Thinking differently institute's director. He told me that that define the experiments that are necessary by Geoff Richards was unthinkable for a junior French to test it. There is little importance as Director of Research Grants, HFSPO scientist. Similarly, in my time at HFSP, I to whether the model is correct. If the have learned from Californian PIs that it experimental data is in accord with the took a while for them to understand that model they will refine it, if not they will some of their post-docs could not say think again and propose a new model. 'no' to an instruction, but rather used 'yes' Traditional biologists have a distinct on a scale of 1 to 10, so that things they approach. They will gather a maximum thought had been agreed were still not of information and then ask a 'modeller' done a month or more later. to design a 'bag' which will contain all the known values, adjusting the 'model' if However, beyond these interactions, new data lies outside of the initial 'bag'. there are fundamental differences in With time HFSP has encouraged teams thinking, even for scientists in the same to involve the computational biologist discipline. I remember the case of a in the initial design of the experiment Japanese post-doc working on a very so that the 'wet lab' results can be delicate purification of components of tested in terms of a model rather than a transcription complex. One Friday he constructing a strange 'bag' post-hoc that demonstrated that he had succeeded in includes most of the data collected. This isolating the sought-after activity. His difference was brought home to me after Since its beginnings, the HFSP grant group leader said that the following I had written a deliberately speculative program has supported international week they would need to scale up the review of how nuclear receptor isoforms collaborations, which encourage purification 50 fold so as to move to the (shown to change following hormonal scientists from different countries next step of the isolation. The following induction) might interact during a time to think about problems as a team. Monday, he was surprised to find the job course following a hormonal stimulus. A Simple as this may seem, there was an done. The post-doc had reasoned that senior colleague said, 'yes, I saw that, but underlying benefit, which also became he was totally reliable in his techniques I would have done all the experiments evident in the fellowship program. and had simply run 50 'mini-preps' in first.' In fact, each region or country has parallel over the weekend and pooled the very different traditions in training its products, something that no-one else in A more general feature of these research scientists which is seen both the team would have contemplated! collaborations is that members of in their behaviour and their way of interdisciplinary teams have to learn to thinking. Some systems are traditionally If HFSP helped to encourage these move from ‘talking at’ the other team hierarchical, others more liberal. During frontier confrontations in its first decade, members when they present in the jargon my doctoral studies at Cambridge, I was thereafter it emphasized a more general of their discipline to ‘talking to’ the expected to discuss ideas with my senior source of differences in thinking, that others by making the concepts clear and colleagues on an equal footing. When comes from scientists trained in different available for discussion. It is to HFSP's after a junior faculty position in the same disciplines. A good example can be found credit that it encourages and supports department, I joined one of France's most in 'modelling' a biological situation, the interaction of these differences in dynamic molecular biology laboratories. which gave rise to an informative the ways of thinking (both cultural and I continued to behave as I had been discussion at the HFSP Awardees discipline related) as they are healthy for trained and remember shocking a friend meeting in Berlin in 2008. Physical creating frontier breakthroughs. As our (since then a Nobelist) by the casual, scientists, notably biophysicists, will French hosts here in Strasbourg are wont but polite, way I exchanged with the construct a theoretical model and then to say 'Vive la différence'.

The 2017 HFSP Nakasone Award

David Julius of the Department of at the University of California, San Francisco was awarded the 2017 HFSP Nakasone Award for his 'discovery of the molecular mechanism of thermal sensing in animals' because it defined a field of sensory reception. Dr Julius will deliver the Nakasone lecture at the 2017 HFSP Awardees Meeting in Lisbon.

You can read more here: http://www.hfsp.org/awardees/hfsp-nakasone-award/2017-award

Issue N° 7 | December 2016 Meet HFSPO's new Director of Fellowships In this issue In September, HFSPO welcomed a new Director of Fellowships, Barbara Pauly, to the team. In the following article she writes about her first impressions of life in the HFSPO Secretariat in Strasbourg.

Thinking differently...... 1 The 2017 HFSP Nakasone Award...... 1 Sometime in August 2016, I packed the Research Grants, lies in the fact that up my belongings and moved from HFSP is willing to sponsor high-risk HFSPO's Director of Fellowships...... 2 Heidelberg, Germany, to Strasbourg, and out-of-the-box-thinking projects Champalimaud Centre, Lisbon, to France, to take up the position of that would often not be funded by host two HFSP meetings in 2017...... 3 Director of Fellowships at HFSPO. national funding bodies. Unfortunately, HFSP fellowship that sowed the seeds for obvious economic reasons, HFSPO In Heidelberg, I had been a scientific cannot fund all applications and for PROTAC drug development...... 4 editor at EMBO thus we, like Greasing up ferroptotic cell death...... 6 reports, one of other funding A tryst with the sky for a peek into the four journals organizations, published on rely on the help of the sea...... 8 behalf of EMBO, active scientists Matchmaking sciences & arts...... 10 for eight years. to participate HFSP Science Meeting, Beijing ...... 12 I was responsible in our various Meet & Greet...... 12 for overseeing the committees assessment and to select the The 16th HFSP Awardees Meeting.... 13 review process most promising Prizes & Awards...... 14 of scientific applications. Awardees' Articles...... 14 manuscripts Prior to starting in the areas of my position at Impressum stem cells, cell HFSPO, I had the death, molecular chance to attend The HFSP Newsletter is issued evolution Barbara Pauly the grant selection on behalf of the Human Frontier and ecology, committee Science Program by the International genomics, and meeting in July Human Frontier Science Program systems and computational biology. I when the members came together to Organization. It contains announcements of HFSP-related enjoyed the diversity of these areas and discuss the submitted letters of intent. matters and other information of the job of an editor very much, as I have I was amazed at how enthusiastic and interest to the support of young always been interested in many different engaged the committee members were. scientists and to interdisciplinary fields of the life sciences. This was also After all, they are all active scientists research in general. Please tell your the reason why, after obtaining my PhD with labs to run, grant applications friends, colleagues, students, etc. about in Germany and a postdoc in the USA, I to write and students to supervise... this mailing list. They can subscribe had decided to leave the lab and become Nevertheless, they actually all seemed via a link on the HFSP home page. an editor. to enjoy meeting in Strasbourg to discuss science with colleagues and Please address any suggestions or But then it was time for a change friends from diverse fields and this comments to: [email protected] and I was very lucky to get the cannot only be attributed to the – chance of transferring to HFSPO, undoubtedly – great food and wine one this unique funding organization that can enjoy in Strasbourg! Maybe it is the suits my interests in diversity and open-mindedness of HFSP towards the HFSP Matters Issue N° 7 interdisciplinary research so well. kind of research it funds that attracts December 2016 Since September, I am overseeing the such open-minded and enthusiastic applications for Long-Term and Cross- review committee members – or the The International Human Frontier Disciplinary Fellowships, as well as other way around. Science Program Organization for the Career Development Awards. (HFSPO) I was lucky enough to join the team, I am very excited about my move to 12 Quai St Jean - BP 10034 not only of very experienced, but also HFSPO and the beautiful Alsace region 67080 Strasbourg CEDEX extremely friendly and helpful members and I would like to take this opportunity France of the HFSPO Secretariat who made my to thank all members of the HFSPO transition very smooth and easy, both office for their incredibly warm and Email: [email protected] professionally and personally. After friendly welcome. I am looking forward Website: www.hfsp.org only a month, I already feel at home to working with them and the scientists Japanese website: http://jhfsp.jsf.or.jp in the job and in the beautiful city of from around the world, be it applicants Strasbourg. or reviewers, in selecting great scientific projects at the frontier of the life HFSP at your fingertips The uniqueness of the HFSP programs, sciences. Quick link to both the Postdoctoral Fellowships and www.hfsp.org

2 2 HFSP Matters Issue N° 7 | December 2016 Champalimaud Centre, Lisbon, to host two HFSP meetings in 2017

The HFSP Awardees Meetings have become an annual event in our calendar, providing a unique environment for scientific exchange. Not only do the meetings bring together awardees from the grant, fellowship and CDA programs, members of the HFSPO Review Committees, Council of Scientists and Board of Trustees but they also offer an ideal opportunity for the scientific community and members of the HFSPO leadership to interact. The 17th Awardees Meeting will continue the tradition of assembling the HFSP community at a scientifically interesting venue as the meeting will take place at the Champalimaud Centre for the Unknown in Lisbon, Portugal from 9 - 12 July 2017.

Champalimaud Centre for the Unknown

This meeting will be special because frontier between the disciplines, and discipline to the other in a comprehensive we plan to combine the HFSP Awardees many studies over the last decade have manner. The workshop will cover these Meeting with a one day meeting on unraveled new ways of understanding, aspects by presenting cutting edge “Cell Physics” on the 9 July. Together for example, morphogenesis during research at the frontier in a way that with two physicists, Daniel Riveline development, signal processing in highlights the interplay between life (IGBMC, Strasbourg) and Karsten Kruse protein and genetic networks, and the scientists and physicists, the difficulties (University of Geneva), we will organize roles of fluctuations for determining the resulting from joining two disciplines, an international workshop that will bring fates of cells and tissues. Mixed teams and the solutions found in successful physics and biology together – probably of biologists and physicists are now collaborations. The meeting will in a way it has never happened before commonly discussing experimental furthermore discuss how young scientists because the discussion will be based methods, genome wide data, as well as can be prepared for similar endeavours around questions on research training in theoretical ideas on a daily basis. Many and provide an open international forum cell physics. successful applications for HFSP funding for scientists in charge of training further underline the importance of this programs to share their experiences and The interface of physics and biology approach. exchange informally. has proven to provide a most fruitful environment for generating new concepts Standard training in biology and in Invitations to register for both meetings and exciting new lines of research. physics focuses on different aspects, and will be sent to all current HFSP awardees HFSPO funds research at this very concepts are rarely translated from one early in 2017.

HFSP Matters Issue N° 7 | December 2016 3 Frontier Science from HFSP Short-Term Fellow Alessio Ciulli

An HFSP fellowship that sowed the seeds for PROTAC drug development by Alessio Ciulli

In 2009, Alessio Ciulli was awarded an HFSP Short-Term Fellowship1 to support his 3-month research visit to Yale University to start a collaboration between his new lab and the lab of Professor Craig Crews at Yale. Crews, Ciulli and co-workers designed potent small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, aiding development of much improved proteolysis targeting chimeric molecules (PROTACs). Today, only a few years after the beginning of this crucial collaboration, targeted protein degradation has emerged as a transformative new modality of therapeutic intervention that is making an impact across the pharmaceutical industry. The following article by Alessio Ciulli briefly recounts how HFSP support helped to seed these important advances, and highlights its impact both academically and commercially.

Targeted protein degradation using Alessio Ciulli graduated in Chemistry from his hometown, small molecules has emerged as Florence, under the late Ivano Bertini and obtained his PhD a transformative new modality of in Chemistry from the University of Cambridge, studying as pharmacological intervention into a Gates Cambridge Scholar under the supervision of Chris biological systems, with increasingly Abell and in collaboration with Astex Pharmaceuticals. recognized therapeutic potential. To Following post-doctoral research on fragment-based drug induce intracellular depletion of a target design with Chris Abell and Tom Blundell, and an HFSP protein, the protein must be recruited Short-Term Fellowship1 to begin a collaboration with Craig in proximity to an E3 ubiquitin ligase, Crews at Yale University, he was awarded a BBSRC David complex enzymatic machineries that Phillips Fellowship to return to Cambridge and start his naturally catalyse the transfer of ubiquitin independent career in 2009. In 2013, Alessio was awarded to substrate proteins. Ubiquitin ‘tagging’ an ERC Starting Grant and moved his laboratory to the leads to the tagged protein being School of Life Sciences at Dundee University to take up a Readership in Chemical degraded by the proteasome, the major & Structural Biology as Principal Investigator within the Division of Biological ‘trash bin’ responsible for the recycling of Chemistry and Drug Discovery. He was promoted to Personal Chair (Professor) in most cellular proteins. October 2016. Alessio is the recipient of the 2014 Talented Young Italian award, the 2015 EFMC Prize for Young Medicinal Chemist in Academia, the 2015 ICBS Young One approach to induce targeted protein Chemical Biologist Award, the 2016 RSC Capps Green Zomaya Award in medicinal degradation is to design bifunctional computational chemistry, and the 2016 MedChemComm Emerging Investigator small molecules called Proteolysis- Lectureship. He is a Fellow of the Royal Society of Chemistry. Targeting Chimeras (PROTACs). Link to the Ciulli lab website PROTACs comprise a ligand that binds Hence, the dream remained elusive for conference, Craig and I had stimulating the target protein of interest, and a ligand a long time. Despite the risk, and against conversations about our own research, for an E3 ubiquitin ligase, joined by a the odds, Crews and I decided to team up and how we could work together on linker. Formation of a ternary complex to tackle this challenge head-on, with the something new. From this beginning, we between the PROTAC, the ligase and the support of HFSP. began to explore funding opportunities target protein results in the latter being and came across the Human Frontier poly-ubiquitylated and subsequently It all started back in September 2007, Science Program. The HFSP Short-Term degraded by the proteasome. First when Craig and I met for the first time Fellowship1 scheme seemed a perfect fit described by Raymond Deshaies, in Manchester on the occasion of a to our purposes: 1) to obtain pilot results Craig Crews and Kathleen Sakamoto symposium entitled “SCIBS: Selective in order to establish the new research in a PNAS article published in 2001, small-molecule Chemical Intervention collaboration; 2) to bring together this approach remained on the sideline in Biological Systems”, sponsored by complementary expertise available within for a long time, largely because first- the UK Biotechnology and Biological our laboratories, so that I obtain training generation molecules that had been Sciences Research Council (BBSRC). in new biological techniques while designed all incorporated long peptidic At the meeting, Craig presented his sharing my know-how in small-molecule recognition moieties for the E3 ligase. lab’s work broadly at the interface of design. It felt like a perfect 'win-win' This led to low cell permeability, limited chemistry and biology, including his situation from the start, and it rapidly stability and poor ‘drug-like’ properties pioneering work on PROTACs. I then crystallized into a proposal entitled for these molecules, which limited their spoke about my research on fragment- “Discovery of small molecules disrupting biological applications. Many in the field based and structure-based drug design, the VHL:HIF-1 α interaction: towards recognized the need to replace these working as a College Research Fellow at next-generation PROTACs”, which I peptide-based moieties with smaller, Cambridge in collaboration with Chris drafted and submitted for consideration more drug-like molecules. However, this Abell and Tom Blundell, co-founders by HFSP, with Craig’s support. meant disrupting a tight protein-protein of Astex Pharmaceuticals and two of interaction (PPI), a task esteemed too the recognized pioneers in the field of The proposal was successful, and I was challenging as PPIs were considered fragments. Throughout the rest of the able to visit Yale and Craig’s lab for ‘undruggable’ targets to small molecules. 1The HFSP Short-Term Fellowship program was terminated in 2010.

4 HFSP Matters Issue N° 7 | December 2016 three months in early 2009. I enjoyed a truly intense and enriching ‘sabbatical’ at Yale. In the Crews lab, I was exposed to several biochemical and cell biology techniques that were new to me, and learnt how to address biological questions. Equally, the exchange allowed me to share my experience in fragment-based drug design with other members of the group and within the departments, which helped to push their science in a new direction. Possibly more importantly, the fellowship exposed me to how the Crews lab integrated chemistry with biology in an academic setting. It was clear to me while I was there that I had made a good choice. I believe in life everything happens for a reason, and it was perhaps fitting that, while at Yale, I was awarded a major individual fellowship to start my own research group. I shortly returned to the UK to set up my own academic lab Figure 1. Crystal structure of first-generation inhibitor designed to disrupt the VHL-HIF at the interface of chemistry and biology, interaction. Inhibitor is shown as sticks, with cyan carbon atoms bound to VHL (green surface, studying and targeting PPIs with small key residues labeled as sticks and with yellow carbons), as determined by X-ray crystallography (PDB 3ZRC). Hydrogen bonds between the inhibitor and the protein are highlighted as purple molecules. The collaboration seeded with dashed lines. HIF-1α peptide (PDB 1LM8, shown as pink carbons) is superposed to reveal HFSP funding continued and expanded both the mimicry and differences in binding modes. Oxygen atoms are colored red, nitrogen, when I returned to Cambridge. blue, and sulfur, dark yellow. back-to-back papers from my lab and disruptive new chemical modalities of The rest is history. In just a few years, others, all published within the timeframe therapeutic intervention in the future - and we achieved the goal that we had set of one month, reported dramatically I am sure many share this belief. ourselves from the outset and discovered improved activities and specificities Undoubtedly, the discovery of small first-in-class, micromolar affinity and of PROTACs, including compounds molecules with high affinity, specificity non-peptidic small-molecule ligands based on our VHL ligand, against and with crystallographically defined for the VHL E3 ligase (Figure 1). These different targets. Parallel discoveries that binding modes for E3 ubiquitin ligases, as discoveries were published in three phthalimide-based immune modulatory is the case with our VHL ligands, greatly back-to-back papers in 2012 and two drugs (IMiDs) such as thalidomide, contributed to these major developments patents were filed. The molecules were lenalidomide and pomalidomide, bind to in the PROTAC area. In a distinct jointly designed between the two labs, the E3 ligase cereblon (CRBN) provided approach, VHL ligands in their own right with important early contributions from new ligands for a different E3 ligase, and have potential to impact also as VHL Julien Michel and Bill Jorgensen on the these were also successfully incorporated inhibitors. My lab has recently developed computational design. The Crews lab into PROTACs. Since then, Merck, a potent, selective and cell-active VHL helped primarily in the synthesis and Genentech, Novartis, Roche and more inhibitor that we have named VH298. assaying of the compounds, with key recently Boehringer Ingelheim, in a major We have characterized the compound contributions from PhD student Dennis collaboration with my lab now at Dundee as a selective chemical probe of the Buckley amongst others. My lab helped University ( hypoxic signaling pathway, providing primarily in the biophysical screening and http://www.fiercebiotech. a new chemical tool to study biological crystallographic characterization, driving com/biotech/boehringer-strikes-deal- systems, per se an attractive starting structure-guided design and supporting to-develop-protein-degrading-cancer- ), have all strongly committed to point for drug development. VH298 fragment-based deconstruction work. Key drugs this promising and exciting new area. will be made available to the scientific contributions came from my group’s first community through the newly established postdoc and Marie-Curie Fellow, Inge van With such a swell of excitement, many Chemical Probes Portal ( Molle. http://www. anticipate that more companies will be chemicalprobes.org/) and via commercial following suit. PROTACs are particularly vendor catalogues, and it is anticipated The impact of our discovery should attractive because of their modularity, that it will lead to many new unforeseen not be underestimated. It promoted their sub-stoichiometric mode of action, discoveries. and bolstered interest in this area, which relieves the need to fully occupy a and big pharma started to invest in it. target’s active site, and because potentially It is unlikely that the successes and GlaxoSmithKline first got involved any cellular target could be degraded advances highlighted here would in 2012, and subsequently founded provided a binding ligand for that target have happened if it was not for the a Discovery Platform Unit (DPU) in is available or can be developed. The enlightened decision of HFSP to support Protein Degradation (2013). Shortly renaissance in interest on PROTACs is my application to visit Yale to begin a afterwards, Yale University and Crews reminiscent of the boom in kinase drug collaboration with Prof. Crews. For this, founded the spin-off company Arvinas to discovery that followed the discovery of I feel privileged and I am immensely further develop the PROTAC technology. Gleevec in the early 2000s, in spite of grateful. Academically, my group published further many years of quiet and sceptic industrial fragment-based and structure-guided approach to that field. I am convinced studies, leading to the optimization of Please refer to the Frontier Science that targeted protein degradation is set to VHL ligands with nanomolar affinities. section of the HFSP website for the rapidly establish itself as one of the most In the late spring of 2015, a series of four list of references relating to this story. HFSP Matters Issue N° 7 | December 2016 5 Frontier Science from HFSP Program Grantees Marcus Conrad, Valerian Kagan and Judith Klein-Seetharaman

Greasing up ferroptotic cell death

Ferroptosis is a novel, yet only partly understood, type of regulated necrotic cell death that may underlie some forms of degenerative diseases including neurodegeneration but that could also be harnessed to treat certain cancers. Oxidation of lipids in cellular membranes has been considered to be a central process in ferroptosis, yet the nature and source of lipid peroxidation has remained enigmatic. Our two recent complementary studies demonstrated that ACSL4 (acetyl- CoA synthetase long chain family member 4), an enzyme involved in the activation of poly-unsaturated fatty acids (also frequently called PUFAs), provides the substrates for the generation of lethal lipid signals, which we identified to be arachidonic and adrenic acids incorporated into a specific class of phospholipids, i.e. phosphatidylethanolamines. Findings obtained in these studies will not only aid better understanding of the molecular mechanisms of this cell death pathway but will also provide novel cues in designing therapeutic strategies against ferroptosis-related diseases and in triggering cancer entities expressing ACSL4.

Cell death, despite the bad press, is an Dr. Marcus Conrad, PhD, is a molecular biologist and group leader essential and daily occurring event in at the Institute of Developmental Genetics, Helmholtz Zentrum multicellular organisms’ lives. For instance, München, Germany. Long before the term “ferroptosis” was coined, deliberate cell death induced by the body’s he and his team developed several transgenic cell and mouse models immune system is required to remove for the study of the molecular mechanisms underlying ferroptotic potentially pro-cancerous cells in order to cell death. In addition, his group has discovered the first class ofin reduce the risk of developing cancer. It is vivo efficacious ferroptosis inhibitors, called Liproxtstatins, that are estimated that during a period of 24 hours in currently being developed for the treatment of degenerative diseases with a ferroptotic signature. He is the coordinator of the HFSP a human body more than 50 billion cells are Program Grant “Oxidized lipidome: the unspoken language of non- lost due to the process of cell death. On the apoptotic cell death”. other hand, massive or premature cell death is the underlying cause of most (and many age-related) degenerative diseases including Dr. Valerian E. Kagan is a biochemist and biophysicist (MV neurodegeneration as evident, for instance, Lomonosov Moscow University, Russia) and is a Professor in patients suffering Alzheimer’s and and Director of the Center for Free Radical and Antioxidant Health, University of Pittsburgh, PA, USA. His lab has focused Parkinson’s diseases as well as amyotrophic on redox lipidomics as it relates to the signaling pathways in lateral sclerosis (ALS). different types of cell death. His group has identified oxygenated cardiolipins as mitochondrial signals of apoptosis and hydroperoxy- The first identified and probably best phosphatodylethanolamines as ferroptotic signals. understood form of cell death is apoptosis (from Ancient Greek: “falling off”). As early Dr. Judith Klein-Seetharaman is a Professor of Biomedicine and as 1842, the German scientist Karl Vogt was Systems Biology at the University of Warwick Medical School, the first to describe the principle of apoptosis. UK. She was the founding co-director, with Raj Reddy, of the The term apoptosis was eventually coined Biological Language Modeling Project at Carnegie Mellon University in a seminal work published in 1972 by exploring the analogy that protein sequences are to their functions Kerr and colleagues. A number of molecules as words to meaning. The practical implication is that computational that drive this kind of death were initially techniques developed originally for language can be directly applied studied in the nematode Caenorhabditis to biological sequences. She has integrated computational and elegans, and later shown to be of general experimental approaches ever since and received prestigious prizes significance to most multicellular organisms. for her work from the Humboldt Foundation, Gates Foundation, NSF CAREER, Margaret Oakley Dayhoff Award of the Biophysical While apoptosis is of utmost importance Society and most recently the EU Marie Curie International Incoming for both embryonic development of many Fellowship. multicellular organisms including man and (GPX4), a highly efficient enzyme specialized in removing these deliberate clearance of aberrant cells by the immune cells later membrane-integrated peroxides. For this crucial function, GPX4 in life, necrotic cell death (i.e. necrosis) was originally and for is now recognized as the key enzyme controlling ferroptosis. a long time regarded to be an accidental and explosive form of Uncontrolled lipid peroxidation, for instance by a malfunction cell death. This would make strategies with the goal to halt this (i.e. inhibition) or absence of GPX4, would otherwise cause form of cell death impossible. Intense research in the last decade, ferroptotic cell death through still unknown cellular processes. however, has unveiled that necrotic cell death is also regulated in many cases and can be subdivided into different cell death To shed light onto the molecular events causing lipid routines, each with distinctive molecular initiation mechanisms peroxidation and death, three research groups (Conrad, and execution pathways. Among approximately a handful of Kagan and Klein-Seetharaman) funded by an HFSP Research these regulated necrotic forms of cell death is ferroptosis (the Grant have applied a multi-disciplinary approach. By using a term was first coined in 2012). Ferroptosis is characterized number of different technologies including cellular, genetic, by iron-dependent lipid peroxidation (hence its name) and is computational and pharmacological tools, as well as mass entirely discernable from many other cell death pathways. Lipid spectrometry analysis and modeling of cells and tissues peroxidation occurs when essential constituents of membranes, undergoing ferroptosis, they identified ACSL4 as an essential the so-called poly-unsaturated fatty acid residues, become regulator in ferroptosis. Its importance for ferroptosis was oxidized and are not detoxified by glutathione peroxidase 4 shown to rely on its ability to activate preferentially long

6 HFSP Matters Issue N° 7 | December 2016 chain, polyunsaturated fatty acids, which can normally fulfill susceptibility. This many different functions in cells, such as energy supply, cell- was found to be Fig. 1 cell communication and integral constituents of membranes particularly valid which surround cells and organelles (Fig. 1). In the context of for tumor cells ferroptosis, however, the resulting activated fatty acid-CoAs need which are hard to to be first incorporated into a specific class of phospholipids, treat by standard which are the central components of any membrane in cells. chemotherapy like Phospholipids are molecules that consist of two chains of fatty the so-called triple- acids and one molecule of phosphate attached to glycerol. The negative breast phosphate group can be modified with simple organic molecules, cancer cells (Fig.2). such as choline or ethanolamine. Due to their chemical Treatment of these properties, phospholipids form lipid bilayers, which are essential cells with ferroptosis- to delimit a cell and its organelles, such as mitochondria and the inducing agents endoplasmic reticulum. As phospholipids can vary dramatically effectively killed in their composition because of the different molecules attached the cells in contrast to the glycerol/phosphate group and the different fatty acids to breast cancer (e.g. number of carbon atoms = length, degree of double bonds cells which do not = unsaturation) there might be thousands or even more than express ACSL4. hundreds of thousands of different phospholipids in cells, This is a highly making their analysis highly complex and extremely difficult. remarkable finding Yet we now show by using so-called redox-lipidomic analysis as the expression of (an analytical approach to look for oxidized phospholipid ACSL4 in tumor biopsies, prior to treatment of patients with species), bioinformatics and computer modeling that only a chemotherapy, may be used in future patient stratification when few phospholipids (i.e. phosphatidylethanolamines) having making the decision which sort of treatment regimen has the either arachidonic acid or adrenic acid, fatty acids with 20 or 22 potential to efficiently eliminate the tumor in the body. carbon atoms and 4 double bonds, respectively, are the preferred oxidation substrates that accumulate during ferroptosis. This is Conclusively, our discoveries presented in both publications highly intriguing as this oxidation appears to be very specific provide previously unrecognized insights into the mechanistic to these phospholipids and is not just a mere random oxidation role of specific lipid peroxidation and the essential players of all phospholipids in the cell. Oxidation of these fatty acids involved in ferroptotic cell death. Yet future studies are still is mediated by another class of enzymes, called lipoxygenases, warranted to further explain how specific peroxides in lipids generating free radicals and causing lipid peroxidation. If indeed cause cell destruction and death and what the suspected not removed by GPX4, lipid peroxides accumulate and can, role of iron in this context is. Yet, the implications of the findings in turn, be targets for iron dependent degradation leading to presented here are manifold. For instance, the recognition that more lipid peroxidation and formation of toxic breakdown a small set of oxidized phospholipids steers the ferroptotic products. Our study also suggests an intriguing function for death process might be exploited in terms of its potential to vitamin E and closely related molecules as it is proposed that be used as a marker (i.e. biomarker) for certain ferroptosis- they are not only excellent general antioxidants in membranes related degenerative diseases. Considering the potential to but could directly and specifically inhibit lipoxygenases. pharmacologically manipulate ferroptosis by blocking ACSL4 Moreover, when the ACSL4 enzyme was inhibited by certain might present a valuable target for novel therapies. Notably, small molecules, including triacsin C and the antidiabetic class existing and yet to be developed ACSL4-specific inhibitors might of compounds glitazones, or it is genetically inactivated in be used in the context of disease conditions, where the early cells, cells became highly resistant to ferroptosis elicited either and massive loss of cells causes organ dysfunction and even by ferroptosis-inducing molecules or by the genetic deletion death. This might be particularly relevant for neurodegenerative of GPX4. This resistance mediated by ACSL4 was highly diseases, such as Alzheimer’s, Huntington’s and amyotrophic specific to this enzyme and unforeseen, as no other enzyme, lateral sclerosis (ALS), where neuronal cell loss eventually when inactivated, has yielded such a strong protective effect causes massive brain damage and death of affected patients. In against ferroptosis. Therefore, inhibiting ACSL4 by novel and fact, a recently performed meta-analysis of patients in Germany specific pharmacotherapeutic agents might represent a highly treated for more than two years with the type II antidiabetic drug efficient strategy in the context of pathologies, where premature pioglitazone (a glitazone which also inhibits ACSL4 as a side cell death occurs, such as in neurodegenerative disease, organ effect) highlighted that patients receiving such medication had a transplantation, kidney and liver poisoning, etc. 47% reduced risk of developing dementia relative to nondiabetic patients. Whether this is due to the expected antidiabetic action of pioglitazone or due to its inhibiting effect towards ACSL4 certainly deserves further studies. Finally, the finding that the presence of ACSL4 determines the outcome of chemotherapeutic strategies to eradicate cancer cell growth is highly intriguing.

Hence, ACSL4 expression analysis of tumor biopsies might aid in deciding what kind of treatment has the potential to be productive and yield the desired outcome in patients suffering from cancer, thereby avoiding treating cancer patients with little Fig. 2 or even non-effective chemotherapies. While being found to be true for a series of breast cancer cell lines, our findings on ACSL4 provide the rationale to further interrogate whether this Additional studies performed by our groups further revealed that holds true for other, still barely treatable tumor entities including the presence (i.e. expression) of ACSL4 in certain different breast pancreatic cancer, liver cancer, ovarian cancer and glioblastoma. cancer cell lines determines their sensitivity towards ferroptosis

HFSP Matters Issue N° 7 | December 2016 7 Frontier Science from HFSP Cross-Disciplinary Fellow Anupam Sengupta

A tryst with the sky for a peek into the sea by Anupam Sengupta

As I opted out of my comfort zone, Anupam Sengupta is an HFSP Cross-Disciplinary Fellow leaving my somewhat deterministic life researching at the broad interface of fluid dynamics, of a physicist, little did I know what marine biology, material sciences and theoretical it would take to retrain myself as a ecology. He is a mechanical engineering graduate of biologist, and to understand the ways the Indian Institute of Technology Bombay, India and of one of the smallest living organisms holds a PhD in Physics for his work on Liquid Crystal in our immediate ecosystem. I work Microfluidics, co-advised by Christian Bahr and Stephan with phytoplankton – organisms which Herminghaus, at the Max Planck Institute for Dynamics abound our lakes and oceans, and and Self Organization, Göttingen, Germany. In 2014, despite their minute dimensions, they Anupam Sengupta switched fields and moved to MIT play a vital role in our daily lives. These in Cambridge, USA with the HFSP Cross-Disciplinary photosynthetic organisms, ranging Fellowship to work on biophysical processes in marine from a hundredth to a thousandth of the environments with Roman Stocker. Since October 2015, size of a sand grain, maintain Earth’s he is based in Zurich, Switzerland, and continues his biogeochemical cycles, produce 50 % of research at the Institute of Environmental Engineering at the oxygen that we breathe, and provide ETH Zurich. Link to Anupam Sengupta’s website an alternative and valuable form of biofuel in a world plagued with incessant rapidly switch its swimming direction Thus, the Gedankenexperiment to environmental challenges. Known to when exposed to physical cues that test this hypothesis should be able to live as passive drifters or as active resembled turbulent eddies in an tune the strength of gravity without swimmers, phytoplankton are constantly ocean. Three years, and a few hundred complicating the surrounding fluid exposed to fluid flow. It is, however, still experiments later, we can say that such flow, while allowing the cells to keep a mystery how numerous phytoplankton behavioral adaptation is triggered by the swimming freely – a combination species are capable of swimming changes in direction of gravity relative that can readily become challenging, through the turbulent ocean waters to to the swimming direction of the cell: and difficult to realize under standard perform their customary diurnal vertical a frequent occurrence in the life of laboratory settings. However, this migrations: swimming against gravity plankton as they regularly get trapped wishful thought experiment turned into to the sunlit surface waters during the in eddies. This discovery (a story I a reality on October 22, 2016, when I day, and downwards, to the nutrient-rich hope to share on another occasion) took off on board a Zero-G flight (also deeper waters, at night. propelled a well-informed hypothesis – known as the parabolic flight), with gravity acts as a cue for phytoplankton two experiments and one question: how One month into my new life as a migration – which if true, would imply does a microscopic phytoplankton cell postdoctoral fellow at MIT, I was that changes in the gravity forces perceive changes in gravity? intrigued to discover how a fraction themselves can potentially influence of a phytoplankton population could these silent phytoplankton migrations. An Airbus A310, although innocuous at a first glance, was remodeled into a Zero-G flight, with designated spots allotted for each experiment to fit in. The phytoplankton experiment was one of the seven experiments selected from a call for the 2nd Swiss Parabolic Flight Campaign, the first full-scale Swiss research expedition into microgravity, which received support from the Swiss Space Office, the State Secretariat for Education, Research and Innovation of the Swiss Confederation (SERI) and University of Zurich’s Swiss Parabolic Flights initiative. The experiments were designed and constructed meticulously over quarter of a year, and tested to a painstaking detail to meet the rigorous safety requirements of the micro- and hyper-gravity conditions on board. Upon receiving the mandatory safety Flyers of the Swiss Parabolic Flight Campaign 2016 pose in front of the Zero-G flight after clearance from Novespace (subsidiary of touch down at the Dübendorf airbase. Image courtesy: Regina S (Novespace). the French Space Agency, CNES, which

8 HFSP Matters Issue N° 7 | December 2016 conducted the parabolic flight), it was time to finally experience weightlessness – for me, my cells, and my team members – all on our maiden voyage to the microgravity environment.

Through a series of parabolic manoeuvers, about 8000 meters above the Mediterranean Sea, we experienced 14 cycles of microgravity, and a cycle each of Martian and lunar gravity, all of them lasting 22 seconds. Alongside a combination of real time visualization set up (imaging individual microscopic cells as they swam) and a molecular experiment (to assess the changes in gene expression as a result of the changes in gravity), we acquired valuable experimental data, which will help reveal the mechano-genetic underpinnings of gravity perception in phytoplankton. Each weightlessness phase was flanked by 20 second long hypergravity intervals, during which the world turned twice as heavy relative to the usual Earth conditions. Interestingly, as scientists, we were (once again) a minority: the majority of my co-flyers were space enthusiasts, and patrons of science, who came from Europe and afar for the pure joy of experiencing weightlessness.

Notwithstanding the invaluable experimental opportunity, for me, the parabolic flight – a journey to the skies to fathom the depth of oceans – carried a special personal meaning: it was a Decking the Airbus A310 into a Zero-G flight. An overhauled passenger jet for conducting perfect example of the vision of cross- experiments under microgravity conditions (top) Image courtesy Regina S (Novespace). The disciplinary science that I have grown phytoplankton experiments on board Zero-G flight: real time visualization set up (bottom, left), up with. This was coming full circle, as and molecular experiment (bottom, right). the very reasons which took me away from the comfortable life of a physicist, take control of our lives on the ground. members, and local media seeking a brought me back to physics again. My The build up to the parabolic flight was quick news bite. It was a feeling of joy, maiden experience of weightlessness – a strenuous but the sheer might of gravity glory and achievement for many. For me, feeling so priceless and unforgettable – or the lack of it – erased away any it was a time to reflect on this incredible – swiftly ferried me to the heart of the inkling of weariness. After the 16 rounds journey – one which came with its fair fundamental laws of physics – the ones of parabolae, we finally touched down at share of daunting challenges, countless which govern us, but often go unnoticed the Dübendorf airbase – to welcoming little anecdotes, and limitless vistas for amidst the mundane things that tend to applause from the ground staff, family the next journey ahead.

On board Zero-G flight. final inspection of the experimental set up after installation in the flight (left), followed by official briefing by Novespace personnel (right). Image courtesy Regina S (Novespace).

HFSP Matters Issue N° 7 | December 2016 9 Matchmaking sciences & arts

by Mason Dean

The interdisciplinary laboratory “Image complex biological Knowledge Gestaltung” of the Herman materials, using the high- von Helmholtz Center for Cultural performing skeletons and Techniques has organized an intriguing teeth of sharks and rays exhibit, which started at the end of as models. The team uses September in the Martin-Gropius-Bau in various material testing Berlin, Germany. techniques to query the properties of the tissues, The “+ultra” exhibit probes the concept visualizes them with of Gestaltung, how we study design and high-resolution microCT form in natural and man-made systems, scanning, and then applies combining science artefacts from the parametric modeling and HFSP Young Investigator Grant holders Mason Dean time of Linnaeus to the present day – high-resolution 3D-printing (left) and James Weaver (middle) with Ahmed Hosny and incorporating the work of HFSP techniques to investigate (right) grant awardees Mason Dean from the their mechanics and Department of Biomaterials at the Max structure. This workflow, ray skeletons lurk next to engineering Planck Institute of Colloids and Interfaces using digital and physical mimics to diagrams of biological assembly and (MPIKG) in Potsdam, Germany and investigate biological form to scale up 3d-printed skeletons and teeth scaled to James Weaver at the Wyss Institute and render even the tiniest objects so 20 times their biological size, all tied for Biologically Inspired Engineering, they can be held in the hand, illuminates together in a neighboring animation of Cambridge, USA. Nature’s design constraints, but also the team’s techniques. The HFSP work queries productive interaction spaces is just one stop on +ultra’s rich tour, The 2013-funded HFSP project - between biology and engineering threading together hundreds of years combining biology and biomaterials sciences. of scientific pursuits. A vitrine likening science (Dean), and high-resolution crab appendages and modern surgical imaging, fracture mechanics, and physical It is this multi-disciplinary approach to tools; 18th century physiognomic studies modeling (Weaver) - was a natural fit to biology that is showcased in the +ultra compared with modern facial recognition the +ultra exhibit. Using HFSP funding, exhibit. The HFSP work is presented in software; urban and architectural plans the team and their colleagues from the a small section co-curated by Dean and echoing fractal and organic forms; steel Zuse Institute in Berlin have developed Ahmed Hosny (an architect working girder constructions and bony filigrees a unique analysis pipeline for studying at the Wyss Institute), where shark and speaking the same structural language.

10 HFSP Matters Issue N° 7 | December 2016 In leading the visitor through a diversity of disciplines, the exhibit always “Knowledge is Gestaltung (design) and Gestaltung produces places careful focus on process more than results: how are current scientific knowledge. However, the fact that that design actively shapes our questions constructed and then posed? perception of the world has been mostly overlooked so far: images, The exhibit’s structure seems designed models and tools are consciously formed, but they also shape the for such contemplation: at a focal point, knowledge they produce. The exhibition +ultra. Gestaltung creates a huge chaise cushion invites visitors to lay back together and immerse themselves knowledge reveals the fundamental role processes of design play in a massive ceiling projection, the in the sciences and humanities. From the hand axe to the digitally development of a tiny tunicate set to monitored organ, from active matter to image-guided actions – pulsing music, at the same time dreamlike and nervous. the exhibition deals with the increasing interdependence of the human and technological spheres and what challenges arise from The exhibit is an exciting, thought- this development. The displays analyze the current emergence of provoking combination of ideas and the digital and the analog, as we are steering towards a completely techniques, but can be enjoyed on many levels, from guided tours, to a scientist- new material culture. Spotlights on historical continuities as well led smartphone app, to self-led study as on profound transformations in the relationship between nature via the beautiful exhibit catalogue, or and culture sharpen our awareness for present developments.” simply by a casual stroll to soak up the captivating forms, sounds and interactive aspects of modern science. (Taken from the exhitbit description)

The exhibition is free of charge and runs from 30/09/2016 - 08/01/2017 in the Martin-Gropius-Bau Berlin, Germany. For more information about the Interdisciplinary Laboratory at Berlin’s Humboldt University or the exhibit “+ultra. Gestaltung creates knowledge” please visit their website at https://www.interdisciplinary-laboratory.hu-berlin.de/en/bwg/clusterausstellung/.

HFSP Matters Issue N° 7 | December 2016 11 Meet & Greet

HFSP at the ICCB meeting

17th HFSP Awardees Meeting HFSP was present as an exhibitor at the 12th International Congress of Cell Biology (ICCB) in Prague in July, 2016. The booth attracted many visitors from the cell biology community seeking information on the funding programs of HFSPO. It was also an occasion to catch up with HFSP alumni and members of our committees who attended the meeting.

Photo: HFSPO President Nobutaka Hirokawa speaking at the ICCB meeting.

HFSPO Secretary General meets Mr Nakasone

During a visit to Japan earlier this year, HFSPO Secretary General Warwick Anderson was honoured to meet with Hirofumi Nakasone, a member of the The 2017 HFSP Awardees Meeting will House of Councilors of the National Diet be held at the Champalimaud Centre for of Japan and son of the HFSP founder, the Unknown in Lisbon, Portugal from former Prime Minister of Japan, Yasuhiro 9-12 July 2017. Nakasone, upon whose initiative HFSP was founded. It was at the Venice G7 More information on this year's Awardees Summit in 1987 that Mr Nakasone Meeting can be found on page 3 of the proposed the launch of the Program newsletter. based on his idea of a long-term, global Hirofumi Nakasone (left) and Warwick Anderson research program fostering international cooperation for the benefit of mankind.

HFSP Science Meeting, Beijing, China

On November 11th, HFSP awardees and alumni from China gathered together with local officials, representatives of the embassies of the HFSPO member countries and members of the HFSPO Secretariat at the Grand Millennium Beijing hotel for a one day meeting.

The meeting featured talks on HFSP funded science and a poster session. It was an occasion to learn more about the Program and a great opportunity for our alumni to network.

12 HFSP Matters Issue N° 7 | December 2016 The 16th HFSP Awardees Meeting in Singapore

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1.The Nakasone Award Ceremony: (left to right) Nobutaka Hirokawa, , , Warwick Anderson 2. A poster session 3. Reception at the National Gallery 4. His Excellency Vivian Balakrishnan, Minister for Foreign Affairs, Singapore

In July 2016, HFSPO held its 16th Awardees Meeting at the Biopolis in "For me, the main advantage in HFSPO meetings is the chance to be exposed Singapore. The meeting attracted almost to cutting edge, high quality and high risk research in biology from all over the 160 Long-Term and Cross-Disciplinary world. These were my expectations and they were fabulously fulfilled.We had Fellows, Young Investigator and Program talks about bats, about mummified birds, about plants and slime moulds as well Grant holders and Career Development as everything in-between. The sheer diversity in biology was beautifully reflected Awardees. In addition, it was a pleasure in the meeting and this gave me a rare snapshot on what's new and interesting - a to welcome over 30 Singapore based snapshot that ideally journals like Nature would give, except they don't. In this scientists to the meeting. way the HFSPO meetings are truly exciting and inspiring. I do hope I can keep coming to them as an alumnus." In Singapore, we continued the success of the three-minute poster talks at previous Singapore for their generous contribution National University of Singapore and the meetings and introduced these shorter to the social program, which included Singapore Minister for Foreign Affairs, talks on all three days of the meeting, a cruise on the Singapore River and His Excellency Vivian Balakrishnan enabling us to accommodate 27 poster a reception at the National Gallery of were also very much appreciated by the teaser talks prior to the afternoon poster Singapore. audience. sessions in addition to 29 longer oral presentations. A total of 80 posters were The plenary speakers at this Awardees Feedback from HFSP awardees who presented. Meeting will be remembered for a very attended the meeting was overwhelmingly long time. It was the first time that the positive regarding the general We are very grateful to the National HFSP Nakasone Award was bestowed on organization and scientific program. Research Foundation of Singapore and two scientists, Emmanuelle Charpentier Awardees particularly appreciate the to A*Star Institute of Molecular and and Jennifer Doudna, who both presented unique interdisciplinary nature of the Cell Biology for their help and support very insightful talks about their work meeting, which enables them to meet in organizing this meeting. In addition on CRISPR. Plenary lectures from local with scientists outside of their field often we want to thank Nanyang Technical scientist Michael Sheetz, the Director leading to exciting new collaborations. University and the National University of of the Mechanobiology Institute at the Two comments from awardees, that are featured in this article, summarize perfectly the expectations and experiences “The meeting was beyond my expectations, and was probably one of the best of participants in the meeting. scientific meetings I've ever attended. The talks were very good and diverse, it's a great opportunity for networking and finding potential collaborators in a relaxed atmosphere and wonderful location. I wish I attended more meetings in the past.”

HFSP Matters Issue N° 7 | December 2016 13 Prizes & Awards You will find more prizes and awards in HFSP's Annual Reports on the HFSP website: http://www.hfsp.org/about-us/annual-reports

 Marina Rodnina (Research Grant awardee), Frank  The 2016 Brain Prize of the Grete Lundbeck European Bradke (Career Development Awardee) and Emmanuelle Research Foundation went to Timothy Bliss, Graham Charpentier (joint winner of the 2016 HFSP Nakasone Collingridge and Richard Morris for “their groundbreaking Award) were amongst the ten winners of the 2016 Gottfried research on the cellular and molecular basis of Long-Term Wilhelm Leibniz Prize from the German Research Foundation Potentiation and the demonstration that this form of synaptic (DFG). Each of the winners will receive 2.5 million euros to plasticity underpins spatial memory and learning”. All support their future research. three winners are HFSP Research Grant alumni who shared a grant in 1990 for a collaborative project on “Functions  The 2016 in Neuroscience was presented to and mechanisms of long-term potentiation and long-term of Brandeis University, Waltham, USA, who depression in the hippocampus”. received HFSP Research Grants in 1991 and 1994. She shares the prize with Carla Shatz and Michael Merzenich “for the  Research Grant alumnus John Diffley of the London discovery of mechanisms that allow experience and neural Research Institute and Francis Crick Institute received the activity to remodel brain function". Louis-Jeantet Prize for Medicine together with Andrea Ballabio.  The European Science Prize of the Koerber Foundation was awarded to Hans Clevers, a 1998 Research Grant  Franz-Ulrich Hartl, a 2011 Research Grant alumnus, has awardee. been awarded the 2016 Ernst Schering Prize.

Catching the unseen: how plasmids organize in bacteria

by HFSP Cross-Disciplinary Fellow Yong Wang and colleagues

A novel arrangement of bacterial plasmids was observed using advanced fluorescence microscopy, shedding light on how bacteria maintain plasmids of multi-copies and the associated antibiotic resistant genes.

Novel red fluorescent proteins enable visualization of two signalling molecules within a single dendritic spine

by HFSP Long-Term Fellow Tal Laviv and HFSP Program Grant holder Ryohei Yasuda and colleagues

Researchers at the Max Planck Florida Institute for Neuroscience and Stanford University teamed up to develop a new molecular tag which allowed visualization of two signalling proteins' activity in a single dendritic spine in real time.

Molecular engineering of acoustic protein nanostructures

by HFSP Cross-Disciplinary Fellow David Maresca and colleagues

Ultrasound is among the most widely used biomedical imaging modalities, revealing babies' first pictures and helping diagnose disease. Yet ultrasound has

Awardees' Articles Awardees' limited ability to image specific molecular targets due to the lack of nanoscale contrast agents.

Read more in the Awardees' Articles section of the HFSP website.

14 HFSP Matters Issue N° 7 | NovemberDecember 2016