LEFT-RIGHT ASYMMETRY / ORIGIN OF LIFE

The asymmetry of the human body begins at the origin of life.

Suppose you are offered one ability from any other animal. You get it for the rest of your life, but you only get one. What would you pick? I’d be tempted with flying, of course, or echolocation. But realistically, outside of a Marvel movie, the most useful animal superpower in our human world is probably unihemispheric sleep — being able to sleep with one hemisphere at a time while the other is awake, an ability mastered by dolphins, whales, seals and some birds, but not by humans. This would come with a tradeoff — since language centers are usually located in only the left hemisphere, half of the time you’d not be able to talk. But — you’d get to stay awake every night. Sounds like a pretty good deal to me.

Unihemispheric sleep is just one example of left-right asymmetry expanding the abilities of an animal. When left is different from right, the body can do more at the same time. Human brains are also asymmetric, but in a different way. In most people the left hemisphere dominates in both speech control and hand use. The latter makes the majority of humans being right-handed (the nerves connecting the brain with the body get twisted along the way, so the left hemisphere controls the right hand.) Although the reasons for this remain murky, it is telling that these “asymmetric” abilities are some of the most evolutionarily advanced things humans are able to do with our bodies: hand use and speech.

It’s not just about the brain: our organs — for example, the heart and the liver — are positioned asymmetrically, which allows more functions to be packed into a compact body. In short, making left different from right makes a body more advanced.

But how does a body know left from right in the first place? At first it seems like a trivial technical question. But the more you think about it, the stranger it becomes.

What’s surprising is not that our body is asymmetric, but that this asymmetry is so consistent: our hearts are almost always on the right, and our livers on the left. Why is it surprising?

Let’s do a thought experiment. As embryos, our bodies begin from a fertilized egg, which looks like this:

How do you go from this ball, which has no orientation whatsoever, to a body with a top, bottom, front, back, left, and right? The simplest explanation is that these directions are assigned randomly. Let’s say that’s what happens. One pole of the ball becomes the top, and the opposite becomes the bottom.

Note that at this point all the balls are the same, regardless of how the poles have been assigned.

If you draw a circle connecting the two poles, it would divide the ball into two hemispheres. Now let’s say one of them randomly becomes the front, and the other the back of the future animal.

Note that the balls are still all the same, even though it can take a second to rotate and align them in your mind.

But now we need to add the third dimension — left vs right. Let’s say that also happens randomly.

Now, the balls are not the same. If left and right are assigned randomly, we end up with two different balls that are mirror opposites of each other.

So if all directionality in our bodies was set up by random chance, we would not end up walking backwards or on our heads. But we would end up with a 50/50 ratio of people that are mirror opposites of each other: 50% with a heart on the left and liver on the right, and 50% vice versa; 50% right-handed and 50% left-handed, and so on. But surprisingly, this doesn’t happen. Somehow, during development, our bodies consistently turn out with hearts on the left and livers on the right. So one of the options from the third drawing is consistently selected over the other. How is this selection made? How could a sphere tell left from right? It seems almost a philosophical quandary, like the riddle about the unstoppable force meeting an immovable object.

It turns out that the sphere — the fertilized egg from which each of our bodies begins — does, in fact, have directionality that allows it to consistently discriminate between left and right. But this directionality is buried very deep.

Occasionally, humans are born with a mirror inversion of their body plan, a condition called situs inversus. In the 1930s, the pathologist Manes Kartagener noticed that many people with this condition also suffer from the build-up of fluid and persistent inflammation in their sinuses and lungs. This peculiar combination of symptoms became known as the Kartagener syndrome, but it made no sense at the time. What could possibly be the connection between an inverted body plan and fluid buildup in sinuses? The puzzle started falling into place when yet another symptom of the Kartagener syndrome was discovered forty years later: male patients with this condition also had immotile sperm. Suddenly the link became clear: cilia.

Cilia are cellular organs of motility, reminiscent of spinning microscopic tails or propellers. Single-celled creatures, as well as sperm cells, use them to swim around. Multicellular creatures like ourselves use them to move around fluids in the body. For example, cells that line the surfaces of sinuses and bronchi have beating cilia that create a flow of dust-clearing mucus, which explains the connection between immotile sperm and fluid buildup in the air passages. But what is the connection between cilia and the left-right asymmetry?

It turns out that the decision on what is left in the developing embryo is made by a special group of cells, a sort of embryonic belly button called the ventral node. Here’s how it looks in a mouse embryo:

As you can see in the picture, the cells sit in a pit, and each cell has a rotating cilium.

Most cilia actually don’t rotate, but beat from side to side. This pushes liquid away from the cell, or — in a swimming cell like a sperm — propels the cell forward. But the cilia in the ventral node are special — they lack a central spike that runs through the cilium, and without that central spike the beating pattern converts to rotational movement, although exactly why is still unknown. The motion looks like this:

As you can see, all these cilia are rotating in the same direction: clockwise. They are additionally tilted slightly to the back (posterior) or the cell, which has a convex surface:

As a result, the right-directed part of the stroke happens close to the cell’s surface and does not scoop up much liquid, whereas the left-directed part of the stroke happens further away from the surface and pushes the liquid more strongly. So overall the rotation of the tilted cilium creates waves in the leftward direction. This liquid contains signaling molecules — hormones that tell cells of the embryo “you are the left side”. Rotating cilia push these molecules to the left side of the embryo, which in turn initiates the development of left-side organs such as the heart but right-side organs such as the liver:

(in this image, you are looking at the embryo’s belly, so the left side is on the right)

So in the end, the consistency of left-right orientation of the human body boils down to a consistent rotation of cilia in the clockwise, rather than counterclockwise direction.

Why do cilia rotate that way, rather than randomly?

The answer is because cilia are made of proteins, and proteins are also asymmetric — they do everything in a particular direction. Proteins consist of smaller building blocks called amino acids. Each amino acid is built around a central atom of carbon attached to four separate chemical units: a carboxy group (COO–), an amino group (NH3+), a hydrogen atom (H), and a side chain (R) that varies between amino acids — there’s a total of 20 different kinds. In principle, each amino acid should come in two symmetric variants:

And yet, this is not so: only L-amino acids occur in proteins. Chemistry says that the two molecules should behave identically, meaning that for each protein built from L-amino acids there could be a D-amino acid-based one that would do everything in mirror reflection. But nature somehow managed to pick a lane.

How it did so remains a mystery. The choice must have happened billions of years ago, at the very origin of life on Earth, since all known lifeforms have consistently asymmetric proteins. Many explanations have been proposed over the years. Some have focused on the amino acids themselves: maybe, for some reason, there was more of one kind available, and that is what was used by the first life forms. A more recent explanation focuses on what happened next: perhaps life actually started with a 50:50 mix of symmetrical molecules, but later one of the directions won over the other.

If this is indeed the case, then we can say that the reason proteins are asymmetric is ultimately the same as why our brains and bodies are asymmetric: by making left consistently different from right, you can achieve more. If all molecules in a cell existed as a 50:50 mix of mirrored opposites, then everything that needed to go left would also always go right, and everything that needed to go right would also always go left. If, by contrast, molecules are asymmetric, then the left-right distinction becomes a source of function and complexity.

It’s interesting to think that symmetry breaking also created the Universe as we know it: in the first moments after the Big Bang, there was no distinction between fundamental forces such as gravity and electromagnetism, and only as the universe expanded and cooled did that distinction arise, producing atoms, galaxies, and living organisms. Symmetry is beautiful because of its simplicity. Asymmetry is beautiful because of complexity.