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Are humans chiral? - Muhammad Yaseen Nivas
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No, the images are not flipped. The heart here is indeed on the right, due to a rare congenital disorder known as dextrocardia.

What’s wrong?

You are the attending surgeon, imagine your surprise during a routine appendectomy…only to find the sigmoid colon instead of the appendix. This unexpected scenario, akin to flipping a CT scan, showcases the rare condition known as situs inversus. 

Situs inversus, as you might know from Latin, literally translates to ‘inverted place’. This refers to the phenomenon where asymmetric organs are mirrored in the body.. It was first identified in humans in the 17th century when Fabricius reported the inversion of the positions of the spleen and liver.


Many with situs inversus go their entire lives without knowing they have it. Even though it only affects 0.01% of the population, as most medical professionals are only trained according to anatomic norma, consideration about situs inversus is important in the prognosis of a condition or like the surgery scenario in the introduction, when treating unrelated conditions..There are two main types of situs inversus.
1. Situs inversus totalis refers to the transversion of all the viscera, both thoracic and abdominal.
2. Situs ambiguous refers to the situation in which there is an alteration to the usual left-right distribution of the organs without a fixed or specific pattern, such as the X-ray in the beginning, where only the heart is inverted (dextrocardia).

Under normal physiological conditions, positioning of organs and viscera is termed as situs solitus.


The embryological basis
Laterality in the embryo is established during the third week of embryonic development, more specifically, before and during gastrulation. The primitive streak forms in the epiblast, near the caudal end of the embryo. It is an indentation of mesenchymal stem cells on the median line that extends from the caudal end of the embryonic disk to the center. A thickening of the primitive streak is found at its anterior end and is called the primitive node. The node produces the factor FGF8 which induces differential expression of the NODAL gene on the left side of the streak. As a result, the gene primarily responsible for left-sidedness, PITX2 is upregulated by the NODAL gene.

Caption: Above is a simplified schematic representation of the embryonic disk and the molecules affecting laterality. 



Serotonin, the neurotransmitter, also makes an appearance here! It is concentrated on the left side of the primitive streak (due to its enzymatic breakdown by Monoamine Oxidase (MAO) on the right side). It acts as an upstream signaling molecule from FGF8, therefore it eventually induces FGF8 activity. Not surprisingly, mothers that take SSRIs, the class of antidepressants that work by preventing reuptake of serotonin, birth children with higher risks of having organ (heart) disformations!


What goes wrong?
The differential localization of the transcription factors and other proteins on each side of the primitive streak is responsible for proper left-right development, situs solitus. Thus, anything affecting the localization of the said proteins is a risk factor for situs inversus. The transport of these proteins could be established due to the motile cilia that are found on the primitive streak. Hence,one possible reason for improper localization of the transcription factors, and ultimately situs inversus, could be the dysfunction of cilia!

Additionaly, Primary Ciliary Dysfunction is mainly due to mutations in the genes DNAI1 and DNAH5 that code for dynein, the protein that ‘walks’ on the microtubule (and thereby generating the motion of the cilia), found in the cilia.














Caption: Structure of a cilium (pl. cilia). The motor protein dynein, essential for motility is found on the periphery as an ‘outer’ and ‘inner’ arm. Caution: Do not confuse the motor proteins indicated as part of the ‘Interflagellar transport raft’ with the one referred to in the article.


Kartagener’s Syndrome
The triad of symptoms, namely, situs inversus, sinusitis and bronchiectasis, caused by primary ciliary dyskinesia is called Kartagener’s syndrome. It is interesting to note,although all cases of the sydrome are due to PCD, only 50% of PCD cases include Kartagener’s syndrome. Men suffering from this syndrome are infertile due to the lack of/poor motility of their sperm. Kartagener’s syndrome is autosomal recessive. It can be diagnosed by a couple techniques:

1. Measurement of nasal nitric oxide (which is low in patients)

2. Electron microscopy of nasal biopsy (to assess ciliary function)
3. Testing for DNAI1 and DNAH5 (important for proper ciliary proteins) mutations.

What does this all mean? For one, it is mindblowing that it only takes the misplacement of molecules at one stage, for entire organs in the body to be inverted. Two, the next time you sit an anatomy exam, it is not wrong to write that the heart sometimes points to the right (only kidding). So what do you think, are humans chiral?



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4. Langman’s Medical Embryology 12. E. T.W. Sadler

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