Not bad, but that still leaves a lot of people without options, especially if their mutations are very rare. To see if drugs like Kalydeco and other CFTR-modulators can help these underserved patients, doctors would need to run clinical trials. But that’s almost impossible, says Beekman, because there are so few of these patients, and they’re scattered throughout the world.
His solution was to build organoids—three-dimensional mini-organs that are grown in the lab from stem cells. Over the last 8 years, scientists have built organoids of retinas, stomachs, livers, kidneys, and even brains. These blobs recapitulate many of the complex features of their parent organs, so you can use them to study how those organs form normally, and how that process goes awry in genetic disorders.
The crucial thing about organoids is that they are personalized blobs. They’re made from an individual’s cells, so they have all the same mutations that person has. They’re not just brains and stomachs in a dish, but your brain and your stomach in a dish. And scientists can use them to predict not just how people will cope with a new drug, but how you specifically will respond.
You can see why Beekman was interested. By making organoids from the cells of cystic fibrosis patients, he could check if their particular CFTR mutations would benefit from Kalydeco and other drugs, without having to do a single injection.
Postdoc Johanna Dekkers painlessly collected cells from the rectums of 71 cystic fibrosis patients and, within four weeks, had grown them into little spherical rectal organoids. (Many people think of cystic fibrosis as a disease of lungs and airways, but it affects the gut too.) Then, she put them through a simple test.
The CFTR gene creates a small pump that shuttles chloride salts in and out of cells, which in turn controls the flow of water. (That’s why this gene affects the thickness of mucus and other bodily fluids.) So, if you make rectal organoids and chemically activate their chloride pumps, fluid should accumulate within them, causing them to swell. If the pumps are missing or broken thanks to mutations in the CFTR gene, nothing happens. And if drugs like Kalydeco can fix these problems, the blobs should swell again. The degree of restored swelling reveals how well the drugs work.
First, the team confirmed that the amounts of swelling seen in organoids with well-studied CFTR mutations match the responses that actual patients with those mutations have shown in clinical trials. The technique had merit.
Next, the team picked two people with rare CFTR mutations, whose organoids responded well to Kalydeco. “Nothing was published on these mutations,” says Beekman. “We didn’t know anything about them. But we did organoid testing and got a large effect.” So they tried both patients on the drug.