What am I looking for?

The previous posts lead me to introduce my Fellowship project: I am exploring the role of some novel G-Protein Coupled Receptor (GPCR) signalling pathways (some particularly structured antennae whose signals and way of signalling is still to be clarified). I’m particularly interested in the physiology of the islets of Langerhans, which are clusters of cells in the pancreas that produce the hormone insulin. Where have you heard of insulin before? Of course, it’s that protein that is needed to regulate blood sugar levels and when there isn’t enough of it or it doesn’t work properly, Diabetes develops. Diabetes is a huge global problem, and around 400 million people worldwide currently have this condition.

My project aims to provide the molecular basis for the development of new medical tools based on the GPCR activity to prevent, treat and eventually cure Diabetes.

So, going back to our image of a cell as a spherical house, a GPCR is a particular antenna that crosses the dome many times. Yes…crazy uh! And if I ever mention a transmembrane territory (TM) in the future posts, you know I am referring to this dome-crossing feature.

This dome-crossing structure consists of 3 parts called the N-terminus (sticking out of the dome) and the C-terminus (sticking out inside the dome) and the transmembrane territories.

Proteins are made from small building blocks called amino acids that link into long chains. We refer to the ends of these chains as N and C termini to orientate the protein. So N and C work for biologists as North and South or East and West do for sailors (or tourists in the USA!)

If you remember the antennae structure, the N-terminal domain is capable to detect the signal (known to biologists as a ‘ligand’) on the outside of the dome, thus it is defined as the Ligand-Binding Domain, while the C-terminal domain is capable to initiate a series of event on the internal side of the dome that results in a specific effect within the cytoplasm.

So imagine that there is a currency in the cytosol. Signals are received by the N terminus and conveyed to the C terminus. The C terminus then can recruit effectors by spending its currency – this GPCR currency is called GTP. When there is no signal, the C terminus does nothing and doesn’t spend GTP and the receptor is at rest. The equivalent of the purse strings tightening.

So my aim is to consider how the cells respond to the money expenses through GPCRs, specifically those belonging to short chain fatty acids families which we think may be involved in insulin secretion mechanisms.

To pursuit these aims I have been appointed as Research Fellow at the division of Diabetes& Nutritional Sciences of King’s College London, as result of being entitled with a Marie Curie Intra-European Fellowship.

Looking for the other half of the Apple

Going now to the concept of a de-orphanised receptor, just imagine your house roof being equipped with as many antennae as it could accommodate, but for some of them you have no idea what information they’re receiving. If, by doing some tech work (or bio-molecular techniques if you prefer), the role of any of these “orphan” antennae is understood together with what signal(s) is being intercepted…well, you have de-orphanised the antenna..oops, the receptor!

It really means that something produced within the body (an endogenous signalling molecule, or ligand as we now know how to call it) is able to talk to a cell or a group of cells expressing the right antenna on the roof, resulting in a specific biological event taking place.

If this role turns out to be responsible for, or involved in, a disease, the receiving capability of the antenna (receptor, remember!) can be used to regulate the system from outside the body. In terms of scientific research, this means that we can use the receptor to control cell function, and this can lead to the development of new drugs, for example that specifically interact with particular receptors!

Signals and antennae

If you know what a receptor is, please knock on the screen!

Ok I have heard little sound…not really convincing though. I can tell there’s a bit of confusion. I can see your perplexed faces!

Cells might be described as medieval fortified cities, with walls (membranes) that protect their lands (the cytoplasm) with an important castle at the centre (the nucleus) where the king resides and dictates order taken from a written constitution (the DNA!)

Now, imagine this in 3D rather than 2D: the walls around the city are not a circle anymore, but they become a spherical dome and everything inside assumes mainly a globular form (thus becoming organelles). This little bubble-shaped city has controlled access through its dome (the plasma membrane) with gated doors/windows and apparatuses to interact with the external environment.

Well, membrane receptors are proteins that are “mounted” onto the cell dome, just like TV antennae and satellite dishes are on top of our roofs. Similarly to them, membrane receptors have the role of collecting signals from outside the cell and transferring the message they codify down to an apparatus like a TV or a decoding box: in our biological system this may lead to interactions with other proteins, initiating a signalling cascade recruiting and informing more players (like a video on youtube that goes viral via sharing) or the message might instruct the nucleus to make new proteins. Although one single antenna on a house roof is capable of receiving all the signals in the air and one TV apparatus can switch from one channel to another without the need of another antenna, this is not the case of a cellular system.

A cell possesses different antennae (receptors) for different signals, to be as specific as possible and not confuse the information sent across a specific channel [to be honest and fair it also happens that one signal can be received by two or more separate receptors or one antenna can get different signals…but this is another story…and I also promised not to allow things to get too complicated!]

If you think that traffic in London is nightmares…trust me, it is Paradise compared to the network trafficking within a human cell!

So, you might have learnt that the antenna is termed receptor in cell language…the signal that antenna is able to intercept is termed ligand instead!

A passion for complicated things

How would you make a complicated thing easy and accessible?

Let’s assume we all have the answer to this question (I personally still don’t): how would you make Science accessible to the non-Science audience?!
Likely, it would be one of the most difficult challenges you have ever embraced.

So I have thought of setting up a sort of diary of my research experience as part of my work as a Marie Curie Fellow at King’s College London. I would like to draw a map to the maze of biology, chemistry (and sometimes myth and legend) so that I might encourage many of you to understand some of my branch of Science. I would like to do it in a simple but not simplistic way, engaging with that portion of the general audience who is interested or intrigued by the work scientists do and might find some difficulty in fully understanding it!

To be completely honest, it is sometimes even more difficult for a scientist to explain his/her work in a simple way rather than troubleshooting the Research itself: writing these few lines is taking me more time than wrapping up my last 5 years of studies.

When trying to explain a process, ignoring all those years spent soaking the brain with “specific language and terminologies” that allow a 2 page concept to be expressed in a single word, a Scientist faces the same grade of difficulty as a non-scientific reader does in doing the opposite. And I think this is true for any scientific subjects, from the more widespread biology to the more specific quantum astrophysics or rocket science (just think how many mathematical equations are behind the so popular E=mc2)

Given the concept I am not a spin doctor as someone might have assumed (wrongly!) and despite my sharp talent for complicating things, I will try my best to fulfil my target of “being as simple as possible”. I hope the reader(s) will accept my sincere apologies if sometimes I am forced to throw in some technical words that might sound gibberish! :)

And if I am not able to shed some light on this mysterious world, at least I would like to invite you to follow my BRiDiT (beta cell receptors in diabetes therapy) blog to have a closer understanding of my project that is aimed at investigating the roles of some newly de-orphanised membrane receptors in the islets of Langerhans.