Every individual on this plant are meant to survive, starting from a single cell bacteria to a more complex multicellular human. But when we restrict our focus field to the animal kingdom, the functional specialisation of organs and mutation in the associated genes becomes a subject of fascination. Why is there a need for this division in function through specific organs? Becoming specific aims at benefits of less work load on the specified organ and a better distribution of function. However, it has its own costs, for example, if your heart fails, the kidney wouldn’t be able to complement the function by performing excess of ultrafiltration.
While stepping to higher phyla in animal kingdom we can observe a significant complexity, however, the functional basis remains the same. One such function is circulation which is very essential for existence. It is via circulation that every part of an organism stays connected and alive. When it comes to specialization, humans have a more evolved heart, although the function remains same in comparison to other invertebrate phyla where instead of specialised heart, open circulatory tubes are present. But what really controls this specificity? Specificity at its molecular level is governed by genes which in turn regulates the functioning of each and every cell of our body by rendering the formation of various complex molecules like proteins, enzymes, etc. This article has its prime focus on one such gene responsible for development of the robust pumping organ, The Heart.
The tinman gene:
The heart of a fruit fly is a simple organ, an open-ended tube that rhythmically contracts, pumping fluid—rather inefficiently—around the body of the fly. Although the heart of a fruit fly is simple and unsophisticated, it is essential, at least for a fruit fly. Remarkably, a few rare mutant fruit flies never develop a heart and die at an early embryonic stage. Geneticist Rolf Bodmer analyzed these mutants in the 1980s and made an important discovery—a gene that specifies the development of a heart. He named the gene tinman, after the character in ‘The Wizard of Oz’ who also lacked a heart.
Bodmer’s research revealed that tinman encodes a transcription factor, which binds to DNA and turns on other genes that are essential for the normal development of a heart. In the mutant flies studied by Bodmer however, this gene was lacking, the transcription factor was never produced, and the heart never developed. Findings from subsequent research revealed the existence of a human gene (called Nkx2.5) with a sequence similar to that of tinman, however the function of this gene remained unknown. Later, in the 1990s, physicians Jonathan and Christine Seidman began studying people born with abnormal hearts, such as those with a hole in the septum that separates the chambers on the left and right sides of the heart. Such defects are diagnosed to result in abnormal blood flow through the heart, causing the heart to work harder than normal and also leading to the mixing of oxygenated and deoxygenated blood.
The Seidmans and their colleagues found several families in which congenital heart defects and irregular heart beats were inherited together in an autosomal dominant fashion. Detailed molecular analysis of one of these families revealed that the gene responsible for the heart problems was located on chromosome 5, at a locus where the human tinman gene (Nkx2.5) had been previously mapped. All members of this family who inherited the heart defects also inherited a mutation in the tinman gene. Further studies on many more patients with same defect uncovered the fact that many people with congenital heart disease have a mutation in the tinman gene. The human version of this gene, like its counterpart in flies, encodes a transcription factor that controls heart development.
Its fascinating and intriguing to observe how the body functions in such a complex manner and yet regulates the functioning so efficiently. While the heart of the fly is significantly simpler, compared to that of ours; they both depend on the same Godfather, which here is tinman. Despite tremendous differences in body size, anatomy and physiology, humans and flies use the same gene to make a heart.
What is a Congenital Heart Disease?
The term “congenital” means the condition is present from birth. Congenital heart disease is a general term which is used for a range of birth defects that impair the normal working of the heart. This type of inborn error is one of the most common types of defect found with a frequency of 8 in every 1,000 babies.
Types of Congenital Heart Disease
Though there are many different types of congenital heart defects, they can be briefly divided into three main categories:
- In heart valve defects: The valves inside the heart that direct blood flow may close up or leak. This significantly interferes with the heart’s ability to pump blood.
- In heart wall defects: The natural walls that exist between the left and right sides and the upper and lower chambers of the heart may not develop correctly. This causes blood to back up into the heart or to build up in places where it doesn’t belong. The defect puts pressure on the heart to work harder, which further leads to high blood pressure.
- In blood vessel defects: The arteries and veins that carry blood to the heart and back out to the body may not function correctly. This henceforth reduces or blocks blood flow, thus leading to various health complications.
Congenital Heart disease and Mutation in Nkx2.5 gene:
Cardiac development is a complex biological process requiring the integration of cell commitment, morphogenesis and many more co-ordinated processes. Cardiac septation is a critical morphogenetic process in which the primordial single atrium and ventricle are partitioned into four chambers. Mistake in these processes occur commonly in humans; 1 in 1500 live births have been found with an atrial septal defect.
Normal atrial partitioning requires sequential growth and resorption of a primitive septum followed by the definitive, right-sided septum secundum. During embryogenesis, a hole is maintained between the atria, through which oxygenated blood is shunted so as to bypass the nonfunctional fetal lungs; this hole however, closes shortly after birth. The molecular signals that regulate cardiac septation are largely unknown, although recent genetic studies of a rare disorder, Holt-Oram syndrome, have shown that TBX5, a T-box transcription factor, plays a major role.
Take your Call!!
The funcional complexity and the cellular functioning lie parallel to each other. The story of tinman gene illustrates the central importance of studying mutation. The analysis of mutation and the mutant fruit fly model becomes a key source for an insight into the biological processes. It can clearly be described that the complexity of the body’s functioning can be explained only by analysing the simplest of the processes. To support my validation, it is critical to mention the example of tinman gene, which being responsible for Congenital Heart diseases in human can be studied via an organism as simple as the fruit fly. Another aspect of this study is to conclude how nature has been simple and complex at the same time when creating an organism. Biologically explaining, its as simple as an organ being controlled by the same gene in two different phyla but as complex as them having enormous differences in cellular complexity and its functioning.
References:
- Congenital Heart Disease Caused by Mutations in the Transcription Factor NKX2-5 August 1998 Science 281(5373):108-11 DOI: 10.1126/science.281.5373.108
- Congenital Heart Defects (CHDs)