By Rosanne Spector
Illustration by Bryan Christie
“It was totally mind-blowing,” says Nachury, who was a Stanford postdoctoral scholar at the time, in 2005, and is now an assistant professor of molecular and cellular physiology. “I had never heard of primary cilia. Not in a single lecture, seminar or meeting. I hadn’t even known they existed, yet they were doing all these things.”
But as has been the case for other biologists, once he knew about it, pieces of biological puzzles began to fall into place. Largely ignored for over a century, the primary cilium has provided a key to the bafflingly diverse symptoms exhibited by certain diseases, most notably polycystic kidney disease — the main reason people go on dialysis. In Nachury’s case, investigations into the primary cilium led him to the cause of a rare but terrible condition, Bardet-Biedl syndrome. With these realizations have come potential new paths for treatments.
The primary cilium is not a recent discovery. Swiss anatomist K.W. Zimmermann described the structure and suggested a sensory role in 1898, but other scientists largely ignored it. In later years it was written off as a quirk of evolution. The outburst of research over the past decade has revealed that the tiny projection is acting as the receiving station for cells’ signaling chains, the communication networks that govern and coordinate cell actions.
For Nachury, knowledge of the primary cilium came out of nowhere. At the time, he was looking for something new and interesting about the cell-division cycle to explore — no easy task because the field was already mature and most of the major questions had been answered.
“I was in the second year of my postdoc, getting bored and feeling the need for a real project. But boredom can bring curiosity: At that time I was all ears for anything exciting that would be worth spending a career studying.”
So when he saw that one of the proteins he had singled out as crucial to normal cell division was also at the root of a rare genetic disease, he perked up. He learned that the disease, Alstrom syndrome, causes a wide, seemingly unrelated range of serious problems, notably obesity starting in childhood, blindness, hearing loss, kidney malformation, heart disease and diabetes.
“I was immediately fascinated by the variety of symptoms. It didn’t make any sense that they could be the result of cell cycle defects.”
Then he read an old article on Alstrom syndrome (Journal of Pediatrics, Michaud et al., 1996) and the plot thickened. There in the last paragraph, he read: “Bardet-Biedl syndrome is a distinct disorder with clinical findings overlapping those of Alstrom syndrome.” He learned that patients with Bardet-Biedl, or BBS, have all the symptoms of Alstrom syndrome as well as postaxial polydactyly — an extra finger near the pinky or an extra toe near the fifth toe.
Nachury continued his digging and eventually found more recent scientific literature suggesting that the culprit proteins in Alstrom and BBS normally helped shape the structure and function of a cell organelle called the primary cilium, and this organelle was important for a variety of developmental and cell signaling pathways. It was like the sky opened up for him.
He had long known about “ordinary” cilia, which are flexible, hairlike outcroppings that usually exist in large groupings, and flagella, those whipping tails that propel single-celled algae across ponds and move sperm up fallopian tubes. But primary cilia?
“I felt like a kid discovering the Internet: A whole world was out there that I had never heard of in four years of undergrad plus five years of grad school plus two years of postdoc. I knew nothing about primary cilia and I wanted to know everything.”
What he gathered paints a portrait of a singularly peculiar cellular structure. A ring of nine filaments forms its internal skeleton, which is surrounded by a thick soup of proteins. A semi-permeable wrapper, the plasma membrane, covers the whole thing. A barrel-shaped base with a mysterious knob on its side sits within the cell; the rest of the cilium shoots out beyond. Molecular motors move the structure’s building blocks up from its base to produce the projection. Then, if the cell it’s attached to divides, these motors dismantle the shaft from the tip down. The complexity of the organelle is such that creationists have argued it’s evidence of an intelligent designer at work.
One of the most unusual aspects of the primary cilium is the manner in which it reproduces. The cilium shaft disassembles so all that’s left is the base. A duplicate base forms — no one knows how — abutting one side at a right angle. Eventually the two separate and form opposite ends of the so-called spindle apparatus that pulls chromosomes apart during cell division. After the single cell has become two, a primary cilium rises up anew in each.
Interest in the primary cilium began building in 2000 when researchers made the first definitive connection between dysfunctional primary cilia and disease — polycystic kidney disease, which affects about 600,000 people in the United States. It escalated when another group of scientists reported in 2003 that in mice, and therefore probably other mammals, one of the cell’s most important means of talking with other cells, the curiously named hedgehog signaling pathway, requires the primary cilium. (The name hedgehog protein comes from the hedgehog-like appearance of fly larvae that have a defect in the protein: They’re more rotund than ordinary maggots and covered with clumps of spiky denticles.)
Researchers studying genetics in fruit flies discovered the pathway decades ago, in the 1970s, leading to a revolution in understanding cell communications.
“Cells all start off the same but they don’t stay that way. So what gets them to change? They get signals telling them what to do,” says professor of developmental biology Matthew Scott, PhD, a longtime researcher of cell signaling, who has recently branched out into primary cilium. “The theory was there would be thousands of signals and it would be impossible to figure out. But it has turned out that it’s a reasonable number of signals, about 20, often in different combinations.”
The hedgehog protein is one of these signals. It starts a molecular game of tag when it lands on the outer covering of a mammalian cell, the plasma membrane, and attaches to another protein there, called “patched.” Patched has been holding the rest of the pathway in check, but once hedgehog binds to it, more molecular interactions ensue. Soon the chemical balance in the region changes, allowing another protein to kick into action, which binds with another molecule, which binds to another, and so on, reaching from the plasma membrane into the cell’s nucleus where molecules bind to particular genes, in some cases switching them on, in others, off.
Finally excited about a project, Nachury convinced his advisor, associate professor of pathology Peter Jackson, PhD, that the primary cilium, with its importance to hedgehog signaling and its connection to Bardet-Biedl syndrome, was a frontier worth exploring. By 2007, he had identified a group of seven proteins that normally work together but lead to BBS if impaired. He also found that the primary cilium needs this complex, which he dubbed the BBSome, to function properly. At the time, he didn’t know what that function was but he suspected it was moving proteins around within the dynamic boundary that surrounds cells — the plasma membrane.
“You can imagine cryptographers all sitting at a desk, ready as soon as the message comes in.”
By this summer, Nachury had confirmed his hunch. His experiments, reported in the June 25 issue of Cell, showed that the BBSome latches on to proteins within the plasma membrane covering the main body of the cell and pulls them through the cordon around the cilium’s base and into the harbor on the surface of the primary cilium. Essentially, the BBSome helps keep the primary cilium crowded with proteins. “Until now, we knew of essentially no molecules that served this purpose,” says Nachury.
“Now the primary cilium is starting to look less like a mere antenna, and more like the communication hub of the cell,” he says.
To understand the distinction, it helps to picture the cell’s plasma membrane, where many protein molecules mill and bob amid the phospholipid molecules that provide its structure. In the membrane covering the primary cilium, the proteins are more concentrated, with a cluster of hedgehog signaling proteins at the tip. The result is a highly efficient setting for conveying chemical messages. Before the discoveries about the primary cilium, most researchers assumed no place on the plasma membrane was specialized for accepting signals. Now it looks like the primary cilium is particularly suited for picking up signals and passing them along, in part because of the high protein concentrations and in part because of its shape.
“A signal goes out, drifts through tissue, lands on the cell that receives it. It’s very important that the signal be of the right intensity, and reach the right cell,” says Scott. “Cilia can serve as antennae that might make a cell respond more to something coming from one direction than another.
“You can imagine cryptographers all sitting at a desk, ready as soon as the message comes in. Once the signal is received, it goes from the cilium to the nucleus of the cell to turn on or off a bunch of genes. That’s what changes the cell,” Scott says.
Meanwhile, Nachury’s discovery of the BBSome has given drug researchers a handle for developing a treatment for BBS. Most of the BBS mutations in patients destabilize the molecular tugboat — so finding chemical chaperones that can restore BBSome stability would be a promising avenue for therapeutics.
“There’s a whole field, called ‘proteostasis,’ where people are attempting to achieve this type of goal, and their main target is currently the cystic fibrosis gene,” says Nachury. “If their strategy works, it could very well be applied to the BBSome.”
Now Nachury and his colleagues are seeing what the primary cilium can tell them about one of biology’s longest-standing mysteries — the brain. In fact, in the primary cilium’s dark days, its only known function was as the point of entry for sensory information en route to the brain. Molecules that waft up the nostrils interact with proteins in the primary cilium of olfactory sensory neurons, which have one end in the nasal cavity and the other in the brain. Similarly, light that strikes the primary cilia on rod and cone cells in the retina gets translated into the brain as vision.
Nachury thinks there must be more to know about the primary cilium in the brain — as nearly every cell in the brain has one.
“What are they up to?” he asks. “From everything we know so far about them elsewhere, they play a role in cell-cell communication. Quite possibly in the brain they’re helping neurons communicate with one another.”
It’s no wonder the primary cilium isn’t better understood. Many of the world’s leading cell biologists had been clueless about the organelle until recently. When Nachury first asked his postdoctoral advisor about them, he discovered Jackson knew no more than he did. The leading text for U.S. college biology majors — Biology, by Campbell et al. — mentioned nothing about primary cilium until the current edition, published in 2008. Now it includes five sentences.
But the primary cilium has become a trendy research subject. Stanford has become a particular hotbed, with nine faculty members exploring everything from how the cilium preserves its unique mix of proteins to how it faithfully reproduces during each cell cycle.
And the scientific literature on primary cilium is growing rapidly. A search through the PubMed health sciences literature database, which contains citations from 1949 to the present, shows the phrase “primary cilium” has appeared in the title or abstract of peer-reviewed biomedical articles only 322 times. But more than half of these articles, 187, were published in the past three years, with 92 in the last year alone.
The cell’s primary cilium doesn’t have the celebrity status of the nucleus and its chromosomes, but it’s gaining — fast.