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Genes

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Title: Genes


1
Genes MedicineHow DNA is Improving Your
HealthU3A Mountford, June 2004
Dr Martin Kennedy Department of
Pathology Christchurch School of Medicine
Health Sciences University of Otago
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What this talk is not about
No, Im not the waiter. Im the genetic engineer.
How would you like your lamb?
3
What this talk is about
  • Why is genetics important?
  • Disease genes
  • inherited disease
  • complex diseases
  • The human genome project
  • Genetically modified animals
  • Treating disease
  • finding new drugs
  • tailored drug treatment
  • gene therapy

4
Conquering disease
  • Recognition and naming
  • Observation and measurement
  • Understanding of aetiology/pathology
  • Understanding of molecular mechanisms

Development of treatments preventative
strategies
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DNA, chromosomes genes
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Chromosome structure
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Why is recombinant DNA needed?
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Recombinant DNA (GM)
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Run for the hills - the recombinant DNA has
escaped!
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Why try to understand genes?
  • To provide a window on the disease process
  • Diagnostic or prognostic markers
  • Drug targets
  • Prediction/prevention

The vast majority of our knowledge about human
genes comes via genetic modification techniques
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Genetics contributes to most disease
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Genetics contributes to most disease
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Genetics contributes to most disease
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Genetic disease
  • Mendelian disease
  • one gene
  • genes are causative
  • genetic mutations
  • environmental influences
  • eg CF, PKU, haemochromatosis

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Genetic disease
  • Complex disease
  • polygenic
  • genes confer susceptibility or risk
  • genetic variants (polymorphisms)
  • environmental influences
  • eg Diabetes, IBD, CAD, autism, anorexia, coeliac
    disease, Alzheimers, asthma, bipolar disorder

17
Genetic disease
  • Congenital disorders
  • loss or gain of genes
  • usually sporadic
  • eg Downs, Williams, PWS

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Cancer
  • All cancer is caused by damage to genes
  • Damage to several or many genes is required to
    initiate and progress cancer
  • Some cancers display an inherited susceptibility

19
The human genome project
20
The Human Genome
This scaffold has been handed down to us from
our ancestors, and through it we are connected to
all other life on earth. Svante Pääbo, 2001
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Molecular characterization of Mendelian diseases
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Understanding major disease
Alzheimers Disease Third leading cause of
death Asthma Affects 150 million people
worldwide Breast cancer Accounts for 20 of
female deaths Heart disease The worlds biggest
killer Migraine 1.4 billion attacks worldwide
each year Depression Ranked 4th in W.H.O.
global burden of disease analysis
27
Isolation of susceptibility genes
Korstanje Paigen 2002, Nature genetics 31, 236-7
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Major outcomes of HGP
  • Discovery of
  • causative genes in Mendelian disorders
  • susceptibility genes in complex disease
  • Improved
  • drug design
  • drug treatment
  • disease management
  • Understanding of human history

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Microbial genomes
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Completed microbial genomes
  • 165 Bacteria including
  • Yersinia pestis
  • Helicobacter pylori
  • Haemophilus influenzae
  • 1790 Viruses including
  • SARS
  • HIV
  • Several herpes viruses
  • Several papilloma viruses
  • Several influenza viruses
  • Polio

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Transgenic organism
  • A plant, animal or microbe that has
    incorporated, in its own genome, genetic material
    from another organism.

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Transgenic mice
  • Adding genes
  • Conventional transgenics (developed early
    1980s)
  • Subtracting genes
  • Knockouts (developed late 1980s)

36
Why? Transgenic animals
  • Understanding gene function
  • Modelling diseases
  • Bioreactors for vaccines, drugs, etc

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Nature Genetics, 2000
  • Approximately 280 research papers. Of these, 80
    (28) directly focused on GM mice
  • Cancer 11
  • Cardiovascular disease 7
  • Development 15
  • Neurological or behavioural 11
  • Reproduction 7
  • Obesity and diabetes 7
  • Vision or hearing 7
  • Technology development 9
  • (including two large scale international programs
    that generated and screened 40,000 mice,
    producing 747 new mutants)
  • Others 6

39
DNA and the treatment of disease
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GE and drug development
  • Identification of new drug targets
  • Production of drugs
  • Structure aided drug design
  • Pharmacogenetics

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Pharmacogenetics
  • The study of genetic variation underlying
    differential responses to drugs

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Adverse drug effects
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Why pharmacogenetics?
  • Prediction of adverse drug reactions
  • 100,000 deaths annually and 2 million
    hospitalizations (USA alone)
  • More appropriate prescribing
  • Medicines targeted for specific genotypes
  • Rescue failed drugs
  • Making better use of existing drugs

44
Antidepressant treatment of depression
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Bronchodilators treatment of asthma
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Inflammatory Bowel Disease
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Pharmacogenomics
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DNA is a potentially powerful drug
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Brave new world?
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Where is GM in medicine taking us?
  • Better understanding of mammalian biology
  • Better understanding of disease
  • Improved ability to predict disease
  • Improved ability to diagnose disease
  • Improved ability to control disease
  • safer, more specific drugs
  • gene guided management
  • gene therapy

57
Controls and constraints
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