Download Human genome project : Pharmacogenomics and drug development

Indi an Journal of Experimental Biology
Vol. 39, October 2001, pp. 955-96 1
Review Article
Human genome project : Pharmacogenomics and drug development
N K Ganguly, Rahmat Bano & S D Seth*
Indian Council of Medical Research, New Delhi
Fax:9 I -11-685779 I ; E-mail : icmrhqds @sansad.nic. in
Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are
emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great
impact on our ability to uncove r the cause of individual variation in response to therapeutics. The study of association
between genetics and drug response is called pharniacogenomics. The potential implication of genomics and
pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual
differences in dru g disposition and effects, thereby enhanc ing the drug discovery and providing a stronger scientific basis of
each patient' s genetic consti tution. Sequence information derived from the genomes of many individuals is leadin g to the
rapid discovery of si ngle nucleotide polymorphisms or SNPs. Detection of these human polymorphi sms will fuel the
discipline of pharmacogenomics by developi ng more personalized drug therapies. A greater understandin g of the way in
which individual s with a particular genotype respond to a drug allows manufacturers to identify population subgroups that
will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to rai se ethical and legal
questions regarding, amo ng other things, the design of research studies, the construction of clinical trials and the pricing of
drugs.
Human genome
The human genome is the twisted strand of
biological text that carries all the instructions for
making and growing a human being. Enors in that
text cause or contribute to the vast majority of human
diseases. Genomics is the study of the genome as a
whole: the total sequence of DNA in the cell and how
this provides the information for the cell to function
and reproduce itself in an organism or individual.
Watson and Crick deduced that DNA within the
nucleus of the cell is a double helix framework, and
positioned along the rungs of the two DNA ladders
are four chemical bases : adenine(A), cytosine(C),
guanine(G), and thymine(T) . The four letters in this
simple alphabet specify all the biological properties of
a human being. In normal DNA, an A on one strand
always pairs with aT on the other, and G alway s pairs
with C. If we know the sequence of one strand, we
know the sequence of the other. Genome has gene as
well as 'junk' DNA. Genome is a pair of 23
chromosomes, and the average chromosome has
around 100 million bases 1• It is assumed that there are
30,000 genes atTanged on the chromosomes . Genome
controls the day-to-day function of the body's 60
trillion cells and guides an embryo's growth into a
li ving, breathing and thinking human . The average
gene, which is a packet of information that carries out
*Correspondent author
a particular instruction, varies from a few thousand to
few hundred thousand bases. Unity is in raci sm is out
- all human beings share an incredible 99.99 percent
of all genetic material 2 •
Human genome project
The Human Genome Project was initiated on
October 1,1990, and successfully completed, and
announced a draft sequence of the human genome on
26 June, 2000 simultaneously by the publicly funded
Human Genome Project (HGP) and the privately
funded Celera Genome Corporation. The HGP is a
publicly funded consortium that includes four large
sequencing centers in the US, as well as the Sanger
Center near Cambridge, England, and laboratories in
Japan, France, Germany and China. Working together
for more than a decade over 1,100 scientists have
crafted the map of the three billion DNA base pairs,
or uni ts, th at make the human genome. In April, 2000
a brash young company called Celera Genomics,
Rockville, Md., beat the public consortium to the
punch, announcing its own rough draft of the human
genome 2 .
The sequencing of the human genome is a brilliant
techno-managerial exercise, which has succeeded in
bringing together molecular biology. genetics and
engineering, especially automation technology and
bioinformatics 3 . The HGP used a hierarchical
mapping and sequencing approach, involving
generation of a series of overlapping clones that cover
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INDIAN J EXP BIOL, OCTOBER 2001
the entire genome and shotgun sequencing of each
clone. The genome sequence was reconstructed by
assembling the fragments on the basis of sequence
overlap and mapping and chromosomal position
information on the clones. Celera took a shorter route:
shredding the encyclopedia all at once.
Celera
Genomics used a whole-genome shotgun sequencing
approach , without generating a series of overlapping
clones, but also incorporated HGP information where
avail able. All of the results of this analysis are
available on web site maintained by the University of
California at Santa Cruz (http://genome.ucsc.edu)
and National Center for Biotechnology Information
(N CBI; http:// www. ncbi .nlm.nih .gov) 4 .
The goals of the HGP were to first construct a
co mprehewive genetic map of the human genome.
Also, libraries of overlapping clones spanning the
entire genome were to be constructed . The final goal
was the sequencing itself. This was to be
complemented by developments in bioinformatics so
as to organize th e tremendous amount of data
generated in a meaningful manner 3 . Beginning with
blood and sperms, the team separated o ut the 23 pairs
of chromosomes that hold human genes. Scienti sts
the n clipped bits of DNA from every chromosome,
identified th e seq uence of DNA bases in each bit, and
finally matched each snippet up to the DNA o n either
side of it in the chromosome. And th ey went on
gradually crafting the sequences for individual gene
segments , complete genes, whole chromosome and,
eventually, the entire genome. Wilson compares thi s
approach to taking out one page of an encyclopedia at
a time, rippin g it up and putting it together agai n.
Other
applications
of
HGP
include
pharmacogenomics and patient counseling about
individual heal th ri sks. Concerns in clude how to
integrate geneti c techno logy into clinical practice and
4
how to prevent genetic-based discrimination •
Equally striki ng is how little of the genome
actually codes fo r prote ins and how those exons are
distrib uted . Celera calculates that just 1.1% of the
genome codes fo r proteins; the public fig ure is 1.5 %.
Human genome contains in tervening seq uence,
so metimes extending thousands of bases, between
exons. Not only does this make for big genes, but it
co mplicates the task of gene identification . Moreover,
genes themselves can be separated by vast "deserts"
of noncoding DNA, the so-call ed junk DNA. Celera
scientists est imate that between 40% and 48% of the
genome consists of repeat sequences: DNA in which a
particular pattern of bases occurs over and over,
sometimes for long stretches of a chromosome. One
of the more common repeats, called Alu's, cover 288
megabases in the Celera human genome-nearly 10%
of the total. And the public consortium's an alysis
shows that older Alu's tend to concentrate in generich areas, suggesting that those Alu's located near
genes may serve some useful purpose and thus were
retained by the genome. "It's like looking into our
genome and finding a fossil record, what came and
went," says Collins 5 .
Among the most common DNA fossils are
transposones - pieces of DNA th at appear to have no
purpose except to make copies of themselves and
often jump from place to place along the
chromosomes. They typically contai n just a few genes
- those needed to promote the transposone 's
proliferation. Both drafts confirm that transposones
may also be a source of new genes. Celera found 97
coding regions that appear to have been copied and
moved
by
RNA-based
transposones
called
retrotransposo nes. Once in a new place, these
condensed genes often decay through time for lack of
any clear function, but some may take on new roles.
And transposone genes themselves become part of the
genome. Until recently, 19 of these tranposo nederived genes were known. The public consortium
just found 28 more. " It almost looks like we are not in
control of our own genome," notes Phil Green, a
bioinformatics expert at
th e
University of
5
Washin gto n, Seattle .
Drug discovery aud development
There are important differences between drug
di scovery and drug development. Drug di scovery is
an expensive process invol vi ng research into the
mechani sms of disease, the selection of biological
targets, and the identification of compounds th at
modulate th e di sease. Drug development is focused
on es tabl ishi ng the efficacy and safety of a single
compound thro ugh phased clinical trials to ach ieve
marketi ng approval. Drug development is constrained
by the high cost of clinical investi gation and the fact
that each day required to achieve marketing approval
can reduce the economic value of a product by many
mill ions of dollars 6 .
The drug discovery and developmen t process can
be divided into several phases. In the discovery phase
lead compounds are identified by the use of high
throughput scree ning against chem ical libraries,
rational design based on knowledge of the threedimensional structure of the target, modification of
known chemical structures or the production of
GANGULY et al.: HUMAN GENOME PROJECT
therapeutic proteins . These are then screened through
a series of increasingly complex assays, eventually
leading to a demonstration of efficacy in an animal
model representing the relevant disorder. The
concerns that exercise the minds of scientists involved
in this process often center around the choice of target
and the drug candidate specificity. Ideally one would
select the molecular target based on its intimate
involvement in the disorder to be targeted and its
limited involvement in the other biological process
that might, if disturbed, lead to unwanted side-effects.
In addition, eveh when the appropriate target is
chosen and lead compounds identified, concerns will
remain as to whether other gene products will be
7
inhibited or activated by these compounds .
Pre-clinical safety and toxicity testing begins
immediately following the drug discovery process,
although some of these activities often take place
concurrently with the final stages of drug discovery.
Safety and toxicity testing comprises acute and
chronic
toxicity
tests,
mutagenicity
assays,
reproductive toxicity and drug disposition studies.
They are normally carried out in rats and one to two
additional mammalian species, although the scientists
involved in these safety assessments are acutely aware
that these species do not necessarily respond to drugs
in the same manner as humans. Compounds that pass
the safety hurdles and are suitable for commercial
production enter clinical trials. However, even after
these efforts, only about I 0-30% of compounds reach
the marketplace. Furthermore, differences in the
pathobiology of a disorder, the underlying cause,
might lead to very similar clinical manifestations.
This would be of significant concern for those
di sorders for which no clear biochemical marker can
be used to measure the pathological process such as
behavioral disorders7 •
One of the most recent revolutions in biology has
begun to generate both the knowledge base and tools
to address many of the current concerns of
pharmaceutical researchers. This revolution comprises
the ability to explore and characterize the structure
and activity of whole genome in a high throughput or
massively parallel manner and as such has been called
genomics. However, in addition to the scientific
benefits it brings, genomics also brings with it
concerns from both the ethical and legal point of view
as individuals are defined , to a great extent. by their
genomes. From the commercial perspective one of th e
current major concerns is the rapid patenting of
human genes to protect their use as therapeutics and
957
more importantly as therapeutic targets. Therefore, in
their estimation only about 0.5-1% of the genome has
been targeted by therapeutics. Obviously not all genes
will encode viable therapeutic targets but it is likely
that a significant number of genes will, and they
remam undiscovered or, as yet undiscovered.
Genomics actiVlttes such as high throughput
sequencing are already reducing this number (as
available targets) through new gene discovery and
patenting. It is also clear that, in the not too distant
future, every human gene will be identified and
characterized, at least by its sequence. In order to
remain compettttve the modern pharmaceutical
company must recognize the fact that it must not only
continually increase the efficiency of its drug
discovery efforts but, in addition, must ensure its
freedom to operate by creating its own intellectual
property rights for the new therapeutic targets in its
pipeline. The tools of genomics will contribute
7
significantly to both of these activities .
HGP and drug development
Presently the human genome sequencing project is
reported to be about 6% completed and is projected to
be fully complete in about 2003. One of the most
valuable contributions that the human genome project
will make to biomedical research is the ability to
study the natural genetic variations in human. The
scale of effort required to fully categorise the genome
comprising 23 pairs of chromosomes made up of 3 x
9
10 base pairs of DNA is immense. In addition to
generating a complete sequence of the human
genome, the HGP has other objectives: (i) to further
develop sequencing technology towards higher
throughput and reduced cost, (ii) to develop
functional
genomics
technologies
through
establishing full length eDNA resources, developing
the tools for the study of nonprotein coding regions of
genes, advancing gene expression analysis, improving
methods for genome wide mutagenesis, developing
the technology for global protein analysis, (iii) to
advance comparative genomics through sequencing
the genome of other organisms such as C. elegans.
Drosophila and the mouse, (iv) to address the ethical ,
legal and social implications of the data. specially the
data on human genome variations, (v) to train
scientists in the specialties created by this and related
efforts 8. For pharmaceutical industry it will mean that
every potential pharmaceutical target will be know n
(at least by neucleic acid and protein sequence) and
mapped.
All
homologous
(paralogous)
will
immediately be known for a new target gene so a high
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INDIAN J EXP BIOL, OCTOBER 2001
degree of drug specificity can be designed in the very
early stages of development program and mechanism
based adverse effects will be avoidable, or the very
best explainable9 .
In the postgenomic era, dramatic increase in the
amount of genomic information will have a
tremendous impact on biomedical research and on the
way that medicine is practiced. When all the human
genes are truly known , scientists will have produced a
Periodic Table of Life, containing the complete list
and structure of all genes and providing us with a
collection of high- precision tools with which to study
the details of human development and disease 10 . As
most of the genome is sequenced, changes in genes
and proteins in disease will be better identified for the
rational designing of drugs. The surprising number of
genetic polymorphism identified in the human
genome indicates the genetic basis of the tremendous
amount of variations in the species. The identification
of the genetic basis of variations in response to drugs,
both in terms of efficacy and toxicity, holds out hope
for individualized therapy. Why a person is more
likely to react adversely than another to a particular
drug, is not well understood.
Proteomics,
offers
an
alternative,
and
complimentary
approach
to
genomic-based
technologies for the identification and validation of
protein targets and for the description of changes in
protein expression under the influence of disease or
drug treatment. Much interest has been expressed by
the pharmaceutical industry in proteomics, in
anticipation of the value of this technology to both
discovery and development of new drugs 11 •
Proteomics
involves
the
identification
and
quantitation of gene expression at the protein level.
Additionally, proteomics may help to identify protein
interaction partners and members of multiprotein
complexes. Furthermore, this technique may assist in
following time-dependent changes in protein
expression levels resulting from selective excitation
of a biological pathway, and thereby delineating from
selective excitation of a biological pathway, and
thereby delineating a cellular protein network, a
methodology that has been referred to as functional
proteomics. Recently, however, considerable progress
has been made in improvi ng detection of low copy
proteins through enhancement of gel-load ing
techniques and enrichment strategies such as affi nity
-based purification two-dimensional gel separation.
Finally, enhanced protein stai ning/detectio n methods
are now becoming available, and mass spectrometry
is pushing the bounds, are now becoming available,
and mass spectrometry is pushing the bounds of
detection
to
even
more
sensitive
limits.
Notwithstanding the technical difficulties that remain,
sufficient evidence exists, even at this early stage of
technology to warrant that proteomics will provide
crucial
information for
the
discovery and
development of novel therapeutic targets 12 .
Post-genome project era has given the name
"Functional Genomics", which will begin early in
millennium and will encompass the many efforts
needed to elucidate gene function. Indeed, the
phenotyping of genetically manipulated animals will
be critical in the determination of biological function
of a particular gene. But, in reality, the discipline of
functional genomics has its foundation in the
physiological and pharmacological sciences. This is
gratifying to the "traditional" pharmacologist, whose
expertise will be drawn on even more in the future to
unravel the mysteries of genetics. Although the
evaluation of genetically manipulated animals will
require a thorough understanding of physiology and
pharmacology, the experimental approach will
involve many new technologies. These methods will
include in vivo imaging (i.e. magnetic resonance
imaging, micro-positron emiSSions tomography,
ultrafast
computed
tomography,
infrared
spectroscopy), mass spectrometry, and microarray
hybridization, all of which should enhance the speed
and accuracy at which functional genomics is
achieved 12 •
The major interest of the pharmaceutical industry
in "gene therapy" will undoubtedly be centered
around in vivo treatment protocols, although more
invasive ex vivo methods (whereby cells are removed
from the patient, transfected with the gene of interest,
and then placed back into the patient) may be
acceptable for certain serious diseases (e.g. cancer).
Currently, genetic information can be transferred into
cells by a number of protocols, including the use of
DNA plasmids, DNA liposomes, or a variety of
viruses. The most effective transforming agents are
viral vector, such as adenovirus, adenoassociated
viruses, and retroviruses. Although retroviruses
require cell division to incorporate the new
information into the genome, adenovirus and
adenoassociated viruses will transfer their information
into nonreplicating cells 12 •
HGP and pharmacogenomics
The new technologies created 111 the Hu man
Genome Project have changed the face of genetics
GANGULY et at.: HUMAN GENOME PROJECT
(like gene identification), creating genomics and
pharmacogenomics, the blending of high technology
and pharmacogenetics. Whereas, pharmacogenetics
takes advantage of high throughput DNA sequencing,
gene mapping, and bioinformatics, the result is a
quantum leap in the ability to discover genes, which
are associated with physical attribute, disease
susceptibility, or the response to drugs 13·•
What are the pharmacogenomic tests likely to be
developed recently? There has been much discussion
about "genetic bar codes" and "genetic profiles",
suggesting that it will be possible to include all gene
sequence information relevant to an individual within
a single test. At this point, we have neither the
knowledge nor the technology to develop such a test.
For the foreseeable future, tests based on
pharmacogenomics will be directed towards single
response. The tests will currently focus on three key
attributes: therapeutic need, clinical utility, and ease
of use 13 . Therapeutic need is a combination of the
number of patients likely to be tested for a particular
drug response, the consequence of that response, and
the alternate means of obtaining an equivalent answer.
For instance, a drug used by many people but which is
frequently ineffective, and has a high incidence of
therapeutic failure, would have a high medical need
for a test to predict efficacy in individual patients 13 .
Although a massive quality of sequence
information is accumulating, the functions of
thousands of genes remain undetermined. Functional
genomics refers to the methods for assessment of
gene function by making use of the information
provided by structural genomics. Pharmacogenomics,
an offshoot of genomics, refers to the application of
genomic technologies in drug discovery and
development. The vision of pharmacogenomics is to
study genetic variances that affect drug action. This
will lead to the development of new diagnostic
procedures and therapeutic products that will enable
drugs to be prescribed selectively to patients for
whom
they
will
be
effective
and
safe.
Pharmacogenomics is the application of genomic
technologies such as gene sequencing, statistical
genetics, and gene expression analysis to drugs in
clinical development and on the market. It applies the
large-scale systematic approaches of genomics to
speed the discovery of drug respon se markers,
whether they act at the level of the drug target, drug
metabolism, or di sease pathways. The potential
implication of genomics and pharmacogenomics in
clinical research and clinical medicine is that the
959
disease could be treated according to genetic specific
individual markers, selecting medications and dosages
14
that are optimized for individual patients .
Two recent developments are responsible for the
increased interest in pharmacogenomics. The first is
the recent recognition that systematic discovery of
genetic variance can provide important, achievable
opportunities for developing new therapeutic and
diagnostic products from genomics. The second is the
emergence of appropriate methods for discovery and
analysis of genetic variation in human populations
that may be employed within the time limits and
constraints of drug development 14 .
Genetics and pharmacogenetics
Genetic variation within a population is the base
upon which evolution operates. It is clear from even
the most cursory observations that a great deal of
genetic variation exists within human populations and
one would expect that variations will be found within
the genes that are involved in both disease processes
and those involved in drug responses. Indeed, it has
been accepted that polymorphism within the genes
involved in drug metabolism can play a critical role in
the variable responses to drugs within patient
populations 15· 16 . The application of genetics to
pharmaceutical discovery and development can be
understood into two broad categories. Firstly, the
application of genetics to the discovery of diseased
genes and describe some of the tools available for
The
second
category
IS
these
analyses.
pharmacogenetics, that addresses the application of
human genetics in understanding drug response.
Over the last few years genetic markers have
become available in ever increasing numbers. These
reagents are used for linkage studies, the aim of which
is to determine how often two loci are separated by
meiotic recombination. If two loci are on different
chromosomes they will segregate independently at
meiosis. However, if they are present on the same
chromosome they have a greater chance of
segregating together, this chance being inversely
promotional to their distance apart on the
chromosome (assuming recombination is randomly
distributed along chromosomes). In order to identify
disease loci in humans, one needs to make use of
genetic markers. These are the Mendelian characters
having sufficient polymorphism such that randomly
selected individuals are heterozygous. The genetic
markers presently in use are DNA polymorphisms
which can be typed by the same techniques and can
be mapped directly onto their chromosomal location
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INDIAN J EXP BIOL, OCTOBER 2001
through physical mapping. DNA polymorphism, such
as microsatellites, are mostly comprised (CA)n
repeats, commonly observed in the 15-30 repeat range
and are found throughout the genome. The advantage
of these markers is that they are highly polymorphic
and therefore highly informative 17 •
Single
Nucleotide
Polymorphisms
(SNPs),
common variations among the DNA of individuals,
are being uncovered and assembled to large SNP
databases that promise to enable the dissection of the
genetic basis of disease and drug response (i.e.
pharmacogenomics). The health care industry is
clamoring for access to SNP databases for use in
research in the hope of revolutionizing the drug
development process. The next phase of HGP will
foc us on, among other things, creating a genome-wide
map of I 00,000 of the most common type of genetic
variation i.e.SNPs. Similarly, a consortium of 10
pharmaceutical companies and the Wellcome Trust
are working toward identifying 300,000 SNPs within
the next two years 18 .
SNP as an alternative set of markers have been
developed, based to a large extent on the data coming
out of the human genome projec t. The single
nucleotide polymorphisms or SNPs represent si ngle
base variations in the genomic DNA sequence at
defined positions that are found at a frequency of over
I% in the human population 19 . SNPs represent the
most common type of human genetic variation. It is
anticipated that SNPs will aid in the identification of
disease genes by family linkage studies, linkage
20
disequilibrium studies in isolated populations and
even association studies of patients and control
healthy subjects21 • As SNPs can only have two alleles,
they are less informati ve than microsatellite markers,
however, they are more abundant and lend themselves
to automation(SNPs can be analysed through direct
hybridization). In a recent study SNPs were used to
design genotyping microarray chips to demonstrate
the feasi bility for high throu ghput genotyping 19 •
Studies of SNPs and disease have become more
efficient when a few more problems are solved. First,
although 82% of SNP variants are found at a
freq uency of more than 10% in the global human
population, the 'microdistribution' of SNPs in
individual populations is not known. Second not all
SNPs are created equal, and it will be essential to
know as much as possible about their effects from
computational analysis before studying their
involvement in disease. For example, each SNP can
be classified by whether it alters the seq uence of the
protein encoded by the altered gene. Changes that
alter protein sequences can be classified by their
effects on protein structure. The non-coding SNPs can
be classified according to whether they are found in
gene-regulating segments of the genome - many
complex diseases may arise from quantitative, rather
than qualitative, differences in gene products. Third,
technology of patients and controls, is not yet fully
developed, although there are some creative ideas
around 22 .
Pharmacogenomics and drug development
Pharmacogenomics is a distinct di scipline within
genomics. It is concerned with genetic effects on
drugs themselves and with the genetic variances that
contribute to the variable effects of drugs in different
individuals. Pharmacogenomics aims to satisfy this
clinical need by focusing on genetic co ntributions to
drug action as opposed to the genetic causes of
disease. Focusing on those genes and variances that
are most likely to have significant pharmacological
effects rather than on randomly selected genetic
markers can further reduce complexity. lnformatic
tools and experimental models of drug action can be
used to identify genes that are most likely to affect the
action of a drug. Molecular methods can also be used
to identify all co mmon variances within a gene and
characterize those variances that alter the structure
and function of the expressed product or its level of
expression 14 • The application of genomic technologies
has expanded the opportunity for identifying genetic
effects on drug action. Studies have begun to identify
common variances in genes that are the targets for
drug action as well as in genes that control the
activation , distribution, or elimination of many drugs.
These discoveries are expected to lead to the
development of diagnostic test drugs in individual
patients. It is likely that such tests will be generally
applicable in medical practice to determine which
drugs, in the armamentarium available to the
physician, are most likely to be effective and safe for
an individual patient. Drugs that will be potentially
toxic will be avoided, effective therapies will be
prescribed sooner, and diseases will be more
14
effectively and economically managed •
The potential benefits of pharmacogenomics on
drug development are profound. Achieving these
benefits requires a clear focus on technologies that
can be applied within the paradigm of conventional
development. With the economics of drug
development already constrained to the point that
many
approved drugs
never recover their
GANGULY et al.: HUMAN GENOME PROJECT
development
costs,
it
is
unlikely
that
pharmacogenomic strategies that require any
significant increase in the scope or cost of
development be adopted by the industry. The
challenge then for pharmacogenomics is to invent
and implement the novel technologies that can meet
14
drug development' s needs • The leading strategies
fo r pharmacogenomics involve selecting candidate
genes on pathways for drug action, activation, and
elimination in humans (or other species) and
identifying variances in the gene sequences. These
variances can then be studied both on a biochemical
level, to assess their functional significance in drug
action, and on a population level, to establish
statistical association which observe phenotypic
variance m drug action. In a managed-care
environment,
pharmacogenomic
strategies
can
provide a competitive advantage and increase the
market potential of certain drugs. The preferred
strategy involves identifying variances that define the
population of patients in whom a drug will be safe
and effective, and marketing the drug together with a
diagnostic product that enables the drug to be
prescribed selectively to these patients. The use of
such products would provide r·0st savings to the
health care provider and payers by increas ing the
effectiveness of the initial prescri bed therapy,
reducing the number of doctor visits, eliminating the
cost of prescribing ineffective pharmaceuticals, and
14
eliminating avoidable toxicity •
Pharmacogenomics also offers strategies for more
efficacious and economical use of conventional
pharmaceutical products without the risks and cost of
this iterative process as well as opportunities for
developing new products that take advantage of the
normal variability of human populations to provide
safer, more effective therapies. Products based on
genetic variances that contribute to drug efficacy and
safety are likely to be the first, and may be the most
14
important, clinical application of genomic science •
Our understanding of the structure and function of
the human genome has, within the last ten years,
increased beyond the most optimistic of predictions. It
is likely that, over the next ten years, our insights into
genome function in development, health and disease
will develop in many obvious and unexpected ways.
Presently our increased knowledge and the
app lication of genomics tools are poised to optimize
drug discovery and development activities as well as
add value to the resulting drugs. Ethical issues are
now a major concern for scientists. Like an ID a
961
person's gene sequence record can be made available
on tap. In the near future, this means an insurance
company, for example may charge a higher premium
from a person who shows a susceptibility for
developing hypertension. Or at the work place,
Darwinian selection may be replaced by managerial
selection as employees are hired or fired, on the basis
of their potential as seen from their genetic profile.
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