Covid-19 and the ILL (2020)
ILL expertise supporting research on the coronavirus (SARS CoV-2)
When we listen to the news, it is easy to get the impression that the current public health crisis has above all exposed a major lack of preparedness on the part of our societies in the face of the threat of new infectious diseases. And it is patently obvious that we could have done better to prepare ourselves. I personally believe that, in particular, more should have been done to prepare our healthcare system. However, despite these legitimate criticisms, we must also understand that we are better equipped than any generation before us to fight this invisible enemy. First of all, there is the robustness of our economy, which makes it possible to mitigate the effects of the vital social distancing measures that will save thousands of lives. Despite the lockdown measures taken to curb the spread of the virus, all essential goods and services can still be supplied and thanks to modern communication tools many of us can continue our professional activities by working from home. On top of this, there are the sophisticated diagnostic and therapeutic weapons that are becoming available to fight Covid-19 directly. One of the main reasons for this resilience is modern science, which of course is also at the heart of the ILL’s core mission. I am fully aware that all of this does little to relieve the pain and suffering of those most severely affected by this terrible disease but perhaps it helps us to keep our peace of mind.
When, on 26 October 1885, Louis Pasteur announced to the National Academy of Science in Paris the first successful vaccination of a 9-year-old boy infected with rabies, a viral disease which at the time was considered to be invariably fatal, he did not even know what enemy he was dealing with. If we compare this to our current situation, we see a very different picture. SARS-CoV-2, the virus which causes Covid-19, was deciphered as soon as it was discovered. Its full genome sequence is available on the internet. With the help of this sequence, the first test kits for diagnosing infection by SARS-CoV-2 were developed. The tests use a DNA-multiplication process that was developed in the mid-eighties and that you find today in all biological research laboratories. Researchers all over the world are working around the clock to develop alternative test protocols that are just as reliable but are faster, cheaper and useable at the point of care (take a look, for example, at what is being done by the Lyon-based company bioMérieux). They are confident that these tests will become available within the next few weeks. Artificial intelligence is being combined with the latest knowledge in cell-virus interaction and DNA manipulation to accelerate this development process. These tests will play an important role during the lifting of lockdown. And, of course, scientists are not only working on diagnostics, they are already looking for a cure. Thanks to our knowledge of the genetic code, many of the proteins that make up the virus have already been identified. Today, less than 3 months after the discovery of the virus, the three-dimensional structures of these proteins are already known, thanks, for example, to the use of synchrotrons (see Linlin Zhang et al., Science 2020, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors). This structural information is already being used to guide pharmaceutical research in search of inhibitors that will make it possible to block the virus’ vital functions, thus impeding its reproduction and helping those most heavily infected.
Let me now say a few words about how we at the ILL are contributing to these research efforts. I apologise in advance for some unavoidable scientific jargon and hope that you will bear with me to the end.
Neutron crystallography is one of the fundamental modern analytical tools for gaining insight into the life cycle of viruses. In simple terms, crystallography provides us with three-dimensional pictures of the various biochemical engines that the virus relies upon for reproduction. If these engines can be blocked, for example by introducing, through appropriate medication, a molecule into the site where the biochemical action takes place, then the viral disease can be cured. In many of the processes that these engines rely upon hydrogen nuclei play an essential role. This is where neutrons come in. Neutrons are ideal for detecting hydrogen nuclei in the structure of viruses. The ILL is the leading neutron facility in the field of biological macromolecular neutron crystallography. Recent studies on the HIV-1 protease (a biochemical engine which - like a pair of scissors - cuts long polymer chains and is essential for the life-cycle of the HIV virus) performed at the ILL’s instrument LADI illustrate this perfectly. The neutron data collected can be used to improve the design of the drug that blocks the scissors in their active site. SARS-CoV-2 offers many potential targets for this type of neutron study. Given the relevance of this research, the ILL has decided - in the framework of the Endurance upgrade programme - to enhance our capacity by adding another instrument (DALI) to its instrument suite. DALI was in the process of being assembled when the lockdown came into effect. The installation work will be completed once the lockdown has been lifted and the instrument will be commissioned during the next reactor cycle.
Many biochemical engines are made up of several subunits. To obtain an accurate picture of these so-called complexes, small-angle neutron scattering is a vital analytical tool. This is due to the fact that the larger the objects under investigation, the smaller the neutron’s scattering angle becomes when scattered by those objects. Neutrons also offer the huge advantage that individual subunits can be marked by advanced deuteration, making it possible to distinguish specific regions (RNA, proteins and lipids) within the complexes. With its excellent suite of small-angle instruments (D11, D22 et D33) and its outstanding expertise in applying them to biological systems, the ILL is perfectly placed to perform such studies on SARS-CoV-2.
Much of the action in a virus’ life cycle happens at the surface. Just as a spaceship docks onto a space station, so the virus must latch onto the cell it intends to infect and create an interlock through which it can dump its genetic material. In the specific case of SARS-CoV-2, which looks very much like a naval mine, the proteins in the spikes dock onto the epithelial cells in the patient’s airways by binding a special enzyme (ACE2) expressed - and therefore present - on the surface of those cells. A great deal of the research on SARS-CoV-2 will focus on these docking processes. Neutron reflectometry, which is the neutron technique sensitive to surfaces, has already shown us how this happens in the case of the hepatitis C virus, thanks to research performed in 2017. The ILL possesses a top-of-the-range reflectometry suite and outstanding expertise in applying this suite to the study of membrane systems.
And we should not forget that viruses are also highly dynamic systems in their physiological environments. Watching them in action by observing how their components move, deform and cluster is essential for optimising diagnostic and therapeutic processes. Neutron spectroscopy, a technique which is ideally suited for observing the motion of a wide variety of matter, from small chemical groups to large macromolecular assemblies, is the tool of choice for providing this information. A typical example is the study of the clustering of monoclonal antibodies. The ILL’s spectrometer suite, which includes the high-resolution spin-echo instrument IN15 used for studying biological processes, is second to none in this respect.
ILL scientists working in the field of biology are fully engaged in putting their expertise to the service of fighting Covid-19. A dedicated task force has been set up for this purpose. Its members are currently conducting intense discussions with their user community in order to identify the most promising experimental avenues to explore. The deuteration and crystal growth capabilities of the Life Sciences group and the membrane and soft-matter preparation opportunities offered by the Soft Matter Science and Support group are particularly important in this context. ILL Management has decided to give priority access to proposals related to Covid-19 research once the reactor has restarted.
I would like to finish on a more personal note. I am forever amazed by the tremendous strides we have made in recent decades in our understanding of the world around us and how this progress has empowered us to improve human life on earth (provided it is used in the right way!). Our capacity to react to the threat of Covid-19 in a way which previous generations could only dream of is just another illustration of how far we have come. While it is only natural that we would like to be even better equipped to fight diseases like Covid-19 and (why not?) even eradicate them altogether one day, I often wonder why we are not a little more grateful for what we have already achieved. The only explanation I have for this lack of gratitude is that, because of the lightning speed of scientific discovery, a completely irrational expectation has developed among us that researchers should be omniscient and provide answers instantly. Only yesterday I read in Le Monde a statement by the economist Robert Boyer that illustrates this attitude perfectly:
les épidémiologistes sont désarçonnés par ce nouveau virus dont ils ne découvrent les propriétés que pas à pas.
Honestly, what else would we expect if not a step-by-step discovery? And shouldn’t we be proud that this step-by-step discovery will probably only take a few weeks, or at most a few months? The global research community certainly deserves our pride and our gratitude!
- Quart de nuit
- [50 ans] LADI et biologie structurale
- [50 ans] La communication
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- D6 et Covid-19 (2020)
- Covid-19 et l'ILL (2020)
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- La détection des neutrons