Hi All
I decided to write a fun article about my project. Hope you like it.
7am! Start of the morning rush hour. We’ve
all been there; flight delays, train cancellations, and if you’re really lucky,
getting stuck in the infamous M6 traffic jam. Everyday as though on autopilot
we habitually follow our set route to various destinations, without noticing
the stress and strain on the transport networks that we so heavily depend on.
Our cells operate much like transport networks and these networks are used to
execute specific functions. A train signal failure can make us late home for
tea, but a fault in the cellular network can often become a deadly disease.
This disease can take away the closest things to us; friends, family and even
your life. This is CANCER.
Cancer – a disease which defies the rules of
biology by stripping away the regulatory mechanisms that dictate when our cells
are destroyed and when new cells are created. In normal cells, signalling
information is transferred down the signalling network and passes through
various checkpoints, like a train stopping at stations before it reaches its
final stop. Certain proteins control the signalling network by interacting with
its downstream partners to ensure the cell’s intended function is achieved. Cancer occurs mainly as a result of malfunctioning proteins
involved in normal cell growth, causing sporadic cell growth that becomes
harmful to the body.
Collectively
known as ‘Ras proteins’, H-Ras, K-Ras and N-Ras, were amongst the first proteins
described as having the capacity to control signalling networks that are
involved in cell growth. Ras proteins are the hub of the cellular network and act like a
switch. When the switch is ‘on’ Ras is activated, triggering a controlled
cascade of signalling information along the pathway to activate proteins to
function. The activity of Ras is partly regulated
by the binding of a protein known as Son of Sevenless (Sos).
Three decades have
passed since the initial identification of Ras tumors and despite 30% of all human tumours known to have Ras mutations,
there still remains no effective commercial therapeutic treatment for Ras
mutant tumors. Understanding the mechanism of Ras
activation via interactions with Sos remains unclear, and poses a challenge for
effective drug designs. The aim of my research is
to understand the interactions of the Ras: Sos complex using techniques such as
Nuclear Magnetic Resonance (NMR) spectroscopy. NMR spectroscopy is a technique
similar to MRI, but is mainly used to detect the structural changes of a
protein at the binding site interface of protein-protein interactions.
The
NMR spectrum of a protein gives rise to NMR signals that are then assigned to a
specific position of the protein. These NMR signals can be imagined as tube
stations of the London underground. Each station represents a unique location
in London. Similarly, each NMR signal represents a specific position in the
protein. If you need to go from the Northern line to the Piccadilly line, you
will need to identify a specific station where both lines are linked together.
Equally, the NMR signals allows me to identify specific regions of Ras where an
interaction with Sos occurs. We have observed and assigned 99% of NMR signals
from all of the functionally significant regions of K-Ras, the variant most
strongly implicated in human malignancies. This work could be a
significant step towards understanding how Ras controls many of the important
signalling networks, which have been associated with cancer.
Why does this matter? Well
the harsh reality is, that not only will cancer affect 1 in 3 of us during our
life-time, but creating new and effective drugs is becoming more
challenging and expensive. Cancer services alone cost the NHS around £5 billion annually. My
PhD project will involve using a new NMR technique to monitor the direct
binding between Ras and Sos proteins simultaneously, under the same conditions
when a drug compound is added. This new technique will aid our endeavours in
identifying potential drug compounds that disrupt the Ras:Sos interactions. I
believe the technique can be commercially applicable by providing a simple and
fast approach to filter out problematic compounds, making the pharmaceutical
industry pipeline more cost-effective in the long term.
It might take a while to
resolve a train signalling problem and like those working towards curing
cancer, we believe there is light at the end of the tunnel. Understanding how
Ras proteins are regulated is fundamental towards creating new anti-cancer
therapies. My project aims to solve this problem. If successful, my project may
influence new anti-cancer treatments to cure and improve the quality of life
for cancer sufferers and their families.
