Transcript Document

Test-tube or
keyboard?
Computation in the life
sciences
A new cancer has been found
• It has a genetic component
o
if one of your parents or grandparents developed it, you are
much more likely to develop it
• But, its inheritance is complex
o
Some people develop it without having affected parents
YOU'RE A MEDICAL
RESEARCHER
Q. WHAT DO YOU DO?
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?
1. Identifying the genetic
cause of the disease
Genetics, Statistics and
Computers
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.
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...
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
2. Identifying how and why
the disease develops
Molecular Biology,
Physiology, Chemistry
and Computers
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
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?
Human
Genome
Project
Protein structure
databases
Identify how & why the disease develops
Now we have some idea of what the normal gene does.
Q. What does the mutated gene do?
1. What does the mutation do to the protein produced by
the gene?
2. What does the mutation do to the other genes and
proteins in an affected cell?
3. What effect does the mutation have on the overall
system/cell?
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
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...
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"
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
3. Developing a
therapy
Chemistry,
pharmacology and
computers
Developing a therapy
1. How can we interrupt/replace/somehow fix the
defective protein?
2. 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