Wednesday, July 22, 2015

Organs Don’t Always Follow The Plan

Biology concepts – internal anatomy, asymmetry, symmetry breaking, primary ciliary dyskinesia, situs solitus, situs inversus



You hold your right hand over your heart for the national
anthem, correct? So what happened here?  Photoshop - they
even reversed the buttons on his jacket and the lapel pin to
sell it.  But notice the medals on the marine behind him; the
photoshopper didn’t switch them back to the left side.
Michelle came much closer to covering her heart. He missed
by a mile. He must be honoring the pack of cigarettes in his
breast pocket.
The national anthem starts. You rise from your seat and place your hand over your heart. But where’s your heart? Most people place their right hand over their left pectoralis major, halfway between the sternum and the armpit. Don’t put your hand in your armpit; nobody wants that.

But the heart is actually located in the middle of your chest, protected by the bony sternum. True, it’s tilted so some of it sticks out to the left side. This is why your left lung is smaller and has the cardiac notch (see this post). The reality is that some of the heart is located right along your midline and some of it is just barely in the left half of your thoracic cavity.

So if you want to cover your heart when the national anthem is played, put your hand over the center of your chest – but your going to look silly next to all those people who don’t really know their own anatomy. Or maybe they do; the heart isn’t always where the anatomy textbooks say it is supposed to be. And neither are the rest of the internal organs.

We’ve talked a lot in the previous weeks about internal and external asymmetries. Despite the fact that most animals are mostly bilaterally symmetric, there are parts of animals that just can’t be symmetric; we only have one of them. Unless they position themselves right along our midline and each half looks exactly like the other, internal asymmetry just isn’t possible.

Even for single organs that are on the midline, they're often not completely symmetric – see our posts on the brain (here and here). The heart itself isn’t symmetric, with the left heart ventricle being much thicker and a stronger pump than the right ventricle. We talked about the thyroid being larger on the right side; the pancreas crosses the midline but the head of the pancreas is much larger than the tail.


The abdomens of most mammals look pretty similar. The rat
on the left has a slightly more centrally located liver, and the
uterus is very different, but you can’t see it here. The spleen
(#6 in rat) is larger and wraps around to the front in the rat
as compared to the human.
The organs of the thoracic (chest) and abdominal (GI) cavities are examples of the asymmetry inherent in most animals. In your abdomen you have one stomach, liver, pancreas, gall bladder, spleen, and one set of small and large bowels. Each is located in a very particular place; like packing for vacation, you have to make the best use of the room you have.

Your thoracic organs are indispensible – you might be able to live without one lung, but every try getting along without both of them? And forget about going without a heart; although the Grinch did fine for a while with one that was three sizes too small.

Paired organs aren’t necessarily symmetric either, but they are most often located symmetrically within their cavity. Each kidney is located pretty much the same distance from the midline. And even though your lungs are asymmetric, their location on each side of the thoracic cavity is fairly symmetric. Part of the advantage of paired organs (kidneys, lungs, adrenal glands, testes, ovaries) is that you have a back up if something goes wrong with one of them.

For single organs, there is no back up. If they go bad, you’re in trouble. You don’t have another source of insulin outside your pancreas, no other organ makes bile besides your gall bladder, and your spleen is crucial for removal of old blood cells and immune complexes. Yet, you can get along without some of your abdominal organs.


If Hannibal Lecter had eaten just part of the census man’s liver and
left him living, it is very possible that his liver would have grown
regeneration. The hepatocytes start to split and regrow the
mass. But they don’t have the signals to produce the original
shape; they just form a functional mass of tissue.
A bunch of people are walking around without a spleen. Some lose it surgically after an injury. The spleen is located to the left of and behind your stomach.  It isn’t protected by bones as your ribs protect your lungs, and it has a thin, brittle covering that is vulnerable to damage. An accident that involves sudden sideways forces can tear the spleen and lead to substantial bleeding.

The injury often involves an automobile, but football players (American football) and rugby players have also lost spleens after tackles. One clinical case detailed a splenic rupture that didn’t occur until 70 days after an abdominal injury. You can get along without your gall bladder too, but you’ll have to read about that yourself - and don't eat potato chips while you read about it.

So how are our pieces fitted together – your heart points to the left of center, the liver and gallbladder are on the right. The stomach is on the left, and so is the spleen. The pancreas is about in the middle. For the digestive tract, the situation makes sense and is driven by the position of the stomach. Food exits the stomach to the right side, so all the things that help digest the food should be on that side – liver for glucose storage from small bowel, gall bladder for fats, head of pancreas for proteins and other things.

The normal arrangement of internal thoracic and abdominal organs (stomach, spleen and heart on left; liver pancreas, gallbladder on right) is called situs solitus. This is the picture you see in your anatomy textbooks and in bodies ripped open by movie werewolves and zombies. But sometimes the pictures aren’t right…. or left.

Some people have mirror image internal organs; what is usually on the right is found on the left, and what usually points to the left now points to the right. This situation is called situs inversus totalis. Luckily, the inversion of organs doesn’t really present a medical problem on its own. Since everything is reversed, the connections from organ to organ and from blood supply to organ are maintained.  Sometimes there is a reason for the inversion, but other times it’s random.

A study from Norway indicated that the chance of situs inversus increases with maternal age, and it is also more common in cultures with small gene pools and higher incidence of inbreeding. However, it is not more common in twins than in multiple single births of a family.

In the cases of situs inversus that are not sporadic (random), what controls the differentiation of right and left and how does it go wrong?


The nodal cilia rotate rather than beat. The third image shows
how they tilt backwards while positioned in the posterior of
each cell.
The identification of how left and right are determined in the embryo has been a long and arduous road, starting in the 1700’s. Different pieces of evidence, usually from mutant animals or from people with diseases, have been added together to form a picture of left-right determination.

The system goes back to the cilia that we talked about last Fall and Spring. The node cells that run along the midline of the embryo have monocilia (one cilium/cell). These are specialized cilia that don’t have the central pair of microtubules, instead they have a 9 + 0 configuration.  They gyrate instead of beating.


Follow the debris to see the leftward flow 
of the fluid.
Nodal cilia gyrate with a long, curved stroke to the left and then a slightly bent return stroke. This movement generates a strong leftward flow of the thick liquid that surrounds the embryo. Normally, gyrating cilia would just create a circular vortex, but these cilia are positioned posteriorly on the nodal cells and tilted posteriorly. Flow studies show that the position and tip are responsible for the leftward flow instead of a whirlpool.

The leftward flow is somehow responsible for turning on different genes in the embryonic cells that will be on the right and left sides, but people and other animals with a defect in nodal cilia are just as likely to exhibit situs inversus as situs solitus. It isn’t that non-functioning nodal cilia cause situs inversus, they just don’t promote situs solitus as they normally would.


Nodal is important for the growth of some cancer cells. If you
harvest lefty from embryonic stem (ES) cells, you can use it to
inhibit nodal and stop the cancers cells from proliferating. This
could be one of the new therapies for cancer in the next few years.
The initial thought was that the leftward flow generated by nodal cilia created a concentration of some morphogen (a shape [morpho] generating [gen] molecule). The morphogen would have a high concentration on the left side and lower on the right, and this would signal for left side genes to be expressed on the left side.

It’s true that there is strong asymmetric gene expression on the left and right sides. The controllers are a couple of proteins related to an immune system protein called TGF-beta (reviewed here and here). The nodal protein is expressed only on the left side, while lefty protein is expressed on the right side. Nodal drives development of a left side, while lefty is a feedback inhibitor of nodal and therefore prevents a left side development on the right side. The asymmetry of nodal and lefty expression was supposedly driven by the concentration gradient of some morphogen generated by the cilia.

However, no one could find the morphogen. Meanwhile, it was discovered that mutations in another type of cilium also resulted in situs inversus. These cilia are immotile; they’re the sensory cilia we also talked about last fall. This led to the two cilia model to compete with the morphogen concentration hypothesis.


In some people with primary ciliary dyskinesia, or immotile
cilia syndrome, the mucociliary elevator isn’t operable, so they
are subject to recurrent respiratory infections.
The two cilia model supposes that the leftward flow generated by the nodal cilia bends the immotile sensory cilia and this sets off a signaling cascade in the cell. The signaling is different on the left and right sides because the left side receives a much stronger current that bends the immotile cilia more, while the right side cilia don’t bend much less or not all.

All this was discovered by accident; different researchers were looking several different diseases. Primary ciliary dyskinesia (PCD) is a rare genetic disease where the motile cilia don’t move. About half the people with PCD have situs inversus, if they do then this PCD is called Kartagener’s Syndrome. Other researchers were looking at polycystic kidney disease (PKD). These people had a defect in immotile cilia in the kidneys, but also had a high incidence of situs inversus.


In polycystic kidney disease (PKD), the defective cilia don’t 
sense flow and they trigger overgrowth of epithelium to 
form cysts. A normal kidney is on the right.
While situs inversus totalis isn’t a problem on its own, patients with PCD and PKD often have other problems. These problems are related to the cilia; it isn’t just the nodal cilia or sensory cilia that are defective, it will be other cilia as well, as well as the organs in which they work. Next week we’ll look the other side of the coin; sometimes organs in the wrong place can cause very big problems.






Babu, D., & Roy, S. (2013). Left-right asymmetry: cilia stir up new surprises in the node Open Biology, 3 (5), 130052-130052 DOI: 10.1098/rsob.130052

Nonaka S, Yoshiba S, Watanabe D, Ikeuchi S, Goto T, Marshall WF, & Hamada H (2005). De novo formation of left-right asymmetry by posterior tilt of nodal cilia. PLoS biology, 3 (8) PMID: 16035921

Shiratori H, & Hamada H (2014). TGFβ signaling in establishing left-right asymmetry. Seminars in cell & developmental biology, 32, 80-4 PMID: 24704359

Resteghini, N., Nielsen, J., Hoimes, M., & Karam, A. (2014). Delayed splenic rupture presenting 70 days following blunt abdominal trauma Clinical Imaging, 38 (1), 73-74 DOI: 10.1016/j.clinimag.2013.09.003




For more information or classroom activities, see:

Situs inversus –

Liver regeneration –

Primary ciliary dyskinesia –

Polycystic kidney disease –