Dr John Lee

Could the lockdown have side-effects no one has considered?

This virus is still evolving

Could the lockdown have side-effects no one has considered?
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‘Nothing makes sense in biology, except in the light of evolution,’ the splendidly named biologist Theodosius Dobzhansky wrote in 1973. It’s a good rule of thumb. Despite near-miraculous advances in medical science we remain biological beings, subject to biological laws. None is more central to our understanding of disease than evolution. Yet this theory remains poorly understood and poorly utilised in medicine. And an evolutionary perspective raises important questions about the drastic action we have been taking to confront Covid-19.

Most doctors are too busy dealing with the day-to-day deluge of cases to have much time for what they may consider abstruse academic ideas. I can see why: it’s hard enough to understand diseases, let alone think about how they might be changing as we watch. But we know a lot about viruses and their evolution, and this perspective seems relevant (if largely overlooked) now.

So far, in most commentary on this pandemic, it has been assumed that we are dealing with an unchanging threat. Sars-CoV-2 is a new type of virus that is attacking people, causing a disease called Covid-19. The extent of the threat is constant and can be assessed by examining what happened in places where the pandemic is ‘further ahead’. We know that a certain proportion of patients develop mild disease. Others suffer a much more severe infection. These figures are assumed to be a consistent feature of the new virus: it affects some worse than others.

But an evolutionary approach suggests a different view. What if there are different versions of this coronavirus — some less deadly than others? All viruses mutate. Typically, a rapidly spreading virus tends to become less harmful as it changes because this helps it survive. If the virus kills too many of its hosts, it is more likely to die out. If it becomes milder, it spreads further. Unlike some viruses that spread slowly and can be fairly quickly suppressed by case isolation, Sars-CoV-2 spreads quite easily. We know that it can evolve, because it has recently colonised humans. To understand why it is still evolving further, you have to grasp just how small a virus is.

Imagine a birthday balloon. A virus is smaller than this by roughly the same amount that the balloon is smaller than the earth (think about that for a moment: balloon, earth; virus, balloon). When a person is infectious with a virus, it is estimated that they may excrete 1011 virus particles a day. Even if 99.99 per cent of the particles were destroyed on contact with the air, there are still a huge number of infectious ones left.

These particles will not all be identical. Evolution is driven by inaccuracies in biological copying. Covid-19 is caused by a single-stranded RNA virus, a type particularly susceptible to copying errors. So much so, in fact, that viruses of this group are often referred to as ‘quasi-species’ because they are so variable. It’s likely that some particles of this virus infect their victims with a slightly less severe form of Covid-19, making them less ill. And so, on average, those people will be more likely to continue with their normal daily activities outside of a lockdown, going to work or out shopping. In short, they will be more likely to spread the virus to others.

In contrast, the particles that cause more severe Covid-19 disease will be spread less since the people who feel worse will circulate less. Hence the evolutionary effect: more severe versions of a new virus tend to decrease quite quickly over time, because the milder versions get spread around more. But change the circumstances — change the environment in which the virus exists — and it could go the other way.

Think about the lockdown. We have substantially reduced the number of people circulating in the community. If lockdown is working, and stopping the spread of the virus, it might be reducing the circulation of milder versions among the population, while at the same time concentrating people with the most severe disease in hospital wards. It is an assumption that those admitted to hospital have severe disease because they mainly have underlying conditions. But what if some of them also have slightly ‘nastier’ virus particles? We are bringing them together in one place where they can infect staff and vulnerable patients. We are giving an advantage to the ‘nastier’ particles in the hospital environment. Despite protective measures, we are helping them circulate at the same time as we slow the circulation of the ‘milder’ particles.

So, lockdown might actually be slowing the tendency of this new disease to get milder with time. Which raises an important question: might the lockdown be causing more harm than good — in this way as well as many others? Are our actions really helping overall? Or are they opposing a helpful evolutionary tendency of the virus, as well as economically hindering our ability to deal with it? The epidemiological models are silent on this. What’s worse, their predictions of how the virus behaves will be inaccurate if such an effect is present.

Lockdown was not a policy that ministers seriously considered using until a few weeks ago. It clearly has major medical side-effects that no one considered. There are obvious ones (which should have been foreseen) such as much vital treatment and investigation for people of all ages, but especially the elderly, being suspended. But there are also more subtle effects such as the one discussed here, which are harder to predict, but potentially very important.

This is why new medical treatments normally have such a long gestation period. Two and a half thousand years ago Hippocrates told us that medicine should ‘First, do no harm’, and this is still a key tenet. Making absolutely sure that the treatment is better than the cure takes a long time and requires that we carefully examine as many angles as possible. Unfortunately, in the rush to apply the lockdown treatment for Covid, this principle was the first casualty.

Hospitals create the perfect viral storm, containing everything needed for rapid evolution: huge numbers of reproducing units (the virus), an environment for rapid reproduction to take place in (patients and staff), and selection pressures (things that alter how the virus spreads, such as density of people, severity of disease, or length of survival).

All of this raises an important question: might lockdown be frustrating a helpful evolutionary tendency of the virus, as well as economically hindering our ability to deal with it? The epidemiological models are silent on this. Most studies so far suggest that this virus is not mutating in a way that meaningfully changes its nature. But we are learning more about Covid all the time.

A recent paper from China employed a more thorough sequencing technique than generally used to examine the virus from a small number of cases. Standard quick-but-superficial sequencing methods have already revealed more than 4,000 mutations in the virus. But the detailed method revealed 19 new, overlooked mutations in just 11 patients, and these mutations altered the infectivity of the virus. The most aggressive strain generated a viral load that was 270 times greater than the weakest one, and also killed cells fastest. This is the first direct evidence for the effects described above, namely that mutations in this virus can affect the severity of disease. And with such a maelstrom of mutation going on below the surface of standard detection methods, it is entirely possible that an intervention as drastic as lockdown could be having negative effects on the evolution of the virus itself that we don’t appreciate.

It’s also worth noting a couple of other points. One is that rapid mutation could easily frustrate attempts to develop an effective vaccine, as the virus mutates away from the immunological controls stimulated in the body by any given vaccine. This is why it is unwise to rely on a vaccine to map a way out of lockdown. The second point is that large differences in the initial virulence of the virus could explain why different places saw such large apparent differences in the severity of their epidemics. Even if we put aside the substantial differences in management of Covid between countries (and even in different regions of the same country), it is possible that local epidemics showed a ‘founder effect’. That is, some people brought back to their homes a more severe version of the virus than others.

Returning to lockdown, it may be that evolution of the virus is occurring anyway. If it is true that Covid-19 has already spread quite widely in the country, it is possible that lockdown won’t be having much additional effect on viral nastiness. (This is something that we should already have been examining with community testing.) But for now the question remains: is it better to lock everyone down in hope of reducing a wave of severe cases, but with no real understanding of the wider effects on the virus or society at large? Or would it have been better to adopt what’s often described as the ‘herd immunity’ strategy and let the virus continue to circulate among younger, fitter people, diminishing its severity, while doing our best to protect and support those with greater vulnerabilities? Should we be rapidly reversing lockdown to help the virus help us? In this view, spread of the virus by people with no symptoms is a good thing because it helps the virus get milder more quickly. We have embarked on a drastic path without even considering the possibility. Now, more than ever, we need robust and open discussion about whether we are on the right course.

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