Frontiers 2014

Perfect Harmony: Pushing the boundaries of biochemistry

A recent study1 found the number of cells in the human body to be just over 37 trillion.  Let’s just consider that for a moment. Some 37 trillion cells in the adult human are functioning in concert to help each and every one of us work, play, eat, sleep and most importantly, live. As life expectancy increases, so too our cells have to work that much harder and longer. And as we know, sometimes things go awry within one cell type, an organ or multiple systems, resulting in disease.

Understanding how a cell functions normally, enables scientists and clinicians to more clearly identify changes that result in the same cells during the course of disease. And though each cell may be a functional unit, without its ability to connect with and communicate to its neighbouring cells, as well as other organs within the body, one risks communication breakdown.

Orchestrating signals

Chemical messengers are routinely utilized by cells to ‘talk’ to one another and they are reliant on the receiving cell having the ability to accept and translate the chemical internally within the cells. What happens next involves the orchestration of signals in a precise and controlled manner dependent upon time, space and degree.

This is ultimately the goal of our institute – to understand two very critical cellular control mechanisms – phosphorylation and ubiquitylation. These chemical modifications which involve addition of a phosphate (phosphorylation) or ubiquitin molecule (ubiquitylation) are utilized by all cell types, and they function to regulate key cellular functions. Our Medical Research Council Unit — The Protein Phosphorylation & Ubiquitylation Unit (MRC-PPU) is based in Dundee, Scotland and is comprised of a team of 20 Principal Investigators. Each is pursuing a specific line of research that involves examining how these chemical modifications occur normally within cells and the implications of alterations to these modifications in diseases such as cancer, hypertension and neurodegenerative disorders.

In inner harmony

When considering the inner workings of a cell perhaps the most apt comparison that serves to convey its complexity can be found through music. A cell has many parts, or organelles, that together work to ensure that the cell functions according to the masterplan laid out in its genome. This is not unlike an orchestra comprised of diverse musical instruments, each of which comes together to play the composition scored in a symphony. One cannot help but think of one of the great symphonies – Beethoven’s 9th – when considering this metaphor.

In a cell, it is critical that each signal is appropriately timed; as each is passed on to instruct the next modification, this precision is critical. Too much or too little of a signal can skew downstream events. Furthermore, the location of the signal is equally important. If an incoming molecule binds to a receptor on the surface of a cell, it is most important the next signal is present in the appropriate place internally to further carry these events to their ultimate conclusion.

The 4th movement of Symphony Number 9 is well known to many. The Ode to Joy Chorale integrates stringed instruments, woodwinds, percussion and a chorus of voices. What if the strings were drowned out by the woodwinds? Or if the chorale singers came in too late? What if the timpani was out of sync with the violins? Worse yet – if there was only one violin, instead of an orchestra full of them? Would this piece have the same impact? I am doubtful. In fact it is more likely that the ode envisioned by Beethoven to be elicited by the harmonious integration of musical instruments and voices would not be very joyous at all.

Instead, there would be a cacophony. Not unlike the disintegration of cellular events that occurs during disease.

The MRC-PPU is dedicated to untangling such cellular cacophony in order to reinstate harmony within the cell. In an effort to accelerate the ability to translate discoveries in the laboratory to therapies, and ultimately to patients, in 1998, the MRC-PPU entered into a partnership with some of the largest biopharmaceutical companies in the world – including Pfizer, Astrazeneca, GlaxoSmithKline, Janssen Pharmaceutica, Merck Serono, and Boehringer Ingelheim.

Implications for health and illness

Many of the enzymes that regulate cellular modifications such as phosphorylation and ubiquitylation have been found to be ‘druggable’, meaning that they belong to a class of proteins for which one can often screen and identify chemical compounds that modify their function. Thus if in a cancerous cell it has been found that there is too much phosphorylation, scientists who have made this discovery in their laboratories in Dundee, can rapidly partner with expert drug developers to screen for molecules which might alter this chemical modification. Though identifying a molecule that can affect the enzyme in cells is but a first step in the long process of therapeutic development, The MRC-PPU lies at the heart of that process. Investigators here are driven to consider the implications of their research towards human health and disease.

It goes without saying perhaps, that much of the scientific research that we carry out would not be possible without the support of government funding, and in turn, UK taxpayers. It is our privilege and duty to convey this work to the public at large and we do not take that lightly. Moreover, we are eager to spark the minds of Scotland’s next generation of scientists through our public engagement directed towards schools.

We are looking forward to being a part of the 2015 Orkney Science Festival.

1Bianconi, et al. 2013. Annals of Human Biology 40(6):463-471

Prof. Dario Alessi will be speaking on how cells communicate, and how communication breakdown leads to diseases as diverse as cancer and neurodegeneration, in this year’s Orkney International Science Festival. His lecture, titled ‘Exquisite Precision’, takes place in the King Street Halls, Kirkwall, on Friday 4 September at 3.30 pm.

About the author

Dario R. Alessi

Professor Dario R. Alessi is one of the world’s leading biochemists. Born in France, he went to school in Brussels and then to the University of Birmingham, followed by postgraduate research at the University of Dundee where he became director of the MRC-PPU in 2012. He has received many awards including the Gold Medal of the European Molecular Biology Organisation.