Wednesday, February 18, 2015

Space – It’ll Mess You Up


Biology concepts –  undulipodia, primary cilia, motile cilia, ependyma, spaceflight, pathology, osteopenia, radiation damage, osteoblast/osteoclast, osteocytes,


No one wanted the elation of the moon visit to
turn to disaster as a moon germ spread through-
out the world and killed every living thing. So
they moved the astronauts from splashdown to
airstream. What a bummer that would have
been to go all Andromeda Strain…. although it
might have saved us from Watergate.
Going into space is an engineering triumph, but it isn’t without its biologic difficulties. When the Apollo 11 astronauts returned from the first visit to the moon, Richard Nixon had to congratulate them through the window of their mobile quarantine van.

Exposing humans to space germs would be bad, but the problems go the other way too. Astronauts have to deal with many changes to their body due to the reductions in sunlight, exercise, circadian rhythm, and perhaps most of all – gravity. You’d be surprised how much microgravity (in space there is still a little gravity) can mess with your body – and alot of it has to do with some of the smallest parts of your cells – the primary cilia.

In fact, a 2004 study showed changes in human gene expression during regular gravitational field changes due to sun and moon right here on Earth. If the small changes in Earth's gravity brought about by the changing position of the Sun and Moon can have measureable effects, imagine how big a deal going into space must be. A 2008 study on Rohon-Beard cells (developmental neurons in fish and amphibians) showed that they lost primary cilia when in microgravity. So gravity matters, and it matters in part because of what it does to primary cilia.

Life on Earth has evolved in gravity. Our bodies have come to expect a pull to the center of the Earth and for all the air of the atmosphere above them to be pressing down on them. These forces must have molded our anatomy and biochemistry to some degree. So if you take us off the Earth, shouldn’t we expect some problems?

Microgravity alters the responses of the body. Processes are lost and balances are shifted. Problems caused by these changes can manifest in two ways; 1) they could cause problems while in space, or 2) they could cause problems when the astronauts return to normal gravity.


Even though the uniforms look Russian, this
footage comes from the US Air Force film
archive. They were in a C-131 doing parabolic
arcs that would provide 15 seconds of
weightlessness. The idea was to see if cats in
space could land on their feet. It turns out they
can only do it if they know which way is down.
I think the ASPCA might have a thing or two to
say about this.
So what are some of the problems associated with long term spaceflight, and how might your primary, immotile, cilia be involved? While some might be considered pathologies, others are merely adjustments that the body makes according to its own regulatory systems. Sometimes, those adjustments then produce unwanted results.

Muscles and Blood Cells
Reduced gravity means that certain parts of the body don’t get stressed. Muscles pull against resistance; no resistance means no work for the muscles. Think about pushing off the walls of the International Space Station (ISS) while floating around. The necessary force is greatly reduced, so the muscle doesn’t get worked. When muscles don’t get exercise they atrophy (a = no, and trophy = food), like the legs of paraplegics.


A 2010 study confirmed that spaceflight has an affect on muscle fibers. The soleus muscle of the back of the leg lost 20% of its fibers over a 180 day mission on the ISS. Peak force was lower by 35%. The types of fibers were different as well, switching mostly to weaker thin fibers. Exercise made a little difference, but if the astronauts were asked to move a bed soon after landing, they’d have to call Two Guys and a Truck.
Your heart is a muscle; the heart does less work in space too, mostly because it can pump easier and still move the same volume of blood. We can’t say that primary cilia aren’t involved in these muscular and cardiovascular adaptations, we just don’t have evidence for it yet.

In similar fashion, it’s possible that primary cilia aren’t involved in the decreased red blood cell production during spaceflight. A 2000 study shows that blood volume is decreased in space, and this triggers lysis (popping) of the youngest red blood cells (neocytolysis).

On the other hand, immune cell function (white blood cells) rather than number is decreased in space. Astronauts are very prone to infections when they return to Earth, and sometimes even in space. A 2012 study showed that a significant percentage of astronauts manifest viral, bacterial, and fungal infections.


The immune synapse is mediated by the
presenting of an antigen by one cell to activate
another cell. Many receptors and co-receptors
are involved, and apparently putting them all in
the right place requires IFT proteins. The bottom
image shows the large synapse between a
dendritic cell (blue) and  a T cell (yellow).
Defects in blood cell function in space lead us to a big exception. Blood cells are some of the few cells that don’t have primary cilia. It probably has something to do with the fact that they circulate; their shape is important for their movement through vessels.

However, immune cells still express IFT proteins. We learned previously that IFT proteins mediate the building and the function of both motile and immotile cilia. A 2011 study suggests that the gap between the immune cell that presents a foreign body (antigen presenting cell) and the immune cell that will react to it (often a T lymphocyte), is controlled by IFT proteins. The hypothesis is that this immune synapse (synapse is Greek for join together) is the functional equivalent of the primary cilium for immune cells. Primary cilia are important even when they aren’t there.

Bones
Extended spaceflight wreaks havoc on your skeleton. The reason is that your bones need gravity to keep them growing. Yep, your bones are always growing, ….of course they’re always breaking down too.

Bones are dynamic. Osteoblasts (osteo = bone, and blast = germ) build new mineralized bone, while osteoclasts (clast = breaker) consume bone. As a result, you basically have a completely new skeleton every seven years, every two years if you're a child. Why is this necessary? Because bones are constantly responding to changes.

Consider weight lifting - the pulling of muscles on the bones to which they are attached stimulates osteoblast and osteoclast activity. Growing muscles are bigger, which means they need bigger attachments to bone. To accommodate this growth, the bones have to remodel themselves; more bone here, less there.


The left micrograph shows the difference between
osteocytes and osteoblasts. The –cytes are in the
lacunae while the –blasts are on the edge of the
matrix. The right image shows a lacuna and the
canaliculi connected to it. The osteocyte with its
primary cilium is in the lacuna. Mechanical loading
moves the fluid in the canaliculi and bends the cilium.
The growth of bone is mediated by the osteoblasts, which exude a dense form of collagen and some bone-specific proteins. This matrix becomes impregnated with calcium to become mineralized bone. Osteoblasts become trapped inside the matrix they lay down, surrounded by a small fluid-filled cavity called a lacuna. All the lacunae are connected by long fluid-filled tubes called canaliculi. This creates a huge network of osteocytes (ie. what osteoblasts are called when they are trapped in a lacuna).

Gravity and other forms of mechanical loading (putting weight or pressure on the bone) affects these osteocytes. Just walking on Earth is a source of mechanical loading on bone. The force produces a signal from the osteocytes to the osteoblasts to lay down more bone. A 2104 study has developed a model system to define how osteocytes signal osteoblasts, but we already know some things.

Like squeezing one of those worry dolls whose eyes bug out, mechanical stress on the lacunae brings movement of the fluid in the canaliculi and the lacunar network. This bends the primary cilia of the osteocytes trapped in the lacunae and triggers the signal that the bone is under a load.

The response to loading is a release hormones and other molecules that both stimulate osteoblast activity and call for the differentiation of bone stem cells to become osteoblasts. Osteoclasts are sill doing their job of dissolving bone matrix, but the stimulation of osteoblasts in the loaded area tips the balance to more bone formation in that area.


NASA and other space agencies try to fend off some
of the space changes in physiology by having the
astronauts exercise in space. It doesn’t work for
muscle, and not much for bone. Usually it works
better if they strap the astronauts down to simulate
some gravity.
In space, there is much less loading of the bones. Walking doesn’t have gravity to deal with, and muscles have to work so little because there is little pushing against them. The net result is that there is less shear stress in the bone lacunar network and therefore less bending of the primary cilia. Therefore, the pendulum swings toward osteoclast activity and results in osteopenia (penia = poverty).

The astronauts don’t have osteoporosis. Osteopenia and osteoprosis are two different things. Osteopenia means less bone production, but the bone that is produced is densely mineralized. Osteoporosis results from adequate bone formation but poor mineralization of that bone.

Osteoporosis is caused by many other things, and can be bad – but not as bad as space osteopenia. An astronaut can lose 10x as much bone as an osteoporosis patient in just a six-month stay in space. You go into space as a virile astronaut and come back as frail as your great grandmother.

Balance
We learned last week about the role of primary cilia in the vestibular system (balance). The semicircular canals in our inner ear track rotation in space, but the utricle and saccule sense gravity and acceleration in a straight line. These otlithic organs use otoconia - little mineralized bits on the ends of sterocilia on hair cells to detect movement and gravity.


The semicircular canals are for rotational changes
and have the cupula to mediate movement. The
utricle and saccule are for gravity responses. The
macula of each is the region where the otoconia
mediate the movement of the hairs in response to
changes in their position relative to gravity.
Two recent studies suggest that primary cilia mediate balance problems in astronauts. First, a 2014 study shows that otolithic organ function is reduced in patients with primary cilia diseases and that at least one reason for this is that they have malformations of the otoconia. Second, microgravity leads to larger than normal otoconia and affects primary cilia function according to a 2000 study. For astronauts, this would be a reactive adaptation, becoming a problem only when normal gravity is re-established. The adaptation is O.K. as long as you remain in space forever. Problem solved.

Radiation
Ionizing radiation is a big problem in space. The atmosphere and ozone layer that protect Earth life from much of the radiation that could damage our DNA. Besides creating mutations in DNA, the radiation of space can mess with primary cilia.

Usually solitary structures on vertebrate cells, ionizing radiation can change primary cilia number. A 2012 study showed that after radiation exposure, some cells had multiple primary cilia. These all came from the same ciliary pocket, and were probably due to aberrant basal body formation. Surely this is going to mess with any affected cell’s function, considering how important primary cilia are for sensing the cell’s immediate environment.

Next week, we should take a look at ourselves in the mirror. Animals may look symmetric, but it's more complicated. Do we have a head to lead our body, or did our evolution of our body give us a reason to have a head?



Finetti, F., Paccani, S., Rosenbaum, J., & Baldari, C. (2011). Intraflagellar transport: a new player at the immune synapse Trends in Immunology, 32 (4), 139-145 DOI: 10.1016/j.it.2011.02.001

Conroy, P., Saladino, C., Dantas, T., Lalor, P., Dockery, P., & Morrison, C. (2014). C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis Cell Cycle, 11 (20), 3769-3778 DOI: 10.4161/cc.21986

Troshichev, O., Gorshkov, E., Shapovalov, S., Sokolovskii, V., Ivanov, V., & Vorobeitchikov, V. (2004). Variations of the gravitational field as a motive power for rhythmics of biochemical processes Advances in Space Research, 34 (7), 1619-1624 DOI: 10.1016/j.asr.2004.02.013

Fitts, R., Trappe, S., Costill, D., Gallagher, P., Creer, A., Colloton, P., Peters, J., Romatowski, J., Bain, J., & Riley, D. (2010). Prolonged space flight-induced alterations in the structure and function of human skeletal muscle fibres The Journal of Physiology, 588 (18), 3567-3592 DOI: 10.1113/jphysiol.2010.188508

Rimmer J, Patel M, Agarwal K, Hogg C, Arshad Q, & Harcourt J (2014). Peripheral Vestibular Dysfunction in Patients with Primary Ciliary Dyskinesia: Abnormal Otoconial Development? Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology PMID: 25226371


For more information or classroom activities, see:

Bone –

Space travel and the body –

Vestibular sense -