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? Protein structure databases Human Genome Project

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