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Discovery touches on sense of touch
25 OCTOBER 2007

A study published this week shows that the primary cilium, an obscure, underappreciated structure found on most animal cells, plays an unexpected role in the sense of touch. Although the primary cilium was discovered more than 100 years ago, until quite recently it was considered vestigial -- a lingering structure that no longer did anything useful.

A biological deadbeat, in other words.

Blue circles have small, neon green streaks across them
Individual cells are stained blue; the primary cilia are the bright streaks (arrows). Courtesy Erica Davis

The primary cilia, and the similar cilia that move mucus in the lungs, are both structurally related to the flagellum, a hair-like structure that allows sperm and the paramecium to move. In case you've forgotten, the paramecium is primitive, single-celled organism that was one of the first forms of life ever seen under the microscope.

But while the flagellum is found on only a few types of mammalian cells, the primary cilium appears on many cells -- if you bother to look, and if you use the correct staining techniques.

One who bothered to look is Nicholas Katsanis, an associate professor at the Johns Hopkins University Institute of Genetic Medicine. Katsanis studied mice that were missing genes for proteins involved in Bardet-Biedl syndrome (BBS). This rare, baffling genetic condition can damage the liver, kidney or brain, and cause mental retardation, blindness and polycystic kidney disease. One hallmark of the condition is a malformation of the primary cilium.

A gray mass of swirls, red arrow points at parallel dark lines, blue arrow points at faint dark circle.
This electron microscope image shows one sensory neuron with its cilium (red arrow) above the basal body (blue arrow). Courtesy Perciliz Tan.

Knockout knockout!
The deleted genes, knocked out with the technology that won this year's Nobel Prize, were known to be active in the basal body, a structure located at the base of the primary cilium.

Katsanis explained that he and others had recently discovered that the primary cilia play roles in hearing, vision and smell. The light-sensitive cells in the retina, for example, carry a hair-like structure that is a type of cilium, he says.

To test whether primary cilia are also involved in detecting temperature and touch, the researchers cobbled together cages with material from the lab equipment department of Home Depot, says Katsanis. "Building them was like a high-school science project. Science is not all about deep thought; sometimes it's about having a little bit of fun."

A dozen mice in small clear cubes are on top of a cage with sensors attached
This homemade scientific apparatus allowed the researchers to poke the feet of the mice (held in plastic containers) with a brush, testing their sensitivity to touch. Courtesy Perciliz Tan

The genetically engineered mice were slow to respond to heat and a poke from a bristle that could measure applied force. Because the mice seemed normal in terms of brain power and controlling their muscles, defective sensory nerves bore the blame for the delayed responses. If the primary cilium is short or not functional, how could that cause mental retardation, blindness or a syndrome that looks like autism?

A new explanation?
The knockout affected two genes that were linked to Bardet-Biedl syndrome in 2003, and Katsanis suspects that the sensory problems in the mice may explain why BBS patients move slowly -- a behavior that is often blamed on mental retardation, which is another symptom of the rare, wide-ranging syndrome.

BBS often causes blindness, but when Katsanis's research group tested nine patients with the condition, they had what he calls "a broad range of sensory defects." This was, he says, the first sign of a generalized sensory deficit in BBS.

The research may help answer a nettlesome question, Katsanis says. "If we have a defect in the cilium that causes it to be short or stubby or not function properly, why do we have mental retardation, blindness, and a list [of abnormalities] that goes on and on?"

Some children with BBS, for example, also suffer something called "autistic-like tendency," which Katsanis thinks might reflect the new-found sensory problems. "I am not saying there is no [brain] processing defect, but I am advocating the very real possibility that there is also a sensory defect."

Although BBS may be as rare as 1 case per 100,000 people, Katsanis says other problems related to cilia may raise the rate of what he calls "ciliopathies" close to 1 case in 2,000 people.

Long, spindley red mass with faint green circle at one end
A single neuron, with the primary cilium stained (arrow). Fluorescent green stain identifies this cell as a neuron. Courtesy Perciliz Tan

Rare, or common
Studying this obscure, mysterious disease could have much broader benefits, he says, if it sheds light on more common conditions that have resisted massive inquiries. Rare diseases can overlap with common, complex diseases like autism, schizophrenias, depression. Kids with Bardet-Biedl syndrome have all of those symptoms."One purpose of studying this rare disease is because it overlaps with complex, experimentally hard-to-track diseases like autism, schizophrenia or depression. BBS kids have all of those symptoms."

From an evolutionary perspective, the primary cilium is not just found in mammals, but also in such remotely related organisms as fruit flies, green algae and nematodes. Since cilia often carry chemical receptors, Katsanis sees them playing a vital role in informing the cell about its environment.

"This tool has been developed a long time ago to help mediate how a cell understands its environment," he says. "The evolutionary basis for associating cilia with sensation goes all the way back to the paramecium. In vertebrates, mammals, we have taken it to a whole new level, but this shows we are nothing but green algae in disguise."

- David Tenenbaum

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• Loss of BBS proteins causes defects in peripheral sensory innervation and function, Perciliz L. Tan et al, PNAS, Oct. 30, 2007.

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