Biomarkers:
distinct indicators that help define the
physiology or state of a living system
Choriogenins
vitelline envelope
precursor to the
chorion
Estrogen-induced
Liver synthesis
of teleost
choriogenins
follicle
cells
HETEROSYNTHETIC
ORIGIN OF
TELEOSTEAN
CHORION PROTEINS
oocyte
micropyle
Biomarkers are not just ANY indicator
Olivia uses this map to
indicate her world travels
Biomarkers are not just ANY indicator
Matt uses his hands to indicate the
size of his endless imagination
Biomarkers represent the complexity of life
When hypoxia sets in, a yawn
indicates the homeostatic mechanism
to increase oxygen uptake
AKA the Boopathy Biomarker
Biomarkers include
Any indicator of a biological phenomenon:
Microbiological biomarkers to indicate cloning
ampicillin resistance; blue-white screen
Expression markers for cell lineage/biosynthesis
gfp protein tagging
Induced biomarkers as evidence of abnormality
Genetic biomarkers of disease in humans
Cell Lineage Biomarkers
2002 Nobel Laureate: Sydney Brenner
Caenorhabditis elegans, Apoptosis model.
Using dyes we can track all 1030 cells.
131 cells always die.
Behavioral
biomarkers
Morphological biomarkers
Larger tympanum = male frog
anatomica
biomarkers
normal female ovaries
abnormal male testes
The Central Dogma of Cell Biology
Induced proteins can be used as useful
biomarkers of normal processes
as well as disrupted processes
Rachel Carson
published
Silent Spring 1962
raising concerns on
DDT
Heptachlor
Dieldrin
Advocating
integrated pest management,
she referred to work by Henry Long who
reported that heptachlor used to treat fire ants
had INCREASED cane borer damage.
Only a small
modification
b/w estrogen
and
testosterone
Conventional Intracellular receptor MOA
Several
environment
al pollutants
have been
defined as
estrogenic:
Endocrine
disruptors
Estrogen imparts a 3 layered effect
Transcription of Primary genes
Transcription of Secondary genes
A stabilization of cytoplasmic mRNA
Final Result:
A gradual and long lasting cell response
such as synthesis of vitellogenin by liver
The Endocrine Disruptor Hypothesis
Compounds from a variety of sources, once
thought to be safe, are having a non-lethal but
devastating impact on normal biological signaling
1. Human Medicine
2. Vertebrate Metamorphosis
3. Invertebrate Sex determination
4. Vetebrate Sex determination
1950 – 1970s DES prescribed to prevent miscarriages
DES mothers with 30% higher breast cancer 1980’s
DES daughters with 9x ectopic preg, 2x miscarriage,
5x premature delivery, 2x pre-cancerous dysplasia,
3-5x cervical cancer , vaginal cancer ages 14-22.
John McLachlan
DES studies, NIEHS, Tulane
biomarkers: transferrin, uterine cancer
Methoprene inhibits mosqui pupation
but bd products
disrupt vertebrate ret acid signalling
Tyrone Hayes: Atrazine effects
biormarker: frog gonadal abnormalities
Lou Guillette and Lake Apopka:
1992 feminization of gators
2002
Lou says
DDE is
still in
water;
gator
sexes
still
confused
Biomarker:
steroid levels
Chain of Causation:
•Chemical spill in 1992 contained DDT, DDE and more
• Juvenile alligator population has decreased
•females have elevated levels of estradiol
•males have depressed levels of testo
•Females have altered aromatase activity
•Males have poorly organized testes
•Males have reduced penis size
•Testes have elevated estradiol production
•Females have poyovular follicles
•Many contaminants bind to alligator est receptors
biomarkers in certain species have become
useful as indicators of environmental health
Biomarkers for estrogen induction can be
applied to test for normal reproductive health
As well as Environmental Stress such as
Endocrine Disruption
By far the most famous endocrine disruption
biomarker is the yolk protein precursor,
vitellogenin made by the liver under estrogen
induction, transported by the blood and stored
in the oocyte
Approach
F. grandis (sw)
Primers designed
against F. heteroclitus
cDNAs were used to
amplify orthologous
mRNA from a group of
other teleosts.
F. chrysotus (fw)
Gambusia affinis (fw)
VITELLOGENINS AND CHORIOGENINS
Choriogenins
vitelline envelope
precursor to the
chorion
Estrogen-induced
Liver synthesis
Choriogenins
and Vtgs
HETEROSYNTHETIC
ORIGIN OF
TELEOSTEAN
CHORION PROTEINS
and VITELLOGENINS
follicle
cells
YOLK
oocyte
micropyle
The Victories and
Dangers of
Genetic Biomarkers
A novel gene containing a trinucleotide repeat that is expanded and
unstable on Huntington's disease chromosomes.
AUTHORS: The Huntington's Disease Collaborative Research Group
aka
MCDONALD,M., AMBROSE,C.M., DUYAO,M.P., MYERS,R.H., LIN,C.S.,
SRINIDHI,J., BARNES,G., TAYLOR,S.A., JAMES,M., GROOT,N.,
MCFARLANE,H., JENKINS,B., ANDERSON,M.A., WEXLER,N.S.,
GUSELLA,J.F., BATES,G.P., BAXENDALE,S., HUMMERICH,H.,
KIRBY,S., NORTH,M., YOUNGMAN,S., MOTT,R., ZEHETNER,G.,
SEDLACEK,Z., POUSTKA,A., FRISCHAUF,A.-M., LEHRACH,H.,
BUCKLER,A.J., CHURCH,D., DOUCETTE-STAMM,L.,
O'DONOVAN,M.C., RIBA-RAMIREZ,L., SHAH,M., STANTON,V.P.,
STROBEL,S.A., DRATHS,K.M., WALES,J.L., DERVAN,P.,
HOUSMAN,D.E., ALTHERR,M., SHIANG,R., THOMPSON,L.,
FIELDER,T., WASMUTH,J.J., TAGLE,D., VALDES,J., ELMER,L.,
ALLARD,M., CASTILLA,L., SWAROOP,M., BLANCHARD,K.,
COLLINS,F.S., SNELL,R., HOLLOWAY,T., GILLESPIE,K., DATSON,N.,
SHAW,S. and HARPER,P.S.
… I count 58 authors in all
Poly-glutamine stretch of huntingtin
coded for by CAG repeats
matleklmka feslksfqqq qqqqqqqqqq qqqqqqqqqq pppppppppp pqlpqpppqa
qpllpqpqpp ppppppppgp avaeeplhrp kkelsatkkd rvnhcltice nivaqsvrns
pefqkllgia melfllcsdd aesdvrmvad eclnkvikal mdsnlprlql elykeikkng
aprslraalw rfaelahlvr pqkcrpylvn llpcltrtsk rpeesvqetl aaavpkimas
fgnfandnei kvllkafian lksssptirr taagsavsic qhsrrtqyfy swllnvllgl
POLYGLUTAMINE EXPANSION LEADS TO
ELEVATED SUSCEPTIBILITY TO APOPAIN
CLEAVAGE AND LIKELY RESULTS IN
ACCELERATED NEURONAL APOPTOSIS
Huntington’s Disease Repeats
Table 1
No. of CAG
repeats
< 28
29-34
35-39
> 40
Outcome
Normal range; individual will not develop HD
Individual will not develop HD but the next
generation is at risk
Some, but not all, individuals in this range will
develop HD; next generation is also at risk
Individual will develop HD
Human ortholog of ced 3 is caspase 3
Huntingtin is cleaved by caspase 3, and this
change is associated with neuronal death
Genetic Biomarkers
Allow the elimination of imperfect embryos
Plus…
Potential for both
Germline or Somatic Gene Therapy
Woody
Guthrie
1930’s
Woody and Arlo, 1950’s
Arlo still performing in 2006
Woody, Krisna, Abe Guthrie
Guthrie Family at Tipitina's Dec 9th
Biomarkers 2008
A semester-long biomarker study
design of biomarker
experimental induction
assay and publication
A survey of biomarker techniques from our
department and the literature
Biomarkers:
distinct indicators that help define the
physiology or state of a living system
Choriogenins
vitelline envelope
precursor to the
chorion
Estrogen-induced
Liver synthesis
of teleost
choriogenins
follicle
cells
HETEROSYNTHETIC
ORIGIN OF
TELEOSTEAN
CHORION PROTEINS
oocyte
micropyle