In Goslar's old town ((c) Philipp Andre)

There are a few seats left for the 5th German Conference on Cheminformatics in Goslar and we’ll extend the deadline a bit to give you the chance to register if you haven’t done so.

The GCC is a great chance to meet with around 200 other participants from all areas of life science informatics and listen to talks about the latest research in the field. This year we have an exciting collection of keynote speakers with topics ranging from modelling of biological systems and systems chemistry via computer-aided material design to the latest developments in ChemSpider.

The program is complemented by 60 posters and again prices will be awarded for the three best posters.

Goslar itself is a wonderful place to visit, with its two UNESCO world heritage sites, the old town centre and the ore mine.

We are looking forward to meeting you in Goslar. Registration is still open.

We now invite papers for our symposium on computational aspects of Metabolomics at the 239th National Meeting
of the American Chemical Society (ACS) in San Francisco next spring.

Metabolomics studies the occurrence and change of concentrations of small molecular weight chemical compounds (metabolites) in organisms, organs, tissues, cells and ultimately cell compartments in the context of environmental changes, disease or other boundary conditions. It does this by means of spectroscopic and chromatographic techniques and by observing at once not only a few but all compounds visible to the particular technique used. As such, it is a field at the boundary between chemistry and biology, helping to answer biological questions using analytical chemistry and cheminformatics techniques.

The metabolomics symposium at the 239th ACS national meeting in San Francisco invites submissions of talks about computing, informatics as well as chemical information aspects of metabolomics. Topics could include the analysis of metabolomics experiments, metabolomics databases, computer-assisted structure elucidation of metabolites and more. Abstracts may be submitted via http://abstracts.acs.org. You’ll find the metabolomics session as part of the CINF division symposiums. Deadline is October 19, 2009. In case of questions, please email Christoph Steinbeck at steinbeck@ebi.ac.uk.

The European Bioinformatics Institute (EBI)

If the pompous title caught your attention, and you are ashamed of that: Don’t worry. It is all true. My cheminformatics and metabolism group at the European Bioinformatics Institute (EBI) is looking for a phd student this year and all you need to do is apply through the regular route.  The range of possible topics is wide open, going from metabolomics via automated structure elucidation of metabolites to mining chemical information from the printed literature, and more. Your own suggestions are of course welcome.

The EBI is the world’s largest open provider of biological and chemical information.We are located, together with the Sanger Institute for Genome Research, on the beautiful campus of Hinxton Hall, a few miles south of Cambridge.

One of the small lakes on the Wellcome Trust Campus in Hinxton

Our PhD students are enrolled with the University of Cambridge.

The important part for now: The application deadline for the Fall PhD selection is July 15, 2009. And: Please drop me a note if you applied.

But this one was different and since this is a blog partly concerned with science in general, I would like to recommend to you “The Trouble with Physics” by Lee Smolin. The book’s subtitle is “The rise of String Theory, the Fall of a Science, and What Comes Next”. You, likely to be a member of some molecular informatics community, may ask, who cares about String Theory, and you may be right at a first glance. This book, however, is about Science in general, the mechanisms that drive it, and about what can go wrong. It is as much a book about science, physics and string theory as it is about the people in science and how they shape the fate of their field and more importantly of the rest of the pack working in it. It if fascinating to follow Smolin’s account of the rise of String Theory as one of the leading theories in physics. It is frightening to realize that 20 years or more of String theory has, if we believe the book, not lead to a single, novel, unique prediction that has been verified afterwards by experiment.

But while the account of the rise of String Theory was very entertaining and informative to read, the rest of the book, dealing with questions of the alternative theories, of science sociology, what science really is and what we can do to keep a finite possibility of fundamental revolutions, is even better.

I’m going to stop here because I feel that this book, once you’ve started reading it, will speak for itself.

Day 3, Morning Session on Macromolecular Interactions: P-P, P-NA, NA-Light

• Sara Linse of Lund report on her group’s work on Protein Interactions, Association and Fibrillation. Systems Chemistry is the study of molecules acting collectively, she proposes. Her focus of course is on proteins interacting and she show some micro array assays for protein association studies (and I learned another buzz word: Interactome ). The second part of her talk is dedicated to studies of the effect of nano particles on protein fibrillation. The nano particles she studies where about 200 nm in diameter, compared to about 70 nm for a typical protein in study. Her conclusions are quite alarming in that there are clear effect of nanoparticles on protein association, because of their small size nano particles can enter the organism by various mechanism – yet, because of the fact that many nano particles are made from known and risk-assessed materials, there no *new* risk assessments done accounting for the new properties that arise from the small size. It should be noted of course, that there is awareness for the new risks arising from nano particles and discussions are going on.
• Michele Vendruscolo of Cambridge talked about “Life on the Edge: Proteins are close to their Solubility Limits”. He shows an incredibly crowded picture of a yeast cell. Yet, a protein can visit most locations in a cell in a fraction of a second. Interestingly, the life time of a protein in a cell is only in the order of about 1 hour, after which it is recycled. He talks about the folding process of a protein and that dispite a well-defined folding funnel there can be many more states being adopted by a protein, potentially leading fibrilles. Michele shows a model to predict aggregation rates of proteins from the sequence. He concludes by giving another definitions of Systems chemistry being a strategy based on chemical principles to make predictions about cellular processes.
• Alexander Heckel of Frankfurt speaks about “Shedding Light on Nucleic Acids and DNA under Construction”. He shows examples from his research on light-induced transcription and light-induced RNA interference. In his second part he talks about DNA constructions. Alexander shows a very impressive animation of ATP synthase that I need to get my hands on.
• The morning session closes with a talk by Justin Roberts from Riverside, CA, USA, on High-Throughput Analysis of Nucleoside- and Nucleotide-binding by Proteins.

Day 3, Afternoon session on Chemical Spaces and Molecular Design

• Joseph Lehár of Cambridge, MA, USA, starts the afternoon talks with the topic “Systems Biology from Synergistic Chemical Combinations”. He is the first to talk about multi-drug (he calls it combination drugs). He highlights various multi-target mechanisms such as “cooperative targets”, “block compensation”, “circumvention of resistance”. His companies looks at combinations of all approved drugs and uses cell-based assays to screen them.
• Holger Wallmeier, independent consultant, speaks about “A Dynamical Supramolecular System for Chemical Biology – a Step towards Contiguous Structural Spaces”.
• The last research talk of the meeting is delivered by Gisbert Schneider of Frankfurt talking about “Molecular Design: Voyages to the (un)known”. He starts with musing about what Systems Chemistry is based on Darwin’s work on the Transmutation of Species. He continues with explaining different levels of abstraction for molecular representations leading to the definition of a pharmacophore space. In the following, Gisbert shows work with Self-Organising Maps (SOMs) on the discovery of pharmacophore spaces.
• My summary and closing remarks: We saw an enormously diverse set of talks, most of them dedicated to the study of biological phenomena. If this workshop was really on Systems Chemistry, this indicates that System Chemistry has to do something with Biology. My theory is that we add the view on molecular details to Systems Chemstry. A lot of reports focus on understanding the parts, but there were indeed interesting insights into the properties of biological systems, such as the talk by Danchin. I enjoyed the meeting a lot and would love to see a follow-up – the problem is far from solved – with a greater emphasis on the fundamental problems of systems simulations on varying scales – dynamic scale switching, so to say. Only the application of first-principles at places where detail is required will allow us to make meaningful prediction, for example in the prediction of drug action on organisms.

• Tom Blundell of Cambridge starts with “Exploring Biological and Chemical Space with High-Throughput Crystallographic, Biophysical and Computational Methods: The new Dimensions of Drug Discovery”. Tom starts with a view on a cell, stating its complicatedness or complexity. He points out the large number of crystal structures of drug targets and a lack of success of the pharma industry to make drugs fast and at reasonable cost. Tom then praises high-throughput automation in his research. A large amount of information will become available from projects like the “1000 genomes”. He describes the projects of his Astex company, soaking crystals with small molecule fragments to identify binders. Essentially, the rest of the talks is on innovative approaches to screening of compound libraries against protein libraries.
• Dave Winkler of Monash University, Australia, announces to talk about Complex Systems. Large molecules are brought home into the chemistry domain. He talks about properties of complex systems, such as emergent properties – unexpected properties apprearing from the interactions of many components or agents in complex systems. Dave mentions the role of networks, Gene networks, metabolic networks, protein-protein interaction networks for System Simulation . Dave states that Systems chemistry might simply be the application of Complex Systems Science applied to Chemistry. The level of simulation is essential when modelling emergent properties of complex systems. His groups builds mesoscale models of stem cell cytokine regulatory networks.
• Douglas Kell from Manchester spoke about Drugs and Xenobiotic Transport via Membrane Carriers. He emphasises the difference between a a biophysical approach vs. a mechanistic analysis. Douglas very nicely points out that a huge amount of work still lies in front of us in studying mechanistic properties of the parts to eventually put them together. He mentions ChEBI for the sake unifying chemical names, highlights the problems with literature mining. In his second part of his talk, he spoke about carrier-mediated cellular uptake vs. a lipid-only theory (logP being important here).
• Tim Clark of Erlangen uses Molecular Dynamics studies to look at Signal Transduction. He mentions that when they started seven years ago they did not know if the force fields were good enough and if they could ever simulate the system for long enough to get meaningful answers. The work was on the Tetracylcine Repressor (TetR) . Tetracyline comes into a cell, comlexes with Magnesium, and then docks to the TetR, and off goes the expression of the antiporter which transports Tetracycline out of the cell. TetR can be used to switch on and off genes in eukaryotes and prokaryotes. They were able to run these TetR MD simulations on the 100 nanoseconds time scale. He showed a low-frequency mode visualization of TetR MD yielding an understanding of induction mechanism of TeTR by Tetracycline. The binding pocket properties change enormously after binding, volume for example shrinking by more than 50 percent. What does that say about docking into rigid pockets?

Wednesday afternoon is, as usual, dedicated to a hike. This time, it goes to a castle on a top of a mountain behind Schloss Korb – very nice walk – we did it in 2004 already.

Following are my notes on the various talks, hopefully helping me to put together the summary in the end. All of the talks were full of subtle, interestingly illustrated scientific details which were absolutely impossible to capture here

Tuesday morning: Life, Living Systems and their inherent properties

Martin Hicks, organizing the Beilstein workshop in Bozen in the twentieth year now, in his introduction highlights the routes between synthetic chemistry and biological systems. He also points to the different views of Chemists and Biologists on Biological Systems. And, as you will probably appreciate, 20 rabbits do not make a horse.

• Günter von Kiedrowski, in “Systems Chemistry and the Origin of Life”, puts the understanding of the origin of life in the centre of interest of Systems Chemistry. Showing a picture of earth from space he points out the number of events necessary to form life on earth, including formation of the hydrosphere, cometary impacts, formation of the RNA world, as well as an DNA-Protein world: Prebiotic chemistry. He calls it “Origin of Life” research and acknowledges Jean-Marie Lehn, Albert Eschenmoser and Manfred Eigen as pioneers. Günter mentions Craig Venter’s minimal Cell and works on Minimal Self-Replicating System: Keypoint is a product inhibition preventing exponential growth of the system. He further shows basic structural and dynamic prerequisites for self-replicating system. My impression was that the kinetic rules for a minimal replicator are well understood. In the last slide, he sites the NASA exobiology program: “Life: A self-sustaining chemical system capable of undergoing Darwinian evolution”

• The second speaker, well-known Hans V. Westerhoff from Amsterdam in “Chemistry in Three Dimensions: How Systems’s Biology may Regulate its System’s Chemsitry”, looks at chemistry from a systems biology view point. He points out that the European Science Foundation has declared Systems Biology a Grand Challenge with implications for the understanding and fight against disease. His talk focused on some fundamental properties of chemical and biological systems which I mostly missed. Mentions plan to make the virtual human in the next 30 years.

• Antoine Danchin started of by talking about using Synthetic Biology (SB) for constructing a synthetic cell . The first aim of SB is to reconstruct life. He introduces the idea that the cell might be Turing machine. Life as a combination of a program running on a cell processor. He points out that while the machines reproduces, the program replicates. Replication accumulates errors. An interesting fact: One fifth of bacterial genomes comes from “outside”, a hint of the separation of program and hardware, kind of an organic open source software exchange. Antoine also introduces the notions of the Paleome, part of the genome responsible for replication and maintenance, and the Cenome , managing Life in context, sensing, etc.

• Athel Cornish-Bowden, in “Catalysis at the Origin of Life” promotes ideas by Robert Rosen in exemplifying an Algebraic Representation of Metabolism, based on Rosen’s Metabolism-Repair/Replacement system theory.

Tuesday afternoon: Catalysis and Chemical Tools for Exploring Biology (Chemical Biology)

• The afternoon session of the first day was opened by Benjamin List, who talked about “New Concepts for Catalysis”. Benjamin highlights progress in the understanding of catalytic properties of small organic molecules without involvement of metals as part of the catalytic principle.
• Steve Ley of Cambridge presented on”New Tools for Molecule Maker: Emerging Technologies”. His main interest is in making molecules, and making these with some goal in mind, such as curing a disease. He starts off with asking how good we really are as organic chemists. A slide with examples of synthesized, quite complicated natural products his lab had synthesized in the past. Pretty impressive, but he points out the limitations: Less severe are lack of reproducibility, scale-up issues, problems with low temperature, material economy. Really bad: Current cost of organic chemistry, time consumption, wastage of man power and questions of sustainability. The solution are flow reactors and lab-on-a-chip devices. Steve shows the synthesis of Epothilones on beads, requiring no washing, no isolation, no chromatography. Flow mode chemistry, combined with the beads concept makes synthesis even more efficient. Like the following speaker, Steve shows a continuous flow reactor chip (lab-on-a-chip), coupled to collectors, HPLC and a recycling loop, pointing out that the whole dynamics of a reaction change (as in “enormous speed-up”) when going from flasks to flow reactors. The close-loop-operation of these devices allow for rapid, even on-the-fly changes and improvements of reaction conditions. An interesting point was that chemists are awfully bad in achieving proper mixing of reaction mixtures and that the ability to pump reaction mixtures back and forth in flow reactors significantly changes the rules of the games, dramatically increasing the reaction rates. These things can then be made in amounts to up to 15 kg in the Ley lab!
• Peter Seeberger of ETH Zürich , who has just accepted a call to become a director of a Max-Planck-Institute near Berlin, also talked about “Microreactors as Tools for Organic Synthesis”. He points out, underpinned by pictures from MIT labs through the ages, that the chemistry lab has not changed much in the last hundred years. Besides advantages also pointed out by Steve Ley, Peter emphasizes the positive safety behaviour of flow-through reactors. The flow reactors that he describes are silicon-based with the advantage that the production process for these reactor is very well understood (think “chip industry”). Like Steve, Peter points out that flow reactors allows a coworker in his lab to run a couple of hundred reactions under different conditions in a few afternoons. Besides making things faster and more efficient, you even make things that don’t work otherwise. He exemplifies this with the synthesis of a particular tetrapeptide, where I missed the point why this was not possible without flow devices.
• Eric Meggers, University of Marburg and Wistar Institute, Philadelphia, concluded the afternoon session, with a talk on “Chemical Biology with Organometallics”. Why is Nature synthesizing complicated secondary metabolites, is his starting question, while drugs, for example, often look so much simpler. He exemplifies by showing how nicely Geldamycin fits into its target pocket – an example already answering his question. The target pocket is flat and wide and Geldamycin adopts a bulky globular shape with all functional groups nicely presented on its surface. No smaller or less complicated molecule could have this function. He then introduced a recipe for morphing indolocarbazole alkaloids into simple and easily accessible metal complexes, leading to potent inhibitors of protein kinases.

I’ll send this off now, because the reception this evening will be in the local wine cellar. No more sensible content to be expected.