Transcript Origins of Pharmacogenomics

Origins of
Pharmacogenomics
Archibald Garrod - 1902
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In 1902 Garrod characterized the condition
of alcaptonuria as one resulting from an
absence of the enzyme homogentisate
oxidase.
Garrod recognized that the condition was
transmitted as a single recessive Mendelian
trait.
Archibald Garrod - 1902
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While studying alcaptonuria in
humans, Garrod advanced the
hypothesis that genetically determined
differences in biochemical processes
could be the cause of adverse
reactions after the ingestion of drugs.
Enzyme defects??
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Garrod went on to suggest that
enzymes were implicated in the
detoxification of foreign substances
and that such a mechanism might fail
in persons lacking a specific
detoxifying enzyme.
Malaria - 1944
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primaquine
African-American soldiers taking the
drug primaquine for malaria showed
primaquine-induced hemolysis at a
rate that was significantly higher than
in Caucasian soldiers.
Tuberculosis- 1940’s
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Peripheral neuropathy occurred in
some patients taking isoniazid but not
others.
Patients that exhibited the adverse
effect were labeled “slow
metabolizers”…..
1950’s - Succinylcholine
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A very small percent of the population
experiences prolonged muscle paralysis
following administration of the muscle relaxant
succinylcholine.
Kalow described differences in patients ability
to metabolize the succinylcholine based on
genetic variability in their plasma
cholinesterase enzyme.
1956 – Primaquine Toxicity
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Researchers identify a “genetic-link”
between primaquine and unwanted
hemolytic reactions
Motulsky - 1957
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After reviewing data from the isoniazid
and succinylcholine trials Motulsky
proposed that the inheritance of
acquired traits might explain the
individual differences in efficacy and
adverse reactions for these drugs.
Vogel - 1959
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First proposed the term
“pharmacogenetics” to describe the
genetic-based differences in drug
response that were being
documented.
Kalow - 1962
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Wrote the first monograph on
“Pharmacogenetics”
(W. Kalow, Pharmacogenetics, 1962,
Saunders, Philadelphia)
1970’s London
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Physicians at St. Mary’s hospital note
that the severe hypotensive response
of a volunteer to the effects of
debrisoquine was due to impaired
oxidative metabolism in that subject.
Identical Twins - 1970
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In the 1970’s Vesell showed that identical
twins were more similar than fraternal twins
with regards to the plasma half-life of
numerous drugs.
 Implication was that multiple genes may
determine individual drug metabolism…..
Advent of Molecular Biology
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Like most of science and medicine,
the young field of pharmacogenetics
benefited greatly from the advent of
molecular biology techniques in the
80’s & 90’s.
Molecular Biology
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In the 1990’s simple PCR-based DNA
tests became available for
debrisoquine and acetylation
polymorphism.
Definition
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Polymorphism - are changes in the genetic
code (like mutations) that occur commonly
enough in the population such that they are
considered a variation on normal. These
may be harmful, helpful or neither to the
persons who have a polymorphism.
The Human Genome Project 1990
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The ongoing effort to characterize and
decode the human genome has
likewise contributed greatly to the
progress made in pharmacogenetics.
The Human Genome Project
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New technologies that arose from the
Human genome Project such as DNA
microarrays and lab card or “lab-on-a-chip”
devices may eventually make it possible to
cheaply and quickly prescreen patients for
certain polymorphisms before drug therapy
is initiated
TPMT Deficiency - 1997
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Polymerase chain reaction used to
detect thiopurine S-methyl transferase
deficiency – a cause of dangerous
complications arising from
mercaptopurine & azathioprine
therapy.
SNP Consortium - 1999
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A collaboration of various companied and
institutions set up to discover the extent of
single nucleotide polymorphisms (SNP’S) in
the human genome.
The original goal was to identify 300,000 but
the final results identified 1.4 million!
Draft Human Genome - 2000
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Human Genome Project leaders
announce the completion of a draft
sequence of the human genome
Complete Human Genome
2003
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Human genome project is officially
completed.
FDA and Pharmacogenomics 2005
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FDA issue guidance to the
pharmaceutical industry for
pharmacogenomic data submission.
Warfarin - 2007
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the FDA announced that warfarin’s
label will carry new information
describing the role of genetics in
dosing.
Table of Valid Genomic
Biomarkers - 2008
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FDA releases a table listing genomic
biomarkers that have established roles
in determining drug response