Written by Alwin Paul
For many years, the concept of genes and inheritance was unchartered to the minds of the common human being, it’s intricate details merely theorized and pondered by philosophers and scientists. The idea of a child being a coalescence of mother and father was simply inexplicable. However, it has now “stranded” it’s way into the heart of many medicinal breakthroughs and advancements of the 21st century with procedures like Genetic Screening, Genetic Engineering and genealogical DNA testing. But how did our microscopic understanding of a microscopic, intertwining, “double-helix” molecule progress into the marching alphabet of A, T, G and C, we know today, paving it’s way into GCSE and A-Level Textbooks, and embedding itself as the focal point within many branches of medicine? It’s time for “Reflection.”
The Historical DNA Dilemma- “Stranded in the Midst of Time”
Deoxyribonucleic acid, or as you and I know it, DNA. The ingredient which accounts for every cell in the human body- the entire human genome. DNA was discovered rather accidentally in 1869 by Swiss physiological chemist Friedrich Miescher. Meischer was appointed the task of researching the composition of leukocytes. He attempted this task by collecting pus coated bandages from a nearby clinic. He washed the pus, filtered the leukocytes and extracted the various proteins. Upon close examination of the cell nucleus he noticed and isolated a new molecule. A molecule that had chemical properties unlike any other protein, including a much higher phosphorous content and a unique phosphorus to nitrogen ratio- This was “nuclein”- the novel substance of DNA. Meischer’s endeavours laid the groundwork for the subsequent molecular DNA discoveries, which would change the face of medicine forever.
Following Meischer’s discovery, other scientists began finding ways to purify this new “nuclein” substance (it was a crude extract and consisted of many proteins). After purification, the extract was named DNA (deoxyribonucleic acid), due to it’s acidity and ribose-based sugar composition. Russian-American biochemist Phoebus Levene then began dismantling the structure of DNA. Levene was the one who discovered the structure of a nucleotide- the building block of DNA- consisting of a base,- one of adenine, thymine, guanine or cytosine (A,T,G or C)- phosphate and sugar. However, Levene had the fallacious belief that nucleotides in DNA always repeated in the same order and had the same number of bases, in every species, as he believed DNA did not have the variation needed to be genetic material. He proposed this ideology in his 1910 Tetranucleotide Hypothesis, which was later disproved. Although, some of his discoveries were flawed, the work of Phoebus Levene, played a crucial role in discovering DNA structure.
In 1949, American biochemist Erwin Chargaff, refuted Levene’s Hypothesis as he noticed the amounts of bases varied between species- an indication that DNA (and not proteins or amino acids, as asserted by Levene) was the genetic material for life. After close analysis of DNA from various species, he was able to make these key observations- the A, T, G and C bases were not found in equal quantities in every species, however, did remain the same for each member of a particular species. Chargaff also found that quantities of A=T and G=C. Using his findings, he devised a set of rules (Chargaff’s rules), which would be fundamental to the eventual deciphering of this enigmatic molecule.
Utilising these, “Chargaff’s Rules” and crucially important X-Ray crystallography work by English researchers, Rosalind Franklin and Maurice Wilkins, the ones to cross the finishing line in this scientific race, were American biologists, James D Watson and Francis Crick. Using this crystallography method, it became discernible that the deflection of the X-Rays, by the atoms held in the crystalline structure of the DNA molecule, a 2-D diffraction pattern was evident. This alluded to the structure of the molecule (This was their eureka moment!), leading to their derivation of a 3-D right-handed, double helical model of DNA, with an antiparallel orientation. Analysis of this model shows the backbone of the DNA molecule consists of alternating layers of phosphates and deoxyribose sugar, which makes up the outside of the helix. The nitrogenous bases are found on the inside, with a hydrogen bond between them. This model explained how DNA replicates and how hereditary information is coded on it and so was quickly accepted by researchers and scientists. It also validated “Chargaff’s Rules” and Darwin’s theory of evolution- a common conviction among many. As a result, Watson, Crick and Wilkins received the Nobel Prize for Medicine in 1962 for their discovery (Franklin had died from ovarian cancer at this point and the prize cannot be received posthumously), thus setting the stage for rapid advancements in molecular biology.
The Molecular Model Which Modelled Modern Medicine
Once James Watson and Francis Crick revealed the revelation of this “Molecule of inheritance”, it paved the way for 50 years of discoveries which has shaped modern medicine today, helping treat a range of maladies. Being able to sequence DNA, has provided patients with invaluable medical intervention e.g. for lifestyle and reproductive decisions, as scientists unravelled inherited diseases at DNA level. One of the first such diseases was sickle cell anaemia- a disease caused by a mutation of the HBB gene (Haemoglobin sub-unit Beta). People with this disorder have an atypical haemoglobin structure (called haemoglobin S), distorting red blood cells into a “sickle”” shape, reducing the oxygen-carrying capacity of the blood (anaemia). Since the HBB gene/allele is recessive, only those who inherit two of the mutated gene, from both parents, suffer severe symptoms.
This discovery told geneticists much about harmful mutations, and heralded ideas to find cures by altering the DNA in one’s genome. This led to the discovery of gene therapy/DNA modification in 1990. The first successful gene therapy patient was a 4-year-old girl with ADA-SCID, an immune system deficiency which left her defenceless against infections. The process involves repairing a defective gene by augmenting it with a healthy version. The new gene is inserted into the cell via a “vector”, which is usually a modified or genetically engineered virus. While still technically challenging, gene therapy is a manifestation of rapidly advancing medical procedures to treat inherited diseases, with increased understanding of DNA on a molecular basis.
DNA discoveries have also advanced medicine in the regard of predicting hereditary diseases- A classic example is cancer; when a series of mutations trigger harmful cellular changes. In rare cases, defects or mutations in one gene such as the breast cancer genes, BRAC1 AND BRAC2, leads to increased predisposition to the same mutation down the familial line- and this is just one in 30 cases of cancer genes which can be sequenced to determine the degree of risk. Understanding this has led to breast-cancer tests to be implemented for family genealogies who carry this gene. Furthermore, genetic screening tests such as amniocentesis and blood tests are also more readily available for those who are more susceptible to a genetic condition. This can be used to test for the presence of chromosomal abnormalities or harmful genes/alleles.
Another major revolution in the branch of DNA and Genetics was the Genetic Engineering of insulin, a process derived in 1982, after the DNA breakthrough, to help treat diabetics. This process manipulates the rapid reproduction of bacteria with the human insulin gene in fermenters, to produce insulin in vast quantities. Genetically engineered microbes have also been utilised for clean medicines e.g. to treat haemophiliacs, who typically lack the protein Factor 8- A clotting agent. Previously, haemophiliacs relied on several blood transfusions, which again predisposed the individual to contracting a viral infection such as hepatitis or HIV from a contaminated donor. Now genetically engineered medicines by artificial means has liberated patients from the prospect of viral defilement.
DNA- “The Secret of Life”
Overall, while still an ethical minefield, the various contributions to the understanding of DNA has advanced medicine profoundly over the last 50-100 years. Boiling down the entire human genome, we are left with the same 4 letters repeating over and over again spontaneously, with the entire sequence filling up to 800 copies of the Bible- information which defines not just our phenotypes, but also our wellbeing- all packed into the nucleus of a microscopic cell. It’s like I said before…DNA is the ingredient which accounts for every cell in our body. Now that’s a recipe for success if you ask me!
Thanks for reading!
Edited by: Simoni Shah and Noelle Darts
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