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Personalized Medicine versus era of "Trial and Error"

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Available online at www.jpbms.info

ISSN NO- 2230 – 7885
CODEN JPBSCT
Review article
JPBMS NLM Title: J Pharm Biomed Sci.

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Personalized Medicine versus era of "Trial and Error"

*Qazi Najeeb1, Rajesh Pandey2, Neeru Bhaskar3, Harnam Kaur4, Sheikh Ishaq5,
Jasbir Singh6, K.S Sodhi7.

*1, 5 Postgraduate
student, 2, 4 Associate Professor, 3Assistant Professor, 6, 7 Professor
Department of Biochemistry, Maharishi Markandeshwar Institute of Medical
Sciences and Research, Mullana, Ambala, Haryana, 133207, India.
Abstract:
The traditional methods of prevention, diagnosis and treatment of a disease are associated with a variety of pitfalls in
diagnosis and mild to severe drug-related adverse effects. Most physicians prescribe a drug, change its dose or even the
drug by a ‘trial and error’ process because it is poorly understood why certain drugs do not work for some patients or why
they induce serious adverse effects in others. Personalized medicine is a concept that emerged with the completion of the
Human Genome Project and conveys information about a person’s genome, proteome and environment. Since these factors
are different for every person, nature of the disease including its onset, course and response to drugs also differs from
person to person. The present review highlights the pros and cons of personalized medicine with special emphasis on the
likelihood of its impact on autoimmune diseases and cancer.

Keywords: Personalized medicine, autoimmunity, cancer, disease, genetics.

Introduction: “Personalized medicine” is a form of medicine that uses

Disease is a fluid perception subjective to social and
cultural factors which changes with time and in response
to latest scientific and medical discoveries. Clinicians
define a disease according to a constellation of symptoms.
As their clinical metaphors became more refined, they
started to classify diseases into different groups, and from
this medical taxonomy new insights into disease etiology
emerged. Also, human genome sequencing will expose
thousands of genetic variations among individuals and it is
presumed that many will be associated with disease. This
will radically alter how we diagnose, prevent, and treat
disease. As genetic variations are progressively discovered
among individuals there will be a scuttle for labelling of
these variations as disease-associated. Disease needs to be
redefined so that it incorporates our growing genetic
knowledge, taking into consideration the possible risks and
adverse consequences associated with genetic variations
[1]. The traditional methods of prevention, diagnosis and
treatment of a disease are associated with a variety of
complications in diagnosis and mild to severe adverse
effects due to usage of drugs. Most clinicians use a "one-
size-fits-all" approach to prescribe medicines. They usually
start with standard doses, and then observe how patients
respond. If necessary, doctors change the dose or drugs by
a "trial and error" process. No one understood the
biochemical reasons why certain medicines did not work
for a small percentage of people or why some patients
experienced serious adverse side effects. Even though
scientists and clinicians suspected that a person's genes
could play a vital role in the response to medicines, genetic
technology was not advanced enough to reveal which
genes and which variations of those genes were relevant [2].
information about the person’s genes, proteins and
environment to diagnose, prevent and treat disease, and is
the vision of future medicine. It is a language of genomics
which is associated to medicine, a revolution rather than
an evolution [3]. Personalized medicine is a young and
rapidly emerging field of healthcare which highlights each
individual’s unique genetic, clinical and environmental
information. Since these factors are different for every
person, nature of the diseases including their onset, their
course, and how they might respond to drugs or other
interventions also differs from person to person [4].
Modern healthcare system and medication saves millions
of lives per year. Still, any one medication may work for
one individual but might not work for another, or it may
cause severe adverse effects to an individual but not to
others [5]. This led to the development of personalized
medicine which means prescription of specific treatment
best suited for an individual to avoid traditional “trial and
error” approach. Pharmacogenomics, pharmacokinetics
and pharmacoproteomics are the basic foundation of
personalized medicine with molecular diagnostics being
the vital tool [6].
Pharmacogenetics is the study of variable drug responses
due to heredity whereas pharmacogenomics is related to
the effect of whole genome on disease susceptibility and
drug response. It identifies genes associated with specific
diseases which can act as potential targets for newer drugs
[7]. Pharmacokinetics deals with association of genetic
variants with drug transporters, metabolizing enzymes
which may lead to alterations in the uptake, distribution
and elimination of drugs. Pharmacodynamics deals with
genetic variation that occurs in the drug target or its
component of the target leading to alteration of drug

1 Journal of Pharmaceutical and Biomedical Sciences © (JPBMS), Vol. 19, Issue 19

 Najeeb Qazi et al. / JPBMS, 2012, 19 (02)
efficacy. These targets include receptors, enzymes,
transducer and regulatory proteins and ion channels [8,9].
Personalized medicine as screening
An interesting story of first-ever integrative 'omics' profile
of geneticist Michael Snyder, PhD, was published on March
16, 2012 issue of Cell, where the study provided a glimpse
into the future of medicine, using a variety of different
techniques of thousands of variables. The researchers
identified about 2,200 genes that were expressed at lower
levels, including some involved in insulin signalling and
response. A number of molecular cues led to the discovery
of Snyder's diabetes mellitus. His genomic sequence
suggested that he had an increased risk for high blood
cholesterol, coronary artery disease (which he knew
already), as well as basal cell carcinoma and type-2
diabetes, which was unexpected. "We are all responsible
for our own health," said Snyder. "Normally, I go for a
physical examination about once every two or three years.
So, under normal circumstances, my diabetes wouldn't
have been diagnosed for one or two years. But with this
real-time information, I was able to make diet and exercise
changes that brought my blood sugar down and allowed
me to avoid diabetes medication"[10].
Personalized medicine: Pros and Cons
Personalized medicine should not be confused with
"genetic medicine". Genetics is the study of heredity and
related diseases. It examines individual genes and their
effects as they relate to biology and medicine. The
advantages of personalized medicine are highlighted below
[3]-
 Capability to make more informed medical
decisions.
 Higher likelihood of desired outcomes due to
better-targeted therapies.
 Reduced possibility of adverse side effects.
 Concentrate on prevention of disease rather than
reaction to it.
 Early disease intervention than has been possible
in the past.
 Decreased healthcare costs.
 Early detection of inborn errors of metabolism and
autoimmune diseases.
 Perinatal detection of genetic disorders.
 Presymptomatic testing for predicting onset of
diseases, including cancers and targeted treatment
for it.
Advances in genetics have increased the potential to
identify a growing number of conditions at a
presymptomatic stage but have also raised many ethical,
legal, and social issues [11]. Lack of available medical
options for the disease may provoke anxiety, risks of
discrimination and social stigmatization which could
outweigh the benefits of testing [12]. No distinct data source
is adequate for developing the evidence base for studying
the operation of emerging personalized medicine
technologies [13]. Genetic tests are not perfect, in part
because most gene mutations do not perfectly predict
outcomes. Clinicians will need to understand the specificity
and sensitivity of new diagnostics. Further, pin-pointing
the genetic markers having the most clinical relevance
limits the off-target effects of gene-based therapies[14].
2 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 19, Issue 19
Let us consider a certain disease, such as female breast
cancer, for which a patient must take medication. She and
her doctor choose a medication based on standard drug
therapy and dosing guidelines. The doctor also takes into
account such factors as her weight, age, medical history
and perhaps how her biological (blood) relatives reacted to
the same medication. Despite all of that, neither she nor
her physician knows how she would actually react to the
medication. She may experience terrible side effects or
none. The medication may put her cancer into remission,
or it may have no effect. Consequently, she may have to
return to her doctor many times to adjust the dosage or to
switch medications. This is how medication choices
generally work today- it's often a matter of trial and error.
However, pharmacogenomics could potentially speed up
that process. Before she takes a single dose of medication,
she may be able to have a test to see which genetic
variations she has. If the test shows that she has a variation
that is likely to adversely affect how she responds to the
medication, her physician can change the dosing or skip
that drug entirely and prescribe a different one[5].
Thus, the traditional process of drug discovery and
development is likely to be replaced by integrated
methods. Patient care will be revolutionized through the
use of naive molecular predisposition, screening,
diagnostic, prognostic, pharmacogenomics and monitoring
markers. However, numerous hurdles need to be overcome
to make personalized medicine a reality so that with the
passage of time, this approach will substitute the habitual
trial-and-error practice of medicine. Modern technology
has added newer aspects to the search of multiple genes
and their expression which affects drug responses [15].
Exploration of characteristic cellular DNA abnormalities in
disease is now beginning to guide the formation of
therapeutic drugs acting on disease specific DNA mutations
[16].
Latest biotechnological advances have led to an explosion
of disease-related molecular information, with the
capability for greatly advancing patient care. Nevertheless,
this development brings new challenges, and the success of
personalized medicine will depend on establishing new
frameworks to regulate, compile, and interpret the influx of
information that can keep tempo with rapid scientific
advancements. Further, it must make health care experts
aware that personalized medicine is no longer just a glitch
on the horizon, and guarantee that it lives up to its promise
[17].
As far as regulatory affairs are concerned, personalized
medicine is expected to proclaim a fast acceleration in the
identification and development of next-generation
pharmacotherapies. At present, medical research
organizations are calling for regulatory bodies to re-
evaluate the regulation of clinical trials, citing markedly
lengthy approval processes as an obstruction to the
effective transformation of basic medical science
discoveries [18]. Besides, personalized medicine will signify
a departure from traditional clinical trial frameworks, with
phase 3 trials concentrating on a more select patient group.
This pointed focus should assist procedural reorganization
and improve clinical and economic effectiveness. New
methods designed at reducing the time from drug
development to clinical application are likely to encourage
similar proposals elsewhere. Eventually, it must get the
balance right, regulatory frameworks must be strong
enough to protect patient’s health and well-being, while
 Najeeb Qazi et al. / JPBMS, 2012, 19 (02)
not stifling development in critical premature phases of the
personalized medicine endeavour. The move towards a
thorough understanding of disease based on molecular
biology will also inevitably impose reclassification of
disease states in order to integrate this knowledge [19].
The present scenario
The most noticeable near-term possible use of genetic data
is to develop diagnostic accuracy, as well as to allow
disease stratification for risk evaluation and treatment
selection [20]. It is likely that genetic data will need to be
pooled with other biomarkers to categorize clinically
meaningful subgroups of patients to lead the treatment of
patients. Such an approach may be especially useful for
early recognition of persons at risk for autoimmune
disease [21]. The latest genetic data implicate new pathways
Table 1: Few examples of personalized medicine drugs and its applications.
Therapy Bio markers
that propose new therapeutic targets. There are varieties
of drugs whose prescription and use entirely depends
upon the genetic status of targeted cells. Nearly 10% of
FDA-approved drugs have labels that include
pharmacogenomics information (Table 1) [22, 23]. In fact,
many of the new biologic therapies seem to be
appropriately matched to these pathways [24]. Keeping in
view the variety of gene associations implicating multiple
disease pathways, future therapeutic advances may
require the application of combination therapies. High-
resolution comparison of association models across
autoimmunity will soon be possible with data acquired
from common genotyping platforms and may offer insight
into which therapeutic targets should be prioritized for
numerous disease subtypes [25]. (Table 2)
Description

Herceptin (trastuzumab)
Erbitux (cetuximab)
Gleevec (imatinib)
Gleevec (imatinib)
Tarceva (erlotinib)
Hormone/chemotherapies
Chemotherapies
Rituximab
Drugs/surgery
HER-2 amplification Breast cancer that overexpresses erbB2 respond to higher doses
of doxorubicin-containing regimes and predict those tumors that
will respond to HER-2 antibodies herceptin (trastuzumab)
EGFR expression, K-RAS mutations Protein and mutation analysis prior to treatment
BCR/ABL fusion In treatment of Philadelphia chromosome (chronic myelogenous
leukemia)
C-KIT Used in stomach cancers expressing mutated C-KIT
EGFR expression Lung cancer expressing epidermal growth factor receptors
(EGFRs)
Oncotype DX test Selection of breast cancer patients for chemotherapy
Aviara Cancer TYPE ID Classifies 39 tumor types using gene-expression assays
PGx Predict (FcRIIIa) Detects CD20 variants that predict response to rituximab in non-
Hodgkin’s lymphoma
MLH1, MSH2, MSH6 Gene mutations related to colon cancers

Table 2: Selected list of autoimmune diseases and their chromosomal loci [27].

Genes involved Chromosome location Diseases Associated

Tyrosine protein kinase 2 (TYK2) 19p13 Psoriasis, type 1 diabetes mellitus, systemic lupus erythematosus,
Crohn’s disease, multiple sclerosis

Major histocompatibility complex 6p21 Most autoimmune disorders

(HLA)
Protein tyrosine phosphatase 1p13 Type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus
nonreceptor type 22 (PTPN22) erythematosus, Graves’ disease, Crohn’s disease

Tumor necrosis factor receptor 20q13 Rheumatoid arthritis

superfamily member 5 (CD40)

Interleukin-12B, p40 (IL12B) 5q33 Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, systemic
lupus erythematosus

Autophagy-like 16L1 (ATG16L1) 2q37 Crohn’s disease

Signal transducer and activator of 2q32 Systemic lupus erythematosus,

transcription 4 (STAT4) rheumatoid arthritis,
primary biliary cirrhosis, systemic sclerosis

Signal transducer and activator of 17q21 Crohn’s disease, multiple sclerosis

transcription 3 (STAT3)

c-Rel (REL) 2p16 Rheumatoid arthritis, Crohn’s disease, ulcerative colitis, celiac disease,
psoriasis

Endoplasmic reticulum 5q15 Psoriasis, ankylosing spondylitis

aminopeptidase 1 (ERAP1)

Insulin locus (INS) 11p15 Type 1 diabetes mellitus

Work pending omics” data, placing new stipulates on medical

Personalized medicine will require usage of multi- professionals, who may be poorly equipped to deal with
parametric data and some expertise in interpreting “- the probable complexity and new dimensions of
3 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 19, Issue 19
 Najeeb Qazi et al. / JPBMS, 2012, 19 (02)
information. Dealing with these challenges will require countries are investing in multibillion-dollar projects to
efficient clinical decision support tools and new employ effective electronic health records. These systems
educational developments. Presently, genetic testing is will gather comprehensive, individual-specific data that
available for nearly 2000 clinical conditions, and the will be crucial as we progress towards personalized
number of existing diagnostic tests is escalating medicine [26].
exponentially (Table 3). The United States and other

Table 3: Selective list of genetic diseases (along with the currently available genetic tests) likely to be benefited by personalized medicine [12].
Diseases Diagnostic Techniques

 Down syndrome  Fluorescence in situ hybridization

 Chronic myeloid leukemia (CML)  Fluorescence in situ hybridization, Polymerase chain reaction

 Acute lymphoblastic leukemia (ALL)  Fluorescence in situ hybridization

 Prader-Willi syndrome  Fluorescence in situ hybridization

 Sickle-cell disease  Restriction Fragment Length Polymorphisms, Polymerase chain

reaction
 Huntington's disease  Restriction Fragment Length Polymorphisms

 Cystic fibrosis (CF)  Polymerase chain reaction, DNA Microarray

 Phenylketonuria (PKU)  Polymerase chain reaction

 Muscular dystrophy  Polymerase chain reaction

 Acute myeloid leukemia (AML)  Polymerase chain reaction

 Thalassemia (α, β)  DNA Microarray

 Ankylosing spondylitis (HLA -B27)  Polymerase chain reaction

 Alzheimer's disease (ApoE4)  Polymerase chain reaction

 Retinitis pigmentosa  DNA Microarray

 Cancers (colorectal, lung, oesophageal, prostate)  DNA Microarray

 Breast cancer (BRCA-1, BRCA-2)  Polymerase chain reaction, DNA Microarray

Future perspective 3. Offit K. Personalized medicine: new genomics, old

Personalized medicine should ensure that patients get the
right treatment at the right dose at the right time, with
minimum ill consequences and maximum efficacy. But it
will change how medicine is practiced and taught and how
health care is delivered and financed. It will change the
way research and development are financed and regulated.
It will deeply affect public trust and the nature of the
patient-clinician relationship, requiring unprecedented
collaboration among health care stakeholders.
Undoubtedly, significant challenges lie ahead, though none
is insurmountable. Yet, expectations must be realistic:
personalized medicine will happen neither automatically
nor overnight. The transition should be steered by
international consortia including leaders from academia,
health care, government, and industry.
Acknowledgement:
The author expresses gratitude to the all co-authors for
their patience and support.
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Corresponding Author:-
Dr. Qazi Najeeb.
Postgraduate student, Department of biochemistry,
Maharishi Markandeshwar Institute of Medical Science and Research (MMIMSR),
Mullana, Haryana, 133207, India.
Cell no: - +91-9729939070.
Landline: 01731-304553.
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