actin out

Cpp_avatar Quick:  what's the difference between an 'amu' (atomic mass unit) and a 'Da' (Dalton)?  Answer: Nothing.  They both represent one-twelfth of the rest mass of an unbound carbon-12 atom in its nuclear and electronic ground state, a.k.a 1.66×10−27 kg.  This is very slightly less than the mass of a proton or a neutron (approximately 1.67×10-27 kg).  When first invented, the Dalton was intended to be a fundamental unit such that one hydrogen atom had a mass of one Dalton.  Helium would be two Daltons, lithium would be three Daltons, etc.  Of course, then we realized that every atom had different numbers of protons, neutrons and electrons, which mean that there was no simple universal mass.  It would be so much easier to memorize if everything on the periodic table was a simple multiple of a fundamental quantity. 

Happily, the universe is not that simple.  Protons, neutrons and electrons make things just a little more complex.  So regardless of whether you prefer the amu or the Dalton, neither is actually fundamental.

I had to look up the difference after attending a seminar last Friday by Kris Noel Dahl from our Neighbors to the North, CMU.  Her topic was the interaction of single walled carbon nanotubes (SWCNTs) with cells.  The extremely high strength of carbon nanotubes make them ideal for applications such as high performance racing bike frames, tennis racquets, and space elevators  – to name just a few.

Nanomaterials surprised the materials and biological sciences communities in multiple ways.  Yes, nanoscale materials have amazing properties that the exact same materials in bulk can only dream about; however, they also have different types and degrees of toxicity.  A material that is harmless in a centimeter-sized chunk becomes a killer when shrunks to nanoscale.

Carbon nanomaterials, especially, have engendered a lot of concern, with early high-profile reports of buckyballs being toxic to fish brains, for example.  There was a lot of backstepping when people realized that as-synthesized carbon materials have a wide range of materials, including graphene, graphite, metal impurities from the catalysts used in some methods to grow the carbon nanomaterials, and even contamination from residual solvents that were used for dispersing the nanotubes in a fluid.  Even though we have better methods for purifying carbon nanotubes and removing impurities, there reamin a wide variety of opinions on the toxicity of carbon nanotubes.  Most of the research has moved from the 'is it or isn't it toxic' type to 'what specifically do carbon nanotubes change in a cell?'  I learned one consequence on Friday that involves an interesting molecules called actin.

 Actin is ubiquitous:   If you're looking for a molecule that is fundamental to life, this is one to consider.  It's a 42-kiloDalton (meaning big) globular protein that varies in structure by less than 20% across species from algae to people. Actin is found in all eukaryotic cells, which are the types of cells that have a nucleus.  Eukaryotic literally means 'good nut' or 'good kernel', so defining is the presence of the nucleus.

F-actinThe globular protein (called G-actin) is a monomer, which means that it assembles with similar momomers to form long-chain polymers.  Thin filament-actin is mostly found in muscle cells, forming a scaffold on which myosin motors move – the mechanism by which the muscles contract.

Microfilament actin (also called f-actin) is a major component of cellular cytoskeletons.  Two long-chain polymers twist together, like two-ply yarn, to form f-actin (shown to the left).  The result is a helix about 7 nm in diameter, with a repeat distance for the twist of about 37 nanometers.

Confession time.  My model of the cell is way dated.  The model I still had in my head was from the last biology course I ever took: the required 9th grade general biology.  We had filled a plastic bag (the cell membrane) halfway with jello (the cytoplasm), let it set awhile, dropped in a maraschino cherry (to represent the nucleus), and then filled it up with more jello.

Jellocell I knew cells were slightly more complicated than that, but I didn't appreciate how much.  On an educational note, jello cell models have also increased in complexity.  The picture at right is from a homeschoolers blog.  Sugar-coated gummy worms represent the rough endoplasmic reticulum, while smooth gummy worms represent the smooth endoplasmic reticulum (which folks in the know call the 'ER').  Gumdrop centrosomes, Sixlet lysosomes, raisin mitrochondria, Gobstopper vacuoles and sprinkle ribosomes complete the cell.  Oops – I almost left out the fruit roll-ups folded accordian-style to represent the Golgi bodies.

I'm getting a sugar buzz just describing this rather colorful model that looks to me way too much like an eyeball to even think about eating it.  Despite it's color and ability to keep kids busy, this model — like almost all models — has a flaw:  You have to make your cell in a mold.  Mother Nature doesn't need a mold.  And cytoplasm isn't really quite as structurally sound as gelatin, but Mom Nature has a secret ingredient: actin.  Actin provides a cell's skeleton.  Actin is why red blood cells are flat and even why cells move.

The micrograph of the rat kidney cells below shows the actin cytoskeleton in green and the nuclei in blue. The image was taken by Christopher Turner's group at Upstate Medical University of New York Cytoskeletonturner
using fluorescence microscopy. The actin filaments adhere to the membrane and provide structural support, but also provide the hard-wiring for cell functionality.

The cellular cytoskeleton is not permanent like our skeletons become:  actin can polymerize and depolymerize, changing from long strands to shorter strands or even back to the original globular form.  This joining and dissolving can  even be used by the cell to move like a snail.  The actin cytoskeleton provides mobility and preserves shape.  If you change the actin cytoskeleton, you change not only the shape and structure of the cell, you can change the cell's function as well.

Since actin defines a cell's shape, you might infer that actin plays a very important role in cell division – and you'd be correct.  The actin forms smaller fibers and distributes itself around the cytoplasm prior to and during cytokinesis (dividing).  In the picture at left of dividing green urchin zygote cells (from the University of Washington Center for Cell Dynamics), the actin is in blue and the gold threads are microtubules.  Cell division is the basis of life, of course, since it is how we (and most everything else on Earth) reproduce.  

DividingcellsChanging the actin structure thus challenges the cell's ability to maintain it's shape, divide, and even to function, which returns us to the subject of the original seminar. 

Dahl and her co-workers studied highly purified carbon nanotubes that had been length-selected to be 150 nm long, which is about the length of the f-actin in the cells they were studying.  A cell, by contrast, is tens of microns in diameter.  Normally, f-actin in HeLa cells concentrates in the cell's base.  Dahl's group found that introducing carbon nanotubes changes the way actin organizes.  Outside the cells, they found that carbon nanotubes make actin fibers bunch up into bundles like twigs tied up in a bunch.  When they looked at the effect of the carbon nanotubes inside cells, the actin again formed clumps, but there was also more actin and the clumps weren't located only in the base of the cell – the clumps were distributed throughout the interior of the cell. The carbon nanotubes also impacted the ability of the cells to divide, producing defects like cells with multiple nuclei and cells that started the dividing process, but couldn't complete it.

This study reinforces a very important issue regarding toxicity.  We sometimes think of toxicity as being when something causes cells to die in large numbers. In this case, the carbon nanotubes didn't kill large numbers of cells directly — but they did hinder the cells from dividing.  If we could target carbon nanotubes so that they only entered cancer cells, for example, we would have a technique to slow or stop the growth of cancer.  Even slowing cancer cell growth would give us more time to treat it.  Carbon nanotubes exposed to a dividing embryo would be bad.

The more I learn, the more I realize that toxicity is a much more subtle phenomenon than I initially appreciated.  It's vitally important for us to understand those subtleties so that we can determine not whether nanomaterials are dangerous, but the conditions under which nanomaterials — or any materials — could be hazardous.  The first step to preventing a potential hazard is to understand it.  

 

 

 

 

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