Genome sequencing: how good is Germany at finding mutants?

The day Sikhulile Moyo discovered the omicron variant of the coronavirus began as everyday as any other. Or at least as ordinary as a virologist’s day in the middle of a global pandemic can be. On that November 19th, Moyo prayed with his family as always, swallowing his cereal, then jet to his work place at the Bostwana Harvard HIV Reference Laboratory while listening to gospel music. There the virologist and his team checked the PCR tests of the positive corona samples – also routine. The team then processed the genetic material taken from the samples to check whether the virus had changed significantly.

The procedure that scientists use for this is highly complex and has found its way from the laboratories to the public under the name of “genome sequencing”. According to the German Center for Infection Research, this is used, among other things, to “examine outbreaks of pathogens”. In the pandemic, researchers are trying to use sequencing to monitor the further development of the coronavirus. This permanent observation, comparable to an early warning system, is also called “Sentinel Screening”. In this way, for example, new virus variants can be identified.

Indian researchers discovered the delta variant as the last mutant of concern. It had established itself worldwide by the end of 2021. Its successor is the omicron variant, which the South African research team around Sikhulile Moyo discovered in November. Just before closing time, when routine sequencing was done, they made a worrying discovery. “There were four sequences that showed very strange patterns that we had never seen before. I felt a lot of emotions in my heart,” said Moyo looking back in the paper “Aljazeera”. Further investigations gave the team certainty: A new variant with at least 30 mutations in the spike protein was in circulation.

Does Britain sequence so much more than Germany?

Since then, Omikron has spread rapidly. In Germany, too, the virus is well on the way to becoming the dominant corona variant by mid-January at the latest, estimates Oliver Harzer, doctor and managing director of the Bioscientia laboratory in Ingelheim. It is one of 29 laboratories that perform around 14,500 sequencing operations per week. According to the laboratory manager, around 11,000 of these are in six larger private laboratories. “The rest is spread across universities and smaller private laboratories across the country.”

Lead in the UK, often cited as a pioneer in genome sequencing according to the National Health Service (NHS) seven laboratories performed this procedure. The NHS was able to determine how many corona samples are sequenced each week star-Inquiry did not say, but referred to the company Genomic England. It brings together 100,000 projects that examine the genetic makeup of patients with rare and tumor diseases. According to its own information, the company wants to expand the medical understanding of how diseases work, who is particularly susceptible and what therapy options there are.

Sequencing has been a tradition in Great Britain since DNA was deciphered by a British and an American at Cambridge University in the 1950s. This was of particular benefit to the genome detectives during the corona pandemic. The British government has invested tens of millions in genome analysis since the start of the pandemic. It is not entirely clear whether the UK is doing better than Germany when it comes to sequencing. One star-The request for sequencing of corona samples was left unanswered by Genomic England. According to British and German media reports, however, around twenty percent of all positive corona tests are sequenced in Great Britain. The Federal Ministry of Health did not answer questions about the current situation in Germany.

Also a question of resources

In any case, Oliver Harzer from Bioscientia can hardly imagine that the British would completely sequence more corona samples than their German colleagues. “If you know how complex and time-consuming this whole process is, then I tend to believe that there is a confusion of terms here.” A distinction must be made between whole genome sequencing (WGS), in which the complete virus genome is sequenced, and variant typing (exome sequencing). Only those sections of the virus genome that contain the mutation in question are examined.

With whole genome sequencing, it can take between 48 and 72 hours from the time the sample is received to the final result. Therefore, from a number of 70,000 positive corona cases, only five percent of all positive corona samples in the laboratory are fully sequenced within a week. “That is enough to discover new variants at an early stage.” In fewer than 70,000 cases, 10 percent of the positive corona samples are sequenced. Anything else would not make economic sense and would have no additional benefit. The main purpose of the procedure is to monitor the background. “In the end, the main thing is to discover variants at an early stage that could be of relevance.”

If a relevant variant is discovered during full genome sequencing, the laboratories carry out what is known as variant typing, for example to identify how quickly the variant is spreading or whether the clinical pictures change as the specific variant spreads. Harzer explains the difference between the two methods as follows: “With full genome sequencing, we read the entire book, so to speak, while with variant typing we only look at a certain page or paragraph on which the mutation, i.e. the critical change, can be found” – so only a certain section in the genome.

At the same time, the amount of sequenced samples is also a question of resources. A full genome sequencing costs 220 euros – rather inexpensive in view of the effort involved. The prices for variant typing are lower. This amounts to between 40 and 50 euros per analyzed sample. Private patients pay a little more than statutory health insurance patients. Above all, technically speaking, the laboratories cannot afford to carry out both procedures excessively, because there are no separate machines available for both. If full genome sequencing is performed, the devices are manned for three days, so variant sequencing has to wait.

Sequencing – not just scientifically useful

The corona samples are currently being examined for the two Variants of Concern (VoC) Delta and Omikron. The variant typing can be used to determine which mutant is spreading more strongly. “This then puts politicians in a position to decide which protective measures are necessary and what the country has to prepare for,” says Harzer. His laboratory in Ingelheim was most recently commissioned by the state governments in Saarland, Baden-Württemberg, Rhineland-Palatinate, Berlin and Hesse with the variant typing. In this way, politicians can get an idea of ​​the current distribution of the Omikron variant in their respective federal state. “This is important because both the state governments have to make appropriate state regulations and the federal government has to be able to curb the picture in the state.”

Harzer sees the German research landscape as well positioned in this regard. “As a medical service provider in the Federal Republic of Germany, coordinated by the RKI and at the request of the government, a good structure for sentinel screening was established at the end of the year before last.” So Germany cannot be said to be lagging behind other countries. “I rather think that we are proceeding in a very balanced and scientifically sensible manner.”

In this regard, Germany first had to develop. If, for example, corona samples have been sequenced in Denmark and Great Britain since the beginning of the pandemic, this method was only used in Germany a good year ago to combat pandemics. At that time, the Charité’s chief virologist, Christian Drosten, said in the NDR podcast: “It is enough to sequence a few viruses a week.” At that time, diagnostics was even more in the foreground. That has changed. In spring 2020, the DeCOI initiative of German scientists called for a better analysis of the genome data. A funding application was initially rejected by the Federal Ministry of Research, but was later accepted.

Mutants will continue to be identified in the laboratories in the future

Watching the virus change is not only of interest to politics. Pharmaceutical companies make use of the information in order to be able to adapt and further develop their vaccines in a timely manner.

However, Harzer does not believe that the end of the pandemic is approaching with Omikron. However, Omikron could help the pandemic condition develop into an endemic one, because the virus is more infectious than Delta. “This will ensure that many more people will be infected with the virus and that a certain basic immunity will develop in the population”, the laboratory manager. The virus has shown that it is very agile and can mutate quickly. “Why should this stop?”

You have to be prepared for the fact that new variants will appear in the future, which will hopefully provoke less serious processes overall. But variants that lead to difficult courses cannot be ruled out in the future. Harzer compares this to influenza. Here, too, there are years in which more or fewer people die from the virus – even if the numbers are not yet comparable with Corona at this point in time. However, the number of cases also depends on the mutations and the accuracy of the fit of the available vaccine, explains Harzer. “That the corona pandemic will finally be over this year and the virus will disappear is something that cannot be expected after the last two years.” At least it would surprise him personally – “Of course, it is not completely impossible either.”

Sources: “Aljazeere”, German Center for Infection Research, “The Independent”, DeCOI, NHS