4 July 2014

Nano technology reveals secrets of cancer molecule

Nano technology

What has previously been perceived as unwanted noise in biological circuits, now turns out to contain secret messages which can mean life or death for cells of the body. Danish and American researchers have collaborated to develop a novel method to listen in on how some of the most important communications proteins in cells transmit information at the single-molecule level. Results show that the proteins add a level of noise, which encodes the actual biological information, for example to start growing. Or even to die. The new results could have massive implications for the development of new drugs against diseases such as developmental disorders and cancer. The results are published in the scientific journal Science.

Original Science article here

Serious diseases can arise when the communication inside cells does not function. For example, cancer frequently occurs when molecular signals for growth can not be turned off again. Now researchers have discovered a previously hidden mechanism that sheds new light on how molecular switches send signals when they are turned on.

Manufactured cell membranes have enabled the researchers to study individual SOS molecules while they are activating, and thus communicating with RAS molecules anchored in the membrane.

'We have worked with certain proteins - Ras and SOS – that are often mutated in cancer and developmental disorders. Ras is known as an ’undruggable protein' because decades of intense research has failed to find effective drugs against it. Our discovery of this previously hidden mechanism may pave the way for drugs that alter the interaction between SOS and Ras', says postdoc Lars Iversen, who is behind the breakthrough.

Message in the noise

In Professor Jay Groves' laboratory at the University of California Berkeley, USA, Lars Iversen and colleagues and researchers at the Nano-Science Center, Department of Chemistry, University of Copenhagen have developed a screening method in which protein communication can be intercepted molecule by molecule, instead of the usual case where millions of molecules are being tapped at once. 

Sensitive microscopes makes it possible to see SOS molecules (the green dots) as they are moving about between the RAS proteins (the red dots). The black colour reveals that SOS has activated RAS in that part of the membrane.

The molecules’ communication lies in how fast they work. The new research shows that SOS and Ras together not just has a single 'on' position, where they operate at constant speed, but can shift between various speeds. These gear change takes place, however, in a random manner, resulting in a bumpy ride. 

'Our results show that SOS is equipped with a Formula 1 engine, but keeps the parking brake engaged, so on average it runs like a family car. Occasionally the brake is released and SOS makes a random spurt. Looking at the working speed as a biochemical signal, these sprints correspond to noise in the signal, which you normally try to avoid. This behavior was a mystery to us, and we therefore used computer simulation to investigate the impact on an entire cell's overall communications. It became clear that the frequency and length of the sprints, and not only the average speed, can affect the cell in a fundamental way. It is fascinating because these sprints - intrinsic noise of the SOS protein - are invisible in traditional measurements.

The researchers believe that the random molecular velocity changes may have general significance. Professor Dimitrios Stamou, Nano-Science Center, University of Copenhagen, is part of the scientific team behind the work done at Berkeley. 

'We have long been focusing on random gear changes in proteins, but the biological consequences have been unclear. With this cooperation, it is clear that these changes may well act as an independent biological signal, "says Dimitrios Stamou.

New knowledge contradicts the accepted view of SOS and Ras function

The new findings turn the existing perception of SOS and Ras' way of working together on its head.

‘It was a little nerve-wracking, but most of all exciting, when our measurements again and again contradicted the existing understanding of how these molecules function. As a researcher, it’s rare to stumble upon discoveries like these’, says Lars Iversen.


Postdoc Lars Iversen, +45 22 57 77 63