Humans are strikingly symmetrical on the outside. Our bodies’ left and right halves are near perfect mirror-images: two legs, two arms, two eyes and two ears are equally split between our left and right sides; our faces bear evenly shaped noses and lips. Interestingly, the same cannot be said about the inside of our bodies. Most organs are asymmetrically oriented around our bodies’ main axis—our heart lies on the left while our liver, stomach and spleen rest on the right.
The quest to explain this phenomenon may have begun during a monumental 1788 human corpse dissection at the Hunterian School of Medicine in London (1). During this study, students were shocked to find that a deceased man had reversed internal anatomy—his heart was on the right and his liver on the left. Scientists have explained some of the causes of this disorder, now known as situs inversus, by further deciphering the process of internal left-right specification.
More specifically, the circulation of two crucial developmental factors, known as Nodal and Lefty proteins, causes developmental genes to be expressed differently on the left and right sides of the embryo.
In early embryogenesis, cells assemble in a symmetrical fashion until a structure termed the left-right organizer, composed of cells with motile cilia on their surfaces, is formed (2). Cilia are small, hair-like protein complexes that have many functions in the body. Embryonic motile cilia play a crucial role in determining the body’s internal order. Due to their constant beating, embryonic cilia cause extracellular fluid surrounding the cells to perpetually flow (1). “It’s like a blender,” explained Dr. Dominic P. Norris, a developmental biologist at the Medical Research Council in England, describing the motion of the cilia (1). “It just goes round and round.”
The flow of fluid around the organizer activates developmental genes that regulate the internal position of the body’s main structures. More specifically, the circulation of two crucial developmental factors, known as Nodal and Lefty proteins, causes developmental genes to be expressed differently on the left and right sides of the embryo (3).
Knowledge of the developmental process of internal specification has already led to some beneficial advances in the health field. While situs inversus doesn’t generally produce any symptoms, there are other disorders of abnormal internal structure that can be life threatening. One that falls under this category is congenital heart disease, structural heart defects that develop before birth. Developmental biologists at the University of Pittsburgh School of Medicine demonstrated a connection between the determinants of congenital heart disease and factors that control the left-right specification of the body. The researchers identified 61 genes that, when mutated, prompted the development of congenital heart defects in mice (4). Interestingly, many of the detected genes are known to be involved with embryonic cilia’s function. These results indicate that the patterning of left-right asymmetry in the cardiovascular system in early development is heavily dependent on cilia and their role in development. The principal investigator, Cecilia Lo, said of the project: “The genes and pathways identified in our study will have clinical importance for interrogating the genetic causes of congenital heart disease in patients” (4). Understanding the internal order of the human body can help explain the determinants of organ-related structural diseases, which in turn can lead to better healthcare and, potentially, more effective treatment.
While there are still questions about the precise mechanism of left-right specification, we now know that cilia are indispensable in determining asymmetry and avoiding internal defects. We can hope that additional study will elucidate the mysteries that remain.
- Zimmer, Carl. “Growing Left, Growing Right.” The New York Times. The New York Times, 03 June 2013. Web. 03 June 2015.
- Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Axis Formation in Amphibians: The Phenomenon of the Organizer.
- Hirokawa, Nobutaka, Tanaka, Yosuke, Okada, Yasushi, and Takeda, Sen. “Nodal Flow and the Generation of Left-Right Asymmetry.” Cell 125.1 (2006): 33-45. Web.
- University of Pittsburgh Schools of the Health Sciences. “Team Identifies Mutations Associated with Development of Congenital Heart Disease.” Team Identifies Mutations Associated with Development of Congenital Heart Disease. Medical Xpress, Science X Network, 25 Mar. 2015. Web. 09 July 2015.
- Eggenschwiler, Jonathan T., and Kathryn V. Anderson. “Cilia and Developmental Signaling.” Annual review of cell and developmental biology 23 (2007): 345–373. PMC. Web. 3 July 2015.
- Juan, and Hamada. “Roles of Nodal-lefty Regulatory Loops in Embryonic Patterning of Vertebrates.” Genes to Cells : Devoted to Molecular & Cellular Mechanisms 6.11 (2001): 923-30. Web.
- Nakamura, Tetsuya, and Hiroshi Hamada. “Left-right Patterning: Conserved and Divergent Mechanisms.” Development (Cambridge, England) 139.18 (2012): 3257-62. Web.
- John Barnard, Dr. “Pediatric Research: Tiny Cilia Determine Body Symmetry.” The Columbus Dispatch. The Dispatch Printing Company, 10 May 2015. Web. 3 June 2015.
Eleni Apostolatos is a staff writer for Brevia. She can be reached at email@example.com.