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Darrell
2017-Feb-09, 09:03 PM
A couple of recent studies have made significant progress in solving a long standing mystery in biology, how do genes involved in directional asymmetric features in bilaterally symmetric organisms know what side of the body they are on? How up – down and front – back are established has been known well for a while, but left – right has been tougher to figure out.

Some quick explanations. There are two types of asymmetric traits, directional asymmetry and antisymmetry. For an excellent explanation see this article (https://whyevolutionistrue.wordpress.com/2017/02/07/directional-asymmetry-how-does-it-develop-and-how-did-it-evolve/) by Evolutionary Biologist Jerry Coyne. (part 2 (https://whyevolutionistrue.wordpress.com/2017/02/08/directional-asymmetry-how-does-it-develop-and-how-did-it-evolve-part-2-mechanisms-for-generating-handedness/), part 3 (https://whyevolutionistrue.wordpress.com/2017/02/09/directional-asymmetry-how-does-it-develop-and-how-did-it-evolve-part-3-artificial-selection-for-handedness/))

Antisymmetry results in random asymmetries, meaning that left-hand and right-hand instances of the feature have a random distribution in the population. Evidence suggests that behavioral / environmental stimulus is the trigger for development rather than a genetic trigger. Directional asymmetry is not random, meaning the handedness is uniform, or nearly so, among the population. Examples are human heart, lungs and other asymmetric internal organs. Evidence has suggested that this type of asymmetry is controlled genetically, but how genes know which side of the body they are on was a mystery.

This study, Left–Right Determination: Involvement of Molecular Motor KIF3, Cilia, and Nodal Flow (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742083/), relates recent research that has solved the crucial part of the puzzle, and it is fascinating enough I wanted to share it. I'll give a very brief overview, but I recommend reading the paper, which is largely understandable even for non-experts (like me).

In a nutshell, the underlying source of handedness in vertebrates (specifically fish, mice & rabbits were studied), has largely to do with fluid dynamics in a fluid filled central cavity (ventral node or nodal pit) that is formed during gastrulation. Cilia in cells lining the floor of the nodal pit create a steady flow pattern in which at the lower layer of the pit there is a steady leftward flow. At the top layer there is a less steady return flow (towards the right).

Cells lining the bottom of the node also produce and release tiny sacks (Vesicular Parcels) that contain signaling molecules. These are moved by the steady leftward flow to the left side of the cavity where they go *splat* and release their contents and thereby are not distributed to other areas of the node by the return flow. So far they have not worked out how the sacks of signaling molecules are opened when they hit the left side of the cavity. And there you have it. The establishment of a left – right chemical gradient that can cue genes to which side of the body they are on. But there is so much more to it, if you like a good mystery go read the study!

Just one more cool thing about this, the direction of flow is, at base, determined by the chiral mechanical structure of the cilia, which because of their atypical structure the researchers initially assumed where not motile. Then there where several more mysteries to solve in figuring out how the cilia and their atypical movement, rotation describing a cone, tilted at a certain angle, could result in the observed flow pattern.

slang
2017-Feb-09, 11:02 PM
Thanks, looking forward to reading that.

publiusr
2017-Feb-11, 07:39 PM
I suppose this means there may be little hope of finding radial symmetry in other life forms--like Elder Things ;)

Noclevername
2017-Feb-12, 12:08 AM
I suppose this means there may be little hope of finding radial symmetry in other life forms--like Elder Things ;)

We find plenty of radial life forms. Go to any seaside town, they sell them in tourist shops.

BigDon
2017-Feb-13, 05:02 PM
So this isn't about handedness?

Because according to anthropologists handedness evolved for precision striking of stone cores over literally millions of years.

Darrell
2017-Feb-13, 06:55 PM
So this isn't about handedness?

Because according to anthropologists handedness evolved for precision striking of stone cores over literally millions of years.

No, this is not about handedness. This is about how genes can tell which side of the body, left or right, they are in. Consider a bilaterally symmetric body plan. Speaking fast and loose, genes need to know where in the body they are in order to execute the correct genetic program to develop whatever feature is supposed to occur in that location. The way this happens is with chemical gradients. A source releases signaling molecules and they diffuse throughout the body (or rather the relatively small group of cells that will become the body). The concentration of the signaling molecules varies with distance from the source. How this all worked has been known for a while with respect to a top-bottom orientation and a front-back orientation. But how it worked for a left-right orientation was a mystery until fairly recently.

Note, this is not necessary in order to develop symmetrical features, for example a left hand and a right hand that are symmetrical. It isn't even necessary in order to develop asymmetric features in which what side develops into what is random. For example lobsters have a cutting claw on one side and a crushing claw on the other and the handedness of the claws is random among lobsters.

But, to develop asymmetric traits that are not random? It was hypothesized that there had to be something happening that allowed genes to know which side of the body they were on. Something like the chemical gradients that allowed genes to know where they are in top-bottom and front-back axes. This paper details how researchers found just that.

Oh, though I said "no" it is actually nearly certain that this is part of the explanation for the type of handedness you mean, but only a part. One clue is that handedness in humans is far from a random distribution.

lpetrich
2017-Mar-04, 08:51 AM
As to what makes the nodal-flow direction one way and not the other, it is likely involved with a protein made from a gene called "Nodal". This gene is expressed on the left side of the nodal pit, that protein seems to make the difference.

Phylogenetic correspondence of the body axes in bilaterians is revealed by the right-sided expression of Pitx genes in echinoderm larvae. (http://www.ncbi.nlm.nih.gov/pubmed/17118013)
Nodal signalling is involved in left-right asymmetry in snails. (http://www.ncbi.nlm.nih.gov/pubmed/19098895) -- and is expressed on the right-hand side there also.

This is connected with dorsoventral inversion: Inversion (evolutionary biology) - Wikipedia (https://en.wikipedia.org/wiki/Inversion_(evolutionary_biology)). Chordates have their dorsal and ventral sides inverted relative to other animals. Combined with the left-right inversion, that means rotation by 180 degrees around the nose-to-tail axis.

Arthropod ventral, chordate dorsal: central nervous system, sog/chordin proteins there
In-between for both: gut
Arthropod dorsal, chordate ventral: heart, dpp/BMP proteins there

lpetrich
2017-Mar-04, 03:30 PM
I suppose this means there may be little hope of finding radial symmetry in other life forms--like Elder Things ;)
As others have pointed out here, there are plenty of organisms with at least partial radial symmetry, and some organisms that become partially radially symmetric as they grow, like echinoderms and cephalopods.

Higher symmetry has the advantage of making multiple parts easier to specify, while lower symmetry has the advantage of greater specialization. So there is a tradeoff between the two.

I've created an Organism-Symmetry Gallery (http://lpetrich.org/Science/Symmetries/OrganismSymmetryGallery.xhtml) and an Organism-Symmetry Demo (http://lpetrich.org/Science/Symmetries/OrganismSymmetryDemo.xhtml), demonstrating rotation and reflection symmetries. I also have a 2D Point-Group Demo (http://lpetrich.org/Science/Symmetries/TwoDimPointGroupDemo.xhtml), a page on Frieze Groups (http://lpetrich.org/Science/Symmetries/FriezeGroups.xhtml) (ASCII-art renderings), and a page on Wallpaper Groups (http://lpetrich.org/Science/Symmetries/WallpaperGroups.xhtml) (ASCII-art renderings where possible).

BigDon
2017-Mar-04, 05:46 PM
That post number 5 in this thread.

I have to apologize Darrel, I didn't know what you were talking about as I hadn't read the OP nearly as well as I should have when I posted that reply.

There, I wanted to say that ever since Ipetrich put the thread back in play.

An Ipetrich, let me guess, you don't make a living as a brick layer, do you? :)

lpetrich
2017-Mar-04, 08:46 PM
An Ipetrich, let me guess, you don't make a living as a brick layer, do you? :)
I don't. Why do you ask?

Darrell
2017-Mar-06, 03:39 PM
No worries Don. I appreciate it but no reason to apologize.

BigDon
2017-Mar-06, 04:36 PM
I don't. Why do you ask?

Because I've been an amateur biologist since 1966 and an experimentalist since 1986. I can induce things to spawn most people can't keep alive. I enjoy conversing with people formally educated on the subject.

lpetrich
2017-Mar-07, 05:12 AM
The world of spatial symmetries is a wonderfully large and detailed one, and I'll do a sketch of it. A transformation of a system is said to be a symmetry of it if the it looks the same after applying the transformation. Thus, something that is left-right symmetric looks the same after doing a left-right reflection.

In general, spatial symmetry transformations or "isometries" are combinations of rotation/reflections and translations (shifts). From real-number vectors x to x':
x' = R.x + D

The rotation/reflection matrix R must be "orthogonal": R.RT = RT.R = I (identity matrix). Meaning that R must preserve angles.

For one dimension, there are only two sets of isometries:
x' = x + D
x' = -x + D
where D can have any value. Shifting only, and reflection and shifting.

A set of isometries that keeps a point fixed is called a "point group", and there are only two of them here, the identity group {1} and identity + reflection {1,-1}.

If the allowed D's are n*D1, where n is an integer for some nonzero D1, then we get a "lattice group" or a "discrete space group". There are only two, {(1,n) for all n} and {(1,n) and (-1,n) for all n}. Obviously related to the two point groups.

-

Turning to two dimensions, we get much more complexity. The point groups divide into two families, the cyclic ones of pure rotations and the dihedral ones of rotations and reflections. The dihedral ones' rotations form a cyclic group, and every reflection has a corresponding rotation, and vice versa. The infinite ones are called SO(2) for cyclic and O(2) for dihedral, "special orthogonal" and plain "orthogonal". The finite ones are C(n) and D(n) or Cyc(n) and Dih(n), for rotations that are multiples of (full rotation)/n.

Most flowers have symmetry Dih(n) or an approximation of it, as do most radially-symmetric animals. Starfish usually have Dih(5), for instance. A rare exception if the Ediacaran fossil Tribrachidium, which has symmetry Cyc(3) -- no reflections.

Bilateral symmetry fits in nicely. It's Dih(1): the identity and one reflection. Its relative Cyc(1) has only the identity, the least amount of symmetry.

Reflection by two orthogonal planes is Dih(2), and it contains Cyc(2), with an 180-degree rotation.


Turning to discrete space groups, the simplest ones involve a one-dimensional lattice, for repetition in one direction. There are 7 "frieze groups", as they are often called.

b b b b b b ... b p b p b p ... b d b d b d ... b q b q b q

b b b b b b ... b d b d b d ... b d b d b d
p p p p p p ... p q p q p q ... q p q p q p

They contain Cyc(n) and Dih(n) where n = 1 or 2.

A two-dimensional lattice gives 17 "wallpaper groups", and some of them can also be represented with ASCII art. These groups contain 12 2D point groups, the 2D "crystallographic groups": Cyc(n) and Dih(n) where n = 1, 2, 3, 4, or 6.

They include the symmetries of honeycombs, bricks in walls, tiles on floors, etc.

-

Going to 3D, there are even more possible groups. The point groups have 7 infinite families and 7 additional members. The 7 infinite families can be understood as the 7 frieze groups wrapped around a cylinder. The additional ones are associated with the 5 Platonic solids. The icosahedral rotation group has 60 members, and with reflections, 120 members. Standard soccer balls and some viruses have icosahedral symmetry.

There are 13 infinite families of 3D "line groups" (1D lattice), understood as wrapping 9 of the wallpaper groups around a cylinder. Restricting the perpendicular parts to the 2D crystallographic groups gives 75 "rod groups". Using a 2D lattice (surface) gives 70 "layer groups", while using a 3D lattice (space) gives 230 "space groups", or 219, counting 11 of them and their mirror images together.

Delvo
2017-Mar-07, 03:10 PM
Have there been any attempts to find out how many different mechanisms are required for the different kinds of left-right asymmetry?:
Internal organs like spleens, which come from the endoderm, for which there's really no sign that bilateral symmetry was ever the plan to begin with; whereas mesoderm and ectoderm act pretty bilateral all along, the endoderm starts as a simple tube (the digestive tract) whose walls some organs later extrude from, and if a tube has any symmetry at all, it's radial
Externally visible (mesoderm & ectoderm) asymmetries in a few species like the crabs with one giant claw or the monkeys with one really long finger, which definitely derive from originally symmetric parts
Asymmetrical brain structure (ectoderm, but a different part of the ectoderm from that of the limbs in the previous item)
Accidentally asymmetric gene expression, not standard for the given species, like a mammal with a blue eye and a brown eye
I can picture these being linked or not. For example, the long monkey finger could always be on the same side as the liver or opposite from it, or it could always be on the same side or opposite side compared to some asymmetrical part of the brain such as Broca's area. Then the occasional individual who is reversed in one way (such as liver & gallbladder on the left or Broca's area on the right) would also have the long finger on the opposite hand because two or more asymmetries keyed off a single original phenomenon. Or they could be unrelated, so a rare individual who's backward in one way doesn't need to be backward in other ways, in which case the asymmetries result from separate unrelated mechanisms...

lpetrich
2017-Mar-07, 08:43 PM
I suggest referring back to Jerry Coyne's posts. From the examples that he mentions, handededness can be determined in several ways.

Genetically
By the environment

Maternal effect on embryonic development
Something in later life, like which claw one uses the most


But are you asking about how these mechanisms induce handedness choices?

Darrell
2017-Mar-07, 09:50 PM
Current thinking is that there are two general types of asymmetry in bilaterally symmetric organisms. One is called Directional Asymmetry and the other is called Antisymmetry. These are not explanations for handedness as in which hand, eye or what not is dominant. Though they are thought to be the basis of such handedness. Rather, these are explanations for different ways that asymmetric features can occur in bilaterally symmetric organisms. Basically, how does a cell "know" to do one thing if it is on the left side of a developing organism or another thing if it is on the right.

DA is asymmetry that occurs in the same way, or mostly the same way, within the entire population of a species. A classic example is the narwhal's tusk. It is always the same tooth (right or left I can't remember off hand). So the puzzle has been, you have two identical groups of cells mirrored on either side of a bilaterally symmetric body plan and the group on one side always grows into an enormous tusk instead of just a tooth. How do those cells know which side of the body they are in? How do they know to execute this genetic program instead of that genetic program. On the other axes, top-bottom and front-back, it is the result of chemical gradients and it has been understood for a while how that all works. It was largely assumed that chemical gradients where the answer here too, but it wasn't until recently that the mechanisms were discovered. The paper referenced in the OP gives an in depth explanation of how a left-right chemical gradient is created.

Antisymmetry is asymmetry in which the handedness is randomly expressed throughout the population of the species. Evidence suggests that rather than variations in the amount of a signaling chemical, in other words a chemical gradient, triggering different genetic programs the trigger for antisymmetric features is environmental and or behavioral. A common example is lobsters which have a crushing claw and a cutting claw. The handedness of the claws is random among lobsters and evidence suggests that which claw develops into which is correlated with which claw the lobster uses the most early in life.

How this relates to the type of handedness such as right hand, eye, etc. dominance is complicated. It certainly plays a key part but there are many pieces to the puzzle. A big clue that DA is a key part of the explanation for that kind of handedness is that hand dominance, for example, in humans is far from randomly expressed. A large majority of people are right hand dominant. But there are other factors. Environment coupled with brain plasticity seems to be able to confound genetic programming at least in some percentage of the population.

Just realized I regurgitated a good bit of the OP, sorry.

Jens
2017-Mar-08, 12:29 AM
I suggest referring back to Jerry Coyne's posts. From the examples that he mentions, handededness can be determined in several ways.

Genetically
By the environment

Maternal effect on embryonic development
Something in later life, like which claw one uses the most


But are you asking about how these mechanisms induce handedness choices?

My understanding is that the question is pretty specifically about the mechanism through which the genetic asymmetry is expressed.

lpetrich
2017-Mar-08, 09:25 AM
My understanding is that the question is pretty specifically about the mechanism through which the genetic asymmetry is expressed.
That'll take a lot of work. How to go from genes to shapes is still not very well-understood.

Jens
2017-Mar-08, 09:43 AM
That'll take a lot of work. How to go from genes to shapes is still not very well-understood.

I would recommend that you go back and read the first post in this thread. It's not actually a question, but a mention of a (IMO) fascinating paper on that subject. Many things are still not understood, but there is a lot that is understood as well. I found it fascinating to learn that part of the puzzle was solved by a brilliant mathematician, Alan Turing.

Darrell
2017-Mar-08, 02:12 PM
As to what makes the nodal-flow direction one way and not the other, it is likely involved with a protein made from a gene called "Nodal". This gene is expressed on the left side of the nodal pit, that protein seems to make the difference.

The OP and the study referenced is about how genes like nodal (and others of course) come to be expressed asymmetrically. The gene Nodal is not a cause of the nodal flow direction, it is a result of it. It had been known for a while that in the early embryo some genes, including Nodal, were expressed on the left side, but not the right.


"In early embryos (7.5 days for mice) at the stage of somatogenesis, genes such as Lefty-2 (Ebaf), Nodal, and Pitx2 are expressed in the left lateral plate mesoderm, a structure located on the side of the embryos (Capdevila et al. 2000; Hamada 2002; Harvey 1998; Levin 2005; Yost 1999). However, the upstream phenomena that cause asymmetrical expression of these genes remain enigmatic." (from the paper quoted in the OP)

The referenced study is about the "upstream phenomena" mentioned in that quote.

The cause of the nodal flow direction comes down to the motion of the cilia that line the bottom of the nodal pit. The genes responsible for the cells lining the nodal pit, and their cilia, are expressed symmetrically throughout the nodal pit. These cilia have a rather unique motion compared to other cilia. At first it was thought that they were not functional, but it turned out they are. They rotate. At first it was thought that this could not be the cause of the left to right flow because individually rotating cilia would not cause a steady directional flow as was observed. Then it was discovered that the rotation of the cilia was not in a flat plane but rather in a distinct cone shaped pattern, and that the cone is tilted to a certain angle and in a non random direction that was a result of the basic structure of the cilia "motor." The tilt of that cone of rotation is the cause of the leftward flow of the fluid in the nodal pit.


"The structural properties of the nodal cilia determine the flow's direction without relying on any a priori L/R asymmetry (Fig. 3E). The clockwise rotation of the cilia reflects the chiral architecture of the nodal monocilia, in which the dynein arms are aligned in a clockwise manner on the side of each doublet microtubule (Fig. 2A) (for the modeling study, see Brokaw 2005)." (from the paper quoted in the OP)

After several attempts at modeling the fluid dynamics in the pit, once the motion of the cilia was finally figured out, and the shape of the nodal pit was taken into account, a successful model was achieved. Of course it is actually more complicated than that. For various reasons the motions of molecules of different sizes through the nodal pit are different. It just so happens that the vesicular sacks of signaling molecules released by the cells lining the floor of the nodal pit, that are what trigger the left-right gradient, are in the size range that is reliably moved by the leftward fluid flow in the lower layer of the nodal pit.

grant hutchison
2017-Mar-08, 03:11 PM
Interestingly, or perhaps not, I was taught in medical school way back in the 1970s that the chiral structure of cilia was the cause of the consistent development of left-right asymmetry in the growing foetus.
This was based on the association of ciliary dysmotility with situs inversus (reversed internal organs) in Kartagener's Syndrome (which is mentioned in the paper cited in the OP), and the (then fairly recent) electron-microscopic evidence of chirality in the ciliary "motors". The assumption was that the preferential rotation of normal cilia maintained fluid flows that triggered the migration of internal organs, and the failure of that flow allowed the development of situs inversus in some people.

Nice to see the details have been fleshed out, but it feels like curiously old news to me.

Grant Hutchison

Darrell
2017-Mar-08, 05:22 PM
Interestingly, or perhaps not, I was taught in medical school way back in the 1970s that the chiral structure of cilia was the cause of the consistent development of left-right asymmetry in the growing foetus.
This was based on the association of ciliary dysmotility with situs inversus (reversed internal organs) in Kartagener's Syndrome (which is mentioned in the paper cited in the OP), and the (then fairly recent) electron-microscopic evidence of chirality in the ciliary "motors". The assumption was that the preferential rotation of normal cilia maintained fluid flows that triggered the migration of internal organs, and the failure of that flow allowed the development of situs inversus in some people.

Nice to see the details have been fleshed out, but it feels like curiously old news to me.

Grant Hutchison

That definitely would be interesting. Are you sure you are remembering that correctly? It had been hypothesized for some time that chiral molecules of some sort were in some way an underlying cause of Left-Right symmetry breaking, but as far as I am aware it wasn't until around the late '90s that people began suspecting that the L-R gradient was being established by activity in the nodal pit, a transient feature, during gastrulation. At that time, however, it was thought that the cilia in the nodal pit were immotile because their structure was similar to other types of cilia and flagella that were known to be immotile.

It has been known since the mid '70s that Kartagener's Syndrome results in defective cilia and flagella in general, such as in sperm and airway cilia, but nothing was known then of the unique (so far) cilia of the cells on the floor of the nodal pit or nodal flow. The referenced study summarizes relevant research as far back as 1976, though mostly from the '90s to the present. Looking at the dates of previous studies and their subjects as related in the referenced study, they don't quite jive with your recollection. Of course I realize that the referenced study may not be thorough in its references or completely accurate in recounting the past history of research on this puzzle.

grant hutchison
2017-Mar-08, 06:09 PM
I'm sure as I can be of the timing, because I have a clear image of the location in which I first heard about. Memories are funny, of course, but given that my postgraduate career avoided histology and embryology entirely, and the topic would be irrelevant to my postgraduate exams, I'm hard pressed to think of another likely occasion.
I suspect the idea was merely speculative at the time - someone trying to come up with a connection between the abnormal cilia and the situs inversus. I don't believe any of my teachers were involved in the research strands that have culminated in the paper you cited, so I don't think I got some sort of privileged preview. I do think ideas sometimes have a long prehistory, and this one is striking because a very early guess on very limited evidence has turned out to be correct.

Grant Hutchison

grant hutchison
2017-Mar-08, 07:09 PM
Ah, here we go: HD Rott (1979) Kartagener's syndrome and the syndrome of immotile cilia (http://link.springer.com/article/10.1007/BF00273308).

Kartagener's syndrome (KS) is a hereditary disease with typical symptoms of situs inversus, bronchiectasis, and chronic infections of the nasal mucosa. Autosomal recessive inheritance cannot be doubted on account of repeated observations of affected sibs and parental cansanguinity. The bronchopulmonary symptoms in sibs, however, cannot be explained by this mode of inheritance.
Recent clinical findings and electron microscope investigations suggest that KS is a special form of manifestation within the immotile cilia syndrome. This disease combines the typical bronchial and nasal symptoms of KS with sterility in the male due to immotile sperm tails and, as a facultative symptom, situs inversus. Thus, sibs with bronchiectasis but without situs inversus are also classified under this syndrome. The symptoms mentioned are caused by an abnormal morphology of bronchial cilia and sperm tails, which can be demonstrated by electron microscopy. The dynein arms normally attached to the nine microtubular doublets and providing a normal ciliary movement are lacking.
It is assumed that during early embryonic life ciliary beats in the growing embryo determine the type of laterality. When ciliary movements are absent laterality may develop fortuitously, thus effecting a situs inversus in about half the affected cases. The numerical evaluation of pedigrees from the literature supports this assumption.
What's explicitly missing in the abstract is my recollection of a discussion of the ciliary motor's intrinsic chirality, but it's difficult to see how the last para above would make sense without invoking the chiral nature of normal cilia.

Grant Hutchison

Darrell
2017-Mar-08, 08:14 PM
Thanks. Yes, that was related in the study in reference to a 1976 paper by Afzelius. I agree, it was a good hypothesis based on little concrete information. But it is accurate only in a very general sense, and I'm sure it was only intended as a very general explanation. How it actually happens took another 30 years to piece together.

An interesting thing is the twist and turns cilia motility / immotility caused. As the HD Rott 1979 quote states it was assumed that motile cilia were a key factor some way, some how, some where. When the nodal pit became of interest it seemed as if they were close to solving the puzzle. Instead, when the cilia on the floor of the nodal pit were first studied it was initially thought that they were immotile because they lacked a key structural feature (the central pair of microtubules) that were associated with immotility in other cilia and flagella. That apparently threw researchers off the trail for a while until they discovered that the flagella were motile, but in a way unlike any other observed cilia or flagella. They expected to see the planar wave like motion typical of other motile cilia that could cause a directional flow, but that isn't what they found. Instead these cilia rotate. They were not normal cilia. That was a puzzle because rotation wouldn't cause a directional flow. Then they discovered that they weren't rotating in a flat plane, but in a cone. Then they discovered that the axis of the cone wasn't vertical, but tilted at a regular angle. That regular angle was the key. The search went something like, cilia are the basis. . . cilia are not . . . they are . . . oh damn, they aren't . . . wait a minute, maybe they are . . . ah ha, they are.

grant hutchison
2017-Mar-08, 10:05 PM
Yes, and for every early hypothesis forming paper which generates that sort of oscillation, probably most end up settling on "false". It's sort of related to a phenomenon in published medical research that Ioannidis called the Proteus Phenomenon - but that relates to an oscillation in the evidence rather than the precise nature of the hypothesis.
Anyway, since I've been blithely telling people about this for the last thirty-odd years, I'm glad it settled on "true". :)

Grant Hutchison