Monday, 22 October 2012

The smallest detail sometimes makes the biggest difference

This latest post comes courtesy of my great friend and fellow scientist, Dr Peter Canning.  We were lab partners at the University of Warwick some 10 years ago and were always the last to leave the lab - mostly because I was so slow!  Having completed his PhD in Structural Biology at Warwick, he is now working as a postdoc for the Structural Genomics Consortium at Oxford University... 

The smallest detail sometimes makes the biggest difference 

Looking at how two molecules "talk" to each other may provide the basis for new cancer treatments

The science of cancer imaging encompasses a wide range of different techniques and disciplines. Imaging technologies allow cancerous cells to be detected, characterized and monitored, or using different kinds of imaging methods, much smaller, molecular-scale events can be observed. In every cell of the human body, millions of times a second, biological molecules signal to one another, create things, destroy things, transport things and carry out thousands of individual tasks needed to keep a cell running. Various factors can cause these highly organised processes to break down, causing the cell to malfunction. These are the kinds of malfunctions that lead to the development of cancers and indeed other diseases.

Fortunately, cells come with a range of quality control mechanisms built in. They are capable of fixing all kinds of damage, or if the damage is too severe, they are even capable of activating a kind of self-destruct mechanism that destroys the cell before the problem gets too severe. Of course, the mechanism to control the self-destruct system is carefully controlled and monitored.

One molecule involved in the control of the self-destruct sequence is called p53, in fact it is more or less the control hub, the big red button. If a cell is damaged and on the path to becoming cancerous, p53 is activated and either shuts the cell down or destroys it for good. It has been a subject of great interest for some time to biologists, because in the vast majority of cancer cells, p53 itself has become damaged and is no longer able to destroy the damaged cells. For some unknown reason, p53 has evolved to be very fragile, and so damage to p53 happens all too easily. With this in mind, scientists are working to find ways to reactivate damaged p53, or alternatively to find a way to trigger the same response that p53 would normally activate, hitting the self-destruct button for the cancerous cells and causing them to destroy themselves.

Under normal conditions (a), when a cell detects that it is damaged, a signal is sent to p53, which activates a kind of "self destruct" mechanism to destroy the cell before it can do too much damage. If p53 malfunctions (b) then it is unable to trigger this response and cells are allowed to become cancerous, growing and multiplying unchecked.

I am currently a Postdoctoral Research Associate at the Structural Genomics Consortium (SGC), at the 
University of Oxford, in the Growth Factor Signaling Group ( The SGC is a not-for-profit organization with labs in Oxford and Toronto which looks to investigate biological molecules (proteins) involved in various diseases and study them on the atomic level using an imaging technique called X-ray crystallography, then put the information into the public domain free of charge. This enables further research by the global scientific community, in particular speeding up the lengthy and expensive process of discovering new drugs.

In a paper published in the Journal of Molecular Biology this month, we use X-ray crystallography to image a communication between two molecules at the the atomic level. We wanted to address the idea of self-destructing a cell in which p53 has failed and to do this we looked at a protein very closely related to p53 called p73. p73 is capable of standing in for p53 and destroying a bad cell, with the added bonus that it is far less fragile, but for some reason this is not a common occurrence in the course of normal cellular events. In our paper we not only look at the molecular structure of p73 and how it is subtly different to p53, but also how p73 is activated. We revealed that a protein known to activate both p53 and p73 called ASPP2 activates p73 in almost exactly the same way as p53. This finding raises some interesting questions. For instance, if the system of activation targets both proteins in the same way then how is one protein chosen over the other? However, it also provides useful information for scientists looking to find a way to get p73 to switch on, stand in for p53 and destroy cancerous cells.

These types of images are used to represent the molecular structure of proteins. Here, the ASPP2 protein molecule (red) is shown interacting with both the p73 protein (yellow) and the p53 protein (blue) in an almost identical fashion. 

If you’re interested, the paper is now available from the Journal of Molecular Biology’s website:

Or you can read more about the group’s activities on the SGC’s website:

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