Inspire Digital: Gene sequencing and the race against Covid-19

The Covid-19 pandemic has required the development of brand new vaccines at an unprecedented pace and scale, which would not have been possible without the groundwork laid by scientists working in the field of gene sequencing. Oliver Bredemeyer explains some of the science that lies behind these new vaccines, and how they work in the fight against the virus.

When the first patient with Covid-19 was taken to hospital on the 21^st December 2019, it would have been hard to imagine how this disease would change the world. Now, less than two years after that date, nearly half of the entire human population has been vaccinated against SARS-CoV-2, the virus that causes it. Due to an unprecedented global effort, each one of these vaccines was developed faster than every other vaccine in history. This remarkable feat would not have been possible without gene sequencing, which allowed the international scientific and medical community to find out critical information about the virus in the earliest stages of the pandemic.

When the outbreak was first identified in Wuhan, China, a team of researchers collected fluid samples from the lungs of patients who were treated in hospital. These samples contained infected cells and viral particles, and the researchers set out to identify the cause of the disease. Using gene sequencing, they found genes similar to previously known coronaviruses. On the 12^th January 2020, they published the entire SARS-CoV-2 genome online, allowing other teams across the globe to start researching the virus without ever having had access to a physical sample. Crucially, anyone could download the sequence, re-assemble the gene, and use it to design vaccine candidates. By the end of April 2020, clinical trials were already underway for two vaccines designed by teams at Oxford University (collaborating with AstraZeneca) and BioNTech (collaborating with Pfizer).

How does sequencing work?

Gene sequencing is the process of taking a sample of DNA and working out the sequence of bases in it. The researchers who sequenced the SARS-CoV-2 genome used two systems to do this. One system, developed by Oxford Nanopore Technologies, pulls the DNA through a small hole which has an electric current flowing through it. It then measures changes in the electric current as the different bases block the hole by different amounts in order to determine the sequence. The other system, made by Illumina, uses proteins found in cells to copy each strand of DNA, but makes the copies with modified bases that glow in different colours after they are added. By adding one base at a time and recording the colours produced under a light source, the sequence can be worked out.

Both systems sequence many thousands of DNA fragments at once. Each fragment, or ‘read’, can be relatively small, but will overlap with others. The reads can then be aligned to each other using a computer to find out the full-length sequence.

A new generation of vaccines

One of the reasons that these vaccines could be developed so quickly is because they used a new approach to train the immune system. Instead of containing viral proteins or inactivated viral particles, these vaccines deliver the genetic code to make the SARS-CoV-2 ‘spike’ protein directly to cells (see Figure). This protein is harmless on its own, but without it, the virus cannot enter cells to infect them. When the spike protein is produced by cells after receiving the vaccine, the immune system learns to respond to it; later on, when your body is exposed to real viral particles containing the protein, it will remove them quickly.

To create the Oxford-AstraZeneca vaccine, researchers in the Jenner institute at Oxford University started with a harmless virus found in chimpanzees, and used gene editing to replace parts of its genome. They removed some of the genes needed for this virus to spread from cell to cell, and added the genetic code to make the SARS-CoV-2 spike protein, which was reconstructed from the sequence that had been published online in January. The result is a ‘viral vector’ that can carry these instructions into your cells and causes them to make the spike protein.

The vaccines made by Pfizer-BioNTech and Moderna use non-viral vectors to deliver the genetic code for the spike protein to cells. These consist of lipid nanoparticles (tiny oil droplets) filled with mRNAs containing the genetic code for the spike protein; the nanoparticles are taken up by cells, which then produce the protein.

Both of these technologies have allowed Covid-19 vaccines to be developed, tested, and produced in record time. How do you think they could be used in the future?

Figure 1: *How SARS-CoV–2 (coronavirus) and the vaccines use your cells to make the spike protein.* SARS-CoV–2 (right) carries genetic instructions to make the spike protein and a number of other proteins as RNA molecules. Both vaccines give your cells the code to make the spike protein without the other proteins, making them harmless. This allows your immune system to learn what the spike protein looks like without you getting infected with the actual virus, so it can stop you from becoming sick with COVID-19.

How does DNA store information?

Each of the cells that make up your body, with a few exceptions, contains a complete copy of your genetic code. This code is stored as DNA, a long molecule made up of a sequence of four different ‘bases’ (like letters in our alphabet) linked together in a specific direction. Cells can read this sequence in order to produce other molecules, including RNAs and proteins. This way of storing information is incredibly efficient – your entire genome fits in under 2 metres of DNA, and a single gram of DNA can store over 450 billion gigabytes!

How do viruses and vaccines work?

A virus is a piece of genetic code that uses your body’s cells to replicate itself, and contains the instructions to make proteins that can help it spread from cell to cell. Vaccines train your immune system to destroy infected cells and viral particles by recognising these proteins.

Oliver Bredemeyer is a 4^th year student in Medicine and Neuroscience at St John’s College