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"Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon will die." That ominous piece of folklore dates back at least to medieval times, and we now know that it likely referred to children with cystic fibrosis. For most of human history, cystic fibrosis was a death sentence. But in the last few years, scientists have developed drugs so effective that for some, they basically reverse the disease. These new treatments have dramatically improved the lives of 90 percent of patients with the disease. Maybe you can see the problem, though. About 10 percent of cystic fibrosis patients have genetic mutations that these miracle drugs do nothing to fix.
So scientists are hunting for a solution that will make up the difference. Here's what the future might hold for these salty babies. [♪INTRO] While cystic fibrosis has been around for centuries, it only got its name in the 1930s, when pathologists observed fibrous cysts in pancreas samples taken from children sick with a then-undefined illness. And while it was first noticed in the pancreas, cystic fibrosis causes problems pretty much everywhere in the body. The disease is caused by mutations in the gene that makes a certain protein in the outside membrane of your epithelial cells.
And it's a very important protein, because it controls salt and water levels in those cells. When that protein doesn't work the way it should, your cells can't hold onto the salt they need and it just kinda leaks out, hence the salty babies. This is very, very bad. People with cystic fibrosis have issues with electrolyte balance, staying hydrated, and crucially, they have really messed up mucus. You probably don't think about your mucus very much unless you've got a cold. But you have it all over the place in your body, and it plays a major role in the function of a lot of organs.
Including our lungs. You have a nice layer of mucus coating the inside of your lungs, where it helps trap pathogens and particles before they can damage the lungs and be absorbed into your bloodstream, and then you can cough it out. But crucially, that mucus needs to be thin enough that it won't clog up the works, so to speak. People with cystic fibrosis have mucus that's thick and tar-like, and they basically can't expel it from their lungs at all. So all those pathogenic baddies that get stuck in the mucus just… stay there, which means that people with cystic fibrosis often get really nasty lung infections. And if you have all these infectious bacteria trapped in your lungs,
you're pretty darn contagious, and these infections are most dangerous if they spread to other people with cystic fibrosis. Which means that cystic fibrosis patients have been social distancing before it was cool - they've had to, so they don't make each other sicker. Because the lungs can't clear out the excess mucus on their own, one long-term cystic fibrosis treatment is manual percussion therapy, AKA pounding on the chest to try and knock this mucus loose. Every day. Several times a day. But remember, you have mucus in more places than just your lungs. It's in lots of other organs too, including the pancreas, as we saw with those first documented cases in the 1930s. That too-thick mucus blocks up the pancreas,
which stops the enzymes made there from getting into your small intestine, meaning that digestion gets all messed up. So people with cystic fibrosis need to take medications with digestive enzymes to correct this. It can even cause fertility issues, because again, mucus is everywhere, including the lining of the cervix. And cystic fibrosis is caused by a mutation in just a single gene, which was identified in 1989. Scientists called it cystic fibrosis transmembrane conductance regulator gene, or CFTR for short. Even if your CFTR gene is mutated, your body still reads it out, and makes the protein it encodes.
It's just probably going to be a messed-up version of the protein. But not all mutations affect the protein in the same way. And the way the gene is broken is just as important as the fact that it's broken, because some of these mutations result in much more severe cases of cystic fibrosis than others. Like, some mutations can make shortened, non-functional versions of the CFTR ion pump. Other mutations impact the protein's stability, so it breaks down too quickly to be useful. So if it's just one problem gene, that may sound like gene editing therapies would be a simple fix. But there are at least 1,200 known mutations in CFTR
that cause disease, and to effectively use gene editing, you'd basically need a custom treatment for each one. The most common mutation is F508del, which about 85% of people with cystic fibrosis in the US have. The F508del mutation causes a single amino acid to be missing from the final protein, and that causes chaos. The resulting CFTR protein is badly folded, breaks down quickly, and the few that make it to the surface are really bad at their jobs. There are a few medications that try to boost the proteins that the bodies of cystic fibrosis patients are already making.
The first one's called Ivacaftor, a drug that helps make existing CFTR proteins more effective at ion transport. This is great if your mutation means your ion pumps aren't super effective, but it doesn't do much for cells without enough CFTRs already on the cell surface. Ivacaftor was tailored to a mutation that about 4% of CF patients have, called G551D, where the CFTR channel is stable and where it should be, but doesn't let salt ions flow through like it's supposed to. Basically, it's like CFTR is a gate, and with the G551D mutation, the gate isn't opening. When Ivacaftor binds to those damaged proteins, it acts like a key, unlocking the gate so ions can flow through.
But for the F508del variant, you have to fix the ion channel and stop it from breaking down, so Ivacaftor was only part of the solution. Mutated CFTR proteins break down faster because they're misfolded, and that means they often deteriorate before they even get transported to the surface. So the next step in treating cystic fibrosis was to find drugs that help mutated CFTR fold correctly. Enter: Tezacaftor and elexacaftor. Both of these drugs bind to F508del CFTR proteins and help fix the folding issue, meaning they are nice and stable and can be transported to the cell surface to be unlocked by Ivacaftor.
Tezacaftor and elexacaftor each bind to a different spot on the protein, meaning they improve the odds of each protein folding up properly, and getting to the cell surface so that Ivacaftor can do its job of opening the ion gate. In 2019, these three medications were approved in a combination medicine called Trikafta, and from the minute patients started taking it, the effects were profound. It starts with what people with cystic fibrosis call the Purge. And in this case, it's not a day where laws stop counting.
This purge has a lot more phlegm. Once a patient takes their first dose of Trikafta, they start to cough up all the thick mucus in their lungs, usually within 24 hours. Once it's out, they can just breathe. Some people have reported being able to run up hills when previously they could barely walk up stairs, and others started training for marathons. Some people with cystic fibrosis even started being able to get pregnant, since CFTR everywhere was functioning normally, including in the cervix.
Lung infections have gone down too, which means people with cystic fibrosis who are on Trikafta no longer need to socially distance. In the time that it's been available on the market, this treatment has radically changed how people view cystic fibrosis. Before Trikafta, the lifespan of someone with cystic fibrosis varied, but few patients lived past their 40s. Now doctors estimate that a patient who stays on Trikafta can expect to have a normal life expectancy. Like, it's so survivable that children with cystic fibrosis also no longer automatically qualify for the Make-a-Wish program, because it's no longer a given that the condition will be life threatening.
They still can qualify, it's just that their case needs to be reviewed first, where before, it was like "Oh, you have cystic fibrosis? Welcome to Make-A-Wish!" This drastic improvement in the prognosis for cystic fibrosis has been described as similar to the AIDS epidemic after the pharmaceutical breakthroughs of the '90s. One new medication turned a death sentence into a manageable illness. Doctors suddenly needed to learn how to care for patients who weren't dying, and some patients even struggled with the reality that they were here for the long haul after all.
Imagine realizing you're going to need a retirement plan when for most of your life you didn't know if you'd live long enough to retire. Trikafta isn't a true cure for cystic fibrosis, because patients need to keep taking it twice daily to stay healthy. But staying on it keeps the tar-like mucus at bay, which is great news. That said, there are also some downsides to the treatment. But before we get into those, all research needs funding, even ours. So here's a quick ad break. This SciShow video is supported by JMP, a statistical analysis software that makes powerful analytics quick and accessible.
…Like, financially accessible. JMP's Marketplace lets you download pre-made applications, add-ins, data connectors, and other JMP extensions all for free! That means you can customize the software to suit your needs without doing any coding of your own. Why spend time reinventing the wheel when someone else has already built the solution you need? Of course, if you do like to dabble in your own code, you can do a ton with JMP's scripting to automate repeat analysis. And the Workflow Builder lets you share processes with colleagues so that you can standardize best practices and boost reproducibility.
You can check it all out at jmp.com/scishow to see the benefits of visual statistics for yourself. JMP offers a 30-day free trial for anyone, anywhere. One major downside of this new medication is that some people have severe side effects, including cataracts, liver issues, and various neurological and neuropsychiatric issues, like insomnia. For some patients, the side effects are bad enough that they've had to stop taking it. Another issue is the money. In the US, a year's supply of Trikafta costs over $300,000 annually before insurance, even though it costs about $6,000 to produce.
That's partially because drug companies have to recoup the cost of developing the drug and getting it through clinical trials. But also, for-profit healthcare sucks when it's the patients staring at their medical bills. It also means that in many lower income nations, Trikafta is basically impossible to get. Some generic versions have been manufactured, and are available at a fraction of the price. They're still $12,000, but hey, that's only 4% of the name-brand sticker price. And there's still a massive demand for these medications.
There are some workarounds, including developing novel ways to get more bang out of smaller doses of the drug. Scientists in South Africa have shown that it could be possible to reduce the dose of Trikafta required, if patients also took medication to slow down how quickly they metabolized the drugs. But the biggest limitation is that not everyone can take Trikafta, and not just because of side effects or access. It just doesn't work for all the possible mutations that lead to cystic fibrosis. More recent research has found that Trikafta works on some of the other cystic fibrosis mutations besides the all-too-common F508del,
but that list is short, only about 270 additional mutations. All in all, about 90% of people with cystic fibrosis can take it, but that leaves the other 10% on the outside looking in. Although the F508del mutation is the most common cause of cystic fibrosis in North America and West Europe, in other populations, it's a much rarer cause of cystic fibrosis than other mutations. So the usefulness of Trikafta varies by country depending on what mutations are common. Vertex, the company that makes Trikafta, has released another combo cystic fibrosis medicine called Alyftrek, but this is taken once-a-day instead of every twelve hours like Trikafta.
Alyftrek also primarily targets F508del mutations, but like Trikafta, it seems to help with some non-F508del mutations too, and maybe even more of them than Trikafta can hit. And aside from the clinical and medical side of things, we haven't even gotten into the social change. As more people are functionally cured, the support communities for cystic fibrosis patients are shrinking, leaving an ever-smaller group of people that are still drowning in their own lungs. There's no guidebook for how to cope with the idea that most of your friends that share your disease can feel better, but you're still sick.
Fixing the mutations that can't be treated with Trikafta or Alyftrek may require a totally different strategy, like the gene therapy we mentioned earlier. And in 2024, researchers were able to develop a CRISPR-based gene therapy that they tested in lab mice. These mice had a CFTR mutation resulting in a shortened version of the protein. So, the gene editing package went in and corrected the mutation so cells could make full-length CFTR. And it worked pretty well! The downside is that this strategy needs to be bespoke to the patient's particular mutation, and as we mentioned there are more than 1,000 known, so it's not broadly applicable. But the good news is that there may be another way.
Instead of editing whatever mutations are present in an existing CFTR gene, scientists have found a way to add a brand-new, full-length, fully-functional CFTR gene to cells. It doesn't matter if the cells make some janky CFTR proteins, because they can make the right ones, too. This therapy is still at the cells-in-a-dish stage, but it could be a game-changer. Other genetic tools are being developed too, with some in clinical trials. Trikafta has been revolutionary for many people with cystic fibrosis.
They can now live practically normal lives. The story isn't over though, since there are still many people with cystic fibrosis for whom Trikafta isn't an option. So scientists continue to work on these problems in the hopes that some day soon, cystic fibrosis will be a thing of the past. [♪OUTRO]
