Guided by chance

Prof. Dr. Ulrich Dirnagl, who is based at Charité's Department of Experimental Neurology, is a neurologist with a special interest in stroke, cerebral circulation and imaging technology. His work, which forms part of the NeuroCure Cluster of Excellence, involves both research and teaching. Prof. Dirnagl is also known as someone who 'builds new bridges', and considers chance occurrences a major driver of innovation.

Prof. Dirnagl, the majority of your work centers around solutions and insights from the field of stroke research. How did you end up working in this field?

One might say I stumbled onto it. I was based in Munich at the time, and working on my doctoral degree, which was based on the clinical care of intensive care patients, and saw me work with Prof. Dr. Karl Max Einhäupl. After my doctorate, there was a clear demand for more basic research, which did not really exist in this context. My remit at the time was to develop research models for meningitis and stroke – and it continues to hold me in its grasp to this day. I effectively stumbled into my field of expertise by chance. I am immensely grateful that I did, as the brain holds enormous fascination for me.

Do you understand the human brain and how it works?

No, not at all. That would be very presumptuous of me. One might even say that my field of research – stroke research – is a little bit like plumbing. Understanding the brain is one thing, understanding stroke is a whole different affair. We are dealing with blood vessels that have been blocked and it is up to us to unblock them. We are dealing with cells that are being starved of oxygen. What we need to do is to figure out how we can re-establish their oxygen supply, how we can get them to survive for longer, and how we can get some of them to regenerate. Basically, no, I do not understand how the brain works. I would even go so far as to say that anyone who claims to understand the brain is just showing off.

Are there any specific events or insights that you remember as particularly significant?

The sort of events that I consider milestones, or which prompt me to say: “wow, this is amazing,” are not associated with the field of medicine. I experience such moments when I hear that physicists are planning to find the Higgs boson in order to finalize their Standard Model. They then go on to build a linear particle accelerator and, a few years later, the combined efforts of a few thousand scientists involved in a huge experiment results in this particle being discovered. I can't say I have ever experienced anything like that in my field. This is partly due to the fact that the way we conduct research today means we often look into a small part of a larger issue. True paradigm shifts are extremely rare. Or, as the Americans might say: “The low-hanging fruits are rare...”. Perhaps we know too much already, and what is left is simply ridiculously complex.

What are you currently working on?

We are currently busy revisiting a question previously addressed in stroke care, but which now seems to offer new hope: whether we can take measures to successfully protect the brain. We refer to this as 'neuroprotection'. In Berlin, the introduction of the stroke emergency response vehicle (Stroke Einsatz Mobil, or STEMO) has opened up new possibilities for neuroprotection.  The vehicle is fitted with a CT scanner and manned by a neurologist. This allows us to reach stroke patients within half an hour, examine them immediately, and start treatment. We can also re-examine the question as to whether it is possible to protect the brain through neuroprotective measures. What is new here is that we can start this process at the earliest opportunity, immediately after the stroke. We now believe that previous studies involved treatments that were started too late. We are also busy studying what happens after the actual cerebrovascular event, i.e. what happens in the rest of the body. Deaths after stroke are often due to the patient developing pneumonia. We are trying to gain a better understanding of the nature of such complications, why they occur, and what we can do to prevent them. Regeneration is another area of interest. The brain is highly plastic. This means that, over time, the brain can reestablish many of the functions lost as a result of damage. We are trying to establish the exact processes involved in this, i.e. how one region of the brain can take over the function of another, how brain circuits are rewired to make new ones, and how we can used drug-based and non-drug-based treatments to support these processes.

Is there a specific hypothesis you are currently pursuing or one that you find particularly fascinating?

We currently believe that the adaptive immune system and its main component cell type – the lymphocytes – play a crucial role in stroke; we believe that this role extends to stroke-related damage, protection and regeneration. This is an entirely new area of research. We know from research into multiple sclerosis that the immune system can attack the brain, so we are already familiar with many of the mechanisms involved. We have established that stroke involves major immune system activity. The next exciting step will be finding out what researchers in the field of multiple sclerosis already know about the way in which the brain and immune cells interact. An interdisciplinary approach will make this next step particularly interesting. Currently, our research focuses on rather small sections of the overall subject area. Personally, I believe that the different fields of research can complement and enhance each other. Spinal cord injuries, for instance, make up a huge field of research in their own right, as do stroke and multiple sclerosis. What can we learn from related research areas, and what can we learn from areas whose focus is far removed from our own? Looking at what cardiology and neurology researchers were doing used to be a well-kept secret among neurology researchers. Nowadays, we no longer just 'look' at what they are doing, we actually work with them.

You are sometimes referred to as someone who 'builds new bridges'. Is this why? The idea of bringing different disciplines together and expanding one's thinking beyond the limits of one's own discipline?

We will probably need a wide range of different approaches if we are to achieve success together. There are some researchers – and I am full of admiration for what they do – who go into minute detail. They spend many years, perhaps even their entire research careers, studying one specific mechanism or process, and produce the most amazing findings. For me, one might say the reverse is the case. I will start by taking five steps back, allowing me to look at a particular phenomenon from a distance, get a bird's eye view, as it were. I look for the full picture and wider context. Only at the very end do I look through the microscope. The crucial point, however, is that our local research environment represents a healthy mix of all that is out there. What we have here at Charité, the MDC, and other Berlin-based research institutions, is simply fantastic. The atmosphere within the field of neuroscience is extremely open and focused on collaboration, allowing us to bring together clinicians and researchers specializing in synaptic plasticity – people who study fruit flies with people who treat dementia patients. You will find them sitting side by side, talking and cooperating on research projects.

How do you explain all of this?

I have never seen this sort of thing anywhere else, not to this extent. One of the reasons behind it is that Reunification acted as a sort of 'reset button'. Everything simply started from scratch, and people were quite willing to take risks.  Sites that have benefited from a long and uninterrupted history also boast researchers with well-established research histories and findings. We, in contrast, are blessed with the right kind of people. The NeuroCure Cluster of Excellence is a perfect example of this. It is an absolute pleasure to see how everyone pulls together and contributes to our inter-disciplinary research aims. The degree to which close collaboration is encouraged between clinical practice and basic research is quite unique.

One of your key objectives is to improve academic standards and the quality of pre-clinical research. What are the main issues involved?

There is one question that has been on my mind for a very long time, particularly in relation to stroke research: how is research being conducted? Is what we are doing – here in our own laboratories, as well as globally – in the best shape it could be? Do we have the right approach? Can we continue as we are and expect to see a breakthrough at some point, or are there things that we might improve upon? There is a myriad of wonderful articles out there reporting on our findings. However, many of the experiments are difficult to replicate and even more difficult to translate into clinical practice. The field of stroke research is a particularly stark example in this respect. Of the many studies conducted on animals, which have all shown amazing effects, only very few have been translated into patient care. The good news is that, for some years now, the biomedical sciences have been busy discussing possible ways to improve the situation. The field of meta-research contributes to this by evaluating our progress.

Bias – a phenomenon that might be referred to as researchers indulging in 'wishful thinking'. Can you explain how this happens and what the potential consequences are?

Dead nerve cells appear red, while living cells appear green. Photo: Experimental Neurology, Charité - Universitätsmedizin Berlin

I am convinced one of the main drivers behind our work is a type of wishful thinking, or bias. A researcher has to be convinced that their hypothesis is correct; they are bound to want this more than anything else in the world. They have to feel a fire burning inside of them. Without it, they'd be nothing more than an opportunist or even a bore. Bias – yes, please, as much as possible. However, it needs to be kept under control. One has to be aware of one's wishful tendencies. As a research scientist, one has to be able to look at oneself dispassionately and one has to be able to say: I firmly believe this to be correct. However, I must free myself from this belief in order to prevent my belief contaminating, and interfering with, my results. This is not an easy thing to do, but researchers have developed methods that are aimed at decoupling results and bias. These include randomization and blinding procedures. Someone who looks through a microscope usually knows exactly what type of tissue they are looking at, and what type of experimental manipulation it has been subjected to. It is in situations such as this that bias can rear its ugly head, as one may be tempted to count a few extra cells where one would like to see them. This has nothing to do with forging results; it is simply the way our brains work. And yet, the question of how I can minimize the likelihood of fooling myself as a researcher does not get asked frequently enough in practice.

Challenges related to bias: Dead nerve cells appear red, while living cells appear green. The experiment involved treating the cells with a drug intended to act as a protective agent. The researcher now has to determine the ratio of red to green cells. If the researcher is aware that they are looking at a cell culture that has been treated, they might interpret faint red or green staining in a way that fits the aim of the study, and count them accordingly.

What lessons do you try to instill in your young researchers in regards to this?

It doesn't require magic to control bias. The biomedical sciences have to show greater engagement with the issue. There also needs to be greater consistency in how we deal with it. Doing so will improve the overall robustness of data. We need people who are competent in methodology. We need better guidance, transparency and, in my opinion, we need to have a little more control over it all. Close engagement with this issue quickly results in concrete instructions for researchers, such as randomization, blinding, as well as clear definitions of inclusion and exclusion criteria, which one must stick to. Then there is the pre-registration of research studies, which prevents researchers from re-defining a study's aims and findings at a later stage, thus making it impossible to make findings fit their expectations. Many of these things are standard requirements in clinical trials. In basic research, however, these tend to be the exception. I also think it is essential for neutral or negative findings to be published. This means the publication of data from studies that fail to deliver the sort of results one might have anticipated or wished for. Some of these rules and guidelines are a little inconvenient; research becomes more difficult, takes longer, and is more expensive. Strict adherence to these rules may also result in fewer spectacular findings. Then again, biology is not really a black-or-white affair; it has more of a grayish tinge. There is absolutely no way of getting around the issue; research resources are limited.

Does this mean we will produce fewer results, but results will more robust?

That is exactly how it should be. There is something else, which I consider of enormous importance: sometimes, the results that appear out of place or inconvenient end up being the ones that trigger the greatest advances. It's the serendipity principle. A chance occurrence will catapult us into a situation that turns out to be incredibly exciting. This, however, is only possible, if one is open to chance occurrences. Or, according to Louis Pasteur: “Chance favors the prepared mind.” Someone who is trying to tell a story by painting everything black-and-white, and who suddenly encounters something gray, may be tempted to simply leave it out of the story. Alternatively, they may be tempted to repeat the experiment until they find something that is black or white. My own research work, and that of my colleagues, has taught me that the most exciting stories we ever had were those, which started by chance; they were always very different from what we might have expected or possibly even looked for. Those who were obsessed with finding out why there was a difference between the observed and the expected were the ones who ended up making new and important discoveries. I consider the ability to be prepared for what is new and different to be an essential quality in any researcher. Another quality, one that is related to this and is just as important, is skepticism. A research scientist has to be driven by curiosity and skepticism in equal measure. Scientific advances are made when what previously appeared to be an established truth is disproved and rejected. And when one encounters a study that is impossible to repeat or replicate, the best-case-scenario is actually that one will end up finding something new. That is how science works.

In what way does your work on, and your insights into, the brain influence your attitude to life?

One thing that has become increasingly clear to me over time is just how complex everything is. Biology as a scientific discipline, our research concepts, the challenge of applying findings to patients, the sheer number of things that can go wrong in the process and, finally, just how naive we are in how we approach things. At the same time, it is absolutely essential that we maintain our naiveté. Without it we would descend into despair and, while we may take only tiny steps, these do gradually get us closer to our goals.

Professor Dr. Ulrich Dirnagl

Ulrich Dirnagl read medicine at LMU Munich (Ludwigs-Maximilians-Universität München), where he later worked as a research associate in the Department of Neurology before moving to the United States to take up a post at Cornell University. Upon his return to Germany in 1993, he moved to CharitéUniversitätsmedizin Berlin. He was appointed Director of the Department of Experimental Neurology in 1999. He is currently a Member of the Board of Directors of the NeuroCure Cluster of Excellence, Director of The Center for Stroke Research Berlin (CSB), Clinical Coordinator of the DZNE site in Berlin, and Program Director for the international MA/MD/PhD program in Medical Neurosciences.