If you believe it can be broken, then know it can also be fixed - Rabbi Nachman of Breslov

Posted by Mark

Following on from Juliette’s post about lung transplants in CF patients, I wanted to talk a little bit about what is actually happening in Sammy’s lungs and other parts of his body that means one day we might have to face the difficult process of looking for a new pair of lungs.

DISCLAIMER! All the science in this post is based on my own understanding of genetics and cell biology that I have learnt since Sammy was diagnosed with CF. I think I've got it right but don't rely on anything here to help you pass your biology GCSEs. 


The various processes and functions that take place inside cells are incredibly complex and yet beautifully co-operative and efficient. I have had to simplify some of the processes somewhat to just bring out the salient points relating to CF. If I have misunderstood or omitted anything, please accept my apologies and let me know.

Anyone looking for a comprehensive yet accessible introduction to cell biology should read 'How We Live and Why We Die - The Secret Lives of Cells' by Lewis Wolpert.

http://www.amazon.co.uk/How-We-Live-Why-Die/dp/0571239129  

So onto the biology: The cells that make up the lining of the airways of your lungs are of a type called epithelial cells, and they look a bit like my very amateur animation below (which you may not be able to see if you are reading this on your mobile). On top of these cells there is a mucus layer that traps bacteria. As you move down through this layer, it becomes more watery. Swaying back and forth in this layer are little hair-like structures called cilia that stick out of the cells, washing away all the bacteria and keeping the airways nice and clear.

At least that is what is supposed to happen.

In people with CF, the watery section that sits on top of the cells is too low and thus the cilia aren’t able to wave back and forth because they are just lying down. Without the watery section the mucus becomes thicker and stickier and is the perfect breeding ground for bacteria. Lungs become prone to infection and each infection causes irreparable damage to the lung tissue. Sadly, eventually there just isn’t enough healthy lung to breathe.

The watery section that should be flowing along the airways is maintained by an intricate process of osmosis. Tiny channels or gates are created in the cell membrane that allow chloride ions to leave the body of the cell, making their way into the water stream above. The movement of these chloride ions, along with the absorption of sodium ions causes an in imbalance between the ionic charge on either side of the cell membrane. In order to redress the balance, water is drawn out of the cell, causing a nice constant stream of water for the cilia to work in.

But someone with CF has problems making those little channels or gates that allow the chloride ions to leave the cell. And if there aren’t enough chloride ions leaving the cell, an ionic imbalance can’t be created between the two sides of the cellmembrane and thus no significant movement of water from the cell to the river above. And as we have seen, without enough water, the cilia can’t move and keep the airways nice and clear.

The little channel that allows the chloride ions to leave the cell is called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) and this is where the problem is in people with Cystic Fibrosis. CFTR is made by a little protein machine in the cell that reads the section of DNA code in the nucleus that tells the machine how to make CFTR. When this machine reads the code, it creates a little strand of protein that folds up on itself to form the CFTR. The trouble is that in Samuel’s DNA there is a mistake – or rather two mistakes – in this part of the DNA that means the CFTR won’t be made properly. One mistake came from me which means half of his CFTR proteins lack a particular element and never make it to the cell membrane, and the other mistake came from Juliette which means that the machine that makes the CFTR is told to stop making the channel too soon.  

So what can be done?

We give Sammy physiotherapy everyday to help try and shift some of that sticky mucus out of his airways. We also give him antibiotics to try to kill any bacteria that might be lurking in the mucus and we have to give him lots of enzymes because as well as his lungs suffering from this thick mucus layer, the tubes from his pancreas are also the same. This means that while his pancreas is trying to send enzymes into his gut to absorb certain nutrients from food, the tubes are too blocked to let the enzymes out. So we have to put enzymes into his gut by giving him scoops of Creon every time he eats.

Can it be fixed?

Yes. It can - but at the moment only in theory. More work is needed to make it happen in practice though. The answer, I am sure, will lie in gene therapy and this is where more research and money is needed because gene therapy is the only thing that truly gets to the underlying cause and actually allows cells to create fully functioning CFTR.

What is Gene Therapy

This incredible science hinges on replacing the faulty section of DNA code with a correct piece of DNA, so that Samuel’s cells will be able to make correctly shaped and functioning CFTR channels. The correct genes are packaged in a virus and sent to the area where they are needed. Initially it was hoped that CF would be fairly easy to treat with gene therapy but it is proving difficult to get the new, corrected gene into the cells because lungs are quite well designed to resist invasion. Still, clinical trials are continuing and we hope that there will be good news on this front soon. Gene therapy is a fascinating topic and I may well post about it again soon.

Gene Therapy is the ultimate goal, but another alternative is using drugs that might help the CFTR to work. Trials are underway for combinations of drugs that will still enable those CFTR channels to allow the chloride ions out, even if they are a bit misshapen or unstable. While not entirely correcting the underlying issue in the way that gene therapy would, such an approach would still allow the cells to do what they are supposed to. Indeed, there is a new drug called Kalydco that does just that. Unfortunately for Sammy, this particular drug only helps people who have a particular mutation in their code, G551D. Trials are underway however to see whether this drug, used in combination with others, might help those with other mutations.