A History of Gene Sequencing

In recent times you may have wondered how rapid tests are carried out to determine whether you are positive or negative for Covid-19, and the answer is, genomic technology! Since the initial discovery of the double-helix structure of DNA, first described by Watson & Crick in 1953 (1), the field of genomics has exploded with new understandings, techniques and promises for current and future therapies to allow intervention in some pretty serious health issues.

Discovering the chemical makeup, and then the structure of DNA, was just the beginning - we’ve come a long way since then, with most advances having been made in the last 30 years or so. This month I’m going to look back at how gene sequencing has evolved in that relatively short period of time.

Gregor Mendel (the father of modern-day genetics; 2), was the first to determine that a genetic blueprint – now known to be our DNA - is what makes us who we are. Subsequently, we came to understand that DNA is arranged into stretches of ‘code’ (a bit like computer code), and that different stretches of that code do different things. Some bits make proteins which then go on to either build structures (tissues), or to carry out chemical reactions inside the body (catalysts/enzymes), whilst other parts of the code work like the conductor of an orchestra, switching segments of DNA on and off, as required, to allow for normal tissue development; function; replication and eventually, death. Our DNA is the operating code that makes us who we are and runs the underlying biology.

So, to understand that DNA-blueprint in more detail, and particularly the mechanisms involved in coding for our very being, then we first needed a method for working out what those long stretches of code (segments of DNA now referred to as genes), actually were. The drive for ‘breaking this code’ is what led to the birth of DNA sequencing.

In the 1970’s two independent groups came up with the first viable methods for sequencing DNA, both of which involved the use of radioactive nucleotides (those small components referred to as G,C,A and T, that make up your DNA structure). First to the table was Frederick Sanger who, after further modifying his technique, was awarded the Nobel Prize in 1980 for developing this method of sequencing (3). Affectionately known amongst researchers as ‘Sanger Sequencing’ this highly reliable method has underpinned even more recent developments and provides very accurate and reproducible results. A chemical cleavage method developed around the same time was Maxim-Gilbert sequencing (4), which used a slightly different approach but still made use of those radioactive nucleotides to work out the DNA code. Either way, the method was essentially to perform a chemical reaction that allowed for replication of the source material but incorporating a radioactive component, which could then be detected by separating out all the bits and pieces in a very long slab of specialised gel, and detecting the radioactive products at the end of the run. It would take perhaps half a day to prepare the gel; one day to perform the chemical reactions, and then 1-2 days to run the experiment. Anywhere then from 1 day to several weeks (or even longer), for taking the dried-down gel and exposing it to photographic plates at -70 degrees (in order to pick up the radiation), and then finally a good couple of weeks or more, for the researchers to manually eyeball the resulting products and with pen and paper (and lots of patience), determine what the code was. Back in the day we thought this was quick!

Fast forward to 1983 and in came the additional tool of PCR (Polymerase Chain Reaction), which allowed researchers to take the tiniest amount of base material and to amplify that DNA, making billions upon billions of copies, so that we then had a lot more material to work with. The principle researcher Dr Kary Mullis who, in 1983, was jointly awarded the Nobel Prize for his fundamental contributions (5), opened the door to new and faster sequencing methods. PCR and many subsequently developed techniques have now changed the entire landscape and contribute greatly to our ongoing understanding of the genetics underlying numerous disease states, and the possibility for gene therapy.

In 1986 , Applied Biosystems launched the world’s first automated DNA sequencing machine, which utilised fluorescent markers instead of radioactive nucleotides and changed that landscape yet again – the technique was now much safer due to the lack of radiation, and could be run by a machine, which really helped to speed things up (6).

Finally, our most recent years have now seen the advent of Next Generation Sequencing (7). This incorporates the fundamental principles of Sanger-sequencing; the amplification benefits of PCR; the use of fluorescent nucleotide technology and fully automated systems that literally take the human element away and can process a sample within minutes to hours, depending on the size of the DNA stretch being coded. The fundamental change with NGS is that multiple strands of DNA can be decoded all at the same time, so not only is the sequencing process itself much quicker, but we can now multiply that effect and achieve in one day what might previously have taken years.

So, back to our opening query about those rapid testing kits! When you understand the advances in gene sequencing techniques as I’ve outlined above, and combine that with other useful technologies such as blue-tooth communication or computer analysis, then its easier to see how a ‘rapid test kit’ can now be developed and test you for specified stretched of genetic code. Recently an Australia company called Ellume developed just such a rapid test kit for Covid-19 which is now on sale through retail pharmacies across the USA and going from strength to strength (7). One can only imagine where the technology will go to from here!









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