The History and Evolution of Molecular Diagnostics Molecular Diagnostics (MDx) is among Introduction Fast-forward to the mid-1800s the most highly complex disciplines in with Charles Darwin at the helm of Molecular Diagnostics is a branch of the modern science, a fact which has made evolutionary biology, promoting the biotechnology industry, and involves the its development both long and arduous. idea that evolution was “descent with detection of genetic patterns in DNA The theoretical gestation of genetics modification”. Then in 1866 Gregor and RNA, as well as patterns in protein spanned well over 2,000 years, from Johann Mendel, an Augustinian friar generation and usage. These detected classical Greek thinkers like Hippocrates whose pioneering work on the pea patterns (both genomic and proteomic) and Aristotle, all the way to the advent plant clearly showed documentable are used by scientists for classification of cellular biology in the 19th Century inheritance patterns. And although his and for the broadening of knowledge and through to modern times. work – which made use of breeding in connected fields, and by clinicians experiments – didn’t gain much traction Deoxyribonucleic Acid (DNA) and for aiding with diagnosis, prognosis and until it was re-discovered in 1900 by Ribonucleic Acid (RNA) were formally therapeutic monitoring. named in the first part of the 20th another team (Hugo de Vries, Carl The industry is a natural outgrowth Century, with the genetic coding Correns and Erich von Tschermak), by of both science and healthcare, and mechanism finally cracked in 1965. 1925 the model known as ‘Mendelian of medical technology and molecular The Human Genome Project (HGP) inheritance’ was widely accepted. biology specifically. Uses of Molecular was begun by the US government in August Weismann’s contribution in Diagnostics are manifold, including 1987, during which time a multitude 1883 of his Germ Plasm theory was clinical pathology, forensics testing, of scientists and clinicians began also instrumental in bringing about the epigenetics, immunotherapy and employing the knowledge that had coming sea change within scientific immunosuppression, metagenomics, thus far been gleaned for their own circles. molecular endocrinology, molecular particular uses. On the clinical side, Oxford physician oncology, toxicology, personalized Sir Archibald Edward Garrod collected The Human Genome Project was medicine and more. completed in 2003, stimulating greater historical information in 1902 about Today the Molecular Diagnostics advances not only in DNA and RNA the family of one of his patients, industry is an exploding field with a sequencing, but in other areas of and concluded that his patient’s current market size of approximately Molecular Diagnostics. Simultaneous alkaptonuria was a recessive disorder $8B. advances in laboratory information passed down through inheritance. systems made it possible not only to Two Millennia of Inquiry This was quite possibly the first time store and copy the growing dataset, but in history that genetics – the idea that Before the rise of Molecular Diagnostics to use cutting-edge digital algorithms human disease can be inherited – was in the 1980s, clinicians were limited to to help extract the meaning within. discussed in a clinical setting. a generalized approach to diagnosing And advances in proteomics and health problems and for creating DNA and RNA metabolomics helped to increase our solutions for those problems. They In 1869 a Swiss physician named understanding of the biosciences in simply didn’t have any tools they could Friedrich Miescher analyzed the pus near equal measure. use to access the genetic information that was in the discarded bandages of The latest MDx technologies include of their patients, or for putting that one of his patients, and discovered that nanopore readers, one of which was information to use. But what they did the discharge contained microscopic recently used to read the Ebola virus have was access to human history, material. He called the substance genome in only 44 seconds. Such which itself is one of the greatest tools ‘nuclein’ because his microscope advances – combined with concurrent for stimulating innovation. allowed him to see that the substance advances in Computational Biology The history of genetics stretches back resided within the nucleus of the cells. and associated areas using software over two millennia to Hippocrates, who Then in 1878, Albrecht Kossel was the algorithms – are helping to dramatically is credited as being the first person to first scientist to isolate nucleic acid, reduce diagnostics times, allowing have speculated about inherited traits, and went on to isolate the five primary clinicians to treat their patients far more which he also suspected involved some nucleobases later in his career. quickly and efficiently. type of material transfer system in the At the beginning of the 20th Century the reproductive process. 1 History and Evolution of Molecular Diagnostics 11/2018 V1 terms DNA and RNA had not yet been experiment was inconclusive, Hershey Nirenberg began working on the enigma invented – but their existence was no went on to win the 1969 Nobel Prize – of DNA coding at the National Institute secret in microbiology circles. In those along with Max Delbrück and Salvador of Health (NIH). His beginning work early days DNA was known as ‘thymus Luria – for their work on viral genetics. was based on experiments in which he nucleic acid’, because the tissue that attempted to show the possibility of The Double-Helix and the Code of was being studied had been extracted RNA-triggered protein synthesis. Using from a thymus gland. In a similar way, Life the cytoplasm of E.Coli bacteria, he RNA was known as ‘yeast nucleic acid’, By the 1950s DNA and RNA were finally tested each of the 20 amino acids on with yeast as the source material. recognized as the containers of the the samples to find out which amino Phoebus Levene identified the genetic information in living systems. acid would be incorporated into the nucleotide unit of yeast nucleic acid in The double-helix model of DNA was final protein. 1909, carefully noting the base, sugar provided by Francis Crick and James In 1961 Nirenberg’s team finally and phosphate components. Then in Watson in 1953, using X-ray diffraction discovered that phenylalanine was the 1929, while studying thymus nucleic imagery (with the famous ‘Photo amino acid which could be forced to acid, he identified deoxyribose sugar. 51’ taken by Raymond Gosling in the form the repeating protein chain with Leven’s ‘tetranucleotide hypothesis’ was previous year). Uracil. It was this experiment which the first to suggest that thymus nucleic In 1953, astronomer George Gamow proved to the team that the genetic acid was composed of four nucleotide created his ‘RNA Tie Club’, for which he code could be broken. units linked by the phosphate groups – hand-picked 20 scientists – a number Because Nirenberg was racing against although he thought that the ordering which matched the number of amino Nobel laureate Severo Ochoa to be the of the nucleotide units was the same in acids in the human body – and had first to crack the code of life, Nirenberg’s every cell. each of those scientists wear a tie which colleagues generously set down their It was Nikolai Koltsov who, in 1927, corresponded to a single amino acid. own experiments to assist in the effort. proposed his idea that hereditary traits His tie club provided Gamow with a way Ochoa decided to give up the race in were carried by two-stranded – or to show society his part in the race that ’62, because he felt that since Nirenberg “mirrored” – molecules, with each was on at the time: who would be the had the lead, his own time would be strand acting as a genetic template. one to crack the genetic code. better spent on a different task. The very next year, Frederick Griffith In 1959, working separately, Marthe After four years of constant toil, with performed an experiment using two Gautier and Jérôme Lejeune each dozens of scientists scrambling about different but compatible bacterial discovered that Down’s syndrome was his lab, Nirenberg finally cracked the species, which provided the first caused by an additional gene in the DNA genetic code in 1965. real indication that DNA – as it was cluster – an extra copy of chromosome later known – was the true carrier of 21 (which is why the disorder was also A Chain Reaction hereditary information. called ‘trisomy 21’). This was absolutely During that same period, H. Gobind In 1944, Oswald Avery noticed that groundbreaking because it was the first Khorana was working on a way to when one pneumococcus species was time that chromosomes themselves completely synthesize a gene using intermingled with another, the first were being identified, using karyotype oligonucleotides. He developed multiple innocuous species suddenly took on the techniques such as Giemsa staining. techniques, some using oligonucleotides deadly characteristics of the second. He After the revolutionary discovery of as structural elements, and others called this the ‘transforming principle’. the double-helix formation of DNA by making use of oligonucleotides as Avery’s finds had a huge impact on Francis Crick and James Watson in 1953, templates and primers. Khorana was fellow researcher Erwin Chargaff, and in they postulated that the strand pairing awarded a Nobel Prize in 1968. 1950 Chargaff published his ‘Chargaff’s suggested the potential of being part of In