Biomarkers: distinct indicators that help define the physiology or state of a living system

Biomarkers are not just ANY indicator

Marcelle uses his fingers as an indicator of how close we came to shit-creek. But that’s not a biomarker

Chris uses a YSI probe to measure dissolved oxygen. But that’s not a biomarker.

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

Expression markers for biosynthesis/ trafficking gfp protein tagging

Genetic biomarkers of disease in humans

Induced biomarkers as evidence of abnormality

2002 Nobel Laureate: Sydney Brenner

Genetic Biomarkers

Caenorhabditis elegans, Apoptosis model

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

 

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qpllpqpqpp ppppppppgp avaeeplhrp kkelsatkkd rvnhcltice nivaqsvrns

pefqkllgia melfllcsdd aesdvrmvad eclnkvikal mdsnlprlql elykeikkng

aprslraalw rfaelahlvr pqkcrpylvn llpcltrtsk rpeesvqetl aaavpkimas

fgnfandnei kvllkafian lksssptirr taagsavsic qhsrrtqyfy swllnvllgl

Poly-glutamine stretch of huntingtin coded for by CAG repeats

POLYGLUTAMINE EXPANSION LEADS TO ELEVATED SUSCEPTIBILITY TO APOPAIN

CLEAVAGE AND LIKELY RESULTS IN ACCELERATED NEURONAL APOPTOSIS

Table 1

No. of CAGrepeats

Outcome

< 28 Normal range; individual will not develop HD

29-34Individual will not develop HD but the nextgeneration is at risk

35-39Some, but not all, individuals in this range willdevelop HD; next generation is also at risk

> 40 Individual will develop HD

Huntington’s Disease Repeats

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 2002

Woody, Krisna, Abe Guthrie

Rachel Carsonpublished Silent Spring 1962 raising concerns on DDTHeptachlorDieldrin

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 environmental 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

Primers designed against F. heteroclituscDNAs were used to amplify orthologous mRNA from a group of other teleosts.

ApproachF. grandis (sw)

F. chrysotus (fw)

Gambusia affinis (fw)

VITELLOGENINS AND CHORIOGENINS

Biomarkers 2005

Expect to teach me what YOU learn

A semester-long biomarker study design of biomarker experimental induction

assay and publication

A survey of biomarker techniques from our department and the literature