Download Find the Disease Genes

FINDING THE DISEASE GENES
PROGRESS AND PROBLEMS
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
Other species are being analysed as well!
Yeast
Worms
Flies
Mice
Cell division/mitosis
Cell death!
Differentiation/patterns
Mammalian studies
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
RNA
translate
Protein
ALL CELLS HAVE THE SAME DNA!!!
So, why do we have so many different cell types
Different cells transcribe different sets of genes
A
B
C
D
E
F
G
H
I
J
Skin cell
Blood cell
Brain cell
SAME GENOME, DIFFERENT TRANSCRIPTOME
We can now start to define a fingerprint for each cell
type - transcriptional profile
Transcriptional profiling by micro-array analysis
Glass Slide
In this way we can define the transcriptome of a cell!
IS ALL THIS INFORMATION HELPFUL IN
CANCER RESEARCH?
transcribe
RNA
translate
Protein
In cancer, the problem always occurs at the level of the genome
-mutation (carcinogens!)
-Inherited disorders
-DNA breakage
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 fire
Please do put your hand in the fire
A
B
C
Blood cell
Leukaemia cell
A cancer causing gene???
Please do drive carefully
Please do not drive carefully
D
E
F
G
H
I
J
Micro-arrays help us to do this on a larger scale!
Normal Cell
Cancer cell
2) Finding new cancer causing genes in days
rather than decades
3) Determining therapy?
In some cancers, one individual may respond to treatment
whilst another won’t
Can we predict this using the new genetic information?
4) Designing new therapies
New cancer genes mean new targets!
THE GENOME INFORMATION IS LIMITED
IN ITS USEFULNESS!
SO NOW WE ENTER THE POST-GENOME ERA
The Post-genomic initiatives 1) Determination of gene function
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 for
novel (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 that
have it switched off?
To generate an animal with altered expression of a gene
we really need to do this at the fertilised egg stage!
Clearly this is a problem!
Embryonal stem cells will help here
ES cells
Blood cells
Cardiac muscle cells
Neurons
Skin cells
Clinical potential
here?
WE CAN GENETICALLY MANIPULATE THESE CELLS
1) Over expressing genes of interest (transgenesis)
Inject into ES cells
PROBLEMS
1)
2)
3)
4)
Generate mouse
Regulating expression is a problem
Insertional mutagenesis?
Lethality
Gene silencing
TRANSGENESIS IS OF LIMITED USE BUT HAS
SOME VALUE
1) Can mimic tumour formation and use animals to study
therapeutics etc
2) Can humanise mouse models for disease studies
3) Eventually in higher animals can use to produce drugs or
other therapeutically or biologically important proteins
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
Can we genetically manipulate ES cells?
2) Removal of gene expression (knockout mouse generation)
Altered RNA and non-functional protein
‘null’ ES cell
‘null’ mouse
Possible outcomes:
1) Embryo lethal
2) Post-natal lethal
3) No phenotype (redundancy???)
3) Is the worst case scenario. How far do you go to analyse
these animals?
The Post-genomic initiatives 2) Determination of protein structure
Without an understanding of protein structure the genome
is meaningless!
Crystal
growth
Diffraction
pattern
Crystal
structure
IEF
Genome
Transcriptome
Proteome
SDS
PAGE
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?
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?
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?
ANIMAL CLONING
ADULT CELL
EGG CELL
Discard
nucleus
Fuse egg cell cytoplasm
with adult nucleus
Remove
nucleus
IMPLANT INTO FEMALE ANIMAL
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
CLONING TECHNOLOGY: THE PROBLEMS
1) What does this tell us about the legal/ethical status of
an 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?
IF CLONING FOR BODY PARTS IS BANNED
ARE THERE OTHER WAYS WE CAN USE THESE
CELLS TO PRODUCE TRANSPLANTABLE
BODY PARTS?
PERHAPS WE CAN DO THIS IN VITRO?
Blood cells
Heart cells
Embryonal stem cell
Brain cells