September 24, 2021

I, Science

The science magazine of Imperial College

In 2000, the human genome, a manuscript containing all the genes that make us human, was completed at a cost of $3 billion dollars. At a cost of nearly $1 a letter, this makes it the costliest script ever bought (its worthiest competitor being Audubon’s ‘Birds of America’, sold for $11.5 million). What, apart from renown, has this exorbitant purchase achieved?

When iron-dark clouds are brewing on the horizon after a period of heat, we expect a storm. With the genome project, we can see the clouds and feel the heat – every day a new gene is found, but has medicine experienced a storm?

Whilst we may not be popping to our GP for a quick genome patch-up, having our futures divined via a 3 billion letter molecule delicately packaged inside each cell, wiping out cancer in the blink of an eye, or cheering as we lower the coffin lid on AIDS – actually, yes, the storm is brewing.

We have identified hundreds of single-gene diseases, thousands of illness-modifying variants, designed hundreds of specific drugs, elucidated hundreds of biochemical pathways from addiction to cancer, persuaded bacteria to churn out human blood products, illuminated the evolution of our ancestors and have made in-roads into the tangled tapestry of genetic psychology. Frankly, the only other thing that has gathered that much information in a few short decades is the internet.

However, to the general public genes seem aloof. Buried deep inside our bodies, deep inside our minds. Few of us, rightly so, stop and wonder what ticking time-bombs we ferry round a few millimetres below our skin. Apart from the obvious, are genes relevant to those who eschew lab coats?

Part of the problem is that we wander around as a complex amalgam of 22,000 genes, hard at work in their weird and wonderful ways, unable to contemplate how they all fit together to produce something as complex as a pomegranate, let alone a human being.

Counter to many arguments, we are reducibly complex. At a basic level, a gene makes a protein. If I could pick just one example to illustrate a gene’s journey, it would be SCN10A. Why? It regulates the heartbeat, an irrefutable symbol of life. Every time you feel your pulse you can imagine this gene nestled away in your heart, one cog in a very big machine.

The gene is found on Chromosome 3, when recruited it is copied letter by letter into a sister form of DNA called messenger RNA.

The messenger RNA (mRNA) is given a little cap and a tail, edited slightly, and thrown out of the nucleus into the cell cytoplasm. The cap then allows the mRNA to stick onto a protein-blob factory called a ribosome. Here, every set of three letters is married to a specific amino acid, producing a structure similar to pearls on a string; a protein. On completion it is released and ferried into a structure called the Golgi apparatus; membranous sheets which fold the protein like microscopic origami. A tag is attached, which identifies where the protein is to be sent to. In this case, it is the cell membrane.

On arrival the protein twines itself up and down across the membrane like a worm, orientating itself with 3 other SCN10A proteins. Together they form a hollow cone that points towards the cell interior. This cone allows sodium to cross the impermeable cell membrane in a regulated fashion.

On command the channel opens, allowing sodium to flow into the cell. This flow causes a voltage change that opens Calcium and Potassium channels. Calcium alters the contractile apparatus of heart cells, causing them to contract as long as calcium is present. Potassium reverses the voltage change and resets the cell; calcium is forcibly ejected and heart cells relax.

This careful ballet of ions across the membrane is choreographed so that heart cells contract to produce a pump effect, with atria first, then ventricles, pushing 5L of blood around the body every minute. Sodium is the pacemaker current, and SCN10A gene variants contribute to the normal heart rhythm. Mice missing this gene have a much faster heart rate than normal.

Why is this relevant? Coronary heart disease is the leading cause of death, with 50% attributable to rhythm changes in the ventricles (3.5 million deaths worldwide per year), which SCN10A can influence. It’s hoped that knowing variants of this gene will help identify people more at risk of fatal arrhythmias, help design targeted drugs and maybe one day enable gene therapy.

So next time you want a grasp on your genome, find the pulse on your wrist and imagine the ebb and flow of sodium in your heart. The result of a gene 97,000 letters long – what literary associations define as a short story!

Journal Ref:
“Genetic variation in SCN10A influences cardiac conduction”, Chambers et al. Nature Genetics, 2010 Feb;42(2):149-52

Image: flickr | sarahfrost