What causes the asymmetry in a symmetrically developing organism?

[DaveC426913]

TL;DR

To put a fine point on it: why are our hearts always on the left and our ascending colons always on the right?

As child, before I got my first X-ray, I used to fantasize that I might have a mirror image anatomy - my heart on the right, my appendix on the right. Why not?

(Caveat: I'm not talking about sci-fi molecular-level mirroring. We're not talking starvation because I couldn't process certain proteins, etc.) I'm simpy tlakng about, when a normal zygote divides, it technically has two options which way to form. Oen would expcet a 50:50 split.

But we all have our heart on the left and our appendix on the right (with the exception of congenital deformities).

It's certainly understandable why we have asymmetry. The small intestine, for example is 20 feet long - it must make complex folds to fit into our abdominal cavity, and therefore must become asymmetrical. A more obvious example of aysmmetry is that the stomach's fundus is on left and the pylorus on the right.

The question I have is: why does the asymmetry always happen the same way? There's clearly a lot evolutionary development leading up to the complexity that is any macrofauna such as a human. Witpu doubt, the aysmmetry will become fixed very early in the foetal development.

But how exactly?

A single cell is symmetrical. I remains so after division. By the time we have developed into dozens or maybe hundreds of cells, every one of us picked the same asymmetry when there are two possible options. Let's arbitarily call them L and R. Every time, the developing foetus chose L.

How did it cross that threshold? It's not enough to say "it's in the genes"; There is no overt handedness to the zygote or even the blastocyst. There must be a root physical cause that always forces this "L symmetry" and never the "R symmetry".

The only thing I can think of is that the original proteins and enzymes and amino acids in that first cell have chirality. Some or all of them will not have mirror forms. And we pick up those proteins, enzymes and amino acids from our parents.

Presumably, tissues will form that have a "bias" of sorts - slightly more rigid in one direction, slightly more bendy in the other. So, as the tissues grow, they will form tissues that presumably will only "sploot" to the correct side, in the preferred direction. Since we all use the same proteins, we all have that handedness baked in.

Yes?

 

[DaveC426913]

To stave off an anticipated response, this is not an issue of evolutionary selection. We're not saying "any R symmetry strains would have been out-competed by the L strains."

That misses the point because it assumes this anatomical handedness is coded into the DNA. But that assumes anatomical handedness can be encoded in the DNA.

And that doesn't answer the question: how exactly could it be encoded? Unless it is via proteins and enzymes that physically constrain the tissues to always "sploot" preferentially as they grow..

 

[BillTre]

There are different kinds of asymmetry found in animals.

The kind you are talking about are kind of subtle deviations from perfect bilateral symmetry, like in the human body.
A lot has become known about this since I was a grad. student (1980s).

This stuff involves things like embryonic axes and how they get set-up in the cells of developing embryos. In general, a lot of this is known from many deep studies on a few organisms like mice, rats, fruit flies, zebrafish, and some lesser know organisms. They are easy to keep in the lab and have embryos that are easy to study, and have had a lot of research done on them.

Even the eggs of some invertebrates have different distributions of special molecules in different places in the cell. When the cell divides, one daughter cell gets a different load of molecules that the other (symmetry breaker). This can trigger a chain of events to produce asymmetries.
Any differences in the eggs would have been laid down when the mother constructed the egg in her ovary.

Normally (in vertebrates and their relatives) there is an embryonic process that sets the normal right and left sides. There is a mutation (situs inversus) that randomizes the process, so there is a 50-50 distribution of the normal and abnormal symmetries.
The mechanism involves the action of cilia on cells of the embryonic node (a thing in gastrulation when the first three basic tissue types are being determined). This makes a little flow in an important part of the developing embryo, which makes some diffusable factors go more to one side than the other. This leads to signally cascades in cells affecting their growth and/or determination (of their embryonic fate).
There may be a chirality in the cilia's microtubules (which is a spiral of tubulin proteins). The microtubules are a major structural component of the cilia and involved in their rotation which drives water flows by spinning one way or the other.
When this system operates properly each side is determined in a reproducible manner. The mutation shows this works, but all the little steps to each different kind of expression of the asymmetry are probably not known. For example, axons of the Mauthner cell (one on each side in the hindbrain) cross in a statistically predictable way (axons from one side usually cross over the top of those from the other side). This may just be from one side being slightly ahead of the other side in growing axons, but as far as I know no one knows.
Anyway the embryonic difference in signally is a symmetry breaker. From there developmental processes carry out further development slightly differently.

There are other examples in the animal world.
Starfish (I guess they're seastars now) and other apparently radially symmetric echinoderms (starfish, urchins, sea cucumbers) start out as bilateral embryos (after gastrulation) and then they transform into the apparently radially symmetric adults we are familiar with. They are not completely radially symmetric due to their single madreporite, off to the side on the top. It lets water into the tubefeet suction control system. They start out bilateral, curve together in a loop somehow and the sprout legs.

There are special cases of asymmetry like fiddler crabs. They have a big claw and a little by doing things like removing one claw or the other, it is possible to reverse the claw size symmetry, but they like to grow back the same. The bigger claw is connected to a bigger nerve ganglion in the body next to the claw. This is also thought to have some influence on the size of the claw that grows back. Innervation affecting regeneration is a common biological thing. The nerves can supply diffusable factors or small electrical currents.

To stave off an anticipated response, this is not an issue of evolutionary selection. We're not saying "any R symmetry strains would have been out-competed by the L strains."

There is an argument for this.
Snails with coiled shells have an asymmetry in that they usually coil in one direction. (there are mutations for that).
Hermit crabs live to occupy old empty snail shells. The shells have a handedness, so the crabs occupying them have a matching handedness. Their bodies that are inside the shell are asymmetrically twisted and weird looking, and their claws are also asymmetric. This is likely be adaptive, and therefore selected for, on the basis of fitting in the shell well provides better protect to the crab.

 

[pinball1970]

TL;DR: To put a fine point on it: why are our hearts always on the left and our ascending colons always on the right?

Presumably, tissues will form that have a "bias" of sorts - slightly more rigid in one direction, slightly more bendy in the other

This is human development specifically.

https://en.wikipedia.org/wiki/Carnegie_stages

Cleft palate and spina bifida are examples of when this development can go wrong.

Here is a paper on events and errors at the cellular level.

https://www.nature.com/articles/s41467-022-34294-6

 

[DaveC426913]

There is an argument for this.
Snails with coiled shells have an asymmetry in that they usually coil in one direction.

Totally. It's just not the kind I'm talking about.

 

[DaveC426913]

Even the eggs of some invertebrates have different distributions of special molecules in different places in the cell. When the cell divides, one daughter cell gets a different load of molecules that the other (symmetry breaker). This can trigger a chain of events to produce asymmetries.

This is the thing I'm talking about. So, that asymmetrical distinction still must be driven by a deeper pattern, or there's no reason why it wouldn't be distributed 50:50.

 

[pinball1970]

there's no reason why it wouldn't be distributed 50:50

Cells are not symetric, not perfectly, sometimes significantly. Why do you expect 50/50?

 

[DaveC426913]

Cells are not symetric, not perfectly, sometimes significantly. Why do you expect 50/50?

You miss the point. Start with a single ovum.
What makes every one of us develop asymmetrically in the SAME way?

We all have our fundus on the left and pylorus on the right; our heart on the left and appendix on the right. How?

 

[BillTre]

You miss the point. Start with a single ovum.
What makes every one of us develop asymmetrically in the SAME way?

We all have our fundus on the left and pylorus on the right; our heart on the left and appendix on the right. How?

If you carry two copies of the situs inversus mutation, there is a 50-50 chance of which side of the body those body parts are on.

 

[DaveC426913]

If you carry two copies of the situs inversus mutation, there is a 50-50 chance of which side of the body those body parts are on.

Sure. It's a mutation.

Does it mean I cannot be confident that you - someone I've never met, who may be living in a different hemipshere for all I know, or virtually anyone else picked at random - have your fundus on your left and your pylorus on your right?

 

[BillTre]

Does it mean I cannot be confident that you - someone I've never met, who may be living in a different hemisphere for all I know, or virtually anyone else picked at random - have your fundus on your left and your pylorus on your right?

Depends on your desired level of confidence.
You should certainly not have absolute confidence since the prevalence of these mutants is about 0.01% of the population. (see article linked to above).

Also from the same article:

Notable individuals with documented cases of situs inversus include:

• Enrique Iglesias, a Spanish singer, songwriter, actor and record producer.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-13"><span>[</span>12<span>]</span></a>
• Catherine O'Hara, Canadian-American actress, writer, and comedian.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-14"><span>[</span>13<span>]</span></a>
• Randy Foye, an American basketball player in the NBA. He has suffered no discernible complications, and the condition is not expected to affect his career as a professional athlete, as all his organs are in reverse.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-15"><span>[</span>14<span>]</span></a>
• Ginggaew Lorsoungnern, a Thai convict executed by firing squad. Her condition was discovered after she was shot in the left side of her chest and survived. After waking up in the morgue she was taken back and executed.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-16"><span>[</span>15<span>]</span></a>
• Tim Miller, director of the Ashtanga Yoga Center in Carlsbad, California.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-17"><span>[</span>16<span>]</span></a>
• Rose Marie Bentley, a Molalla, Oregon woman who unknowingly had the rare variant situs inversus with levocardia, and lived to 99 years without any complications. She donated her body to Oregon Health & Science University, where her condition was discovered during an anatomy class after students noticed the unusual arrangement of her heart's blood vessels, prompting further investigation of the cadaver.<a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-18"><span>[</span>17<span>]</span></a><a href="https://en.wikipedia.org/wiki/Situs_inversus#cite_note-19"><span>[</span>18<span>]</span></a>

 

[DaveC426913]

Depends on your desired level of confidence.
You should certainly not have absolute confidence since the prevalence of these mutants is about 0.01% of the population. (see article linked to above).

It is a mutation in one part. But I'll bet the rest of their organs (and innumerable other asymmetries) are still the same.

When we get up to about eight cells or so, one side is chosen as left and the other is chosen as right (that's a gross oversimplication). Even if they look the same, I assume the left cell has coding that is slightly different from the right cell. So I assume the asymmetry is already baked in by that point, and I can intuit how it progress from there.

But go back the first cell. It may or may not already have a distinction. As pinball(?) said, sub-cell components collect in different places in the cell. Sure, but how is it always "this stuff on this side and that stuff on that side"?

It's got to come down to some immutable asymmetry in the underlying molecules. This (these) amino acids are only ever left-handed and that provides the initial pointer to handedness that is baked into everything built on top of it.

I mean, it does raise the hypothetical: if there is an anti-chiral counterpart to every building block, then one could - in theory - have a macrofaunum that is a perfect molecular mirror image (provided it is also nourished with anti-chiral molecules).

So I guess our DNA does code for handedness - inasmuch as it keeps producing proteins and enzymes that have the same chirality. Consistent chirality in the building blocks would certainly make organisms that develop the same macro-scale asymmetries across the tree of life.

Then if we follow that back, one must wonder if, in the primordial soup, there were molecular building blocks of both chiralities. They would compete for some resources (though only the non-chiral ones). Eventually, one chorality would outcompete the other.

The question remains: do all building blocks (I assume we start with the amino acids) have anti-chiral counterparts, and was it just a matter of which one outcompeted the other for resources?

 

[BillTre]

You are making a lot of assumptions and not reading my previous posts or the article I linked to.

 

[DaveC426913]

You are making a lot of assumptions

Well, yes. of course.

and not reading my previous posts or the article I linked to.

OK. I saw the links but knowing that Catherine O'Hara - along with a dozen other people - have the mutation isn't really very useful.

I will read the initial article on situs inversus, but, for now, I suspect that it does not address the root of my question.

Situs invertus affects a couple of organs. It is a reversal on top of the existing constistency in asymmetry that we (and Catherine O'Hara and presumably all other vertebrates) all have. I'm going to bet Catherine O'Hara's appendix and ascending colon are still on her right side.

And it is that overall consistency in asymmetry that I am after. Does that clarify?

However, I will read the article.

[UPDATE]

"For example, if an individual with situs inversus develops appendicitis, they will present to the physician with lower left abdominal pain, since that is where their appendix lies."

"The condition affects all major structures within the thorax and abdomen. Generally, the organs are simply transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gall bladder on the left side. The heart's normal right atrium occurs on the left, and the left atrium is on the right. The lung anatomy is reversed and the left lung has three lobes while the right lung has two lobes. The intestines and other internal structures are also reversed from the normal, and the blood vessels, nerves, and lymphatics are also transposed."

Well, I stand corrected.

Thank you @BillTre. I would not have gone back to read that article in-depth without your reiteration.

So, our specific asymmetry is coded into the DNA. And it can be corrupted.


I wonder if it reverses everything. For example, would heritable defects (like certain moles) be reversed from their parents? Hands, breasts, testicles and other body parts have asymmetry in size. I wonder if they are reversed, but too trivial to consider.

 

[DaveC426913]

Also, somehow, I seem to have completely missed almost all of @BillTre's post #3. (even though I managed to quote a passage at the very end of it).

I must have been called away and gotten distracted.

Apologies.

 

[Astronuc]

TL;DR: To put a fine point on it: why are our hearts always on the left . . . ?

Not in my case. That has caused some confusion for some doctors and radiologists.

My ascending colon is on the right side looking forward.

My brother's ascending colon was misoriented nearly parallel with his transverse portion of the colon; he had digestive problems as a consequence.. A team of surgeons performed abdominal surgery in which they removed small intestines in order to rearrange his colon, then repacked his small intestines. It took him a while to recover.

DNA, RNA and proteins, etc, are not symmetric. DNA/RNA replication does not occur symmetrically

 

[DaveC426913]

Not in my case. That has caused some confusion for some doctors and radiologists.

My ascending colon is on the right side looking forward.

You mean your ascensing colon is on your left?

Fascinating.

 

[BillTre]

The symmetry of eggs seems to be a point of misunderstanding.
There is a big diversity in the symmetry of a pre-fertilized egg.
To begin with eggs are eukaryotic cells and have an axis defined by the location of the nucleus and golgi complex.
Most mammalian cells are small and pretty simple since they don't need to store many supplies to carry them through development since the mother supplies nutrients via the placenta.
Chicken eggs (and other birds (avian dinosaurs)) are very large single cells loaded with lots of nutrients and possibly other molecules that can organize how they proceed through development. There are well documented cases in several invertebrates where localized determinants determine the developmental fate of some of the daughter cells based on the determinant molecules that they inherit due to unequal sorting of these products at division. These large cells are constructed by ovary cells around the incipient egg cells transferring materials to the enlarging egg. These materials are not always distributed evenly through out the egg.

Post-fertilization, the sperm entry point on an egg can be important in determining embryonic axes. A wave of calcium ion influx is often involved in this effect.

 

[256bits]

.

The symmetry of eggs seems to be a point of misunderstanding. Post-fertilization, the sperm entry point on an egg can be important in determining embryonic axes. A wave of calcium ion influx is often involved in this effect.

Biology isn't mature by any means, especially in the one field as to how you describe "localized determinants determine the developmental fate of some of the daughter cells based on the determinant molecules that they inherit due to unequal sorting of these products at division."
We are inundated with how the DNA makes the organism, but with to a much lessor extent as to by what means the gene expression is accomplished to produce the various organs and parts of the functioning organism, rather than being a blob of similar cells. Cytoplasmic inhomogeneities and immediate environmental gradients surrounding a cell leads to differentiation.

Handedness, twisting ( thorax ), and symmetry ( anterior/posterior, ventral/dorsal, bilateral, and I should include radial, cylindrical, spherical, and fractal in some organisms and body parts) were all laid out by some ancient ancestor(s) eons ago, and subsequent, but not necessarily fixed as the explosion of different types of creatures came about. Some of this, or these, can have a Darwinian explanation, while others are perplexing as to why they came about.

 

[pinball1970]

One for you @DaveC426913 zebra fish too @BillTre

https://www.nature.com/articles/s41567-025-03122-1

 

[DaveC426913]

One for you @DaveC426913 zebra fish too @BillTre

https://www.nature.com/articles/s41567-025-03122-1

"... generating radial gradients of cell volume and nucleocytoplasmic ratio. These gradients generate mitotic phase waves, with the nucleocytoplasmic ratio determining individual cell cycle periods..."


Ah yes. Mitotic phase waves. Just what I suspected.

I will try to navigate this paper in a padded environment, for the inevitable eventuality when my head explodes.

 

[pinball1970]

"... generating radial gradients of cell volume and nucleocytoplasmic ratio. These gradients generate mitotic phase waves, with the nucleocytoplasmic ratio determining individual cell cycle periods..."


Ah yes. Mitotic phase waves. Just what I suspected.

I will try to navigate this paper in a padded environment, for the inevitable eventuality when my head explodes.

Dave it's just one paper but embryology research has been going on for a while.
You asked a technical question...

 

[BillTre]

Dave it's just one paper but embryology research has been going on for a while.
You asked a technical question...

However, embryology has built up its own set of terms among the great variety of embryos. This can be pretty obscure to most people.