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FINDING THE DISEASE GENES
PROGRESS AND PROBLEMS
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THE HUMAN GENOME MAPPING PROJECT SEEKS TO READ THE FULL SEQUENCE OF THE HUMAN GENOME
3 Billion bases so this is a huge task and uses DNA from blood cells
YeastWormsFliesMice
Other species are being analysed as well!
Cell division/mitosisCell death!Differentiation/patternsMammalian studies
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THE HUMAN GENOME MAPPING PROJECT
3 Billion bases in each cell
Most of our DNA has no known function but 3% is divided into genes (30,000)
transcribe
translate
RNA
Protein
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ALL CELLS HAVE THE SAME DNA!!!
So, why do we have so many different cell types
Different cells transcribe different sets of genes
Skin cell
Blood cell
Brain cell
A B C D E F G H I J
SAME GENOME, DIFFERENT TRANSCRIPTOME
We can now start to define a fingerprint for each celltype - transcriptional profile
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Transcriptional profiling by micro-array analysis
Glass Slide
In this way we can define the transcriptome of a cell!
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IS ALL THIS INFORMATION HELPFUL IN CANCER RESEARCH?
transcribe
translate
RNA
Protein
In cancer, the problem always occurs at the level of the genome
-mutation (carcinogens!)-Inherited disorders-DNA breakage
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IS ALL THIS INFORMATION HELPFUL IN CANCER RESEARCH?
1) Understanding the basic causes of cancer- In cancer the cell has become confused!
Please do not put your hand in the firePlease do put your hand in the fire
Please do drive carefullyPlease do not drive carefully
A cancer causing gene???
Blood cell
A B C D E F G H I J
Leukaemia cell
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Normal Cell Cancer cell
Micro-arrays help us to do this on a larger scale!
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2) Finding new cancer causing genes in days rather than decades
3) Determining therapy?
In some cancers, one individual may respond to treatmentwhilst another won’t
Can we predict this using the new genetic information?
4) Designing new therapies
New cancer genes mean new targets!
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THE GENOME INFORMATION IS LIMITED
IN ITS USEFULNESS!
SO NOW WE ENTER THE POST-GENOME ERA
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The Post-genomic initiatives 1) Determination of gene function
AHYETONCGFPSOIUTEMOREOYELHQWBZCXAURELSANGHYALPONDONCEMOREYEMYRLOISGHWIYSPLAICMBZVTLESBROWNWOPANG
AHYETONCGFPSOIUTEMOREOYELHQWBZCXAURELSANGHYALPONDONCEMOREYEMYRLOISGHWIYSPLAICMBZVTLESBROWNWOPANG
JUST BECAUSE YOU CAN IDENTIFY A GENE DOESN’T
MEAN THAT YOU KNOW WHAT IT DOES
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TRANSGENICS IN CANCER RESEARCH
How do we analyse the functions and role in disease fornovel (or even known) genes?
1) In vitro analyses: OK but associated with artefacts
2) In vivo would be the ideal: can we generate animals that are either over-expressing the gene or thathave it switched off?
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To generate an animal with altered expression of a genewe really need to do this at the fertilised egg stage!
Clearly this is a problem!
Embryonal stem cells will help here
ES cells Blood cellsCardiac muscle cellsNeuronsSkin cells
Clinical potential here?
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WE CAN GENETICALLY MANIPULATE THESE CELLS
1) Over expressing genes of interest (transgenesis)
Inject into ES cells
Generate mouse
1) Regulating expression is a problem2) Insertional mutagenesis?3) Lethality4) Gene silencing
PROBLEMS
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TRANSGENESIS IS OF LIMITED USE BUT HAS SOME VALUE
1) Can mimic tumour formation and use animals to studytherapeutics etc
2) Can humanise mouse models for disease studies
3) Eventually in higher animals can use to produce drugs orother therapeutically or biologically important proteins
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SOMETIMES THE BEST WAY TO ANALYSE THE
FUNCTION OF A GENE OR PROTEIN IS TO
REMOVE IT AND SEE WHAT HAPPENS!
This involves gene targeting or gene knockout technology
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Can we genetically manipulate ES cells?
2) Removal of gene expression (knockout mouse generation)
Altered RNA and non-functional protein
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‘null’ ES cell ‘null’ mouse
Possible outcomes:1) Embryo lethal2) Post-natal lethal3) No phenotype (redundancy???)
3) Is the worst case scenario. How far do you go to analyse these animals?
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The Post-genomic initiatives 2) Determination of protein structure
Crystalgrowth
Diffractionpattern
Crystalstructure
Without an understanding of protein structure the genome is meaningless!
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Genome
Transcriptome
Proteome
IEF
SDSPAGE
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Genome information: The hype!
1) The Book of Life? - don’t know the function of most genes- can’t yet use it to really understand proteins- can we use this information to understand life?
2) Genetic determinism?-there are probably too few genes
3) New cancer causing gene discovery (oncogenes)- in the short term more of a curse?
4) What does this mean for your life?
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Genome information: The hype!
1) The Book of Life? - don’t know the function of most genes- can’t yet use it to really understand proteins- can we use this information to understand life?
2) Genetic determinism?-there are probably too few genes
3) New cancer causing gene discovery (oncogenes)- in the short term more of a curse?
4) What does this mean for your life?
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ALL CELLS CONTAIN THE SAME DNA
So, is it possible that a skin cell could become a blood cell?
Could an adult cell become equivalent to a fertilised egg or an embryo?
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ADULT CELLEGG CELL
Discardnucleus
RemovenucleusFuse egg cell cytoplasm
with adult nucleus
IMPLANT INTO FEMALE ANIMAL
ANIMAL CLONING
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HOW MIGHT THIS TECHNOLOGY BE USEFUL?
1) Can address questions about aging
2) Can clone animals with useful traits
3) Can produce transgenic animals
4) Protection of endangered species
5) Cloning of extinct animals
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CLONING TECHNOLOGY: THE PROBLEMS
1) What does this tell us about the legal/ethical status ofan adult cell?
2) Reproductive cloning
3) Cloning for body parts
4) Cloning of a dead child
5) Generation of a human sub-class
WHO SHOULD POLICE THIS?
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IF CLONING FOR BODY PARTS IS BANNEDARE THERE OTHER WAYS WE CAN USE THESE
CELLS TO PRODUCE TRANSPLANTABLE BODY PARTS?
PERHAPS WE CAN DO THIS IN VITRO?
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Embryonal stem cell
Blood cells
Heart cells
Brain cells