WTF is the CFTR Gene?
Written by Marc Cotterill.
Input!
CFTR, which stands for ‘Cystic Fibrosis Transmembrane Conductance Regulator’, has become an acronym that we casually drop into conversations, social media posts and captions, almost as if it’s an easy concept to grasp.
But the other day I sat thinking about my previous articles—which all reference the term—asking myself, how many of us actually know what it means?
Inspired by the mantra of my favourite 80s robotic movie star, when I don’t understand something, I often find myself echoing his famous line: “Input!”
His name is ‘Johnny 5’ and he is the main character in the film "Short Circuit" from 1986, which revolves around a robot originally named "Number 5", the fifth in line of a new group of experimental military robots. Throughout the film, Johnny 5 develops an enthusiastic appetite for information, or as he calls it—input!
What has this got to do with the CFTR gene? Well, I think our community is a bit like Johnny 5, we’re constantly seeking information to learn more about our condition, and the more we learn, the more we grow.
For copyright reasons, I can’t share a picture of Johnny 5, so the one below will have to do, but I will insert some film clips at the end for you to enjoy.
My mission for this article is to be like Johnny 5—to gather input—and to document what I find to share with you, the CF community. And even though we’d all like to believe that our memory is way more advanced than Jonny 5’s impressive upgrade in Short Circuit 2—“five hundred megabytes on-line”—if I capture it here, we all know where to look when we inevitably forget.
I’ll use our friend Johnny 5 throughout this article, in an attempt to provide a consistent analogy throughout. If nothing else, writing about him will be a fond trip down memory lane for me, but I’m hoping it also helps you to embed the CFTR science.
Let’s go.
CFTR Gene: Where is it?
Right, cast your mind back to science lessons during your high school days.
What can you recall?
Like me, you probably retained some, but not all of it. So let’s refresh our minds and make it relevant to Cystic Fibrosis, starting with ‘chromosomes’, ‘DNA’, and ‘genes’.
In the nucleus of each cell (the bit at the centre), there are tiny structures called ‘chromosomes’. Each chromosome is formed from a single, enormously long DNA molecule packaged into thread-like structures which look like a twisted ladder, tightly coiled many times around proteins that support its structure.
If our DNA wasn’t coiled into chromosomes like this, in total it would be around 6 feet long from end to end!
By the way, ‘DNA’ stands for:
Deoxyribonucleic acid
And is pronounced: ‘dee-ox-ee-RYE-boh-nu-KLAY-ik’ acid.
In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46.
Each chromosome pulls together at the centre which gives it a characteristic ‘X’ shape, dividing the chromosome into two sections, or ‘arms’.
The shorter arm of the chromosome is referred to as the ‘p arm’ and the long arm is referred to as the ‘q arm’. You might remember how chromosomes and DNA structures look from your high school science textbooks. Chromosomes on the left, DNA on the right:
Still with me? Great.
So what about genes?
Genes are segments of DNA, a section of the twisted ladder structure.
As we know, every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 per cent of the total) are slightly different between people. These small differences contribute to each person’s unique physical features.
Genes are measured by ‘bases’.
A base in DNA is a molecule that acts as the basic unit of genetic code, and there are four types:
Adenine (A) - (pronounced ‘AD-uh-neen’)
Thymine (T) - (pronounced ‘THY-meen’)
Cytosine (C) - (pronounced ‘SY-toh-seen’)
Guanine (G) - (pronounced ‘GWAR-neen’)
These bases pair up with each other in a specific way, referred to as ‘base pairs’.
Adenine pairs with Thymine, and Cytosine pairs with Guanine, and the order of these base pairs along the DNA strand determines genetic information.
So as you can see there is a hierarchy. It starts with the cell and its nucleus, moves to chromosomes and DNA, and then drills down into genes and their constituent bases. This hierarchy helps us understand how genetic information is organised and expressed in living organisms.
To bring it all together, let's 'disassemble' Johnny 5 just like in 'Short Circuit’ (don't worry, we're not actually taking him apart!) and compare his structure to the makeup of human cells:
Here’s how it could work:
Let’s imagine his ‘motherboard’ as if it were the nucleus of a cell in the human body, which houses all the principal components of his internal computer.
Now imagine his ‘CPU’ (central processing unit) as a chromosome, a key component of his computer that acts as the control centre for all the processes that execute tasks vital for function.
Johnny 5’s ‘operating system’ is like DNA. It’s the software system that coordinates all programs, governing his every action, from movements to responses and everything in between.
Within the operating system, he has a number of ‘applications’, which we can liken to genes—snippets of software that control distinct skills and responses.
Finally, Johnny 5’s underlying lines of ‘computer code’ are like bases. They are fundamental instructions that serve as a blueprint for everything he does.
While Johnny 5 is obviously vastly different from humans, the parallel hierarchies—from cell to genes in humans, and from motherboard to lines of code in Johnny 5—highlight that genes, much like lines of code, are the fundamental instructions that shape the essence of life.
So what do we know about our ‘CFTR gene’?
The CFTR gene spans a region of DNA which is around 200 to 250 ‘kilobases’.
1 kilobase (kb) is equal to 1,000 base pairs, so the CFTR gene's size can therefore be understood as ranging from between 200,000 and 250,000 base pairs of DNA, which takes up a specific area on the long (q) arm of one of the chromosomes in our bodies—chromosome 7.
To be even more specific, the precise location is ‘7q31.2’ which is pronounced exactly as it reads: ‘seven q thirty-one point two’:
'7' refers to chromosome number 7.
'q' refers to the long arm of the chromosome.
'31.2' refers to the section of DNA where the CFTR gene is located.
The size and precise location of the CFTR gene are critical in understanding its role and implications in CF. I’ll leave the reference links for these numbers below.
CFTR Gene: What does it do?
These 200,000 to 250,000 base pairs of DNA are the genetic code that instructs cells on how to make a very important protein, via a process called ‘protein synthesis’.
The protein created is rightly called the ‘CFTR protein’.
The creation of the CFTR protein occurs via two sub-processes in the cell known as ‘transcription’ and ‘translation'. I like to think of these processes as reading (transcription) and building (translation).
Here’s how it works:
Transcription (Reading): The cell reads the sequence of DNA bases in the gene and creates a corresponding strand of mRNA—a ‘messenger RiboNucleic Acid molecule’ (RYE-boh-nu-KLAY-ik)—that is 6,129 bases long.
Translation (Building): The mRNA then serves as a template for building the CFTR protein. It works via a cellular structure called a ribosome (RY-boh-zohm), that reads the sequence of bases on the mRNA. The ribosome then assembles amino acids in the order specified by the mRNA to form a protein chain.
The CFTR protein consists of a single chain of 480 amino acids. Once all the amino acids are linked together to form the protein, they are able to fold into a complex three-dimensional shape that allows the protein to perform its specific function in the body.
So, coming back to our analogy, imagine Johnny 5 wants to connect with other computer systems in order to learn new information.
Here’s how it could work:
Transcription (Reading): This is like Johnny 5 scanning his internal code to find the blueprint (mRNA) for a communication channel (CFTR protein) that enables him to connect with other systems. The blueprint (mRNA) provides the instructions he needs to create the communication channel.
Translation (Building): Now he has the blueprint, this step is like Johnny 5 building the channel (CFTR protein). Using the blueprint's instructions (mRNA), he creates a wireless connection to other computer systems, allowing him to receive and understand new data, satisfying his growing desire for ‘input’.
CFTR Protein: What does it do?
When discussing CF, there is a particular type of cell that is important.
Epithelial cells (ep-ih-THEE-lee-ul) are cells which line the surfaces of the lungs and digestive tract. These are particularly important because they’re involved in the production and management of mucus.
As we in the CF community know—probably too well—mucus is a protective secretion with a primary function to trap and help eliminate foreign particles and pathogens, like bacteria and viruses.
What does this have to do with the CFTR protein?
Well, remember how we said that the protein forms a complex three-dimensional shape? Well, think of this shape as a tiny channel (or tunnel) that sits at the edge of the cell wall to let ‘chloride ions’ move in and out of the cell.
Chloride ions are important in terms of mucus production because they help regulate its water content. Chloride ions carry a negative charge and therefore draw water molecules towards them, and this attraction helps water to move where the chloride ions move (a process called osmosis). This process is essential for keeping mucus moist and fluid.
In CF, the CFTR protein that should form this channel is defective due to the genetic mutation in the CFTR gene. In other words, given that the cell is reading incorrect instructions from the gene, it ends up having issues building the CFTR protein.
And, depending on the specific mutation or error in the CFTR gene, it could lead to one or more negative outcomes:
The CFTR protein may not be built at all
The protein could be built but it doesn't change shape and move to its correct location at the cell wall
Or, the protein is built correctly and reaches the cell wall, but it doesn't open efficiently to allow the chloride ions to pass through
These are some of the key issues we see in people living with CF. Without an effective CFTR channel, chloride ions are unable to travel through it, therefore water doesn’t follow and mucus isn’t hydrated. This lack of water causes the mucus in the lungs and digestive system to become much thicker and stickier than normal.
In other words, if the blueprint Johnny 5 uses to build his new communication channel is incorrect due to a flaw in his underlying code, much to his dismay:
He either can’t build the communication channel at all
He manages to build the channel but is unable to connect to other systems
Or he builds it and makes the connection, but is unable to interpret the data received
If Johnny 5 cannot take in and understand new information effectively, he can’t grow, and he is unable to learn and appreciate the subtle nuances of human behaviour.
CFTR Protein: How does it work?
As we now know, the CFTR protein is made up of 480 amino acids. But within this make-up, there are five distinct parts, known as domains, each with a specific function.
Two parts of the protein are called ‘MSD1’ and ‘MSD2’:
MSD stands for ‘Membrane-Spanning Domain’. These are regions of the protein that are structured to cross the cell wall, which together form the channel which can open and close to allow the chloride ions to pass in and out of the cell.
The second two parts are called ‘NBD1’ and ‘NBD2’:
NBD stands for ‘Nucleotide-Binding Domain’. These are regions of the protein that bind with nucleotides like ‘ATP’. ATP stands for adenosine triphosphate (ah-DEN-oh-seen try-FOSS-fate) and is responsible for providing energy.
The energy provided by ATP is necessary for three reasons:
To change the shape of the MSD1 and MSD2 regions to form the channel
To transport the CFTR protein to the cell wall where it needs to function
To allow it to function properly at the cell wall by opening and closing the channel
The final part of the protein is called the ‘regulatory (R) domain’:
The regulatory (R) domain, is a region of the protein that contains something called ‘phosphorylation sites’ (fos-for-uh-LAY-shun). Phosphorylation sites are like little docks on the protein where a tiny particle, called a phosphate group, can attach which sends a signal to activate the protein.
Let’s simplify all of this back to our Johnny 5 analogy:
MSD1 and MSD2 domains: These represent the communication channel Johnny 5 uses to connect to other systems and receive and interpret data (chloride ions).
NBD1 and NBD2 domains: These are like Johnny 5's batteries that provide the energy (ATP) required to power the communication channel and receive data.
R domain: Think of this as a function that Johnny 5 uses to initiate the transmission of data, opening and closing the communication channel to manage the flow of data from the other systems.
CFTR Modulators: How Do They Work?
CFTR modulators are groundbreaking treatments that currently benefit around 90% of individuals with cystic fibrosis, tailored to specific genetic mutations. However, for the remaining 10%—primarily those with rare or Class I mutations where the CFTR protein is not produced—these modulators are unfortunately not suitable.
Thankfully, ongoing research is dedicated to addressing these gaps, and I am filled with optimism that new therapies will emerge soon. I’ll share more information about these research areas in future articles.
As a representative example for this discussion, I want to use ‘Kaftrio’ (known as Trikafta in the U.S.) as the CFTR modulator example, which has been a game-changer for many of us lucky enough to be taking it.
Kaftrio is composed of three substances: ‘elexacaftor’, ‘tezacaftor’, and ‘ivacaftor’. These components work together to enhance the function of the CFTR protein.
We can separate these component substances into two categories: correctors and potentiators.
Correctors like elexacaftor and tezacaftor help the CFTR protein in forming its proper three-dimensional shape that we talked about earlier (the channel) and they assist in getting it to the place where it needs to function at the cell wall.
Potentiators like ivacaftor then increase the function of the protein, helping to open the channel and allowing the chloride ions to pass through, which helps in normalising mucus consistency.
CFTR modulators are often inaccurately described as a 'root cause' solution for cystic fibrosis. However, as we have discovered in this article, the true root cause of CF is a genetic mutation within the CFTR gene.
While CFTR modulators don’t correct the underlying genetic code, they do work to improve the function of the defective protein. They address the primary consequence of the genetic mutation rather than the mutation itself - or in other words, not quite the root cause, but the next best thing.
Finally, let's frame it with Johnny 5 (spoiler alert!):
Shortly after Johnny 5 was built, he was struck by lightning, and as a result, developed a malfunction leading to behaviours unintended by his manufacturer—a bit like how our CFTR gene has a malfunction.
The amazing thing about Johnny 5 is that his malfunction turns into a defining moment, it brings him to life and sets him apart from all other robots.
While his basic code might not grasp the subtle nuances of human behaviour, which sometimes means he makes mistakes or sounds a little too robotic, we can think of CFTR modulators as ‘input’ in the form of lessons from his human friends—small, daily adjustments that help him communicate better and mimic human interactions more naturally.
In my view, it’s a lot like living with CF. CF makes us resilient and unique, and it allows us to truly appreciate life—just like Johnny 5. In the same way that the guidance Johnny receives from his human friends doesn't alter his fundamental programming, it empowers him to grow and live a more fulfilling life, just like CFTR modulators do for those lucky enough to have access to them.
Stay Hungry for Input
Admittedly, the science can seem a little daunting, but I think having some level of understanding is particularly useful when discussing the importance of CFTR modulators—which for the vast majority of those lucky enough to have access, have changed the game for what it means to live with CF.
Together—with the help of our friend Johnny 5—we’ve learned a lot:
Our CFTR gene, spanning around 200 to 250 kilobases of DNA, which can be found in section 31.2 on the long (q) arm of chromosome 7, creates the all-important CFTR protein through the cellular processes of transcription (reading) and translation (building).
This protein, composed of 480 amino acids, forms a channel in cells which line the surfaces of the lungs and digestive tract (epithelial cells). The channel then opens and closes to allow the movement of chloride ions between cells which consequently leads to the proper hydration of mucus.
In CF, our genetic mutations cause the CFTR protein to malfunction—it either isn’t created, it doesn’t change shape and reach the right location at the cell wall, or it doesn’t open correctly to allow chloride ions to flow.
Thankfully for many of us, CFTR modulators work by correcting the function of the defective CFTR protein, therefore helping to improve the debilitating symptoms of CF. It’s not quite a root-cause solution, but pretty damn close.
So there you go, that’s how it works.
And as always, stay hungry for ‘input’—just like Johnny 5!
Class dismissed!
Short Circuit - The Trailer:
Short Circuit - Input:
Short Circuit - J5 is alive:
Sign the global access to CFTR modulators petition
References:
Short Circuit
My Favourite Johnny 5 Quotes:
“Hey, laser lips, your mama was a snow blower!” - As J5 takes on the other robots sent to take him down.
“Attractive! Nice software” - As J5 notices Stephanie in the bath.
“Number 5 stupid name... want to be Kevin or Dave. Maybe Johnny... Yeah, Johnny 5!” - After J5 has finally proven that he is in fact ALIVE!
Thanks Marc, I won’t pretend I could take in all the scientific info but now I can understand how the Modulators work