Introduction into PPPM as a new

paradigm of public health care services: from knowledge of the past, through today’s expectations to strive for

the promising reality of tomorrow

Dr Sergey Suchkov, MD, PhD Professor in Immunology & Medicine

I.M.Sechenov First Moscow State Medical University, Moscow, Russia

A.I.Evdokimov Moscow State Medical & Dental University, Moscow, Russia

EPMA (European Association for Predictive, Preventive and Personalized

Medicine), Brussels, EU

Prof. Dr. Olga Golubnitschaja, PhD

Prof. Dr. Olga Golubnitschaja, PhD

Secretary-General, European Association for Predictive, Preventive and Personalised

Medicine (EPMA), Brussels, EU

Predictive, Preventive and Personalized Medicine

associated with Subclinical Diagnostics

GENERAL CONCEPT

www.springer.com

Predictive, Preventive and

Personalized Medicine (PPPM) as applicable to:

1. Diabetes Care

2. Neurodegenerative Diseases

3. Cancer

4. Cardiovascular

Diseases

5. Reproductive Medicine

&

Paediatrics

6. Body culture & Sport Medicine

2-years

cycle

of 6 issues

Predictive Diagnostics as the first step to

Predictive Diagnostics

Professional Education

Medicine

Biotechnology

Bioinformatics

Targeted European Programmes

Research Budgets

Targeted National & EU Calls

Knowledge Transfer

Standardisation Patenting, Licenses, Publications

Industrial Production

Issue-related multifunctional activities

Insurance

Long-lasting cost-benefit concept in favour of prevention

Laboratory Diagnostics

Application of optimal standardised approaches

Medical practice

Preventive Measures & Personalised Patient Treatment Ethics

Targeted Prevention & Personalised Treatment

The Genomewide Association Study The genomewide association study is typically based on a case–control design in which single-nucleotide polymorphisms

(SNPs) across the human genome are genotyped.

Panel A depicts a small locus on chromosome 9, and thus a very small fragment of the genome.

In Panel B, the strength of association between each SNP and disease is calculated on the basis of the prevalence of each SNP in

cases and controls. In this example, SNPs 1 and 2 on chromosome 9 are associated with disease, with P values of 10−12 and

10−8, respectively.

The plot in Panel C shows the P values for all genotyped SNPs that have survived a quality-control screen, with each

chromosome shown in a different color. The results implicate a locus on chromosome 9, marked by SNPs 1 and 2, which are

adjacent to each other (graph at right), and other neighboring SNPs

EPITOPES

Common serum cancer-associated

biomarkers & biopredictors (proteomics)

Genes and loci implicated into the inheritance of common

malignancies and serve as genomic biomarkers (according to the risks among heterozygotes)

Subclinical (cryptic) latency

(1) to predict the likelihood of developing disease;

(2) to estimate the length of the asymptomatic

period;

(3) to provide predictive information about disease

course, severity, and complications;

(4) to serve as a warning to avoid potential disease-

triggering factors;

(5) to identify high-risk individuals who might be

suitable candidates for preventive intervention

trials

Impacts to be assumed for

the practical implementation of

predictive biomarkers and biopredictors

into PPPM

This illustrates a functional state of a cell

at the level of metabolism illustrating all

metabolic pathways in the cell at a given

time span

• How the human genome has opened up a broad

spectrum of predictive approaches for genetic

diseases by screening individual genes, SNPs,

and haplotypes

• How protein and RNA microarrays are

providing new insight into the nature, subclinical

and clinical courses, and prognosis of certain

ongoing diseases

• How autoantibodies (autoAbs) which now are

known to be present years before the clinical

onset of a number of autoimmune diseases are

being used as predictive biomarkers to enter

high-risk subjects into therapeutic intervention

trials

Two key objectives of PPPM are:

(i) detection of subclinical

abnormalities with a selection of

suitable pharmacotherapeutic

targets for the next step of PPPM

protocol, i.e., drug-based

prevention

(ii) drug-based correction of the

abnormalities detected under

preventive measures.

PPPM thus uses diagnostic tests of newer

generations, particularly genomic, proteomic, and

metabolomic biomarkers, to individually determine

the health conditions a person is predisposed to and

to reveal the agents of the probable or the already

existing pathological processes.

The predictive branch is mainly designed

to meet the interests of healthy individuals, its

purpose being to determine whether susceptibility to

a particular disease is increased or not.

Preventive medicine is aimed at taking

measures to avoid disease development rather than

cure or treat it on manifestation

Personalized medicine proposes the

customization of healthcare, with all decisions and

practices being tailored to the individual patient by the

mutual integration of clinical information, stable and

dynamic genomics, and molecular phenotyping through

bioinformatics.

Personalized medicine generally

promises to result in both higher quality in treatment for

individual patients and in lower costs in healthcare since

patients will be offered only such therapies that are more

effective for them and treatments that will not be safe or

effective will be avoided. Recent advancements in

biomedical and genomic sciences have paved the way to

translate such research into clinical practice and health

policies.

Immune

response

genes

HLA-

genes

Nuclear related

metabolism

Mitochondrial

metabolism and

redox metastasis

Ribosome

genes

Ribosome

and

translation

genes

Cytoskeleton

genes

Metal ion

homeostasis

Extracellular

matrix and

adhesion

CD antigens

and plasma

membrane

signals

Human gene co-expression

networks

Disease- and

oncogene-related

gene networks

Deafness

Cardiomyopathy

OBESITY

Asthma

Leukemia

Colon

cancer

T1D

Ovarian

cancer

GB

Disease-related

gene networks

Genes and loci implicated into the inheritance of common

malignancies and serve as genomic biomarkers (according to the risks among heterozygotes)

Deafness

Cardiomyopathy

OBESITY

Asthma

Leukemia

Colon

cancer

T1D

Ovarian

cancer

GB

Disease-related

gene networks

Common serum cancer-associated

biomarkers & biopredictors (proteomics)

Subclinical (cryptic) latency

Subclinical stage

Clinical stage

T1D

Первичный

патоген-инфект

(например, ВЭБ)

1. Стадия

индукции РС

(доклиническая

стадия)2. Стадия

формирования

ПИФАС

3. Стадия начала

воспаления и

демиелинизации

4. Стадия развернутой

клинической картины ПИФАС

1. Subclinical stage

of MS (symptom-free) 2. A stage to illustrate

PIFAS formation (symptom-free)

3. A stage to illustrate

starting up of

inflammation

4. A stage to illustrate formation

of clinical manifestations

Brain-Blood Barrier

APC

APC

HLA II

IL4/IL10

IL12

Multiple sclerosis

MS: autoimmunity, demyelination and neurodegeneration Anti-myelin autoAbs and autoreactive CTLs are able to to make

oligodendrocytes and axons damaged in direct and indirect ways to result in

demyelination and neurodegeneration, respectively

Blood

TCR

Neuron

Myelin sheath

Axon

Antimyelin Abs

Damage

Microglia Oligodendrocyte

Damage

Complemen

t

T cell

CTLs

CTLs

CNS

Autoantibodies (by green fluorescence)

in human islets exposed to blood from a patient with IDDM1 (the surrounding area is dark because it lacks islets because of еру autoimmune inflammation/insulitis)

Major Histocompatibility Complex

(MHC-HLA) in Humans

HLA Class II HLA Class III HLA Class I

Differential Roles of Risk Loci in the Pathogenesis of T1D

Many risk loci for

IDDM1 may exert

their effects through

the immune system

(HLA, presumably).

Within the immune

response, these

genes can act at

multiple levels,

affecting the

establishment of the

immune repertoire,

the function of cell

types in the immune

system, or the

regulation of

cellular responses

that can lead to

autoimmunity.

Subclinical (cryptic) latency

Autoantibodies (by green fluorescence)

in human islets exposed to blood from a patient with IDDM1 (the surrounding area is dark because it lacks islets because of еру autoimmune inflammation/insulitis)

Subclinical (cryptic) latency

Three different steps are described during cancerogenesi:

initiation is a rapid and irreversible DNA lesion which

occurs after exposure to a carcinogen (physical

carcinogen, chemical carcinogen, viral carcinogen)

promotion is due to prolonged, repetitive or continuous

exposure to substances which maintain and stabilise the

initiated lesion,

progression is the acquisition of non controlled

multiplication properties, independence acquisition, loss of

differentiation, local invasion and metastasis.

• The strategy of preventive therapy should contain, at least, two critical steps.

For chronic autoimmune diseases:

(i) arrest of autoagression; and,

(ii) restoration of structure and functions of the

tissue affected.

For cancerogenesis:

(i) prevention of the initiation and metastatic

activity; and,

(ii) restoration of structure and functions of the

tissue affected.

• Prevention of the initiation of the cancer process involves the

protection of cells from carcinogenic agents like tobacco, benzol,

various chemical products, radiation, and so on). Prevention is

dictated by knowledge acquired through human epidemiological

studies as well as experimental cancers in animals.

• Preventing the promotion of the cancer process also involves

protecting the organism from various products and situations, like

alcohol, tobacco, viruses, local irritation processes, and so on).

Prevention results from the same type of epidemiological and

experimental studies. Knowledge of other diseases linked to

developing cancers (such as genital infections or hereditary

syndromes) also facilitates cancer prevention.

• Preventing the progression of cancer is possible through the

same studies but also by active, well designed policies for the

screening of pre-cancerous lesions and small cancers, when policies

are applicable.

• The strategy mentioned can be

accomplished by:

•gene therapy, or

•stem cells technologies.

• System approach to the formation of an innovative

infrastructure regarding predictive and preventive

algorithms is an ultimate approach that will contribute

to the modernization of the world healthcare services

drastically. Our challenge is that the new guidelines

should create the robust juristic and economic

platforms for advanced medical services utilizing the

cost-effective models of risk assessments followed

by tailored preventive treatments focused on the

precursor stages of chronic diseases. Recently

developed economical models clearly demonstrate

the efficacy of PPPM, if introduced as the integrative

medical approach into the healthcare services.

• Individuals to be under regular

monitoring that helps to detect

pathological shifts at subclinical

stages of a disease have a higher life

expectancy and are able-bodied up

to 8–15 years more than those under

traditional treatment. This means that

the society saves more than

US$20,000–40,000 per person

annually.

• In general, we see the following main obstacles to

the advancement of PPPM:

• the scientific challenges (a poor

understanding of molecular mechanisms or a lack of

molecular biomarkers, for example);

• the economic challenges (poorly

aligned incentives), and

• operational issues in public healthcare

systems.

The operational issues can often be largely resolved

within a particular stakeholder group, but correcting the incentive

structure and modifying the relationships between stakeholders

is more complex

The true era of PPPM, while perhaps

decades away, is impacting the pharmaceutical

and healthcare industries today.

The Saint Trinity, in particular,

• translational research,

• biomarker-based studies and

• careful patient segmentation in

clinical trials,

have led to successes such as new biomarker-

based drugs; drugs with companion diagnostics

and highly targeted therapies.

Future

Neurology Antibody-associated

proteolysis in

surveillance of

autoimmune

demyelination:

clinical and

preclinical issues

“Antibody proteases

can be considered to

be a promising

molecular tool in

monitoring [multiple

sclerosis] patients…”

Alexander Gabibov,

Mihail Paltsev &

Sergey Suchkov

Dmitry Kostyushev,

Ivan Tsarev,

Dmitry Gnatenko,

Mikhail Paltsev,

Sergey Suchkov

Open J Immunology,

2012, Vol.1, No.3, 80-86 Myelin-associated

serological targets as

applicable to diagnostic

tools to be used at the

subclinical and transient

stages of MS progression

Who should be screened ?

Should screening include the general population, or rather first-degree relatives of patients, genetically prone HLA groups? Those special groups may benefit more from the screening compared to the general population. Accordingly, testing high-risk groups may change the positive diagnostic or predictive value of the panel tests used.

When should individuals

be screened?

The best age for screening varies in different diseases. For example, while cancer-associated biomarkers or diabetes-associated antibodies appear by 3-5 years of age, thyroid antibodies uncommonly appear before 20 years of age.

Which biomarkers

should be screened for?

Different biomarkers appearing in the same diseases have different diagnostic and predictive values as individual screening test, as well as in combination.

How should the screening

be performed?

Specificity and sensitivity of different laboratory assays must be considered.

How should we interpret

changes found outside of genes?

No answer yet…

Core question:

Who should be informed?

Once biomarkers have been found, a risk of future disease is established. This information may have great implication regarding one’s future, and thus its distribution should be handled with great care. Should family members be informed, especially taking into account their associated risk?

How should we effectively communicate

the results to patients in ways that will

improve health without inducing neurosis?

No comments.

Should one be informed to expect a disease for

which, at least currently, there is no cure ?

No answer yet.

Should employment authorities be notified?

Should such information be available to all

caring physicians?

Should military authorities be informed? Or

should one be obligated to inform

insurance companies?

More crucial questions and

ethical issues

be considered :

EPMA-World Congress 2011 September 15th19th, Bonn, Germany

Creation and setting up an international youngers’ research

and clinical team in the area of PPPM and allied fields under

the aegis of:

EPMA (Brussels) :

Moscow State Medical & Dental University

Russian Academy of Sciences

National Research Center “Kurchatov’s Institute”

National Center “Higher School of Economy”

75

EPMA-World

Congress Bonn, 2011

77

The First Anglo-Russian Students’ Workshop

on PPPM and Translational Medicine Lancaster University

4th September 2012

Location: TR1/TR2 Gordon Manley building

Chairs: Professors Frank Martin, PhD (UK)

Director, Environmental and Biophotonics Center, and

Chairman, Dept for Biochemistry, Lancaster University, UK

Professor Sergey Suchkov, MD, PhD (Russia)

Dept of Pathology, School of Pharmacy, I.M.Sechenov First

Moscow State Medical University, and Dept of Clinical

Immunology, Moscow State Medical & Dentistry University,

First Vice-President and Dean, School of PPPM, University of

World Politics and Law, Moscow, Russia

78

PPPM is driving key changes in the biopharmindustry The true era of personalized medicine, while perhaps decades away, is impacting the pharmaceutical and

healthcare industries today. Most notably, this vision is impacting the landscape of how clinical research and

trials are conducted. Translational research, biomarker-based studies and careful patient segmentation in clinical

trials, have led to successes such as new biomarker based drugs; drugs with companion diagnostics and highly

targeted therapies. Fundamental to biomarker research is access to quality biospecimens that have been

extensively annotated with clinical, molecular and patient data. While many organizations have invested heavily

in the IT infrastructure of biospecimen management, or biobanking, such systems are facing challenges to

effectively drive investigative biomarker-based research

We offer and propose: 1. To set up several international research teams in the areas defined

under the aegis of EuroBioForum and EPMA in the topical fields pre-selected (e.g., T1D, MS, cancer, etc.) to accelerate investigations and obtaining the productive outcome including basic knowledge, products to be translated into the medical practice and products finalized to be marketed and distributed

2. To set up an International Team of professionals on the interdisciplinary basis to start up developing a new Program in the Higher Medical and Biomedical Education as applicable to PPPM and Translational Medicine as High-Tech Tools for Training students, researchers, clinicians, and biotechnologists to secure the Progress in the areas mentioned

3. To develop a series of different models of Centers for Medical and

allied Health Services as applicable to PPPM

WHAT CAN WE OFFER?

1. Political support

2. Financial support

3. Assistance in bridging cooperative and

collaborative efforts coming from

particular countries or enthusiastic

individuals

WHAT ARE WE LOOKING FOR?

1. To accent a special attention on:

● most advanced areas of medical research and

● to define subareas to identify existing teams with the best outcome

and

● to set up newer international teams under the aegis of EuroBioForum and EPMA in the

topical fields pre-selected (e.g., T1D, MS, cancer, etc.)

2. To set up an International Team of professionals on the interdisciplinary

basis to start up developing a new Program in the Higher Medical and

Biomedical Education as applicable to PPPM and Translational Medicine

as High-Tech Tools for Training students, researchers, clinicians, and

biotechnologists to secure the Progress in the areas mentioned

3. To develop a series of different models of Centers for Medical and allied

Health Services as applicable to PPPM

TOP 3 recommendations for achieving tangible results