Fighting pandemics with science

Biomedicine in the time of Covid

d'Lëtzebuerger Land vom 15.05.2020

Pandemics have decimated human populations since ancient times and until the 19th century, they were routinely considered to be acts of God. Yet, once it became clear that germs can cause disease, scientists realised that pandemics could be tackled. In this context, it is difficult to exaggerate the importance of the identification of microorganisms as agents of disease. The coronavirus disease-2019 (Covid-19) pandemic, which is caused by the Sars-CoV-2 virus, does illustrate the dependence of human societies on biomedical research.

In some ways, the current pandemic resembles the so-called Spanish flu pandemic, which erupted in 1918, towards the end of World War I, and lasted until 1920, causing the deaths of 20 to 50 million people in three waves, the deadliest of which was the second. Despite its name, the disease reached Spain only in May 1918, weeks and months after its appearance in France and the U.S. The reason why it became known as the Spanish flu has to do with the fact that the press of neutral Spain was uncensored and therefore free to report on the outbreak.

Then, as now, basic hygiene practices (washing your hands, covering coughs and sneezes) were advocated, populations were quarantined, makeshift hospitals were created, the usefulness of face masks was debated, and footballers played to empty stadia. Just like today, there was widespread hoarding, blaming, quackery and fixation on the numbers of the reported dead. Like Boris Johnson, British Prime Minister David Lloyd George was laid low by the disease for several weeks.

Yet one factor that has changed for the better is our understanding of disease. Compared to one hundred years ago, we now have many more means at our disposal for the long fight ahead.

The 1918 influenza pandemic killed Guillaume Apollinaire. Franz Kafka contracted the disease, but survived, only to die of tuberculosis six years later. After the death of his son Kingsley from the 1918 influenza, Arthur Conan Doyle started devoting himself to spiritualism. In 1920 Sigmund Freud published Jenseits des Lustprinzips, following the death of his daughter Sophie from the influenza. He put forward the idea of the ‘Todestrieb’, later acknowledging that Sophie’s untimely death had influenced him. Unlike Covid-19, this pandemic preyed on young to middle-aged adults.

For quite some time the bacterium Haemophilus influenzae was believed to be responsible for the 1918 influenza pandemic, though the outbreak was, in fact, caused by the H1N1 strain of influenza virus A. Incidentally, the viral nature of influenza only became known in the 1930s. Whereas the 1918 pandemic was caused by an influenza virus, the current pandemic is the result of infection with a coronavirus.

Significantly, since the beginning of the 21st century, three coronaviruses have crossed species barriers (probably from a bat reservoir via an intermediate host, with bats harbouring several thousand coronaviruses) to cause deadly pneumonia in humans: severe acute respiratory syndrome coronavirus (Sars-CoV), Middle-East respiratory syndrome coronavirus (Mers-CoV) and Sars-CoV-2. At least four other coronaviruses that are less dangerous, and cause around 25 per cent of common colds, have infected humans.

Coronaviruses owe their name, coined in the U.K. in 1968, to the spike-like glycoprotein that protrudes from the viral surface in a solar corona-like fashion, when viewed under a conventional electron microscope. Sars-CoV-2 enters human cells through binding of the spike protein to angiotensin-converting enzyme 2 at the cell surface.

While DNA, as the genetic material, became known in 1944, the genetic code and the role of RNA were elucidated in the 1960s. First methods for sequencing DNA and RNA became available in the 1970s and subsequent developments have dramatically increased the speed of sequencing. Often scientific advances which are crucial for public health originate in basic research and Covid-19 is no exception. Thus, first sequences of the RNA genome of Sars-CoV-2 became available within weeks of the emergence of the Covid-19 epidemic in China. Testing for viral RNA using quantitative polymerase chain reaction began immediately and several candidate vaccines were developed. Currently, at least six vaccines are being assessed for safety in people. Since the new virus is 79 per cent similar to Sars-CoV at the nucleotide level, it was given the name of Sars-CoV-2 (Mers-CoV is more distantly related).

Fortunately, the mistaken identification of the agent responsible for the 1918 influenza pandemic had no major practical consequences. At a time when antibiotics had not yet been discovered, many infected people were to die from secondary bacterial pneumonia. Now, however, the widespread availability of antibiotics means that bacterial pneumonia is only rarely the cause of death following infection with Sars-CoV-2.

Other viral pandemics have occurred in recent years. Thus, the Aids pandemic, which has been with us since 1981, has so far claimed the lives of 32 million people. It is caused by infection with human immunodeficiency virus (HIV, mostly HIV1).

HIVs are retroviruses with an RNA genome. They produce reverse transcriptase, which converts viral RNA into DNA that is then incorporated into the host cells’ DNA (while the genetic material of corona and influenza viruses is not incorporated into the host cells’ genome). Reverse transcriptase was discovered in Rous sarcoma virus, another retrovirus, in 1970. Without this work, it would have been difficult to make sense of Aids. In fact, sexual acquisition of HIV requires only a handful of viral particles. It is followed by a rapid burst of replication, which causes a dramatic reduction in the number of helper T lymphocytes, which play important roles in the body’s immune system and response to infection. Their reduction is the major cause of Aids.

Until 20 to 30 years ago HIV/Aids was uniformly fatal. Since then, thanks to combination therapies that inhibit viral replication, Aids has become a more manageable, chronic disease. The development of such antiviral treatments is a triumph of modern medicine!

Meanwhile, swine flu, the first pandemic of the 21st century, began in 2009 and lasted for about 20 months, killing around 19,000 people. Like the 1918 influenza pandemic, it was caused by an H1N1 strain of influenza A. Genome sequencing has shown that the new strain contained genes from avian, human and swine influenza viruses. When pigs become infected with more than one influenza virus, entire genome segments are reassorted, giving rise to new variants. At the time, it was feared that swine flu could turn into a serious health problem for humans. Luckily, this did not happen.

By the end of 2009 safe and effective vaccines against the pandemic H1N1 influenza strain were available. They contained either killed or weakened live virus. In the end, the virus responsible for swine flu was less lethal than those causing other pandemics, in that it killed only around 0.02 per cent of those infected.

In the meantime, annual seasonal influenza epidemics affect around ten per cent of the world population. Although most cases of disease are relatively mild, these outbreaks still cause around 500,000 deaths each year.

Whereas the 1918 influenza pandemic had a case fatality rate of two to three per cent, that of Covid-19 is believed to be 0.5 to one per cent. So far, we lack safe and effective treatments, hence the need for the current social distancing and lockdown. Ro, the basic reproduction number of a virus, has entered popular discourse, as has the concept of exponential growth.

In many ways, the current means of dealing with the Covid-19 pandemic are similar to what was used in the past, yet there is now light at the end of the tunnel. The expectation is that in due course effective vaccination and/or anti-Sars-CoV-2 chemotherapeutics will put an end to the nightmare that Covid-19 has become. Until then, we will have to live with Sars-CoV-2. Life as we know it is bound to change.

The present situation constitutes not only a health emergency, but also a major social and economic crisis, with implications for mental health. It is important to remember that infections tend to hit the economically disadvantaged hardest. For the future, large-scale testing for Sars-CoV-2 is of particular importance, with smaller countries being able to lead the way out of lockdown. Hopefully, no country will (have to) choose between its economy and the lives of its most vulnerable, largely elderly, citizens. Some of the most vulnerable have already been left exposed.

In the longer term, the current pandemic is likely to change many people’s work and social habits. We may realise that it is unnecessary for some city workers to spend several hours each day commuting between home and office. As a result, working from home might very well become the ‘new normal’. Will the Covid-19 pandemic mark the end of globalisation as we know it? Will future policies link the twin threats of climate change and new pandemics? Some would argue that new opportunities often rise out of a crisis situation.

Looking back, one has to acknowledge that the current pandemic has caught the world off guard, despite repeated warnings by global health experts. It will almost certainly result in the creation of stronger defences, with research into unknown pathogens and the development of antiviral substances being high on the list. Simultaneously, the relative ease with which the Sars-CoV-2 virus can spread through human populations, kill a substantial number of people and paralyse whole countries, makes one wonder about the potential future use of modified viruses, with an ‘optimal balance’ of virulence and contagion, as biological weapons.

Suddenly, biomedical sciences, especially epidemiology and virology, have moved centre stage. Since scientific research is about the unknown, it embraces doubt and uncertainty. A favourite aphorism of Max Perutz was: ‘In science, truth always wins.’ One is tempted to add: ‘eventually’, as establishing scientific truths often takes time. At one point we will know if infection with Sars-CoV-2 confers lasting immunity and if it can have long-term effects on health; we will have effective vaccines and we may have antiviral substances. But we cannot know when this will be the case.

Meanwhile, political decisions must be taken, and it is good to base them on scientific advice. It would be wrong, however, to believe that there is a single and undisputed body of scientific knowledge. In the current crisis, governments sometimes present incomplete scientific understanding as if it were the ultimate truth.

In order to thrive, science must be based on the open exchange of knowledge, which is why it is essential for the scientific underpinnings of political decisions to be made public. Without the possibility of peer review, science rapidly turns into wishful thinking and ideology. When faced with the unknown, scientists suffer as much (if not more) from ‘cognitive biases’ than others. At the outset, scientists in South Korea and Hong Kong saw Covid-19 as a disease like Sars and Mers, whereas many of their European counterparts considered it to be a severe form of seasonal influenza. The different death tolls speak for themselves.

On a wider scale, it is baffling that many countries failed to heed the advice of the World Health Organization, which was, from the start of the outbreak, to test aggressively (‘Test, test, test’), and to track and isolate as many individuals with Covid-19 as possible. If politicians and their scientific advisers disagree with this analysis, it should be incumbent on them to explain why. After all, how can one fight a virus when one does not know where it is?

Michel Goedert is a Programme Leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, and an Honorary Professor of Experimental Molecular Neurology at the University of Cambridge.

Michel Goedert
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