Perverse Genetics

Covid-19 is not only a new nasty virus, but the techniques used in its discovery, monitoring and medical management are also new, particularly from my perspective as someone old enough to be in the highest priority group for vaccination. If the prime minister had suffered from the virus when I was a junior doctor at St Thomas’s Hospital, he wouldn’t have been treated in the Intensive Care Unit, because there wasn’t one. Residents of Lambeth with severe respiratory problems – and there were many because cigarettes were cheap and sulphurous smogs were common – were given oxygen on thirty-bed Nightingale wards, with tracheostomies if they were really sick. Monitors didn’t bleep. There weren’t any.

Nobel Prizes are meaningful milestones for medical advances. My longevity, and hence increased susceptibility to Covid, has been helped by cardiac catheterisation (André Cournand, Werner Forssmann, Dickinson Richards: Nobel Prize, 1956) and the placement of stents into my left circumflex and right coronary arteries. My wife broke her hip on 21 December 2020, had a total hip replacement on the 23rd, and was discharged from hospital after physiotherapy on the 31st. A CT scan was needed to make the definitive diagnosis of the fracture (Allan Cormack, Godfrey Hounsfield:; Nobel Prize for the development of computerised tomography, 1979).

CT was used to diagnose pneumonia in patient number 1, admitted to hospital in Wuhan on 27 December 2019. Traditional virology – cell culture using human airway epithelial cells – showed that there was something infectious in lung washings, and electron microscopy (Ernst Ruska: Nobel Prize, 1986) showed coronaviruses. The electron microscope technique used was negative staining, invented by Sydney Brenner (Nobel Prize, 2002) and Bob Horne, and used by June Almeida at St Thomas’s in 1966 to discover the first human coronavirus. The polymerase chain reaction (Kary Mullis; Nobel Prize, 1993) was used to rule out 22 known pathogens. The results of genome sequencing (Frederick Sanger; Nobel Prizes, 1958 and 1980) were published on the Global Initiative on Sharing All Influenza Data website on 12 January. The coronavirus was new. The Wuhan lockdown started on 23 January.

In the mid-1980s, Brenner said that for ten years biology had been in a new epoch, AD, ‘after DNA’. Covid exemplifies its progress and application. In the olden days a virological diagnosis would be made by looking for the causative virus by growing it in susceptible cells, or directly by immunological tests or electron microscopy, or by measuring antibodies induced by the infection. Coronaviruses don’t grow well in cell cultures and antibodies take a couple of weeks to appear. The gold standard and commonly used test for the causative virus in Covid cases is RT/PCR, in which virus RNA is converted into DNA by the reverse transcriptase enzyme, discovered by Howard Temin and David Baltimore (Nobel Prize, 1975).

Brenner was a big advocate of the Human Genome Project. It started in 1990, took ten years, and cost $2.7 billion. But in 2008 genome sequencing costs started to fall like a stone, outpacing Moore’s Law, and by 2015 enabling the $1000 human genome. Sequencing a bacterium or virus genome costs twenty times less than that, giving a massive boost to genomic epidemiology.

The UK Covid-19 Genomics consortium (COG-UK) was established in March 2020 with a £20 million grant from the Department of Health and Social Care, UK Research and Innovation and the Wellcome Sanger Institute. So far it has sequenced more than 100,000 genomes and identified hundreds of variants. Of particular concern are B117, first seen in England in autumn 2020, and 501YV2, identified in South Africa. Mathematical modelling has calculated B117 to be more transmissible than its precursors. Directly measuring the transmissibility of a virus spread from person to person by the respiratory route could be done experimentally by infecting immunologically virgin volunteers. It is very unlikely that any ethical committee would give its approval. So such a measurement is trans-scientific; a question that can be asked of science but cannot be answered by it.

The hypothesis of increased transmissibility would be supported by evidence if individuals infected with B117 excrete more infectious virus, or are infectious for longer, or cause bigger outbreaks, or cause them more often; or if virus particle infectivity lasts longer in the air or on fomites. Information about these things is awaited. Another possibility is that the number of virus particles needed to start an infection is smaller – another question that could only be answered accurately by volunteer studies. Seventy years ago, the infectious dose and pathogenicity of Salmonella were established after ‘human volunteers were secured at a nearby penal institution’ in Chicago. That example is unlikely to be followed.

Brenner called the traditional hunt for mutants ‘forward genetics’: mutations were precisely identified by their effects before the genes containing them were identified. ‘Reverse genetics’ is done the other way round. Brenner also described a third form, ‘perverse genetics’, in which everything is done by sequencing and computers without much recourse to biology. Covid-19 mutant hunts haven’t moved far enough away from this for my liking, yet.