lecture 9 bio flashcards

Flashcards covering key concepts from the lecture on Cystic Fibrosis, its physiology, history, and treatment breakthroughs.

What was the median life expectancy for someone with cystic fibrosis in 1987, and what is it now in Canada as of February 2023?

In 1987, the median life expectancy was in the 20s; by February 2023, it reached 60 years in Canada.

Who is Tim Wotton, and what impact has the drug Trikafta had on his health experience as a CF sufferer?

Tim Wotton is a cystic fibrosis sufferer and blogger. Trikafta has significantly improved his health, allowing him to go four years without intravenous treatment compared to three times a year previously, although issues like respiratory viruses and bacterial infections can still occur.

When did cystic fibrosis first appear in medical literature as a published case study?

1938.

What significant observation about people with cystic fibrosis was made in 1953, and what diagnostic tool did it lead to?

It was realized that people with CF had abnormally high levels of sodium and chloride ions in their sweat, leading to the 'sweat test' for diagnosis.

What ancient German folk saying is thought to reflect the early recognition of cystic fibrosis symptoms?

'Woe the child who tastes salty from a kiss on the brow, for he is hexed and soon must die.'

How did an ancient German folk saying, recalled by a former student, lead to a diagnosis of cystic fibrosis in a 21-year-old patient?

A former Biology student, now a doctor, recalled the saying about salty-tasting children, asked the patient's mother, received a 'yes,' and subsequently performed a sweat chloride test, which confirmed CF.

What specific physiological defect was identified in the 1980s in tissues from people with cystic fibrosis, particularly in lung cells?

A chloride-selective channel in epithelial cells was found to be either not present or not working properly, leading to defective salt absorption and secretion.

In airway cells of people with cystic fibrosis, what is the consequence of defective chloride channel activity?

Reduced salt and water secretion, resulting in a build-up of thick, sticky mucus, leading to colonization by pathogenic bacteria, respiratory infection, and chronic airway inflammation.

What is the primary difference between a channel protein and a carrier protein in terms of how they transport substances across a membrane?

Carrier proteins have selective binding sites, undergo conformational changes, and act like enzymes, often moving one or more things at a time. Channel proteins provide a direct pore or diffusion pathway, allowing large flows of specific ions when open.

Describe the normal process by which water is secreted across epithelial cells in the lungs to dilute mucus.

Functional sodium and chloride channels allow sodium chloride to move from inside the cell to the lung surface. This increases solute concentration on the surface, drawing water through specific channels via osmosis, which dilutes the mucus and creates a protective barrier.

How does a non-functional chloride channel in cystic fibrosis affect water secretion and mucus in the lungs?

If chloride cannot move out, sodium also stops moving. This prevents the build-up of sodium chloride on the lung surface, stopping osmosis and water secretion. As a result, mucus becomes thick and sticky, accumulates, and becomes an ideal breeding ground for bacteria.

How does the defective chloride channel in cystic fibrosis affect the function of sweat glands and lead to salty sweat?

In normal sweat glands, chloride and sodium channels reabsorb sodium chloride from the initial plasma-like fluid back into the body. In CF, these channels don't work, so excess sodium chloride remains in the sweat, making it abnormally salty.

How is the activity of the chloride channel (CFTR protein) regulated in normal cells?

The channel activates in response to an increased concentration of cyclic AMP (cAMP), a nucleotide, which then interacts with an enzyme to turn the protein on and open the channel.

When was the gene responsible for cystic fibrosis discovered, and what was its immediate impact on understanding the disease?

The gene was discovered in 1989. Its sequencing allowed scientists to predict the primary structure of the CFTR protein.

How did analyzing the primary structure (amino acid sequence) of the CFTR protein predict its classification as an integral membrane protein?

Scientists found 12 stretches of 19-22 non-polar amino acids. This configuration is characteristic of integral membrane proteins because non-polar amino acids form stable alpha helices that can span the hydrophobic lipid bilayer of a membrane.

What is the full name of the protein defective in cystic fibrosis, and why was it given this specific name initially?

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). It was named this because it was known to be a transmembrane protein involved in regulating chloride ion conductance, though it wasn't immediately proven to be the chloride channel itself.

What did later research confirm about the CFTR protein's function?

It was confirmed that the CFTR protein is, in fact, the chloride channel itself, opening and closing to allow chloride ions to flow across the membrane.

How do hydrogen bonds stabilize alpha helices and beta-pleated sheets in proteins?

In alpha helices, hydrogen bonds form between a carbonyl oxygen and an amide hydrogen 3.6 amino acids along the chain. In beta-pleated sheets, hydrogen bonds form between carbonyl oxygens and amide hydrogens of amino acids that are distant from each other in the polypeptide chain, often running antiparallel.

What is the overall impact of mutations in the CFTR gene on the protein's function?

Mutations change the nucleotide sequence of the gene, leading to errors in the amino acid sequence of the CFTR protein. While some mutations may have no effect, many cause the protein to malfunction, preventing it from acting as a functional chloride channel.

What is the most common mutation causing cystic fibrosis, and what specific effect does it have on the CFTR protein?

The Delta F508 mutation (ΔF508) causes the CFTR protein to be missing a single phenylalanine amino acid at position 508. This causes the protein to adopt an incorrect tertiary structure, preventing it from being properly trafficked to the cell surface.

For patients with Class II CFTR mutations (like Delta F508), what is the primary problem with the CFTR protein?

The protein is produced but is stuck inside the cell and is not correctly trafficked to the cell surface, where it needs to be to function.

What are the three types of molecules in Trikafta, and how do they work together to treat cystic fibrosis?

Trikafta consists of two 'correctors' (Alexacaftor, Tessacaftor) and one 'potentiator' (Ivacaftor). Correctors help the misfolded CFTR protein achieve a shape that allows it to be trafficked to the cell surface. The potentiator then increases the activity of the CFTR channel once it reaches the cell surface, helping it to open and allow chloride flow.

What has been the extraordinary effect of Trikafta on people with cystic fibrosis?

Trikafta brings patients back almost to normal functionality, significantly improving their health and dramatically increasing their life expectancy.

How does inhaling salty seawater mist or nebulized saline help cystic fibrosis patients, and what is the underlying principle?

Inhaling salty water creates a high osmolarity (high salt concentration) on the surface of the lungs. This draws water out across the lung surface via osmosis, effectively diluting the thick mucus and providing a protective barrier, mimicking the function of a healthy CFTR channel.

According to 2023 data, what was the median age of death for CF patients in 2022, and how does it compare to individuals without CF?

In 2022, the median age of death for CF patients was 66 years, compared to 75 years for individuals without CF, showing a significant reduction in the life expectancy gap from previous years.

What is the next-generation drug after Trikafta from Vertex, and what advantages does it offer?

The next-generation drug is AlifTrek (also called Kaftrio in Europe in some regions). It works on 31 additional mutations not responsive to Trikafta, showed non-inferiority to Trikafta in trials, further decreased sweat chloride, and requires only once-a-day dosing.