Genes & Medicine:How DNA is Improving Your Health

U3A Mountford, June 2004

Dr Martin KennedyDepartment of PathologyChristchurch School of Medicine &

Health SciencesUniversity of Otago

What this talk is not about

No, I’m not the waiter. I’m the genetic engineer. How would you like your lamb?

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

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

Development of treatmentsDevelopment of treatments& preventative strategies& preventative strategies

DNA, chromosomes & genes

Chromosome structure

Why is recombinant DNA needed?

Recombinant DNA (GM)

1980

Run for the hills - the recombinant DNA has escaped!

1978

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 The vast majority of our knowledge about human knowledge about human genes comes via genetic genes comes via genetic modification techniquesmodification techniques

Genetics contributes to most disease

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDSadult onset

diabetes

Genetics

Environment

Genetics contributes to most disease

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDS

Genetics

Environment

depression

Genetics contributes to most disease

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDS

Genetics

Environment

coronary artery disease

Genetic diseaseMendelian disease

– one gene – genes are causative– genetic mutations – environmental influences

eg CF, PKU, haemochromatosis

Genetic diseaseComplex disease

– polygenic– genes confer susceptibility or risk– genetic variants (polymorphisms)– environmental influences

eg Diabetes, IBD, CAD, autism, anorexia, coeliac disease, Alzheimer’s, asthma, bipolar disorder

Genetic disease

Congenital disorders– loss or gain of genes– usually sporadic

eg Down’s, Williams, PWS

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

The human genome project

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

Molecular characterization of Mendelian diseases

Understanding major disease

Alzheimer’s Disease Third leading cause of death

Asthma Affects 150 million people worldwide

Breast cancer Accounts for 20% of female deaths

Heart disease The world’s biggest killer

Migraine 1.4 billion attacks worldwide each year

Depression Ranked 4th in W.H.O. global burden of disease analysis

Isolation of “susceptibility genes”

Korstanje & Paigen 2002, Nature genetics 31, 236-7

Major outcomes of HGP• Discovery of:

– causative genes in Mendelian disorders

– susceptibility genes in complex disease

• Understanding of human history

• Improved:– drug design – drug treatment – disease management

Microbial genomes

Completed microbial genomes165 Bacteria including:

– Yersinia pestis– Helicobacter pylori– Haemophilus influenzae

1790 Viruses including:– SARS– HIV– Several herpes viruses– Several papilloma viruses– Several influenza viruses– Polio

Transgenic organism

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

Transgenic mice

• Adding genes“Conventional” transgenics (developed early 1980s)

• Subtracting genes“Knockouts” (developed late 1980’s)

Why? Transgenic animals

• Understanding gene function • Modelling diseases• “Bioreactors” for vaccines, drugs, etc

Nature Genetics, 2000Approximately 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

DNA and the treatment of disease

GE and drug development

Identification of new drug targets

Production of drugs

Structure aided drug design

Pharmacogenetics

Pharmacogenetics

The study of genetic variation underlying differential

responses to drugs

Adverse drug effects

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

Antidepressant treatment of depression

Bronchodilators treatment of asthma

Inflammatory Bowel Disease

Pharmacogenomics

DNA is a potentially powerful drug

Brave new world?

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

Controls and constraints