Cystic Fibrosis

Many of us have heard of cystic fibrosis and know very little about the disease, its full spectrum of symptomsSubjective experiences reported by the patient (e.g., nausea, fatigue)., and its origin.  Cystic fibrosis is a genetic disease that can be inherited from two parents without the disease.  The parents are known as carriersMembrane proteins that transport substances across a cell membrane., passing down the trait but not expressing the trait.  The piece of DNA passed down from parent to child holds the recipe for creating a protein called the cystic fibrosis transmembrane regulator or the CFTR protein.  

This protein is embedded in the cellsThe basic structural and functional units of life. lining the trachea (windpipe) and other linings of the respiratory systemThe organ system responsible for gas exchange (oxygen and carbon dioxide). such as the bronchiThe large airways that branch from the trachea into the lungs, dividing into smaller bronchioles..  This is why this protein is called a “transmembrane” protein; it spans the entirety cell membrane.  Cells that line an open space (called a lumenThe inside space of a hollow organ or structure.) in the body, called epithelial cells, are responsible for maintaining a fluid mucus barrier between the cells and the open air rushing in and out of the windpipe. Without this protein channel, mucus becomes thick and immovable, a characteristic of cystic fibrosis disease.

In cystic fibrosis, the CFTR protein could be malformed, it could be inserted into the wrong place in the cell membrane, or it just might not be made at all.  There are various versions of cystic fibrosis, all originating from mutation(s) in the DNA that hold the recipe for making, inserting, and regulating the production of the CFTR protein.

When the CFTR protein is working normally, chloride ionsCharged atoms or molecules. are free to move through the plasma membraneThe outer boundary of a cell that controls what enters and exits. according to their electrochemical gradientThe difference in charge and ion concentration across a membrane..  Although the chloride ion is more abundant in the extracellular fluid(ECF) Fluid outside cells, including plasma and interstitial fluid., the net sum of the electrical and chemical gradients causes the movementA fundamental property of life involving motion of the body or its parts. of chloride ions from the inside of the cell to the external surface that is in contact with the dry air of the trachea.  The abundance of the chloride ion draws waterThe universal solvent essential for life. to the outside of the cell.  The CFTR protein can malfunction, preventing the movement of the chloride ion and thus preventing the movement of water.  Without functioning CFTR proteinsLarge molecules made of amino acids with various functions in the body., the chloride ion and water remain inside the cell.  As a consequence, the mucus lining the lumen of the trachea becomes dry and thickened. 

When the cystic fibrosis transmembrane regulator (CFTR) protein is defective, as in patients with cystic fibrosis (CF), epithelial cells can’t regulate the way that chloride ions pass across cell membranes. This disrupts the balance of salt and water needed to maintain a normal thin coating of mucus inside the lungs and other passageways. The mucus becomes thick, sticky, and hard to move, and can result in infections from bacterial colonization.  

Like people, cells need to communicate and interact with their environment to survive. One way they go about this is through pores in their outer membranes, called ion channelsProtein passages in the cell membrane that allow specific molecules to pass through., which provide charged ions, such as chloride or potassium(K⁺): Major ICF cation; essential for muscle and nerve function., with their own personalized cellular doorways. But, ion channels are not like open doors; instead, they are more like gateways with high-security locks that are opened and closed to carefully control the passage of their respective ions.

Among the numerous ion channels in cell membranes, there are two principal types: voltage-gated and chemically-gated (formally called ligand-gated). Voltage-gated channels are triggered to open and shut their doors by changes in the voltage (or potential) of the membrane cell. Chemically-gated channels, in contrast, require a special “key” to unlock their doors, which usually comes in the form of a small molecule.

CFTR is a chemically-gated channel, but it’s an unusual one. Its “key” is ATPThe energy currency of cells used for muscle contraction., a small molecule that plays a critical role in the storage and release of energyThe capacity to do work or cause change. within cells in the body.  Constantly produced by mitochondria, ATP requires glucoseA simple sugar that is the main source of energy for cells. and oxygen while producing water and carbon dioxide as waste products.  The CFTR protein requires ATP to open its channel and allow chloride anions to flow to the surface of the cell.  This flow direction is determined by the electrical forces of the electrochemical gradient.  Chloride anions are more abundant outside the cell in the ECF, but are repelled by the numerous negative charges created by the proteins inside the cell.  As the chloride anions flow out of the cell, a hypertonicA solution with a higher solute concentration than the inside of a cell, causing water to leave th environment is created which draws water out of the cells to flood the mucus coating the airway. 

Imagine a door with key and combination locks on both sides, back, and front. Now imagine trying to unlock that door blindfolded. This is the challenge faced by David Gadsby, Ph.D. (picture below), who for years struggled to understand the highly intricate and unusual cystic fibrosis chloride channel.  His findings detail the type and order of molecular events required to open and close the gates of the cystic fibrosis chloride channel (CFTR).  Ultimately, the research may have medical applications, though ironically not likely for most cystic fibrosis patients. Because two-thirds of cystic fibrosis patients fail to produce the CFTR protein altogether, a cure for most is expected to result from research focused on replacing the lost channel.

As detailed in the picture below, there are various types of genetic mutations that could lead to the condition of cystic fibrosis.  Of course, the mutationA change in DNA sequence that can affect gene function. in the CF gene could be so severe that no protein is created at all, but many mutations in the CF gene disrupt the folding of the CFTR protein, the quantity of the protein, or the movement of it through the organellestructures within a cell that perform specialized functions. that create proteins (ribosomesSmall structures responsible for protein synthesis, either free-floating or attached to the rough ER, Golgi body, and rough ER).  Problems with folding, quantity, or trafficking all result in cystic fibrosis.

As with the structure of any protein, the CFTR protein has an amino acidThe building blocks of proteins, consisting of an amino group, carboxyl group, and side chain. sequence dictated by the original DNA.  This amino acidA substance that releases hydrogen ions (H⁺) in solution. sequence determines the folding into alpha helices or beta-pleated sheets, tertiary structures, and the final quaternary structure of the protein.  This final shape is the functional shape that can effectively interact with the chloride anionA negatively charged ion. and ATP.  Mutations in the original amino acid sequence will disrupt the folding, creating a differently shaped protein that is unable to interact with the chloride anion and ATP and result in the osmosis of water to the surface of the cell.

However, some people have the correct DNA sequence, create the correct amino acid sequence, and create a completely functional CFTR protein.  The problem is that the amount of CFTR produced and the placement of it in the cells lining respiratory organs such as the trachea and bronchi is also regulated by sequences of DNA.  Mutations in these sequences can make it so that not enough CFTR is made or that an organelle of the endomembrane system, responsible for the transcription and translationThe process of converting mRNA into a protein. of proteins, is malfunctioning.  For example, problems with the Golgi’s management of the CFTR protein will ship the protein to the wrong place in the cell membrane. 

Dr. David Gadsby 1947-2019