Snails have nodal!

Posted 13 April 2009 by PZ Myers

My first column in the Guardian science blog will be coming out soon, and it's about a recent discovery that I found very exciting…but that some people may find strange and uninteresting. It's all about the identification of nodal in snails.

Why should we care? Well, nodal is a rather important — it's a gene involved in the specification of left/right asymmetry in us chordates. You're internally asymmetric in some important ways, with, for instance, a heart that is larger on the left than on the right. This is essential for robust physiological function — you'd be dead if you were internally symmetrical. It's also consistent, with a few rare exceptions, that everyone has a stronger left ventricle than right. The way this is set up is by the activation of the cell signaling gene nodal on one side, the left. Nodal then activates other genes (like Pitx2) farther downstream, that leads to a bias in how development proceeds on the left vs. the right.

In us mammals, the way this asymmetry in gene expression seems to hinge on the way cilia rotate to set up a net leftward flow of extraembryonic fluids. This flow activates sensors on the left rather than the right, that upregulate nodal expression. So nodal is central to differential gene expression on left vs. right sides.

What about snails? Snails are cool because their asymmetries are just hanging out there visibly, easy to see without taking a scalpel to their torsos (there are also internal asymmetries that we'd need to do a dissection to see, but the external markers are easier). The assymetries also appear very early in the embryo, in a process called spiral cleavage, and in the adult, they are obvious in the handedness of shell coiling. We can see shells with either a left-handed or right-handed spiral.

Chirality in snails. a, Species with different chirality: sinistral Busycon pulleyi (left) and dextral Fusinus salisbury (right). b, Sinistral (left) and dextral (right) shells of Amphidromus perversus, a species with chiral dimorphism. c, Early cleavage in dextral and sinistral species (based on ref. 27). In sinistral species, the third cleavage is in a counterclockwise direction, but is clockwise in dextral species. In the next divisions the four quadrants (A, B, C and D) are oriented as indicated. Cells coloured in yellow have an endodermal fate and those in red have an endomesodermal fate in P. vulgata (dextral)15 and B. glabrata (sinistral)28. L and R indicate left and right sides, respectively. d, B. glabrata possesses a sinistral shell and sinistral cleavage and internal organ organization. e, L. gigantea displays a dextral cleavage pattern and internal organ organization, and a relatively flat shell characteristic of limpets. Scale bars: a, 2.0 cm; b, 1.0 cm; d, 0.5 cm; e, 1.0 cm.

Until now, the only organisms thought to use nodal in setting up left/right asymmetries were us deuterostomes — chordates and echinoderms. In the other big (all right, bigger) branch of the animals, the protostomes, nodal seemed to be lacking. Little jellies, the cnidaria, didn't have it, and one could argue that with radial symmetry it isn't useful. The ecdysozoans, animals like insects and crustaceans and nematodes, which do show asymmetries, don't use nodal for that function. This suggests that maybe nodal was a deuterostome innovation, something that was not used in setting up left and right in the last common ancestor of us animals.

That's why this is interesting news. If a major protostome group, the lophotrochozoa (which includes the snails) use nodal to set up left and right, that implies that the ecdysozoans are the odd group — they secondarily lost nodal function. That would suggest then that our last common ancestor, a distant pre-Cambrian worm, used this molecule in the same way.

Look in the very early mollusc embryo, and there's nodal (in red, below) switched on in one or a few cells on one side of the embryo, the right. It's asymmetrical gene expression!

Early expression of nodal and Pitx in snails. a, 32-cell stage L. gigantea expressing nodal in a single cell. b, Group of cells expressing Pitx in L. gigantea. c, Onset of nodal expression in B. glabrata. d, A group of cells expressing Pitx in B. glabrata. e, 32-cell L. gigantea expressing nodal (red) in a single cell (2c) and brachyury (black) in two cells (3D and 3c). f-h, brachyury (black) is expressed in a symmetrical manner in progeny of 3c and 3d blastomeres (blue triangles in g), thus marking the bilateral axis, and nodal (red) is expressed on the right side of L. gigantea in the progeny of 2c and 1c blastomeres, as seen from the lateral (f) and posterior (g, h) views of the same embryo. i, A group of cells expressing nodal (red) in the C quadrant and Pitx (black) in the D quadrant of the 120-cell-stage embryo of L. gigantea. j, nodal (red) and Pitx (black) expression in adjacent areas of the right lateral ectoderm in L. gigantea. L and R indicate the left and right sides of the embryo, respectively. The black triangle in b and i, the green, yellow and pink arrows in f and i, and the black and pink arrows in f and h point to the equivalent cells. Scale bars: 50µm.

Seeing it expressed is tantalizing, but the next question is whether it actually does anything in these embryos. The test is to interfere with the nodal-Pitx2 pathway and see if the asymmetry goes away…and it does, in a dramatic way. There is a chemical inhibitor called SB-431542 that disrupts this pathway, and exposing embryos to it does interesting things to the formation of the shell. In the photos below, the animal on the left is a control, and what you're seeing is a coiled shell (opening to the right). The other two views are of an animal treated with SB-431542…and look! Its shell doesn't have either a left- or right-handed twist, and instead extends as a straight tube.

Wild-type coiled and drug-treated non-coiled shells of B. glabrata. Control animals (e) display the normal sinistral shell morphology. Drug-treated animals (f, g, exposed to SB-431542 from the 2-cell stage onwards) have straight shells. f and g show an individual, ethanol-fixed, and shown from the side (f) and slightly rotated (g).

What this all means is that we've got a slightly better picture of what genes were present in the ancestral bilaterian animal. It probably had both nodal and Pitx2, and used them to build up handedness specializations. Grande and Patel spell this out:

Although Pitx orthologues have also been identified in non-deuterostomes such as Drosophila melanogaster and Caenorhabditis elegans, in these species Pitx has not been reported in asymmetrical expression patterns. Our results suggest that asymmetrical expression of Pitx might be an ancestral feature of the bilaterians. Furthermore, our data suggest that nodal was present in the common ancestor of all bilaterians and that it too may have been expressed asymmetrically. Various lines of evidence indicate that the last common ancestor of all snails had a dextral body. If this is true, then our data would suggest that this animal expressed both nodal and Pitx on the right side. Combined with the fact that nodal and Pitx are also expressed on the right side in sea urchins, this raises the possibility that the bilaterian ancestor had left-right asymmetry controlled by nodal and Pitx expressed on the right side of the body. Although independent co-option is always a possibility, the hypotheses we present can be tested by examining nodal and Pitx expression and function in a variety of additional invertebrates.

It's also, of course, more evidence for the unity of life. We are related to molluscs, and share key genes between us.

Grande C, Patel NH (2009) Nodal signalling is involved in left-right asymmetry in snails. Nature 457(7232):1007-11.

21 Comments

Henry J · 13 April 2009

That’s why this is interesting news. If a major protostome group, the lophotrochozoa (which includes the snails) use nodal to set up left and right, that implies that the ecdysozoans are the odd group — they secondarily lost nodal function.

That or they branched off the common ancestor first? http://tolweb.org/Bilateria/2459 doesn't distinguish which two of deuterostomia, ecdysozoa, or lophotrochozoa are closer to each other than to the third. Henry P.S. - I didn't come from no snail!11!!one!!

Pete · 13 April 2009

This is essential for robust physiological function — you’d be dead if you were internally symmetrical.

Why would I be dead?

The ecdysozoans, animals like insects and crustaceans and nematodes, which do show asymmetries, don’t use nodal for that function

Do insects have the nodel gene? If not, and assuming comment 1 is not correct about which shares a more recent common ancestor, isn't this breaking the nested hierarchy?

Stephen Wells · 14 April 2009

Perfect internal symmetry would make it pretty much impossible to pump anything from one side of your body to the other- your body has to operate asymmetrically. Re. the heart specifically, the left ventricle is pumping blood all round the body while the right is only pumping it around the lung loop; a perfectly symmetric heart would not be well suited to this.

A secondary loss of nodal among the ecdysozoans wouldn't break nested heirarchy because, well, why should it? No reason why one branch of a heirarchy can't lose something like that.

Torbjörn Larsson, OM · 14 April 2009

Stephen Wells said: Perfect internal symmetry would make it pretty much impossible to pump anything from one side of your body to the other- your body has to operate asymmetrically.

The African elephant in the symmetry garden must be the front-end asymmetry though (to get something in and out), and the Asian elephant the (other) front-back asymmetry (mainly for movement, I think). Though I assume one could in theory, before the pesky contingencies of the body plan made it impossible, to have a more symmetric organism that only distinguished between in and out. I have often wondered what would have happened if cells had happened to develop an efficient active oxygen transport system? (Which I will assume they don't have, since people mentions oxygen as a, probably diffusion, limit on cellular size.) Perhaps we would have seen huge macroscopic cells float around. [Actually I believe we do see that in the sea, but those cells are mostly hollow water blobs.] But movement would have forced at least one other direction asymmetry, possibly angular for rotation as some use. Most cells with flagella have such asymmetries, don't they? So unless an organism just sit or float around, it must AFAIU have at least two broken symmetries, one each in order to metabolize and to move. To be efficient (in an individual adaptive sense) an organism should have as many as we have dimensionality (blood circulation is an excellent example), and that is what we see. Trees have one less broken symmetry, they can be huge (and they are efficient in an evolutionary population adaptive sense, i.e. fit), but they don't move very fast when their environment becomes less habitable. :-o [Hmm. Speaking of asymmetries vs dimensions, it hits me that organisms mostly have a broken time symmetry as well. Enforced by the causality of the process, for sure. ("Mostly" because clonal cells in principle could be eternal, and one could fuzzify metabolism, growth and cloning in such simple organisms sufficiently to say that they are roughly static over time.)]

eric · 14 April 2009

Torbjörn Larsson, OM said: The African elephant in the symmetry garden must be the front-end asymmetry though (to get something in and out), and the Asian elephant the (other) front-back asymmetry (mainly for movement, I think). ...[Hmm. Speaking of asymmetries vs dimensions, it hits me that organisms mostly have a broken time symmetry as well. Enforced by the causality of the process, for sure.

Interesting, but I think the article says this gene only accounts for left-right asymmetry. Front-back and top-bottom asymmetries are, I expect, controlled by other genes. And like you say, past-future asymmetry is imposed by the outside environment, not genetics.

Torbjörn Larsson, OM · 14 April 2009

Thinking further, it is perhaps obvious these symmetries and their breaking are mixed up with each other due to the contingencies of functionality.

The original front-end symmetry breaking could have been primarily caused by functionality of movement. Dunno, but as it involves invaginations in body plans I believe, I think that it soon started to be about feeding.

And the front-back symmetry breaking is perhaps more specifically primarily enforced for movement on surfaces. Fishes and similarly functional organisms may swim up-side down if they like. (But they are mostly less efficient that way for a number of reasons.)

Torbjörn Larsson, OM · 14 April 2009

eric said: And like you say, past-future asymmetry is imposed by the outside environment, not genetics.

Yes, I was thinking on what accounts for broken symmetries in general. On this point it's not clear to me what you want to say. In my mind it is the causality of the evolutionary process, acting on populations and including genetic heredity, that enforces an asymmetry. Eternal, more or less, static organisms and/or static populations aren't described by evolution. (And would likely soon be out-competed, why else don't we see them?) If you wanted to say that it is the environment that is the main driver, or encapsulation, of the process, I agree. Though a perfectly error-free genetic mechanism is not in evidence either.

Torbjörn Larsson, OM · 14 April 2009

Or, to use biologists terms, I guess roughly both adaptation and drift.

Stephen Wells · 14 April 2009

I think Eric's saying that organisms don't need a gene to establish future/past asymmetry; that, at least, comes free with the universe :)

harold · 14 April 2009

Pete -

This is essential for robust physiological function — you’d be dead if you were internally symmetrical.
Why would I be dead?

If you're sincere, this question indicates that you may need to take some steps back and get some basic education in the life sciences. If you're not from a physical sciences background, I'll remind you that some basic physics, chemistry, math and statistics are needed for an understanding of the biomedical sciences. Beyond the obvious asymmetries in mammalian lineages needed for a functioning heart and liver, the human brain is also well known to have subtle but important asymmetrical functioning. (However, substantial variations on brain structure symmetry can be compatible with life.) I'm not trying to sound excessively critical, and I may be biased by my background - I've seen the tragic results of chromosomal abnormalities that lead to disruptions of basic body plan development - but to me the answer to this question seems as if it would be obvious. Seriously, I'd think even someone who had seen an animal butchered would realize that in the mammalian body plan, the major internal organs are organized in an asymmetrical way.

The ecdysozoans, animals like insects and crustaceans and nematodes, which do show asymmetries, don’t use nodal for that function
Do insects have the nodel gene? If not, and assuming comment 1 is not correct about which shares a more recent common ancestor, isn’t this breaking the nested hierarchy?

This is a somewhat interesting question. If it's intended as a creationist "gotcha", it doesn't work; as a sincere question, it is somewhat interesting. I'm not an entymologist, and it isn't obvious to me that insects require as much left-right asymmetry as mammals do. Does anyone know the answer? Are there examples of serious asymmetry in insect body plans? Do they express nodal?

mharri · 14 April 2009

"It’s also, of course, more evidence for the unity of life. We are related to molluscs, and share key genes between us."

I don't think opponents of common descent reject the mountains of genetic evidence, so much as the application of Occam's razor that says it wasn't just a mass coincidence or a Conspiracy of One. (Curse you scientists and your insistence on explanations that actually sound sane!) So yeah, it's cool, but it's not going to convince anyone who didn't already find science's explanation convincing.

Personally, though, my interest was piqued by the link connecting cilia rotation to asymmetry. Because fluid mechanics means equations, which means something I might actually be able to wrap my brain around.

Dale Husband · 14 April 2009

harold said: Pete -

This is essential for robust physiological function — you’d be dead if you were internally symmetrical.
Why would I be dead?
If you're sincere, this question indicates that you may need to take some steps back and get some basic education in the life sciences. If you're not from a physical sciences background, I'll remind you that some basic physics, chemistry, math and statistics are needed for an understanding of the biomedical sciences.

Harold, I suggest you can the condescending attitude. It's that more than anything that makes scientists look arrogant and thus makes science itself unpopular.

Ravilyn Sanders · 14 April 2009

Are the right handed corckscrews rare among the shells?

eric · 15 April 2009

Stephen Wells said: I think Eric's saying that organisms don't need a gene to establish future/past asymmetry; that, at least, comes free with the universe :)

Yep. It might be an interesting problem but its not a problem that the ToE needs to - or can - explain.

harold · 15 April 2009

Dale Husband -

Harold, I suggest you can the condescending attitude. It’s that more than anything that makes scientists look arrogant and thus makes science itself unpopular.

Bullshit. It's the exact opposite. You're the one who's being condescending, with your snide, no-information, insult-only post. I gave a polite but honest answer. Not the least bit condescending. We all say or do less-than-brilliant things sometimes. I gave Pete the respect of an honest and informative answer. I told him what he needs to do (if he wants to learn about the life sciences). I'll even recommend specific books, if he's interested. Guess what, you do need some knowledge and education to understand the topics here. If you can't understand why the asymmetric organization of the heart and liver (*actually shown in the main picture for the post*) is necessary for normal human life, then you need to think harder and maybe do more reading. (Of interest, reverse asymmetry, with heart on the right and liver on the left, is compatible with life, but lack of asymmetry would not be. A fascinating topic that I don't have time for right now.) The reason I know what I'm talking about is because I made the effort - a substantial effort at my own expense - to get an education in the topics at hand. If someone wants to talk about biology and evolution in an intelligent way, they need to educate themselves. They don't necessarily need a formal degree, but they need to know something. If you consider intelligent, informative comments and honest, constructive criticism to be "condescending", that's your problem. Education does have some value.

Dale Husband · 16 April 2009

harold said: Dale Husband -
Harold, I suggest you can the condescending attitude. It’s that more than anything that makes scientists look arrogant and thus makes science itself unpopular.
Bullshit. It's the exact opposite. You're the one who's being condescending, with your snide, no-information, insult-only post. I gave a polite but honest answer. Not the least bit condescending. We all say or do less-than-brilliant things sometimes. I gave Pete the respect of an honest and informative answer. I told him what he needs to do (if he wants to learn about the life sciences). I'll even recommend specific books, if he's interested. Guess what, you do need some knowledge and education to understand the topics here. If you can't understand why the asymmetric organization of the heart and liver (*actually shown in the main picture for the post*) is necessary for normal human life, then you need to think harder and maybe do more reading. (Of interest, reverse asymmetry, with heart on the right and liver on the left, is compatible with life, but lack of asymmetry would not be. A fascinating topic that I don't have time for right now.) The reason I know what I'm talking about is because I made the effort - a substantial effort at my own expense - to get an education in the topics at hand. If someone wants to talk about biology and evolution in an intelligent way, they need to educate themselves. They don't necessarily need a formal degree, but they need to know something. If you consider intelligent, informative comments and honest, constructive criticism to be "condescending", that's your problem. Education does have some value.

You did exactly what you accused me of, harold, and it disgusts me that you would behave so rudely and dishonestly in a public forum like this. It seems obvious that you came here to make trouble. Do you ALWAYS insult people like that, in the name of "honesty"? Why are you so insecure that you have to slam people for asking simple questions? I would never want YOU teaching science to MY kids, if I had any. By obvious contrast, Stephen Wells gave a far better answer than you, so you should have kept silent.

Stephen Wells said: Perfect internal symmetry would make it pretty much impossible to pump anything from one side of your body to the other- your body has to operate asymmetrically. Re. the heart specifically, the left ventricle is pumping blood all round the body while the right is only pumping it around the lung loop; a perfectly symmetric heart would not be well suited to this. A secondary loss of nodal among the ecdysozoans wouldn't break nested heirarchy because, well, why should it? No reason why one branch of a heirarchy can't lose something like that.

The dumbest people are often the loudest and most arrogant.

Ian · 16 April 2009

Why is it surprising that snails have no 8th letter of the Arabic alphabet?

Dave Lovell · 16 April 2009

Dale Husband said:
harold said: Pete -

This is essential for robust physiological function — you’d be dead if you were internally symmetrical.
Why would I be dead?
If you're sincere, this question indicates that you may need to take some steps back and get some basic education in the life sciences. If you're not from a physical sciences background, I'll remind you that some basic physics, chemistry, math and statistics are needed for an understanding of the biomedical sciences.
Harold, I suggest you can the condescending attitude. It's that more than anything that makes scientists look arrogant and thus makes science itself unpopular.

I have to agree with you on this Dale. Not only is "Why would I be dead?" a reasonable question, but PZ's original assertion...

PZ wrote: You’re internally asymmetric in some important ways, with, for instance, a heart that is larger on the left than on the right. This is essential for robust physiological function you’d be dead if you were internally symmetrical.

...is challengable too (Cries of Heresy!). Would front/back asymmetry, resulting in front and back ventricles not perform as adequately as left and right ones? The "alternative" of only two axes of asymmetry rquires a left and right version of everything not on the centre line of the body. Would a body plan with an esophagus splitting into two identical digestive tracts sharing a common rectum not be possible if our ancestors had followed this path? Indeed, it might even offer some redundancy. On reading the original article, it was instantly obvious to me, with a physics and engineering background. that having both front/back and left/right asymmetry offers many advantages, but I have to confess it had never crossed my mind that exploiting these advantages was the essential cause of the organisation of our internal organs. Others might need more explanation. To an organism starting with a long tubular body plan, packing a long gut into a new shorter body clearly requires exploitation of both left/right and top/bottom(front/back) asymmetry unless the structures are just randomly squeezed into the available space, but how much of the apparent left/right asymmetry of structures associated with the gut is the result of evolutionary shunting around of structures that are originally derived from front/back (of couse originally top/bottom) asymmetry anyway?

Kevin B · 16 April 2009

Dave Lovell said: Would front/back asymmetry, resulting in front and back ventricles not perform as adequately as left and right ones? The "alternative" of only two axes of asymmetry rquires a left and right version of everything not on the centre line of the body. Would a body plan with an esophagus splitting into two identical digestive tracts sharing a common rectum not be possible if our ancestors had followed this path? Indeed, it might even offer some redundancy. On reading the original article, it was instantly obvious to me, with a physics and engineering background. that having both front/back and left/right asymmetry offers many advantages, but I have to confess it had never crossed my mind that exploiting these advantages was the essential cause of the organisation of our internal organs. Others might need more explanation. To an organism starting with a long tubular body plan, packing a long gut into a new shorter body clearly requires exploitation of both left/right and top/bottom(front/back) asymmetry unless the structures are just randomly squeezed into the available space, but how much of the apparent left/right asymmetry of structures associated with the gut is the result of evolutionary shunting around of structures that are originally derived from front/back (of couse originally top/bottom) asymmetry anyway?

I seem to recall that, not so long ago, there was a post about the evolution from the 2-chamber to the 4-chamber heart (somewhere in the reptiles?). Might it be that left-right asymmetry is necessary for the 4-chamber heart? Also, is some sort of left-right "gradient" a prerequisite for getting the gut to coil up neatly without tangles? And would the worms with notocords(?) have been able to evolve into vertebrates if they couldn't have a long gut in a short body? Incidentally, aren't both left-right and front-back asymmetries both much less dramatic than head-tail asymmetry?

Dave lovell · 17 April 2009

Kevin B said: I seem to recall that, not so long ago, there was a post about the evolution from the 2-chamber to the 4-chamber heart (somewhere in the reptiles?). Might it be that left-right asymmetry is necessary for the 4-chamber heart?

I don't see any reason that it is necessary to have left/right asymmetry for the heart to function efficiently. It may have been necessary to make it "evolve-able" from a three chambered heart, but by that stage in evolution other left/right asymmetries must have already existed in the animal.

Kevin B said: Incidentally, aren't both left-right and front-back asymmetries both much less dramatic than head-tail asymmetry?

That was sort of my point. The need for left/right asymmetry is not at all obvious, The need for the other two is apparent just from looking at complex animals, even to someone who could not otherwise visualise the problem. Any creature with a gut with a direction of flow (as opposed to an ingest, digest, discard waste cycle through a single orifice) must have one axis of asymmetry, and any creature living with reference to a surface can't evolve very far without having another one.

Dov Henis · 29 November 2009

Upgrade Evolution Comprehension Beyond Darwin

A. From "Asymmetry switched in snail (by manipulation)"
http://www.the-scientist.com/blog/display/56187/

This altered handedness, however, did not pass from generation to generation; offspring of (manipulated) reversed-coiled snails reclaimed the pre-manipulated orientations of their ancestors, suggesting the physical manipulations by researchers did not affect the genetically programmed structural pattern.

B. Again and again: Upgrade Evolution Comprehension Beyond Darwin

Physical manipulations that do not result in augmented energy constrainment by the organism do not affect the expression of its primal organism, the gene. (PS: why refer to an organism as "genetically programmed structural pattern"?. Are we genetically programmed structural patterns?)

Please consider the following concept of the origin and nature of life and organisms, of the origin and nature of cosmic and life evolution:

- Genes, Earth's primal organisms, and all their take-off organisms - Life in general - are but one of the cosmic forms of mass, of constrained energy formats.

- The on-going cosmic mass-to-energy reversion since the Big-Bang inflation is resisted by mass, this resistance being the archtype of selection for survival by all forms of mass, including life.

- The mode of genes', Earth's primal organisms, response to the cultural feed-back signals reaching them from their upper stratum take-off organism is "replicate without change" or "replicate with change". "Replicate with change" is selected in case of proven augmented energy constrainment by the the new generation, this being "better survival". This mode of Life's normal evolution is the mode of energy-mass evolution universally.

Dov Henis
(Comments From The 22nd Century)
Updated Life's Manifest May 2009
http://www.the-scientist.com/community/posts/list/140/122.page#2321
Implications Of E=Total[m(1 + D)]
http://www.the-scientist.com/community/posts/list/180/122.page#3108