EMBO goes East
Transcription
EMBO goes East
5/2015 CELL SIGNALING TECHNOLOGY EPIGENETICS: DISCOVERY THROUGH VALIDATION 69 CST antibodies for epigenetic-related targets, including histone modifications, epigenetic regulators, and general transcription factors. 22 CST antibodies validated for ChIP according to ENCODE* Consortium guidelines. Validated Tools for Discovery: » SimpleChIP® Kits to facilitate Chromatin IP from cells and tissue. » PTMScan® Kits and Services to enable MS-based discovery of methylated and acetylated proteins. Molecular model of chromatin. www.labtimes.org » Most ChIP-validated antibodies approved for additional applications like IHC, Flow, IF and WB. Learn more at: www.cellsignal.com/epigeneticdiscovery *Landt S.G. et al. (2012) Genome Res. 22, 1813–1831. © 2015 Cell Signaling Technology, Inc. Cell Signaling Technology, CST, PTMScan, and SimpeChIP are trademarks of Cell Signaling Technology, Inc. U FA CT AN U 15PADEPIGNONE0079ENG_00 M TI EN N G P R AC T GOOD RI cGMP CE • CUR R © 2015 Cell Signaling Technology, Inc. Cell Signaling Technology, CST, PTMScan, and SimpeChIP are trademarks of Cell Signaling Technology, Inc. 15PADEPIGNONE0079ENG_00 LT_515_OC_OC.indd 2 03.09.15 13:17 LT_515_IC_IC.indd 2 03.09.15 12:50 Editorial 5-2015 Lab Times page 3 When Scanning Through… Photo: www.publicdomainpictures.net/Kevin Casper …the latest articles of the German newspaper Süddeutsche Zeitung (SZ) and the French francetvinfo.fr, which denunciate the disgusting and nasty habits of some producers and sellers of Fetal Calf Serum (FCS), the Lab Times editor experienced a peculiar sense of déjà vu. The story sounded strangely familiar – and then it hit him. Wasn’t there an almost identical story that appeared in the German weekly news magazine, Spiegel, more than 20 years ago? That’s right! Searching the Spiegel archive, he had quickly dug up the old article, dated January 25th, 1993. Under the heading “Science”, the magazine, based in Hamburg, circumstantially reported on the dubious practices in the FCS business (Spiegel 4/1993, pg. 190-3). In the introductory part of the article, it says: “Every year, two million cattle fetuses are tapped for their blood, to produce culture medium for GM technology and pharma industry. Serum procurement is often controlled by traffickers and a slaughterhouse mafia. ‘Blood brokers’ sell unpurified, possibly contaminated, products from South America on the black market.” The Spiegel article from 1993 already mentions a certain Henner B. or Henner Brettschneider, who, as (former) owner of the French serum producer, Biowest, headquartered close to the north-west French town of Cholet, did his business with the help of slaughterhouses in the Brittany and the Normandy, supported by German middlemen. And already back in 1993, the Spiegel editors noticed there was something fishy about the Austrian serum seller, PAA, which was bought by GE Healthcare in 2011 and, shortly after, turned out to be a serum adulterer. In Lab Times 6-2013, we reported on page 39 (“Undeclared Extras”) about the company’s rise to stardom in the FCS scene and its recent crash. Twenty years earlier, the Spiegel editors also had their doubts about PAA’s integrity: “The Austrian company, PAA, in Linz, is a typical example for the inconsistencies in the serum business. In a newsletter, it offers serum batches of two tonnes each, originating from Hungary, ‘sterile-filtered, in plastic bottles’. It is, however, impossible for Hungary (monthly yield: about 90 litres) to produce such enormous batches.” The “current” revelations from the Süddeutsche Zeitung and francetvinfo are nothing new – and that’s the real scandal. Thanks to the Spiegel and Lab Times reports, everyone involved with Fetal Calf Serum, including the scientists as serum ‘consumers’, must have known for at least two decades, what goes on behind the scenes of FCS production. Despite that knowledge, FCS usage increases year by year. Even the increasingly exorbitant prices over recent years, do not appear to deter scientists from adding FCS to their cell culture medium. LT_515_03_03.indd 3 But likewise, for decades, suitable alternatives to FCS have been in existance. The pioneers in the serum-free cell culture of mammalian cells, David Barnes, Gordon Sato and Leonard Keay, developed defined cell culture media back in the 1970s, already. Almost ten years ago, the US-American stem cell expert, James Thomson, and his group introduced a defined medium for culturing stem cells that contains merely eight essential ingredients and that is now also commercially available. And Gerhard Gstraunthaler’s group in Innsbruck, Austria, has been experimenting with human platelet lysate prepared from common platelet units as a substitute for FCS for some time. There are so many more examples for serum-free cell culture media, if you only look for it. Perhaps you don’t even have to look further than our latest product survey, which lists cell culture media from several producers (pg. 48). The portfolio of almost any producer of cell culture media includes serum-free and/or chemically-defined media. Why then is it so hard to forgo the beloved calf serum and switch to serum-free media? The US-American science portal, Science Advisory Board, asked 377 bioscientists whether they currently use serum-free cell culture media. Not less than 56 per cent of the survey participants responded, Yes. As a reason, a quarter of the scientists said they do not want components of animal origin in their experimental set up. Another quarter said they use serum-free media because they get more consistent results. Why did the other 44% still rely on FCS-containing media? The three most common reasons were: “difficulties adapting their cells to the new medium” (40%), “high costs” (28%) and “lack of commercially available alternatives” (28%). And how about you? Do you still use Fetal Calf Serum? Can you do without FCS, or won‘t your cells grow without it? At least since the latest revelations, it’s hard to keep on ignoring the facts. The scientific community has to stand up to this topic and seriously look for ways out of the dependencies on shady profiteers. This editorial also appeared in our German-language sister journal, Laborjournal. 04/09/2015 09:29 page 4 Lab Times Contents 5-2015 News Photo: www.mascarille.com Picture of the issue / The future of genetics and genomics research / Mass retractions at Springer and the Serbian Archives of Biological Sciences / Recently awarded / Digital technology controversy / Singapore is first non-European EMBC Associate Member / Special arrangements for refugees at German universities / Why rabbits are relatively immune to prion diseases_____ 6-13 Opinion Observations of The Owl (56): Take Time to Think____________________________________ 14 Research letter from... Russia: When is Right to be Left?_______________________________ 16 Over the Line? (23): Swallowing the Ball__________________________________________ 17 Adding a few data points here, modifying graphs there, Charles-Henri Lecellier prefers convenience. Even worse, his employers seem to prefer convenience, too (p. 24). Analysis Cover Story Ironically, even an accredited WADA antidoping laboratory seems to have major problems in performing correct and reproducible doping analyses _______________________________ 18 Scientific Misconduct Two friends don’t take Good Scientific Practice very seriously ___________________________ 24 Excellent research Funders and politicians want more “excellent research”. But what does ‘excellence’ mean? _____ 28 Photo: Gergely Balázs Journal Club Helsinki/Finland Which factors drive brain evolution in threespine sticklebacks?___________ 32 Brno/Czech Republic Chromosome painting reveals the origin of Boechera species’ genomes__ 34 They look like jelly babies but these are formalin-fixed fish brains. Studying evolution, Juha Merilä revealed that neural tissue does not have severe genetic constraints (p. 32). Publication Statistics Cell biology research in Europe_________________________________________________ 36 What’s behind paper retractions? (30): Want to End Fake Peer Reviews? ___________________ 39 Biobusiness Photo: Inge Matthies News Funding: CRISPR-Cas9 on the advance / FDA releases biosimilar naming guide______________ 40 Mitochondrial replacement therapy (MRT) under fire The clinical introduction of MRT in the United Kingdom raises the question of whether we know as much as necessary about MRT. Our Lab Times author argues that we don’t_______________ 42 Company portrait The five-member start-up, Zetadec, located in the Dutch centre of life science and research, is pursuing exceptional approaches for the food industry________________________________ 45 Service Foto: American Chemical Society Photo: Tobias Frygar The Dutch company Zetadec assists their industrial clients in developing new foodstuffs, as well as testing ingredients and propagating surprising new paths in nutrition (p. 45). Product survey: Cell culture media_____________________________________________ 48 Methods Tips and tricks of the trade: Quick, easy and cheap protein visualisation___________________ 55 Bench philosophy: Isothermal DNA amplification____________________________________ 56 New products _____________________________________________________________ 58 Book reviews Grandmother Fish. A child’s first book of evolution. By Jonathan Tweet & Karen Lewis__________ 59 The Story of Everything. A pop-up book with pops, flaps and tabs. By Neal Layton____________ 59 Careers Career strategies for young European scientists (LVI) Quirky career paths (1): From cell biologist, via Nature editor to social studies of science _______ 60 Jobs____________________________________________________________________ 62 Calendar________________________________________________________________ 63 Researchers have developed various isothermal DNA amplification techniques, which function significantly faster than PCR and without expensive thermocyclers (p. 56). LT_515_04_05.indd 4 Humour Paul the Postdoc___________________________________________________________ 06 Contact__________________________________________________________________ 64 Laboratory Tales____________________________________________________________ 67 03.09.15 14:38 Visit us at the BIOTECHNICA 2015 HALL 9, BOOTH F13 Generation E Multipette® E3 & E3x: Dispensing without compromise The new electronic dispenser is the one pipette missing in your set. It is perfect for special tasks going beyond the limitations of a standard pipette. In addition, the motor drive minimizes operation forces, thus reducing the risk of repetitive strain injuries following the Eppendorf PhysioCare Concept ®. > Save time by pipetting up to 100 times without a refill > Achieve correct results handling nonaqueous liquids without extra effort > Work safely as the hermetically sealed piston provides protection from radioactive or toxic liquids www.eppendorf.com/multipette-system Frost & Sullivan® is a registered trademark of Frost & Sullivan Corporation, USA. Eppendorf®, the Eppendorf logo, Multipette®, and PhysioCare Concept® are registered trademarks of Eppendorf AG, Germany. U.S. Design Patents are listed on www. eppendorf.com/ip. All rights reserved, including graphics and images. Copyright © 2015 by Eppendorf AG. LT_515_04_05.indd 5 03.09.15 14:38 Lab Times News 5-2015 Picture of the issue Through Ecologists’s Eyes W Photo: Mark Auliya/CC-BY 4.0 ho’s in danger? Counter-intuitively, it’s not the farmer in the back but the Oriental Rat Snake (Ptyas mucosa) in front. “Since the early 20th century, the species is involved in the international skin industry. In 1990 the species was listed on Appendix II of CITES (Convention on International Trade in Endangered Species of Fauna and Flora) that regulates trade by an export permit, which is granted through the relevant management authorities. Particularly populations on Java (Indonesia) are intensively harvested for their skins,” says Mark Auliya from the Helmholtz Centre for Environmental Research in Leipzig, Germany. With this photo, he recently participated in an image competition, hosted by BMC Ecology. Even though he didn’t win, his photo earned a “highly commended” seal of approval in the Need for Protection section. “The proximity of the snake to the person is nicely demonstrated in this image, silently emphasizing even more the vulnerability of this highly sought-after animal,” the judges ruled. Held for the third time, the BMC Ecology Image Competition was originally launched to showcase ecologists’ view of nature, or in more flowery words: “Across the four oceans and seven continents, ecologists study the wondrous organisms, interactions and locations that, combined, make up our own house, the planet Earth […] They are the connoisseurs of the beauty and mystery of our natural surroundings, so who better to act as field guides to show us our collective home.” This year, the judging panel had to wade through over 200 image submissions. In the end, they picked an image of “quiet beauty”, depicting a Palestinian sunbird seeking nectar in a prickly thistle (Echinops sp.), to be the overall winner. The image was taken by Mohamed Shebl from Suez Canal University Ismailia, Egypt. -KG- Paul the Postdoc Even during The holidays... LT_515_06_13.indd 6 Photo: Mohamed Shebl/CC-BY 4.0 page 6 by Rafael Florés science is always present for true scientists. 03/09/2015 13:09 Intuitive Programming at Your Finger Tips Most Advanced Sample Preparation System Available! Delivers the Most DNA, RNA and Proteins from the Most Resistant Samples in 40 seconds or Less! •Most Powerful - Highest speed, shortest proces sing improves yield and purity of the analyte. •Most Versatile - Optional adapters process from 2-50mL, ambient or cryogenically. •Best Software - Intuitive, user friendly programming, over 70 recommended protocol programs. •Most Complete - Lysing Matrix Tubes and FastPrep® Purification Kits from One Source for best results! Request a Demo from MP Biomedicals! www.mpbio.com/FP24-5G MP Biomedicals Europe, Tel: 00800 7777 9999 • email: [email protected] LT_515_06_13.indd 7 03/09/2015 13:09 Lab Times News 5-2015 Future of genetics and genomics Predictive Power Recently Awarded It can be said with some certainty that more than a few would give their right arm for a glance into the future. Sadly, not even science can make this wish come true but it at least allows some educated guesses. Recently, PLoS Biology invited eight experts in genetics and genomics research to predict where their discipline is going within the next ten years (PLoS Biol, 13(7):e1002216). Among the fortune-telling Eight are Ian Dunham from the European Bioinformatics Institute (EMBL-EBI), at Hinxton, UK; Peter Donnelly and Gil McVean, both at The Wellcome Trust Centre for Human Genetics, University of Oxford, UK. Dunham, who, according to his website, has been “involved in genomics since around the time the term was coined” muses about the challenges that must be overcome within the next decade. Methods must be developed, he says, that “seamlessly connect” genome-wide data obtained Honouring the “most creative and productive stars in their field”, the Boston-based Bert L and N Kuggie Vallee Foundation picked three young scientists from Europe to receive the foundation’s 2015 Vallee Young Investigator Award. The lucky trio is: Martin Jinek (University of Zürich, Switzerland), Fabiana Perocchi (Ludwig Maximilian University, Munich, Germany) and Rickhard Sandberg (Karolinska Institutet, Stockholm, Sweden). Jinek studies the CRISPR-Cas9 system, focussing on the Cas9 part. With his research, he wants to overcome current limitations of the system, when used as a genetic engineering tool. Perocchi’s work revolves around mitochondrial signal transduction cascades in health and disease. Amongst others, she is interested in mitochondrial calcium uptake. In Stockholm, Rickhard Sandberg employs single-cell genomics and bioinformatics to work out how gene expression is regulated during early embryonic mouse development. The award comes with a prize money of $250,000 (approx. €235,000), which is to be used for basic research. -KG- LT_515_06_13.indd 8 Photo: www.publicdomainpictures.net/Junior Libby His entire life, Enrico Coen from the John Innes Centre, Norwich, UK, has been “obsessed” with shapes and colours, of leaves and flowers that is. For his work, he has now been awarded the Croonian Medal from the UK’s Royal Society that entails a lecture and a gift of £10,000 (ca. €14,000). Coen’s research involves a range of methods, including microscopy, computational as well as molecular biological approaches, and model organisms (Arabidopsis, Antirrhinum, Utricularia). With Arabidopsis, he, for instance, wants to decipher the role of microtubules and nuclear movements in the control of leaf cell division and growth, to understand leaf development better. Antirrhinum species or dragon flowers are perfectly suited to study the evolution of flower colour. Therefore, Coen uses them to “identify key genes controlling flower colour that are under selection”. tronic health data,” he predicts. This data can then be used to answer complex genetic questions, like the consequences of a certain mutation on the carrier’s health or the safety of a specific drug, in silico. Last but not least, Gil McVean, who specialises in statistical genetics and contributed to, for instance, the International HapMap Project, shares his futuristic view on big data. “The coming years will only see the data rush grow: bigger samples, new species, extinct species, data linked to phenotype, temporal data, and so on.” We shouldn’t, however, be afraid of the data deluge coming upon us but take advantage of it, to finally find answers for the big questions in evolution. Because these questions can be best answered with a comparative approach, he says. “What I’m looking forward to is, of course, more data. But this time I don’t just want it from one (albeit mildly interesting) species. I want it from all of them,” McVean proclaims. So, what can we expect from genetics and genomics research in the next decade? A lot more data, that’s for sure, but also answers to until now open scientific questions, which may even lead to medical advances. Or could it be, as corresponding author Chris Tyler-Smith from The Wellcome Trust Sanger Institute, at Hinxton, points out, that “the future will almost certainly be stranger and, consequently, even more exciting”? Retractions at Springer and ABS Summer Sort-Out One doesn’t need to be a psychic to predict the future of genetics and genomics research: more data from the likes of genome-wide association studies (GWAS), chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing, to, for instance, cell-specific behaviours in health and disease. This would “really bring biology in silico”. Mathematician Peter Donnelly looks into the future of clinical medicine. “The cost of high-coverage whole human genomes has plummeted to the point at which this information is starting to be collected as part of clinical medical care. […] Within 15 years, there may be one billion humans whose genomes have been sequenced, in many cases with links to elec- In a new wave of setting the scientific record right, two publishers recently flushed out a host of papers that should never have been published in the first place. The first tsunami has its origin in Serbia. As Retraction Watch reported, the open access journal Archives of Biological Sciences (ABS), a multidisciplinary journal published by the Serbian Biological Society, recently retracted 16 articles and corrected two. An internal investigation had made this cleanup operation necessary, which also included replacement of the entire editorial board. “In the summer of 2014, the Archives of Biological Sciences was singled out as a scientific journal that had veered away from the ethical publishing practice of scientific journals and was placed on the list of predatory journals. Members of the scientific public in Serbia directly affected by the accusations were mobilised, and after thorough investigation it was concluded that many of these ac- 03/09/2015 13:09 10.018 sign-berlin.de page 8 ISO 9 0 0 1 CERTIFIED COMPANY ISO 13485 Iron Overload? Molecular test for hemochromatosis risk IVD Mutations in the HFE gene are responsible for more than 90% of all hemochromatosis cases. Our LightMix® Kit HFE detects the most impor tant mutation Cys 282 Tyr as well as His 63 Asp and Ser 65 Cys. Order number 40-0340 LightMix® Kit HFE 282/63/65 The LightMix® Kit HFE has been developed to work with the LightCycler® Instruments 1.2/1.5, 2.0 and 480 using the channels 530 (F1) and 640 (F2). The kit contains the Roche Diagnostics LightCycler® FastStart DNA Master. 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Email: [email protected] Tel. +39 010 362 83 88 Fax +39 010 362 19 38 ESPAÑA TIB MOLBIOL sl Email: [email protected] Tel. +34 91 344 6642 Fax +34 91 344 6670 03/09/2015 13:09 page 10 Lab Times Photo: www.publicdom ainpictures.net/Ge orge Hodan cusations were founded,” the new editorial team, led by Goran Poznanovic, from the Institute of Biological Research in Belgrade, wrote in an announcement in June. The journal’s current issue features six retractions; two had already appeared earlier this year, in issue 1. Behind the retractions is plagiarism, in most cases. Either the authors had copied the entire paper (or the majority of it) word for word or they reused data from an earlier publication without proper referencing. “The new editorial team will continue to correct all mistakes while striving to ensure accurate, timely, fair and ethical publication of scientific papers that the ABS has been traditionally known for. We have invited all readers of the journal to directly contact the editorial office to report cases of publishing malpractice,” Poznanovic told Retraction Watch. Plagiarism is not what caused a second tidal wave of retractions, this time at Springer. Sixty-four articles in ten Springer titles, including Molecular Neurobiology, Tumor Biology and Molecular Biology Reports, were withdrawn from the scientific record In the bin! More than 70 papers have recently been disposed of by Springer and a Serbian biology journal for faked peer reviewing. “After a thorough investigation we have strong reason to believe that the peer review process on these 64 articles was compromised. We reported this to the Committee on Publishing Ethics (COPE) immediately,” the publisher said in a statement. This scam to manipulate the peer review process seems to be on the increase in recent times. Not long ago, BioMed Central had to pull more than 40 articles after realising that “some author-suggested reviewers appeared to be fabricated”. But publish- LT_515_06_13.indd 10 News 5-2015 ers have been sensitised and are ready to take action. “The peer-review process is one of the cornerstones of quality, integrity and reproducibility in research, and we take our responsibilities as its guardians seriously. We are now reviewing our editorial processes across Springer to guard against this kind of manipulation of the peer review process in future,” the publishing house assures. Digital technology controversy Solid Base Can Facebook trigger autism in young people? Or do computer games make us more aggressive? Does Google make us dumb? The answer to all those questions is yes – that is, if you buy into the claims made in the 2014 popular science book, Mind Change, by British neurophysiologist, Susan Greenfield. Through appearances and interviews, Greenfield has promoted her views extensively but now three researchers counter her claims in an editorial for BMJ, asking Greenfield to adhere to the scientific method and publish her hypotheses in peer-reviewed journals. “As scientists working in mental health, developmental neuropsychology, and the psychological impact of digital technology, we are concerned that Greenfield’s claims are not based on a fair scientific appraisal of the evidence, often confuse correlation for causation, give undue weight to anecdote and poor quality studies, and are misleading to parents and the public at large,” write Vaughan Bell (University College London), Dorothy Bishop (University of Oxford) and Andrew Przybylski (University of Oxford). To prove their point, the three scientists, amongst others, cite research, showing the exact opposite of Greenfield’s claims to be true. Thus, playing action video games has been shown to have a positive effect on the neuropsychological performance, for instance. Replying in the Australian, Greenfield clarifies: “I have never suggested that reasonable use of the internet damages the adolescent brain.[…] However, intense use of the internet and video games does indeed lead to changes in the physical brain comparable to drug abuse”. Obviously, any claim made in public should be based on solid scientific studies. In her book, however, Greenfield had to “synthesise the literature in a meaningful way that would be accessible to the general reader”. The three researchers, writing in BMJ, think otherwise. “There is al- ready much research into the many concerns about digital technology, and the public deserves to participate in the debate fully informed of all the evidence.” Singapore becomes EMBC member state EMBO goes East For some, it’s the perfect holiday destination, for others, Singapore provides all the amenities for a happy and successful researcher life – great infrastructure, good atmosphere and generous funding (see also LT 3-2013 and 4-2013). And the investment in research has certainly paid off. Our own publication analysis, for instance, consistently lists the Southeast Asian city-state as one of the best when it comes to citations per article, in a wide range of research disciplines. Reason enough, to take advantage of all the expertise, thought the European Molecular Biology Organization (EMBO) and its funding body, the European Molecular Biology Conference (EMBC). Recently, they made Singapore the very first EMBC Associate Member State. “We are extremely pleased to welcome Singapore as the first EMBC Associate Member State. Since it was founded, EMBO has viewed cross-country cooperation as an essential foundation for the growth of science. The scientific community in Singapore, with its strengths in research and technology development, is a perfect partner for the exchange of expertise and we look forward to further collaboration in the years ahead,” EMBO director, Maria Leptin, said in a press release. The agreement between the government of Singapore (represented by the Agency for Science Technology and Research, A*STAR) and EMBO will come into effect at the beginning of next year and is scheduled to run for three years. Building on an earlier agreement, signed in 2011, that allowed scientists based in Singapore to apply for EMBO Short-Term and LongTerm Fellowships as well as the EMBO Young Investigator Programme, the cooperation has now been renewed and intensified: Singapore scientists can still apply for Fellowships and one group leader per year is eligible to join the EMBO Young Investigator Network. Other activities include: Funding for an EMBO workshop in Singapore, support for keynote lectures given by EMBO members at conferences in Singapore and travel stipends to attend EMBO courses and workshops, and the EMBO meeting in Europe. Scientists based in 03/09/2015 13:09 my lab balance because it is just as individual as I am. #passionforscience Cubis®. The first modular-designed lab balance series. Combine your choice of display unit, weighing module and draft shield to configure the balance you really need. Customize it with downloadable Q-Apps and meet even future requirements. Share your #passionforscience on www.passionforscience.com Weighing | Lab Water | Centrifugation | Liquid Handling | Filtration | Microbiological Analysis | Services LT_515_06_13.indd 11 03/09/2015 13:09 page 12 Lab Times News 5-2015 Europe can, in turn, apply for financial support to attend EMBO workshops in Singapore. The next one, on “Telomeric chromatin and telomere fragility”, for instance, takes place at Nanyang Technological University, between December 7th and 10th. “We are confident that this agreement will spur international collaborations in world-class scientific research, which will pave the way for new biomedical discoveries and global healthcare solutions”, Lim Chuan Poh, Chairman of Singapore’s A*STAR is certain. Help for refugees at German universities University Support Hardly a day passes without news that another non-seaworthy boat full of people, in desperate search for a better life in Europe, has crossed the Mediterranean Sea. According to the UNHCR, the UN refugee agency, more than 100,000 people, mainly from Syria, Afghanistan and Iraq, have ar- rived on Italian, Greek, Maltese and Spanish shores in 2015, to-date. Although university access might not be the first thing on the refugees’ minds, after arriving in Europe, in the long run, academic training might be key to making the dream of a better life come true. Setting a good example, German universities started to make special arrangements for refugees and migrants, wanting to study in Germany. In August, for instance, the Saarland University announced, refugees and migrants who don’t have proof of their university entrance qualification, can still enrol in STEM courses like systems engineering and informatics by simply passing a qualifying examination and a German language course. “With this programme, we want to create a non-bureaucratic access for refugees, to give these talented young people a bright future in Germany,” said university president Volker Linneweber in a press release. Other activities at German universities include financial help, waiver of semester fees, psychosocial support, information Y events, legal advice, help to find accommodation and free rides in buses and trams. A recent survey by the German Rector’s Conference (HRK), the political and public voice of universities in Germany, revealed that more than 60 of the country’s universities had such arrangements. Especially many activities are at the Universities in Bremen, Erlangen, Hildesheim, Ulm, Hohenheim and Munich, according to the HRK press office. “We are concerned to see that people are reacting with uncertainty to the influx of refugees and that in some places xenophobia is increasing. Through activities like these, universities are making an important contribution to the social integration of refugees and sending out a signal for an open, forward-looking society,” said Horst Hippler, HRK president in a press release. “I would like to encourage universities to make full use of the scope allowed by law to offer refugees encouraging prospects”, Hippler added. -KG- Carrot-Nibbler Offers Resistance Rabbits are relatively immune to prion infections. French scientists wanted to know why. Vincent Beringue from INRA Virologie Immunologie Moléculaires, Jouy-en-Josas, France, and colleagues tried to answer that question by creating transgenic rabbits, expressing a scrapie-susceptible ovine PRNP allele of the PRNP gene (encoding the PrP protein) on a rabbit wildtype PRNP background (PLoS Pathog, 11(8): e1005077). Then they exposed their test subjects to sheep prions via intracerebral inoculation and waited half a year. All animals with the sheep transgene showed clear signs of TSEs (PrP deposition and vacuolation in the brain, vision loss, loss of balance, disordered gait, etc); the control wildtypes, however, stayed healthy. “This demonstrates that rabbits do not bear non-PrP factors that make them intrinsically resistant to prions,” Sarradin et al. concluded. When analysing the brains of infected rabbits closer, the scientists found only ovine PrPSc’s. This finding made the scientists hypothesise that the sinister transformation of normal PrPC to sickening PrPSc perhaps just takes a bit longer. They assume that the conversion rate of rabbit PrPC is very low. Summing up, Beringue and colleagues have come to realise that neither “rabbit genetic background and rabbit PrPC (can) explain the apparently low susceptibility of rabbits to prion infection. What makes the rabbit species comparatively resistant to prion disease remains to be clarified”. So, for now, the little furballs can keep their secret. Photo: www.publicdomainpictures.net/Jamie Hutt P rions – six letters that send a frightful fear down many peoples’ spines. These proteinaceous pathogens are believed to be triggers of, for instance, mad cow disease, scrapie (in sheep and goats) and Creutzfeld-Jakob disease in humans – all of them fatal neurodegenerative diseases, collectively known as transmissible spongiform encephalopathies, TSEs. On the molecular level, prions are nothing other than misfolded isoforms of the natural-occurring prion protein, PrP. Strangely, the abnormal form (PrPSc) somehow “coaxes” the normally folded protein (PrPC) to follow suit and fold wrongly, leading to protein accumulations and, eventually, cell death. PrPC’s normal function in neurons is still in the unknown; some studies, however, suggest that it binds copper and could be involved with copper sequestration and internalisation or protection against oxidants. Many mammals can fall ill from TSEs but there’s one tiny creature that seems to somehow defy the odds: the rabbit. For many decades, scientists tried to transmit Kuru, Creutzfeld-Jakob disease or sheep scrapie; alas, with little success. Rabbits were thought to be a prionresistant species. Only three years ago, an international team of researchers proved the dogma to be wrong (PNAS, 109(13):5080-5). “Despite rabbits no longer being able to be classified as resistant to TSEs, an outbreak of ‘mad rabbit disease’ is unlikely,” the authors commented, as quite some effort was needed for that result. So, what makes rabbits “relatively resistant” to prion infection? -KG- (More research results from European labs on pp. 32-35) G B F U LT_515_06_13.indd 12 03/09/2015 13:09 Your Power for Health My first choice for cell culture products ... Read more ... because I rely on a competent partner! 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Ltd., [email protected] l Netherlands: Greiner Bio-One B.V., [email protected] UK: Greiner Bio-One Ltd., [email protected] l USA: Greiner Bio-One North America Inc., [email protected] www.gbo.com/bioscience LT_515_06_13.indd 13 03/09/2015 13:09 page 14 Lab Times 5-2015 Opinion Observations of the Owl (56) Take Time to Think N o doubt about it, science needed – which most of the time is reeeeally monotonous work. needs heroes. Oh, yes – I No wonder, therefore, that Bushtit inevitably started thinking can virtually see how many about his “problem”, while endlessly flying back and forth to the of you immediately wrinkle your nest. And once he had finally realised that something must be funbeaks and noses upon that asserdamentally wrong with his extraction strategy (around flight no. tion. But don’t you think it’s simply 820), it wasn’t much longer before his brain identified the “error” appropriate to honour and praise (around flight no. 900) and produced the solution (around flight those, to whom we owe some of no. 980). Only a couple of weeks later, Bushtit proudly presented the most important insights into the long-sought moulting factor to the scientific bird world. our world and lives? Regardless of Nice little anecdotes, aren’t they? Did you notice something? their sometimes admittedly... well, Perhaps some kind of common pattern? Yes, that was easy: all special characters. three developed their critical breakthroughs or had their eureka A more important point, however, is that in this way they can moments, while primarily engaged in completely different activiserve as pretty good role models – at least as far as the ways of deties – somewhat boringly monotonous activities, in fact. veloping really great ideas are concerned. Even if I might risk borMany say that monotonous and largely mindless activities ing the feathers off my winged colleagues, let me tell you three can trigger your brain to fly to unknown heights. But I don’t think exemplary stories of eminent “heroes” in our avian life sciences... that this is the crucial point here. Actually, most of the practiFirst of all, there is famous Professor Sandpiper, who, decades cal laboratory work is extremely monotonous – and be honest, is ago, discovered how, by applying an inner compass, the brains of your brain flying particularly high when pipetting hundreds and my migratory fellows build up a mental map and use it to precisethousands of probes over days and weeks? ly navigate their marathon flights over several thousand kilomeI think what’s more important, is that you simultaneously tres to their final destination. And guess when she developed the take a step back from your currently pestering but often deadkey idea and concept, which finally led to the experimental revelocked problem. And by gaining some distance you may suddenly lation of the whole process? Exactly! During one of her seemingly get a clearer and broader view, allowing you a deep new insight never-ending flights to her southern-winter domicile. “Aside from into the question from different and hitherto neglected angles. navigating, there were obviously still some free neurons in my At least, this is what obviously happened to Sandpiper, Kiwi brain for thinking – and believe me during the flight I had plenty and Bushtit. And fortunately, every bird scientist will always find of time to do exactly that,” was one of her famous quotes. time to step back and take a new look at their problem(s), since Then there is the grand old man of bird immunology, Proover and again, as in the examples above, our ornithological nafessor Kiwi. He belonged to a Kiwi species, where incubating ture leaves us no other choice than to let go of them for a while. the eggs is solely the male’s job – for a reThe same is apparently not true for you hucord-breaking period of up to 90 days! A peri“The whole theory was hatched mans. I remember a conversation on this isod leaving no time at all to put claw, beak and and developed while doing noth- sue with my human friend Renaldo, in which wing to any experiment, logically. This, howing other than sitting on an egg.” he quite angrily ranted about an article in your ever, doesn’t necessarily mean that this time Nature magazine. Over three pages, the article is completely void of science. Kiwi proved this in a most imprespretty much lauded a certain researcher for demanding that his sive way. One year, when his offspring had freshly hatched, he PhDs and postdocs spend more than 120 hours over seven days stepped out of his breeding burrow, spread his wing-stumps and per week in the lab – as he was doing himself, of course. What a triumphantly said, “I think I now know how our immune system load of chicken shit! Fortunately, this is not every PI’s maxim. Reactually manages to produce and coordinate those myriads of difnaldo continued to tell me about a wise and considerate research ferent, highly specific antibodies.” So, what has since gone into director who, instead, advised his our textbooks as the “select and link theory” of the avian immune students to always try schedulsystem was actually hatched (scuse the pun) and developed while ing their experiments, so that they doing nothing other than sitting on an egg. have the weekends free to do someAnd, lastly, there is the story of Bushtit. He was still a postdoc thing completely different. In fact, when, one spring long ago, he desperately tried to extract and that was how he had been handling identify a certain molecule, which he suspected to operate as the it ever since his own PhD. And this key signal for starting the regular feather moult. For weeks, his specific guy, Renaldo emphasised, experiments brought no results – but with each failed extraction, as the final icing on the cake, had he grimly attacked the next one with even more grit and determieven won a heroic Nobel Prize for nation. Until one day, when from one moment to the next, he was his postdoc work. forced to halt his experiments completely – no longer could he esSo, who is the better role modcape his hormones, which were screaming at him to start building el: This noble “hero” or Mr. Chicka nest right now. Well, I should mention that bushtits build very en-Shit? complex nests; it takes weeks alone just to collect all the materials Comments: [email protected] LT_515_owl.indd 14 03.09.15 15:13 *onlLianb Times is also availab le as e-pa e or offlin per for e r e a ding on yo tablet, no ur compu tebook or ter, smartpho ne – it’s f ree! LT_515_15_15.indd 1 07.09.15 13:19 page 16 Lab Times Opinion 5-2015 Research Letter from:… Russia When is Right to be Left? By our corresponding author, Kakiye Storony M ost humans are right-handed – they favour their right hand over their left when doing things. But why? The origins and significance of handedness in humans are unclear but theories and ‘studies’ are in abundance (as shown in the Wikipedia entry on ‘Handedness’). Now, however, a group of Russian researchers claim to have obtained the first demonstration ‘at the population level’ of handedness in animals, other than humans. In their recent article, Andrey Giljov et al. see a “Parallel Emergence of True Handedness in the Evolution of Marsupials and Placentals” (Curr Biol, 25(14):1878-84). Observing seven species of marsupial in zoos and nature reserves, they looked at how these animals use their ‘forelimbs’ and found that two species of kangaroo (eastern grey and red) are ‘left-handed’, preferentially using their left forelimbs. But what does this mean, biologically? For a decade, the research group at Saint Petersburg State University has been navigating its way across the animal kingdom in a search for examples of ‘laterality’ – the preferential use of one side of the body over the other. Lateral speculations Photo: www.publicdomianpictures.net/Lilla Frerichs In their study of fish, ‘Eye as a key element of lateralized response in fish’ (Anim Cogn, 16(2), 287–300) Giljov had fish swim through a perspex tank, in which images of other fish were displayed to the left or right (or they saw themselves in a mirror). These pond-living fish (Perccottus glenii) apparently preferred looking at other fish (or their own reflection) with their left eye, although it is not explained how this might work when two fish are swimming side-by-side – if you’re on my left, aren’t I on your right? Nevertheless, Giljov speculates that there must be a lateralised social response if the fish are showing “a significant left-eye preference for the inspection of social stimuli”. This idea is extended to whales – a tendency to swim on one side of a fellow whale must reflect “social” tendencies in the other brain hemisphere. In ‘Visual laterality of calf-mother interactions in wild whales’ (PLoS ONE, 5(11):e13787), baby beluga whales were seen to preferentially swim to the right of their mothers, i.e. on the baby’s left-side. Based on theories of handedness and brain crossover in humans, Giljov speculates that this is due to “right-hemispheric advantages in social responses”. Similarly in killer whales (orcas), the lateral bias in mother-infant pairs was “assumed to be caused by calves’ rightbrain hemisphere specialisation for social processing” (Anim Behav, 86(6),1225–31). Throughout, there is also an undercurrent of evolutionary theory. For example, they seek to establish when laterali- LT_515_16_17.indd 16 ty first appeared in evolutionary history. In their study, ‘An eye for a worm’, they compared the lateralisation of feeding behaviour in species of fish, frog and newt (Laterality, 14(3), 273– 86). The fish and the newt both showed right-eyed preferences when inspecting food items. Meanwhile, the frog had a balanced vision of its food and displayed no laterality. Clearly, Giljov says, these results “extend our knowledge of lateralisation in the visual system of vertebrates and allow speculation on its evolutionary history”. In fact, by plotting their fish/frog/newt onto the evolutionary map, they claim to have dated back the history of visual laterality in vertebrates to the Devonian Period (over 350 million years ago)! Human-kangaroo parallel universe? In this latest study, Giljov et al. find that certain kangaroos have a consistent left-forelimb bias when grooming, feeding, or propping themselves up. This discovery of ‘left-handedness’ in kangaroos leads to even more evolutionary speculation – the results “challenge the traditional belief in the evolutionary uniqueness of human handedness”. They even told BBC News (18/06/15) that this confirmed that “we are not alone in the Universe; we are two – humans and kangaroos”! Furthermore, this must be ‘parallel evolution’ because handedness is observed in two separate branches of the ‘evolutionary tree’ – primates (placental mammals) and kangaroos (marsupials) – but not in related animals between them. Posture is the major factor, says Giljov, pointing to the ‘postural origins’ theory for primates, in which the transition from an arboreal lifestyle favoured the emergence of functional specialisations of the left and right hands. Giljov claims to have found similar differences between arboreal marsupials – which walk on four legs – and the terrestrial species that stand upright on their hind legs and use their forelimbs for tasks other than walking. All of which continues to justify even more speculation about the underlying meaning, for example, for neuroscience. The article’s press release says its findings will “encourage more careful study of the marsupial brain” because there are links between human neurological disorders and handedness. Such studies of ‘left-handed’ marsupials might “yield important insight into neuropsychiatric conditions, including schizophrenia and autism”! Presumably, the next step will see Giljov trying to get marsupial brain scans using magnetic resonance imagery (MRI). Now that could generate lots of lateral data, not least from trying to force the kangaroos into the scanner. 03/09/2015 13:14 Opinion 5-2015 Lab Times page 17 Swallowing the Ball N ero, One Swallow does not make a summer. Rather, a swallow followed by rain, to the power of three months, makes a British summer. This uncertainty has a profound impact on our summer sporting rhythm. Here, I refer to Cricket, the nation’s defining summer pursuit, rather than the chirping relative of the grass hopper. Our meteorological uncertainties meant that early cricketers needed to set aside five full days for a single game. I know you are a big fan of the bat and ball game and the sight of a player from one team projecting a red leather-clad ball at an opponent 22 yards away. This projectile aimed at a mock-up privet fence or “wicket” is at the game’s heart. The integrity of the wicket is guarded by Over the Line? a man holding a bat, who should swot the ball away. The batsman can then run the 22 yards to a wicket precisely aligned at the opposing end and, if he does this before the ball is returned to the wicket, he scores a run. Should the batsman miss the ball and the bowler is accurate Dispatches from the enough to hit the wicket, the batsman is borderlands of science out. Similarly, if the ball is hit into the air and a colleague of the bowler, a fielder, catches the ball before it hits terra firma, the batsman is out. A team has eleven players and the batting team is dismissed when 10 batsmen are out. The batsmen then become the bowlers. This is all played out by gentlemanly folk, dressed in white. A full game, weather permitting, will see each team bat and bowl twice. Brutality, strength and aggression can work but this belies the fact that exquisite timing can ensure heroic batting. The games subtleties extend to the fine art of bowling, as dexterous manipulation of the ball’s trajectory by skilled bowlers can deceive batsmen and trick them to mistime or miss the ball completely. One can expect a team to deliver up to 600 bowls in a day and these deliveries are packaged up into small portions of six, called ‘overs’. This produces a game with the kind of ebb and flow that makes tidal rhythm seem frenetic. Indeed, when dovetailed with British weather, the game’s rules seem designed to provide a sporting strategy, in which the result is an honourable but always a well-fought draw. Bio-rhythms I often feel cricket has parallels with the slow increments, upon which science is really played out. Rarely with the ‘biff bang bosh’ of rapid endgame. Rather, the slow considered progress reflected in the preferred, densely documented reporting of a pre1970s’ submission to the learned society journals. Abstracts were precise, introductions historic, material and methods exhaustive, and discussion addressed events in their entirety. This displayed science as it is, rather than in the form of the 15-minute highlight package that distorts the drama, or lack of, when immersing oneself in a full day’s play. Not to say light bulb moments were not possible in these more sober scientific times. However, bouts LT_515_16_17.indd 17 of scientific pursuit that broke the mould of a more sedate increase in iterative understanding were just rare and normally recognised retrospectively, not currently. These moments are all the more uplifting when they are unexpected and particularly exciting when they reward a previously put-upon colleague, who goes on to undermine the certainties of a mortal enemy. Resurrection from the Ashes This summer saw the rains and a visit from Ingerland’s mortal enemies. Cricket has a global reach that shadows the British interest that the sun never set on. Foremost, among the cricketing nations are the ancestors of the Banished, sent “Down Under” in the 1700s for heinous crimes, like stealing bread. These displaced petty criminals have grown into a mongrel race in the penal colony that became Entrailia. Here, they nurtured uncultured cricketing traditions, like winning. Indeed, they set about bastardising the game into a villainous truncated pursuit that involved dressing in pyjamas and playing for half an afternoon or with a white ball at night. Outrageous! No time for a swift aperitif, let alone lunch and tea. These bastardised forms of purity resonate the modern scientific preference for punchy papers, with pithy titles and “clear messages” and, horror upon horror, no or hidden methods sections. Ingerlish cricket played at 19th century pace just could not compete and our penal cousins arrived having thrashed us most recently by five matches to nil (a whitewash). Indeed, we expected a disaster as great as the first defeat we suffered at the hands of the visiting robbers in 1882. This led to the wicket being burnt and stored in an urn to symbolise the death of English (and by inference) civilised cricket. Oh a summer of humiliation was the expectation, so good and cocksure were our penal cousins that not even the weather could intervene to win us a few draws. But to the cries of ROOOOOOOOOOOOOOOOOT! ROOOOOOOOOOOOOOOOT! and B-ROAD, we enjoyed a renaissance. Our saviours, Joe Root and Stuart Broad had been mentally bombarded by the Entrailians – both on the pitch and in the terraces. Their crime was to be prettier and more “bantiful” than their dull-head opponents (http://tinyurl.com/nq2ls3a). Despite these onslaughts, these fine young men (as they are known to their mothers) stood tall, and batted and bowled with such abandon that the Entrailians were toasted. Ingerlish cricket, traditionally built on the considered pace that allowed it to fill a five-day pursuit, was transformed. Yes, the summer was full of unexpected light bulb moments. Root’s batting and Broad’s bowling delivered victory with all the panache and certainty of a 1,000 word Nature news and views. Nero, I think I can see a swallow holding an umbrella, must mean rain. No problem! The cricket’s over and the Ashes are regained. Who needs a methods section when victory is ours? Yours in ROOOOOOOOOOOOOOOOOOOOOOT. FintaN O’Toole 03/09/2015 13:14 page 18 Lab Times Analysis 5-2015 When the Rome-based, WADA-accredited anti-doping laboratory tested the race walker Erik Tysse (photo) for misuse of rEPO, good repeatability was definitely not achieved Problems at a WADA-accredited anti-doping lab Puzzling Discrepancy Photo: private Doping tests are very important to ensure fair competition but the test results should, of course, be correct and above doubt. Ironically, an accredited WADA laboratory seems to have major problems with the latter. A noteworthy article by Garribba and co-authors, all at the World Anti-Doping Agency (WADA)-accredited laboratory in Rome, appeared in the June 2014 issue of Bioanalysis (6(12), 1605–15). This article, entitled, A modified procedure based on a vacuum-driven blotting system for the detection of erythropoietin and its analogs, is not only noteworthy due to errors and an inaccurate presentation of results but also because the presentation is made by a professional and WADA-accredited analytical laboratory. It is disturbing that sloppiness and errors can dramatically influence the life and career of athletes, when tested for performance-enhancing drugs by this laboratory. We have earlier demonstrated (Nissen-Meyer et al., Weak Evidence. Lab Times 1/2013, pages 18– 23) and will give further evidence here that these concerns must be addressed. Detecting erythropoietin in urine In their study, Garribba and co-authors examined the specificity and repeatability of WADA-approved methods – and slightly modified versions of these methods – for detecting recombinant erythropoietins (rEPOs) in urine. The amounts of rEPO in rEPOspiked urine samples were measured and mean values, standard deviations (SD), and coefficient of variation (CV%) were reported. The authors concluded that the methods for detecting rEPOs I n fo rm a t io n b ox : S a me u r i n e s a mp l e b ut different results The adjacent Figure 1 shows three analyses for the presence of rEPOs in Erik Tysse’s urine sample. The results are from the laboratory’s documentation that was presented at the Court of Arbitration for Sports (see source below). The athlete's A-sample was tested three times using isoelectric focusing (IEF) and double-immuno-blotting. We [the Lab Times authors] have cut out the athlete's lanes from the three IEF gels and placed the lanes side-by-side in order to more easily compare the results. The same urine sample was used in these three analyses, and the same concentrated urine sample was used in the first and second test (i.e. the samples applied to the gel were taken from the very same test tube). Source: Laboratorio Antidoping–FMSI, Documentation Package Sample A code 3511158 (www.eriktysse.com/Dockuments/The%20report%20for%20the%20A-sample.pdf) LT_515_Doping_part_2.indd 18 Figure 1 03.09.15 12:37 Analysis 5-2015 Lab Times page 19 have good repeatability, specificity and accuracy and are consequently reliable. Ironically, that conclusion is undermined by inconsistencies and mistakes in many of the numerical results presented to support the conclusion; there are, in fact, obvious and serious mistakes in five of the eight datasets shown for rEPO in the article’s main table (their Table 1). For instance, a mean value for the amount of rEPO is presented as 14,179,217 with an SD of 71,58,031 and a CV of 9%. Aside from the use of too many significant digits and the unconventional and confusing use of commas in the SD, at least one of these numbers must be wrong; 7.1 million is 50% of 14.1 million, not 9%. In this case the SD value is wrong. An SD with exactly the same numerical value also appears in a completely different dataset in Table 2; the SD has most likely been “copied and pasted” from Table 2 to Table 1. The exact same mistake is encountered in the next dataset in Table 1, where the SD value (presented as 18,40,893) is wrong. This SD has also been erroneously copied and transferred from Table 2. For another dataset in Table 1, it is the mean value for the amount of rEPO (presented as 198,886,367 with an SD of 3,783,711) that is wrong; it is 10 times too large and should − judging from the electrophoresis data − be about 20 million. 5-2015 Lab Times page 19 Biometra TRIo Triple powered PCR Biotechnica 2015 Stand #e46 06. - 08. october 2015 hannover | Deutsche messe Serious mistakes in five out of eight datasets… One might think that this is not so serious. After one of us (JNM) made the editor aware of the mistakes, a correction appeared in May 2015 (issue 9) of Bioanalysis and corrections have now also been made in the electronic version of the relevant Garribba et al. article. It should be noted that there is no information in the new version that changes have been made; as the original version has been removed from the website, the numbers we refer to above can only be found in copies taken before the corrections were performed. But why are we worried about these mistakes? Are we being too picky, considering that the mistakes and inconsistencies are so obvious that a reader can, at a glance, identify and correct them? No. We rather find it is worrisome that these obvious inconsistencies and mistakes were not identified by any of the six authors, all working at a professional and WADA-accredited analytical laboratory that each year tests thousands of athletes for doping. … not identified by any of the six authors The good repeatability reported in the article was definitely not achieved when this Rome-based, WADA-accredited laboratory tested the race walker Erik Tysse for misuse of rEPO (see the adjacent information box and Lab Times 1/2013, pages 18-23, for details about the Tysse case). This information box (see opposite page 18) shows the results of three repeated tests of Tysse’s A-sample urine. Four of the six authors of the Bioanalysis article were involved in this test and they reported it as positive for CERA (a form of rEPO). The first test (first lane in Figure 1) is the one that most clearly reveals the athlete’s normal endogenous EPO, whereas the bands in the CERA region are not clear (see Lab Times 1/2013, page 18ff, regarding interpretation of bands in the CERA region). The second test (second lane in Figure 1) reveals a large and unexplainable amount of material in the CERA region. Remarkably, the samples used in the first and second tests were from the very same test tube and the experiments were car- � ThRee BloCk SySTem: Three independent sample blocks for ultimate flexibility � RAC TeChnology: Superior sample block temperature control � WhISPeR QUIeT: low noise emission of max. 45 dB � hIgh PeRFoRmAnCe SmART lID (hPSl): Defined pressure control for highly reproducible results � TemPeRATURe oPTImIzATIon STeP (ToS): ToS-technology to determine the optimal annealing temperature � ADVAnCeD USeR mAnAgemenT (AUm): Individual rights settings for each user RAC HPSL HPSL LGT RAC RAC WhisperLGT Quiet LGTWhisper HPSL AUM Quiet Whisper RAC Quiet AUM AUMLGT www.bio.analytik-jena.com LT_515_Doping_part_2.indd 19 03.09.15 12:37 Lab Times Analysis 5-2015 Photo: WAADS page 20 Francesco Botrè was president of the World Association of Anti-Doping Scientists (WAADS) from 2006 to 2008 and is the acting Scientific Director of the WADA-accredited Laboratorio Antidoping FMSI, located in Rome, Italy. It is his laboratory that performed the analyses described in the article. The Laboratorio Antidoping FMSI A-sample report from June 2010. On page 22 (top right) you can see black rectangles hiding information about sample numbers; similarly on page 38 (bottom right) for the retesting of samples. We [the authors] believe that the 'R' after the sample number for Tysse (A4433) on this page means 'retesting'. Why are the other sample numbers hidden? No need for secrecy if everything is OK because you need the code to deduce from whom the urine samples were obtained. ried out in the same manner. The two results should, therefore, have been identical. In the third test of the same urine sample (third lane in Figure 1, page 18), hardly any of the athlete’s normal endogenous EPO was detected but the relative amount in the CERA region had increased even further, resulting in an extraordinary 400-fold increase in the relative amount of CERA from the first to the third test. Considering how poorly CERA is secreted to urine, the results of the third test indicate an unrealistic amount of CERA in the urine; they imply a concentration of CERA in Tysse’s blood that is almost 10,000 times greater than the concentration of his natural EPO. The discrepancy is simply too large The results shown in Figure 1 (page 18) do not fulfill WADA’s own stability criteria, which say that the distributions of the most intense bands appearing in the initial testing procedure (i.e. the first and second test in Figure 1) and confirmation testing procedure (i.e. the third test in Figure 1) should be similar [WADA Technical Document – TD2009EPO]. It is indeed difficult to imagine that one and the same urine sample should give the results shown in Figure 1; the discrepancy between the tests is simply too large. No one has been able to explain this discrepancy. At the Court of Arbitration for Sport (CAS), representatives from WADA-accredited laboratories stated that this lack of reproducibility might have been due to a contamination in the first test and that the discrepancy, regardless of cause, does not really matter: “… it cannot be excluded that lane 3 [the athlete’s sample lane] was contaminated with retentates from the neighbouring Ba c k g ro u n d : T h e d o p i n g c a se s a g a i n st Er ik Ty sse and Alex Sc hwazer Re-Analysis by Another Laboratory Rejected The Norwegian athlete Erik Tysse participated in a race-walking competition in Sesto San Giovanni, Italy, in May 2010. Tysse came in second, after the Italian race-walker Alex Schwazer. Schwazer is well-known for winning the Olympic gold medal in race-walking in 2008 and for testing positive for rEPO before the Olympic Games in 2012. Subsequent investigations by Italian authorities indicate that he also used performance-enhancing agents before 2012 and that officials for athletic organisations might have been aware of this (see article in The New York Times: http://mobile.nytimes.com/2013/06/19/sports/olympics/ officials-accused-of-covering-up-italian-olympians-doping.html). Schwazer also used the Italian “doping-doctor” Michelle Ferrari as a “training-consultant” (as did cycling professional, Lance Armstrong) and, in fact, contacted Ferrari immediately after the competition in Sesto San Giovanni in 2010. LT_515_Doping_part_2.indd 20 Urine samples from six athletes − among these were Tysse and Schwazer − who participated in the competition in Sesto San Giovanni were sent to WADA’s laboratory in Rome. The laboratory reported the presence of CERA in Tysse’s urine; he denied use of CERA and asked for his urine to be re-analysed at another WADA laboratory but the request was rejected. Screening tests indicated that the urine of another athlete also contained rEPO, however, this was not reported by the laboratory as an adverse finding because the signal in the following confirmation test, which was run on the same gel as Tysse’s confirmation test, was reported to be not good enough. Judging from the band-tailing and streaking that was obtained in this test, it appears that the sample was either destroyed after the initial screening test (which was positive) or that it was inadequately applied to the gel. 03.09.15 12:37 Analysis 5-2015 lane... In any case, due to quality issues, the data from the first screening [i.e. the first test shown in Figure 1] was not accepted by the laboratory and the IEF analysis was repeated from the same retentate. Consequently, the data from this initial screening [i.e. the first test shown in Figure 1] was nullified and the data from the second screening [i.e. the second test shown in Figure 1] was considered as the valid data for assessment purposes.” [a quote from Expert Opinion given by Günter Gmeiner, Laboratory Director, WADA-accredited Doping Control Laboratory, Seibersdorf, Austria]. Same urine, different results It is not at all clear to us how contamination of the first test is compatible with the results shown in Figure 1. If contamination did in fact cause the discrepancy, it must instead have been the second and third tests that were contaminated. Also, it is not clear to us why the first test should be “nullified”. Of the three test results shown in Figure 1, it is the first lane in the figure that seems to be most reliable, since Tysse’s natural EPO (which everyone produces and is thus present to a lesser or greater extent in one’s blood and urine) is most clearly detected in this lane (Figure 1). The above quote from Expert Opinion implies that the second test was initiated after the results of the first test were known. Francesco Botré (Director of the WADA-accredited laboratory in Ease your labwork with HandyStep ® electronic Lab Times page 21 Rome and corresponding author of the article in Bioanalysis) also stated (both orally at CAS and in a written witness statement) that the second test was initiated because of the results they obtained in the first test. However, the laboratory’s Documentation Package reveals that the second test was started before the results of the first test were known. The laboratory was, thus, either sloppy when writing their laboratory report, or Botré’s statement is incorrect and it needs to be clarified. Only two credible explanations In view of the apparent good repeatability that is reported in the Bioanalysis article, we see only two credible explanations as to the complete lack of reproducibility in the results obtained in the three tests shown in Figure 1. Either… 1. the IEF analysis method and/or the work performed in the laboratory was so unreliable − possibly due to unspecific staining or degradation of proteins in the sample − that the entire test must be discarded; it is then likely that the staining seen in the CERA region is not due to CERA, or… 2. someone in the laboratory has – on purpose or by accident – altered or manipulated some of the concentrated urine samples, in which case the laboratory in Rome may be accountable for serious misconduct. Repeated Accuracy Easy, motorized repetitive pipetting! 7.01 µl or 11.4 ml? Any volume you require from 1.0 µl up to 50 ml Automatic tip-size recognition with BRAND® dispenser tips Compatible with most common dispenser tips Versatile 3 operating modes Biotechnica: hall 9/booth C33 BRAND GMBH + CO KG LT_515_Doping_part_2.indd 21 P.O. Box 11 55 · 97861 Wertheim · Tel.: +49 9342 808-0 · [email protected] · www.brand.de 03.09.15 12:37 page 22 Lab Times Analysis 5-2015 one such processed version that was presented at CAS as a, “falsification of a document used in a court case”. Franke also wrote, “In conclusion, there is no scientific evidence contained in these documents (i.e. the Documentation Package) which proves the presence of CERA in the athlete's (i.e. Erik Tysse's) urine.” A declaration stating the same has been signed by more than 40 professors and scientists in chemistry, biochemistry and molecular biology, including one Nobel Prize winner. Photo: private ...and the second example Erik Tysse is interviewed during a break at the Court of Arbitration for Sport (CAS) trial in Lausanne by the two main Norwegian TV channels. In this trial, representatives from WADA-accredited laboratories stated that the lack of reproducibility, regardless of cause, does not really matter. A declaration, signed by more than 40 scientists, offers the opposite opinion. The documentation package that covers the Tysse case reveals several other irregularities that indicate bad laboratory procedures and may, in the worst case, suggest serious misconduct. Some of this has already been discussed in a cover article in Lab Times 1/2013, so in the following we will present just two additional examples. Two additional examples of irregularity: the first... The first example: In the laboratory's Documentation Package, one of the original gel images was inverted (i.e. presented upside-down and right-side to left). As a consequence, the order of the sample lanes in the original image is inverted relative to the lanes in the computer-processed version of the image. A more serious consequence of the inversion of the original image is that it made it more difficult to discover that the laboratory had, in the computer-processed version used for evaluating the results, suppressed the staining intensity of the negative control lanes and simultaneously increased the staining intensity of the lane that contained the athlete's sample (Source: Laboratorio Antidoping-FMSI, Documentation Package Sample B code 3511158; www.eriktysse.com/Dockuments/The%20report%20 for%20the%20B-sample.pdf). The Rome laboratory thereby camouflaged the fact that the negative control lanes contained the same bands as the athlete's lane (i.e. the negative control sample which did not contain CERA was virtually identical to the athlete's sample) and that this analysis did not present any evidence for the presence of CERA. In a letter (dated 29th June 2011) to all participants at the CAS hearing, Werner Franke, a highly recognised biochemist from Heidelberg University, Germany, who played a major role in revealing the doping culture in the former GDR, characterised LT_515_Doping_part_2.indd 22 Urine samples should, according to WADA’s regulations, be handled in such a way that the likelihood for contamination and degradation is minimised. It is thus remarkable and bad laboratory practice that the seal on Tysse’s urine sample, which the laboratory received Sunday, 2nd May 2010, was broken and aliquoted for EPO-testing on Monday, 3rd May 2010, four days before the test actually started (on Friday, 7th May 2010). Furthermore, the test was started on a Friday, thus resulting in the concentrated urine sample being left over the weekend – two extra days – before the test was completed on the following Tuesday (the first lane in Figure 1, page 18, is from this test). Moreover, after having obtained the results from the second screening test (the second lane in Figure 1 is from this test), the laboratory waited for one week before the confirmation test was started (the third lane in Figure 1 is from this test). And again, Tysse’s urine was aliquoted for the EPO-test (on Monday, 17th May 2010) three days before the test started (on Thursday, 20th May 2010). Just one month earlier (in April 2010), when reporting that the Rome laboratory found the B-sample from the Italian cyclocross rider Vania Rossi negative for CERA, despite a positive Asample, Botré excused their negative B-test by saying that CERA is unstable and degraded in urine, more so than in blood. The delayed testing after seal breakage and sample aliquoting of Tysse’s urine sample is therefore puzzling. Puzzling delays Because of these delays, more than three weeks elapsed from the time the laboratory received Tysse’s urine sample (Sunday, 2nd May 2010) until their report was mailed (Wednesday, 26th May 2010) to the International Association of Athletics Federations (IAAF). In contrast, when Alex Schwazer was tested positive for rEPO in 2012 (see the "background box" on page 20 for details about the Schwazer case) it took only seven days from the time his urine sample was collected and analysed in the WADA-laboratory in Cologne to reports of the positive test appearing in the press. WADA’s regulations state that there should not be more than ten working days from when the sample is received to a positive finding being reported, such that a blood sample can be taken in order to confirm the results obtained with urine. Blood is, especially when testing for CERA, much more sensitive and reliable. The long delay meant that the following test of Tysse’s blood, which was negative for CERA, could not be used as reliable evidence to prove that he was innocent. This seriously reduced Tysse’s chances of clearing himself of the doping charges. No will to deliver relevant information We have contacted the laboratory in Rome as well as WADA, IAAF, the Norwegian Athletics Association and Anti-Doping Norway and its board of directors, in order to get access to some spe- 03.09.15 12:37 Analysis 5-2015 cific information that we think might clarify whether or not Erik Tysse used CERA and reveal the reasons for the inconsistent laboratory results. None of the above-mentioned organisations have, however, been willing to reveal any further relevant information. Thus, we have not received information about the amount of CERA standard protein applied to the gels, which would help to estimate the amount of CERA that, according to WADA, is detected on the gels. Moreover, we have not been allowed to see information that is hidden by black rectangles at several places in the report for Tysse’s A-sample (see images on page 20); we do not see any reason to hide this information if the analytical work has been performed as it should have been. We also wanted to know why 20 ml of Tysse’s A-sample urine is missing. We can only find three possible explanations: u the laboratory is sloppy when writing their reports, u they have spilled some of the athlete's urine (exactly what is required for one analysis), or u they have carried out an additional and unreported EPO test – the delayed testing mentioned above might indicate this. It is unacceptable that the information we are seeking is not freely available, since it is required to establish clearly how the analyses were performed and should therefore be part of the laboratory report. Lab Times page 23 A ban on information, but why? Finally, the recent investigations by Italian authorities that officials of athletic organisations were aware of Alex Schwazer’s doping (see background information box on page 20), combined with the earlier report by Alessandro Donati describing involvement of officials for sport organisations and the previous antidoping laboratory in Rome to hiding or assisting doping, makes it even more important that all information regarding the analysis of Tysse’s sample is made available (Donati, A., Anti-doping; the fraud behind the stage. www.playthegame.org/news/news-articles/2000/anti-doping-the-fraud-behind-the-stage). If not, one might suspect that the irregularities we have described in this case are the result of a cover-up action, taken to protect Schwazer, who delivered a urine sample for doping analysis in the same race as Tysse. Jon Nissen-Meyer (University of Oslo), Erik Boye (Oslo University Hospital & Univ. of Oslo), Bjarne Østerud (University of Tromsø), Tore Skotland (Oslo University Hospital & Univ. of Oslo) Lab Times readers who have information to contribute, questions or any other comment to make on this article should contact the corresponding author, Tore Scotland: [email protected] Our Selection Speaks Volumes • • • • • • • • • Scissors Retractors Magnifiers Probes & Hooks Bone Instruments Animal Identification Hemostats Forceps Surgical & Laboratory Equipment • Feeding Needles • • • • • • • • • • Spatulae & Spoons Wound Closure Surgical Plates Instrument Care & Sterilization Rongeurs Scalpels & Knives Clamps Pins & Holders Needles & Needle Holders Student Quality Instruments & Much More FINE SURGICAL INSTRUMENTS FOR RESEARCHTM Visit us at finescience.de or call (0) 6221 905050 LT_515_Doping_part_2.indd 23 03.09.15 12:37 page 24 Lab Times 5-2015 Analysis Scientific misconduct Photo: Fotolia/michaklootwijk French Connection This is a story of two friends with a dubious understanding of science integrity. But even more, it is the story of how academic and industrial research networks keep protecting them from facing the consequences of their malpractice and misconduct. T he names of the two French protagonists and long-term friends are Charles-Henri Lecellier and Guillaume Vetter. Their friendship, however, is obviously not a relationship of equals: despite being two years younger, Lecellier clearly plays the dominant role – and Vetter that of his loyal follower. At least four major institutional players have been providing the setting for their actions, namely the 2003 founded University of Luxembourg (Uni.Lu), the French Centre national de la recherche scientifique (CNRS), its subsidiary Institut de Génétique Moléculaire de Montpellier (IGMM), as well as the French biotech company Theradiag. All of them were apparently involved in covering-up several cases of dubious scientific practice by Lecellier and Vetter – including deliberate falsification of data. have, meanwhile, been found to contain potential data manipulation; one of them has already been retracted (Dunoyer et al., Plant Cell 16:1235-50). In his only email response to Lab Times, dated April 7th, 2015, Lecellier wrote in this regard: “Neither am I aware nor am I implicated in the handling of that affair because I chose to get away from Olivier Voinnet ten years ago. I would appreciate, if you respect my past and avoid me today to pay the double penalty." At first glance, this seemed to be a statement by an honest scientist who left Voinnet in protest against the poor practice of data handling in his lab. In fact, however, some first-hand reports are inclined But let’s go back to the start. From 2004 to 2006, Charles-Henri Lecellier worked as a postdoc in the lab of the French plant scientist Olivier Voinnet, well-known for his research in plant immunity and the biology of small non-coding RNA. Just recently, Voinnet was found to have committed misconduct and data misrepresentation throughout his entire academic career by the external investigation of his current and past employers, ETH Zurich and CNRS (see Lab Times online, July 12th 2015, and earlier reports). Since the start of his postdoc time in Voinnet’s laboratory at the CNRS Institut de Biologie Moléculaire des Plantes (IBMP), Lecellier has focused his work on the studies of small non-coding RNAs (precisely miRNAs) in mammalian cell models. Several publications resulting from that time and co-authored by Lecellier and Voinnet LT_515_24_27.indd 24 Photo: www.mascarille.com In Voinnet's laboratory Good Scientific Practice seems to be a foreign concept for Charles-Henri Lecellier to cast a different light on the real reasons for the break-up between Lecellier and his mentor Voinnet. Violent and arrogant A former IBMP employee described Lecellier to Lab Times as follows: “CharlesHenri was extremely violent (verbally and physically) and arrogant. I’ve never met anybody as violent as him in a research laboratory. He was always with Olivier Voinnet.” Furthermore, this witness added that Lecellier was “one of the followers of Voinnet who had a totally inappropriate behaviour. It was, however, tolerated by the institute because Voinnet published in Science, Nature and Cell. Other IBMP directors even watched it with amusement. But it was not fun for those people of the institute who had to cope with all this inappropriate behaviour in the everyday life of the lab”. As Lab Times learned from another first-hand source, Voinnet himself admitted that he did not trust his postdoc’s experimental data and finally forced Lecellier to leave his lab in 2006. Thus, the CNRS relocated Lecellier to its Institut de Génétique Moléculaire de Montpellier (IGMM). In retrospect, it seems more than ironic that Lecellier’s alleged lack of attitude towards science integrity might have been even too much for Voinnet, whose own publications have subsequently accrued four retractions and twelve corrections due to incorrect data presentation, so far. Equally interesting is that, in the meantime, the publication discussion platform PubPeer has been providing evidence for even earlier forays of Lecellier into “creative” data presentation, namely from his time as a PhD student in the virology lab of Ali Saïb at the CNRS Hôpital Saint-Louis in Paris. Saïb himself stated on the sus- 03/09/2015 13:44 Analysis picions against his former lauded PhD student (Mention très honorable avec les félicitations du jury): “During his PhD, nothing could suggest any misconduct.” Yet, Lecellier’s two first-author publications on foamy viruses show strong evidence for manipulative re-use of blot images, in utterly different contexts and across the separate publications (J Virol, 76(7):3388-94 and 76(14): 7220-7). Accordingly, the journal’s editorin-chief, Rozanne Sandri-Goldin, promised in an email to Lab Times: “Given the public and sensitive nature of this case, we will follow our well-established process to investigate the allegations as they appear on PubPeer.” Lecellier’s conflict with Voinnet at the IBMP in Strasbourg ultimately emerged in 2006 over his first research project as an independent scientist and his first collaboration with Vetter (who was also previously employed at the IBMP, in the laboratory of David Gilmer). The majority of the data for the project was produced by Vetter, who, in the meantime, had moved to Luxembourg for a postdoc at the C RP-Santé (now named Luxembourg Institute of Health), where he mainly operated a DNA micro array platform managed by the Uni.Lu pro- 5-2015 fessor Evelyne Friederich. Despite Lecellier’s conflict with Voinnet and rejections by two journals, the resulting paper was eventually published in Blood, with Lecellier’s wife Anna Saumet being first and Vetter second author (113(2):412-21). The Blood paper described the role of various miRNAs on the expression of cancer-relevant genes in leukaemic cells carrying the common oncogenic mutation PML-RAR. Potentially, this study could have been very important for clinical applications and patient therapies. If it were reliable, that is. On PubPeer, once again a duplicated miRNA blot was flagged for that publication, while purportedly showing completely different miRNAs under different experimental conditions. Spot the difference! Yet, this is not all. Lab Times has obtained the original manuscript version from March 2008, which Lecellier initially submitted to Blood. We compared it with the revised manuscript, which Lecellier resubmitted after peer review and which was finally published by the journal. The exercise was similar to the popular children’s game of spotting the differences between Lab Times page 25 two similar images – and in the figure below the reader is invited to do the same. To conclude, it quickly became clear that certain values inside several gene expression analyses had been selectively altered, while other values of the same experiment as well as their error bars had remained exactly the same. Apparently, neither the editors nor the peer reviewers had noticed any of those oddities, which are, at the very least, unacceptable in terms of a properly controlled experiment. To our inquiries, Blood journal’s senior manager for peer review, Virginia Ramsey, only replied that the data “have been forwarded to our Data Integrity Manager and are being processed accordingly”. After that successful publication, Lecellier and Vetter moved on to a new project, which Vetter again largely performed in the Uni.Lu lab of the cell biologist and cytoskeleton specialist, Friederich. The outcome was an Oncogene paper, in which Vetter, Lecellier and Co. postulated an active role for a certain miRNA (miR-661) in the promotion of tumour cell invasiveness in breast cancer, by inducing the epithelial to mesenchymal transition. According to the authors, they had identified the epitheli- The panel in figure 7D, showing a luciferase assay for the miRNA effect on reporter gene expression, was modified upon resubmission. It was extended by two new experimental conditions (marked red), with a key positive control (“mixed LNAs”) significantly changed. (The latter modification made the impact of certain anti-miRNA treatments appear significantly greater). All other values (including their error bars) remained exactly as before. This practice by Lecellier and Vetter suggests, to the least, an inappropriate patchwork of intra-variable experiments, which prohibits any reliable comparison of values. Nevertheless, Lecellier insisted in his revision letter that the added values can be directly compared to the previous ones, despite the profound intra-experimental variability. He only forgot to mention the introduced sudden, dramatic change in the positive control (“mixed LNAs”)! LT_515_24_27.indd 25 03/09/2015 13:44 Lab Times al genes Nectin-1 and StarD1 as key targets for miR-661. Soon after publication, however, senior author Evelyne Friederich and her co-workers themselves discovered irregularities in some of the data presented in the paper, and initiated an investigation into possible misconduct at the Uni.Lu. In the end, an external commission found that the entire experimental data on Nectin-1 had been manipulated by Vetter. Thus, retraction of the paper was the logical next step. Correction instead of retraction Curiously, exactly this move was strongly opposed – not only by the CNRS, Lecellier’s employer, but also by parts of the U ni. Lu. A deal was therefore made to pursue the commission’s alternative recommendation: to correct the paper, despite its proven fraudulent data. Yet, even for this route no agreement could be achieved among the parties involved, mainly because Lecellier continuously insisted that there had actually never been any misconduct but that, instead, pure “personal conflicts” had led to the accusations against his innocent friend Vetter. Also, the IGMM group leader and co-author, Charles Theillet, fully concurred and wrote to Friederich: “None of the elements you came up with support overt and deliberate manipulation of data.” On June 10th, 2015, Lab Times first reported online on the details of the dispute surrounding the Oncogene publication by Vetter et al. (29, 4436-48) and the misconduct investigation by the Uni.Lu. The entire affair can actually be summarised as follows: In the end, almost anyone wanted to protect Vetter from the consequences of Friederich's accusations, despite all the clear evidence and even despite the incriminating results of the formal institutional investigation. But why? The University of Luxembourg is rather young (founded 2003) but it has already been shaken by some cases of data manipulation. The first case, which resulted in Uni. Lu’s first external misconduct investigation, was that of the German bioinformatician Carsten Carlberg. After intervention by the Luxembourg funding agency, Fonds National de la Recherche (FNR), Carlberg was finally sacked from his professorship position at Uni.Lu for being involved in scientific misconduct, which had led to the retraction of two of his publications (see LT 4-2011:12). Following this experience, an Ethics Review Panel was established at Uni. Lu. It wasn’t too long before it was needed. An assistant professor at the Life Science LT_515_24_27.indd 26 Analysis 5-2015 Research Unit (LSRU), Eleonora Morga, was found to have manipulated data in a neurobiological study, which was later retracted by the journal Glia (62(3):491). The paper’s last author was Morga’s former PhD advisor Paul Heuschling, Dean of the Science Faculty at Uni.Lu. Apparently, Heuschling, with the help of the thenChancellor of Uni.Lu, Eric Tschirhart (now vice-president for academic affairs), tried their best to prevent an external investigation and to avoid the retraction. All this, despite the clear evidence presented by Morga’s own lab members that she had, in fact, manipulated data (in the Glia publication and elsewhere) and despite the fact that Morga failed to provide her co-authors with the corresponding primary data. Eventually, Morga was sacked. Money-back policy tionship. As soon as Friederich began to question Vetter’s scientific data, Tschirhart quickly moved him to his own team, away from her oversight and control. Just when Vetter was supposed to be questioned by the investigative commission, he slipped away to his friend Lecellier in Montpellier – with the help of a vacation permit issued by Tschirhart. It would not be fair to claim that Tschirhart did not take Friederich’s misconduct accusations against Vetter and Morga seriously. Indeed, he very much did. When Friederich invited senior scientists to the “extraordinary LSRU (Life Sciences Research Unit) meeting” on October 24th 2011, to discuss the accusations against Morga and Vetter, Tschirhart immediately reminded her that by initiating this meeting, she might have breached the Règlement d’Ordre Intérieur (ROI, internal code of conduct) – which could, in turn, result in her own dismissal (Vetter and Morga were co-recipients of Tschirhart’s email). Furthermore, during the actual meeting, Tschirhart openly accused Friederich of being in breach of confidentiality as well as acting outside of her authority. One of the reasons for the initial resistance against taking the appropriate measures, in this case, might have been money: the FNR has a policy of demanding back their research funding, if it has been invested in a publication that later has to be retracted due to misconduct. Putting blame on others Concerning Vetter’s Oncogene paper, the Soon after his arrival at Lecellier’s lab officials from Uni.Lu obviously also feared in Montpellier, Vetter had the audacity to that the FNR would claim its money back blame Friederich and her co-workers for his in the eventuality it might be retracted. In own misconduct. He justified his data maa letter from October 9th, 2013, Heuschling and the vice-president for research, Ludnipulations with allegedly having been “a wig Neyses, informed Friederich that the mobbing victim” and suffering under “morFNR “is willing to reconsider its decision al pressure” in the lab. Rumours spread that of having the University reimburse the enVetter was even thinking about taking legal tire budget of your actions against Uni. FNR project, if we Lu. The Friederich can prove that the team, therefore, asjournal Oncogene is sembled a protest indeed willing to acnote to the Uni.Lu’s cept, pending apEthics Review Panproval, a corrected el, which remained version of your pubunanswered. lication instead of This way, V etter a complete retracremained largetion”. And they furly unscathed for ther stated that “the the time being but University must the Oncogene paseize this opportuper was doomed. nity”. Thus, not only In October 2014, the CNRS was keen Blames others for his own misconduct: Heuschling, Neyto avoid a retraction Guillaume Vetter ses and Behrmann, of Vetter’s work as a together with the consequence of the misconduct confirmathen Uni.Lu president Rolf Tarrach, cotion by the formal investigation but also the signed an official request to the journal to Luxembourg science directorate, including retract the paper. Nothing happened, probthe head of LSRU, Iris Behrmann. ably because the CNRS as well as Tschirhart Money, however, was only one aspect. and even the Ethics Review Panel at Uni.Lu Another was some obscure personal relastill disagreed with a retraction. A couple Photo: Friederich lab page 26 03/09/2015 13:44 Analysis United again at biotech company Four years ago, Lecellier together with IGMM founded the biotech company Prestizia, for the purpose of miRNA diagnostics and personalised medicine. Prestizia was later acquired by the diagnostics company Theradiag, which then went on to win the Worldwide Innovation Challenge from the President of France for its activities into miRNA applications. As IGMM proudly announces on its website, their staff scientist Lecellier has since been supervising the collaboration with Theradiag on the HIV diagnostics research. And, perhaps unsurprisingly at this point, Vetter was installed as Head of miRNA Laboratory at PrestiziaTheradiag, directly after he had had to flee from Luxembourg, in order to avoid facing the responsibility for his misconduct. When contacted by email, Theradiag declined to comment on Vetter’s employment but wished to know the names of those people, who had provided Lab Times with this information. Given all this, is it too farfetched to speculate that the CNRS might still be pinning some high hopes on Lecellier and Vetter, in the light of their particular involvement with the biotech industry? Also, in 2012 IGMM and Lecellier teamed up with the US company Thomson Reuters, to apply their bioinformatics analysis platform, MetaCore, to the prediction of candidate miRNAs and their interactive networks with transcription factors and gene expression. Lecellier’s previous experience with a similar but academically-generated LT_515_24_27.indd 27 Lab Times page 27 bioinformatical database, however, is very revealing indeed. In fact, shortly after the accusation of misconduct at the Uni.Lu, Lecellier and Vetter, in their next publication, boldly misappropriated and misrepresented bioinformatics data and mathematical calculations from the Friederich lab. For this paper, Lecellier and Vetter applied the unvalidated bioinformatics approach from MIR@NT@N, mixed with additional calculations from MetaCore, to retrospectively predict their cell biological results. Le Béchec was named, despite his protest, in the Acknowledgements and, in this way, was assigned the responsibility for the The convenient way statistically poor calculations in Figure S2 of These were originally generated by the publication. Those were even deemed the bioinformatician, Antony Le Béchec, by the journal’s editorial board as incorwho was explicitly rect, namely found funded to establish a to have been based web interface methon the wrong primod that would preers. Le Béchec: “I did dict high-confidence not validate the [bio miRNA targets and informatics] data degene-mRNA-miRNA scribed in this publiinteraction networks cation, neither the involved in the eppreliminary methithelial to mesenod used to generate chymal transition. these data [in FigBack then, Lecelliure S2]. I informed er proposed testing Evelyne Friederich wants to bring the data Lecellier that he Le Béchec’s predic- manipulations to light but is accused of actcould not use and tion software, named ing outside of her authority. publish these prelimMIR@NT@N, experinary data because imentally in his own lab, by focusing on of the poor statistical relevance of the remiRNAs and transcription factors in breast sults and the not yet, and probably never, cancer cells. According to Le Béchec, howvalidated method used.” ever, the determined Montpellier researchMissing letter er apparently chose a more convenient apAs soon as Friederich became aware of proach of retrospectively fitting the predicthis Molecular BioSystems publication, she tions of the immature bioinformatics pipeand Neyses expressed their “concerns reline to match his own wet-lab data. It went garding data ownership, co-authorship and so far that Lecellier even insisted on using funding” on behalf of Uni.Lu to the journal’s statistically non-validated calculations (sochief editor (letter available to Lab Times). called “candidate approaches”), as long as Later on, when the publisher, the Royal Sothey looked supportive of his theories. And ciety of Chemistry, started its investigation finally, he even arranged co-authorships in into the case, this letter from June 3rd 2013 his proposed publication manuscript for could not be found, neither by Molecular Vetter and his wife Anna Saumet, so that BioSystems nor by the Uni.Lu. Nevertheless, they would actually share the first-author the Royal Society’s Publishing Ethics Spemerits with Le Béchec. cialist, Emily Skinner, assured Lab Times: Friederich and Le Béchec, as well as an“I am currently reviewing the matter in corother senior co-author, the bioinformatics respondence with the University of Luxemgeneticist Wyeth Wassermann from the bourg”. Centre for Molecular Medicine and TherOf all these problematic Lecellier/Vetapeutics in Vancouver, Canada, protestter papers, not one has been corrected or ed against such use of unvalidated and inretracted, so far. The CNRS remains siconclusive data. In the end, they decided lent. And the Uni.Lu now has another case to cease the collaboration with Lecellier, in of misconduct to deal with: the German order to further validate their MIR@NT@N neuroscientist Jens Schwamborn. Shortly software. This work was later published, after he was recruited as professor at Uni. without Lecellier and Co., in BMC BioinforLu, Schwamborn was found to have commatics (12:67). mitted misconduct and data manipulation Lecellier, on the other hand, pubin two, meanwhile retracted, publications lished his own wet-lab results from the from his time as PhD student at the UniverIGMM separately in Molecular BioSystems sity of Münster. (8(12):3242-53), with Anna Saumet and Leonid Schneider Vetter as first and second author. Photo: Friederich lab of days after the first Lab Times report had gone online on June 10th, Nature Publishing Group finally announced the retraction would appear by June 29th. But, as it transpired, they weren't able to make it happen. Instead, the back-and-forth negotiations about the precise wording of the retraction notice and, in particular, about the question of whether or not to mention that the formal investigation found Vetter exclusively responsible for the data manipulation, was still continuing when this issue went to press. In contrast to the Uni.Lu, the CNRS always stood united – albeit on the side of Lecellier and Vetter. Unfortunately, all Lab Times email inquiries in this case went completely unanswered by the French side, a situation we had already become rather familiar with during our investigations into the Olivier Voinnet case. Nevertheless, there are at least some possible indicators for CNRS’ somewhat unfathomable “overprotective” behaviour. 5-2015 03/09/2015 13:44 What does ‘excellence’ really mean? ‘Excellence’ or Non-Sense Photo (2): Foto lia/C laud ia Pa F or years, we seem to have been bombarded with claims that everything must be done in the name of ‘excellence’. Only research that is excellent can be funded, only universities that are excellent will continue to do research, only researchers who are excellent can hope to get a job. And of course, all of the administration and management who decide upon the criteria for ‘excellence’ must, by association, be somehow excellent in their good taste and judgement. But what, when you come down to it, does this magical quality called ‘excellence’ actually mean? Given the importance of these decisions, it may surprise some that the definitions of excellence are not so clear-cut (see text box on pg. 30). Traditional excellence The traditional view of universities has been based on trust. It assumes that academics in universities are ‘excellent’ at doing what they do, that is, that they are ‘fit’ for the purpose of teaching and research. It believes that professors and scientists are mainly engaged in research because they are interested in understanding the world they live in, and because they are motivated to come up with new explanations and solutions. “Academic work was not assessed systematically, since it was tacitly assumed that academics would strive for excellence without having to be forced to do so.” The government merely determined the amount of money that was paid to universities and set the legal framework for science and teaching. In terms of research, the government did not impose specific policies. And this was generally the situation until around the 1980s. But the Swiss economist Mathias Binswanger admits this was not a perfect LT_515_28_31.indd 28 uluss en ‘Excellence’ is currently a word used to justify many funding decisions in research and higher education but what do we actually mean by excellence? Jeremy Garwood looks at how traditional notions of academic excellence have been transformed by the application of ‘free market’ dogmas. system – there were huge differences in quality between individual scientists. “Scientific geniuses and lame ducks jointly populated universities, whereby even during the scientists’ lifetimes it was not always discernible who was the lame duck and who the genius.” Nevertheless, he argues that the system that has replaced it is far worse (How Nonsense Became Excellence: Forcing Professors to Publish in ‘Incentives and Performance. Governance of Research Organizations’ 2015, springer.com). Now, instead of making funds directly available to universities, governments insist that their research and teaching should be evaluated first. Universities are then ranked relative to one another in league tables. More funds are provided to higher-ranked institutions – only the best get a chance to do more research. Binswanger says this resulting competition for funds has made universities forget about their ‘noble purpose’ of increasing knowledge. Instead, they have “degenerated into ranking-minded fundraisers and publication factories”. Furthermore, he says, this degeneration is firmly rooted in the now-fashionable and omnipresent ‘search for excellence’, in which universities are supposed to outperform each other and everybody tries to appear more ‘excellent’ than everybody else. This is what Binswanger terms the ‘contest illusion’. In these artificially-staged competitions, the major challenge for universities has now become how to get additional funding by creating a good impression with the relevant research commissions. Demonstrating measurable excellence increases the probability of getting more funds. The problem is that no-one really knows what excellence is “least of all the politicians who launch such excellence initiatives”. It is simply assumed that these competitions will automatically enable the best to rise to the top, without any need to care about either the content nor the purpose of the excellent research. The rise of New Public Management During the 1980s, the ‘contest illusion’ was first applied to science in the UK, where it was part of an entirely new approach to the organisation and operation of public services called New Public Management. This was not confined to universities and academics. In his essay, “If You’re So Smart, Why Are You under Surveillance? Universities, Neoliberalism, and New Public Management” (Critical Inquiry, 2012), Dutch philosopher Chris Lorenz describes how New Public Management began in the USA but found its most fertile ground in the UK under Margaret Thatcher’s government. It has subsequently spread worldwide. As Lorenz explains, New Public Management (NPM) is the neoliberal dream of the free market economy and ‘Homo economicus’ applied to the public sector. At its heart is a free market conception of how everything can be done more efficiently by following its central dogma: free market = competition = best value for money = optimum efficiency for individuals as both consumers and owners of private property. NPM redefines the public sector as a service sector that functions best when it operates in accordance with the principles of the free market. In the UK, the arrival of NPM was marked by the introduction of private sector management techniques and management strategies. For universities, the Thatcher government developed league tables that 03/09/2015 14:16 Analysis relied on quantifiable indicators and were claimed to rank institutions by the quality of their teaching and research. Evaluating ‘excellent’ research The Research Assessment Exercise (RAE) was introduced in 1986 to rate UK research “in order to facilitate allocation of funds and to strengthen the international competitiveness of the UK academic research base”. It was essentially a peer review process, based on assessments made by panels appointed to examine research in UK universities. The process was repeated in 1989, 1992, 1996, 2001 and 2008. It was then ‘rebranded’ as the ‘Research Excellence Framework’ (REF). The first REF took place in 2014. For this, UK universities had to submit four ‘research outputs’, usually peer-reviewed articles, for each participating academic faculty member. In total, 154 UK universities submitted 191,150 research outputs from 52,061 academics. Each of these outputs was evaluated by a panel of peer-reviewers, who provided it with a score of 4-star (quality that is “world-leading in terms of originality, significance and rigour”), 3-star (quality that is “internationally excellent”), 2-star (quality “recognised internationally”) or 1-star (“recognised nationally”). These REF ratings are very important in UK academic circles – they determine the distribution of £1.6 billion per year. While REF results have no implications for a given individual, they have “huge implications for the relative standing of fields, the research funding of universities, and funding allocated within universities to different research groups” (PLoS ONE, 10(7):e0132990). Yet throughout all these evaluations, no-one knows for certain what is meant by ‘excellence’. For example, when introducing the RAE in 2000, Scotland’s Higher Education Funding Council helpfully explained that “excellence is generally taken to mean outstanding, or of a quality that surpasses a defined threshold in a particular field”. However, “in the case of research, there is no agreed way in which excellence is defined or measured uniformly across different disciplines at the international level, although some attempts have been made using bibliometric analyses, with limited success”. Therefore, the UK Higher Education Funding Councils (including Scotland) “currently seek to measure the quality of research at the national level in all subject areas through periodic Research Assessment Exercises. The RAE does this by assessing research against assumed measures of in- LT_515_28_31.indd 29 5-2015 ternational excellence. It does not however seek to benchmark quality against international comparators since there are no internationally agreed measures of quality”. Matters were not much clearer for the REF 2014. Overall, research submissions were assessed by an ‘expert sub-panel’ for each one of the 36 subject areas (‘units of assessment’). In total, there were 36 subpanel chairs, 1,052 members and assessors, and 25 specialist advisers. These subpanels worked under the guidance of four main panels (consisting of four main panel chairs, 23 international members and 17 user members). It was the responsibility of the main panels to ensure the assessment criteria and standards were consistently applied. The international members were expected to provide assurance about the international benchmarking of standards. Yet, nowhere is it clear how these ‘standards’ are to be measured. Instead, the panels were expected to ‘calibrate’ their own quality standards: “Each main panel and its sub-panels will undertake calibration exercises at an early stage in the assessment to develop a common understanding of the assessment standards and the application of the quality levels. International and user members of the main panel will participate in these exercises to assist in benchmarking judgements. The main panel chair and members of the main panel will attend a selection of the subpanel meetings that deal with calibration exercises and main panels will receive and discuss reports from sub-panel chairs on these exercises.” (paragraph 107e from the REF’s ‘Panel criteria and working methods’). However, the ‘quality’ of the resulting evaluations has been heavily criticised. For example, between 2008 and 2014, the REF 2014 reported an astonishing 103% increase in ‘world leading’ 4-star research outputs in UK life science and medicine (Times Higher Education, 27/07/15). Meanwhile, such evaluation exercises cost a lot of time and money. It was recently estimated that, in total, UK universities spend £1 billion meeting such demands for ‘quality assurance’ (Times Higher Education, 30/06/15). Spreading excellence Other countries have followed the UK’s lead and introduced their own national frameworks for evaluating the research output of universities as a basis for funding decisions. The European Commission’s 2010 report on ‘Assessing Europe’s University-Based Research’ identified 14 countries Lab Times page 29 – Australia, Belgium, Denmark, Finland, France, Germany, Italy, the Netherlands, New Zealand, Norway, Portugal, Spain, Sweden and the UK. Most of these systems emphasise an assessment of the ‘excellence’ of research, using peer review and/or bibliometric approaches. Germany began its ‘Exzellenzinitiative’ in 2005, allocating 4.4 billion euros between 2006 and 2015. Spain launched its Campus of International Excellence competition in 2009 that gave its ‘excellent’ universities the chance to carve up 200 million euros. Meanwhile, France has become ‘excellent’ at finding new names for its schemes. In 2008, it launched ‘Operation Campus’, a competition aimed at creating ‘campuses of excellence’. This was followed by competitive projects with names like ‘Equipex’ (Equipment of Excellence), ‘Labex’ (Laboratories of Excellence) and ‘Idex’ (Excellence Initiatives). But it is never clear what is actually meant by ‘excellence’. European research excellence? The definitions are no clearer at the European level. The European Research Council (ERC) awards large five-year grants in three categories – Starting grants (up to 2 million euros), Consolidator grants (up to 2.75 million euros) and Advanced grants (up to 3.5 million euros). There is considerable competition for these grants. Under the EU’s Horizon 2020 programme (from 20142020), the ERC plans to distribute around 7,000 of them. The ERC states that the “sole evaluation criterion” for their grants is the “scientific excellence” of researchers and research proposals. Under ‘Evaluation Panels’ this is reiterated: “The selection of scientific and scholarly proposals for ERC funding is based on international peer review with ‘excellence’ as the sole criterion.” But the ERC does not provide a definition of ‘excellence’. Instead, you are told to look elsewhere: “The evaluation criteria are established in the Horizon 2020 Rules for Participation.” However, the ‘Horizon 2020 Rules for Participation’ (at ec.europa.eu) only discuss ‘excellence’ in “Article 15: Selection and award criteria. 1. The proposals submitted shall be evaluated on the basis of the following award criteria: (a) excellence; (b) impact; (c) quality and efficiency of the implementation. 2. Only the criterion referred to in point (a) of paragraph 1 shall apply to proposals for ERC frontier research actions.” 03/09/2015 14:16 page 30 Lab Times Analysis 5-2015 In fact, nowhere is there an explanation of how the ERC actually measures the elusive quality of ‘excellence’ when distributing its funds! says, we should be giving more chances to young researchers who are currently ‘good’ because we do not know how they will develop and cannot identify, who among them will come to be recognised as tomorrow’s excellent scientists. Given the limited funds available to funding agencies, he suggests it would be better to give more small grants to many researchers (say 50%) rather than to give a few large grants to small numbers of elite researchers (<5%). Especially since large grants would only be more effective if it could be shown that scientific impact increases as a growing function of grant size. But instead, quantitative studies of this funding problem indicate that strategies the pursuit of excellence is only the mirage reflection of an ideological and unrealistic dogma.” (Not) Seeing Excellence Lars Walløe, President of Academia Some arguments against excellence Europaea, discussed the problems of recMany critics oppose the use of ‘excelognising excellence in a 2009 talk on ‘The lence’ as a buzzword to justify all kinds of meaning of excellence and the need for exdecisions about the funding of researchers cellence in research’ (transcript at: ae-info. and projects, the reorganisation of univerorg). Walløe, a physiology professor in Norsities and research centres, the waste of reway, has been on many funding commitsearch resources, and a demoralising sense tees and chaired a panel deciding on ERC’s that science is getting lost. Starting Grants. He said they constantly The ‘Dogma’ of Excellence faced the problem of deciding which proFrancesco Sylos Labini, co-founder of posals seem to be the most promising. He Italy’s research forum ‘Return on Academagrees that we can’t really predict excelic ReSearch’ (ROARS), condemns what he lence in the future and goes further, by saycalls the ‘dogma of excellence’. ing that even assessments of This pretends to assign the largpast excellence have often est part of available research been shown to be matters of funds only to the best scientists subjective understandings (Euroscientist, 29/01/14). But of the relative importance Labini questions whether we of certain lines of study and What is excellence? - In the case of research, there is no agreecan really assess who will be exdiscovery, and the personal ment regarding the definition of excellence and its measurement cellent in the future and if this is claims for credit in this reacross different disciplines at the international level. the best way of supporting new search. Is excellence absolute or relative? - Excellence is a highly relaand productive research. Hence, in the present – tive concept. It implies a judgment that evaluates if and to what extent Currently, researchers are now – how do you judge exsomething or someone possesses some definite intrinsic characterisforced to compete with each cellence? It’s a problem. tics to be considered excellent (in relation to oneself and others) other for the allocation of reYou have bibliometrics An alternative definition of ‘Excellence’: an intangible noun desources, yet only a small fracwhich are popular because rived in recent decades from an adjective meaning anything that is not tion will be able to obtain the they are pseudo-objective directly in opposition to a mission statement. Basically it is supposed funds needed to fully develop but Walløe says you can’t to mean ‘good-ness’, but better than good, really good. But without their own research projects. This tell much from impact facany increase in quality of work to back it up. So it can be anything has two negative consequences. tors and citations. Moreover, from poor to mediocre to decent to great to outstanding. In all conFirst, although some competihe asserts that many citation crete reality, excellence means nothing but you’ll see it everywhere to tion is good for public research, chasers are not so good at redescribe everything. it is clear that there is a threshsearch. “I often meet scienExcellence as “bullshit”: Modern management of universities old, beyond which competition tists who see obtaining high creates more adverse than posbibliometric factors as the and scientific research has produced its own “official bullshit.” Three itive effects. He argues that an prime goal of their work. types of statements play a key role: excess of competition stimulates Too many of them are not re“Excellence-speak” (or “Top-speak”): statements that identify misbehaviour (for example, ally excellent but have been the underfunded public universities (of the US, the Netherlands, Gerfraud and stealing of credit in lucky or work in a field where many, France, etc.) with the top private universities in the US; scientific publications) and an it is easier to obtain many ci“Valorization-speak”: statements that identify the academic invasive pressure on the choice tations.” worth of research with economic market value; of research topics made by indiSo, then we have ‘peer re“Quali-speak”: statements that identify the quality of education viduals. Second, faced with the view’. But again, Walløe says with quantitative educational output. risks of excessive competition, people fail to realise just how young scientists are becoming subjective and narrow these Sources: ‘The concept of excellence in higher education’ a report by the European increasingly conservative in judgements can be. It only Association for Quality Assurance in Higher Education, 2014; www.urbandictionary. their approach to research, infunctions well if the chosen com; C. Lorenz “If You’re So Smart, Why Are You under Surveillance? Universities, vesting research time in mainpeers are not only good sciNeoliberalism, and New Public Management”, Critical Inquiry, 2012. stream ideas that conform to entists themselves but also peer pressure and job market rehave a broad-minded apquirements rather than explorproach to what constitutes ing innovative ideas. excellent scientific contributions in their targeting research diversity, rather than The basic problem is that today’s deciown field. “Too many scientists who are ‘excellence’, are more likely to be producsions to finance researchers are based on excellent researchers consider somewhat tive in the long-term. who and what is judged to be excellent at naively that the only right way to do sci“The evaluation of scientists needs to this particular timepoint. Instead, Labini ence is exactly the way they themselves do give space to different degrees of quality: The Definition of Excellence LT_515_28_31.indd 30 03/09/2015 14:16 Analysis it.” And often these scientists become referees, advisors or even the decision makers at various levels. “This attitude to excellence can have serious consequences, since really promising scientists or projects may get lost in the selection process.” Walløe said he often found it necessary to remind a committee of peers of the truism that excellent contributions to science can be made in very different ways and at very different levels in the research process. Good better than excellent Furthermore, Walløe questions the obsession with excellence – “Is excellence in research always needed? I believe not. Sometimes we need good reliable science but not necessarily excellent science, because there is a piece of standard research work which has to be done and done reliably. A new treatment may, for example, need to be compared to an old method to determine, which is better, or a new piece of equipment needs to be developed. “There are many ways to do good science and even excellent science. One researcher may formulate a new hypothesis based on the failure of an older one. This may be an important contribution, even if the scientist involved is not able to test the hypothesis herself. Other scientists may develop important new methods or equipment, or painstakingly collect data in a laboratory or in the field using established methods. Similarly, just collecting the necessary data or doing the right experiments to test a new hypothesis formulated by someone else could also constitute excellent and valuable science. Critical reanalysis of other people’s published or unpublished works, with full acknowledgement of the original author, can result in important new insight and thus represent excellent work in science. There are many different scientific activities which can be excellent if they are done in the right way.” Antisocial Excellence Jack Stilgoe wrote an article ‘Against Excellence’ (The Guardian, 19/12/14). He claims the traditional definitions of excellence applied to scientific research are at odds with new perceptions of what science ought to be about. It is not enough to say that the research is being performed to the highest standards of integrity and reason, it must also have a sense of social ‘responsibility’. “Is science just about letting researchers pursue their own favourite explorations through their chosen topics? Are we really saying that researchers who have been LT_515_28_31.indd 31 5-2015 Lab Times page 31 given the ‘excellence’ label/brand are completely free to do what they like with the public funds entrusted to them?” Stilgoe, who teaches science policy at UCL London, helped draft the ‘Rome Declaration on Responsible Research and Innovation in Europe’. He argues that making excellence the main justification for funding science tells us nothing about how important the science is and everything about who decides. “Excellence is judged by peers and backed up by numbers such as h-indexes and journal impact factors, all of which reinforces disciplinary boundaries and focuses scientists’ attention inwards rather than on the problems of the outside world.” Prioritising excellent research perpetuates the reproduction of scientific elites and the concentration of scientific research in particular disciplines and places. Although he agrees we need ERC and other ‘blue-skies’ funding as part of the innovation ecosystem, the danger is that, by identifying this as ‘excellence’, it “damns” everything else to mediocrity, including applied science, user-driven innovation, open science, meta-analysis, regulatory science, social innovation, and engagement with policymakers and the public. In the last thirty years, our sense of excellence has narrowed, not broadened. Against the assumption that quality is one-dimensional, it becomes harder to make the case for diversity in science. important both for individual scientists and for universities. As a result, they have become “publication factories, bound to maximize their publication output”. The ideal professor in these modern universities is a mixture of fundraiser, project manager and mass publisher (mostly as a co-author of publications written by his or her assistants since “he or she has no more time to do research”), whose main concern is a measurable contribution to scientific excellence rather than increasing our knowledge. In order to make sure that professors will deliver their contribution to excellence, faculty managers have been recruited for each department in addition to traditional deans. “They act like CEOs in private companies and they are supposed to implement new strategies for becoming increasingly excellent.” Research becomes a means in the battle for ‘market shares’ of universities and research institutions. Winners are rewarded with elite or excellence status “notwithstanding the fact that many projects and publications do not have the slightest importance for people outside and often even inside the academic system”. Nevertheless, notes Binswanger, these measurable outputs play a central role in today’s research rankings; for example, in the ‘CHE Research Ranking of German universities’ where they are advertised under labels, such as ‘more excellence’ and ‘more efficiency’. Stop using the word Motivation fosters excellence Responsible research and innovation (RRI) in the service of grand challenges also means transforming the way we fund science. In many ways, this means revisiting models used in the past but forgotten with the rise of excellence. Stilgoe concludes that “if we cannot find a way to expand our sense of what counts as scientific excellence, let’s stop using the word”. Excellence as Nonsense Mathias Binswanger analyses ‘how nonsense became excellence’ in universities and scientific research. He argues that modern universities are no longer focused on gaining knowledge. Instead, they have become exclusively committed to measurable excellence and “the search for truth often does not help much in this respect”. Universities are now “fundraising institutions determined to receive as much money as possible from government researchfunding programs or private institutions”. This entails a competition for rankings based on publications and citations that are Another serious consequence of the permanent competition for publication is the demotivating effect on scientists. “More and more people employed in the research system spend more and more time on things that have nothing to do with true research.” Their intrinsic motivation for pursuing scientific knowledge is being increasingly ‘crowded out’. For Binswanger, a scientist who is not truly interested in his work will never be a great scientist. Yet exactly those scientists, who are intrinsically motivated, are the ones whose motivation is usually crowded out the most rapidly. “They are often rather unconventional people who do not perform well in standardised competitions, and they do not feel like constantly being forced to publish just to attain high scores.” And if intrinsic motivation is lost, so will a lot of potentially valuable research, because intrinsic motivation is a necessary condition for ‘true excellence’. Jeremy Garwood 03/09/2015 14:16 Lab Times Journal Club 5-2015 Brain evolution in Helsinki, Finland Fishing for Evidence Which factors drive brain evolution in threespine sticklebacks? Juha Merilä and colleagues in Finland and Hungary answered this question with a trip to the seaside at Helsinki, where they caught wild fish with a seine net. T hreespine sticklebacks (Gasterosteus aculeatus) are of particular interest to both ecologists and evolutionary biologists. That’s because the 5 cm fish evolved into many divergent, locally adapted populations after the last ice age; they are also easy to breed and keep in aquaria, feeding mainly on chironomid larvae; they have a short generation time and last but not least, their genomic make-up has been known since 2006. Their name-giving spines, together with bony lateral plates, are their defence against predators and make the fish difficult to swallow. In the wild, threespine sticklebacks live in fresh water, estuaries and coastal seas throughout the Northern hemisphere. During the winter, they are pelagic and can be found over 500 km offshore. Sex-life on tv breeders. They crossed wild fish in vitro by mixing surgically-gained sperm with eggs. Finally, 231 sticklebacks had their brains dissected, fixed in formalin, photographed and measured. “Technically, after the delicate work of dissecting and of measuring the size of brain regions, the biggest challenge was informatics. We waited and hoped that the computer did not crash while running models, which we used to get estimates of heritability and genetic correlations for different brain regions,” recalled Kristina Noreikiene, first author of the publication and Merilä’s PhD student. Independent brain parts “Our results suggest that neural tissue, at least in sticklebacks, does not have severe genetic constraints and could, therefore, quickly respond to environmental demands through plasticity. This indeed may be adaptive, especially in a rapidly changing and sometimes unpredictable world,” Noreikiene explained. In contrast to the brains of primates, rodents and birds, fish brains show lifelong growth and neuro genesis. The data also suggest an effect of maternal influences on the brain size of offspring, which could stem from the quantity of nutrients deposited in the eggs or other sources. The evolvability of different Photos: James Mills, Nobertas Noreika The creature is known for its complex mating behaviour, which was described by Nobel Prize Laureate Niko Tinbergen. The male builds a nest from plant material, to which it lures the female by performing a zigzag courtship dance. After the female has deposited hundreds of eggs in the nest, the male fertilises them. Male sticklebacks even guard and ventilate the eggs and young. The BBC illustrated the dramatic love life of sticklebacks in a gripping video: http://tinyurl.com/q9afsoy Thus, threespine sticklebacks are great animal models, also for brain evolution. In one of his latest studies, ecologist/evolutionary biologist, Juha Merilä, discovered that additive genetic effects were responsible for about 40 per cent of the variation in the size of the fish brain and its different regions. Surprisingly, he and his colleagues could not detect any impact resulting from different rearing conditions (Proc R Soc B, 282:20151008). For their brain evolution study, the scientists from the University of Helsinki and from the Eötvös Loránd Scientists in their outdoor lab: University, Budapest, also acted as fish Juha Merilä and Kristina Noreikiene LT_515_32_35.indd 32 Photo: www.publicdomainpictures.net/Petr Kratochvil page 32 brain parts was moderate and the genetic correlations among different brain regions low. “Our data support the mosaic model of brain evolution, according to which natural selection can change brain areas fairly independently,” Merilä said. By contrast, brain and body size were strongly genetically correlated in threespine sticklebacks and brain size most likely evolved as a response to selection on body size. For their experiments, the scientists fitted some of the labs’ aquaria with tubes and artificial plants to provide a more complex environment compared to plain aquaria. Earlier studies with salmon had suggested that a more stimulating environment, surprisingly even a single rock in the basin, influenced the size of the cerebellum. On the contrary, this decoration did not produce any major change in the size of the stickleback’s brain or its parts. There are, however, still some unknown factors, which were not analysed, e.g. social interactions with conspecifics. Currently, Merilä’s group is performing quantitative trait locus mapping studies to identify the genomic regions relevant to brain size variation. “Our main interest is to see if the same phenotypes in different stickleback populations are underlined by different sets of genes,” he noted. Tough times for basic research The idea for the recently published study came about by serendipity. Merilä’s grant-based position as an Academy Professor involves few teaching and faculty tasks and, thus, allows him to devote most of his time to the management of research projects. “I compensate for my reduced teaching obligations by supervising and mentoring many PhD students and postdoctoral researchers,” he said. Additionally, Merilä is a member of several review and evaluation panels. In the past 15 years, science in Finland has profited from a good funding situation. “Recently, the times have been getting 04/09/2015 09:41 Journal Club 5-2015 tougher for basic research as the Finnish government has made some serious cuts to the research and education budget,” the ecologist noted. He worries about the many young researchers who have to compete for the few available permanent positions in Finland. Shortly before his departure to the ‘Eighth International Conference on Stickleback Behavior and Evolution’ at Stony Brook University in New York, Merilä gave Lab Times some insights into his career. “I learned the fundamentals of evolutionary biology as a PhD student at Uppsala University, Sweden,” the Finn recalled. “My scientific interests were inspired by the wonderful crowd of people at the old Zoology Department. Further important influences were papers about natural selection and quantitative genetics of wild populations by Russell Lande, Arie van Noordwijk, Stevan J. Arnold, Peter and Rosemary Grant and their students,” he said. From feathery to slippery During his doctoral studies, Merilä participated in a long-term project investigat- ing the inheritance and selection of quantitative traits in birds, which has been going on for more than three decades. “Most of the individuals in the Collared Flycatcher population (Ficedula albicollis) on Gotland are now marked. The knowledge of the pedigrees and generations of birds is necessary for quantitative genetic studies,” the researcher explained. In his analyses, he increased and decreased clutch size and analysed whether this affected morphological traits such as body size or genetic correlations between traits and their heritability. “I observed that heritability was not constant. It was lower when the environmental conditions were bad and, thus, reduced the expected evolutionary response to selection,” he elaborated. For his postdoctoral work he chose another research object. On his website he commented on this transition: “After tramping the same trails in forests of the island of Gotland for six years in a row banding massive amounts of fluffy fledglings, I grew to think that the grass could, after all, be greener somewhere else. Hence, I regressed to amphibians....” The ecologist investigat- Lab Times page 33 ed the adaptation of frogs to the acidification of water courses in Sweden, due to environmental pollution and to enhanced UV-B irradiation. “I was interested in the heritability of tolerance traits,” he noted. Into the wild! His current research interests focus on the mechanisms of animal adaptation to local and changing environmental conditions. Together with his team at the Ecological Genetics Research Unit at the University of Helsinki, he is also analysing the relative roles of drift, phenotypic plasticity and genes in differentiation among populations. Field work is now mostly done by the junior academic members. On rare occasions, however, the evolutionary biologist manages to get out into the wild for research purposes, as the accompanying photo shows. But Merilä does not spend his entire time undertaking research on tiny fish, birds and frogs. In his leisure-time, he is a keen angler with a preference for really big salmon. Bettina Dupont Precision and innovation for professional laboratory applications ■ Menu-guided Profi electronic controller with user-friendly text display for precise temperature setting ■ Visual and audible temperature-, door open- and power-failure alarms ■ Integrated data-logger records alarm events and internal temperatures ■ Integrated 12 Volt battery maintains data-logger and alarm functions of the electronic controller in case of mains power failure ■ Infrared data transfer, RS 485 serial interface and volt-free contact for external temperature and alarm documentation ■ 3-point calibration for high-precision temperature control www.lab.liebherr.com LT_515_32_35.indd 33 04/09/2015 09:41 page 34 Lab Times Journal Club 5-2015 Plant Cytogenomics in Brno, Czech Republic Treading in Mendel’s Genomic Footsteps Unusual chromosome numbers are a characteristic of North American rockcress species. With a technique called comparative chromosome painting, Martin Lysak and colleagues have revealed what lies behind this phenomenon. P lants have an extraordinary variety of genome structures. Genomes vary, for example, in their base chromosome numbers and ploidy (i.e. number of chromosome sets), while individual chromosomes have different sizes, morphology and composition. How are these genomescale differences linked to speciation, life strategies, and the immense collection of shapes and sizes of plant species? This is just one question that fascinates Martin Lysak, leader of Plant Cytogenomics research group based at the Central European Institute of Technology (CEITEC), Masaryk University, in the city of Brno, Czech Republic. constructed the evolutionary origin of the Böcher’s rockcress (Boechera) genome. They also revealed the formation of unusual chromosomes in apomictic rockcress species (Plant J, 82(5): 785-93). Boechera species are not easy to study, as hybridization and apomixis are prominent in this genus. “Apomixis is a kind of asexual clonal reproduction,” says Terezie Mandáková. The apomictic forms are often odd-numbered polyploids, e.g. with three or five sets of chromosomes, while some diploid Boechera apomicts are aneuploids, i.e. have an uneven number of 15 chromosomes instead of the normal 14. “Chromosome pairing and meiosis in these plants is problematic and leads to sterility. Apomixis allows these aneuploid and odd-level polyploid plants to set seeds without fertilisation,” Mandáková explains. Photos(2): Lysak lab chromosomes, while their number can increase by fissions when a chromosome breaks within the centromere.” What factors cause such rearrangements? “In nature, knowing the actual trigger is not easy. There could be chemical or physical triggers, for example, UV radiation or temperature. Mobile DNA elements can also cause chromosome rearrangements.” To elucidate the origin of Boechera chromosomes, Martin Lysak and his team started to paint. Taking advantage of a technique called chromosome painting, Lysak and his team marked conserved g enomic blocks on chromosomes and then compared these patterns to the so-called AnFrom Mendel’s peas to Böcher’s cress cestral Crucifer Karyotype (ACK). “ACK is Brno has a legacy of plant genomic a theoretical concept resulting from mulresearch: the famous father of genetics, tiple lines of evidence. The basic idea was Gregor Mendel, carried out his pea-breedthat many present-day crucifer species have ing studies in an Augustinian abbey in this chromosome numbers based on eight. We On the origin of chromosomes very city. By the way, Brno is celebrating hypothesised that also an ancestral genome A species-specific set of chromosomes the 150th anniversary of the publication of could have eight chromosomes. Later on, Mendel’s original observations this year! As is called karyotype. “As single genes and comparative genetic mapping and chromoa continuation in plant genetics, some painting analyses showed Lysak and his team aim to find that some species (e.g. Arabidopout if chromosome rearrangesis lyrata, Capsella rubella) in difments influence plant genome ferent genera have eight chromodiversification and speciation – somes. These genomes represent and whether this has any importhe ancestral genome still survivtance for evolution. ing today,” explains Lysak. Instead of peas, the Lysak Arabidopsis thaliana, the first lab’s model plants belong to the plant species with a sequenced mustard family, Brassicaceae, genome, was also the first plant also known as the crucifers acto have its chromosomes paintcording to the cross-like struced. This work was actually done ture of the four petals in their Paint the lab red... green & yellow: Martin Lysak and Terezie Mandáková by Lysak himself, when he was flowers. There are more than working as a post-doc in the labwhole genomes, karyotypes are also sub3,500 Brassicaceae species distributed oratory of Ingo Schubert at the Institute jected to evolution,” explains Martin Lyworldwide, including several important of Plant Genetics and Crop Plant Research sak. “The structure of individual chromocrops and vegetables, such as canola, broc(IPK), Gatersleben, Germany. “We took adsomes can be altered by chromosome recoli, Brussels sprouts, cabbages and radish. vantage of the sequenced A. thaliana gearrangements, such as inversions, transloIn the lab’s recently published research nome and started to test whether libraries cations and deletions. Some chromosome article, Terezie Mandáková, postdoc in Lyof chromosome-specific BAC clones (Bacterearrangements, particularly chromosome sak’s group, and Martin Lysak together with rial Artificial Chromosomes) can be used to translocations can reduce the number of their Dutch and German collaborators, revisualise its chromosomes,” he tells. LT_515_32_35.indd 34 04/09/2015 09:41 Journal Club During the painting process, the DNA of chromosome-specific BAC clones is isolated, pooled and labelled by fluorochromes with different emission spectra. These probes are hybridised to target chromosomes with sufficient sequence similarity. Painting signals are visualised and analysed using a top-end fluorescence microscope. “First, we successfully painted a single chromosome and later on, the whole five-chromosome set of A. thaliana. This was the first successful attempt to paint entire plant chromosomes,” Lysak remembers. In follow-up studies, the team tried to see whether the Arabidopsis painting probes could be used to identify homeologous chromosome regions among other, closely or more distantly related, crucifer species. “It turned out that one can indeed identify shared chromosomes and chromosome re- Chromosome painting in the Alpine Pennycress. Differentially labelled painting probes (red, yellow and green signals) identify particular chromosome regions. gions, and thus, reconstruct the course of evolution from common ancestral genomes across the whole family,” Lysak says. Solving the chromosome puzzle Using this approach, the team was able to solve the origin and structure of three Boechera genomes (the sexually reproducing B. stricta, two apomicts B. divaricarpa and B. polyantha) by colouring conserved genomic blocks (GB) within individual chromosomes. “GBs are chromosome segments, which are conserved in different Brassicaceae species. They can be viewed as some sort of building blocks, which are rearranged to build up genomes of different structure,” explains the group leader. The ancestral karyotype is divided into 24 GBs, spread on eight chromosomes. Modern Boechera species ‘squeezed’ the same number of blocks to only seven chromosomes. How did they do it? Mandáková and colleagues showed that three Boechera chromosomes kept their ancestral-like 5-2015 Lab Times page 35 structure, while the remaining four underwent specific rearrangements. For instance, the chromosome number was reduced when one ancestral chromosome fused together with fragments of two other chromosomes, while one of the centromeres has become inactive and was eliminated. The team obtained even more interesting results when looking at the origin of unusual chromosomes present in apomictic Boechera plants. A larger chromosome, called Het, is found in diploid apomictic species like B. divaricarpa, while two smaller ones, Het’ and Del, are present in, for instance, B. polyantha, with an aneuploid (2n=15) chromosome number. Het closely resembles one of the Boechera stricta/divaricarpa chromosomes but has longer stretches of heterochromatin around its centromere. Why this accumulation has happened and whether this is somehow linked to the apomictic trait is a question, still waiting to be answered. Regarding the two tiny chromosomes Het’ and Del, Terezie Mandáková and her colleagues found an answer already. They originated from the bigger Het chromosome through centromere breakage. This breakage is the reason for the uneven number of chromosomes in B. polyantha, which would normally cause trouble during meiosis. “Our study shows that extra chromosomes and, generally, certain types of chromosome rearrangements can become fixed and be propagated to next generations due to the apomictic mode of reproduction,” says Lysak. Reproduction without sex does seem to offer an escape route for plants with chromosomes gone wild! Future plan(t)s This summer, Lysak’s team, in collaboration with Ute Kraemer from the Ruhr University Bochum, has published another interesting study on a different cress species – the Alpine Pennycress (Noccaea or Thlaspi caerulescens). Chromosomes in this wellknown hyperaccumulator of heavy metals have been altered by an unusually high number of inversions, which could have facilitated the evolution of enhanced metal homeostasis gene expression. With important results like these, Martin Lysak’s research group, of course, continues their studies on the karyotype evolution in crucifers. Together with Duke University in the US, they are about to embark on a bilateral project, focusing on many more Boechera species native to North America. Johanna Rajasärkkä Boost your sample prep Introducing The fastest enzymatic PCR cleanup method: NEW HT ExoSAP-IT Fast High-Throughput PCR Product Cleanup ® n n n n Half the time of standard enzymatic protocols One simple pipetting step 100% recovery and only 5 μl of PCR product needed Ideal for automated platforms and multi-channel pipettes Learn more at: usb.affymetrix.com/fastercleanup © 2015 Affymetrix Inc. All rights reserved. LT_515_32_35.indd 35 04/09/2015 09:41 Lab Times 5-2015 Publication Analysis 2007-2013 Cell Biology Ranking Image: Heiti Paves/CC BY-SA 3.0 page 36 Microfilaments, mitochondria and nucleus in fibroblast cells Although Germany clearly leads the nations’ ranking, one French lab dominates European cell biology research. Programmed cell death and stem cells are hot topics. “F or, as to the first, since our Microscope informs us that the substance of Cork is altogether fill’d with Air, and that that Air is perfectly enclosed in little Boxes or Cells distinct from one another.” These famous words, uttered by Robert Hooke in 1664, weren’t perhaps the kick-off for cell biology research as such but it, at least, gave the discipline its name: the “little boxes” Hooke observed, reminded him of a cellula, a small room. Hence, he named them “cells”. Modern cell biology’s moments of glory came a few hundred years later. Especially in the 1960s and 70s, cell biologists churned out momentous discoveries about the cell. Micro tubules, for instance, were first described in 1963 in hydra (JCB, 18(2):367-88) and in plant cells (JCB, 19(1):239-50). In the same year, Margit and Sylvan Nass, back then at the WennerGren Institute for Experimental Biology in Stockholm, published their findings on “intramitochondrial fibers with DNA characteristics” – the first description of mitochondrial DNA (JCB, 19(3):593-611). Fifty years on, we know a cell inside out. Or do we? Cell biological research is still hotly debated. Just last year (LT 4-2014), LT reporter, Karin Hollricher, unsuspectingly went to a scientific conference on aneuploidy and got roped into a heated discussion about mitosis. So, does research on mitosis attract the most citations? That’s what we will explore in this publication analysis. No changes at the top First, as you’ll perhaps know from past issues, we turn our attention to Europe and the individual countries’ performance in cell biology. For this, we rely on so-called expert journals, as defined by Thomson Reuters’ Web of Science database. In the last cell biology ranking from 2009 (LT 5-2009), covering papers, proceedings papers and reviews published between 1996 and 2007, Germany came out on top, followed by England and France, Italy and Switzerland. Six years later, nothing much has changed. As a matter of fact, the first 14 countries all kept their positions. Only one country took a major step up the ranking ladder: Portugal climbed six spots from 23rd to 17th place. Comparing the average citations per article, Switzerland performed best (42.7), followed by Scotland (36.6) and the Netherlands (36.4). It’s also worth mentioning that cell biologically-themed articles are, on average, cited twice as often as, for instance, articles on reproductive biomedicine or parasitology, our last two publication analyses. LT_515_36_39.indd 36 In the “battle” between Europe and the US, as usual, European cell biologists wrote more articles published in cell biology specialist journals. These articles, however, were cited less often than those penned by their US peers, in total (1,265,428 vs 1,649,744) and on average (26.7 vs 36.5). Outside of Europe, Japan performed very well, scoring the second most total citations; and Singapore, although not one of the top nations when it comes to total citations, got ahead of many others, even Germany and France, with their average citations per article (32.1). So, what are then the most cited papers and reviews in cell biology, published between 2007 and 2013? The undisputed number one, with more than 8,000 citations to-date, is Douglas Hanahan’s and Robert Weinberg’s update article on the “Hallmarks of Cancer: The Next Generation”. In second place, Tony Kouzarides informs the scientific community about chromatin modifications and functions. Also among the top five articles are two publications dealing with microRNAs. Interestingly, none of the highly-cited articles is about those hot topics, which occupy the majority of our most-cited cell biologists in Europe. Hard to separate This, eventually, brings us to the said top 30 list. Once again, we had to come up with a few criteria to limit the vast amount of researchers taking advantage of cell biological techniques, to those, who can be considered true cell biologists. Not an easy task, as we had to find out. While there are still many basic cellular mechanisms waiting to be fully elucidated, the best way to attract many citations is to combine cell biology with other disciplines. Hence, many of our top 30 authors appeared in other rankings, too. Guido Kroemer, for instance, topped both the Immunology and Cancer Research rankings. Boris Zhivotovsky was among the top 30 in Toxicology Research and Maria Blasco scored 9th place in the Ageing Research publication analysis. So, we decided to include only those scientists, who published a considerable number of their articles and reviews in cell biologically-themed specialist journals. In addition, ‘cell biology’ must have been listed among the top two Web of Science categories for a given scientist. Interestingly, Europe’s top cell biologists are based in 13 different countries. England and France are home to five top cell biologists each. The French mecca for cell biology seems to be located in Villejuif, 7 km from the centre of Paris, in Guido 03/09/2015 14:38 Ranking Kroemer’s lab, to be more precise. Including Kroemer (1st), four of the five French cell biologists work or have worked there: Lorenzo Galluzzi (6th), Maria Chiara Maiuri (21st) and Oliver Kepp (24th). And what are they working on? Programmed cell death in health and disease. Most of us are perhaps familiar with one way for a cell to die by choice – apoptosis – but there are many other death strategies, such as autophagic cell death, programmed necrosis, mitotic catastrophe and entosis (cellular cannibalism) as Kroemer informs on his website. Hence, one of his goals and that of his lab fellows is to “resolve the fundamental enigma: through which molecular and cellular mechanisms do cells die in normal tissue”. In cancer cells, however, these vital ways to bite the dust voluntarily are severely disturbed. Kroemer, thus, “launched a quest into the mechanisms that determine cell death resistance or connect different cell death modalities in cancer cells”. Cell death, stem cells and enzymes The four French aren’t, however, the only ones interested in a cell’s final moments; also David Rubinsztein (4th), Peter Vandenabeele (8th), Gerry Melino (16th), Mauro Piacentini (18th), Boris Zhivotovsky (25th) and Terje Johansen (30th) all study cell death. Stem cells, on the other hand, usually mark the beginning of a cell’s life cycle. Hans Clevers (2nd); Austin Smith (20th); JuanCarlos Belmonte (27th) and Hendrick Stunnenberg (29th) have dedicated their professional lives to these undifferentiated cells. Directing the Center of Regenerative Medicine in Barcelona for many years, Juan-Carlos Belmonte has, in the meantime, transferred his office fully to the Salk Institute for Biological Studies in San Diego. While still in Spain, his lab made major headlines with “mini-kidneys” grown from human pluripotent stem cells (Nature Cell Biol, 15:1507-15). Between birth and death, a cell’s life is full of action. Johan Auwerx (9th), for instance, wants to decipher metabolic pathways; Carlos Lopez-Otin (10th) has zeroed in on novel human proteases, such as metalloproteinases of the MMP and ADAMTS family, as well as serine and cysteine proteases. Benoit Viollet (12th) focusses on different but not less important enzymes, the energy sensor AMP-activated protein kinases. Ivan Dikic (22nd), on the other hand, follows the ubiquitin pathways to learn how they regulate endocytosis, immune responses, DNA repair and proteasomal degradation. Last but not least, a few top 30 cell biologists have a weakness for a cell’s genetic material. Jiri Bartek (17th) in the Prague-based Laboratory of Genome Integrity wants to understand the DNA damage response and DNA double strand breaks. Telomeres and their role in ageing and cancer are Maria Blasco’s (19th) scientific passion. What’s the future of cell biology? Will it merge with other disciplines like oncology or immunology and disappear from the scientific world stage? Or will it perhaps just take a new direction? In a 2010 contribution to Molecular Biology of the Cell (21(22):3822), Kai Simons, former director of the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, gazes into the crystal ball, “I predict that engineers, who today lack training or knowledge of cell biology, will in the future take their inspiration from all the wonder machines that nature has produced. Molecular cell biologists are continuously unravelling the workings of the cellular nanomachineries. This will be a real source of future welfare and wealth globally, and not like the virtual dividends that result from manipulating the financial markets.” Kathleen Gransalke LT_515_36_39.indd 37 5-2015 . Lab Times page 37 Europe... Country Citations Articles Cit./Art. 1. Germany 2. England 3. France 4. Italy 5. Switzerland 6. Netherlands 7. Spain 8. Sweden 9. Scotland 10. Israel 11. Belgium 12. Austria 13. Denmark 14. Finland 15. Norway 16. Poland 17. Portugal 18. Ireland 19. Hungary 20. Czech Rep. 332,217 272,709 193,619 150,860 107,965 106,879 91,608 62,306 59,211 49,425 49,373 39,705 36,798 30,381 21,890 18,439 17,829 17,447 15,339 14,644 10,803 7,957 6,103 6,107 2,526 2,933 3,818 2,040 1,619 1,479 1,463 1,324 1,111 934 689 1,530 717 653 631 700 30.8 34.3 31.7 24.7 42.7 36.4 24.0 30.5 36.6 33.4 33.8 30.0 33.1 32.5 31.8 12.1 24.9 26.7 24.3 20.9 Articles appearing between 2007 and 2013 in ‘Cell Biology’ journals as listed by SCImago and Thomson Reuters’ Web of Science. The citation numbers are accurate as of July 2015. A country’s figures are derived from articles, where at least one author working in the respective European nation is included in the authors’ list. Israel is included because it is a member of many European research organisations and programmes (EMBO, FP7 of the EU...). ... and the World Citations Articles Cit./Art. Europe 1,265,428 47,312 26.7 USA Japan China Canada Australia South Korea 1,649,744 251,505 179,933 161,045 100,926 70,329 45,174 10,653 11,538 5,826 3,402 4,269 36.5 23.6 15.6 27.6 29.7 16.5 03/09/2015 14:38 page 38 Lab Times Ranking 5-2015 Publication Analysis 2007-2013 – Cell Biology Most Cited Authors... Cit- Artations icles 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Guido Kroemer, Inst Gustave Roussy, Villejuif Hans Clevers, Hubrecht Inst, Utrecht Jürg Tschopp, Univ Lausanne, † 22.03.2011 David C. Rubinsztein, Med Genet, Univ Cambridge Douglas Hanahan, Swiss Inst Expt Canc Res, Lausanne Lorenzo Galluzzi, Inst Gustave Roussy, Villejuif Peter Carmeliet, VIB Vesalius Res Ctr, KU Leuven Peter Vandenabeele, VIB Inflamm Res Ctr, Univ Ghent Johan Auwerx, Lab Integrat & Syst Physiol, EPFL, Lausanne Carlos Lopez-Otin, Biochem & Mol Biol, Univ Oviedo Kari Alitalo, Inst Biomed, Univ Helsinki Benoit Viollet, Inst Cochin,Univ Paris Michael P. Lisanti, Inst Canc Sci, Univ Manchester Jiri Friml, Inst Sci & Technol, Klosterneuburg Josef M. Penninger, Inst Mol Biotechnol, Vienna Gerry Melino, Toxicol, Univ Leicester Jiri Bartek, Inst Mol Genet, Prague Mauro Piacentini, Biol, Univ Rome Maria A. Blasco, Mol Oncol, Spanish Natl Canc Res Ctr, Madrid Austin G. Smith, Stem Cell Inst, Univ Cambridge Maria Chiara Maiuri, Inst Gustave Roussy, Villejuif Ivan Dikic, Biochem, Univ Frankfurt Tony Kouzarides, Gurdon Inst, Univ Cambridge Oliver Kepp, Inst Gustave Roussy, Villejuif Boris Zhivotovsky, Toxicol, Karolinska Inst, Stockholm Dario R. Alessi, Coll Life Sci, Univ Dundee Juan-Carlos I. Belmonte, Ctr Regenerat Med, Barcelona Reinhard Fässler, Mol Med, Max Planck Inst Biochem, Martinsried Hendrik G. Stunnenberg, Mol Biol, Radboud Univ Nijmegen Terje Johansen, Med Biol, Univ TromsØ ... and Papers 32,352 15,248 15,001 12,655 12,597 11,390 10,124 9,336 8,663 8,477 8,008 7,473 7,459 7,255 7,181 7,126 7,123 7,072 7,071 7,056 7,004 6,878 6,659 6,521 6,312 6,286 6,267 6,155 6,149 6,103 312 149 99 107 38 131 197 115 120 108 131 146 217 112 167 161 98 75 89 60 48 80 27 94 81 78 116 107 105 37 Guido Kroemer (1.) David Rubinsztein (4.) Douglas Hanahan (5.) Carlos Lopez-Otin (10.) Jiri Bartek (17.) Maria Blasco (19.) Ivan Dikic (22.) Terje Johansen (30.) Citations of articles published between 2007 and 2013 were recorded up until May 2015 using the Web of Science database from Thomson Reuters. The “most-cited papers” had correspondence addresses in Europe or Israel. 1. Hanahan, D; Weinberg, RA Hallmarks of Cancer: The Next Generation CELL 144(5): 646-674 MAR 4 2011 2. Kouzarides, T Chromatin modifications and their function CELL 128(4): 693-705 FEB 23 2007 3. Valadi, H; Ekstrom, K; Bossios, A; Sjostrand, M; Lee, JJ Lotvall, JO Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells NATURE CELL BIOLOGY 9(6): 654-U72 JUN 2007 4. Haass, C; Selkoe, DJ Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide NATURE REVIEWS MOLECULAR CELL BIOLOGY 8(2): 101-112 FEB 2007 5. Landgraf, P; Rusu, M; Sheridan, R; [...] Sander, C; Zavolan, M; Tuschl, T A mammalian microRNA expression atlas based on small RNA library sequencing CELL 129(7): 1401-1414 JUN 29 2007 LT_515_36_39.indd 38 Citations 8,222 4,067 1,979 1,833 1,770 03/09/2015 14:38 Opinion 5-2015 Lab Times page 39 What’s behind paper retractions? (30) Want to End Fake Peer Reviews? Retraction Watch’s Adam Marcus and Ivan Oransky tell you how easily it can be done. B Shockingly simple Photo: Photocase/zettberlin y now, you may have heard about a relatively new – but alarming – phenomenon: researchers figuring out how to get their papers published without true peer review. In August, Springer announced it was retracting 64 papers for this reason, while SAGE said it was retracting 17. At the time of this writing, publishers have retracted 250 papers since 2012 because authors either did their own peer review or had others do the peer review, sometimes unbeknownst to them. How did this happen? (“And why didn’t I think of it?,” you’re probably muttering.) The answer is: quite easily. Indeed, gaming the peer review system turns out to be shockingly simple to do – and just as easy to prevent. As we’ve recounted elsewhere (Nature, November 26th, 2015, Publishing: The peer-review scam), when journal editors ask authors to suggest potential reviewers for their manuscripts, the authors provide names, “sometimes of real scientists and sometimes pseudonyms, often with bogus e-mail addresses that would go directly to him or his colleagues”. A vulnerable editorial system The problem has affected major publishers, from Elsevier to Springer to Wiley. The most recent cases were from China and Iran, but the practice has also been found in South Korea and Pakistan. What the cases have in common are two factors: one, editors asked authors to suggest reviewers when they submitted the papers; two, the people submitting the papers – who were not always the authors – were able to enter fake email addresses for those suggested reviewers, or reassign reviewers, without editors knowing, thanks to the particular editorial systems those publishers use. LT_515_36_39.indd 39 Thankfully, that makes eliminating the problem fairly straightforward. For one, journals could stop asking authors to recommend reviewers – or do as some editors do and use those lists to eliminate possible reviewers, figuring they were chosen because they wouldn’t be terribly critical. Some editors may insist that the hyper-specialisation of their fields makes asking for suggested reviewers necessary. That’s fair enough and it’s also a strong argument for implementing the second way to end fake peer reviewers – namely, doing more to verify digital identities. Currently, journals (like anyone else at the other end of an electronic exchange) can’t be sure that an author or reviewer is who she says she is (although, in the case of research misconduct, most malefactors are male.) The systems for collecting peer reviews that journals use could close the loophole by forcing editors to verify entered email addresses, or, even better, requiring them to connect with the ORCID database of authors to validate identities. What’s the next big scam? Of course, fraudsters are clever and they’re probably already thinking about – or even implementing – the next big scam. And other hoaxers, trying to expose the lack of peer review at some journals, have managed to get completely fake papers published. We’d need to eliminate the causes of this kind of fraud – pressures to publish or perish come to mind – to really end such scams. But taking these initial steps can’t hurt. Adam Marcus and Ivan Oransky (The authors run the blog Retraction Watch: http://retractionwatch.com) More than 26,000 products... A NEW WEBSITE ...in our online shop! Clear structure User-optimised More features Improved Search feature Up-to-date technologie International www.carlroth.com LABWARE LIFE SCIENCE CHEMICALS CARL ROTH GmbH + Co. KG Schoemperlenstr. 3-5 · 76185 Karlsruhe Tel. (+49)721/5606-0 · Fax (+49)721/5606-149 [email protected] · www.carlroth.com 03/09/2015 14:38 A Veritable Niche Poland, with a population of 38.5 million, houses far less than 100 biotech companies. That is just a sixth of the number in Germany (about 580 companies) and a tenth of the UK’s biotech companies number (over 900). Even Poland’s eastern European neighbours, such as Hungary, are further developed when it comes to biotechnology. Nevertheless, there are bright spots, such as the Selvita Group with headquarters in Krakow. For the first half-year of 2015, they have reported a pretty respectable operating profit of €5.8 million. And compared to the first half-year of 2014, the group’s revenues even experienced 34 percent growth. According to Selvita, this is the third consecutive six-month period with an operating profit. Selvita is almost unknown in Western Europe. The company, founded in 2007, researches oncology drugs, currently employing over 230 scientists, with offices near Boston, USA and Cambridge, UK. Their first candidate is SEL24, an orally-administrable small molecule. It works as a selective inhibitor of PIM and FLT3 kinases. Potential applications could be acute myeloid leukemia (AML), nonHodgkin’s lymphoma and multiple myeloma. At the end of March 2015, Selvita signed a service agreement with US pharmaceutical services company, Aptuit, for the preparation of selected studies. But the promising financial data have a different cause: Selvita also provides integrated drug discovery, chemistry and biology services. The company offers pharmacodynamic in vitro studies to analyse biosimilar products’ activities in comparison to reference compounds. Generic approval of this area is becoming increasingly important. Health systems can achieve immense savings by using generic drugs. That registration trials outside the EU can become problematic was recently shown in the scandal over falsified data at GVK Biosciences, an Indian company (see Lab Times 1/2015, page 35: “Fishy Trials”). In addition to its own research projects, Selvita has thus found a veritable niche. -MvdH- Funding: CRISPR/Cas9 on the advance Flushing Cash into Coffers a Series A investment round. That is a good portion less than across the ocean but more than enough to start drug development operations. Michael van den Heuvel UK: Shire plans next billion takeover CRISPR/Cas9 pioneer Emanuelle Charpentier (left) has so far raised €102 million to push the revolutionary gene-editing technology with CRISPR Therapeutics (Basel, Switzerland), while her former colleague Jennifer Doudna collected €145 million for her USbased startup, Editas Medicine. CRISPR/Cas9, a new and promising geneediting technique, has revolutionised genetic engineering since August 2012 – not only in academia but also in industry. This astonishingly successful method raises hopes for the far more rapid and easier development of new drugs and therapies. One of the most important CRISPR/Cas9 companies has once again collected huge sums of capital: Editas Medicine received a further €107 million from a group of investors. The US company wants to use CRISPR/Cas9 technology to develop drugs against cancer, retinal disease and sickle cell disease, among others. The new financing round was led by Boris Nikolic, former chief advisor on Science and Technology at the Bill & Melinda Gates Foundation and now managing director of an investment company with the strange name of Bng0. Gates is also among the new investors, as well as a number of other wealthy people who want to remain anonymous. Editas had previously received €38 million in capital and is one of a number of non-listed biotech companies that collect a lot of money for advanced genetic therapies in the United States. But what about European CRISPR/Cas9 competitors? Are they also bathing in funding capital like their US counterparts? It looks that way. CRISPR Therapeutics, located in Basel, Switzerland, has also successfully raised funds several times. At the end of April 2015, the company announced the closure of a Series A and Series B financing totalling nearly €80 million. The year before, they raised another €22 million in Fusion Replaces Innovation The Ireland-based pharmaceutical manufacturer Shire wants to swallow its US rival Baxalta for €27 billion. The project is likely to go ahead despite resistance from Baxalta management, Shire announced. Shire’s CEO Flemming Ornskov wants to use the acquisition to transform his company into a global group, specialised in medicines for complaints like blood diseases, cancer and immunological illnesses. Photo: Shire Po lan d : Selv i ta o n th e r i se LT_515 Business.indd 40 Biobusiness 5-2015 Photo: Cailey Cotner/UC Berkeley Lab Times Photo: Helmholtz/Hallbauer&Fioretti page 40 The 57-year-old Dane, Flemming Ornskov, Shire’s Chief Executive Officer since April 2013, is going to make the Ireland-based drug maker a big player. But is he also capable of contributing real inventiveness? This has been a fairly common strategy amongst large drug manufacturers for many years: Lack of inventiveness will be offset by the acquisition of other companies. This need is also driven by high research costs and by the expiration of patents. In July, Shire sent its original offer to Baxalta but without success. Ornskov then decided to contact shareholders directly. The management has offered Baxalta shareholders a premium over the closing price of their shares on August 3, 2015. After a successful merger, Baxalta shareholders would hold approximately 37 per cent of the new group. At the time of the bid, Baxalta was valued at $45.23 (about €40) per share. Baxalta has only been on its own for a few weeks, after the company was cleaved from the US medical technology company Baxter. Baxalta currently has 16,000 employees with an annual revenue of around €5.3 billion. Shire has 5,300 employees, with an annual revenue in the same range as Baxalta’s. Michael van den Heuvel 03.09.15 12:47 Biobusiness UK: Parexel dismisses employees… again Made in Vain In December 2014, British pharmaceutical company, GlaxoSmithKline (GSK), announced a restructuring that affected the Research Triangle Park in North Carolina, USA, causing some 900 employees to lose their jobs. Many research and development activities were shut down. A possible reason: None of the biggest blockbusters made it through Phase III trials. Fortunately for the dismissed workers, GSK signed an agreement with a multinational contract research organisation (CRO), Parexel, to create a new sub-unit. 500 of the endangered GSK jobs were transferred to Parexel. But these positions were a poor match. The tide has turned again, and Parexel has announced that it will cut as many as 850 jobs, starting this year and ending mid-2016; 125 of the layoffs affect the beleaguered ex-GSK staffers. The cuts will be implemented worldwide. The background: R&D activities have declined in the industry, and fewer firms are using CROs like Parexel. But the board of directors still has an option left. In April 2015 Parexel acquired Quantum Solutions India, which provides specialised pharmacovigilance services. This will enhance Parexel’s ability to deal with the adverse effects of new pharmaceutical products. Is it inappropriate to ask whether they will soon shift some former GSK jobs to India? Michael van den Heuvel Biosimilar naming Same but Different The name “biosimilar” already implies its meaning: The relevant drug is estimated to be similar but not identical to the reference product. Being synthesised in organisms or cells, there’s a problem: Different cell lines as well as slightly variant culture media can cause marginal differences, resulting in less effective or even ineffective copy drugs. Patient safety organisations and reference drug firms have long been demanding different generic names for biosimilars to ensure patient safety and correct side effect reporting. Now they have succeeded. Recently, the first biosimilar made its debut The original... on the US market (the granulocyte-colony stimulating factor Zarzio, made by Sandoz), and the authorising authority in charge, the FDA, proposed a four letter suffix for the generic name of both the reference and the biosimilar product (see “Nonproprietary Naming of Biological Products Guidance for Industry“ at www.fda.gov/downloads). The FDA’s attempt implies an unwieldy new nomenclature. Amgen’s reference product, Neupogen, for example, would carry the byname “filgrastim-jcwp” while Zarzio would be “filgrastimbflm”. The same-day statement of Bertrand Liang, chairman of the Biosimilars Council, already gives a foretaste of an upcoming lively debate, “Adding a random collection of letters to the product’s nonproprietary name confers no additional safety benefit, LT_515 Business.indd 41 5-2015 Lab Times page 41 and in fact would require the healthcare professional to be armed at all times with a code-breaking reference”. ...and the biosimilar copy. Nice wording, but what Liang probably wanted to say is that the new FDA regulation is jcwp-bflm – or, in short, bullshit. Lucie Proksch Biogen to build huge factory in Solothurn Dawn of the Excavators US biotech giant Biogen is to invest €920 million in Switzerland.The US-headquartered company aims to build a huge production plant for biopharmaceutical drugs in Luterbach (Canton Solothurn, not far from the Basel area), Biogen’s officials announced in July. After the buildings are finished in 2019, they will house up to 400 employees. Biogen develops therapies for the treatment of neurodegenerative, hematologic and autoimmune diseases, such as the groundbreaking MS drug Tecfidera which earned revenues of almost €2 billion alone in 2014. In total, the Biogen and Swiss officials signing US group’s 7,500 employthe contract for the building project ees generated €9 billion last year, with a whopping profit of €2.7 billion. And Biogen is still on the run: A novel drug candidate to treat Alzheimer’s patients, Aducanumab, is currently being investigated in phase II trials. According to study data, the therapeutic antibody successfully targets and removes aggregated forms of beta amyloid. Few are aware that Biogen’s roots lie in Switzerland. The organisation was founded in Geneva in 1978 by a group of biologists including the later Nobel laureates, Walter Gilbert und Philip -wkSharp, and moved its headquarters to the US in 1982. 03.09.15 12:47 Lab Times Biobusiness 5-2015 Photo: Fotolia/Dmytro Sukharevskyy page 42 Mitochondrial replacement therapy (MRT) under fire A Showcase for Public Engagement with Science? The clinical introduction of Mitochondrial Replacement Therapy (MRT) in the United Kingdom could allow women, carrying pathogenic mitochondrial mutations, to have genetically-related but healthy babies. MRT has, therefore, been hailed a success story of science engaging with the public. Klaus Reinhardt provides an opposing personal view. A notable day: On 3rd February 2015, members of the British Parliament (MPs) voted in support of allowing legislation to introduce clinical application of Mitochondrial Replacement Therapy (MRT), also dubbed the three-parent baby technology. Followed by a similar vote in the House of Lords, legislation now proceeds. Mark Henderson, head of communications at the Wellcome Trust, that funded research into MRT and its publicising over several years, called the public debate preceding the vote a success story of communicating science to the public. I wonder how many MPs, how many patient organisations and how many of the 40 prominent scientists that supported the immediate clinical introduction of MRT, rather than supporting further research before its introduction, knew that the evidence for the safety of MRT is based on trials involving oocytes from only 15 human individuals, three macaques and ten mice. LT_515 Business.indd 42 Henderson’s phrasing that a battle has been won (Guardian, 5th Feb 2015) raises two questions: Who was the enemy – technophobic, progress-avoiding, pro-life treatment deniers? And how was the battle fought? One strategy in the battle was to replace “oocyte nuclear transfer” with “mitochondrial donation”. “Oocyte nuclear transfer” was probably too close to “somatic cell nuclear transfer” (SCNT), employed to create Dolly the sheep. A battle has been won. Really? “Oocyte nuclear transfer” is, however, what actually happens during MRT, not mitochondrial donation. The nucleus is placed alongside novel mitochondria and cytoplasm in the enucleated donor oocyte. The altruistic “donation” demonstrates MRT’s good intentions. But do we know as much about MRT as about organ donation to warrant it being communicated like this? No. Was the British government organisation in charge, the Human Fertilisation and Embryology Authority (HFEA), justified in stating that SCNT results are irrelevant because nuclear transfer between somatic cells is not comparable to placement into germ cells? Or was this argument a hybrid between evidence and the battle that needed to be won? This will be difficult to determine. But using other criteria for science communication with the public, I oppose Henderson and argue that the debate has failed in many aspects. Treating evidence Technology promising healthy children to suffering mothers creates high hopes but disappointments would be particularly painful. Even rare or small risks would concern individuals. Communicating that a technology alters heritable material – thereby crossing one of the few red lines that humankind agrees about – would require a 03.09.15 12:47 Biobusiness Placing the nucleus: without risk? HFEA provides two reasons: 1) interactions between specific mitochondrial and nuclear alleles (mito-nuclear interactions, MNI) cannot be important because sexual reproduction generates as many novel MNI as MRT does, 2) negative consequences of MNI only came from inbred animal lines. Known to HFEA (and also the Science and Technology Committee of the British parliament), the latter statement was incorrect (www.plosgenetics.org/annotation/listThread.action?root=80535). Why reason 1) is also wrong was explained in a paper (Science 341 (2013):1345) that HFEA dismissed within hours of its publication (www.hfea.gov. uk/8178.html). HFEA and the IRP ignore the fact that 100% of the nuclear genome is new to all mitochondria during MRT but only 50% is new in sexual reproduction. And that’s the successful 50% of alleles that had allowed the mother to reproduce. HFEA suggested that mixed-race children do not perform worse than other chil- LT_515 Business.indd 43 dren, so the nucleus can’t have problems with foreign mitochondria. HFEA should be reminded that mixed-race children also have mothers, who inherit 50% of their genome to their children. The head of the Wellcome Trust, infection disease specialist, Jeremy Farrar, had not understood this problem either but thought he had and joked about it as late as two days before the vote in Parliament (https://twitter.com/jeremyfarrar/status/561478 338104287233?refsrc=e mail&s=11). Lab Times page 43 for the pathogenic mutation). Such recommendations were not made by HFEA. Instead, its former chief calls safety concerns a “red herring”. The IRP suggests that MNI are of no concern because the molecular mechanism causing phenotypic effects in mismatched mito-nuclear pairings are not known. This ignores empirical evidence in favour of Considering evolutionary data to be irreleMitochondrial Replacement Therapy (MRT) vant may be caused by the biomedical focus of IRP (and HFEA) members. Did IRP and HFEA, then, critically consider theoretical considerations. It may be jusbiomedical studies on MNI? I suggest not. tified but not with the theoretical argu MRT treatment effects in flagship ment provided: studies were overlooked (EMBO Rep (2015) “…assume that a child born after MR embr.201439110). has slightly different energy metabolism Most oocytes were from the same docompared to his or her parents. Will this nors preventing cross-individual (epidemiomatter? Assuming the child is healthy, I logical) risk predictions. very much doubt it will concern anyone.” Disappointing! An afternoon’s search (New Scientist, 17th Oct 2014). The IRP is free to call differences of up to 20% “slight”. in the medical literature by an evolutionary I had seen a quantification of metabolic efbiology colleague of mine produced at least fects from published studies as the IRP’s job 15 papers reporting MNI, including in Gene before any communication. Moreover, asand Trends Mol Med. One showed a highsuming a priori that a child will be healthy, er prevalence of Parkinson’s disease for mt when actually this was the matter to be haplotypes carriers other than haplotype J studied, is as far removed from good sciMark Henderson ence (communication) as I can imagine. (Wellcome Trust) (The American Journal of Human Genetics (2003) 72: 804). Therefore, if the donor’s mitochondria are not of haplotype J, MRT might result in a higher likelihood that offspring will develop Parkinson’s disease. Far removed from good science Other studies show interactions between more specific loci of the mt and the nuclear genome (e.g., Human Molecular Genetics (2014) 23: 3527) that could not be met by haplotype matching. Donor and recipient’s compatibility will be guaranteed if their mt genomes are identical (safe Illustration: OHSU Overlooked effects Photo: Worfolk Lectures particularly stringent examination of the available evidence. Was the Independent Review Panel (IRP) created to assess existing evidence the stringent examiner? No. Studying epistatic interactions between mitochondrial and nuclear genomes in animals, evolutionary biologists have screened 27,000 offspring from 3,000 putatively healthy, maternal subjects of several species (about 15 papers, see Science 341 (2013):1345). The offspring phenotype depends on specific combinations of mitochondrial and nuclear genomes. Health consequences occurred more often with novel mtDNA than with original (or some control) mtDNA, resulting in reduced fertility, accelerated ageing, developmental, respiratory and cognitive impairment. These symptoms are a small risk for sufferers of devastating forms of mitochondrial diseases. For mutation carriers, whose offspring do not express the disease (19 in 20 to 49 in 50) and so may be treated unnecessarily, these symptoms may be a consideration. How can this data justify HFEA’s communication to the public that placing the nucleus (of a usually asymptomatic woman carrying a mitochondrial mutation) into the cytoplasm of a randomly chosen donor is without risk for the resulting offspring? (Later, some kind of haplotype matching was proposed – see below). 5-2015 Addressing economic interests In an ideal world, the research interest of the laboratory would be detached from universities’ interests in performing clinical MRT. The downside of this is that expertise is inevitably lost. Private economic interests also exist for the immediate clinical introduction of MRT. In one case, these interests were originally not declared, yet safety concerns were dismissed and, instead, it was suggested that reproductive treatments had always represented a risk for affected families (PLoS Genetics (2014) 10:e1004315). This publication’s editor had been a co-author within the last two years – nothing to convince me of an apparent showcase on how science should influence society. Calculating incidences The majority of mutation carriers will have offspring that are not severely affected. Desirably, the number of sub- 03.09.15 12:47 page 44 Lab Times Biobusiness 5-2015 jects treated unnecessarily should be low. I would have, therefore, expected the IRP to review from published studies the incidence of MNI after mitochondrial transfer. My own preliminary, unpublished analysis place the incidence of negative effects of MNI as high as one in 27 maternal subjects (calculated from the studies listed in Science (2013) 341:1345). Unless the number is wildly off, it confirms the obvious – that the majority of off- one healthy person resulting from accidental MRT as evidence that problems are unlikely – as done by the BBC and editorials in the highest-profile science journals – is not. Extra caution for heritable alterations Altering inherited material in humans will be controversial, no doubt. Extra caution, such as the application of exaggerated safety standards may be useful to broaden If something goes wrong, serious side effects (right) are an undesirable result be upheld after proponents of the immediate clinical introduction of MRT suggested that, per year, 150 women at risk of mitochondrial diseases could benefit from MRT (NEJM (2015), 372: 885)? And is the conclusion by the BBC (published one week before the vote by MPs) extra careful that annually 150 three-parent babies could be born? Or would responsible communication rather have included the notion that the 150 women at risk include about 100 asymptomatic, first-degree relatives and women, whose offspring will have mild symptoms (some of which may not need the therapy)? Photo: Aliaksei Lasevich/Fotolia Is “easily passing” a quality feature? spring born after MRT are expected to be healthy. It also suggests that the total number of 28 maternal subjects examined to date could statistically have revealed only one case of mismatch. We may see more (EMBO Reports (2015) embr.201439110). Carrying out a risk analysis and explaining it to the public would have been responsible science communication. Using the consensus. It is not extra caution, when currently HFEA and IRP consider five studies that report no side effects (ignoring actual treatment effects – see above) as safety-relevant but consider about 30 studies as irrelevant that do show MNI. HFEA suggested introducing MRT for women who have a history of children with diseases. Will this careful approach “…building a winning coalition of support for mitochondrial donation” (Mark Henderson) is important. How the battle was fought, we have seen. But who was the enemy? I doubt that the available evidence will allow the conclusion that calls for an immediate clinical introduction of MRT are morally superior to calls for further research. “That mitochondrial donation has passed so easily through the Commons […] shows how this engagement can benefit science, as well as society” and, “will have a direct impact on the lives of families affected by a devastating disease” – Henderson, of course, knows how to make his case in the media. However, such communications easily nourish hope and influence MPs and Peers – all necessarily non-experts – and should have been based on underlying evidence. Scientific evidence would have been a superior advisor to MPs than the “national sense of pride” (Science (2015) 348:178). Klaus Reinhardt Get your own copy – it’s free! Lab Times is free of charge for non-profit institutions all over Europe. 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LT_515 Business.indd 44 03.09.15 12:47 Biobusiness 5-2015 Lab Times page 45 Possibly edible insects, investigated at Zetadec Developing offbeat food source solutions: Zetadec, Wageningen (The Netherlands) The Bug Track A five-member start-up, located in the Dutch centre of life science and research, is pursuing exceptional approaches for the feed industry. A rriving in the Wageningen business park, Zetadec B.V. is not easy to find. Like many other small biotech startup companies it is located in a huge grey building with lettering heralding “AGRO BTC” above the main entrance. Two information boards listing all of the companies located here are standing to the side, their names given in tiny letters, hardly visible to the wandering visitor. After going inside and being welcomed by the receptionist, I make the acquaintance of Oriane Guerin and her colleagues. She excuses the unexpected absence of the company’s boss, Menno Thomas. Unfortunately, Thomas broke his foot motorcycling on vacation and comes in only for a moment to pick up some important work, before proceeding to the colloquium of his master student, Guizhao, who is doing an internship at Zetadec. Mid August is vacation season in the Netherlands, so it is nearly impossible to meet the entire staff of any firm. At Zetadec, some staffers are still enjoying their holidays, like Marcel van Culembourg and Frederiek Simons, both MScs in agrotechnology and plant sciences, respectively. The two work at Zetadec on, amongst other things, sustainable feed production and application strategies. The other three colleagues, pictured below, can be met personally, putting faces to the international backgrounds of this start-up venture. Zetadec’s founder, Menno Thomas (the injured company leader), completed his PhD in Wageningen in 1998, researching the physical quality of pelleted feed. After a couple of years working in the industry, he decided to found his own company in 2007. Zetadec’s name is taken from a French sawmill (Ets Zetadec). Thomas stum- Photo: Inge Matthies Liya Yi, Oriane Guerin and master student, Guizhao (from left), discussing their last experiment and obviously having fun in their office at Wageningen business park. LT_515 Business.indd 45 03.09.15 12:47 Lab Times 5-2015 bled upon the sawmill whilst doing practicals in France around 1987. When the time came to start his own “consultancy and contract R&D organisation for the feed, food and biomass industry“, the name stuck and so it became Zetadec B.V. What is Zetadec’s core business? The Dutch company assists their industrial clients in developing formula and recipes for new foodstuffs, as well as testing the functionality of ingredients and performing lab-scale to full-scale operation tests. They, “conceptualise new food product lines for new products, and enhance the performance of existing production lines”. For this purpose, they own two lab units: one is for product development, equipped with wet-chemistry analytical tools, and the other is used for developing milling, extruding, granulating and coating procedures in pilot experiments before upscaling. Improving food quality Zetadec’s other main aim is to improve the quality of feed and food stuff. Thomas and his co-workers are working, for example, on the optimisation and improvement of starch gelatinisation and protein denaturation processes. Biomass can be converted to biofuels or bioplastics by thermal, chemical or biochemical processing strategies. Calculations of the energy balance based on specific electric and thermal energy (SME and STE) consumption figures are performed. Zetadec is a research partner in the French “Equienergie” project, led by Photo: Inge Matthies Liya Yi with her recently accomplished PhD thesis. Her knowledge of insects is now rewarded at Zetadec LT_515 Business.indd 46 Biobusiness GreenResearch, and also participates in a SBIR (Small Business Innovation Research) programme for agrologistic and biomass from the Biobased Economy. Since process optimisation and statistical analysis of big data in bioscience is nowadays increasingly important, Zetadec is also focusing on that by developing new client-oriented solutions. The goal of the company is to create a link between raw material and the resulting product, concentrating on the improvement and optimisation of physical processing and corresponding technologies. Nowadays, they focus more and more on processing and data, since data analysis has also become more and more important in this field. Furthermore, they Oriane Guerin with feed pellet operate various individual projects to samples do with recycling food waste, such as its conversion into bioplastics. They also give independent adtein sources (other than “meat” from livevice to their clients about the use of stock) is urgent. Marcel Dicke, Professor of certain machines and the equipment needEntomology at Wageningen University and ed in feed or food processing like mills and Research Centre (WUR) is, together with devices for coating and pelleting. For exhis colleagues Arnold van Huis and Henk ample, milling processes are simulated in van Gurp a great ambassador for eating inthe Zetadec lab before upscaling to indussects to overcome the world hunger. They trial settings, requirements honed in close even wrote a special insect cookbook with cooperation with customers in their own the subtitle “Food for a sustainable planet” factories. and promote insect food in several student Will insects be the food of the future? pubs in Wageningen and other Dutch cities Last but not least, the Dutch scientists by treating the guests to various little dishdeal with – yummy! – edible bugs. es freshly prepared from insects. That’s no joke. Edible insects Roasted bugs and mealworm pizza contain high quality proteins, vitaYour Lab Times reporter’s experience mins and amino acids for humans. of eating fried grasshoppers wrapped in Insects have a high food conversion Chinese spring rolls, roasted bugs, smoked rate. So, for example, crickets need salty ants and mealworms in pizza was not six times less feed than cattle, four that bad. The taste is comparable to eating times less than sheep, and half as conventional food like ham or shrimp and much as pigs and broiler chickens to not all disgusting, in fact surprisingly deliproduce the same amount of protein. cious. Even Kofi Annan, the former SecreIn addition, they emit fewer greentary-General of the United Nations, is cithouse gases and less ammonia than ed in Dicke’s book. He appraised crickets conventional livestock. And, best of and locusts as quite delicious, according to all, insects can be grown on organic the authors. waste, according to the Food and AgThe FAO supports eating insects and has riculture Organization of the United worked since 2003 on topics pertaining to Nations (FAO). edible insects in many countries worldwide. So insects are a promising source As overall demand for food, particularly for the conventional production (mimeat, increases due to population growth ni-livestock) of protein, either for diworldwide, there is a need to increase the rect human consumption, or indisupply of protein from sustainable sources. rectly in recomposed foods (with exEdible insects have the potential to overtracted protein from insects); and as come future shortcomings because most of a protein source into feedstock mixthem, as we mentioned above, are protein tures. The need for alternative pro- Photo: Inge Matthies page 46 03.09.15 12:47 Biobusiness rich and can thus deliver a valuable contribution to a healthy diet. However, there is a problem: In many countries, especially those in the West, eating insects is not widely accepted. Edible insects, funded by the EU Research on edible insects is funded by the EU with public money. Up until now, however, little work has been done. Nobody really wants to start using insects in food and feed as a protein source because the legal framework is not yet resolved, according to Zetadec’s Oriane Guerin. So she and her colleague Yi are among the few doing pioneering work on edible insects. Oriane Guerin, deputy CEO at the moment, has plenty of expertise. She holds three diploma and/or master degrees, obtained in three countries; firstly a degree in agriculture (Toulouse, France), secondly a degree in European animal management (Wales, UK and The Netherlands), and thirdly a MSc in animal nutrition (The Netherlands). Since 2010 she has been engaged as a researcher in feed technology at Zetadec. Her colleague, Liya Yi, is working on protein isolation and purification in insects as a postdoctoral project in collaboration with WUR, studying the characteristics of several insect proteins and how to use them in food and feed. 5-2015 ed still to be investigated. The first question to solve for Zetadec is, therefore: How can we extract proteins from different insects? Liya Yi recently wrote her PhD thesis about this very topic. She and her co-workers at Zetadec are currently performing pilot studies on the specific characteristics of certain edible insects, including their protein content and nutritional impact. They are also developing suitable diets for feeding different kinds of insects. Still active at University Thomas, our founder in a plastercast, is also still active at Wageningen University, where he gives guest lectures to the students about feed technology. He is part of the “zzp-people-group”, which is a collaboration between several consultants in the food and feed business arena. The Dutch abbreviation “ZZP” means ‘zelfstan- Lab Times page 47 fast the company has grown in the last few years: In 2011, there were only two people doing the work, namely Menno Thomas and Oriane Guerin, and in 2014 they were already a team of five. Strong intention to stay independent Zetadec wants to remain independent, according to its founder, and is doing “correct” research (according to ethical guidelines and scientific truth). They are not writing “biased reports”, Thomas affirms, not even when certain clients would like them to do so. In close cooperation with their industrial clients they are working on improving the actual customer product. They also have various cooperations with the Dutch government and the European Union. Thomas and Guerin prefer employees who can “think outside of the box”, and an, At Zetadec’s wet-lab facilities for pilot experiments, Oriane Guerin is analysing the latest data Comparable to the ongoing discussion surrounding GMOs, it is still not clear whether the harvesting of insect proteins creates possible environmental or health risks when used for human or animal consumption. Those issues have to be investigated before one can think of developing technologies for processing insect material in feed or food on an industrial level. Another notable issue is whether people will consider the possibility of using insect protein in their meals. Ethical considerations when killing insects also play a role along with cultural barriers to do with the fact that insects were raised on organic waste and used as a source of nutrition later. The strict definition of feedstuff does not seem to cover insects, “Animals (which are classically used later for human consumption, e.g. poultry, cows, pigs) do not eat animal protein”. Given the lack of a legal framework these questions are yet to be answered. Moreover, little to almost nothing is known about the potential for allergies when eating insects. The possible side effects of insects used as feed or in food products need- LT_515 Business.indd 47 Photo: Inge Matthies The risks are not yet clear dig zonder personel’ and stands for small start-ups which began as one-person companies. Within this network (and other similar relationships), they train together and learn from one another. Zetadec is also a member of Food Valley NL, which boosts innovation performance by fostering collaboration between businesses, knowledge institutions and government. Since the interest in insects as a protein source is growing, Zetadec is a founding father of the Insect Centre, a network organisation working on the introduction of insects in feed, food and pharmaceuticals products. Zetadec is also listed in the “Edible Insects Stakeholder Directory” map of the Food and Agriculture Organization of the United Nations. It is remarkable how “open and free working atmosphere”, too. All colleagues, including the boss, regularly have lunch together. According to them, it feels like a real “family company”. As it is a typical part of Dutch work culture, they have a team meeting at least once a week where they report the progress of their projects and exchange news on internal and external developments, activities with clients, and so on. Speaking different languages (Dutch, English, French and Chinese) is no problem for them. Since they are a small company, tasks are not strictly divided and they are good at team work, they affirm. Your Lab Times reporter didn’t ask them the delicate question, however, of whether they are obliged to participate in regular inInge Matthies sect test meals. 03.09.15 12:47 page 48 Lab Times Products 5-2015 Product survey: Cell culture media No More Excuses The cell culture community is shaken by scandals of adulterated and mislabelled fetal calf serum (FCS) almost on a regular basis. At the same time, the number of serum-free media is steadily increasing. How many more FCS frauds will it take, to stop the “FCS business as usual” attitude of many researchers? FCS broker gang That was basically the game plan of one FCS broker gang operating in the nineties from abattoirs in northern France, utilising the French FCS supplier, Biowest, as a distribution platform for the adulterated FCS. The illegal practices were uncovered when LT_515_Product survey.indd 48 Photo: Jonathan Franks I t’s time to switch from cell culture media, supplemented with fetal calf serum (FCS) to serum-free, chemicallydefined media. That was the tenor of the product survey “Cell Culture Media” in Lab Times 4/2007 (page 53). Eight years later, however, many life science researchers still seem to be hanging on to their accustomed use of FCS − despite sky rocketing FCS prices, repeated frauds of adulterated fetal calf sera and a constantly growing list of chemically-defined media. Prices for raw FCS derived from US cattle, which accounts for almost half of the worldwide FCS supply of approximately 600.000 litres (from which only 200.000 litres are assumed to be suitable for GMP manufacturing), exploded in the last years to 700 dollars per litre. FCS from Australia and New Zealand, producing another 20 % of the worldwide FCS supply, is even more expensive and sells well above 1.000 dollars. The major reason for the soaring prices is a multi-year drought in the USA, forcing ranchers in 2012 to dramatically cut down their livestock roving around the great western plains, leading to a severe FCS shortage. FCS extracted from South American cattle, however, is a bargain compared to FCS from Oceania or the US: it goes over the counter for around 100 dollars. This tenfold price span between the different origins is a perfect scenario for tricksters and dubious FCS brokers. It’s fairly easy to imagine their business strategy: simply buy cheap FCS from South American abattoirs, adulterate and expand it with low-grade sera or other obscure liquids and use false certificates from European slaughterhouses to sell the mixture as expensive, high quality FCS to clueless European customers. Harvested whole blood with white blood cells, activated platelets and red blood cells. Platelet lysate extracted from expired human platelet units may replace FCS in cell culture. the Danish FCS producer, Sera Scandia, notified an ownership interest (i.e., purchasing considerable amounts of stocks or other assets to control a company) in Biowest in 1994 and acquired the company completely in 2004. Obviously, the Sera Scandia management had never heard of a due diligence examination, which is a standard investment business procedure, to audit a potential investment. It took them ten years to notice that something was wrong with their new daughter. Finally, the responsible manager was fired in 2004 and the case was put forward to the French police for further investigations. But as you might guess, that was not the end of the FCS fraud story. According to a Fetal Bovine Serum hand-out, available at the Biowest website (www.biowest. net/download/fetal-bovine-serum-handout), it was just the beginning. The French investigators more recently unravelled another FCS broker gang in eastern France, which had mislabelled and adulterated 110.000 litres of Brazilian FCS between 2004 and 2014, and had shipped 50.000 litres as CEmarked FCS to Germany. Clueless customers? Meanwhile, the Biowest managers have taken the case to court in Baden-Baden, Germany, blaming competing FCS suppliers for having sold adulterated FCS and violating ethical standards, by not informing the clueless customers. The unappetising details of this recent FCS scandal were also reported in the German newspaper Die Süddeutsche and in the French gazette Le Courrier de l’Ouest. But are FCS customers, i.e., life scientists, really that blank-faced, blissfully ignorant to what’s happening behind the FCS scenes? Come on! Researchers are no dummies, so they should definitely know what’s going on in the FCS business. And besides, which reasonable researcher really wants 07.09.15 13:09 Products 5-2015 to depend on the weather conditions in the USA and the number of livestock in Texas? Let alone the ethical issues of FCS extraction and the not too unreal danger of FCS contamination with exotic viruses, bacteria, fungi or other obscure components. So, the time has definitely come to throw away outdated habits and switch to serum-free, chemically-defined cell culture media. Even more so, since the often heard excuse that chemically-defined media supporting the growth of a specific cell line are hard to find, is becoming more obsolete − especially in stem cell research. A recent review on the cultivation of human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) in xeno-free culture systems, lists 14 different, commercially available, serum-free media for hESC and hiPSC culture (Desai et al., Reprod. Biol. Endocrinol. 13, DOI 10.1186). Some of them, like TeSR1 and E8, have been on the market for almost ten years. Others, such as StemFit, which has been developed in the lab of stem cell pioneer Joseph Itskovitz-Eldor at the Technion - Israel Institute of Technology in Haifa, are brand new. All specified media are basical- ly composed of a simple, but highly defined, mixture of amino acids, vitamins, trace elements and growth factors. The same holds true for the culture of standard cells, such as CHO-cells, fibroblasts or cancer cell lines. You may find commercial, serum-free media for maintaining the growth of almost every cell type. And even better: the number of completely chemically-defined media is also steadily increasing. Completely defined, allround media Cancer researchers may, for example, check out a new chemically-defined medium supporting the growth of different cancer cell lines. It has been elaborated by Rodney Nash and his co-workers at the Emory University School of Medicine, Atlanta, USA. Nash seems very convinced about the potential of his media formulation. He quit his postdoc position shortly after his invention in 2014 and founded the company Jeevan Biosciences to commercialise the medium under the brand name NeuroPure. According to a recent paper from Jeevan Biosciences, Nash’s chemically-defined medium supports the growth of neuronal cells, cancer cells and fibroblasts (Ann. Lab Times page 49 Transl. Med. (10):97. doi: 10.3978/j.issn). His start-up company is currently investigating, whether it is also suitable for other cell types such as iPSCs. Human platelet lysate (hPL) extracted from expired human platelet units is another promising alternative to FCS (though it is not chemically-defined), which is especially useful for the expansion of mesenchymal stromal cells (MSCs). It is generated from platelet units by a simple freezethaw cycle process developed by Gerhard Gstraunthaler’s group at the University of Innsbruck, followed by centrifugation and filtration to remove cell fragments (Cytotherapy, 16: 170-80). Platelet lysate delivers a complex mixture of growth factors and is applicable for different cell types, especially human MSCs, endothelial cells and fibroblasts. It is offered by specialised cell culture media companies and is also produced in small quantities by laboratories related to blood products or transfusion medicine, such as the Centre for Clinical Transfusion Medicine at the University of Tübingen, Germany. Harald Zähringer Labvolution & Biotechnica 6/10–8/10 2015, Hannover, Germany The new trade fair “Labvolution” provides a platf t orm for the entire world of lab tf equipment for the chemical and pharmaceutical industries, environmental technology and the food industry. More Information at www.labvo v lution.de/ vo e/e e/ /en T o trade fairs. Tw One exhibition ground. One admission ticket. Crossover Visitor Traffic The lab technology trade show “Biotechnica” – Europe’s No.1 event for Biotechnology, Life Sciences and Lab Te T chnology – is taking place in parallel. More Information at www.biotechnica.de/ e/e e/ /en LT_515_Product survey.indd 49 Come and meet the Lab Ti Tim imes Te T am at Stand G74 in Hall 9. Yo Y u will not only enjoy meeting many interesting people, this is also your opportunity to pick up a personal copy of the latest Lab Times, along with a variety of giveaways. Share your valued opinions with our ever-zealous editors r over a glass of sparkrs ling wine or other refreshments. We look forward to welcoming you at “Labvolution”. 07.09.15 13:09 page 50 Lab Times Products 5-2015 Cell Culture Media Company/Distributor Name of product Supported cells Price [EUR] AMS Biotechnology Wide range of general and specific culture media including Various cells On request BioCat Adipocyte and preadipocyte basal, maintenance and differen- Omental preadipocytes, omental adipocytes, subcutaneous preadipocytes, subcutaneous adipocytes (human, mouse, rat) Depending on medium All common cell lines 75.– (100 ml) unique ranges of media for growth of stem cells Abingdon, U.K. www.amsbio.com Contact: [email protected] Phone +44 1235 828 200 tiation media Heidelberg, Germany www.biocat.com DMEMgfp-2 Antibleaching Live Cell Visualization Medium Contact: Elke Gamer Phone +49-6221-7141516 [email protected] Biomol Great number of various cell culture media from US Bio and Conda Available for a comprehensive spectrum of diverse cell lines Starting at 65.– Biowest Classical media such as: BME, CMRL 1066, DMEM, GMEM, Ham’s F10, Ham’s F12 , Ham’s F14, IMDM, Leibovitz L-15, McCoy’s 5A, Medium 199, MEM and RPMI 1640 Various cells On request LymphoGrow Medium AmnioGrow Plus Medium MarrowGrow Medium Primary human blood lymphocytes Primary human amnion and chorionic villi cells Leukaemic bone marrow cells On request UltraCulture Serum-free Medium, General Purpose Medium without L-Glutamine Cultivation of adherent and non-adherent mammalian cells; generation of viral particles for vaccine production 57.– ProFreeze-CDM, NAO Freeze Medium For cryopreserving many cell types in the absence of fetal bovine serum (FBS) 88.– X-VIVO Serum-free Hematopoietic Cell Media, chemically defined; X-VIVO10/15/20 For a variety of cells From 46.– Transfected and non-transfected CHO cell lines; HeLa cells; human leukemia cell lines From 58.– Madin-Darby Canine Kidney (MDCK) and other kidney cells; HEK 293 (adherent and suspension); Vero cells From 36.20 Hamburg, Germany www.biomol.de Contact: Edgar Lipsius Phone +4940 853260 37 [email protected] Nuaillé, France www.biowest.net Contact: Phone +33 241 464 242 [email protected] Biozym Scientific Hessisch Oldendorf, Germany www.biozym.com Contact: Anja Roeben Phone +49 5152 9020 [email protected] Distributor of BioWhittaker CHO Expressionsmedia: UltraCHO Serum-free CHO cell Medium; ProCHO Protein-free CHO Media; Media from Lonza in PowerCHO Serum-free CHO Media Germany Renale Media: UltraMDCK Serum-free Renal Cell Medium, chemically defined; Pro293 Serum-free Media, chemically defined; ProVero 1 Serum-free Medium Insect-XPpress Protein-free Insect Cell Medium, with L-Glutamine For insect cell lines, e.g. Sf9 and Sf21 From 28.– Hybridoma media: UltraDOMA Serum-free Hybridoma Medium; For cultivation of murine, human, and chimeric hybridomas ProDoma Serum-free Hybridoma Media, chemically defined From 25.– Karyotyping Medium: Lymphochrome Medium For the cultivation of lymphocytes from peripheral blood From 31.– Cytogenetic media: Amniochrome II Modified Medium; Amniochrome Plus Medium; Amniochrome Pro Medium For the culture of human amniotic fluid cells obtained from amniocentesis From 53.– Dulbecco’s Modified Eagle’s Media (DMEM) in various variations Wide range of mammalian cell culture From 6.30 DMEM:F12 medium in different variations From 8.– Used to demonstrate the effect of various hormones and growth factors on target tissues | Clonal density cultures Iscove’s Modified Dulbecco’s Medium (IMDM), various variations For fast growing cells | Formulas contain HEPES for added buffering From 8.30 Carl Roth Minimum Essential Medium – Eagle (MEM Eagle / E-MEM) in various variations For a diverse spectrum of mammalian cell types From 6.30 RPMI 1640 in various variations Mammalian cells, especially hematopoietic cells From 5.50 Insect media: Grace’s; Schneider’s; TC-100 Insect cell lines, organs for the propagation of entomopathic viruses From 13.40 Other classical media e.g.: Medium 199; Glasgow Minimum Essential Medium (GMEM); Ham’s F10 and F12; L-15 (Leibovitz) Medium; McCoy’s 5A Medium Wide range of mammalian cell culture applications From 6.30 Roti-CELL DMEM High Glucose Broad range of mammalian cell lines and primary cells 10.80 to 16.– Mammalian adherent cell lines 10.80 to 13.50 Broad range of mammalian cell lines 13.– Broad range of mammalian cell lines and primary cells 14.– Roti-CELL Eagle’s MEM / Earle’s Roti-CELL Eagle’s MEM / Hanks’ Broad range of mammalian cell lines and primary cells, including transfected cells 10.80 to 12.50 13.50 Roti-CELL Eagle’s MEM-Alpha Bone marrow cells, amniotic cells 12.20 to 23.50 Roti-CELL RPMI 1640 Suspension cell lines, primary B- and T-lymphocytes, leukocytes, myeloma cells, hybridoma cells 10.80 to 43.80 Roti-CELL Ham’s F12 Various mammalian cell lines (particularly CHO), hybridoma cells 12.– Roti-CELL Leibovitz’s L15 Various mammalian cell lines 19.– Roti-CELL McCoy’s 5A Primary cells and mammalian cell lines in general 18.– Karlsruhe, Germany Roti-CELL DMEM Low Glucose www.carlroth.de Roti-CELL DMEM:F12 Contact: Stefanie Seipp Phone +49 721 5606 1038 Roti-CELL Iscove’s MDM [email protected] LT_515_50_54.indd 50 04.09.15 13:59 Visit us at the BIOTECHNICA 2015 HALL 9, BOOTH F13 Impress Yourself The new Eppendorf Cell Culture Consumables The all new product line of Eppendorf Cell Culture Consumables will truly delight your cells. Its outstanding design, reliability and purity is based on more than 50 years of experience. Products created by experts, developed for perfectionists. Impress yourself! > Unsurpassed quality, clarity, purity and sterility, providing reliable cell culture conditions > Significantly improved design for more safety and consistency > Maximum safety and confidence during storage and transportation www.eppendorf.com/ccc Eppendorf ® and the Eppendorf logo are registered trademarks of Eppendorf AG, Germany. U.S. Design Patents are listed on www.eppendorf.com/ip. All rights reserved, including graphics and images. Copyright © 2015 by Eppendorf AG. LT_515_50_54.indd 51 04.09.15 13:59 page 52 Lab Times Products 5-2015 Cell Culture Media Company/Distributor Name of product Supported cells Price [EUR] Carl Roth Roti-CELL Medium 199/Earle’s Fibroblasts and various cell lines 16.– Contact: see page 52 Roti-CELL TC100 | Roti-CELL William’s E Sf9 cells | Adult, primary hepatic epithelium cells 22.– | 18.– Roti-CELL Hanks’ BSS | Roti-CELL DPBS Cells and cell lines in general 9.50 to 12.50 11.– to 18.– CellGro DC (Serum-free) On request CellGenix PSC Kit Generation of dendritic cells | Expansion of T-cells Expansion of hematopoietic stem and NK cell culture | Generation of retroviral and lentiviral vector-producing cells Multipotent stromal cells derived from umbilical cord matrix and blood Feeder-free expansion of human pluripotent stem cells (hPSC) HyClone Media, HyCell CHO; HyCell TransFx-C CHO lines On request CDM4CHO | SFM4CHO CHO cell clones | CHO cells On request HyCell TransFx-H HEK293 cell lines On request CDM4PerMAb Production of human antibodies and recombinant proteins using PER.C6 technology On request CDM4MAb; CDM4NS0; SFM4MAb Hybridoma and myeloma On request SFM4Insect | SFX-Insect Many key insect cell lines, including Sf9, Sf21, etc. | Insect cells On request SFM4MegaVir Anchorage-dependent cell lines incl. Vero, MDCK, COS-7, MDBK cell On request DMEM; MEM; RPMI; Ham’s; McCoy’s Various cells On request HyCell STEM; AdvanceSTEM Stem cells On request MEXi-CM Culture Medium MEXi HEK293E cells (1,000 ml) 75.– Goettingen, Germany MEXi-TM Transfection Medium www.iba-lifesciences.com Contact: Ricarda Busse Phone +49 551 506720 [email protected] MEXi HEK293E cells (1,000 ml) 75.– InSphero 3D InSight Tumor Microtissue Media kit Tumor cell line-derived spheroids 346.– 3D InSight Human Liver Maintenance Medium 3D InSight Human liver microtissues (Incl. 3D Insight microtissues) 306.– 3D InSight Rat Liver Maintenance Medium 3D InSight Dog Liver/Minipig Liver/Cynomolgus Liver Maintenance Medium 3D InSight rat liver microtissues 3D InSight dog liver/minipig liver/cynomolgus liver microtissues 297.– 306.– 3D InSight HepG2-Microtissue Maintenance Medium 3D InSight HepG2 liver microtissues 252.– 3D InSight Human Islet/Rat Islet Maintenance Medium 3D InSight human islet/rat islet microtissues 306.– 3D InSight Human Cardiac/Rat Cardiac/Human Brain Microtissue Maintenance Medium 3D InSight human cardiac microtissues/rat islet/human brain microtissues 306.– CellGenix CellGro SCGM (Serum-free and Xeno-free) Freiburg, Germany www.cellgenix.com Contact: [email protected] CellGro MSC (Serum-free) Phone +49 761 888 890 GE Healthcare LifeSciences Little Chalfont, UK www3.gehealthcare.com IBA Schlieren, Switzerland www.insphero.com Contact: Phone +41 43 515 04 90 [email protected] 3D InSight Rat Brain Microtissue Maintenance Medium 3D InSight rat brain microtissues 306.– Lonza Group Classical media such as: DMEM, MEM, RPMI, IMDM and insect media Speciality media: CHO Expression Media; Cytogenetic Media; General Use SF Media; Hematopoietic Media (X-VIVO); Hybridoma Media; Insect-XPress Protein-free Insect Cell Medium with L-Glutamine; ProFreeze-CDM Various cells Please contact your local distributor Merck-Millipore Cellvento CHO chemically-defined cell culture media Cellvento BHK cell culture media Standard media Customised cell culture media CHO cells BHK21 suspension cell lines Various cells On request Miltenyi Biotec StemMACS iPS–Brew XF, human (Xeno-free) StemMACS Repro–Brew XF, human (Xeno-free) Maintenance of human ES and iPS cells under feeder-free conditions On request mRNA reprogramming of human fibroblasts into induced pluripotent stem cells (iPS cells) StemMACS HSC Expansion Media XF, human | StemMACS HSC–CFU Media, human Human hematopoietic stem and progenitor cells (HSPC) On request StemMACS MSC Expansion Media, human StemMACS MSC Expansion Media XF, human (Xeno-free) StemMACS AdipoDiff Media, StemMACS ChondroDiff Media, StemMACS OsteoDiff Media, human Human mesenchymal stem/stromal cells (MSCs) MSCs Generation of adipocytes/chondrocytes/osteoblasts from human MSCs On request Mo–DC Differentiation Medium, human On request Mo–DC Maturation Medium, human Differentiation of human monocytes into immature monocytederived dendritic cells (Mo-DCs) Maturation of human monocyte-derived dendritic cells (Mo-DCs) MACS Neuro Medium | DendriMACS GMP Medium TexMACS Medium, research grade TexMACS GMP Medium CHOMACS CD | HybriMACS CD Neural cells from human, mouse, or rat | Human dendritic cells Human and mouse T cells and regulatory T cells Human T cells and regulatory T cells Chinese hamster ovary (CHO) cells | Hybridoma cells On request Neuron Growth Medium / Astrocyte Growth Medium Neurons / Astrocytes 238.– Mouse Embryonic Fibroblast Growth Medium Mouse embryonic fibroblasts 219.– Basel, Switzerland www.lonza.com Contact: [email protected] Phone +41 61 316 81 11 Darmstadt, Germany www.merckmillipore.com Bergisch Gladbach, Germany www.miltenyibiotec.com Contact: Jürgen Eiberger Phone +49 2204 8306 6641 juergen.eiberger@ miltenyibiotec.de MoBiTec Contact: see next page LT_515_50_54.indd 52 04.09.15 13:59 Products 5-2015 Lab Times page 53 Cell Culture Media Company/Distributor Name of product Supported cells Price [EUR] MoBiTec (continued) Mesenchymal / Neural Stem Cell Growth Medium Mesenchymal stem cells / Neural stem cells 238.– Mouse Embryonic Stem Cell Growth Medium Mouse embryonic stem cells 734.– Adipose-Derived Stem Cell Growth Medium Adipose-derived stem cells 255.– Mesenchymal Stem Cell Adipogenic / Chondrogenic / Osteogenic Differentiation Medium Mesenchymal stem cells 298.– / 536.– / 206.– Embryoid Body (EB) Formation Medium Mouse embryonic stem cells 224.– Cryopreservation Medium Non Controlled-Rate Cryopreservation Media Non Controlled-Rate Protein-Free Cryopreservation Media Stem cells and primary cells (20 ml / 50 ml) 64.– / 129.– 83.– /153.– 89.– / 165.– Pericyte Growth Medium / Pluripotent Stem Cell Medium Human pericytes / Human pluripotent stem cells 182.– / 225.– Keratinocyte Growth Medium Kit classic, low BPE / enhanced, defined / enhanced Human keratinocytes 122.– / 139.– / 133.– Oral Epithelial Cell Growth Medium Kit enhanced, defined Human oral epithelial cells 143.– Airway Epithelial Cell Growth Medium Kit, defined / Airway Epithelial Cell Differentiation Medium Human airway epithelial cells 174.– 153.– Mammary Epithelial Cell Growth Medium, defined Human mammary epithelial cells 153.– Corneal Epithelial Cell Growth Medium Kit enhanced, defined Human cornea epithelial cells 164.– Mesenchymal Stem Cell Adipogenic / Chondrogenic / Osteogenic Differentiation Medium Human mesenchymal stem cells 299.– / 549.– / 229.– Smooth Muscle Cell Basal Medium classic Human smooth muscle cells 85.– Cellovations Endothelial / Cellovation Microvascular Endothelial Cell Growth Medium Kit enhanced, defined Human endothelial cells 229.– / 249.– Fibroblast Growth Medium Kit defined Human fibroblasts 229.– Goettingen, Germany www.mobitec.com Contact: Arne Schulz Phone +49 551 70722 0 [email protected] Pelobiotech Planegg, Germany www.pelobiotech.com Contact: Peter Frost Phone +49 8951728659 0 [email protected] PromoCell Xeno-free Mesenchymal Stem Cell Medium Kit classic/Enhanced Human mesenchymal stem cells 179.– / 199.– Supplement Kit for Cellovations Endothelial Cell Growth Medium Kit defined Human endothelial cells 179.– Please find an extended list of media on our website Various cells Endothelial Cell Growth Media (4 media types) Human endothelial cells from large vessels, human microvascular endothelial cells 123.– to 137.– Human vascular smooth muscle cells, human smooth muscle cells from hollow organs 183.– Normal human epidermal keratinocytes / melanocytes 107.– 162.– / 267.– Fibroblasts Growth Media (3 media types) Normal human fibroblasts from dermis, lung, aortic adventitial tissue, heart ventricle, uterus 145.– to 149.– Preadipocyte/Adipocyte Media (3 media types) Human white preadipocytes (subcutaneous, visceral) 162.– to 228.– Airway/Small Airway Epithelial Cell Growth Media (2 media types) 209.– / 208.– Primary human epithelial cells from nasal mucosa, trachea, bronchium; primary human epithelial cells from bronchiole/alveoli Mammary Epithelial Cell Growth Medium Primary human mammary epithelial cells 111.– Myocyte Growth Medium Human cardiac myocytes 182.– Skeletal Muscle Cell Media (2 media types) Human skeletal muscle cells (myocytes) 163.– / 129.– Various Growth Media for other types of primary cells Human primary osteoblasts, chondrocytes, hepatocytes, renal ep- 131.– to 210.– ithelial cells, placental epithelial cells, follicle dermal papilla cells Heidelberg, Germany www.promocell.com Smooth Muscle Cell Growth Medium 2 Contact: Phone: +49-6221-649340 Keratinocyte Growth Medium 2 / Melanocyte Growth Media [email protected] (serum-free or serum-free and PMA-free) Sartorius Goettingen, Germany www.sartorius.com Contact: [email protected] Phone +49 551 3080 LT_515_50_54.indd 53 M1-/M2-Macrophage Media DXF | Dendritic Cell Media DXF, Human mononuclear cells (freshly isolated), human monocytes completely defined, xeno-free (w/o cytokines / with cytokines) (freshly isolated) 157.– / 579.– 157.– / 570.– Dendritic Cell Media (w/o cytokines or with cytokines) Human mononuclear cells (freshly isolated or cryopreserved), human monocytes (freshly isolated or cryopreserved) 118.– / 284.– Mesenchymal Stem Cell Growth Medium DXF, completely de- Human mesenchymal stem cells (from bone marrow, adipose fined, xeno-free/Mesenchymal Stem Cell Growth Medium/Mes- tissue, umbilical cord matrix) enchymal Stem Cell Differentiation Media (4 media types) 280.– 198.– 157.– to 367.– Pericyte Growth Medium Human pericytes 182.– Hematopoietic Progenitor Expansion Medium DXF, completely defined, xeno-free Human hematopoietic progenitor cells, human CD133+ cells, human CD34+ cells, human mononuclear cells from cord blood 184.– Pluripotent Stem Cell Growth Medium DXF, completely defined, Human iPS cells, human embryonic stem cells xeno-free 320.– X-Vivo 20 w/ gentamycin and phenol red, 1 L High-density LAK 92.– X-Vivo 10 contains recombinant transferrin, w/ L-glutamine, w/o gentamicin and phenol red, 1 L X-Vivo 15 contains recombinant transferrin, w/ L-glutamine, gentamicin and phenol red, 1 L w/ L-glutamine, w/o gentamicin and phenol red, 1 L Tumor-infiltrating LAK and lymphocytes GLS Permexcis virus production med, 1 L PER.C6 and related cell lines 129.– 111.– 138.– 73.– 04.09.15 13:59 page 54 Lab Times Products 5-2015 Cell Culture Media Company/Distributor Name of product Supported cells Sartorius Insect-XPress w/ L-Glutamin, 1 L Insect cell lines derived from Spodoptera frugiperda (Sf9 and Sf21) 47.– Contact: see page 55 ProCHO5 w/o glucose, 1 L | STD PowerCHO-2 CD, w/o L-Glutamin w/o PR, 1 L | Mod PowerCHO1 w/ 3g/L Gluc & 4mM L-Glutamin, 1 L CHO 60.– 69.– 69.– ProMDCK (2D)/1 L | ProMDCK (3D), 1 L MDCK 93.– / 81.– ProNS0 1 CD | ProNS0 2 CD | ProDoma 1 serum-free medium, 1 L | ProDoma 3 wo L-Glutamin, phenol red w/ 0.1% Pluro F68, 1 L CHO / Hybridomas 69.– | 69.– 65.– | 63.– UltraCHO w/ L-Glutamin, 1 L CHO 74.– UltraCulture serum-free w/o L-Glutamin 500 ml Adherent and non-adherent mammalian cells 59.– UltraDoma serum-free w/o L-Glutamin 500 ml | UltraDoma-PF Hybridoma Medium, 500 ml Murine, human and chimeric hybridomas 26.– ProPer-1 w/o L-Glutamin, phenol red w/ 0.1% Pluro F68, 1 L PER.C6 and related cell lines 63.– Classical Media: DMEM/F12 Media; Ham’s F-10 and F-12 Media; Medium 199; MEM; RPMI 1640 Media; etc. Various cells On request Serum-free media for different platforms, e.g., CHO, Hybridoma, Insect and Vaccine Various cells On request mTeSR1/TeSR2/TeSR-E8 | Human embryonic stem cells and induced pluripotent stem cells 315.– /339.–/ 208.– | 174.–/ 181.–/203.– Human embryonic stem cells and induced pluripotent stem cells, Hematopoietic stem and progenitor cells 197.– STEMdiff APEL/ STEMdiff APEL LI | STEMdiff Neural Induction Medium Human embryonic stem cells and induced pluripotent stem cells 133.– 199.– STEMdiff Neural Progenitor Medium Human ES/iPS-derived neural progenitor cells 299.– STEMdiff Neuron Differentiation Kit / STEMdiff Neuron Maturation Kit Human ES/iPS-derived neural stem & progenitor cells, neurons (available also for dopaminergic neurons, astrocytes) From 149.– STEMdiff Definitive Endoderm Kit Human embryonic stem cells and induced pluripotent stem cells, definitive endoderm 299.– ImmunoCult Human CD3/CD28/CD2 T Cell Activator Regulatory T cells, T cells 98.– MesenCult Mesenchymal stem cells 72.– to 558.– MesenCult Osteogenic Stimulatory Kit (Mouse) Mesenchymal stem cells, Mouse embryonic fibroblasts, Osteoblasts (mouse) 423.– StemSpan SFEM/StemSpan SFEM II | Hematopoietic stem & progenitor cells 158.– to 530.–/ 175.– to 592.– 186.– to 616.– MyeloCult Hematopoietic stem & progenitor cells (mouse or human), stromal feeder layers 86.– to 305.– MethoCult Hematopoietic stem & progenitor cells 619.– NeuroCult Neural stem & progenitor cells (mouse, rat or human) 143.– to 261.– NeuroCult SM1 Neuronal Culture Kit Neurons 106.– IntestiCult Intestinal epithelial organoids 247 PneumaCult-Ex / PneumaCult-ALI Bronchial epithelial cells 125.– to 185.– Cellartis DEF-CS 500 Xeno-Free Culture Medium GS1-R GS2-M Human iPS Cells Rat embryonic stem (ES) and embryonic germ (EG) cells Human and mouse embryonic stem (ES) and induced pluripotent stem (iPS) cell lines On request Mouse embryonic stem (ES) cells Human embryonic stem (ES) and induced pluripotent stem (iPS) On request NDiff 227 RHB Basal/RHB-A Neural differentiation of mouse embryonic stem (ES) cells Human and mouse neural stem (NS) cells On request Classical Gibco cell culture media Mammalian cells On request Mammalian Classical Media; Mammalian Protein Expression Media; Hybridoma Media; Primary Cell Media; Stem Cell Media; Neurobiology Media; Insect Media; Microbiology Media; GlutaMAX Media; Reduced-serum Media Various cell types On request Serum-free media for example: CHO Cell Culture Media; Various cell types PER.C6 and 293 Media; Insect Cell Media; Immunology Media, Stem Cell Media; Hybridoma Media; Primary Cell Media On request CHO Medium | CHO Feed – customised formulation On request Sigma-Aldrich St. Louis (MO), USA www.sigmaaldrich.com Stemcell Technologies TeSR-E5/TeSR-E6/TeSR-E7 Cologne, Germany www.stemcell.com Contact: Repro-TeSR Phone +49 221 888 7990 [email protected] StemSpan-ACF Takara Clontech www.takara-bio.eu Contact: orders@ clontech-europe.com [email protected] iSTEM Phone +33 1 3904 6880 PrimeSTEM-XF Thermo Fisher Scientific Waltham (MA), USA www.thermoscientific.com Xell K1, GS, DHFR-, DG44 HEK Medium | HEK Feed – customised formulation HEK and other human cell lines Bielefeld, Germany Contact: Tim Beckmann Hybridoma Medium | Hybridoma Feed – customised formulation Hybridoma cell lines Phone +49 521 96989200 Customised media products for other cell lines BHK, Vero, MDBK, MDCK, etc. [email protected] LT_515_50_54.indd 54 Price [EUR] On request On request 04.09.15 13:59 Methods 5-2015 Lab Times page 55 Tips and tricks of the trade Quick, Easy and Cheap Protein Visualization Tryptophans are not the most abundant of protein residues. But you don’t need a lot of tryptophans for staining proteins in polyacrylamide gels. Lab Hin t CBB Ferricyanide N Oxidising tryptophans My group at the Department of Life Sciences, Institute for Multidisciplinary Research, University of Belgrade, looked for a new way to employ proteins’ constituent fluorophores in visualization and came up with a method that relies on the oxidation of tryptophan (Trp) residues (Pristov et al., Anal. Biochem. 480, 6-10). We tested several oxidising agents and tuned the method using different concentrations, incubation times, and pH values. The best performance was obtained for the following protocol: Place gel in water solution of K3[Fe(CN)6] (100 mM) and NaOH (1 M). Incubate it in the dark at room temperature for 30 min. Transfer the gel to water (no washing is needed) and voilà, it is ready for scanning. Potassium ferricyanide (III) oxidises Trp at 25 °C and high pH. LT_515_Tips and Tricks.indd 55 Killing two birds with one stone Photo: Ivan Spasojevic ative and sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) is one of the most frequently applied techniques in life science labs. Following PAGE, protein bands are commonly visualized using the Coomassie Brilliant Blue (CBB) protocol, silver staining, or different fluorescent stains. Each of these staining procedures, however, fails to meet at least one of the dream features from the title: CBB is not quick (although the overnight staining is rather popular), silver is everything but easy (e.g. very sensitive) and well-performing fluorescent stains are not cheap, at all. So, novel approaches for in-gel protein visualization are more than welcomed. serum albumin (3 Trp per chain) as a standard, the sensitivity was comparable to CBB and about 3.5 times lower compared to the optimal settings. In other words, under optimal scanning settings, the sensitivity of ferricyanide staining equals the sensitivity of CBB multiplied by the number of Trp per chain. For example, if you invest a lot of time isolating some protein that is luckily Trp-rich, the application of ferricyanide staining can save much of your precious sample. Native PAGE gel of human plasma (5 µL per lane) stained with ferricyanide or CBB. Potassium ferricyanide is light-sensitive, so the solution should be freshly prepared for staining and kept in the dark. It is also important to have in mind that a high concentration of NaOH provokes protein denaturation (in order to bring “buried” Trp residues to the surface). A short exposure of stained gels to light as well as repetitive scanning, do not have negative effects on sensitivity. No special equipment needed Fluorophore that is produced via ferricyanide-provoked Trp oxidation shows maximal excitation/emission at 345/460 nm. At the moment, this would require non-standard equipment. Fortunately, the fluorophore can be excited with wavelengths between 300 to 450 nm, with emission in the 420 to 550 nm range; these settings are met by a number of commercial gel scanners. With excitation/emission at 395/525 nm and bovine Band fluorescence intensity is directly proportional to the number of Trp in the band. And here lays yet another advantage with this method: it can be useful in Trp quantification. Calibration fit for band fluorescence intensity and the number of Trp (nmol) per band is created using equimolar (subunit) amounts of a set of proteins with different number of Trp per chain/subunit. Another calibration fit is prepared for band intensity and the amount of proteins (µg) using CBB staining. With these two, the amount of Trp per µg of protein can be calculated for experimental gels. This might be useful in the process of identifying proteins in biological samples, by narrowing down the list of ‘‘suspects’’ according to the number of Tryptophans. Erase instructions Of note: if, at some point, you are not satisfied with the results of this staining protocol, the gel can undergo post-staining with CBB without any loss of sensitivity. Ivan Spasojevic Do you have any useful tips? Contact at: tips? Do you have anyususeful Contact us at: [email protected] [email protected] 07.09.15 13:10 page 56 Lab Times Methods 5-2015 Bench philosophy (58): Isothermal DNA Amplification PCR's Smart Isothermal Cousins W Temperature issues of PCR So thank you, Taq, and your small band of similar, tough-skinned polymerases. You have solved the heat problem. Well, sort of. The temperature issue rules PCR out for a lot of applications. First of all, forget about applying PCR to living tissues. And that's a LT_515_Bench Philosophy.indd 56 Handheld "Paper machine" for easy molecular diagnostics in four steps, applying loopmediated DNA amplification. big loss, considering the huge interest in detecting DNA or RNA sequences in living cells. Take microRNAs for example. Given our comparative ignorance of the biological roles of miRNAs and their possible roles in disease, it is vital we find ways of accurately measuring what miRNAs are being expressed in tissues. So wouldn't it be nice to be able to do the whole thing at the same temperature? That would make the amplification much more efficient and save a bit of time – after all, amplification only takes place at one part of a PCR thermocycle. And while we're at it, another real plus would be if that temperature happened to be one that doesn't cook tissues. Can this be done? Yes it can – indeed, isothermal amplification is a fastmoving and exciting field that has been somewhat eclipsed by PCR and its variants. Byzantine in complexity Isothermal amplification refers to amplification methods that take place at a constant temperature. The lack of cycling means that all the time is being spent on amplification, not just part of a cycle. And it means cheaper equipment, such as a water bath – good news for the lab budget. On top of all that, isothermal strategies are often more sensitive and more specific. So what isothermal amplification strategies are available? How good are they and do they compare well against good ol' PCR? Furthermore, who is using it and for what? The answer to the first question is simple – there is a whole host of them. Their sheer variety defies any attempt to classify them. Often almost byzantine in complexity, they are an illustration of the ingenuity of their developers and show what can be done with some imaginative cobbling together of different molecular tricks and tools. And yet, there is just one thing they all have in common – they all incorporate a trick to get the newly-synthesised DNA strand to move off out of the way and allow further rounds of extension to take place. Different approaches So how do they do this? Take a method called Strand Displacement Amplification (SDA) as an example. This uses a primer against your DNA target that also includes a HincII recognition site. You let the DNA polymerase do its work and extend the target but you include in your mix some deoxyadenosine 5'-[α-thio]triphosphate (dATP[αS]). The new strand incorporates the HincII site but the HincII can't nick the dATP[αS]. The result is that the primer, and not the target, gets nicked. This leaves a 3' hydroxyl end, which gets extended by the DNA polymerase, displacing the original primer. And so the cycle continues. Clever. And that was just plain vanilla SDA. There are also some new, more elaborate here would we be without PCR? Whenever you find yourself wanting to amplify up a bit of DNA, that famous TLA (three-letter acronym) springs to mind in a flash. It stands for Polymerase Chain Reaction, by the way, and it is the cornerstone of molecular biology, allowing tiny amounts of DNA to be amplified. And as with PCR, so with many other tools in our molecular toolbox: it all comes down to a gift of Nature. All the clever stuff in PCR is done by the DNA polymerase enzyme, which grabs nucleotides kindly chaperoned by the transfer RNA and attaches them to a template strand. The in-built complementarity of Nature's four nucleotides ensures (at least with reasonable fidelity) that the new strand is a fair copy of the original – only in mirror image, so to speak. This strict complementarity means PCR is sensitive and specific. The biology takes care of it all. But much as we love it, PCR has its limitations and one of those is the awkward regime of temperature cycles it needs to get it to work. Indeed you need to get up to some sweltering temperatures, all because, once the polymerase has done its job, you have to pull the complementary strands off the target. In the lab this is done by heating the DNA up: when things get hot, the two DNA strands part company as the DNA simply melts apart. The problem is, this happens at about 70 °C, which is more than warm enough to cook most enzymes (just try putting your finger in water that hot), including the polymerase enzyme. However, rescue came from a thermophile bacterium, which kindly gave us a super, heat-resistant polymerase called Taq, which made PCR easy and Cetis Corporation very rich. Foto: American Chemical Society Most researchers associate DNA amplification with PCR. Nucleic acids may also be amplified isothermically, avoiding PCR's time-consuming temperature cycles and sloppy specificity. 07.09.15 13:11 Methods variants on the block, including "SDA-Ligase-G-quadruplex peroxidase detection" strategy. This is so specific that it has been used to detect variations of a single nucleotide with incredible sensitivity. How does it do this? To start with, three probes are used. Two of them are specific to either wild-type or mutant (called the discriminating probes) and a third can bind to either. If the discriminating probe binds perfectly with the target, it ligates with the third probe and rounds of SDA can proceed. If it doesn't match perfectly (because of a polymorphism or mutation), ligation doesn't occur and neither does SDA. Superior specificity This approach has been used to identify specific miRNAs in single cells and in breast cancer patients – RuiXue Duan and colleagues at the Huazhong University of Science and Technology, China, could detect just nine strands of miRNA in a 15 µL sample (Duan et al., 2013, J. Am. Chem. Soc.). Another isothermal method is best suited for detecting RNA and it is called Nucleic Acid Sequence-Based Amplification (NASBA). This starts with a primer (RNA+) that is complementary to the target RNA(+) but also contains a T7 promoter sequence. The primer directs synthesis of a single strand of DNA(-), resulting in a DNA-/RNA+ hybrid. Meanwhile, RNAse H digests the original RNA+ primer, leaving the single-stranded DNA exposed as a template for reverse transcriptase generation of double-stranded DNA. This dsDNA is the entry point for the amplification cycle, as its T7 promoter sequence (it was in the original primer, remember?) directs the synthesis of lots of new RNA(-) molecules. These, in turn, are bound by a reverse primer and, once again, the DNA+/RNA- hybrid is produced, which, when RNAse H has digested the RNA(-) strand, leaves another single stranded DNA(+). Just like before, this is turned into dsDNA, which directs the synthesis of RNA(-), and so the cycle goes on generating RNA(-) exponentially. Smart amplification strategy SMART – Signal Mediated Amplification of RNA Technology (see what they did there?) – uses a three-way junctional complex. The idea is to have two primers that bind flanking regions of the target DNA. Only when the two primers bind do they form a stable bond with each other. One of the primers is longer than the other, and LT_515_Bench Philosophy.indd 57 5-2015 contains a T7 promoter and a transcription template (used for recognising the RNA). Once the three-way junctional structure has thus formed, the longer primer directs elongation of the shorter one. The T7 promoter drives RNA synthesis from the resulting dsDNA, resulting in many copies of RNA, which can be detected by many different possible methods. Loop-mediated amplification One of the most popular isothermal amplification strategies is called LAMP, which stands for Loop-Mediated Amplification. LAMP works using two pairs of primers (two forward and two backward primers). Each pair consists of an inner primer and an outer primer. The inner primer also contains a sequence (F1c) complementary to a region (F1) slightly further along the target sequence. As this strand gets synthesised (we'll call this strand S1) it picks up a second F1c from the F1 on the target sequence. Meanwhile, the outer primer starts extending, pushing S1 off, while the F1c originally present in the primer, folds over and binds to the new F1c. This gives a dumbbell shape at the 5'-end. The same happens at the 3'-end thanks to the work of the backward pair of primers. Result: a double dumbbell structure looking a bit like a closed staple. A bit more work by the DNA polymerase turns the dumbbell into a stem loop structure and this stem loop undergoes a proliferative recycling phase. If all that was just too much to follow, the Eiken Chemical company has a pretty animation to show the whole process (http://loopamp.eiken.co.jp/e/lamp/anim. html). Faster and cheaper So how does LAMP compare with its older cousin, PCR? First of all, it is faster and cheaper. It is faster because there is no thermocycle involved and cheaper for the very same reason. But many labs have also found it to be more robust and more sensitive than PCR, and this is credited to the fact that it recognises no less than six separate sequences in the target. In the original paper, in which LAMP was announced, its inventors showed evidence that LAMP amplified just six copies of target molecule (Notomi et al. 2010, Nucleic Acids Research). LAMP is also claimed to have higher specificity than PCR. Indeed, one of the problems with PCR is it is often thrown off the scent by irrelevant DNA present in a sample. Again, in the original paper, just six pieces of target were successfully amplified Lab Times page 57 up, despite the contaminating presence of 100 ng of human DNA in the LAMP reaction mixture. This robustness against interfering materials makes LAMP particularly appealing in clinical diagnostic applications. And as far as simplicity goes, all you need to do LAMP is have the four primers, DNA polymerase and a laboratory water bath. No wonder then that LAMP has established itself as a standard tool for molecular diagnostics in the field, such as identifying species. Most often, it has been used for identifying pathogens, either in the field or in biological samples. LAMP has been shown to be successful in signalling the presence of Neisseria meningitidis, the bacterium that causes meningitis and other serious illnesses, in cerebrospinal fluid (Lee et al., 2015, PLoS ONE). Paper-based DNA amplification But the prize for the most amazing application of LAMP must surely go to George Whitesides and his group at Harvard. In a recent issue of Analytical Chemistry, Whitesides announced a hand-held, paper-based (yes, you read that right – paper based!) isothermal DNA amplification device that can detect E. coli bacteria in a sample, and all it needs is a UV source and a camera phone (Connelly et al., Anal. Chem., 87, 7595-601). It uses paper microfluidics and a multilayer gadget that allows you to add the sample, push in a slider, and then add buffer and LAMP master mix again just by pushing in another slider. After an hour's incubation at 65 °C, you add a bit of SYBR Green, shine your UV onto it and take a snap with your camera phone. And with as few as five E. coli in the sample, it glows bright green to give a positive signal. Isothermal DNA amplification is not new but it seems to be going through its own proliferative amplification stage, as researchers are finding more and more novel applications, especially in contexts where either low temperatures are required (such as in vivo applications) or where economic (when you can't afford a thermocycler) or strategic (developing hand-held, in-field devices) considerations are important. Steven D. Buckingham Fancycomposinganinstallmentof“BenchPhilosophy”? ContactLabTimes E-mail:[email protected] 07.09.15 13:11 page 58 Lab Times Products 5-2015 New Products Nanoscopy ensures that measurements are performed without influence of environmental factors. Advantages: The system provides accurate and highly quantitative measurements over a wide six-order dynamic range, from 10-13 to 10-7 mol/L. Furthermore, the lifespan of the xenon arc lamp has been increased greatly to approximately 2,000 hours. More Information: www.shimadzu.eu/rf-6000 Sample Storage Product: Fluorescence lifetime imaging (FLIM) for STED Name & Manufacturer: STED FLIM from Abberior Instruments Technology: Based on TCSPC hardware from Becker&Hickl STED FLIM is integrated into our STED platform. Advantages: The integrated STED FLIM allows the user to acquire simultaneously FLIM data in up to 4 channels; calculate & display lifetimes in STED mode online; separate dyes in STED mode via their lifetimes; scan fluorescence correlation spectroscopy and other single-molecule spectroscopy applications through off-line analysis; auto-save TCSPC photon streams that can be directly loaded into MATLAB, Python, C/C++, ImageJ and perform a workflow based on a full software integration of STED FLIM into Imspector. More Information: www.abberior-instruments.com Photometry Product: Screw caps for storage tubes Name & Manufacturer: Low profile screw caps from Micronic Technology: The low profile screw caps are available in 12 colours thereby providing an easy visual identification tool for labs operating cap colour coding practices. The Silicon O-rings around the base of the low profile screw caps produce the most secure seal possible, enabling unmatched sample integrity for long-term storage. The single twist closing ensures an easy and tight sealing for sample storage tubes. Advantages: The low profile screw caps are ideal for biobanks and other laboratory facilities that need a space-saving solution for their long-term sample storage at low temperatures. Since the tube height with low profile screw caps is now identical to the tube height with a TPE-cap – the same low profile rack cover can be used for both types of caps. More Information: www.micronic.com/product/screw-caps-in96-format Histopathology Product: Spectrofluorophotometer Name & Manufacturer: RF-6000 from Shimadzu Technology: The instrument offers the highest sensitivity and signal-to-noise ratio (SNR) in its class. The high sensitivity allows for very low limits of quantitation, easily achieving quantitation of fluorescein to concentrations of 1 × 10-13 mol/L. In addition, an auto-gain control function LT_515_New Products.indd 58 Product: Modular embedding system Name & Manufacturer: HistoCore Arcadia from Leica Biosystems Technology: The embedding system is a combination of the paraffin-dispensing module Arcadia H and the cold plate Arcadia C. The large workspace area of the Arcadia H allows the user to set out multiple cassettes and molds. The paraffin tank holds up to 4 liters of paraffin which in most cases is sufficient for a complete working day. The temperature of the different compartments and surfaces of the instrument can be adjusted individually. The cold plate HistoCore Arcadia C can hold more than 60 cassettes. Cooling efficiency is critical so the cold plate was designed with an environmentadaptive control module to stabilise the operating temperature at around -6 °C. Advantages: The new station is designed with the user in mind and incorporates comfortable wrist-pads that increase comfort and stability, an optional magnifier to facilitate specimen orientation of small and complex biopsies and an LCD touchscreen for increased control. More Information: www.LeicaBiosystems.com Immunology Product: Kits targeting cells of the adaptive and innate immune system Name & Manufacturer: T-Track ImmunoScan and T-activated ImmunoScan Cocktail from Lophius Biosciences Technology: The T-Track ImmunoScan detects cell-mediated immune functions through the measurement of interferon gamma (IFNg) in combination with an ELISpot readout. The ImmunoScan Cocktail contains a mixture of stimulants outside the IFNg ELISpot kit format to measure other cytokines. Advantages: The kits are intended to be typically used in solid organ or bone marrow transplant recipients to measure alterations in immunosuppression. More Information: www.Lophius.com 07.09.15 13:11 Book Review 5-2015 Lab Times page 59 Books on evolution for pre-schoolers Apes Don’t Celebrate Birthdays! It may be that “The first book on evolution for pre-schoolers”, reviewed here, isn’t the very first at all. Your Lab Times reviewer was nevertheless full of praise. I n recent years, I have written several reviews of children’s books about evolution for my German blog (http:// wissenskueche.de). All of the books were for school children aged eight and above and I tried to find books for smaller children without success. This was surprising, given that, in my experience, even four-year-olds show a strong interest in dinosaurs and fossils, which is a great start for first steps to scientific literacy in evolution. I found out that pre-schoolers can grasp the basics of evolutionary biology when the kindergarten teachers of my child invited me to talk at a science project last year. Knowing that I am a biologist, I was asked to answer the kids’ questions, including “What were the first animals on Earth?” and “When did the first humans live?” The kids and I enjoyed a lively chat about how we scientists know about things that happened long ago and why we think the ancestors of all the animals and plants changed over time. They knew a lot already, not only about dinosaurs, but on similarities and differences between humans and their nearest relatives, too. I was amazed by statements like “Apes don’t celebrate their birthdays”. After this experience, I knew for sure that there is no good reason for the lack of books on evolution for young children. Crowd-funded project So, I was excited when I discovered the crowd-funded book project Grandmother Fish, by Jonathan Tweet, a US designer of tabletop, role-playing games, who applied his storytelling talents to create a book that he, as an atheist and father, had found was missing. His idea and text came to life with the help of drawings by Karen Lewis, an experienced illustrator of science for children. To make the book accessible for the very young, it is conceptualised as being read interactively, coaxing the children to wiggle and chomp like grandmother fish, LT_515 Books.indd 59 crawl and breathe like grandmother reptile, squeak and cuddle like grandmother mammal, grab and hoot like grandmother ape, and walk and talk like grandmother human. With its engaging texts and charming drawings of animals and their evolutionary family tree, the book manages to get basic concepts across in a very child-friendly way – of a common origin of all life, and of ancestral and derived traits of the organisms living on earth right now. As Jonathan Tweet told a US newspaper, “It’s a very simple story but a lot of thought has gone into it.” Natural selection explained simply In the last section of the book, the author added information for grown-ups and older children to tackle some misunderstandings about evolution people tend to have. Here, names, facts and dates are given, and natural selection is explained in admirably simple terms; even more importantly, in words avoiding the line of thought associating nature with “red in tooth and claw”. To me, this is a clear sign that Jona than Tweet is aware of the fact that the religious conservatives aren’t the only influence which might let us shy away from talking about evolution with our kids. For many church-critical progressives the stories about evolution have a bad taste, too, as far-right ideology has often used biologistic evolutionary explanations to fight against an open, egalitarian society. In my view, Grandmother Fish isn’t primarily written as a challenge to the belief of God creating earth and life on it. It is rather written for the liberal science-loving parent or teacher, who accepts evolution but has trouble with the bad vibrations that result from the twisted and malicious use of evolutionary thinking in social Darwinism. Jonathan Tweet does a great job in avoiding the pitfalls of inept associations that might reduce the enthusiasm of people when talking with their children and pupils about our evolutionary ancestry. In his book, the idea of the survival of the fittest isn’t a tale about killing and being killed, it is one about safety. The pictures show animals and humans enjoying their lives, caring and being social. And in the science notes at the end of the book Tweet writes, “Baby animals are born with differences, and some differences make them safer. Animals that keep themselves safer have more babies.” A tale of belonging together The book surely is about basic science facts, but it also wants to tell a humanist’s tale of interconnection and of belonging together. When it comes to Homo sapiens it says, “We are all closely related, and we are one human race.” Grandmother Fish is at the printer right now with its Kickstarter investors waiting to get their copy of the 32-page hard cover book. Pre-orderers can join them for $20. Unfortunately, the shipping fee outside of the US is quite high ($30). But according to the author, the book will be available on Amazon, too. In the meantime, you can check out the PDF of a draft version (to be downloaded at www.grandmotherfish.com/ grandmotherfish.pdf) – or you can while away your children’s time with an equally recommendable alternative that your Lab Times reviewer finally picked out, when investigating for this review: Neal Layton’s The Story of Everything (published in 2006). Brynja Adam-Radmanic u Grandmother Fish. A child’s first book of evolution. By Jonathan Tweet & Karen Lewis (Illustrator). 2015, Hardcover, $20 (plus shipping fees to Europe: $30). ISBN13 9780986288401. More at www.grandmotherfish.com. u The Story of Everything. A pop-up book with pops, flaps and tabs. By Neal Layton. Hodder Children’s, 2006. 30 pages, 3 to 6 years, €14. 02.09.15 21:57 o: ot Ph Lab Times Careers 5-2015 ki be em / lia to Fo page 60 Career strategies for young European scientists (LVI) “I’m Interested in Different Types of Questions about Science” For our irregular series “Alternative Careers in Science”, we talked to Emma Frow, who at some point realised cell biological research couldn’t excite her anymore. That’s when her career path took a detour. E mma Frow is an assistant professor at Arizona State University. She start ed her career with studying Natu ral Sciences and doing a PhD in cell biolo gy at Cambridge University. She left the lab to work as a sub editor for Nature in London, and then turned to social sciences, gaining an MSc in Science and Technology Studies from the University of Edinburgh. We spoke with her about a life between science and society. Lab Times: Emma Frow, obviously two souls are dwelling in your chest. Why did you study biology and even do a PhD, but then turn to social sciences? Frow: Actually, I almost didn’t take biol ogy at High School in Canada. But my mum suggested that it was probably a good idea that I take it. When leaving school, I wasn’t sure whether to study languages or science. In the North American university system you can combine arts and sciences, but this isn’t typical in the UK, where I went to uni versity. In the end, I decided that I would rather keep languages as a hobby and it felt a bit harder to do science as a hobby. So I de cided to study science as an undergraduate. LT: You continued doing science. How did you pick cell biology as your favourite? Frow: One day in college, I walked by a notice advertising summer student posi tions in a lab in the Department of Med icine. I thought it looked interesting and hadn’t yet made summer plans. So I started working in this lab and I really enjoyed it. I had a great summer and I even managed to publish a journal article from the research. I realised I had quite green thumbs when it came to lab work. At the end of the summer, LT_515_60_61.indd 60 my supervisor invited me back to do a PhD. It wasn’t something I had planned to do but I enjoyed the lab work, the people and the atmosphere in the lab, so I ended up stay ing there for my PhD. to discussions with colleagues and friends about how science is funded, about the re producibility of experiments, and so on. In my free time, I would go to talks and lec tures by people who were communicating about science and the relationship between science and society, and in the final year of my PhD, I started volunteering for a science policy initiative based in London. LT: And what prompted you to move away from the lab? Frow: Well, by the end of my PhD, the questions that I found most interesting were not ones that could be answered by doing LT: How did you move into the field called scientific experiments. I was doing eight to social studies of science? ten hours a day of cell culture, repeating Frow: It took me a while to discover the experiments under various conditions but field of science studies but once I found it, I was starting to question whether the work I knew it was what I had been looking for. was biologically relevant, whether it would As a scientist, the options that seemed most make any difference. I found myself in a sit visible to me when I was thinking about uation where the questions that excited me moving away from the lab bench included most were not “does that protein interact science communication, history and philos with this protein under these conditions?”, ophy of science, and bioethics. I wasn’t sure which is what some of my friends went to that any of these offered quite what I want bed dreaming about. In Cambridge, people ed. Science and technology studies is an are often completely ab interdisciplinary field that sorbed by their work and “I was starting to question distinguishes itself from whether my work would I wasn’t sure that I want philosophy of science and make any difference.” ed to enter into competi bioethics by being explic tion with my fellow PhD itly concerned with prac students for the next round of postdoc and tice, with looking at what scientists do, how faculty positions; I just didn’t feel commit they do it and why they do it, and what this ted enough to laboratory work. means for the knowledge that is created and its relationship with society. LT: Did you think you were a bad or, at How did I move into this field? It has least, not a really enthusiastic scientist? happened gradually. I started retraining Frow: No, I don’t think I ever felt like when I moved up to Edinburgh in 2006, I was being a bad scientist. I think, often, to take up a postdoc in a unit called the people assume that if you leave the lab, you Genomics Policy & Research Forum. I have are not a good scientist. Well they can think gotten several jobs thanks to friends and what they want (laughs). That doesn’t re colleagues, who have spotted positions they ally bother me. I’m still very interested in thought sounded like me: I was working at science but I’m just interested in different Nature when a friend sent me a notice for types of questions about science. the postdoc position in Edinburgh. A similar thing happened with my current position LT: So what were you dreaming of if it at Arizona State University. You could say wasn’t your next experiment? that my jobs have tended to find me. Sor Frow: It took me quite a while to refine ry for not being straight forward (laughs). the questions that I’m really interested in. You said you were interested in quirky ca When doing my PhD, I found myself drawn reer paths! 03/09/2015 14:44 Careers 5-2015 Lab Times page 61 Careers in academia LT: So you got your first position in soFrow: It’s a tricky problem. I think you edge from biology are coming together in cial sciences without any training in social have to start with an understanding of what synthetic biology. There are some very in sciences? scientists’ working lives are like – what con teresting similarities and differences be Frow: Not exactly, I would never have straints they face, what issues they encoun tween how engineers and biologists ask gotten a postdoc position as a social scien ter, and what kinds of questions might be questions and develop projects. tist without any training. But I was lucky relevant and interesting to them. You can’t that the Genomics Forum was a unique force scientists to engage with broader LT: Are there clear differences between place. It was designed as a kind of institute questions but in practice most scientists biologists and engineers? or space that was charged with designing have their own experiences of them, even if Frow: Well, they certainly present activities to bring together all types of stake they’re in quite practical settings – for exam themselves as having different approach holders with an interest in genomics and ple, you should have some understanding es to the world! Often, in synthetic biol the life sciences, includ of the broader con ogy we hear caricatures that biologists “One approach is to make ening social scientists, bio text of your work to are more interested in understanding the logists, physicians, mem gagement with the social dimenwrite a grant propos world, while engineers are more interested bers of the public, policy al that will be persua in building with biology. This does shape sions of science compulsory.” makers, industry, and so sive to your funder. I the kinds of questions that researchers from on. To help do this, the Genomics Forum often start informally by just seeing who different disciplines ask and the ways that hired postdocs with training in quite differ shows interest, finding out what interests they organise their practices in the labo ent fields. When I started, there were seven them and then developing discussions from ratory. There are also differences in how of us with very different backgrounds: eco there. I’ve been at ASU now for six months engineers and biologists are trained as un nomics, theology, microbiology, psycholo and I have had three or four engineering dergraduates, with engineers typically fol gy, law, ethics and me. We were charged students, who have approached me saying lowing more structured and rigid curricu with identifying themes and developing ac they are interested in policy aspects of their la than biologists. Engineering is a profes tivities to foster interdisciplinary dialogue. research. I’m starting with them and let’s sional degree but you don’t need the same It was through this work that I really started see where we end up! kind of formal certification to practice as a engaging with social scientists: asking them Another approach is to make engage biologist. about their research and asking them to ex ment with the social dimensions of science plain to me why it mattered. After a couple compulsory. To give you an example from LT: What other issues are you interested of years, I was convinced that the sorts of Edinburgh: about five years ago, the uni in, what would you like to study? questions that researchers in science and versity was setting up a new Masters pro Frow: Right now I have several syn technology studies were asking, were things gramme in Systems and Synthetic Biolo thetic biology projects underway; there’s a I was interested in exploring myself. gy and was looking for faculty to propose great appetite among biological engineers new courses. A colleague had been studying for social scientists to be involved in the de LT: What is your current job at the Arizothese fields for a while and decided to pro velopment of this field. I’m still very inter na State University? pose a social science course on Systems and ested in image production and also in the Frow: Again, it’s an unusual job. I have Synthetic Biology for role that journals play “There’s a great appetite among a split position, with 50% based in the the students. It must in the production of School of Biological and Health Systems En have been a timely biological engineers for social sciscientific knowledge. gineering, and 50% in the Consortium for proposal because our entists to be involved in the develI’m not aware of any Science, Policy & Outcomes, which is one course ended up be anthropological stud opment of synthetic biology.” of the larger departments in the US with ing one of three com ies of how journals a focus on science policy and science stud pulsory courses in the degree programme. operate, I think that would be really inter ies. My office space and my ‘lab space’ are So, any student who takes that masters in esting and fun to do. based in Engineering, and I have a remit to Edinburgh has to spend 30 hours with us help embed policy and society considera – lucky them! We approach the course by LT: Don’t you miss the wet lab? tions into the engineering teaching curric identifying issues that scientists in the field Frow: (laughs): You know, I have found ulum, and to encourage the growth of re are talking about (e.g. in journal editorials a substitute for lab work: cooking! It’s not search collaborations between engineers and commentaries) and then providing a ambitious nouvelle cuisine but I like to try and social scientists. These are things that social science paper that analyses the same and test new recipes. I find it relaxing to several of the engineers and social scien issues but offers a different perspective or come home from work and cook – it’s phys tists in my departments are interested in way of understanding what is going on. It ical, repetitive and requires some preci and already working on, and my position can be challenging for the students but, ac sion. Cooking is like doing a complete ex as a ‘bridge’ is a visible demonstration of tually, the reviews of the courses are usually periment within less than an hour and the this commitment. very good, and the students welcome hav results are usually satisfying! To be serious ing the time and space to think about their though: I don’t imagine going back to work LT: Thinking about the meaning and science in a different way. in a wet lab. But in my research I do get to sense of science is time consuming. PhDs or go and spend time visiting and hanging in postdocs, however, rarely have any spare LT: What issues do you study right now? other labs, which is fun. It’s really the best time beyond lab work. Which strategies do Frow: One of the research questions of both worlds, getting to keep a foot in both you think are the most promising to encourright now that I’m actively exploring is how natural and social sciences. age lab scientists to think outside of their box? knowledge from engineering and knowl Interview: Karin Hollricher LT_515_60_61.indd 61 03/09/2015 14:44 page 62 Lab Times Job Appointments 5-2015 Postdoctoral or PhD position in Intestinal Lipidomics The Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and the Center for Regenerative Therapies Dresden (CRTD) invite applications for a position as Postdoctoral fellow or PhD student in Intestinal Lipidomics INTERNATIONAL PhD PROGRAM Applications are invited for internally funded PhD student fellowships at the FMI in Basel, Switzerland. Our research focuses on epigenetics, mechanisms of cancer and neurobiology. We employ state-of-the-art technologies to explore basic molecular mechanisms of cells and organisms in health and disease. Application information: www.fmi.ch/phd > Epigenetics > Mechanisms of Cancer > Neurobiology Affiliated with the University of Basel IN BASEL, SWITZERLAND Application deadline: 2SZIQFIV , 2015 The project is funded by the European Research Council (ERC Starting Grant) and aims at the characterization of lipids and lipid antigens involved in the crosstalk between metabolism, immunity, and cancer in the intestine. We are looking for candidates interested in applying lipidomics approaches to the study of lipids in the context of intestinal inflammation and cancer. The proposed study is a joint project between the groups of Dr. Andrej Shevchenko at the Max Planck Institute of Molecular Cell Biology and Genetics (www.mpi-cbg.de/research/research-groups/andrej-shevchenko) and Dr. Sebastian Zeissig at the Center for Regenerative Therapies Dresden (www.crtdresden.de/research/crtd-core-groups/zeissig). The position offers an excellent opportunity to join a group of enthusiastic researchers in a cross-disciplinary environment. Moreover, the CRTD (www.crt-dresden.de) and the MPI-CBG (www.mpi-cbg.de) provide outstanding facilities for the proposed studies including a state-of-the art lipidomics facility. We seek candidates with expertise in analytical chemistry of lipids and, in case of postdocs, expertise in lipidomics. Funding is available for 3 years. Salary is according to E13 (100% for postdocs, 65% for PhD students). Please send your application by September 30th 2015 by e-mail as a single PDF to: [email protected] and [email protected]. www.fmi.ch Affiliated with the Novartis Institutes for BioMedical Research References 1. Olszak et al., Nature. 2014 May 22;509(7501):497-502. 2. An et al., Cell. 2014 Jan 16;156(1-2): 123-33. 3. Papan et al., Anal Chem. 2014 Mar 4;86(5):2703-10. 4. Zeissig et al., Nat. Med. 2012. Jul;18(7):1060-8. 5. Sampaio et al., Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1903-7. 6. Shevchenko et al., Nat Rev Mol Cell Biol. 2010 Aug; 11(8):593-8. 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For further information please contact: Lj-Verlag OHG, Lab Times, Ulrich Sillmann Merzhauser Str. 177, 79100 Freiburg, Germany Phone +49-(0)761 292 58 85 Fax +49-(0)761 357 38 Email: [email protected] Please subscribe at www.labtimes.org More jobs at www.labtimes.org/labtimes/career LT_515_62_66.indd 62 04.09.15 15:12 Conferences 5-2015 page 63 Lab Times Calendar 2015 21/9-22/9 Strasbourg (FR) Mitochondria at the Crossroad – Symposium 2015 of the MitoCross LabEx Consortium, Info: http://mitocross.unistra.fr/ symposium-2015 21/9-24/9 Oxford (UK) 12th Conference of the European Society for Reproductive Immunology, Info: http://esri.org.hu/2015-meeting 21/9-25/9 Funchal, Madeira (PT) 17th Congress of European Mycologists, Info: www.mundiconvenius. pt/eventos/2015/xviicem2015 21/9-25/9 Warsaw (PL) 44th European Muscle Conference: Muscle Research in Health & Disease, Info: www.emc2015.org.pl 22/9-24/9 Basel (CH) MipTec 2015: European Conference and Exhibition for Drug Discovery, Info: www.miptec.com 22/9-24/9 Grenoble (FR) 2nd Symposium Signaling Through Chromatin, Info: http:// epigenetics.fr/symposium2015 23/9-25/9 Basel (CH) 5th Basel Postdoctoral Network Retreat, Info: https://postdoc retreat.biozentrum.unibas.ch 23/9-25/9 Tuebingen (DE) Novel Concepts in Innate Immunity, Info: www.innateimmunity-conference.de 23/9-26/9 Dresden (DE) 12th Dresden Symposium on Autoantibodies: From Autoantibody Research to Standardized Diagnostic Assays in the Management of Human Diseases, Info: www.gfid-ev.de/dsa.htm 23/9-26/9 Šibenik (HR) Central European Symposium on Antimicrobials and Antimicrobial Resistance (CESAR2015), Info: http://hmd-cms.hr/cesar2015 LT_515_62_66.indd 63 24/9-25/9 Hannover (DE) 3rd International Symposium on Peripheral Nerve Regeneration, Info: www.ispnr.eu 24/9-28/9 Ajaccio (FR) EMBO Conference on Nuclear Receptors: From Molecules to Humans, Info: http://events. embo.org/15-nuclear-receptors 26/9-29/9 Stresa (IT) Meeting of the International Society for Autonomic Neuroscience – Bringing the Latest in Autonomic Neuroscience From Around the World, Info: www.isan2015.org 27/9-2/10 Elche (ES) 12th International Meeting on Cholinesterases and 6th International Conference on Paraoxonases, Info: www.12thChE.org 27/9-2/10 Mandelieu-l.-Nap. (FR) EMBO Conference: The Multidisciplinary Era of Endocytic Mechanics and Functions, Info: http:// events.embo.org/15-endocytic 28/9-30/9 Cambridge (UK) Abcam Conference on Cancer and Metabolism Conference 2015, Info: www.abcam.com/ events/cancer-and-metabolismconference-2015 28/9-30/9 Greifswald (DE) International Symposium on Sulfation Pathways (SUPA 2015), Info: www.supa2015.org 28/9-30/9 Heidelberg (DE) DKFZ-ZMBH Alliance Forum: Tumor Microenvironment, Metabolism and Metastasis, Info: www.vwfb.de 28/9-1/10 Berlin (DE) 10th International Conference on Behaviour, Physiology and Genetics of Wildlife, Info: www.izw-berlin.de/234.html 29/9-30/9 Essen (DE) Supramolecular Chemistry on Proteins – 1st International CRC 1093 Symposium, Info: www.uni-due.de/crc1093 29/9-2/10 Goettingen (DE) 6th European Conference on Prokaryotic and Fungal Genomics, Info: www.prokagenomics.org 29/9-2/10 Paris (FR) EMBO Conference: Genetic Control of Development and Evolution, Info: www.gene-control-2015.org 29/9-3/10 Porto (PT) 11th International Meeting on Yeast Apoptosis (IMYA 2015), Info: www.imya11.com 30/9-1/10 Basel (CH) 14th Annual Biotech in Europe Forum for Global Partnering und Investment, Info: www.sachsforum.com/basel14 30/9-2/10 Copenhagen (DK) International Conference on One Health Antimicrobial Resistance (ICOHAR), Info: http://icohar.org 30/9-3/10 Marbella (ES) TOLL Conference 2015: Targeting Innate Immunity, Info: www. toll2015.org 1/10-3/10 Berlin (DE) Dual Role of Arthropods in Human and Animal Health, Info: www.leo poldina.org/de/veranstaltungen/ veranstaltung/event/2311 1/10-4/10 Estoril (PT) 17th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy, Info: www.esh.org/conference/17thannual-john-goldman-conference 4/10-9/10 Pultusk (PL) ESF/EMBO Symposium on Interaction Between the Immune System and Nanomaterials: Safety and Medical Exploitation, Info: http://nanomaterials.esf.org 5/10-6/10 London (UK) Cells: From Robert Hooke to Cell Therapy – a 350 Year Journey, Info: https://royalsociety.org/ events/2015/10/cells-fromrobert-hooke-to-cell-therapy 5/10-7/10 Berlin (DE) 2nd Next Generation Sequencing & Bioinformatics Conference, Info: www.gtcbio.com/conferences 5/10-8/10 Berlin (DE) Biomarker Summit Europe 2015: 9th Biomarkers in Drug Discovery & Development & 4th Biomarkers in Diagnostics, Info: www.gtcbio.com/conferences 5/10-9/10 Cape Sounio (GR) EMBO Conference: The DNA Damage Response in Cell Physiology and Disease, Info: http://events.embo.org/15-ddr 6/10-8/10 Hannover (DE) Biotechnica 2015: Biotechnology, Life Sciences and Lab Technology – Trade Fair, Info: www.biotechnica.de/home 6/10-8/10 Hannover (DE) Labvolution – World of Lab Technology – Trade Fair, Info: www.labvolution.de 6/10-10/10 Heidelberg (DE) EMBO-EMBL Symposium: Seeing is Believing – Imaging the Processes of Life, Info: www.embo.org/events 7/10-8/10 Hannover (DE) Advances in Lab Automation and Robotics Conference, Info: https:// selectbiosciences.com/ALR2015 6.10.-8.10.2015, Hannover, Germany Europe’s No.1 Event for Biotechnology, Life Sciences and Lab Technology World of Lab Technology for the chemical and pharmaceutical industries, environmental technology and the food industry Two trade fairs. One exhibition ground. One admission ticket. More Information: www.biotechnica.de www.labvolution.de 04.09.15 15:12 page 64 Lab Times Lab Times Founded 2006. Issue 5, 2015 Lab Times is published bimonthly ISSN: 1864-2381 Publisher: LJ-Verlag OHG Office: Merzhauser Str. 177, 79100 Freiburg, Germany, Phone +49 (0)761-286869; Fax +49 (0)761-35738 Management: Kai Herfort, Phone +49 (0)761-286869 Editors: Ralf Neumann (Editor-in-chief), Kathleen Gransalke, Kai Herfort, Winfried Koeppelle, Harald Zähringer, Phone +49 (0)761-2925884, [email protected] Conferences 5-2015 7/10-8/10 Hannover (DE) Genome Engineering Conference, Info: https://selectbiosciences. com/GE2015 7/10-9/10 Berlin (DE) 11th VAAM Symposium on Molecular Biology of Fungi, Info: www. vaam.de/index.php/termine.html 7/10-9/10 Budapest (HU) Integration of Pharmacogenomics in Clinical Decision Support – 3rd Conference of the European Society of Pharmacogenomics and Personalised Therapy (ESPT), Info: www.esptcongress.eu 13/10-16/10 Freiburg (DE) Symposium on Methodological Challenges in Biomedical Research, Info: http://portal.unifreiburg.de/imbi/symposium2015 14/10-16/10 Cambridge (UK) Wellcome Trust Conference on Infectious Disease Genomics, Info: https://registration. hinxton.wellcome.ac.uk/ display_info.asp?id=501 14-16/10 Noordwijk aan Zee (NL) 9th European Meeting on Molecular Diagnostics (EMMD 2015), Info: www.molecularmeeting.com 7/10-11/10 Isle sur Sorgue (FR) EMBO Conference on Nuclear Structure and Dynamics, Info: http://events.embo.org/15-nucleus 15/10-18/10 Antalya (TR) 2nd International Congress on Stem Cell and Cellular Therapies, Info: www.stemcell2015.org 8/10-10/10 Stuttgart (DE) Bone-Tec 2015 – International Bone-Tissue-Engineering Congress, Info: www.bone-tec.com 15/10-18/10 Antalya (TR) Endobridge 2015: Bridging the World of Endocrinology, Info: http://endobridge.org/2015 Cover Photo: RazoomGames@iStock, Editing: Kai Herfort 8/10-10/10 Vienna (AT) International Symposium on Flaviviruses: Structure and Immunity, Info: www.virologie. meduniwien.ac.at/flavi-symp 17-22/10 S. Feliu de Guixols (ES) EMBO Conference: Exploring the Genomic Complexity and Diversity of Eukaryotes, Info: http://events. embo.org/15-eukaryotes Sales: Advertising Manager: Bernd Beutel Top-Ad Bernd Beutel, Schlossergäßchen 10, 69469 Weinheim, Germany Phone +49(0)6201-29092-0 Fax +49(0)6201-29092-20 [email protected] 8-11/10 Mont-Saint-Odile (FR) Hormones, Metabolism and Cancer – 40th Symposium on Hormones & Cell Regulation, Info: http://hormones-cell-regulation.eu 18/10-21/10 Heidelberg (DE) EMBO-EMBL Symposium: The Non-Coding Genome, Info: www.embo-embl-symposia.org/ symposia/2015/EES15-08 11/10-14/10 Bamberg (DE) Annual Meeting of the International Cytokine & Interferon Society, Info: www.cytokines2015.com 19/10-20/10 London (UK) Chimeric Antigen Receptor Therapy in Haematology and Oncology: Current Successes and Challenges, Info: www.biochemistry.org/Events Reporters: Latika Bhonsle, Steven Buckingham, Florian Fisch, Jeremy Garwood, Karin Hollricher, Madhuvanthi Kannan, Karin Lauschke, Alejandra Manjarrez, Rosemarie Marchan, Alex Reis, Ralf Schreck Graphics, Design and Production: Ulrich Sillmann (Art Director), Kathleen Gransalke, Kai Herfort, Winfried Koepelle, Ralf Neumann, Harald Zähringer Recruitment: Ulrich Sillmann, Phone +49(0)761-2925885, [email protected] Printed at: Stürtz GmbH, Alfred-Nobel-Straße 33, 97080 Würzburg, Germany Web: www.labtimes.org, Webmaster: Carsten Rees, [email protected], Phone +49 (0)761-1563461, Prices & Subscription rates: - price per issue: €4.90 - research institutes/units: free of charge - annual subscriptions for companies and personal subscribers: €27.Subscribe at http://www.labtimes.org/ kontakt/sub.html, or mail to: [email protected] Bank Account: Volksbank Freiburg KTO: 319 0 315; BLZ :680 900 00; BIC: GENODE61FR1; IBAN: DE24 6809 0000 0003 1903 15 LT_515_62_66.indd 64 11/10-14/10 Cambridge (UK) Abcam Conference on Epigenetics, Obesity and Metabolism, Info: www.abcam.com/EOM2015 11/10-14/10 Heidelberg (DE) EMBO-EMBL Symposium: New Approaches and Concepts in Microbiology, Info: www. embo-embl-symposia.org/ symposia/2015/EES15-07 11/10-16/10 Hagoshrim (IL) Tetrapyrrole Photoreceptors of Photosynthetic Organisms, Info: www.fems-microbiology.org 19/10-21/10 Basel (CH) Annual Biocontrol Industry Meeting (ABIM 2015), Info: www.abim.ch 20/10-21/10 London (UK) Microfluidics Congress, 2nd Synthetic Biology Congress and 3rd qPCR & Digital PCR Congress, Info: www.globalengage.co.uk/ microfluidics.html Missing an event? Let us know: [email protected] 21/10-22/10 Cambridge (UK) BioData World Congress 2015 – Harnessing the Power of Big Data in Biomedical Research, Info: www. healthnetworkcommunications. com/conference/biodata 21/10-23/10 Leipzig (DE) World Conference on Regenerative Medicine, Info: www.wcrm-leipzig.com 21/10-23/10 Paris (FR) 3rd World Congress on Targeting Microbiota, Info: http://microbiota-site.com 22/10-24/10 Heidelberg (DE) 17th EMBL PhD Symposium: Just by Chance? – Randomness and Variability Shaping Biology, Info: http://phdsymposium.embl.org 22/10-25/10 Berlin (DE) 3rd International Congress on Controversies in Stem Cell Transplantation and Cellular Therapies, Info: www.comtecmed. com/costem/2015 26/10-28/10 Paris (FR) Fungal Cell Wall 2015, Info: www.fcw2015.org 26/10-29/10 Edinburgh (UK) Organelle Crosstalk in Membrane Dynamics and Cell Signalling, Info: www.biochemistry.org/Events 28/10-30/10 Berlin (DE) 6th World Congress on Targeting Mitochondria, Info: www.targeting-mitochondria.com 28/10-30/10 Cambridge (UK) Wellcome Trust Conference on Functional Genomics and Systems Biology: From Model Organisms to Human Health, Info: https:// registration.hinxton.wellcome. ac.uk/display_info.asp?id=517 28/10-30/10 Perugia (IT) Microbial Diversity 2015: the Challenge of Complexity, Info: www.fems-microbiology.org 1/11-4/11 Heidelberg (DE) EMBL Conference on Cancer Genomics, Info: www.embl.de/ training/events/2015/CAN15-01 04.09.15 15:12 Conferences 2/11-4/11 Munich (DE) Bio-Europe 2015 – Partnering Conference Serving the Global Biotechnology Industry, Info: www.ebdgroup.com/bioeurope 2/11-4/11 Weimar (DE) 19th Joint Meeting „Signal Transduction – Receptors, Mediators and Genes“, Info: www.sigtrans.de/meeting.html 3/11-5/11 London (UK) Antibiotic Resistance and Antibiotic Alternatives: Looking Towards the Future, Info: www. regonline.co.uk/Antibio2015 3/11-5/11 Milan (IT) Abcam Conference on PI3Klike Protein Kinases, Info: www.abcam.com/Milan2015 4/11-5/11 Birmingham (UK) Lab Innovations 2015, Info: www.easyfairs.com/ index.php?id=65877 4/11-5/11 London (UK) 10th Conference on Meningitis and Septicaemia in Children and Adults, Info: www.meningitis.org/ conference2015 4/11-6/11 Tutzing (DE) ATMP 2015 – Issues and Challenges from Bench to Bedside: Production, Analytics & Regulatory Aspects of Cell-based Therapies, Info: http://events. dechema.de/ATMP2015.html 5/11-6/11 Heidelberg (DE) Emerging Biotechnologies: Hype, Hope & Hard Reality – EMBO/ EMBL Science & Society Conference, Info: http://events.embo. org/science-society-conference 6/11-8/11 Cluj-Napoca (RO) International Conference on Molecular Biology: Current Aspects and Prospects, Info: http:// icmb.conference.ubbcluj.ro/en 8/11-11/11 Berlin (DE) Basic Epigenetic Mechanisms in Cancer – Conference of the European Association for Cancer Research (EACR), Info: http://eacr.org/basicepigenetics LT_515_62_66.indd 65 9/11-10/11 London (UK) Industrial Applications of Metal– Microbe Interactions – Focused Meeting of the Society for General Microbiology (SGM), Info: www.sgm.ac.uk/conferences Clinical Practice and Targeted Therapies in Personalized Medicine 5th Munich Biomarker Conference December 1st – 2 nd, 2015 9/11-10/11 London (UK) Cell & Gene Therapy Congress 2015 & 4th Annual Cell Culture & Bioprocessing Congress & 2nd Annual Stem Cell Congress, Info: www.celltherapy-congress.com RAMADA Hotel & Conference Center München Messe 9/11-11/11 Basel (CH) 11th Annual European Antibody Congress – Discover, Develop, Get to Market, Info: www. terrapinn.com/conference/ european-antibody-congress Keynote Speakers: Yves Champey | ITEEC, Genopole, Paris | France Thomas Deisboeck | ThinkMotu LLC., Boston | USA Michael Hallek | University Hospital, Cologne | Germany Lorenz M. Mayr | AstraZeneca, Cambridge | UK Kári Stefánsson | deCODE genetics, Reykjavík | Iceland 9/11-11/11 Dresden (DE) International Conference on Crossing Biological Barriers – Advances in Nanocarrier Design for Targeted Drug Delivery, Info: http://events. dechema.de/CBB2015.html Interdisciplinary conference program 12/11-13/11 London (UK) 3rd Annual Single Cell Analysis Congress, Info: www.singlecell-congress.com 12/11-14/11 Heidelberg (DE) EMBO-EMBL Symposium: Biological Oscillators – Design, Mechanism, Function, Info: www.embo-embl-symposia.org/ symposia/2015/EES15-09 One-to-one partnering Sponsoring options and exhibition Panel discussions and poster session Register now - Early bird until October 9th, 2015 11/11-12/11 Berlin (DE) 3rd International mRNA Health Conference, Info: www.mrna-conference.com 11/11-12/11 Trondheim (NO) 1st National Symposium on Biodiversity and DNA Barcoding, Info: http://norbol.org/ symposium2015 page 65 Lab Times 5-2015 Goldsponsor www.bio-m.org/mbc 15/11-17/11 Borstel (DE) Lipidomics Forum 2015, Info: http: //lipidomics-forum.fz-borstel.de 16/11-18/11 Montreux (CH) NanoBioTech-Montreux Conference, Info: www.nanotech-montreux.com 16/11-19/11 Heidelberg (DE) EMBL/Stanford Conference on Personalised Health, Info: www. embl.de/training/events/2015 17/11-19/11 London (UK) The 2015 Innate Immunity Summit, Info: www.regonline. co.uk/Innate2015 26/11-27/11 Durham (UK) Metal-Related Antimicrobials Event, Info: http:// prospect.rsc.org/MiB_NIBB/ metal-related-antimicrobials 29/11-1/12 Munich (DE) 36th New Phytologist Symposium – Cell Biology of Plant–Microbe Interactions, Info: www. newphytologist.org/symposiums 1/12-2/12 Munich (DE) 5th Munich Biomarker Conference, Info: www.m4.de/mbc 12/11-15/11 Sitges (ES) EFB Conference on Microbial Stress: From Molecules to Systems, Info: www.efb-central. org/index.php/microbial_stress 21/11-23/11 Glasgow (UK) Action on Infection – Federation of Infection (FIS) Societies Meeting, Info: www.actiononinfection.com 1/12-3/12 London (UK) Pathology 2015: Molecular and Cellular Pathology / Diagnostic and Disease Pathology / Cancer Pathology, Info: www.regonline.co.uk/Path2015 13/11 London (UK) Modelling Approaches in Molecular Signalling, Info: http://yls2015.org.uk 23/11-25/11 Vienna (AT) Microbe-Assisted Crop Production – Opportunities, Challenges and Needs, Info: www.micrope.org 2/12 London (UK) Abcam Meeting on Epigenomics: New Marks, New Horizons, Info: www.abcam.com/events 04.09.15 15:12 page 66 Lab Times 2/12-3/12 Brussels (BE) Cell Therapy Manufacturing and Gene Therapy Congress, Info: www.informa-ls.com/event/ celltherapy15 2/12-4/12 Berlin (DE) Revealing Prometheus‘ Secrets: Current Technologies for Tissue & Organ Regeneration – 6th PhD Symposium of the Berlin-Brandenburg School for Regenerative Therapies (BSRT), Info: www.bsrt-phdsymposium.de 7/12-9/12 Cambridge (UK) MetaboMeeting 2015 – Partnering with the Metabolic Profiling Forum (MPF), Info: https://selectbiosciences.com/ Metabo2015 8/12 London (UK) New Developments in Protein Structure Modelling for Biological and Clinical Research, Info: www.biochemistry.org/Events 8/12-10/12 Cambridge (UK) Conference on Target Validation Using Genomics and Informatics, Info: https://registration.hinxton. wellcome.ac.uk/Conferences.wt 8/12-10/12 London (UK) The Science of Pain and its Management, Info: www.regonline.co.uk/pain2015 14/12-16/12 Berlin (DE) IUBS 2015 – Frontiers in Unified Biology: 32nd IUBS International Union of Biological Sciences – General Assembly and Conference, Info: www.iubs2015.org 15/12-17/12 London (UK) Pharmacology 2015, Info: www.bps.ac.uk/meetings/ Pharmacology2015 2016 5/1-7/1 London (UK) Biobanking 2016, Info: www. regonline.co.uk/banking2015 19/1-21/1 London (UK) Bacteriophage 2016, Info: www.regonline.co.uk/Phage2016 LT_515_62_66.indd 66 Conferences 5-2015 26/1-27/1 Cambridge (UK) Epigenetics in Drug Discovery, Info: http://selectbiosciences. com/EGDD2016 26/1-29/1 Heidelberg (DE) EMBO-EMBL Symposium: A New Age of Discovery for Aquatic Microeukaryotes, Info: www. embo-embl-symposia.org/ symposia/2016/EES16-01 28/1-29/1 London (UK) The New Bacteriology – A Royal Society Meeting, Info: https:// royalsociety.org/events/2016/1/ new-bacteriology 30/1-5/2 Lucca/Barga (IT) Gordon Research Seminar and Conference: Ligand Recognition & Molecular Gating – Molecular Basis of Ligand Recognition and Gating in Transmembrane Signaling and Transport, Info: www.grc.org/programs. aspx?id=12689 2/2-4/2 London (UK) Cell Culture 2016, Info: www.regonline.co.uk/Cell2016 9/2-10/2 Cambridge (UK) Selectbio Conference on Antibodies in Drug Discovery, Info: http://selectbiosciences. com/ABDD2016 9/2-11/2 Cambridge (UK) Wellcome Trust Conference on Mouse Models of Disease: Improving Reproducibility of Pathology Endpoints in Challenge Models, Info: https://registration. hinxton.wellcome.ac.uk/ display_info.asp?id=488 14/2-16/2 Rehovot (IL) EMBO Conference: From Host Genomes to Microbiome – Immunity in the Genomic Era, Info: www.weizmann.ac.il/ conferences/NGI2016 15/2-16/2 Lausanne (CH) Life Sciences Switzerland Meeting 2016: Interdisciplinary Sciences, Info: www.ls2-annual-meeting.ch 16/2-18/2 Cambridge (UK) Flow Chemistry Europe 2016: 6th International Conference of the Flow Chemistry Society, Info: https://selectbiosciences.com/ FCE2016 20/2-26/2 Lucca/Barga (IT) Gordon Research Seminar and Conference: Angiotensin, Info: www.grc.org/programs. aspx?id=15143 23/2-24/2 Munich (DE) Cell Culture World 2016 – Enhancing and Innovating Your Cell Culture Process, Info: www.terrapinn.com/conference/ cell-culture 6/3-11/3 Lucca/Barga (IT) Gordon Research Conference: Glycolipid & Sphingolipid Biology – Glycolipid and Sphingolipid Homeostasis and Function in Health and Disease, Info: www. grc.org/programs.aspx?id=12366 9/3-11/3 Heidelberg (DE) EMBO Conference on Visualizing Biological Data (VIZBI 2016), Info: www.embo.org/events/ conferences 11/3-13/3 Athens (GR) International Conference on Aging and Hematological Malignancies: Biology and Therapy, Info: www.esh.org/ conference/internationalconference-on-aging 12/3-18/3 Lucca/Barga (IT) Gordon Research Seminar and Conference: New Antibacterial Discovery & Development – Enabling the Next Generation of Antibacterial Drugs, Info: www. grc.org/programs.aspx?id=14326 14/3-15/3 London (UK) Genetics in Forensics Congress, Info: www.forensicgeneticscongress.com 15/3-16/3 Madrid (ES) Lab-on-a-Chip Europe, Info: http://selectbiosciences. com/LOACE2016 More events at www.labtimes.org/labtimes/calendar 15/3-16/3 Madrid (ES) Single Molecule & Single Cell Analysis, Info: http://selectbiosciences. com/SMSCA2016 15/3-17/3 Cambridge (UK) BMP Signalling in Cancer, Info: www.biochemistry.org/Events 15/3-17/3 London (UK) Immunosuppression Summit 2016: Problems of Immunosuppression and Overcoming Them, Info: www. regonline.co.uk/Immuno2016 29/3-30/3 Valencia (ES) 6th International Conference on Bioinformatics, Info: http://bioinformatics. conferenceseries.com 31/3-2/4 Mosbach (DE) 67th Mosbach Kolloquium: Protein Design: From First Principles to Biomedical Applications, Info: www.gbmonline.de/detail/events/id-67mosbacher-kolloquium.html 2/4-6/4 Soelden (AT) 18th International Neuroscience Winter Conference, Info: www. winterneuroscience.org/2016 3/4-6/4 Heidelberg (DE) EMBO-EMBL Symposium: Tumour Microenvironment and Signalling, Info: www.embl.de/training/ events/2016/ETC16-01 4/4-5/4 Chester (UK) The Grey Area: Ageing in Extracellular Biology and Pathology, Info: www.biochemistry.org/Events 4/4-5/4 Chester (UK) Quantitative Proteomics and Data Analysis, Info: www.biochemistry.org/Events 5/4-6/4 Cambridge (UK) Selectbio Conference: Organ-on-a-Chip Europe, Info: http://selectbiosciences. com/OOACE2016 6/4-10/4 Leipzig (DE) 10th International Congress on Autoimmunity, Info: http:// autoimmunity.kenes.com 04.09.15 15:12 LT_515_IC_IC.indd 2 03.09.15 12:50 5/2015 CELL SIGNALING TECHNOLOGY EPIGENETICS: DISCOVERY THROUGH VALIDATION 69 CST antibodies for epigenetic-related targets, including histone modifications, epigenetic regulators, and general transcription factors. 22 CST antibodies validated for ChIP according to ENCODE* Consortium guidelines. Validated Tools for Discovery: » SimpleChIP® Kits to facilitate Chromatin IP from cells and tissue. » PTMScan® Kits and Services to enable MS-based discovery of methylated and acetylated proteins. Molecular model of chromatin. www.labtimes.org » Most ChIP-validated antibodies approved for additional applications like IHC, Flow, IF and WB. Learn more at: www.cellsignal.com/epigeneticdiscovery *Landt S.G. et al. (2012) Genome Res. 22, 1813–1831. © 2015 Cell Signaling Technology, Inc. Cell Signaling Technology, CST, PTMScan, and SimpeChIP are trademarks of Cell Signaling Technology, Inc. U FA CT AN U 15PADEPIGNONE0079ENG_00 M TI EN N G P R AC T GOOD RI cGMP CE • CUR R © 2015 Cell Signaling Technology, Inc. Cell Signaling Technology, CST, PTMScan, and SimpeChIP are trademarks of Cell Signaling Technology, Inc. 15PADEPIGNONE0079ENG_00 LT_515_OC_OC.indd 2 03.09.15 13:17