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Staying a step ahead of the virus

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Back in 2002, SARS (Severe Atypical Respiratory Syndrome) was rampant in Asia and threatened to spread to other continents, including Europe. At the time, and more by luck than design, a sample from a patient affected by the disease found its way into the hands of virologist Christian Drosten. Working with colleagues, he was able to identify the virus and developed a rapid laboratory test, virtually overnight. Prof. Drosten did not hesitate in making his results available to the rest of the world. Three years later, he was awarded the Order of Merit of the Federal Republic of Germany (Bundesverdienstkreuz) in recognition of this achievement. Now based at Charité in Berlin, the predictability of epidemics remains one of his primary interests.

Prof. Drosten, over the past ten years you have been busy establishing and leading the University of Bonn's Institute of Virology. What direction are you hoping to take with your work in Berlin?

Our research work is centered around the diversity and evolution of viruses. We want to understand how epidemics develop, and we want to be as prepared as possible for the next big outbreak. This area of research is known as pandemic preparedness research. In a globalized world, it represents one of the most wide-reaching forms of preventive medicine. It forms part of public health and involves working on infectious disease agents. As such, we are effectively following in the footsteps of Robert Koch and his work in Berlin. We still have an enormous amount of work to do in the field of basic research on the evolution and development of viral epidemics. I will continue to pursue this work as part of existing research collaborations. However, Berlin offers me something else, something very interesting indeed, namely the implementation of this research.

What possibilities do you see in relation to its implementation?

So far, diagnostic methods have made up the bulk of what the research has to offer public health authorities. Yet, basic research can offer far more advanced technological developments. When we get an outbreak at a hospital, for instance, we can do so much more than simply give a test result as ‘positive’ or ‘negative’. And soon, we are hoping to be in a position to tell the authorities:  ‘the virus in question has a high potential for transmission’. Infectious agents transmitted via the respiratory organs provoke the greatest fear among the general population. Charité is one of a number of centers currently developing new models for respiratory infections, which involve either lungs or a laboratory surrogate being infected with a pathogen. There has been a definite trend towards finding ways to determine whether a specific infectious agent, perhaps a recent arrival from Asia or Africa, should be classed as dangerous. This work performs an important function and directly serves the interest of public health providers. I am hoping to further strengthen and enhance this aspect of our work in Berlin.

It is also your aim to develop new research concepts. What direction would you be hoping to follow?

New concepts often develop as a result of the exploration of other areas of research which use a completely different approach. It is particularly interesting for me, as a physician, to discuss issues with ecologists, for instance; they have a completely different take on things, including when it comes to population-based processes. Occasionally, we try to use this approach in human epidemiology, such as when we were dealing with the MERS virus. MERS represents a typical example of animal-to-human transmission. However, as far as its evolutionary biology is concerned, it is far more complex than a virus merely passing a simple species barrier. Most of the serious viral infections originally came from animals, including those typically seen in humans, such as measles and the common cold. In most cases, these came from other mammals. What we really need to know is: how long has it been since they changed their primary host? A wide range of views exist on the matter, which need to be further examined and defined. Paleovirology and paleoepidemiology represent brand new areas of interest in this regard, and both are bound to deliver some surprising insights.

Clearly it is precisely these new concepts that we need to develop in order to understand current epidemics?

That is correct. Take the MERS virus, which continues to circulate in the Arab world. It was discovered in 2012, with our involvement, but has probably been around for much longer. It did not suddenly appear out of nowhere. What we know so far is: the virus affects camels, and is found wherever camels are bred, from Africa to India. Every so often, the virus will infect a person and cause a devastating outbreak – approximately 30 percent of infected persons will die. These events are referred to as spillover events, i.e. they refer to infections that spill over from animals to humans. The most important question, and one which absolutely needs to be asked, is: how many more attempts will it take for the virus to adapt to humans so well that outbreaks will no longer be self-limiting, consisting of just three to four transmissions before they stop? We do not really know how many mutations a virus of this kind has to undergo in order to become a human virus, in order to switch hosts permanently. In the case of a respiratory virus such as MERS, the inevitable result of this development would be a pandemic with a large number of victims. We are not yet in a position to predict the future, but we are working on methods that will allow us to gain better insights. It can also be helpful to have a look into the past. Recently, we discovered that one of the viruses responsible for the common cold came from the same source as the MERS virus, namely from camels. It had to undergo different stages of adaptation along the way, a development we can reproduce in the lab (see illustration below). What MERS is trying to do at each new spillover event, and what this particular virus has already done, is spread throughout the global population, most likely as the result of a pandemic. Is it possible that this pandemic was recorded somehow, in spite of the fact that nobody knew the identity of the infectious agent? It would be fantastic if we could determine through testing which infectious agents were responsible for triggering the pandemics of the past. We could then use this information to determine just how frequently the human population “catches” a new virus. Unfortunately, we are still very much at the beginning of this process. Growth of a human common cold virus in cultured cells (virus = green color, cell nucleus = blue color). Depicted next to it, the unadapted precursor virus seen in camels. According to laboratory tests looking at functional differences, the unadapted camel virus showed a good level of replication inside human cells, but showed limited capacity for transmission out of infected cells (from Corman et al., PNAS 2016*).

Viral epidemics and pandemics appear to be on the increase. Infectious agents are spreading faster and starting to get closer. What do we need to do in order to be optimally prepared for future outbreaks?

First of all, we need early detection. Approximately five years ago, we had what could be considered a test case in the Sauerland region of Germany. It involved the Schmallenberg virus, and resulted in severe limb deformities and other birth defects in lambs. What has emerged so far is that we are dealing with a new virus, that it is spread by midges, and that it swept through all of Europe after being imported from Africa. Investigators looked very carefully at whether it is capable of infecting humans. Thankfully, they found no evidence of this. Just imagine this sort of virus no longer being limited to hoofed animals, but infecting humans as well. We would have a catastrophe on our hands, similar to what happened with the Zika virus in South America. As for what we need to do, there are two things that are of paramount importance: firstly, we need to get our public health system to a point where it is no longer playing catchup but anticipating these events. For instance, we could ensure a complete diagnostic workup of every single patient, covering the entire spectrum of viruses, not just one or two specific pathogens. In terms of the technology available, we are nearly there thanks to next-generation sequencing, also known as deep sequencing. The second thing we need to do is take preventive measures. We need a preemptive plan that involves the development of antivirals, i.e. drugs and vaccines. A MERS vaccine is already undergoing evaluation. This is done with the simple aim of stockpiling it, to ensure it is available should an outbreak occur.

Your name is inextricably linked with the discovery of the SARS virus. What did you and the research community, learn from the SARS experience?

People keep saying that it was the first pandemic of the new millennium. It was certainly a warning shot, one that warned us of what was to come, and was then followed by H5N1 – or bird flu – and so on. The SARS scenario was straight out of a nightmare. It was obvious we were dealing with a new disease; it was obvious it involved pneumonia, and it was obviously contagious. Yet, researchers failed to find a viral or bacterial culprit. The epidemiological data showed us that the disease was spreading further and further, yet we had no infectious agent to look for. In terms of the technology available, we are in a far better position today. The technology I used at the time to identify the virus was rather primitive in comparison. I used an old technique that is very simple, and combined it with what was the first step towards a new technology now known as next-generation sequencing. The latter had not been invented at the time, so we effectively had to perform all of the steps involved by hand. What the international health care community learned from the SARS experience is that a new virus can emerge as a disease long before we have identified a virus or developed a diagnostic test. A virus appears out of the blue, taking the world by complete surprise because it belongs to a family of viruses so far only known to veterinary medicine. The moment it appears, the world is already facing a pandemic. Within the research community, this case certainly instilled a new level of respect for the systematic identification of new viruses, something that had not been taken terribly seriously before.

At the time you did not hesitate. You immediately made all of your data and the SARS test freely available to others. Was that because you found yourself in extraordinary circumstances, or was it because you see a general need for more open access resources for researchers?

At the time, there was a technical reason for why I was in a position to make details of the diagnostic test available to rest of the world. There was also a growing interest in communicating with other public health experts via the internet, for instance via ProMED-mail, an online blog site that allows infectious disease specialists to connect with colleagues from all over the world. We spent weeks sending out letters. These were exceptional circumstances, as it was considered a public health emergency. This was also a classic example of intellectual property rights being relinquished in the interest of public health. Not all developments since then have been positive. Disease outbreaks always result in attempts to restrict the flow of information. Many of these cases involve researchers who, instead of making the relevant data directly available to the public, endeavor to secure advantages arising from their publication.

What does the future hold for virology in Berlin?

Our initial focus will be to get the laboratories working. Naturally, as we are dealing with communicable diseases, this also includes high security laboratories. Within our own virology department, we will have a fully refurbished and modernized biosafety-level-3 laboratory. In conjunction with the Robert Koch Institute, we will be working on biosafety-level-3 infectious agents, and may later even progress to biosafety-level-4 agents. Lab-based epidemiology research will be one of our areas of research focus. This involves the study of the distribution of known and new viruses, particularly in humans, both at home and in faraway countries. This opens up new opportunities in the field of individualized diagnostic testing – and personalized medicine – and will be of huge benefit to patients at Charité, many of whom are seriously ill. As far as basic research is concerned, my main aim is to establish a solid research network dedicated to viral evolution, and to secure joint funding streams to support its work. Berlin offers many good starting points in this regard. We already have high levels of enthusiasm; we just need to connect up whatever missing links remain.

Professor Dr. Christian Drosten

After passing his State medical licensing examinations in May 2000, Christian Drosten moved to the German Red Cross (DRK) Institute for Transfusion Medicine and Immunohaematology in Hesse, where he completed a doctorate on the development of a high-throughput virus screening system for blood donors. Shortly after completing his doctorate, he moved to the Bernhard Nocht Institute for Tropical Medicine in Hamburg, where he specialized in Microbiology, Virology and Infectious Disease Epidemiology. During his time in Hamburg, he developed a research program dedicated to the diagnosis of tropical viral diseases. His discoveries include the infectious agent responsible for SARS. As its Founding Director, Prof. Drosten led the University of Bonn's Institute of Virology, from 2007 to early 2017. He is now the Director of Charité's Institute of Virology and Head of the Department of Virology at Labor Berlin – Charité Vivantes GmbH.

Institute of Virology

*Corman VM, Eckerle I, Memish ZA, Liljander AM, Dijkman R, Jonsdottir H, Juma Ngeiywa KJ, Kamau E, Younan M, Al Masri M, Assiri A, Gluecks I, Musa BE, Meyer B, Müller MA, Hilali M, Bornstein S, Wernery U, Thiel V, Jores J, Drexler JF, Drosten C. Link of ubiquitous human coronavirus to dromedary camels. Proc Natl Acad Sci U S A. 2016 Aug 30;113(35):9864-9. doi: 10.1073/pnas.1604472113.

Title photo: Volker Lannert.