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How neurons communicate…

Prof. Dr. Benjamin Judkewitz is driven by a sense of curiosity. He wants to see nerve cells at work: wants to understand how they are interlinked and how they interact with each other. Prof. Judkewitz was still a PhD student when he realized that many research questions remain unanswered simply because the necessary technology had not yet been developed. He accepted the challenge and developed a new focus for his research: the development of new optical technologies.

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Prof. Judkewitz, would you be able to briefly explain, in simple terms, what you and your team are working on?

Imagine if people were as transparent as jelly fish – the huge impact this would have on the life sciences. Instead of having to study tissue samples, tissue sections or biopsy samples, researchers would simply be able to observe living organs at work. Unfortunately, we are anything but transparent – we cannot even see through the skin. The major hurdle we are facing is light scattering within living tissues. It is the reason why we are working hard to develop new imaging techniques, which will allow us to overcome the problem of light scattering and enable us to see parts of biological tissues that have so far been inaccessible. As a neuroscientist, I am of course particularly interested in the tissues that are found inside the human brain. I combine this interest in biological mechanisms with an interest in new technologies and methods, in the hope of developing a new generation of optical microscopy devices.

What are you hoping to achieve with your research?

The Judkewitz Lab. Photo: Krupp-Stiftung/ Brigitte Kraemer

In almost all of the life sciences – be it in neurobiology, cancer research or developmental biology – the aim of research is to gain a better understanding of how a particular organism works. So far, we have been limited to, and limited by, the use of tissue preparations. Unless we harvest cells for tissue cultures or prepare tissue sections – say, from brain tissue – microscopical examination is limited to studying the surface of the organism, i.e. the skin. The crucial question, however, is this: how does the organism work when it is alive and intact, not divided into tissue samples or sliced into sections. In order to be able to answer these questions, we must improve those imaging technologies that allow us to penetrate deeper into living tissues. Of course, some of the technologies available are already capable of doing this. For instance, we have x-rays, magnetic resonance imaging and ultrasound-based technologies, but these work at an entirely different order of magnitude, where one single pixel of an MRI scan contains thousands of neurons.  Our current technologies allow us to study the macroscopic structures of the brain. However, they are incapable of providing us with the tools to discover how individual cells communicate. That is precisely what we are hoping to do.

How close are you to your goal? And what has been the greatest challenge?

We are hoping to gradually close in on our goal. There are many hurdles, but we are making good progress. The interesting thing is that many different disciplines are coming together in order to help solve the problem. Our group consists of biologists, neuroscientists, engineers, mathematicians and physicists. Together, we are working on further developing a technology that has really only been available for the past ten years, and which was originally developed by physicists who were studying titanium oxide particles. So, this was all very far removed from biology. It took a while before anyone could even contemplate using these kinds of methods in the field of biology, but we are now ready to do just that: to finally bridge that gap. One of the challenges we are facing is creating cohesion and cooperation within an interdisciplinary group of researchers. Every discipline has its own language and every member of the group has to learn how to understand and communicate with the others.

You are a biologist, a physiologist, a neuroscientist, and an engineer. Which of these do you identify with the most?

That very much depends on the environment I happen to find myself in. It also depends on what the people in my environment see when they look at me. During my time at the California Institute of Technology, surrounded exclusively by engineers, I was very much the biologist. However, when I returned to Charité, all of my colleagues from the biological sciences saw me as an engineer or a physicist. I would probably say that I am a biologist at heart, and that I do not merely develop these new devices because I happen to enjoy developing new gadgets. I do get a lot of enjoyment out of tinkering with microscopes and developing new techniques; however, my motivation for doing so is not borne out of a passion for taking things apart and screwing them back together again. I am motivated by the prospect of the biological research we will be able to conduct using these techniques.

You have set yourself an ambitious goal, which is effectively to “re-invent” optical microscopy. Are seemingly audacious goals a must if you are hoping to make an impact?

Sometimes, it is important to have audacious goals, even if this is not always an easy thing to do in today's research environment, where funding options for risky project proposals are few and far between. It is usually easier to choose a safer project, one that may not be as bold in its ambitions. In the United States, people are far more willing to support riskier projects. Naturally, the majority of these projects end in failure. However, those that are successful are truly groundbreaking. In Europe, things are perhaps slightly less extreme. Funding providers tend to like projects that are conservative in nature, and which carry fewer risks as a result. Both of these approaches are useful, and both are important.

Your project is certainly a risky one. Could it turn out to be groundbreaking?

As far as the work of my laboratory is concerned, it is impossible to guarantee that our project will break new ground. However, we will certainly do our very best to ensure it is successful.

You are using a process known as optical time reversal in order to overcome the problem of light scattering in living tissues. How does this process work?

Reversing the light scattering process Photo: Wiebke Peitz, Charité

If you direct a beam of light to go through a person's hand, this beam will be bent and scattered in many different directions – a fact that explains why hands are not transparent. By the time the light exits the hand on the other side it does so at different angles and in all possible directions: a process we refer to as scattering. Light can also be described as consisting of particles. Now, imagine that each particle exiting the hand is caught and sent back after undergoing a 180-degree turn. Each particle would effectively retrace its own path and, after traveling through the hand, would exit as a beam of light, in a straight line, at the precise location it started from. This is similar to what happens on a billiard table. Light particles, known as photons, are like billiard balls. At the beginning of the game, when the racked triangle of balls is broken by the cue ball, the billiard balls will disperse in all directions. The balls then bounce off the side of the table a few times, or collide with other balls, before coming to a rest forming a random pattern. If it were possible to send all of these balls back along the exact trajectories taken, they would go through the same collisions with the side of the table or other balls, only in reverse, and end up in the exact triangular formation they started from. It would be like playing a video in reverse. Just like in our game of billiards, light scattering is not a random process, but a direct result of the collisions that occur. All we need to do now is to figure out how to 'reverse the video' as it were. And that is precisely what we are trying to do.

It sounds like you will need to develop some rather complex devices in order to do so?

It may sound rather complex, but everything we need is already available. The components needed are lasers, cameras, and what are known as 'wave front modulation devices'. This technology is used in every video or image projector – it is the chip responsible for producing the actual image. As these are technologies used in the film and television industry, they are undergoing rapid developments and are constantly being improved upon. Because of this, they are also becoming increasingly more suited to our purposes.

How confident are you that your plans will lead to success?

Throughout my entire research career, I have never felt certain of success in any of my endeavors. A sense of certainty would probably take away some of the suspense. However, I do feel that a successful outcome would be a hugely significant step for our field of research. That is what motivates me to conduct this type of research. I am a neurobiologist – I want to understand how neurons communicate with each other, and how their interactions lead to things such as perception, learning, and memory. I am pretty certain that we will not have fully answered this question by the time I retire, but I am hopeful that we will have made a number of advances by then: that we will be able to observe larger neural networks inside the brain at the cellular level of resolution, and that we will be at the stage of testing our first theories regarding the manner in which these networks process information.

You have been back in Germany for two years now. Would you say you have been able to find your place within the research community?

I thought long and hard about returning to Germany, and it was certainly not an easy decision to make. I had my reservations from my undergraduate years, which I spent at a fairly conservative university, with a clear hierarchical order, which meant students did not really interface much with their professors. I did not want to become a part of this type of system. Luckily, I had the opportunity to find out more about the research environment that exists in Berlin and at Charité, where things are far more flexible. I was hopeful that a young professor at the start of his career might be able to have more of an impact here. It is perhaps partly due to the city's history that the local research environment is characterized by newer and less rigid structures. Berlin has an incredibly vibrant research community. Within my own field of study, Berlin is not quite at the top of the research rankings. However, if current developments continue, we are not far off.

Professor Dr. Benjamin Judkewitz

Benjamin Judkewitz is Professor of Bioimaging and Neurophotonics. He studied biology at the universities of Heidelberg and Berkeley, specializing in cell biology, biochemistry and zoology. After completing a PhD in Neurobiology and Physiology at University College London, he moved to the California Institute of Technology, where his research focused on photonics and engineering, and where he successfully completed the habilitation process. In 2014, Judkewitz became Head of the Bioimaging and Photonics Working Group at Charité's NeuroCure Clusters of Excellence.