Personalized medicine a new medical and social challenge

Europeanization and Globalization 2

Nada Bodiroga-Vukobrat
Daniel Rukavina
Krešimir Pavelić
Gerald G. Sander Editors

Personalized
Medicine
A New Medical and Social Challenge


Europeanization and Globalization

Volume 2

Series editors
Nada Bodiroga-Vukobrat
Rijeka, Croatia
Sinisˇa Rodin
Luxembourg, Luxembourg
Gerald G. Sander
Ludwigsburg, Germany


More information about this series at />

Nada Bodiroga-Vukobrat • Daniel Rukavina •
Kresˇimir Pavelic´ • Gerald G. Sander
Editors

Personalized Medicine
A New Medical and Social Challenge


Editors
Nada Bodiroga-Vukobrat
Jean Monnet Department of
European Public Law
University of Rijeka
Rijeka
Croatia
Kresˇimir Pavelic´
Department of Biotechnology
University of Rijeka
Rijeka
Croatia

Daniel Rukavina
Croatian Academy of Sciences and Arts
Rijeka
Croatia

Gerald G. Sander
University of Applied Sciences
¨ ffentliche Verwaltung
Hochschule f€
ur O
und Finanzen Ludwigsburg
Ludwigsburg
Germany

ISSN 2366-0953
ISSN 2366-0961 (electronic)
Europeanization and Globalization
ISBN 978-3-319-39347-6
ISBN 978-3-319-39349-0 (eBook)
DOI 10.1007/978-3-319-39349-0
Library of Congress Control Number: 2016956105
© Springer International Publishing Switzerland 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
or information storage and retrieval, electronic adaptation, computer software, or by similar or
dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, express or implied, with respect to the material contained
herein or for any errors or omissions that may have been made.
Printed on acid-free paper
This Springer imprint is published by Springer Nature
The registered company is Springer International Publishing AG Switzerland


Preface

When we use the term personalized medicine, it implies the systematic use of
information about the individual patient with the goal of choosing optimal prevention and/or welfare therapy. The main focus of personalized medicine in current

medical treatment is to generate innovative treatments and drugs while reducing
negative side effects. Recent achievements in life science have created novel
opportunities to monitor and assess the progression of each individual patient’s
condition. The merit of these new capabilities lies mainly in the development and
application of high-throughput technologies that provide global insights into the
genomic-proteomic profile of diseases. New accomplishments in high-throughput
technologies such as transcriptomics that provides an entire insight into gene
activity in an organism, proteomics that gathers knowledge on global protein profiles, or metabolomics that provides information on metabolite status, will dramatically change molecular medicine and life science. At the same time, it should be
noted that genes and proteins cannot explain everything. One needs to consider
other complex elements, including molecular pathways, protein structure, secondary protein modifications, epigenetics, and many others. New methods to provide
some novel insights into biological mechanisms could include lipidomics,
glycomics, metabolomics, nutrinomics, and even complex structural genomics
methodologies and approaches. The use of these methods in medicine may allow
an individualized service for each patient and boost the progression in medicine
from the traditional focus on discovering new drugs to a new and more preemptive
approach. This change will bring about substantial social shifts that will change
socio-humanistic relationships and raise a whole series of important questions:
moral-ethical, legal, and socio-economic. These issues will result from current
challenges in medicine and humanity that are both faced with multiple processes
of globalization and fast changes in society. Some of the current issues relate to new
severe and fast-spreading infectious diseases, changes in the “behavior pattern” of
certain diseases, demographic change resulting from an aging population, and fast
and dramatic climate changes.

v


vi

Preface

This book offers comprehensive coverage of the various aspects of personalized
medicine as an original approach to classifying, understanding, treating, and
preventing disease based on individual biological differences. In the introductory
section, it defines personalized medicine as a way toward new medical practices
and addresses the question: what can personalized medicine offer citizens, medical
professionals and reimbursement bodies, and stakeholders? Subsequent chapters
discuss the technological aspects of personalized medicine: data collection, comprehensive integration and handling of data, together with key enabling factors in
developing the requisite technological support for personalized medicine. Lastly,
the book explores the main issues shaping the implementation and development of
personalized medicine—education, stakeholder participation, infrastructure, a
revised approach to the classification of disease and medical tests, regulatory
frameworks, and new reimbursement models—together with ethical, legal, and
social issues. Ultimately, the book calls for interdisciplinarity and a radical change
in the way we approach the health and well-being of individuals.
Target groups are medical doctors and researchers in the field of biomedicine, as
well as experts from social sciences dealing with legal, economic, and social
aspects of health system issues in general. The primary beneficiaries are therefore
from these groups of professional experts, but the presented content may attract the
widest possible readership as it deals with the issue of paradigm change in one of
the major society pillars—the health system.
We express our thanks to the University of Rijeka for their helpful support that
was essential for this enterprise. This publication is supported by the Croatian
Science Foundation project No. 5709 “Perspectives of maintaining the social
state: towards the transformation of social security systems for individuals in
personalized medicine” and the University of Rijeka project No. 13.08.1.2.03
“Social security and market competition.”
Finally, we owe our sincere gratitude to the Springer Verlag for recognizing the
value of our efforts and for its continuous support to our scientific endeavors.
Rijeka, Croatia

Rijeka, Croatia
Rijeka, Croatia
Ludwigsburg, Germany
10 March 2016

Nada Bodiroga-Vukobrat
Daniel Rukavina
Kresˇimir Pavelic´
Gerald G. Sander


Contents

Personalized Medicine: The Path to New Medicine . . . . . . . . . . . . . . . .
Kresˇimir Pavelic´, Sandra Kraljevic´ Pavelic´, and Mirela Sedic´

1

Legal Aspects of Personalized Medicine . . . . . . . . . . . . . . . . . . . . . . . . .
Ulrich Becker

21

Challenges of Personalized Medicine: Socio-Legal Disputes
and Possible Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nada Bodiroga-Vukobrat and Hana Horak

31

Embryonic Stem Cell Patents and Personalized Medicine

in the European Union . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Jasmina Mutabžija

53

Personalised Medicine and Public Health . . . . . . . . . . . . . . . . . . . . . . .
Vladimir Mic´ovic´, Iva Sorta-Bilajac Turina, and Ðulija Malatestinic´

81

Personalized Medicine and Technology Transfer . . . . . . . . . . . . . . . . . .
Petra Karanikic

95

Economic Evaluations of Personalized Health Technologies:
An Overview of Emerging Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Ana Bobinac and Maja Vehovec
Computational Methods for Integration of Biological Data . . . . . . . . . . 137
Vladimir Gligorijevic´ and Natasˇa Pržulj
The Role of Proteomics in Personalized Medicine . . . . . . . . . . . . . . . . . 179
Djuro Josic´ and Urosˇ Andjelkovic´
The Role of Radiology in Personalized Medicine . . . . . . . . . . . . . . . . . . 219
D. Miletic´, P. Valkovic´-Zujic´, and R. Antulov

vii


viii

Contents

Implantation of Toric Intraocular Lenses: Personalized Surgery
on the Lens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Iva Dekaris, Nikica Gabric´, Ante Barisˇic´, and Alma Bisˇcˇevic´
Personalized Medicine of Central Nervous System Diseases
and Disorders: Looking Toward the Future . . . . . . . . . . . . . . . . . . . . . . 241
Miranda Mladinic´ Pejatovic´ and Srđan Anzic´
Personalized Medicine in Gastroenterology . . . . . . . . . . . . . . . . . . . . . . 257
Davor Sˇtimac and Neven Franjic´
Personalized Medicine in Clinical Pharmacology . . . . . . . . . . . . . . . . . . 265
Dinko Vitezic´, Nada Božina, Jasenka Mrsˇic´-Pelcˇic´, Viktorija Erdeljic´ Turk,
and Igor Francetic´


Personalized Medicine: The Path to New
Medicine
Kresˇimir Pavelic´, Sandra Kraljevic´ Pavelic´, and Mirela Sedic´

Abstract Personalised medicine is a new paradigm that represents a shift from
current simplified consideration of the patient as a member of the population
sharing common fate of disease towards the view that each patient is a unique
individual. Every person has specific genomic/proteomic and metabolic signature
that could account for specific clinical features of disease, response to treatment and
disease severity. Therefore, disease and the treatment itself should be considered
individually. Due to a number of reasons for introduction of new paradigm in
medicine, implementation of personalised medicine is envisaged in several consecutive steps where projections of the levels of technology, medicine and integration need to be coordinated.

1 Introduction
Modern medicine faces great challenges, including rapid social changes resulting

from globalization, emerging new infectious diseases that spread quickly, alterations in clinical patterns of some diseases (e.g., drug-resistant tuberculosis),
and abrupt climate and demographic changes (i.e., aging). These are only some
of the issues that traditional medicine is likely to cope with great difficulties.

Professor Kresˇimir Pavelic´, M.D. Ph.D., Head of Laboratory for High-Throughput Analytics,
University Centre for High-Throughput Technologies, Department of Biotechnology, University
of Rijeka, Rijeka, Croatia.
Professor Sandra Kraljevic´ Pavelic´, Ph.D., University Centre for High-Throughput
Technologies, Department of Biotechnology, University of Rijeka, Rijeka, Croatia.
Assistant Professor Mirela Sedic´, Ph.D., University Centre for High-Throughput Technologies,
Department of Biotechnology, University of Rijeka, Rijeka, Croatia.
K. Pavelic´, M.D., Ph.D. (*)
Laboratory for High-Throughput Analytics, Department of Biotechnology, University Centre
for High-Throughput Technologies, University of Rijeka, Rijeka, Croatia
e-mail:
S. Kraljevic´ Pavelic´, Ph.D. • M. Sedic´, Ph.D.
Department of Biotechnology, University Centre for High-Throughput Technologies,
University of Rijeka, Rijeka, Croatia
© Springer International Publishing Switzerland 2016
N. Bodiroga-Vukobrat et al. (eds.), Personalized Medicine, Europeanization and
Globalization 2, DOI 10.1007/978-3-319-39349-0_1

1


2

K. Pavelic´ et al.

Consequently, the need for new, personalized medicine has arisen that would bring

about radical changes in health care systems. Such approach represents a shift from
the era of blockbuster drugs designed to treat all patients suffering from the same
disease towards individualized treatment based on unique features of each patient.
Medicine has been lately fragmented, which has produced a certain fragmented
approach towards patients. A paradoxical situation occurs where medicine has
reached a high level of technological advancement on the one hand, but on the
other hand, an integrated perception of the patient functioning as a result of overall
organ activities has been neglected. It is the personalized medicine approach that
places emphasis on the patient with all his/her biological features.1 Personalized
medicine is a new paradigm that represents a shift from current simplified consideration of the patient as a member of the population sharing common fate of disease
towards the view that each patient is a unique individual. Indeed, medicine should
primarily deal with an individual rather than with the majority. Every person has
specific genomic/proteomic and metabolic signature that could account for specific
clinical features of disease, response to treatment and disease severity. Therefore,
disease and the treatment itself should be considered individually. Previously, the
pharmaceutical industry assumed an attitude that “one drug fits all.” However, such
concept is about to change. Today, personalized medicine supports the idea that
drugs should be designed and prescribed according to an individual pharmacogenomics profile.2 To put it simply, up to now science and medicine have studied
diseases and drawn conclusions based on only a few parameters. Nowadays, we
know that humans have more than 20,000 genes and million different protein forms.
If we want to ascertain the roles of all these genes and proteins along with different
metabolites, lipids, glycolipids, etc. in disease pathogenesis, we have to explore all
of them. This makes the essence of new, complex, and comprehensive molecular
view of life and the world. It is rather naive to believe that studying a few
parameters would allow us to learn more about disease mechanisms and thus
prevent or treat diseases. Medicine has been so far successful in studying diseases
on the basis of the reductionist view. However, reductionism provides limited
answers to basic questions such as how biological systems function as a whole,
how they process dynamic information, and how they respond to perturbations such
as diseases. It is the complexity of biological systems that urges us to adopt a new

approach to medical research. Biological functions are the result of combined
activities of multiple molecular and cellular functions. Live systems act in a
nonlinear fashion, i.e., one input often produces multiple outputs. Therefore, there
are justified reasons to introduce a new paradigm in medicine so as to expand
current knowledge of disease origins and causes, biological markers for early
detection or disease stage, and molecular factors that affect the efficiency of
potential drugs.3

1

Pavelic´ et al. (2015).
Bosˇnjak et al. (2008) and Kralj and Pavelic´ (2003).
3
Catchpoole et al. (2010).
2


Personalized Medicine: The Path to New Medicine

3

It is easy to imagine that the application of such new paradigm, i.e. studying the
complex patterns of life, would contribute to early disease detection even before the
occurrence of clinical symptoms, discovery of new more efficient drugs, and more
precise disease diagnosis. The implementation of high-throughput methods into
medical practice holds great promise to facilitate development of personalized
medicine. The main application of these methods in medicine is prevention, and
secondary, design of new, more efficient drugs.4
New challenges that medicine has to cope with, its relative inefficiency and
development of sophisticated high-throughput global analytical methods that could

be easily implemented into clinical practice have led to the idea of establishing a
whole new paradigm in medicine. At the 55th Plenary Session of the committee of
European Medical Research Council, European Research Foundation in Copenhagen, Denmark, one of the authors of this paper put forward the project termed
“Forward look on personalized medicine for European citizens”, whose goal is to
implement state-of-the-art scientific and technological achievements (the so-called
high-throughput analytical methods) into everyday medical practice so as to make
health care better and more efficient. It comes without saying that an innovative
approach in medicine raises many scientific and social issues. The project has been
successfully completed, and personalized medicine has become one of the most
important medical topics under Horizon 2020.5

2 Definition and Elements of Personalized Medicine
Personalized medicine is a term coined to describe systematic usage of information
on individual patients with the aim to select and optimize prevention and treatment.
In other words, personalized medicine is a model of health care that customizes
individual differences of the patient in all phases—form prevention, diagnosis and
treatment up to post-treatment monitoring. Synonyms like genomic medicine,
stratification medicine, and precise medicine can be commonly found in literature.
Although these are undoubtedly important aspects, the term personalized medicine
is multidimensional and broader and encompasses pharmacogenetics, pharmacogenomics, pharmacoproteomics, predictive medicine, rational drug selection, systems medicine, individually tailored therapy, translational medicine, etc. All of
them represent elements of one integrated, new medicine.6
Genomic medicine is an important part of personalized medicine. The necessity
for development of personalized medicine stems from large quantity of data
obtained by the human genome sequencing. Personalized medicine largely relies
on predicting disease risk, treatment response, and safety profile based on genome
sequence data. Several important projects, in particular human genome sequencing

4

Bosˇnjak et al. (2008), Kraljevic et al. (2006), and Van’t Veer and Bernards (2008).

ESF Forward Look (2012).
6
Aspinall and Hamermesh (2007).
5


4

K. Pavelic´ et al.

in 2003, preceded personalized medicine, followed by the phase 1 and Hap-Map
projects in 2005 aimed at haplotypic mapping of human genome. The ENCODE
pilot project ensued, i.e., generation of the DNA elements encyclopedia in 2007
(identification and analysis of functional elements in 1 % of the genome). Subsequently, DNA sequencing of the genome was carried out with the aim to establish
diversity in 1000 human genomes.7
The most common perception of genomic medicine is providing information on
an individual risk of developing disease based on obtained genome sequence. These
data should be combined with other -omics methods, data gained by collecting
environmental samples, and data on the lifestyle of the patient. Only one approach,
e.g. genome sequencing, is not sufficient. Genome does not remain stable during
lifetime somatic mutations in different cell types can play the key role in the
development of many different diseases such as cancer, as well as in other polygenic diseases. During lifetime, changes can occur at both genomic sequence and
epigenetic level. It is not recommended to confine analysis to only one genomic
sequence and one cell type. Many valuable data can be lost if analysis is restricted
solely to peripheral blood cells, which are most commonly used due to their
availability. For personalized medicine, tissue analysis is more important than
peripheral blood cells, but invasive approach for collecting tissue samples does
not allow the usage of tissues as primary sample source for analysis. For this reason,
it is indispensable to figure out noninvasive methods, minimally invasive methods,
and single cell analyses.8

Stratified medicine is limited to identification of the patient subgroups with
particular diagnosis that respond to a specific treatment, and therefore it represents
only one but important element of personalized medicine, as evidenced by a few
examples of its current clinical application, including the drugs gefitinib and
erlotinib used to treat nonsmall cell carcinoma patients bearing the mutation in
EGF-R gene or vemurafenib designed for treating metastatic melanoma patients
with the V600 mutation in BRAF gene.9
Third and most commonly used synonym for personalized medicine is precise or
-omics-based medicine that points to specific elements underlying pathology of a
particular subject at a single point in time. Simply, it means getting the right drug to
the right patient at the right time. This term encompasses stratification tools and
takes into account a huge number of diverse factors that can impact disease
development in a particular subject (not only genomic and biological but also
environmental factors and lifestyle as well) and efficiently predicts disease (preventive medicine). In summary, personalized medicine should be perceived as a
whole, genomic, layered, and precision medicine involving four proactive principles. It also implies the transfer or responsibility from medical personnel to
individual subjects (excluding old and helpless subjects and infants).10

7

Goldstein et al. (2003).
Aspinall and Hamermesh (2007), Goldstein et al. (2003), and Van’t Veer and Bernards (2008).
9
Clark et al. (2006).
10
ESF Forward Look (2012), Bosˇnjak et al. (2008), Petricoin et al. (2002), and Li et al. (2008).
8


Personalized Medicine: The Path to New Medicine

5

3 Difference Between Traditional and Personalized
Medicine
Even now one can notice great differences and advantages of personalized medicine. Traditional medicine relies on the trial-and-error method. The patient presents
with symptoms, and the doctor establishes the most probable diagnosis and treatment. Drug dose is determined by the subject’s weight. If the drug does not work,
the new dosage or drug is prescribed. Alternatively, the doctor establishes new
diagnosis and new treatment. The cycle is repeated until the right or more accurate
diagnosis has been reached and the new treatment plan has been set. On the other
hand, personalized medicine means to diagnose more precisely onset of the exact
disease. This is followed by selection of the most adequate treatment and dosage by
using personalized medicine tools taking into consideration the patient’s specific
physiology, tumor, viral or bacterial physiology (if possible), and patient’s ability to
metabolize a specific drug. What stands in the way of the transition from traditional
to personalized medicine? According to Aspinall and Hamermesh, there are several
key obstacles, among which the pharmaceutical industry stands out, i.e., historical
success of blockbuster drugs (one drug fits all). The next obstacles include regulatory environment, which is not fit for personalized approach, and irrational economy, which is reflected by exaggerate costs of medical examinations and drugs
instead of supporting diagnosing in the function of prevention. One of the hurdles is
also linked with medial doctors’ habits heavily relying on trial-and-error
medicine.11
Pharmaceutical industry nowadays is most likely faced with a breakdown of
blockbuster drug system. Although the financial support for drug R&D has
increased (almost three times since 1990), the number of new molecular entities
approved by FDA (1993–1997) has dropped from 33 to 26 a year. This resulted in
the inability of the pharmaceutical industry to design a sufficient number of new
drugs. There is the impression that in spite of this, the pharmaceutical industry does
not express too much interest in developing targeted therapy and does not approve
drugs associated with prevention and diagnostics.
There are certain disciplinary presumptions for personalized medicine, above all
radical changes in the mode of an individual approach to the patient. The challenge

of personalized medicine is, besides interdisciplinary, how to reach interdisciplinary consensus that allows specific challenges—regional, organizational, and disciplinary. Furthermore, it is of utmost importance to integrate data at multiple levels:
statistical biological data with dynamic physiological data, data on environment,
lifestyle, and geographical location of the patient.
Key factors that may influence the development and implementation of personalized medicine include education, participation of the third, multidisciplinarity
(and beyond), infrastructure, revised disease classification, revised test models,

11

Pavelic´ et al. (2015) and Aspinall and Hamermesh (2007).


6

K. Pavelic´ et al.

regulatory frameworks, models of health service payment, and ethical, legal, and
social issues. All participants in this process will be assigned some new roles.
Health professionals will have to make decisions based on complex biological and
environmental information and lifestyle. Bioscientists and technologists will have
to closely cooperate and fulfill the needs of medical professionals responsible for
patients’ care. Citizens will have a unique opportunity as well as responsibility for
their own health via active monitoring, prevention and measures, and even direct
treatment selection.

4 What Personalized Medicine Has to Offer?
This question should be considered from the point of view of individuals, medical
staff, and health insurance, i.e., stakeholders. When it comes to an individual, this
primarily means a deviation from the one-size-fits-all approach towards the system
in which health care is based on the individual biological feature of each subject
within the framework of specific sociocultural and environmental context. For a

patient, it implies safer and more efficient treatment. For those wishing to participate in such system for a long-term period, it means individually tailored therapy
and preventive strategy based on continuous monitoring of biological profile.
When it comes to health professionals, safety and accuracy of therapeutic
decision will be raised due to more efficient individualized therapy. Better therapy
will be the consequence of better diagnostics (and improvement of the decisionmaking system due to the advancement of information and communication technology). All of these will result in better relation between the patient and medical
doctor. Great amount of information poses new challenges to the medical doctors,
including education. Personalized medicine will be developing in parallel with
disease reclassification. Current classification is based on the symptoms characteristic for one organ or system. With the advent of biology, classification will be
based on molecular pathways involved in the process. This change in disease
taxonomy is of particular importance to chronic diseases (e.g., inflammatory), as
many of them share common aetiology in spite of differences in individual phenotypes. New disease reclassification will allow the current drugs to be administered
with higher success rates and will provide the opportunity to successfully apply
those drugs in particular stratified patient groups that were previously shown to be
ineffective. Personalized medicine will allow collection and monitoring of data
during lifetime. Such approach allows better prevention and an early intervention.
Individuals will be able to create their own databases of physiological data and to
promptly identify pathological changes without the need to study data obtained in
larger population.


Personalized Medicine: The Path to New Medicine

7

5 Influence of Personalized Medicine on Participants
Great impact of personalized medicine will be visible in the health insurance
system and stakeholders. Although personalized medicine is often referred to as
an expensive medicine, a personalized approach will eventually reduce health
insurance costs. The examples of savings are numerous, particularly those found
in stratification medicine. For example, EGFR mutation testing in France required

1.7 million € but led to the savings of 69 million € during the treatment of nonsmall
cell lung carcinoma with gefitinib. Similarly, savings of 30,000 € per patient
afflicted with colon cancer bearing K-Ras mutation and tested for EGFR were
achieved in nonresponders to EGFR antagonists. There are many other similar
examples.
Initially, the costs of expensive diagnostics may rise, but in the perspective, the
savings will be evident due to more efficient prevention and early intervention,
especially in chronic patients. The costs of investment into new technologies and
infrastructure will provide cheaper and more efficient protection for future generations. Drugs inefficient in a preponderance of the population members may prove
efficient in the particular defined cohort. Although perhaps more expensive at the
beginning, health care will be ultimately cheaper for the aforementioned reasons
derived from personalized medicine.
When speaking about the influence on medical industry, it is difficult to predict
the outcome. Maybe drugs will be produced that would be efficient in the particular
defined cohort, which is useful for both the industry and patients. Clinical investigations could be more accurate by selecting more adequate patient samples. New
test models will have to be developed. In silico studies will represent an important
step forward in the development of precise clinical tests. It is likely that the
development of biotechnological and medical technology will be fostered in comparison with the drug industry.
Destiny of personalized medicine will depend on the ability to integrate complex
information derived from multiple sources and on the preconditions; among the
most important ones includes advanced technology (with the aim to produce and
manage data). Technological and other preconditions include, among others,
advanced high-throughput -omics technology (genomics, epigenomics, proteomics,
metabolomics, lipidomics, etc.), microbiomics, molecular imaging, physiological
monitoring, environmental exposure, lifestyle, the ICT analysis and data management, and their conversion to useful outcome.
The following scenario is possible: collection of clinical data is ensued by
-omics analysis in one day that encompasses individual metabolic profile, protein
expression and localization, mRNA expression, epigenomic signature in specific
cell type, data integration and interpretation and prediction of individual risk and
disease course, and finally treatment response, i.e., adverse side effects.

Informatics-computational technology is an important component of personalized
medicine. So far, it has been exploited in physics for demanding experiments and
show business. In biomedicine, its application commenced with genomic era.


8

K. Pavelic´ et al.

Quantity of data obtained by -omics methods significantly exceeds current analytical ability. Data storage currently represents an irresolvable issue. There is neither
careful and systematic storage nor genuine data integration.

6 Technological and Infrastructural Presumptions
One of the keys of success of personalized medicine is infrastructure. Development
of European infrastructure will facilitate harmonization of protocols, integration,
and interpretation of data derived from multiple population. This poses a challenge
of interdisciplinarity: the concept of personalized medicine, although straightforward, includes radical changes in the approaches of health care system towards an
individual person. Therefore, there is a need for restructuring the health care
system—detachment of health care professionals from the so-called organ-based
specialities.
In order to understand technological challenges for future personalized medicine, it is indispensable to focus on three areas: (1) defining the requirements of
medicine and the health care system – determine if technology can meet the
expectations of the key groups involved in the implementation of personalized
approach; (2) what the technology has to offer to personalized medicine – due to
significant technological improvements in the field, one can expect major breakthrough in the future; (3) how to efficiently integrate information as to ensure
complete systematic “readout” of individual health status in defined environment.
It is necessary to say a few words about the importance of high-throughput
methods to make personalized medicine become a reality, although this issue has
already been specifically covered by several chapters in this book. Development of
high-throughput methods and their application in medicine are the key to the

development of personalized medicine. High-throughput methods and
nanomedicine representing the technological foundation of -omics are generally
expected to bring about more personalized approach to treatment of many diseases,
increase efficacy of pharmaceutical therapy, reduce adverse drug effects. The
-omics methods such as transcriptomics, proteomics, metabolomics, lipidomics,
glycomics, structural genomics, etc are already based on nanotechnologies. This
particularly applies to the so-called DNA and protein arrays. The term -omics
encompasses global characterization method of all or majority of members belonging to the particular molecular family in a single step or analysis. Transcriptomics
represents systematic analysis of all genes in an organism, while proteomics
denotes systematic analysis of protein expression under specific conditions, which
include separation, identification, and characterization of protein in an organism.
The term proteome, which was coined in 1994 as a linguistic equivalent of the term
genome (Protein complement to a genome), denotes complete protein content that


Personalized Medicine: The Path to New Medicine

9

genome expresses during lifetime.12 These methods can give a global insight into
the molecular profile of the affected subject.
Human genome studies involving around 23,000 genes encoding for much larger
number of different transcripts result in better understanding of disease process at
molecular level. However, changes at genome and transcriptome level are mirrored
by proteome aberrations. Challenge in the comprehension of proteome complexity
lies in the determination of a number of different protein species that may surpass
one million and in a large number of regulatory levels of protein expression and
activity that sustain cellular function and tissue homeostasis.13
Functional components such as molecular complexes, signalling networks, and
whole organelles are very important regulators of cellular processes. Proteins are

individual components of these functional parts with multiple levels of regulation,
which includes protein “circulation” (recycling and degradation), posttranslational
modifications, subcellular localization, and protein–protein interactions. The latter
leads to formation of complexes such as those implicated in the cell signal transduction or cellular architecture. It is a huge challenge and, at the same time, of
enormous importance to integrate knowledge gained through global highthroughput studies, in particular genomics and proteomics, in order to obtain better
understanding of the molecular nature of diseases and develop a “cellular map.”14
Proteomics is a method with progressive and fast development that greatly
benefits from the development of mass spectrometry and other high-throughput
analytical tools with the aim of comprehensive bioinformatic analysis. Obtained
results are already encouraging and complementary to those obtained at genome
and transcriptome level. The result is better understanding of the disease, such as
glioma, from the perspective that includes protein expression, interaction, and
function. The potential benefit of understanding disease process based on proteome
is not questionable since it includes the possibility of diagnosis, classification,
prognosis, and assessment of therapeutic effect and ultimately leads to genuine
personalized medicine based on the patient’s proteome.15

7 The Impact of Personalized Medicine and Implementation
The impact of personalized medicine will be significant for both patients and the
medical profession. Medical doctors will expect integrated information from many
different sources, including -omics and molecular imaging. Obtained data should
provide support for the right decision and the sequence of actions for each individual patient. One can presume that proof of principle would be achieved in the

12

Petricoin et al. (2002) and Espina et al. (2004).
Editorial (2003).
14
ESF Forward Look (2012), Editorial (2003), and Ferrari (2005).
15

Sedic´ et al. (2014).
13


10

K. Pavelic´ et al.

following 5 years. Clinicians should be convinced that the new technology will
offer tangible results. It is important to prove clinical applicability, value, and
relevance of all new technologies; identify stable biomarkers; validate known
biomarkers; and confirm their application in the risk assessment and prediction of
outcome. Diagnostic tests for preselective screening should be 100 % reliable. It
will be indispensable to prove to health professionals the clinical benefit of new
biomarkers, in particular in asymptomatic, apparently healthy subjects. There is
also a possibility of inflating the risk of overdiagnostics and false positive results. It
is necessary to forward particular technological steps and interpretations such as
exploitation of biobanks and clinical sample collection program so as to ensure
global approach to technological support and infrastructure (path to integrated
model, including central reference database). Perhaps in this context of proof of
principle the focus should be placed on some specific diseases such as diabetes,
asthma, rheumatoid arthritis, cardiometabolic diseases or on some subgroups, e.g.,
nonsmall cell lung carcinoma, where tangible results could be observed in a short
period.16
One can presume that implementation of personalized medicine will last for
20 years. In the first 5 years, it will be necessary to confirm the personalized-omics
proof of principle. Determination of genomic, transcriptomic, proteomic,
metabolomics and auto-antibody profiles means that the same type of analysis
will be carried out several times in the same individual. The generation of dynamic
integrative personalized-omics profile (iPOP) will ensue; destiny of personalized

medicine is an emphasis on individual data rather than on an average population
data. Important data obtained individually can be lost or masked in population
study. iPOP can serve to guide lifestyle changes in order to prevent disease. It will
be necessary to address the issues such as data interpretability, patient’s choice,
privacy, ethical usage of personalized data, etc.
In the next 10 years, one could expect that health professionals would be more
eager to accept and support personalized approach once the technology confirms
clinical value. It is a must to develop algorithms based on the interaction between
different -omics and environmental data (e.g., lifestyle). These data would be
integrated with those obtained by molecular imaging methods. Technology would
have to be developed and adapted for a lifetime monitoring of individual health.
Long-term vision means the creation of personalized database that will accompany
each individual from birth (and even prenatal), taking also into account geographical locations in which this person resides. This also implies management of data
that are sensitive and personal, construction of sensor for real-time data monitoring
for each subject, the matter of exchange and limitation of those personalized data.
One of the greatest challenges would be translation from “bench to bedside.”
When personalized medicine enters clinics, technological requirements would
be to increase preciseness and reduce the time necessary to respond. Molecular
imaging technologies may possibly undergo changes. The current problem lies in

16

Walker and Mouton (2006), Pavelic´ et al. (2015), and Kraljevic´ et al. (2004).


Personalized Medicine: The Path to New Medicine

11

data processing and interpretation. It is necessary to integrate imaging technology

with real-time monitoring of health status and treatment efficiency. The processing
period should be shortened while maintaining preciseness. Advancement in this
area will be crucial for the complete integration of personalized medicine into
clinics. This will largely depend on the availability of nanodevices and nanotools.
It is important to identify which technologies could be realistically employed in
clinics. One must validate technology and gain insight into its reproducibility for
technological procedures, data collection, and manipulation. Quality assurance
protocols for laboratories have to be developed and made available at all levels.
Harmonization represents a decent basis for data management and obtaining realistic databases that can be used later. The current problem is that more data are
collected than can be processed or even stored.17
One option includes the application of in silico models that use only variable
data, which represents a significant reduction in the volume of invariable data to be
stored. In the next 20 years, the implementation of integrated models follows: the
need for systematic, longitudinal data collection, then setting rigid standards for
data collection, processing, and recording. Harmonization and establishment of a
framework for data disposal will be the key to success of personalized medicine.
One could also expect the establishment of electronic data and personalized
medicine portals like the existing PatienstLikeMe and Quantified Self.
PatientsLikeMe is an electronic source of clinical and scientific data, i.e., electronic
platform generated with the aim to help affected subjects to share and learn from
real-world, outcome-based health data. This includes information on symptoms,
quality of life, treatment options, specific disease variables, and other factors.
Quantified Self is a platform for citizens who collect their own data on their
lifestyle, eating habits, physical activities, physiological variables, and emotional
condition. The usefulness of such data for personalized medicine is generation of
data on profitability and monitoring of long-term effects of personalized
interventions.

8 Personalized Preventive Medicine and Diet
One of the major goals of personalized medicine is setting up efficient disease

prevention. Preventive medicine implies disease discovery before symptoms appear
or detection of disease susceptibility with the aim to prevent. It will be important to
integrate novel genetic information on epidemiologic studies so as to reveal the
causal relation between lifestyle and genetic factors in order to assess the risk of
disease. An illustrative example is given by atherosclerosis: arachidonic acid
(polyunsaturated n-6 fatty acids) in the presence of enzyme 5-lipoxygenase gives
rise to inflammatory mediators leukotrienes. Variants of 5-lipoxygenase genotype

17

Bosˇnjak et al. (2008) and Kraljevic´ and Pavelic´ (2005).


12

K. Pavelic´ et al.

are identified in the individuals with increased susceptibility to atherosclerosis.
There is also a relationship between genes and diet: n-6 polyunsaturated fatty acids
facilitate, while n-3 fatty acids originating from sea inhibit leukotriene-mediated
inflammation leading to atherosclerosis.18
Nutrition plays the key role in health and disease. With the development of
molecular biology, there had been a shift from epidemiology and biochemistry to
understanding the molecular mechanisms of action of diet. A new discipline has
emerged, nutrigenomics, which represents the study of the effects of nutrition on
genomic level. Nutrigenomics analyzes the complex relation and consequences of
the interaction between individual genes and environment, including diet.
Nutrigenetics is related to nutrigenomics, and it investigates the effects of genetic
variations on diet–disease interaction. Food components may have adverse effects
on molecular processes like DNA structure, gene expression, and metabolism.

Major methodological challenges would be to integrate genomics, transcriptomics,
proteomics and metabolomics to define the so-called healthy phenotype. Classical
high-throughput methods will be used in parallel with RNAi and
nanobiotechnology. There is urgent need for generation of big versatile ethical
database of genomic profile.19
Nutrigenomics and functional food create the need for further and intensive
studies on interactions between genes and diet so as to achieve rational selection of
functional food, which paves the way for optimal health and reduction of risks of
chronic diseases. The purpose of such approach is to establish useful personalized
nutritional counselling. Individual genetic variations are important determinants of
differences for nutritional ingredients. This is exemplified by common genetic
polymorphism C/T substitution in the gene coding for methylene tetrahydrofolate
reductase (MTHFR), which results in metabolic changes that modulate the risk of
chronic disease defects of neural tubes in the absence of folate. Increased folate
uptake has different consequences in affected subjects (T/T) in comparison with
normal (C/C) or heterozygotes (C/T).
In future, it will be necessary to adapt nutritional advice on the basis of genotype
and establish a so-called personalized diet. Nutrigenomics is likely to revolutionize
clinical and public nutritional practice by providing more precise “targeting” of
nutritional interventions. In particular, this will prove useful for diseases related to
metabolism and diet such as diabetes, cardiovascular diseases, some neurological
disorders, age-related diseases, cancer. Individual response to diet varies.
Chemicals from food can bind to receptors and thus regulate gene activity. For
example, genistein (coumarin-like isoflavone derivative) from soya binds to estrogen receptors (ER) and induces gene regulation. Individual variations in ER
determine different response to genistein. Interaction between genotype and diet

18
Pavelic´ et al. (2014), Catchpoole et al (2010), Subbiah (2007), and European Science
Foundation (2005).
19

Astley (2007).


Personalized Medicine: The Path to New Medicine

13

influences severity of disease such as obesity, atherosclerosis, asthma, and other
chronic diseases.20
Functional food represents nutrients with beneficial effects on human health
irrespective of supply of essential physiologic needs. Due to varying individual
response, it is difficult to make general recommendations and statements. Efficacy
of nutrients is affected by polymorphisms in genes regulating absorption, circulation, and metabolism. An example is n-3 polyunsaturated fatty acids or
epigallocatechin-3-gallate. More research into interaction between genes and diet
should be conducted to achieve rational selection of functional food, which leads to
optimal health and reduction of the risk of chronic diseases with the aim to establish
useful personalized nutritional counselling.21
Important component of personalized medicine is the role of citizens in maintaining
their own health and prosperity and in providing data that will aid in achieving
prosperity for others through understanding individual variations, population needs,
and response to therapy and preventive measures. Development of individually tailored therapy and preventive medicine will depend on our ability to interpret the
relevance of biological and environmental variations by using data obtained in large
population. Patients can no longer be only passive acceptor of information given by
medical professionals but should be active participants in the generation and interpretation of own data. Medical doctors are expected to actively participate in the development and adoption of new technologies and decision-making systems and
diagnostic algorithms. The sustainability level of the trial-and-error approach is
astonishing, even in cases where knowledge of the abovementioned exists!22

9 Studies Indispensable for the Development of Personalized
Medicine
Similar to clinical investigations, studies necessary for the development of personalized medicine include analysis of data obtained from large population studies

(groups of individuals sharing the same or similar characteristics such as the
environment in which they were born or grew up, age, etc.) and collection of
biological samples (biobanks).23
Combination of carefully classified biological samples and detailed relevant
clinical information obtained from biobanks comprise the instrumental components
of research infrastructure that will facilitate the generation of much better, more
detailed classification of disease subtypes and act as impetus for the development of
personalized medicine of the twenty-first century.
20

M€uller and Kersten (2003).
Ries and Castle (2008).
22
Aspinall and Hamermesh (2007).
23
Hewitt (2011) and Spaventi et al. (1994).
21


K. Pavelic´ et al.

14

In order to better comprehend factors responsible for the biological basis of
individual differences and environmental and lifestyle factors, it is necessary to
analyze data from hundreds and thousands of subjects covered by these studies.
Such studies are extremely expensive, so that it is important to manage their results
in the right and professional way. It is the results of such studies that are important
for the development of personalized medicine. Methods for collection of data on
phenotype, diagnostic criteria, lifestyle, and environment will be used. Some of

these parameters change during lifetime. Furthermore, with the advancement of
knowledge, new questions would arise demanding new studies and new patient
cohorts, demographic data, which may not exist in the previous research. Therefore,
it is crucial to update and improve phenotypic and environmental databases to
advance research that should lead to truly personalized medicine. For this reason,
the path to truly personalized medicine is long.24
Studies in particular groups provide knowledge of diseases with respect to the
combination of internal and environmental factors. Even more important is the fact
that they ensure a prospective approach in which disease development can be
analyzed during time in the population that is better defined.
It is assumed that genetics is an important factor that determines susceptibility of
the particular individual to disease. In the last years, a breakthrough in methods
such as genome sequencing and whole genome association studies has resulted in
the identification of link between 1888 single nucleotide polymorphisms (SNP) in
210 different diseases.25 Although this link accounts for only a small portion of
genetic predisposition to common diseases, such and similar studies have already
yielded numerous potentially significant results.
Genetics is only one path towards understanding individual disease variations.
Research priorities in personalized medicine include analysis of data on life events
and environmental factors in relation to epigenomic, proteomic, metabolomics, and
transcriptomic features. To make sure that the results of these studies are truly
valuable, data should be carefully processed and continuously updated so as to take
into account demographic changes and progress in knowledge.

10

Timeline for the Development and Implementation
of Personalized Medicine

According to some scenarios, implementation of personalized medicine could take

up to 20 years. All the while, projections of the levels of technology, medicine, and
integration need to be coordinated (Table 1). In the EFC Forward Look document,
predictions over the period of 5, 10, and 15 years with tasks and phases defined to
detail can be found (Table 2).
24
25

ESF Forward Look (2012).
accessed on January 1st 2016.


Personalized Medicine: The Path to New Medicine

15

Table 1 Projections for technological, medical, and integrational consideration for implementation of personalized medicine (modified from ESF Forward Look 2012)
Projections
for
Technology

5 years
Linear technologies
Genomics,
trancriptomics,
metabolomics, etc.
Environmental
monitoring

Medicine

Integration

10 years
Building interaction
networks
Molecular interactions

20 years
Measuring dynamic
networks in vivo
Real-time monitoring

Gene–environment
interactions
Human resources

Remote sensing

Proof of principle

Introduction

Target available technology on one disease area

Cumulative data to follow
the person

Identify available
resources (electronic
health records, cohorts,

etc.)
Enhance biobanks and
clinical sampling
Expand measures for
healthy individuals

Dynamic qualitative/quantitative measures

Discovery
Core, -omics
technologies
Epigenetics
Prototype model

Synergistic outputs from
multiple markers
ICT infrastructure to support real-time health care
delivery across regions
Noninvasive information
collection and sharing
Increased precision of
imaging technologies and
therapy
Validation
Definition of purpose
Achievabe targets
Testing of infrastructure

Alerting mechanisms
Responsive user

interfaces
Implementation and
refinement
Integration of imaging
technology in physiological monitoring
In silico model for
individual patients

Real-time monitoring
(nanomaterials)
Remote monitoring/
personalized
telemedicine

Implementation
Nanotechnology
Longitudinal data
Systematic data
collection
Enforcemet of
standards
Data sharing
E-learning


K. Pavelic´ et al.

16

Table 2 Timeline for the development and implementation of personalized medicine (modified

from ESF Forward Look 2012)
Phase 1
Education
Regulatory
frameworks
Public dialogue

Phase 2
Applicaton of metrics
Responsible governance frameworks

Phase 3
In silico models
Remote sensing

Patient-centered partnerships

Infrastructure
planning
Collection of reference data
Stakeholder
participation
Proof of principle
Biomarker validation
Data standardization

Harmonization of procedures

E-learning and adaptable
interfaces

Real-time monitoring

Interaction networks (molecular and
environmetal)
Infrastructure testing

Systematic data collection

Data integration
Data sharing
Dynamic monitoring

The development and the implementation of personalized medicine will occur in
three precisely defined phases. In the first phase, next to education and regulatory
framework, an important role will be played by the dialogue with the users,
stakeholder participation, standardization, and proof of principle.
The second phase will be marked by action harmonization, creation of an
interacting network (molecularly as well as environmentally), data integration,
and monitoring.26
The third phase will be labeled by in silico models, systematic collecting of data,
and nanomedicine implementation. All the while, one has to keep in mind possible
issues and key factors that could influence the development and implementation of
personalized medicine, e.g., education, participation of a third party,
multidisciplinarity, infrastructure, revised disease classification, regulatory framework, models for compensating the costs of medical care, ethical, social and legal
questions (Figs. 1 and 2).
Acknowledgements This text is supported by the Croatian Science Foundation project “5709 –
Perspectives of maintaining the social state: towards the transformation of social security systems
for individuals in personalized medicine” and University of Rijeka research grants 13.11.1.1.11
and 13.11.1.2.01. We greatly acknowledge the project RISK “Development of University of
Rijeka campus laboratory research infrastructure”, financed by European Regional Development

Fund (ERDF).

26

Huser et al. (2014).