Cilium and Intraflagellar Transport: More Irreducibly Complex than Ever
Michael Behe’s introduction of irreducibly complex (IC) molecular machines in Darwin’s Black Box is a gift that keeps on giving. Many readers probably had never heard of cilia or flagella back in 1996. The fact that those machines still make useful illustrations of IC now, even more powerfully than they did 25 years ago, is a strong affirmation of his thesis that IC gives evidence of intelligent design. The bacterial flagellum tends to get more mentions because it is such a cool outboard motor that laypersons can immediately relate to. No less wondrous, though a little more obscure, is the cilium.
Behe updated his description the cilium in his second book, The Edge of Evolution (2007), but research has continued apace. The cilium nails the case for intelligent design more than ever, especially when considering how the organelle is built. Inside those tiny hairlike projections is an advanced transportation system that looks for all the world like a motorized two-way railcar inside a mine shaft!
In Current Biology, Gaia Pigino wrote a “Primer” on Intraflagellar Transport (IFT). It’s called intraflagellar because a cilium is a type of flagellum (Latin for whip), which in the generic sense means a whiplike structure that can move. Both cilia and flagella use the IFT system for construction because both need to transport their building blocks down a shaft from the base to the distal tip. From the railcar’s perspective, the tip would seem a long way away.
There are motile cilia, like the ones that keep our windpipes clean and propel sperm cells, and “primary” cilia, which act as sensory antennae on almost all cells. Accurate construction of cilia is vital. When things go wrong, a host of problems called ciliopathies can result in severe diseases and death. Evolution News has mentioned these briefly in previous years (here, here, and here).
Consider first how many players are needed to build a cilium. Pigino’s parts list begins with microtubules in a 9+2 arrangement going up the cilium from base to tip. The two center microtubules are singlets; the outer ring of 9 are in doublet pairs. Riding on those rails are two engines: kinesin-2, which travels from base to tip (anterograde), and dynein-2, which goes from tip back to the base. Kinesin-2 has a head, stalk, hinge and two “feet” (called heads) that walk on the microtubule while carrying a load; the engine contains six protein subunits. Dynein-2 also has a motor, stalk, linker and tail, and is powered by two AAA+ domains that spend ATP for power. Those are the two engine types, and they work in teams along the microtubules.
IFT proteins are numbered, such as IFT8 and IFT176. IFT complexes, such as IFT-A, is composed of six IFT proteins. IFT-B, with 16 IFT proteins is another complex. These ride along the trains to the tip, acting as adaptors for the cargo, which include tubulin proteins, dynein parts, membrane proteins and other IFT proteins.
At the base, a basal body structure called the BBSome forms out of eight BB proteins. It functions as the cargo adaptor for the anterograde train. It authenticates other molecules trying to enter the cilium and moves cargo exiting the retrograde train. Overall, “About 24 different proteins constitute the theoretical minimal functional unit of IFT,” Pigino says, although much needs to be learned.
To address the many fascinating questions that remain about the function and mechanisms of IFT within the cilium and beyond will require the development of new technologies. Fortunately, recent years have seen the introduction of approaches such as cryo-FIB scanning electron microscopy, cryo-correlative light and electron microscopy, and expansion microscopy. The opportunity to combine such approaches with in situ protein tagging for EM, isolation of active IFT complexes, and in vitro reconstitution and reactivation of IFT machinery suggests that IFT studies will continue to yield important insights long into the future. [Emphasis added.]
A precise sequence of amino acids is required for each protein’s function, and the longer the protein, the more improbable that chance could get it right. IFT proteins are large. For instance, BBS1 in the BBSome has 593 amino acid residues; IFT172 (part of the IFT-B complex) has 1,749. The improbability is exacerbated when proteins have to work together. It’s not necessary to belabor the point again, but it’s instructive that Pigino never mentions evolution in her article.
Riding the Train
Moving cargo up and down the cilium takes place in five steps. First, the train assembles at the base. Kinesins line up along a microtubule doublet, their “heads” touching the tracks. Parts of dynein (the return engine) are loaded so as not to touch the tracks, avoiding a “tug-of-war” between the engines. Membrane parts and other cargoes are loaded with the help of IFT-A and IFT-B. Like a well-organized monorail car, the completed train “walks” up the track aided by multiple kinesin-2 engines powered by ATP.
At the tip, the third phase begins. Cargo is unloaded and ferried to the growing cilium (microtubules and membrane). Concurrently, the dynein engines are assembled in an “open configuration as an intermediate state to ensure a controlled activation.” The kinesins are disassembled for transport back to the base. The fourth stage activates the dyneins and starts the train moving, carrying both IFT complexes and waste products to the base. The fifth and final stage unloads the cargo, disassembles the retrograde train and recycles the parts. If you conceive of railcars in a narrow mine shaft carrying tools needed by miners at the far end, and returning the carts with waste products, the analogy seems apt — only the cell’s actions are all automated.
It All Has to Work
Pigino spends much of her Primer discussing ciliopathies: the diseases of broken cilia. When the IFT or engine parts have mutations, or the cilium fails to develop properly, terrible things happen — really terrible things. That’s if the organism (or person) survives at all. Many ciliopathies are not witnessed because the defect causes “major issues during early embryonic development that lead to neonatal death in vertebrates.” She lists 14 known ciliopathies that cause named syndromes, like Bardet-Biedl Syndrome, which causes “rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction,” or Retinitis Pigmentosa, which causes blindness. Without getting into the gory details, these ciliar defects can harm the skeleton, eyes, kidneys, brain, or multiple systems in the body at once.
Usually, It Does Work
For the majority of people born with working cilia, here is what they do for us:
Cells need to be able to sense different types of signals, such as chemical and mechanical stimuli, from the extracellular environment in order to properly function. Most eukaryotic cells sense these signals in part through a specialized hair-like organelle, the cilium, that extends from the cell body as a sort of antenna. The signaling and sensory functions of cilia are fundamental during the early stages of embryonic development, when cilia coordinate the establishment of the internal left–right asymmetry that is typical of the vertebrate body. Later, cilia continue to be required for the correct development and function of specific tissues and organs, such as the brain, heart, kidney, liver, and pancreas. Sensory cilia allow us to sense the environment that surrounds us; for instance, we see as a result of the connecting cilia of photoreceptors in our retina, we smell through the sensory cilia at the tips of our olfactory neurons, and we hear thanks to the kinocilia of our sensory hair cells. Motile cilia, which themselves have sensory functions, also work as propeller-like extensions that allow us to breathe because they keep our lungs clean, to reproduce because they propel sperm cells, and even to properly reason because they contribute to the flow of cerebrospinal fluid in our brain ventricles…. Thus, the proper function of cilia is fundamental for human health.
Professor Behe did a wonderful service in introducing these marvelous machines to a wider audience. In 1996, he introduced cilia as examples of irreducible complexity. In 2007, with a decade of new knowledge to draw from, he called cilia examples of “irreducible complexity squared.” Pigina’s Primer on cilia cannot argue with that. If you can breathe, eat, smell, taste, hear, and walk, thank the intelligent designer of cilia that makes these pleasures possible.