Test-tube or keyboard?

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Test-tube or keyboard?

• Computation in the life sciences

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A new cancer has been found

• It has a genetic component
• if one of your parents or grandparents developed
  it, you are much more likely to develop it
• But, its inheritance is complex
• Some people develop it without having affected
  parents
•  

YOU'RE A MEDICAL RESEARCHER   Q. WHAT DO YOU DO?
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What do you do?

• 1. Identify the genetic cause of the disease
• What changes in the DNA cause the cancer to
  develop?
•  
• 2. Identify how and why the disease develops
• What is the mechanism of the disease?
•  
• 3. Develop a therapy
• Can we develop drugs to stop the disease?

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1. Identifying the genetic cause of the disease

• Genetics, Statistics and Computers

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Identify the genetic cause of the disease

• Q. What genetic differences are there between
  people with the disease and people without?
• A. Unfortunately, lots
• People vary a lot - around 0.1 of their DNA is
  different on average. 
• That's 6,000,000 differences
• Of course, this depends on a lot of things -
  mostly, how related you are.

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Identify the genetic cause of the disease

• Q. How much DNA in a human?
• A. Unfortunately, lots
•  
• Q. How much DNA do you need to look at?
• A. All of it.
• Q. What are we looking for, exactly?
• A. Probably one tiny change...

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Identify the genetic cause of the disease

• Q. So how do we find the causative mutation(s)?
• A. Look at the DNA of lots of people with, and
  lots of people without, the disease. Then use
  some complex computational statistics.

For complex diseases like cancer you need to look
at thousands of people. And you need to analyse
at least 1,000,000 different locations in their
DNA
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2. Identifying how and why the disease develops

• Molecular Biology, Physiology, Chemistry and
  Computers

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Identify how why the disease develops

• What does the identified gene do?
• Can we come up with some ideas about why it might
  cause cancer if it stopped working properly?
•  
• Genes produce RNA, which in turn produces
  proteins, which are the 'workers' of the cell
•  

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Identify how why the disease develops

• Q. What protein does the gene produce? 
• Do we know what it does? 
• What does it do in other species?
•  

Protein structure databases
Human Genome Project
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Identify how why the disease develops

• Now we have some idea of what the normal gene
  does. 
•  
• Q. What does the mutated gene do?
•  
• What does the mutation do to the protein produced
  by the gene?
• What does the mutation do to the other genes and
  proteins in an affected cell?
• What effect does the mutation have on the overall
  system/cell?
•  

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Identify how why the disease develops

• What does the mutation do to the protein produced
  by the gene?
• Computational chemistry 
• Molecular modelling and molecular dynamics

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Identify how why the disease develops

• What does the mutation do to the other genes and
  proteins in an affected cell?
•  

One gene can affect many others    We can measure
changes  that result from the mutation by looking
at the genes that are turned on in cells that
have the mutation and comparing to normal cells
Typically, we end up with large datasets that
need complex processing...
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A bioinformatics success story

• Dec 2009 Lung and melanoma cancer genomes
  sequenced at the Sanger Centre, UK
•  
• "In the case of the lung cancer patient,
  scientists discovered 23,000 mutations that were
  exclusive to the diseased cells. Almost all were
  caused by the 60 or so chemicals in cigarette
  smoke that stick to DNA and deform it. "We can
  say that one mutation is fixed in the genome for
  every 15 cigarettes smoked," said bioinformatics
  head Peter Campbell"

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Identify how why the disease develops

• What changes to the biological system develop as
  a result of the mutation?
•  
• For instance, what effect is there on the genetic
  networks that result in cancer?
• Systems and 
• Physiology Modelling

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3. Developing a therapy

• Chemistry, pharmacology and computers

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Developing a therapy

• How can we interrupt/replace/somehow fix the
  defective protein?
• Can we design a drug that will bind to the
  defective protein and stop it doing what it does?
• In silico drug screening and drug design