1 Waar Leiden wij trots Science op zijn Our Talents & Discoveries OF 2013 de ontdekkingen van Faculty of Science Faculteit der Wiskunde & Natuurwetenschappen
2 Colofon Leiden Science, Our Talents and Discoveries of Editorial team Geert de Snoo, Ron van Veen, Marjolein van Schoonhoven Contributing writers Nienke Beintema, Willy van Strien, Anouck Vrouwe, Bruno van Wayenburg, Marcus Werner, Marjolein van Schoonhoven Photography Pim Rusch, Philip Mynott (photo Gerard van Westen) Florian Maucher (photo Sandra Scanu) Beeldbank Leiden University English translation Wilkens C.S., Marcus Werner Design Printed by De Bink Leiden Contact Faculty of Science, Leiden University Marketing and Communications P.O. Box RA Leiden The Netherlands All rights reserved: Faculty of Science, Leiden University. Privacy and publicity rights apply. Reproduction of (parts of) this publication is only prohibited after written permission from the publisher. Enquiries can be sent to:
3 Content 3 4 Facts & Figures 27 C.J. Kok Jury Award 5 Foreword Dean 32 Faculty Award for Education 6 C.J. Kok Awards and Faculty Award for Education 36 Awards and Prices in 2013 education 7 C.J. Kok Public Award 37 Science Campus 24 Awards and Prices in 2013 research 38 Our science community
4 Facts & Figures Institutes Institute of Biology Leiden Institute of Environmental Sciences Leiden Academic Centre for Drug Research Leiden Institute of Advanced Computer Science Leiden Institute of Chemistry Leiden Institute of Physics Leiden Observatory Mathematical Institute Research profile areas Fundamentals of Science Bioscience: the science base of health Translational drug discovery and development (National) Facilities Cell Observatory Hortus botanicus Leiden Lorentz Center Metabolomics Center NeCen Paramagnetic NMR facility Total turnover 100 ME Scientific staff 122 full professors 114 associate and assistant professors 165 Post doc s 640 PhD s (including guests) Graduate School of Science (MSc programmes and PhD) BSc programmes students Astronomy Bio-Pharmaceutical Sciences Biology Computer Science (including Computer Science and Economy) Life Science and Technology (joint programme with Delft University of Technology) Molecular Science and Technology (joint programme with Delft University of Technology) Mathematics Physics MSc programmes students Astronomy Bio-Pharmaceutical Sciences Biology Chemistry Computer Science (including Bioinformatics) ICT in Business Industrial Ecology (joint programme with Delft University of Technology) Life Science and Technology Mathematics Media Technology Physics If appropriate with MSc specialisations: Science Based Business, Science Communication and Society Education
5 5 Foreword Dean The Faculty of Science; Science for Impact! At the Faculty of Science of Leiden University we are aiming to excel in both research and education in a broad range of disciplines. In each of our institutes, mathematics, computer science, astronomy, physics, chemistry, bio-pharmaceutical sciences, biology and environmental sciences, the leading criteria in building a strong research and education portfolio are scientific impact, technological innovation and societal relevance. To enhance our impact and visibility the Faculty of Science has organized most of its activities around two large and recognisable profile areas: Fundamentals of science and Bioscience: the science base of health. These areas offer new opportunities for fundamental research across the boundaries of our disciplines and connect with important societal challenges. We are attracting top talent to Leiden from The Netherlands and abroad with our excellent research environment and high-tech facilities. This year, more than 120 of our PhD students successfully defended their thesis. We consider the start of the construction of the new Science campus (February 2013) a milestone in the further development of the Faculty. In recent years the number of BSc and MSc students enrolled within our Faculty has grown rapidly. We anticipate the number of international master students and PhD students in the Faculty wide Graduate School of Science to increase further. Teachers, tutors and students are intensely working together in our education programmes that are characterised by a strong interrelationship between research and education. We aim to challenge talented students, to inspire and amaze them and to educate them to become the successful scientists of tomorrow, who will be able to make important contributions to science and technology, and to a better global environment and society. We are proud of our science community, staff and students, and of their achievements and of the distinctions and awards that they have obtained in the past year. The Board of the Faculty of Science, Geert de Snoo Han de Winde Gert Jan van Helden Rembrandt Donkersloot
6 C.J. Kok Awards and Faculty Award for Education 2013 C.J. Kok Fund The C.J. Kok fund was formed from the assets of Mr C.J. Kok, biology tutor from The Hague, who was highly committed to the natural sciences. On his death in 1965 he left his entire estate to Leiden University. The C.J. Kok fund was established with this inheritance. In his will Mr Kok determined that annually both the Faculty of Science and the Leiden University Medical Center would be given the opportunity to use the fund s revenues to award outstanding performance to those demonstrating a pronounced, significant talent for mathematics or solving medical problems. The will also stated that the assessment of performance should be on pure scientific grounds and that no distinction should be made regarding rank, status, race, national character, origin, relationship and so on. C.J. Kok Awards The Faculty of Science grants two C.J. Kok awards annually: the C.J. Kok Public Award, also known as the award for the Discoverer of the Year and the C.J. Kok Jury Award, the award for the best PhD thesis from the past year. All institutes within the Faculty are given the opportunity to nominate candidates for both awards. Education Award Education and Research are closely interrelated in our Faculty. Mono-disciplinary education and multi-disciplinary cooperation give our students the competences they need to become the scientists of tomorrow. Excellent education is of inestimable value in this. Being able to translate research findings successfully into high-quality educational programmes at the Bachelor and Master level is of great importance to stimulate and enthuse students for science and developing a new generation of successful and motivated (natural) scientists. For this reason, in addition to the C.J. Kok Award, the Faculty also grants the annual Award for Education, a student initiative. Students from the education committees nominate tutors for this award. In a short presentation, they justify their nomination to the jury. The jury, comprising the chairpersons of the study associations and the assessor from the faculty board, subsequently assess each nominated tutor. Most of time it s a close call between two or more tutors, in that case the jury visits one or more lectures to decide who will be granted the award. Both C.J. Kok Awards and the Faculty Award for Education are presented at the Faculty s annual New Year s reception.
7 C.J. Kok Public Award Nominees Discoverer of the year Nienke van der Marel Leiden Observatory Diego Garlaschelli Leiden Institute of Physics Marco Streng Mathematical Institute Fons Verbeek Leiden Institute of Advanced Computer Science Sandra Scanu Leiden Institute of Chemistry Gerard van Westen Leiden Academic Centre for Drug Research Maurijn van der Zee en Chris Jacobs Institute of Biology Leiden Laura Bertola Institute of Environmental Sciences
8 Asymmetric dust tra Nienke van der Marel Leiden Observatory Our first response was: What the heck is this?, says Nienke van der Marel, a PhD student at the Sterrewacht astronomical institute in Leiden. When she and her colleagues analysed telescope images of a disk of dust and gas around a star, a puzzling asymmetry showed up. We really had no clue as to what we were looking at, Van der Marel says. By Bruno van Wayenburg The asymmetry turned out to be an accumulation of dust on one side of the star, an asymmetric dust trap. It a phenomenon important for the formation of planets from discs of dust and gas around stars, so called transition discs. The unexpected discovery resulted in a Science publication for Van der Marel and eleven co-authors. Nienke van der Marel (1986) studied Astronomy and Instrumentation in Leiden. She became a PhD student in 2011, working with astronomer Ewine van Dishoeck on transitional disks. The main goal is to resolve the molecular gas inside the holes of transitional disks, using millimeter interferometry with the Atacama Large Millimeter Array (ALMA). The first, surprising result became Van der Marel s first science publication. Initially, van der Marel dreamt of becoming a writer and later a science writer. After the experience of doing my own research and looking at things that nobody had even seen or done before, I truly became passionate with research. The original idea was studying the gas around the star, explains Van der Marel in her office in the Huygens-building. A conference poster is hanging on the wall, showing images of the transition disk. In such a disc, dust and gas can cling together and form ever bigger accumulations, pebbles and rocks, finally yielding full blown planets like earth or even Jupiter. That has happened in our solar system. And also around mamy other stars, as has become clear over the last decades, in which more than a thousand exoplanets have been discovered. The exact processes of planet formation, however, are still very much the subject of research.
9 9 p Coalescing of dust is a process that takes place over many different length scales. Dust particles smaller than a micro meter have to grow over twelve orders of magnitude to become earth-size planets. When they grow above 1 km, they start to attract each other by gravitation, but long before that, you have to solve the problem of growing up to 1 millimeter, says Van der Marel. For this to happen, dust particles have to collide so they can cling together. But colliding also means that they might fragment into smaller particles, which isn t beneficial for growth. And there is another problem, adds Van der Marel. By some subtle gas pressure effects in the disc, gas moves slightly slower than the dust particles. This slows down the dust by friction, so that particles fall down from their orbit, into the star, before they can even start to grow. Originally, Van der Marel and her colleagues wanted to image and research the special, ring shaped transition disc around Oph IRS 48 in the constellation Ophiochus. So they applied for observation time on ALMA, the Atacama Large Millimeter/submillimeter Array. ALMA is a new radiotelescope, consisting of 66 separate antenna dishes in the ultra-dry Chilean Atacama desert. It can image radiofrequencies from the universe with wavelengths around a millimeter. In that stretch of the radio spectrum, several molecules in gas clouds show up by characteristic frequencies. We wanted to image a particular peak in the gas spectrum, says Van der Marel, but by design, ALMA also delivers part of the neighbouring spectrum for free. That part of the spectrum show dust particles measuring around a millimeter. We expected that dust to form a ring-shaped cloud as well, but surprisingly, all of it was centered on one side of the star. First, Van der Marel and her PhD advisor Ewine van Dishoeck, didn t understand one bit of it. We thought: something must have gone wrong, so we checked and we rechecked. But the result didn t go away. So we switched to: Suppose it is real, van der Marel says. The researchers got in touch with Kees Dullemond at the Institute of Theoretical Astrophysics in Heidelberg, Germany, an expert in modelling gas and dust in transition discs. And he got all excited. This is fantastic, he said, Exactly what our models predicted. Models of ring-like transition discs where the inner part has been cleaned out by an earlier planet, show a certain swirling motion in the gas, called a Rossby instability. Mathematically, it s a relative of the meandering swirls of air in the atmosphere, but it s also related to the swirling of creamer in a cup of coffee. This slow vortex can trap dust on one side of the star, Dullemond s models predicted. Appropriately calles a Dust trap, this prevents dust from falling into the star. But, warns Van der Marel, that doesn t mean that the problem of planet formation has been fully solved now. As the dust particles grow, they will eventually escape the dust trap, she says, and they will spread out in a ring shape again. We ll certainly do more research into this, van der Marel says. New observation proposals have been filed already. We want to look at the disc again, and with better resolution, but we also target transition discs around other stars. The Science paper was Van der Marels first publication, I expect to publish more about this, but this was certainly a huge high point for me. Quite overwhelming.
10 Diego Garlaschelli Leiden Institute of Physics The angle, long before the banking cri The interrelationships between banks were changing long before the recent banking crisis materialized, theoretical physicist Diego Garlaschelli found out when he analyzed data from the Dutch central bank De Nederlandsche Bank. The discovery was news, says a modest Garlaschelli. It certainly was the changes went unnoticed in the analysis methods economists routinely use. By Anouck Vrouwe There, three years before the banking crisis exploded. Something s clearly changing there. Pointing to an angle in a graph, followed by a downward slope, Diego Garlaschelli recounts: The transition attracted my and my colleague Tiziano Squartini s attention. We realized how important it was when De Nederlandsche Bank researcher Iman van Lelyveld showed his enthusiasm for the result. We were collaborating on the project. So we abandoned the original research question, and continued with this. Garlaschelli is no economist. He even confesses to knowing very little about economic theory. Nonetheless, his latest research paper delves into the stability of inter-bank networks. But Garlaschelli has his desk at Leiden University s Lorenz Institute for Theoretical Physics. He s often been asked the why question, and has his answer handy: Economists work with economic theories. They want to understand why the market behaves as it does. I don t do that. I only study how the economy behaves. Garlaschelli is an Econophysicist a researcher who looks at interesting patterns in economic data from a physicist s viewpoint. The team-up with the De Nederlandsche Bank came about more or less by chance. A colleague of Garlaschelli s knew someone there, and Garlaschellli visited the bank to see if there was any shared ground in the research being done there. In fact there was: Van Lelyveld was looking into mutual relationships between banks. Banks loan each other money back and forth, and so form inter-bank networks. Garlaschelli happens to specialize on networks. He s familiar with the best analytical methods for dealing with such networks methods he himself develops, together with his co-workers. If I do my job properly, every project turns up two publications. One in theoretical physics, on the methods, and one in the field the methods are being applied in. In this case, the theory was already well-developed. Garlaschelli and Squartini wanted to test their analysis method on real data, from actual networks. We used the banking network here, but I analyze social networks too. And in the past I worked on the stability of ecosystems. Using the same methods. That s the beauty of my field. De Nederlandsche Bank provided Garlaschelli with data on the banking network in the Netherlands; all mutual loans from one and a half million euro and upwards, anonymised. No, we weren t hunting for early signals of the looming bank crisis. We were mostly playing with our methods and their
11 11 sis data, Garlaschelli confides. But then there was that exciting angle in the graph. A crook the economic models just didn t spot. Whereas formerly banks were loaning back and forth, hedging in case the opposite party would go bankrupt, the number of these back-andforth transactions clearly declined from 2005 onwards. For the explanation of these changes, ask the economists. But it has something to do with banks covering themselves less, Garlaschelli explains. Banks apparently judged their risks otherwise than before. How could economists have overlooked these changes? Garlaschelli: The economists at De Nederlandsche Bank also analyze these data, of course. They look at how much the real economy deviates from the models. They noticed a change in the network, too. But that was in By then everyone knew the banks were having problems. We were taking differences between banks into account a little more; that there are a few large banks that have many interactions, and many small ones with less interactions. We identified the dangerous debt-loops that remained invisible in the standard analyses. This is precisely the strong point of network theory, says Garlaschelli: You study indirect shifts in complex systems, at the same time taking important differences between parties into account. These indirect changes flagged strong warning signals of the coming crisis. Could he have foreseen the crisis, where the economists failed to do so? Woah, Garlaschelli returns. We re not Diego Garlaschelli (1977) studied Physics in Rome, his birthplace. He took his Ph.D. in Siena, Italy, on ecological networks. He followed this up with research on economic networks, in England and elsewhere. Garlaschelli came to Leiden in 2011; the university was looking for a university lecturer in Econophysics. This is a young field. It s nice that positions are becoming available. claiming we could have predicted the crisis. We re saying that the network changed in an unusual way, following a period of stability. I would be extra alert, if I were supervisor. For actual predictions, Garlaschelli would need more data, covering a longer time period and from other countries as well. The Dutch banking network is closely entwined with international banks. Van Lelyveld is now discussing access to foreign counterparts data. In the meantime, Garlaschelli is furthering his work on social networks. That s fun, too.
12 Marco Streng Mathematical Institute Faster number theor Complex polynomials related to elliptic curves are at the heart of current number theory research. Elliptic curves also have the interest of cryptographers, as they can be used to make cryptographic keys that are hard to break. The research of Marco Streng concerns curves that are more complex than elliptic curves. The related polynomials are too large to work with efficiently, but Streng is developing a method to simplify them. By: Willy van Strien During the first years of his studies in Utrecht, Marco Streng (1982) studied both mathematics and computer science, but he found mathematics more fascinating. He came to Leiden for his PhD research in number theory, then moved with his young family to Warwick (UK) for a post doc position, followed by another post doc at VU University Amsterdam. When he won an NWO-Veni grant, he returned to Leiden. Like many mathematicians, Marco Streng had no interest in mathematics at school. In fact, it was quite boring to him. But his participation in mathematical Olympiads, and the training before that, changed his mind. He discovered that mathematics was exciting, and now he is involved in challenging problems in number theory, combining analysis, algebra, and geometry with large-scale computer experiments. To explain his research, he starts with a problem that was solved more than 250 years ago: (which prime numbers can be written as the sum of two squares: p = x2+y2?) In number theory, we always start with prime numbers, Streng explains before giving the answer. For primes are the building blocks of all numbers: every number is the product of primes. They are easier to handle than non-prime numbers. It turns out that the prime numbers that can be written as x2+y2 are the sum of any number that can be divided by 4 plus 1. For instance, 5 (4+1) = 22+12; 13 (12+1) = So, the prime numbers for which the equation can be solved can be represented by a formula: p = 4a+1.
13 13 y, safer cryptography Number theory is full of such peculiarities that may seem magic, but that can be explained by theory. There also are formulas that describe the primes that can be written as x2+2y2, or as x2+3y2, etcetera. Mathematicians wondered how far this goes. They asked for instance: which prime numbers can be written as: p = x2+71y2? And they found formulas to describe the primes that obey such requirements. These formulas are polynomials, sums of several terms that contain different powers of the same variable v, each coupled to a coefficient a (a1, a2v, a3v2, a4v3, and so on). The polynomial for the equation p = x2+71y2 has eight terms and is surprisingly long. Its coefficients are so large that the formula stretches over several lines, Streng shows: And when you go further, you get coefficients that have thousands of digits. That is horrible to work with, of course. But Heinrich Weber ( ) found a way to reduce the coefficients considerably. Streng: The original polynomials are based on several symmetries. To reduce the coefficients, one needs to let go of some symmetries. But when removing too many symmetries, everything stops working, so there is a delicate balance. The polynomials that solve the x2+...y2 problem come from the theory of elliptic curves, which are curves of the form: y2 = x3+ax+b. Solutions of equations involving these polynomials can be transformed to elliptic curve descriptions, and vice versa. So, by reducing the coefficients in the polynomials, it becomes easier to create these elliptic curves as well. Elliptic curves are a hot topic in current number theory, but they also have the interest of cryptographers. Currently, websites, data and messages are secured with keys that are based on the product of prime numbers, which need to have several hundreds of digits to avoid being broken by hackers. Cryptography based on elliptic curves is an alternative that needs only a few dozen digits. A point on such a curve is agreed upon and operations are performed from this point to generate a secret code. According to Streng, it is as yet impossible to break such a key thanks to the complex algebraic structure of elliptic curves. And because such keys are much smaller than keys that are based on products of primes, communication would be much faster. Reduced coefficients in related polynomials make it possible to construct suitable elliptic curves faster and to construct more of them. When Streng attends conferences on elliptic curves, he not only meets mathematicians and cryptographers, but also employees of security and information agencies, illustrating the wide interest in elliptic curve cryptography. The idea is from 1985, and now Google is among the first to apply it, he says. His own research is ahead of these developments. It concerns curves that are more complex than elliptic curves, and the related polynomials, which also have very large coefficients. Streng is trying to find a way to reduce these coefficients, analogous to the work of Weber. For these curves this is more complex and needs more theory, but patterns are surprisingly comparable, he tells. He was already able to show that a reduction of coefficients is often possible, and now hopes to design a strong general method. If he succeeds, this would be an important contribution to number theory, and it would help provide an alternative to elliptic curve cryptography, involving even smaller numbers.
14 Fons Verbeek Leiden Institute of Advanced Computer Science Zebrafish, countless zebrafish Do you have more digital pictures than you could ever properly catalog? Biologists have a similar problem: their microscopes take image after image. Bioinformaticist Fons Verbeek develops computer software that orders and analyzes this digital horn of plenty. By Anouck Vrouwe Fons Verbeek apologizes for the piles of paper covering the meeting table in his office. All of the data, all the analysis programs, everything important is in my computer, he says: What s lying here can wait and then this is what you get. He had wanted to clear up. But it s been busy these days, the bioinformaticist explains. Verbeek likes doing several things at once, working simultaneously on several projects was a good year. Everything came together. Methods we had developed for the one project proved suitable for the other things like that. Many of my PhD students completed their thesis this year. The results of years of work became visible. Meanwhile, Verbeek is scrolling through his presentation, conjuring up superb movies of tiny fish with big eyes. The images are built up of green dots or colored surfaces. The fish revolve around their longitudinal axes, can be viewed from any angle. The three-dimensional images are of zebrafish: more precisely, zebrafish embryo s, transparent little animals that are used in genetics studies and in experiments in the field of developmental biology. Verbeek, pointing to the screen: Look, here you can see how tuberculosis bacteria are spreading through the fish. Not that Verbeek himself studies tuberculosis. His research group, Imaging and Bioinformatics, is part of the Leiden Institute of Advanced Computer Science (LIACS). But Verbeek does collaborate closely with biologists who perform these types of studies. Thanks to better and faster microscopes, biologists can gather more images than ever before. Beautiful pictures, folders full of them. They still need analyzing, though. The microscope used to be the bottleneck, nowadays the biologist is. You can t process all that by hand anymore, Verbeek explains. Ever growing stacks, just like the papers on his table: too much effort, too little time. Verbeek develops methods that can tackle the microscope images. Sometimes by adapting the microscope s software. This microscope rotates the specimen, the better to be able to compare images. Most often, however, it s computer programs that retrospectively analyze the footage, automatically. Verbeek demonstrates an analysis program that snips the zebrafish out of an image and measures it s length. It also recognizes body parts such as spinal chord and eyes. Just as security firms do face recognition, we do zebrafish recognition, Verbeek grins. Zebrafish-recognition software, outlandish though it may sound, is in demand. Verbeek has even started a small company to market the software. The foundation stands, refining it further is no longer scientific research. Wait, this is good too, says Verbeek, clicking his mouse rapidly. A film starts, showing vague white blobs in a dark background: Look, cancer cells. Biologists are interested in
15 Fons Verbeek (1960) is Associate Professor. He studied Biology, subsequently training in Computer Science, and taking a PhD in Applied Physics. Verbeek started his research career as a bioinformaticist at the Academic Medical Center (AMC), Amsterdam, moving on to the Hubrecht Institute for Developmental Biology and Stem Cell Research (Royal Netherlands Academy of Arts and Sciences), Utrecht, in As of how mobile the cells are an indication 2003, he is group leader Imaging and of the speed with which the cancer may Bioinformatics at the Leiden Institute of Advanced Computer spread. The software developed by Verbeek s Science (LIACS). group recognizes individual cells and follows them through time, then calculates their speed. It automates tiresome laboratory work. And then there is the Internet. Verbeek emphasizes the importance of new ways of presenting biological research data on the Internet in a comprehensible way. The everrising tide of publications is making it more difficult for scientists to keep an overview of their field of study. Research is specialist work, and biologists are often busy on their own little islands, not knowing how their work relates to other research islands. They appreciate having a clear picture of related work on the Internet. This is why Verbeek presented a zebrafish digital atlas in 2012, bringing together all the available research. It includes countless high resolution images, with explanatory keys to the body parts on view. The atlas also contains a database of genetic information, facilitating looking up which genes are active at any point in development. Presenting the information in a spatial and clear way leads to new insights, says Verbeek, justifying the mammoth project. A biologist can for example see that the genes he is studying in the brain are active too in the gut at the same time in development. And an advantage the digital atlas has over past paper atlases, is that further items of information can easily be added. The man who is such a stickler for order in the digital world casts another glance at the growing disorder on the meeting table. His clever software doesn t sort papers. Oh well, maybe I should throw the whole of it away. That s a form of order too. 15
16 Sandra Scanu (1981) studied Biotechnology in Milano, Italy. Between November 2008 and January 2013, she was a PhD student at the Leiden Institute of Chemistry, where she studied proteinprotein interactions using paramagnetic NMR spectroscopy. She is currently a postdoc researcher at the Technische Universität München, Germany. My main scientific interest is to understand what is really going on in living cells. There are so many biochemical processes taking place at the same time, with such perfect coordination and together they give rise to life! Sandra Scanu Leiden Institute of Chemistry How proteins meet and Theory had already predicted it, but no one had been able to prove it in the lab: that certain protein complexes are held together not only by electrostatic forces, but also by hydrophobic interactions. Sandra Scanu was the first to produce the experimental evidence. By Nienke Beintema Proteins play a vital role in virtually all biological processes. From growth and reproduction to pathogen defence and molecule transport: proteins are the workhorses of all living systems. They rarely work alone. Usually they join forces to form intricate, three-dimensional complexes with very specific tasks. But how do proteins find and recognize each other? How do they balance speed and specificity when joining forces? And, ultimately, how can we relate mistakes in this process to human diseases? The answers to these and similar fundamental questions help scientists to unravel the molecular mechanisms that lie at the basis of life. Over the years, scientists have made various theoretical models that describe how proteins recognize each other and then bind, says Sandra Scanu, who just finished a PhD project at the Leiden Institute of Chemistry. These models are based on the different forces that act between the molecules. These can be electrostatic forces, as she explains, which result from local charge differences. They can also be hydrophobic forces, which act between amino acids on the outside of the proteins. These amino acids are hydrophobic: they repel water, and therefore tend to cluster together with other hydrophobic amino acids. Although theoretical models have proposed a leading role of hydrophobic forces in protein complex formation, scientists had never been able to prove this experimentally. All proven models describe protein interactions solely driven by electro-
17 17 bind static forces. The hydrophobic interactions are much trickier to identify, says Scanu. This is because they are difficult to measure, and also because it is a challenge to describe them in mathematical terms. Yet Scanu, her supervisor Marcellus Ubbink and other colleagues succeeded in showing the presence of hydrophobic forces in protein interactions. They used a unique multidisciplinary approach: they combined advanced NMR spectroscopy with computational techniques that simulate protein interactions. Quick transition Protein complex formation is a stepwise process. While the free components evolve to the final complex, they pass through a so-called encounter state. The transition through this intermediate state increases the probability that a productive complex can be formed, because it helps the proteins to find the right orientation relative to each other. Scanu studied the encounter complex that is formed in the association between plastocyanin and cytochrome f: two proteins that play an important role in electron transfer during photosynthesis. This is the process by which plants and cyanobacteria use sunlight to convert carbon dioxide and water into sugar and oxygen. Electron transfer complexes such as plastocyanin/cytochrome f are notoriously difficult to study, as Scanu explains, because they form very fast, in a matter of milliseconds. Scanu used a specific type of nuclear magnetic resonance (NMR) spectroscopy to track this process: paramagnetic relaxation enhancement (PRE) NMR spectroscopy. NMR in itself is a technique to identify atoms in a molecule on the basis of their electromagnetic properties in a magnetic field. Atoms in a molecule absorb and re-emit electromagnetic radiation in a typical pattern. This pattern can be visualised in a spectrogram, which yields a unique fingerprint for each molecule. In combination with PRE, this technique also provides information about the distances between atoms, in this case the atoms in two different proteins. Using this information in combination with computational simulations, says Scanu, we can reconstruct exactly how the two proteins are positioned relative to each other during their bonding process. It turned out that there was no clear distinction between the encounter complex and the active complex. Our data showed that in the encounter state, plastocyanin makes hydrophobic contacts with cytochrome f, allowing a quick and efficient transition from the encounter complex to an active complex, explains Scanu. I believe that this model can also be applied to other systems involving multiple interaction partners, for instance proteins involved in signal transduction. Acclaim Scanu published her findings in the prestigious Journal of the American Chemical Society (April 2013). Among other things, her research was awarded a prize at the International Conference on Magnetic Resonance Microscopy in Lyon, France (August 2012). I think this is mostly because of the unconventional multidisciplinary approach that we used, says Scanu. We feel lucky that it worked out this way. And although she was able to propose a new model to describe protein complex formation, Scanu acknowledges that some pieces of the puzzle are still lacking. We still need to understand the individual roles of the different hydrophobic amino acids, she says. Some could be more important than others. Yes, these are also very fundamental questions. How are hydrophobic interactions modulated in living systems? You have to understand this on a fundamental level before you ll be able to manipulate the process.
18 Gerard van Westen Leiden Academic Centre for Drug Research Computer power in the hunt for new Bringing together information on the properties of small molecules and their targets in the computer makes fast identification of potential new drugs possible and can help reduce side effects. Gerard van Westen: The approach makes use of the ongoing exponential growth in computer power and the increasing availability of public databases containing the necessary information. By Marcus Werner Stupendous numbers of small molecules are theoretically possible. The class of, literally, relatively small organic compounds has since the 20th century been the dominant source of pharmaceuticals. In general, small molecules bind to protein targets in living cells, thereby either promoting or inhibiting their activity. In fact this is how most drugs exert their effect in treating illness and disease. But just a minute fraction of small molecules have actually been made in the lab, and even fewer are currently in use as drugs. Computational chemists like Van Westen train computer models to sift through libraries of existing small molecules with unknown bioactivity, even those that only exist virtually in the computer, and look for potential new drugs. Such searches were until recently mainly based on the concept of molecular similarity small molecules that are similar in chemical structure are most likely to have similar biological effects and be useful as drugs. Van Westen has taken the concept a step further by also taking the molecular similarity of target proteins into account: That way, you get a better handle on the interaction between potential drugs and the proteins they re aimed at. Van Westen didn t originally plan to be a computational chemist: I wanted to study medicine, but discovered that the training is mainly focused on making a diagnosis and less on research. Doing medical research attracted me, and I opted for Bio-Pharmaceutical Sciences at Leiden University. Leiden University at the time was the sole Dutch university offering a Master s program in this field coincidentally in Van Westen s home town. Disappointing results in Van Westen s first research project during a nine-month internship at the Leiden Academic Centre for Drug Research (LACDR) set him off towards his future calling: We were investigating how a particular protein involved in vascular disease interacts with blood vessel walls, but just couldn t hit on the binding location. A friend in the Bio-Pharmaceuticals student s association Aesculapius suggested ing someone he knew was involved in computational methods in the pharmaceuticals industry. It proved to be a springboard to an internship with the Tibotec pharmaceuticals company in Belgium, where Van Westen used computational methods in research on anti-hiv drugs: I decided that this was what I wanted to do. The Belgian sojourn led to a Tibotec-funded PhD position at LACDR, on predictive computational models using small molecule and protein similarities simultaneously, dubbed Proteochemometric modeling (PCM). Much of the research is published in top ranking journals. One study focused on HIV the virus causing AIDS. Although incurable, AIDS is now controlled by combinations of several anti-viral drugs. The anti-viral cocktail used for a particular patient is based on
19 19 drugs the genetic fingerprint of the infecting viral strains, which in turn determines the properties of the viral proteins targeted by drugs. In this way drugs to which the strains are resistant can be avoided. By including data on drug similarities as well as viral genomes in a PCM model, Van Westen achieved a high correct resistance prediction rate, as well as identifying 17 as yet unpublished resistant viral strains. Predictions like these could be used for provisional treatment before viral resistance is determined in the lab, which takes time. Another study tackled a class of related cell-surface proteins which are targets in the treatment of a number of diseases, including diabetes and Parkinson s Disease. A PCM model including some 11,000 small molecules and several of the targets turned up six novel small molecules, the activity of which was confirmed experimentally. Van Westen: Typically drugs bind to several similar protein targets, but that have different functions. Side effects are the result. Studies like this can help identify more specific drug-target interactions and cap side effects. Van Westen is continuing his computer-aided quest for novel drugs at the European Bioinformatics Institute in Cambridge, UK. One line of research concerns protein targets of the human influenza virus, in collaboration with researchers in Grenoble, France: Instead of the highly variable proteins on the outside of the virus, we re looking at targets inside which are shared by all strains. That could lead to more universal influenza vaccines. Asked as to what he would be proud to do on completion of the Cambridge project in 2015, Van Westen muses: Returning to Leiden would be ideal. Settling down there would be good for my two children s schooling. And I like an academic setting. Explaining things to students helps my thinking, too. Gerard van Westen (1983) studied Bio-Pharmaceutical Sciences in Leiden. Following a PhD in computational chemistry (Leiden Academic Centre for Drug Research, 2013), Van Westen currently works as a post-doctoral researcher in Cambridge, UK (Marie Curie/ European Molecular Biology Laboratory Fellowship).
20 From his study time at Utrecht University, Maurijn van der Zee (1976) has been interested in animal evolution and embryonic development. During his PhD in Keulen (Germany), he discovered the potentials of the red flour beetle as a model organism for this research field. In 2010, after a few post doc positions, he came to Leiden with a NWO-Veni grant and brought the beetles with him. He now is assistant professor on a tenure track position. Chris Jacobs (1986) joined him, first as a master student and then for his PhD research. Jacobs interest in biology has been evident from childhood. After finishing his thesis, he intends to apply for a post doc position abroad. Maurijn van der Zee en Chris Jacobs Institute of Biology Leiden Thanks to an innovative egg Biologists Maurijn van der Zee and Chris Jacobs identified one of the key factors that made the insects flourish on earth. In contrast to their marine ancestors, insect embryos enfold themselves in a second membrane within the maternally derived egg shell. The two showed that this second membrane, the serosa, prevents the eggs from drying out. It is an evolutionary novelty that freed the insects from the need to live close to water and enabled them to disperse over land. by Willy van Strien The insects have done extremely well since their ancestor left the sea to invade the land, five hundred million years ago. It is difficult to overestimate the changes that are needed to turn a marine animal into a terrestrial one. So, it is no wonder that the insects underwent radical modifications after descent from their marine ancestors. A novel egg design is one of those. All arthropods, the animal group to which the insects belong, have eggs in which embryo develops within the maternally derived egg shell. But only the insect embryos surround themselves with two membranes below this egg shell, the amnion and the serosa. The embryos of chelicerates (spiders, scorpions, mites), myriapods and crustaceans (crabfish, lobsters, shrimp, prawn) do not.