Why does the heart grow on the left? This has to start before it begins to develop. Some genes are expressed for several hours during this period and no longer appear. It is these "retired" genes that make you and me healthy. In a dream, you are fighting a bad man with a blurred face. You were gradually in a weak position and were forced to the edge of the cliff. At this time, he punched you hard. You felt that you began to fall down, and then you were startled and woke up. You realize that you are in a familiar environment, but you are still a little scared, so you subconsciously move your hand to the left of your chest. The constant, steady and powerful beating there makes you gradually settle down. If 10000 people wake up from this nightmare at the same time, one person may not touch the left side of his chest, but the middle or more right side. They have encountered a special situation - Heterotaxis, that is, the location of their heart or other internal organs is different from that of most people. According to some scientific observations, if a person has a situs inversus totalis, the visceral position is mirror symmetrical with that of a normal person, it may be harmless. According to a review article published on developmental cell, the oldest woman in Europe lived 126 years old, and she was total visceral inversion. The biggest problem may be that when she is ill, it will be more troublesome to see a doctor or operate on her. Total visceral inversion | pixabay If it is not total visceral inversion, the situation may be worse. This means that this person's body may have left-r axis defects, and he is likely to suffer from some congenital diseases. Moreover, there is little chance that we can see him, because he may have died in the fetus. Symmetrical body, asymmetrical heart Including human beings, 99% of animals are mirror symmetrical in appearance, which is also called bilateral symmetry in biology. The human body has two basic axes: the front rear axis and the upper lower axis. The front rear axle determines the direction of the human body, and the organs that sense the environment and contact food will be located in front of the human body. When the human body moves forward, the symmetrical body on both sides can help us reduce resistance and save energy. In the ancient times when resources were scarce, the key to the sustainability of life lies in the efficient acquisition and preservation of energy. It can be seen that the external form of human and animals is 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, but the weight distributed on the left and right sides is roughly the same. The real situation is also true. Two thirds of the human heart is located on the left and one third on the right of the central axis of the human body. The stomach and liver are mainly symmetrically distributed on the left and right. As mentioned at the beginning, this organ distribution pattern is "copy paste" in 99.99% of people. This is a precise biological development process, but why must it be? Recently, scientists from Singapore published a study in nature medicine, revealing the genes that play a key role in the early development of the human body and solving the mystery: why does the living heart beat on the left side of the body? "Organizer" in embryo In the late 20th century, Japanese scientists found that when the mouse embryo was in the blastocyst stage, there were some cells in the lateral plate mesoderm (the inner side of the mesoderm would attach to the endoderm to form the visceral layer) that could guide the embryonic development, and there were movable fibers on them, which could make the embryonic fluid flow clockwise, that is, from right to left. They believe that this process may be common in animals - this flow activates some genes expressed only on the left side of the cell, which can promote the asymmetric development of the left and right sides of the embryo - so that internal organs can form and develop in the right position. However, this view was quickly refuted. Some subsequent studies found that in the embryos of birds, pigs and other animals, the cells that can guide embryonic development will form a temporary organ - left right organizer (LRO), but there is no movable "cilia" on it. There are 8 micron cilia on the left and right tissue organs of human, fish and amphibians, but not in some animals such as reptiles, birds, pigs and whales. The picture comes from the paper In fact, LRO exists in all animals and is key to determining the arrangement of organs from the left to the right of the body. In many animals, LRO refers to a layer of cells with cilia on the surface. In mouse embryos, the cilia on the cells in the middle area of LRO can be up to 8 microns, which mainly promotes the flow of embryonic fluid from the right to the left, while there are 4 microns of cilia around it. They do not move, but only act as baroreceptors. What the LRO of bird and pig embryos does not have is those 8 micron cilia. The right picture shows the left and right organelles of human beings, and the left picture shows the left and right organelles of reptiles, birds and other organisms. The picture comes from the paper Fortunately, like mice, this organ has movable "cilia". In other words, the findings of Japanese scientists may make sense in the human body. In the new study, the researchers cleverly used the findings of the above study: there are no "cilia" on the LRO of birds and pigs, but there are people, mice, fish and amphibians, which also means that during the period when the "cilia" appeared, some genes will only be expressed in these animals mentioned later, which may play a key role in the determination of organ development sites. Not surprisingly, the researchers found five genes. Mutations in organs In fact, these five genes are involved in the protein encoding LRO cells. Among them, three genes (pkd1l1, mmp21 and dand5, respectively) were confirmed to be related to visceral ectopia. Another gene, cirop, was newly discovered in this experiment. It can express a metalloenzyme. The researchers speculate that the reason why it was not found before may be that it was only expressed in early blastocysts for a few hours, and then it didn't work. They first conducted an experiment with zebrafish: knock out the cirop gene of female zebrafish before ovulation. In this way, it will not affect fertility, and zebrafish embryos without cirop gene can be obtained. They observed ectopic organs in developing zebrafish embryos. When the organs in animals begin to develop asymmetrically, the heart is one of the earliest developing organs. They found that after 48 hours of development, zebrafish fertilized eggs lost the cirop gene, and their developed cardiac looping, which initially turned into a spiral wound ring in the heart, usually counterclockwise, would become messy and random. And not only the heart, but also the development of other organs will be affected. Previously, it has been found that the developmental location of left and right brain, left ventricular circulation and pancreas are affected by genes such as lov, myl7 and INS, respectively. The researchers found that the loss of cirop gene will also affect the asymmetric development of these organs. In up to 75% of zebrafish embryos, the development position of at least one of the above three organs is abnormal. The researchers tried to randomly inject the mRNA corresponding to the cirop gene (which can be translated into the corresponding protein) into zebrafish embryos to save the embryonic development process, and found that the number of embryos randomized to the cardiac circulation tube could be reduced to 13%. They also found that in Xenopus embryos, inhibiting the expression of cirop gene on the left side of LRO would affect the asymmetric development of organs, while removing cirop gene on the right side had no effect. Subsequently, the researchers further confirmed that the flow of embryonic fluid controlled by LRO can regulate the expression of cirop gene on the left, which can control the asymmetric development of organs. Ectopic organ Considering that humans, fish and amphibians have the same LRO, the researchers speculate that if there is a mutation in cirop in human body, there may be the same problem as zebrafish and Xenopus laevis, that is, ectopic organs. They sequenced 186 people with coronary heart disease and found 12 families with cirop gene mutations living in different regions. Among these 12 families, 21 people have cirop gene mutations in their genomes, with a total of 9 mutation forms. For patients with visceral inversion (right), the position of each chamber of the heart will be confused, which may lead to coronary heart disease. The picture comes from the paper Among the 21 people with mutations in the cirop gene, 8 people have no ectopic organs except the heart. Some people's hearts are isolated dextrocardia (the heart is located on the right), but their development is normal. There are 5 people with blurred visceral distribution (situs ambiguus), and 8 people with total visceral inversion (situs inversus totalis), Similar to the woman who lived 126 years ago. This congenital abnormality led to almost all of them suffering from coronary heart disease. Of course, this situation does not mean that cirop gene plays a decisive role in the location of organs, because researchers have observed the presence of this gene mutation in zebrafish and Xenopus laevis experiments, but the organs are still in the normal position. They estimated that in coronary heart disease caused by congenital ectopic organs, the mutation of cirop gene accounted for about 6.5%, which was higher than that of mmp21 (5.9%). To the researchers' surprise, although these five genes are distributed in different positions on the animal chromosome, they can work together. The researchers speculate that the reason why birds and fish lose these five genes at the same time may be that as long as one gene is lost, the remaining four genes will not work and will be lost. However, the specific process of bird and fish organ development and the specific mechanism of determining their organ location need to be further studied. (Xinhua News Agency)