Figure | Pixabay
Why does the heart grow on the left? It had to start before it even started to develop. Some genes are expressed during this period for hours and then no longer appear. And it is these "retreat" genes that have made you and me healthy.
In a dream, you are fighting a bad guy with a blurred face. You are gradually in a weak position, forced to the edge of the cliff, when he throws a punch at you, you feel like you start to fall down, and then you are frightened and woken up. You realize you're in a familiar environment, but still a little insecure, so you subconsciously move your hand to the left side of your chest. The constant, steady and powerful beat there will gradually calm you down.
If 10,000 people wake up from this nightmare at the same time, there may be 1 person who does not touch the left side of his chest, but touches the middle or further right. They encountered a special case —heterotaxy (organs are not where they should be), meaning that their hearts or some other internal organs are not in the same position as most people.
According to some scientific observations, if a person appears with situs inversus totalis (the position of the internal organs is mirror symmetrical to that of a normal person), it may be harmless. According to a review article published in Dimension Cell, the longest-lived woman in Europe lived to be 126 years old, and she is a total visceral reversal. The biggest problem may be that when she is sick, it can be a little more troublesome to see her or perform surgery.
Total visceral transversion | Pixabay
If it is not a total visceral reversal, the situation may be worse. This means that the person's body may have L-R axis defects, and he is likely to suffer from some congenital disease. Moreover, we have little chance of seeing him, because he may have died in the fetal period.
Symmetrical body, asymmetrical heart
Including humans, 99% of animals have a mirror symmetry, also known biologically as bilateral symmetry. The human body has 2 basic axes, namely the front-rear axis and the up-down axis. The front-posterior axis determines the orientation of the human body, and the organs that perceive the environment and come into contact with food are located in front of the person. When the human body moves forward, the symmetrical body on both sides can help us reduce resistance and save energy. In ancient times when resources were scarce, the key to whether life could continue was whether energy could be obtained and preserved efficiently.
It can be seen that the external forms of people and animals are largely shaped by the environment. However, the influence of the environment on the internal organs is not so strong, at least the internal organs do not need to be symmetrical left and right, only the weight distributed on the left and right sides is roughly equal. The real situation is also true, 2/3 of the human heart is located on the left side of the human body axis, 1/3 is located on the right, and the stomach and liver are mainly symmetrically distributed left and right.
As mentioned at the beginning, this pattern of organ distribution is "copy-paste" in 99.99% of people. This is a precise biological development process, but why does it have to be so? A recent study published in Nature Medicine by scientists from Singapore sheds light on genes that play a key role in the body's early development, unraveling the mystery: Why does a living heart beat on the left side of the body?
The "organizer" in the embryo
At the end of the 20th century, Scientists in Japan discovered that when mouse embryos were in the blastocyst stage, the lateral plate mesoderm (the inner side of the germ layer would be attached to the endoderm to form an visceral layer) with some cells that could guide embryonic development with movable cilia, allowing the embryonic fluid to flow clockwise, that is, from right to left. They believe that this process may be common in animals — this flow activates genes that are expressed only on the left side of the cell, causing the left and right sides of the embryo to begin to develop asymmetrically — so that internal organs can form and develop in the right place.
However, this view was quickly refuted, and some subsequent studies have found that in the embryos of birds, pigs and other animals, the cells that can guide the development of embryos will form a temporary organ - left-right organizer (LRO), but there is no "cilia" on it.
There are 8 micron cilia on the left and right organizers of humans, fish, and amphibians, while some animals such as reptiles, birds, pigs, and cetaceans do not. The image comes from the paper
In fact, LRO is present in all animals and is critical to determining the arrangement of organs from the left to the right side of the body. In many animals, LRO refers to a layer of cells with cilia on the surface. The cell-length cilia in the middle region of the LRO in mouse embryos, up to 8 microns long, mainly promote the flow of embryonic fluid from the right side to the left, while there are 4 micron cilia around it, which do not move, but only act as pressure receptors. What the LRO of bird and pig embryos does not have is the 8 micron cilia.
The picture on the right is the left and right organizers of people, and the left picture is the left and right organizers of reptiles, birds and other creatures. The image comes from the paper
Fortunately, like mice, this organ has "cilia" that can move. In other words, the discoveries of Japanese scientists may make sense in humans. In the new study, the researchers cleverly used the findings of the above study: there is no "cilia" on the LRO of birds and pigs, but humans, mice, fish and amphibians do, which also means that during the period when "cilia" appeared, some genes were only expressed in the bodies of the animals mentioned later, which may play a key role in determining the site of organ development. Not surprisingly, the researchers found 5 genes.
Mutations on organs
In fact, all 5 genes are involved in proteins in cells that encode LRO. Three of these genes (PKD1L1, MMP21, and DAN5) were confirmed to be associated with visceral ectopicity. Another gene, CIROP, was newly discovered in this experiment, which expresses a metalloid enzyme. The researchers speculate that the reason it wasn't previously discovered may be that it only expressed itself in early blastocysts for a few hours and then didn't work after that.
They first conducted an experiment with zebrafish: knocking out the CIROP gene in a female zebrafish before it ovulated normally. This will not affect fertility and allow for zebrafish embryos without the CIROP gene. They observed the presence of organ ectopia in developing zebrafish embryos.
When the organs in the animal's body begin to develop asymmetrically, the heart is one of the earliest to develop. They found that after 48 hours of development, zebrafish fertilized eggs lost the CIROP gene, and their developed cardiac looping (initially the tubes in the heart became a spiral-wound ring, usually counterclockwise) became cluttered and random. And not only the heart, but also the development of other organs will also be affected.
It has been previously found that the developmental positions of the left and right brains, left ventricular circulation and pancreas are affected by genes such as lov, myl7 and ins, respectively. The researchers found that the loss of the CIROP gene also affects the asymmetric development of these organs at the same time, and in as many as 75% of zebrafish embryos, at least one of the above three organs has an abnormal developmental location. The researchers tried to randomly inject mRNA corresponding to the CIROP gene (which can be translated into the corresponding protein) into zebrafish embryos to save the embryo's developmental process and found that the number of embryos randomized by the cardiac circulation tube was reduced to 13%.
They also found that in the embryos of Xenopus laevis, inhibiting the expression of the CIROP gene on the left side of the LRO affected the asymmetric development of the organ, while removing the CIROP gene on the right side had no effect. Subsequently, the researchers further demonstrated that LRO-controlled flow of embryonic fluid regulates the expression of the CIROP gene on its left side, which in turn can control the asymmetric development of the organs.
Organ ectopic
Considering that humans, fish and amphibians have the same LRO, the researchers speculate that if there is a mutation in CIROP in the human body, it may also have the same problem as zebrafish and Xenopus laureus, that is, organ ectopia. They sequenced the genes of 186 people with coronary heart disease and found 12 families with mutations in the CIROP gene that lived in different regions. In these 12 families, a total of 21 people have MUTATIONs in the CIROP gene on their genomes, with a total of 9 forms of mutations.
In patients with visceral reversal (right), the position of the various chambers of the heart will be confused, which may lead to coronary heart disease, etc. The image comes from the paper
Of the 21 people with mutations in the CIROP gene, 8 were not ectopic in organs other than the heart, some had an isolated dextrocardia (the heart on the right) but developed normally, situs ambiguus had 5 positions with a vague distribution of internal organs, and 8 people had situs inversus totalis, similar to the previous 126-year-old woman who had lived. And this congenital abnormality caused almost all of them to suffer from coronary heart disease.
Of course, this situation does not mean that the CIROP gene has a decisive role in the location of the organ, because in the zebrafish and Xenopus laevis experiments, researchers have observed the presence of this gene mutation, but the organ is still in a normal position. They estimated that mutations in the CIROP gene accounted for about 6.5 percent of coronary heart diseases caused by congenital organ ectopia, higher than the other gene in the five genes, MMP21 (5.9 percent).
To the researchers' surprise, these 5 genes, although distributed in different locations on the animal's chromosomes, can work together. The researchers speculate that birds and fish may lose these 5 genes at the same time because as long as 1 gene is lost, the remaining 4 genes will not function, and then will be lost. But the specific processes of organ development in birds and fish and the specific mechanisms that determine the location of their organs have yet to be studied in greater depth.
bibliography
[1]https://pubmed.ncbi.nlm.nih.gov/18661581/
[2]https://www.science.org/content/article/gene-pinpointed-helps-put-human-hearts-right-place
[3]https://www.science.org/doi/epdf/10.1126/science.8480173
[5]https://en.wikipedia.org/wiki/Lateral_plate_mesoderm
Written by | clefable
Review | Li Shiyuan
This article is reprinted from Universal Science (ID: huanqiukexue) with permission, please contact the original author for secondary reprinting.