The Foundation for Polish Science (FNP) celebrates its 25th anniversary this year. To mark the occasion, we have invited 25 beneficiaries of our programmes to tell us about how they “practise” science. What fascinates them? What is so exciting, compelling and important in their particular field that they have decided to devote a major part of their lives to it? How does one achieve success?
The interviewees are researchers representing many very different fields, at different stages of their scientific careers, with diverse experience. But they have one thing in common: they practise science of the highest world standard, they have impressive achievements to their credit and different kinds of FNP support in their extensive CVs. We are launching the publication of our cycle; successive interviews will appear regularly on the FNP website.
Development Depends on People
Professors Krzysztof Palczewski and Maciej Wojtkowski, who together conduct interdisciplinary research on the mechanism of human vision, talk to Patrycja Dołowy.
PATRYCJA DOŁOWY: You are both winners of the FNP Prize from 2012. You met at the presentation ceremony in Warsaw, talked to each other and decided to join forces. The collaboration you started back then has brought some very promising results. How did you get to this point? What were your scientific paths?
KRZYSZTOF PALCZEWSKI: Some time ago I graduated from the University of Wrocław, where I majored in Organic Chemistry. Biology had always fascinated me, but I wanted to understand biological processes at the chemical level. After graduation, I attended the Wrocław University of Technology, where I obtained a PhD in Enzymology. I continued my formal education as a postdoctoral fellow in the United States, and so began my career in the visual sciences. I worked at the University of Florida in Gainesville, then at the Oregon Health Sciences University in Portland where I first established my own research laboratory. For 13 years, I conducted research as a member of the faculty at the University of Washington in Seattle, and since 2005 I have been the director of the Department of Pharmacology at Case Western Reserve University in Cleveland. I used fundamentals of chemistry that I learned as a student in Poland to understand the visual system. I wanted to know how light is converted into visual signals; how these signals are modified as a consequence of different diseases; and how we can treat such diseases, both hereditary and acquired. To investigate diseases at such a basic level, you need to apply principles derived from chemistry and genetics.
You and your team were the first to crystallize and describe the structure of rhodopsin and discover the mechanisms causing macular degeneration in the retina, which leads to loss of vision.
KRZYSZTOF PALCZEWSKI: I studied different proteins which participate in phototransduction and the visual cycle. Key to these efforts were my interests in receptors, proteins that mediate cellular communication with the world. Rhodopsin is one of them. These proteins receive signals from the cellular surroundings and transmit them as biochemical events within cells. Owing to this process, cells can receive an external signal and respond to it. Understanding how these receptors work in the cell membrane is also extremely important in the context of seeking new drugs to treat disparate diseases. Most drugs act through such receptors. However, chemical analyses alone are not enough to realize the full picture. To observe the changes taking place in the eye over time, we need non-invasive imaging methods. Many such methods have been developed. Maciej is one of the most important pioneers in this field. It was personally gratifying to return to Warsaw and meet such a young, good-looking man (laughs). Professor Wojtkowski applies different aspects of engineering and physics to develop new methods of non-invasive imaging. He has designed and built a tomograph for examining the retina to observe pathological changes which occur during such diseases as glaucoma and macular degeneration. His devices have been manufactured and are currently used by physicians in the clinic. It was obvious from the beginning that we had shared interests, and we simply had to engage in a collaboration to more fully achieve our research objectives.
MACIEJ WOJTKOWSKI: I, on the other hand, became interested in vision by accident. As a student, I had the opportunity to go on a research trip to Vienna. At the University of Vienna, I acquired new knowledge from interacting with Professor Adolf Fercher and members of his research laboratory. They had expertise in both theoretical imaging and applied medical equipment. Imaging the eye was a big challenge at the time and involved a relatively small group of specialists. Fortunately, those scientists had formed a very elite, unrivalled team. I decided to become a member of this specialized group, which turned out to be an excellent decision. Vision is a truly fascinating subject. Sight is our main sense, it enables us to interpret the world, while on the other hand, in a cognitive sense, damage to the visual system restricts us the most. Eye diseases and their aetiology are still the subject of limited investigation. It’s mainly because they are mostly connected with ageing. The study of age-related diseases does not have a long history. In olden times, it was more important to know how to stitch someone up properly after they had been slashed with a sword. I first heard of Krzysztof Palczewski as one of the leaders in biochemical research related to how the eye functions. However, I wasn’t bold enough to contact such an important person. When I saw him at the FNP Prize presentation, I knew we were being afforded a unique opportunity. I immediately thought it would be great to work with and learn from Kris. There are Polish physicists involved in vision science, but there are very few groups studying visual processing at the biological or chemical levels. Of course, they include the team of Professor Tadeusz Sarna at Jagiellonian University, with whom we also collaborate. It turned out that Professor Palczewski was interested in new optical possibilities, so we were equally enthusiastic about meeting and the FNP meeting provided us with that opportunity.
Why was this so important?
KRZYSZTOF PALCZEWSKI: Access to the eye, even though it is transparent to light, isn’t easy. It is hard to obtain high-quality images of the eye, especially if you want to observe pathological changes taking place over many years. Also, if someone wants to develop a drug for any eye disease, they need a method for checking its effects, potentially over a lifetime. It makes no difference whether it’s the heart, the eye or other organ or tissue. For many organs, you can analyse blood, liver enzymes, blood pressure, heartbeat, etc. To analyse visual effects, we only have limited electrophysiological and imaging methods. You can apply these approaches to mice, but only observations of the human eye will reveal what happens specifically in humans. This makes functional imaging a key approach for diagnosing patients and finding a drug that will halt or reverse the disease process. Over many years Maciej developed different imaging methods, designing and making optical instruments. He has great people in his laboratory, which is critical for success. The aim of our collaboration is to develop the most innovative method for functional imaging of the eye. The last 15-20 years have brought incredible developments in this discipline. Before, there was only fluorescence. Fluorescent detectors were injected into the circulation and changes in the eye were then observed. However, you could only obtain images of blood vessels in the eye. Professor Wojtkowski is a pioneer in methods to evaluate other structures as well as the functional status of the eye. Principles in physics provide us with new means of using the interaction of different light wavelengths with matter to study endogenous fluorophores in the retina and thereby obtain functional information not attainable with current instrumentation. Therefore, we are able to develop new instruments to answer questions related not only to eye structure but to function as well.
What will the new technology involve?
MACIEJ WOJTKOWSKI: It turns out that if we use a laser that produces light largely invisible to the eye (infrared light) and shine it into the eye, our eye is capable of detecting the light along the same principle as when we use colour lasers: green, yellow, blue, i.e. visible light. This process takes place at the photodetectors: the rods and cones located in the retina of the eye. This is a process known in physics as two-photon absorption, very often used in microscopy. As a consequence of two-photon absorption, light is emitted from fluorophores in the retina and can be registered using optical detection. In our case, the eye itself is the detector that is activated as a consequence of two-photon absorption. Until now the scientific world (myself included) believed that humans were able to see the effect of two-photon absorption just twice in a lifetime: once with one eye and once with the other. The energy density needed for the effect to occur seemed so great that it had to destroy the retina. However, as sometimes happens in experimental science, it turned out by pure accident that we can see light that is safe for the eye, has no side effects and is strong enough for the ordinary vision process to occur. For us the eye is also good for checking the physical limitations of optics, because it is such an exquisite detector. The eye is also a very complex and sensitive projection of the brain. In fact, by studying the eye we can invent applications for any kind of microscopy methods, and we can do it live, in a short time.
Pictured: prof. Maciej Wojtkowski, photo by Magdalena Wiśniewska Krasińska
Did you yell: Eureka?
MACIEJ WOJTKOWSKI: We observed the effect but had no idea what to do about it. We didn’t fully understand what it was. And that’s when Kris paid our team a visit. This is an excellent example of how much we need a collaborator who knows everything about the eye. He saw our results and gave them a completely new meaning. He knew that the phenomenon we observed was something that should be studied and developed further. Professor Palczewski organized a group of international collaborators – an interdisciplinary team that quickly helped explain the phenomenon we’d observed. A paper on the subject was then published in PNAS (Proceedings of the National Academy of Sciences). Afterward, we started thinking about applications. As a consequence of our collaborative efforts, we are building a new device – a prototype, for use beyond the laboratory. The device will be able to shine infrared light onto the human retina. Patients will experience it as visible light, while we will be able to diagnose eye diseases in their early stages. That’s our goal. We are currently establishing collaborations with ophthalmologists to conduct clinical trials.
Are you starting to think about implementation?
MACIEJ WOJTKOWSKI: It’s true of all medical devices that before implementation you must be sure they serve a useful purpose. We are at the stage of developing a device that will help validate the usefulness of our technology. The validation requires collaboration with practicing physicians, which we are in the process of establishing.
Tell us something about this stage.
KRZYSZTOF PALCZEWSKI: It’s the most exciting stage in building a device. We will have the results soon; that’s the most interesting part of science. We already have sufficient data to anticipate that the device will be useful. It is no longer a concept in a lab. We have a prototype intended for use with people. My university has permission to use such a device, and so we are enrolling a group of patients with defined eye diseases to show what new possibilities our instrument offers compared to existing devices. In addition to clinical testing, I hope that within the next few years these new devices will not only be used for functional eye testing but also for more precise and sensitive imaging still needed for research purposes. Ultimately, completion of our objectives will enable us to diagnose and eventually treat diseases important from a social viewpoint, such as glaucoma, age-related macular degeneration and diabetic retinopathy. Maciej and I have made an excellent start, and I think it marks only the beginning of a long-term collaboration.
Does this mean that a collaboration showing great potential for fundamental research could develop towards building very useful devices?
KRZYSZTOF PALCZEWSKI: What you have in mind is what is known as ‘implementation research’ in Polish and translational research in English – translating what we analyse scientifically and experimentally into a specific application. I don’t believe it’s possible to plan a scientific project whose aim is implementation. That’s not science. The thing that Maciej and I and our teams have in common is that we can study fundamental physical, optical, biochemical, and pharmacological phenomena at the same time. Based on the knowledge derived from these studies, and taking into account prior knowledge and other factors, we can consider an application. To implement anything, you first need an in-depth understanding of and respect for fundamental research. Once you have that, you can start thinking about implementation. Two-photon absorption, for example, was discovered in 1931 by Maria Goeppert-Mayer, who later received the Nobel Prize (making her the second female Nobel Prize winner in physics after Maria Skłodowska-Curie), during work on her PhD. Maria Goeppert-Mayer theoretically proved the possibility of molecular two-photon absorption, but this phenomenon was not confirmed until the 1960s when the appropriate lasers were built. An application was not found until the 1980s. After that, laser technology developed extremely fast, enabling us to conduct our collaborative studies. By the way, Maria Goeppert-Mayer was born in Katowice and spent her childhood in Silesia. Her father was a professor of medicine, who contributed to overcoming a meningitis epidemic in Katowice in 1905. Her grandfather was a law professor, and a statue of her great-grandfather, also a professor, stands in Wrocław in the Botanical Garden which he created.
MW: When you work on interesting problems, ask the right questions, then sooner or later these questions lead to things that likely will be useful. Sometimes it’s a matter of usefulness on a scale of 200 years. That was the case with theoretical physics. If we really attempt to understand the natural world around us, then the knowledge we obtain will become useful one day and likely in a manner which could not have been appreciated at the first moment of discovery. That is also how I see the role of the Foundation for Polish Science – supporting and reinforcing the development of science. That’s why it’s so effective. Take our case. We can work, ask interesting questions, answer them, and at the same time do something useful. Our case shows that if you create the right conditions, everything moves forward freely in science. In this sense, today’s science is just like it always used to be. Someone stepped out of their hut, scratched their head and started looking under the mulch. They kept looking for something and finally found it, on condition that no one disturbed them and that they themselves wanted to keep doing it. If someone is interested in asking smart questions par excellence, then a collaboration develops naturally. It only takes a small fuse.
In your case, it was that meeting at the FNP Prize ceremony.
KRZYSZTOF PALCZEWSKI: The interaction between our teams shows how important the FNP is for the development of science, for linking different labs, in Poland and abroad. These collaborations established between Poland and both Germany and the United States, which are supported by the Foundation, are important not just for Poland but for science in general. Professor Żylicz and his predecessors have been extraordinarily inquisitive and persistent, managing to develop something that will benefit humankind. This isn’t a political statement, rather my personal and sincere thoughts. I see all the Foundation’s initiatives, and their standards and the people involved as very inspiring. The Foundation has done a great many good things. I am extremely grateful for the prize I received in 2012. I think it’s an excellent example of how unplanned and unexpected interactions can generate new knowledge. What Maciej and I are doing together, thanks to the Foundation, enables us to reach new insights and to develop innovations of the highest quality.
Pictured: prof. Krzysztof Palczewski (private archive)
KRZYSZTOF PALCZEWSKI: Our first instruments developed by combining the disciplines of engineering, physics and physiology will be able to detect functional changes in the retina indicative of a disease process much earlier than with current methods. Such instruments also will be able to evaluate the efficacy of new treatments and further the need for individualized medical care. These outcomes will be possible due to Professor Wojtkowski’s creative mind coupled with his collaborative spirit. He is a world-class researcher and the leader of a great team.
MACIEJ WOJTKOWSKI: It’s all about the hard work of people and trust. Kris is great at motivating people. I find it interesting to learn about his world, how great it is to manage such structures. Over here, we still have a ways to go.
Tell me about your teams.
KRZYSZTOF PALCZEWSKI: I’ll go first because I’m less modest. I have a large, about 20-strong team. Most of them work on crystallography and pharmacology. There’s also a group of 2-3 people involved in imaging implementation. My wife is one of the people in this group. I proposed to her many years ago because I thought it would be good to marry such a smart girl. Grażyna previously worked in Seattle at a Siemens lab. She learned a lot, working on acoustic methods. Many USG devices in US hospitals are her products. When we moved to Cleveland, she switched wavelengths.
MACIEJ WOJTKOWSKI: Grażyna Palczewska is an excellent manager of our projects. Together with my people she forms a very good optical team. Communication between us is excellent, thanks to which we get a lot done in a short time. My associate Katarzyna Komar is leaving for the United States right now, then Patryk Stemplewski. This exchange of staff is crucial. Grażyna also has industrial experience as well as excellent knowledge of optics and acoustic methods. This gives us additional knowledge on the final form of our devices. She is an expert in imaging small animals, too. From this July (2016) I’ve been assembling a new team at the Institute of Physical Chemistry of the Polish Academy of Sciences, to which I was invited as part of the CREATE project financed from the ERA Chairs European funds. Taking advantage of previous experience, I can create an even more professional and dynamic group. Moving like this is very good for motivation and enables one to shed the ballast of unnecessary habits. We already have a group of properly qualified people. That’s the heart. We provide the face.
KRZYSZTOF PALCZEWSKI: And the neck for medals. (laughs)
MACIEJ WOJTKOWSKI: For the development of science, promoting people is our most important goal. Science is very dynamic. When you look at the people we have helped develop as accomplished scientists, we have cause for satisfaction.
Does this mean there’s hope that things will improve in Polish science?
MACIEJ WOJTKOWSKI: Things will go as well as our ability to support the people who conduct research.
KRZYSZTOF PALCZEWSKI: I’d like to underscore once again: the strength of the FNP lies in supporting people. Constructing buildings and buying equipment is easy. Meanwhile, most of the funding from the FNP goes to people. All science is one. Its progress will depend on people, not buildings. We now have the third generation after World War II. A country thrives by supporting talented people. Also, there is no such thing as local science. The acquisition of knowledge is not national, it’s global. Young people need to be given a spark of interest in life. How do things occur? How do things work? How can this be changed? How can it be fixed? If we instil intellectual curiosity, the rest will develop by itself. After the kind of degradation that took place during the war, rebuilding everything takes time.
MW: And you need to take advantage of the resources that appear, enable people to work effectively. Often the difficulties lie in simple solutions related to management, the lack of which is a barrier to development. But all this can be handled. It just takes a little determination. You must fight for it, that’s all.
PROF. KRZYSZTOF PALCZEWSKI (born 1957 in Syców) heads the Department of Pharmacology at Case Western Reserve University in Cleveland (USA). A recipient of the FNP Prize in 2012 in the life and earth sciences.
PROF. MACIEJ WOJTKOWSKI (born 1975 in Włocławek) heads the Department of Physical Chemistry of Biological Systems being set up at the Institute of Physical Chemistry of the Polish Academy of Sciences in Warsaw. A recipient of the FNP’s START stipend (2003), the POWROTY/HOMING grant (2006), a European Young Investigator Award (EURYI) from the European Science Foundation, which in Poland was coordinated by the FNP (2007), a grant in the TEAM programme (2011) and the FNP Prize in 2012 in the mathematical, physical and engineering sciences.