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Read more: “Instant Expert 36: Human cell tails“

Some of our inner tails still do what you expect a tail to do: wag. But the solitary tail found on most cells cannot actively move. Instead, these tails have taken on a very different role as cellular sensors. They play a role in the development and maintenance of all kinds of tissues, and even in learning and memory. As a result, mutations that impair the function of tails or prevent them from developing altogether can have serious consequences, from cognitive defects to blindness. While genetic diseases by their very nature are difficult to treat, developments in other fields and the rapid advances in our understanding of these diseases are opening up new possibilities

Memory and learning

It seems our inner tails play a key role in all kinds of processes, from development to vision. We can now add learning and memory to the list. Both primary and moving cilia are abundant throughout the brain, where they are found both on neurons and on the various kinds of support cells.

Somatostatin receptors located on brain-cell cilia are required for mice to learn to recognise new objects or to recall familiar ones. Mice without working receptors lose the ability to recognise objects they have seen before. Cilia in the part of the brain central to memory, called the hippocampus, are also required for the formation of adult neural stem cells. Without a fresh supply of stem cells learning is impaired. Mice with cilia dysfunction cannot find their way around.

Primary cilia are also important for the migration of brain cells and so are vital for the developing brain. Several inherited disorders caused by mutations in cilial genes are associated with cognitive defects. In Joubert syndrome, for instance, there are major posterior brain abnormalities resulting in muscle weakness, poor coordination and an abnormal breathing pattern.

A most extraordinary tail

Growing a tail poses a challenge for cells. How do you get the building blocks of tails from the body of the cell, where they are made, to the tip of the tail where they are needed? Large molecules cannot move freely along cilia and flagella, so some kind of active transport is essential. The answer evolution came up with was a kind of train that travels up and down (see diagram), using one of the microtubules that make up the tail as a rail.

These trains assemble themselves at the base of the tail and pull themselves along it, carrying cargoes such as microtubule components and receptors destined for the cell membrane. At the tip, they drop off their cargo and rearrange themselves, swapping “up tail” motors for “down tail” motors. They then move down the tail carrying cargoes such as signalling proteins destined for the cell interior.

This highly sophisticated “intraflagellar” transport system is essential for making and maintaining tails, and, through its role in carrying receptor and signalling proteins, for sensing the environment. Some recent studies suggest : the trains may attach themselves to proteins in the cell membrane that are in turn bound to something outside the cell. That means each train is anchored in place, so when the engine is active the trains remain stationary and the microtubule rail moves instead – and with it the cell.

Because tails play such a wide range of roles in the body, mutations that affect the intraflagellar transport system can produce a wide range of defects, from kidney diseases to developmental abnormalities and even various forms of blindness. But why should a faulty system for transporting things along tails lead to blindness? Well, it turns out that the light-detector in our eyes is essentially a highly modified tail.

“It turns out that the light detector in our eyes is essentially a highly modified tail”

The tip of this tail – the outer segment of photoreceptor cells – is greatly enlarged and contains all the light-detecting machinery. But the rest of it, the part that connects the outer segment to the main body of the cell, still consists of a narrow tube, known as the connecting cilium. The upshot is that all the proteins needed for detecting light have to be carried along this cilium to the outer segment.

Light-detecting proteins are frequently damaged, so there is a very high turnover of proteins in the outer segment. As a result, our vision depends on the intraflagellar transport system working well. A number of degenerative diseases that lead to blindness in childhood or adulthood, including those known as retinitis pigmentosa, have now been linked to mutations that disrupt the transport system, possibly leading to a buildup of toxic waste products.

While the precise mechanisms still aren’t fully understood, treatments are already being developed for a number of these disorders. For instance, a team of doctors at London’s Moorfields Eye Hospital and University College London is conducting the first human gene therapy trials to treat Leber’s congenital amaurosis, a type of inherited childhood blindness caused by a single faulty gene that affects intraflagellar transport. The results so far have been promising.

Fixing faulty tails

The list of disorders known to be caused by faulty tails, called ciliopathies, is growing rapidly. Because these disorders are caused by genetic mutations in the genes coding for cilia, there seemed little prospect of developing effective treatments. But the prospects have brightened with recent advances in biology.

In particular, it now seems likely that it will be possible to use gene therapy to prevent the degeneration of retinal cells leading to blindness, as caused by some cilial mutations. The cells in the retina are easily accessed for both treatment and monitoring, and several human trials are already in progress (see “A most extraordinary tail”).

Using gene therapy to restore cilial function in solid organs such as the kidneys is a much greater challenge. However, in at least some cases it may be possible to find drugs to alleviate symptoms or even slow the progress of a disease. Some trials are now under way involving drugs already approved for other purposes. The use of such drugs is very attractive because their mode of action is usually known and they have already passed safety tests. Because cilial mutations can have very different effects in different tissues, some people might need to take a combination of drugs to treat their symptoms.

Last but not least, it might be possible to use small-molecule drugs – which can be swallowed in pill form – to at least partially compensate for the underlying genetic defects. An antibiotic called gentamicin can force cells to ignore mutations that halt protein production prematurely, before a protein is complete. This antibiotic has some nasty side effects, but newer, safer compounds have been developed and will be used to try to treat diseases such as Duchenne muscular dystrophy. Where ciliopathies are due to these kinds of mutations, this approach might work too.

This article appeared in print under the headline “The tale has only just begun”