.nl

Cyrus Park, MSc, MBA

Strategic Advisor – Trial

Development U-TRIAL

initiative to stimulate

innovative, impactful

clinical research to benefit

UMC Utrecht and society.

Clinical Trials in UMC Utrecht

1,546

studies

1,335

medical conditions

Pediatric Clinical Trials in UMC Utrecht

315 trials in children

226

interventional

89

observational

169

industry

funded

collaborations

146

other funded

collaborations

Source: clinicaltrials.gov

UMC Utrecht - Child research 45


EDUCATION AND TALENT

Attracting and

advancing talent

Berent Prakken, acting dean: Child Health has a strong focus

on education, and for a very good reason: Education holds the

key to our future. Our education program is aimed at different

audiences ranging from patients to health professionals and

scientists. We specifically support targeted programs for talent

management that help young researchers focus their efforts

towards real and sustainable societal impact.



Education

holds the

key to our

future.

- Berent Prakken


There are no better

teachers for

upcoming physicians

than patients and

their loved ones.

- Joost Frenkel

46 UMC Utrecht - Child research


EDUCATION AND TALENT

TULIPS program

New researchers within the Child Health

program are actively stimulated to

participate in the national TULIPS program

(Training Upcoming Leaders in Pediatric

Science), an initiative of the Dutch Society

for Childcare. The vision of TULIPS is that

high-quality research is required to

improve child health. TULIPS has the

mission to empower young clinician

scientists to become international

competitive researchers. Therefore, TULIPS

provides distinct, selective 2-year curricula

for PhD students and Postdoctoral fellows.

Both curricula provide interactive training

sessions and weekend educational retreats

to create opportunities for collaboration

and to enhance competences required to

become successful in Pediatric Science.

bprakken@umcutrecht.nl

Berent Prakken, MD, PhD

Pediatric Immunology,

Acting Dean, Education

Director Biomedical

Education Center

Summer Schools

The Child Health program hosts several

Summer Schools during the summer.

These educational activities introduce

global child health to young doctors and

master’s students and stimulate working

together in an international environment.

The Summer School on translational

medicine is organized together with

students from the international Apollo

Society (https://www.apollosociety.eu/)

and hosts an impressive international

faculty. By organizing joint events between

summer schools, we are building a lasting

network of young researchers.

EUREKA Institute

The Eureka Institute of Translational

Medicine is the result of a close

collaboration between the UMC Utrecht,

various other top universities (Stanford

University, Duke/NUS Medical School,

University of Arizona, University of Miami,

University College London and the

University of Toronto), research institutions

(TIP, Center for Translational Molecular

Medicine), foundations (Dutch Arthritis

Foundation) and industry (Nutricia

Research). Nature Medicine and Nature

Biotechnology have supported the

program, in addition to providing learning

materials. The Eureka Institute was initiated

to develop an international community of

translational medicine professionals

equipped to catalyze the application of

discoveries for the benefit of human

health. The Institute offers a unique

translational medicine course, the

International Certificate Program and

within this framework we’ve developed a

special program for researchers appointed

within Child Health. This program

stimulates new researchers in crucial areas,

such as teambuilding and collaboration;

critical thinking and problem solving;

translational medicine and valorization. In

collaboration with the Eureka Institute, we

also organize masterclasses with internationally

renowned facilitators for young

talent in Child Health.

jfrenkel@umcutrecht.nl

Joost Frenkel, MD, PhD

is a pediatric rheumatologist

with a keen interest in

mechanisms of inflammaton.

He is an excellent

clinical teacher, putting

patients and families center

stage. Current research

involves both patientcentered

education and

disorders affecting the

innate immune system.


Boost Grants

One of the main strategic themes of the

Child Health program is interdisciplinary

research. To stimulate young investigators

to share their research experiences with

colleagues outside their own professional

expertise, we have launched annual Boost

Grants. Young investigators within the

program are asked to submit research

proposals in collaboration with one or

more investigators in the program with

whom they have never worked before.

Each year, this produces 15-20 new

research ideas that are presented and

discussed during general Child Health

meetings. The three best ideas are

rewarded with an amount of 15,000 Euros

to start the project and generate pilot data

for future larger grant applications.

Doctors must understand a patient’s

perspective to establish a balanced

relationship. This calls for novel education,

both in the classroom and at the bedside -

education that gives patients a voice that

physicians hear, so they can jointly reach a

shared decision.

- Joost Frenkel

UMC Utrecht - Child research 47


Science

for life

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