By Sarah Zhang

In October 2019, Jordan Janz became the first person in the world to receive an experimental therapy for cystinosis, a rare genetic disease. The treatment was physically grueling. Doctors extracted blood stem cells from Janz’s bone marrow and genetically modified them in a lab. Meanwhile, he underwent chemotherapy to clear out the remaining faulty cells in his bone marrow before he got the newly modified ones. The chemo gave Janz sores in his mouth so painful that he couldn’t eat. He lost his head full of pale-blond hair.

But Janz, then a 20-year-old from Alberta, Canada, had signed up for this because he knew that cystinosis was slowly killing him. The mutated gene behind this disease was causing toxic crystals of a molecule called cystine to build up everywhere in his body. He threw up constantly as a kid. Visible crystals accumulated in his eyes. And his kidneys were now failing. Cystinosis patients live, on average, to 28.5 years old.

Fortunately, the experimental gene therapy seemed to work; Janz began to feel better. His hair grew back in a stubble, but to his shock, it came in a different color: dark, almost black. In the two and half years since, his hair has settled into a dark blond, which is still markedly different from the “almost white blond” of before. “My girlfriend actually said the other day that she feels like she’s dating a different person,” Janz told me.

Of all the things the experimental gene therapy was expected to alter—such as the severity of his cystinosis symptoms—hair color was not one of them. “That was very surprising,” Stephanie Cherqui, a stem-cell scientist at UC San Diego and the principal investigator of the gene-therapy trial, told me. But as she and her colleagues dug into the literature on the disease, they found that darker hair wasn’t a sign of something going awry; instead it might be a very visible sign of the gene therapy working.

Doctors had observed years ago that cystinosis patients tend to be paler than their families. Many—though certainly not all—have blond hair and pale skin. One study in mice found that the gene that’s mutated in cystinosis patients normally plays a role in the production of the dark-brown pigment melanin. Janz had always been a bit self-conscious about how pale he was. His whole family is “pretty pale,” Janz said. “But I'm, like, a whole different pale—or I was.” The hair change, as far as he’s concerned, was a nice surprise.

But how did genetically modifying his blood cells change his hair color? While the mutation that causes cystinosis affects virtually every cell in his body, gene therapy did not change the DNA of every cell in his body, only a tiny fraction of them. Scientists chose to genetically tweak blood stem cells because they have a special ability: Some eventually become white blood cells, which “travel to all different parts of the body,” Jeffrey Medin, who studies gene therapy at the Medical College of Wisconsin, told me. White blood cells normally go into all our different tissues and organs to patrol for pathogens.

Janz’s new white blood cells were genetically modified to express the gene that is mutated in cystinosis, called CTNS. Once they traveled to his eyes, skin, and gut, the white blood cells began pumping out the missing protein encoded by the gene. Cells in the area began taking up the protein and clearing away long-accumulated cystine crystals. In Janz, the anti-cystine proteins from his modified blood cells must have reached the hair follicles in his skin. There, they cleared out the excess cystine that was blocking normal melanin production, and his hair got darker. The same phenomenon has played out in other people: So far in the gene-therapy trial, four of the five patients—all of whom are white—have gotten darker hair. (The fifth patient’s hair is just starting to grow back post-therapy.) The investigators have since added hair biopsies to the trial in order to track the color changes in a more systematic fashion.

The sudden hair-color changes were surprising to Cherqui and her colleagues, but they are consistent with the role of the cystinosis gene in hair pigments, says Robert Ballotti, a melanin researcher at the French National Institute of Health and Medical Research. But he has also found that pigmentation and cystinosis can interact in unexpected ways. Not all people with cystinosis are pale, and in particular, Black patients tend not to have skin or hair that is any lighter. “Maybe there is not a strict correlation between the gravity of the disease and pigmentation,” Ballotti says.

Hair color is one way in which patients in the clinical trial are teaching scientists about the full scope of the CTNS gene, which is still not fully understood. Cherqui had helped discover the gene, as a graduate student more than 20 years ago, and her research has hinted at other functions for it in cell growth and survival, too. “More and more, we understand that there are many functions of the protein that we didn't know,” she said.

That’s why patients on the standard treatment, a drug called cysteamine, still get sicker and die of their disease, Cherqui said. “Removing cystine is not enough.” It doesn’t help that cysteamine has some pretty nasty side effects: It causes stomach pain, nausea, and diarrhea. When Janz was very young, he needed a stomach tube to get the medication around the clock. Cysteamine also has a rotten, fishlike smell. “I had a lot of difficult times as a younger kid,” says Jacob Seachord, another patient in the trial whose hair went from blond to brown. “I smelled really bad from medication, so I didn't make a lot of friends.”

Gene therapy actually replaces the missing protein, theoretically filling in all of its functions, known and unknown. All five patients in the gene-therapy trial have gone off their oral cysteamine, and preliminary data show they now have fewer cystine crystals in their eyes, skin, and gut. Their vision has gotten slightly better, too. But improvements in kidney function are more elusive. Seachord had a kidney transplant before the gene therapy and is doing well. Janz had advanced kidney disease before the trial, and he will need a kidney transplant in a few months.

For adults with cystinosis, Cherqui said, it may be too late for gene therapy to help their kidneys. They have already accumulated a lifetime of kidney damage from cystine. Gene therapy can’t reverse the damage that’s been done, but “we can correct it going forward,” Medin said. “We can stop progression.” In diseases like cystinosis, patients may have to get gene therapy at a young age, probably before 10, Cherqui said. If it works, a future kid who has cystinosis might be cured through gene therapy—preventing them from needing a lifetime of cysteamine or a kidney transplant. And it just might change their hair color, too.