In the isolated hollows of rural Kentucky, they were known as the blue Fugates and the blue Combses. For more than a century, these Appalachian families passed along an exceedingly rare genetic blood condition that turned their skin a disarming shade of blue.
Embarrassed by their bluish hue, the families retreated even further from society, which only exacerbated the problem. Cut off from contact with the wider population, they married cousins, aunts and other closely related kin, which greatly increased the odds of inheriting the condition.
As scientists discovered in the 1960s, the mutation that causes the Smurf-like skin is carried by a recessive gene, and it takes two people with that same gene to produce a blue child.
"If you took any random person in the population, maybe one in 100,000 would carry this gene, if that many," says Ricki Lewis, a science writer and author of the textbook "Human Genetics: Concepts and Applications," now in its 13th edition. "But if you're marrying your cousin, it's one in eight. The risk skyrockets if you're sharing blood."
When Two Strangers Lost the Genetic Lottery
Martin Fugate arrived in the unsettled frontier of Kentucky in 1820. He was a French orphan who knew nothing of his lineage. Legend has it that Martin himself may have had a blue tinge to his skin, but not the dark blue color of later Fugates.
Martin married a red-headed American woman named Elizabeth Smith and the two set up a homestead on the banks of Troublesome Creek near Hazard County, Kentucky. Elizabeth had pale white skin, almost translucent. What neither she nor Martin could have known is that they both carried the recessive gene for a rare hereditary blood disorder called methemoglobinemia.
"The beginning of this story is so wild because Martin moved to Kentucky from Europe and married a complete stranger, a nonrelative who just happened to have the same mutation," says Lewis. "That's crazy."
Martin and Elizabeth had seven children, four of whom were "bright blue" according to Fugate family lore.
Since rail lines and paved roads didn't make it out to Troublesome Creek for nearly a century, the blue recessive gene was passed down to generations of Fugates and neighboring families, all of whom came to be known as "the blue people of Kentucky."
Why Their Blood Turned Blue
Methemoglobinemia is a blood condition, not a skin condition. It has nothing to do with melanin, the amino acid that gives people darker skin tones. In people with methemoglobinemia, the skin appears blue because the veins beneath the skin are coursing with dark blue blood.
If you stayed awake in high-school biology, you might remember that blood is red because red blood cells are packed with proteins called hemoglobin. Hemoglobin gets its red color from a compound called heme that contains an iron atom. That iron atom binds with oxygen, which is how red blood cells circulate oxygen throughout the body.
Oxygen, or a lack of oxygen, is what turns the blood from red to blue in people with methemoglobinemia. A mutated gene causes their bodies to build up a rare form of hemoglobin called methemoglobin that can't bond with oxygen. If enough blood is "infected" with this faulty type of hemoglobin, it changes from red to an almost purple-ish dark blue.
For the Fugates, family members expressed the gene to varying degrees. If their blood had a lower concentration of methemoglobin, they might only blush blue in cold weather, while people with higher concentrations of methemoglobin were bright blue from head to toe.
Is There a Cure for Blue Skin?
Methemoglobinemia is one of the rare genetic conditions that's treatable with a simple pill.
The man who discovered the cure for methemoglobinemia was Madison Cawein III, a hematologist (blood doctor) at the University of Kentucky who heard tales of the "blue people" and went looking for specimens in the 1960s.
Cawein got lucky when a brother and sister named Patrick and Rachel Ritchie walked into a Hazard County clinic. "They were bluer'n hell," said Cawein in a 1982 interview with Science 82. "I started asking them questions: 'Do you have any relatives who are blue?' then I sat down and we began to chart the family." He remembered that the Ritchie siblings "were really embarrassed about being blue." However, the disorder didn't seem to cause any special health problems.
The condition was clearly genetic, but the key for Cawein was reading reports of hereditary methemoglobinemia among isolated Inuit populations in Alaska where blood relatives often married. He knew the same thing was happening in this secluded corner of Appalachia.
In the Inuit communities, scientists had pinpointed the problem, a deficiency of an enzyme that converted methemoglobin to hemoglobin. Studying the problem, Cawein figured out that he could convert methemoglobin to hemoglobin without the enzyme. All he needed was a substance that could "donate" a free electron to the methemoglobin, allowing it to bond with oxygen.
The solution, oddly enough, was a commonly used dye called methylene blue. He injected the Ritchie siblings with 100 milligrams of the blue dye and didn't have to wait long to see results.
"Within a few minutes. the blue color was gone from their skin," Cawein said. "For the first time in their lives, they were pink. They were delighted."
What Happened to the Blue People?
When young people started moving away from the farms surrounding Troublesome Creek in the mid-20th century, they took their recessive blue genes with them. Over time, fewer and fewer babies were born blue, and those who were took a methylene blue pill once a day to put the pink back in their cheeks.
There are other ways to get blue skin without inheriting it, though. Methemoglobinemia can also be caused by reactions to certain topical pain relievers like benzocaine and xylocaine. And at least in one famous case, a man turned his skin permanently blue from drinking too much colloidal silver supplements and rubbing colloidal silver cream on his skin (the condition is called argyria or silver poisoning). See the video below.