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Editorial

6-2013

Lab Times

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Reproducibility...
... is agreed to constitute a bedrock principle in the conduct Any experienced chemist knows that a [...] catalyst from one and validation of experimental science. Consequently, a scientific supplier may well not be the same as one from another supplier, result is usually not regarded to be actually true as long as it hasnt for example [...]. To pick another issue, HPLC columns come in been reproduced. as many varieties as there are manufacturers how are you supThat is also the main reason behind the clear demand to deposed to honestly list your experimental details if you cant say scribe the materials, methods and experimentation in your publiwhose columns you used? cations always with sufficient detail and accuracy. After all, eveA commenter thereupon added: ry other lab should be able to exactly re-cook your experiments There are few greater insults to my experimentalist personand reproduce your results. ality than I couldnt reproduce your results. I dont believe you. In the real world, however, publications properly fulfilling this And if ACS journals wont let me say where I buy my NMR solrequirement rather seem to be the exception. vents, but so-and-so cant reproduce my purity because their acidA truly disillusioning exic chloroform chews up the material, I dont want my I followed exactly what reputation to suffer. There are other journals I can pubample has just recently been provided by a group of relish in. they wrote But they searchers led by first author And another contribution finally boiled it down to !! never mentioned Nicole Vasilevsky of the Orethe central point: gon Health & Science UniverIf an editor were to ask me to redact the supplier sity. After analysing the manames, I would definitely defend the right to include terials and methods sections the names for the sake of reproducibility. of 240 papers from 80 differGood to hear that there are researchers out there ent life science and multidisciwho do indeed give reproducibility the high value it abplinary journals, they claimed solutely deserves. Unfortunately, one must fear that that in more than half of them they are actually in the minority. Just take the growreagents, constructs, cell lines, ing complaints that ever more papers do present results model organisms, etc. were only via two or three final summarising graphics, for described in such insufficient ways that, as a clear consequence, which several data sets have already been combined, converted, reproduction of the respective results cannot be possible (PeerJ 1: further analysed and processed in a way that no one might ever e148; http://dx.doi.org/10.7717/peerj.148). be able to repeat the underlying experiments. In their paper, the authors wrote: And last but not least, there is another, darker aspect, which The results of this experiment show that 54% of resources runs sharply contrary to reproducibility: intentionally omitting are not uniquely identifiable in publications, regardless of doimportant information by base motives. Quite recently, for exammain, journal impact factor, or reporting requirements. For example, bioinformatician Mick Watson from the Roslin Institute in ple, in many cases the organism strain, in which the experiment Edinburgh meant exactly that when denouncing via Twitter: was performed or antibody that was used, could not be identiPlenty of molecular biologists have made their entire career fied. Our results show that identifiability is a serious problem for from sitting on and publishing their private data. [...] I know reproducibility. plenty who have published [phylogenetic] trees for decades withWell, of course, this finding itself still awaits reproduction and out releasing sequences. independent confirmation. If proving true, however, it doesnt exIntentionally holding back crucial information in order to actly cast a positive light on authors, reviewers and editors as it keep competitors at a safe distance thats the name of this game. would mean that practical reproducibility is actually not regarded Taken together, all this even adds to the 54% non-reproduca key criterion when writing or reviewing a manuscript. ible papers in Vasilevsky et al. No wonder, therefore, one is left Another recent story seems to further feed this suspicion, with the notion that, obviously, only in a fraction of the life sciat least exemplarily. Last March, US pharmaceutical industry reence studies does the published information indeed allow for searcher Derek Lowe in his popular blog, In the Pipeline, reported proper and complete repetition. Not good! that the Journal of Organic Chemistry (JOC) asked authors to remove the names of vendors and manufacturers in their Experimental Sections, over concerns that this might be seen as some form of advertising. Indeed, JOC explicitly states in its Guidelines for Authors that sources of reactants, reagents, and solvents should not be identified. And despite adding three scenarios when, as exceptions to the rule, sources might nevertheless be disclosed, Lowe and his commenters did not understand JOCs move. Lowe himself, for example, wrote:

THIS

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Lab Times

6-2013

Contents

News
Picture of the issue / Former free-to-access plant database starts to charge users / Cell line contamination leads to retraction / Recently awarded / Crowd-funding platform launched / Nepalese institutes win Portuguese Award / UK scientists watch genes in motion as they get silenced____ 6-12

Opinion
Research letter from... England: The Wisdom of the Beasts!____________________________ 13 Observations of The Owl (46): Seeing the Truth_____________________________________ 14 Over the Line? (12): Deadline Daze______________________________________________ 15
Many maize, wheat and potato fields dedicated to GM research lie idle in Europe. Did the anti-GMO protesters win the battle? Is plant biotechnology really dead? (p. 16).

Analysis
Genetically-modified plants Anti-GMO activists sabotage field trials. Is there a future for GM plant research in Europe?______ 16 Biocuration The massive amount of biological data created with modern technology needs to be tamed. A new breed of computer scientist is eager to tackle the task. ___________________________ 22

Journal Club
Vienna/Austria Whats behind the deterioration of mummies in a Sicilian catacomb?________ 28 London/UK How do cells control their shapes?____________________________________ 30 Stockholm/Sweden Theres a certain cardiovascular risk to those out in the cold. Why? ______ 32

Publication Statistics
Chris Bakal and his team discovered that cells can adopt only a limited number of shapes. Are their findings of use for cancer logy? (p. 30). bio

Immunology in Europe_______________________________________________________ 34 Whats behind paper retractions? (19): Doing the Right Thing ___________________________ 37

Biobusiness
News BASF acquires enzyme hunter / Nanion presents another patch clamp robot / Massive attack against cystic fibrosis___________________________________________________ 38 Fetal bovine serum (FBS) la surprise For years, an Austrian lab provider sold nutrient media without informing their customers about a secret admixture of ingredients___________________________________________ 39 Company portrait Switzerlands Devirex pulls on the gloves for an unusual fight against a common disease_______ 40 Oxfordshire Biotech Roundup Is British biotech edging out of recession or are recent successes just a flash in the pan?_______ 43

Service
What is behind the worldwide delivery block on GE Healthcares cell culture media? Your Lab Times reporter investigated and found out an almost unbelievable story. (p. 39).

Product survey: Hand-held dispensers __________________________________________ 48 New products _____________________________________________________________ 55 Methods Tips and tricks of the trade: The neatly organised lab_________________________________ 54 Bench philosophy: Digital PCR_________________________________________________ 52 Book review Genome-Wide Association Studies and Genomic Prediction, by Cedric Gondro et al.__________ 56

Careers
Career strategies for young European scientists (XLV) A frustrated life scientist vents his spleen and has some advice for his peers________________ 57 Job Ads_________________________________________________________________ 60 Calendar________________________________________________________________ 61

Humour
Digital PCR is coming of age. Combining it with the latest techniques in droplet fluidics is making it faster, more sensitive and more affordable. (p. 52).

Paul the Postdoc___________________________________________________________ 06 One fine day in the lab (41)___________________________________________________ 27 Cynical Sid (17)____________________________________________________________ 66 Contact__________________________________________________________________ 46

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Lab Times

6-2013

News

Picture of the issue

Treasures from the Past

Paul the Postdoc

Picture: Unive

rsity Library

ans of the German language and botany, listen up! The University Library Johann Christian Senckenberg, Frankfurt/Main, in cooperation with the Botanic Garden and Botanical Museum in Berlin, recently finished a two-year digitalisation project, making close to 200 rare German botanical journals from 1753 to 1914 available to everybody. At www.vifabio.de/digital-collections/botany, plant aficionados can rejoice in artistic, true-to-detail and colourful hand drawings that, until now, have led a lonely existence behind thick library doors. Project coordinator Judith Dhne from the University Library Frankfurt said that especially experts of systematic botany would benefit from the collection. For them, its now very easy to glance at those rare journals that often are scattered throughout the world and very hard to access. What makes the project even more valuable is the fact that many of the digitalised collections contain first descriptions of species. The Icones plantarum rariorum horti Regii Botanici Berolinensis, published in the 1840s, for example, shows the first portrait of the South American nasturtium species, Tropaeolum moritzianum (pictured left). -KG-

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Lab Times

6-2013

News

Plant database starts to charge users

Recently Awarded
Since 1990, the K.J. Zlch Prize honours scientists for outstanding achievements in basic neurological research. In 2013, the two neuroscientists, Wolfram Schultz, University of Cambridge, and Raymond J. Dolan, University College London, share the award and the honorarium of 50,000 for their work on structure and function of the brains reward system. Schultz wants to relate brain activity to certain behaviours, especially in non-human primates like Rhesus monkeys. Dolan, on the other hand, takes advantage of fMRI and MEGs to study the influence of emotions on decision-making in humans. This year, the Balzan Prize, worth CHF 750,000 (ca. 630,000), was again awarded in four very different categories: Medieval History, Sociology, Quantum Information Processing & Communication and Infectious Diseases: Basic and Clinical Aspects. Pascale Cossart, Pasteur Institute, Paris, won the latter for her seminal discoveries on the infectious lifestyle of Listeria monocytogenes, a food-borne pathogen causing nasty diseases like encephalitis, meningitis and gastroenteritis. Her studies got behind the bacteriums invasion and conquest strategy on all levels: molecular, cellular, tissue as well as on the whole animal level. In 2014, plant and forest ecologists can keep their fingers crossed for winning the next Balzan Prize. Only one European scientist was named winner of a 2013 Lasker Award. Together with Graeme M. Clark and Blake S. Wilson, Ingeborg Hochmair, won the 2013 Lasker~DeBakey Clinical Medical Research Award for her contribution to the development of the modern cochlear implant. In the 1970s, Hochmair and her husband, Erwin Hochmair, designed the first microelectronic cochlea implant with multiple electrodes, improving earlier devices immensely. Today, Hochmair, is the managing director of the Austrian company, MED-EL, selling several types of hearing implants. -KG-

Costly Access
In 2010, Eva Huala, director of The Arabidopsis Information Resource, TAIR, which hosts genetic and molecular biology data for A. thaliana, told Lab Times in an interview Unless a significant source of new grant funding is found, TAIR will no longer exist in two to three years. I strongly believe that subscriptions for academic researchers are not a good idea. (...) We depend on the goodwill and sense of ownership from the community that motivates them to submit data. This goodwill could easily be damaged if we start charging for data that was freely sent to us (LT 2-2010, pp 16-21). Three years later, the database does still exist but the funding problems are worse than ever before, leaving the TAIR team with no other choice but to instate the subscription-based funding model they so badly wanted to avoid. From October on, researchers at companies will have to pay a fee if they want to use the service and in spring or summer 2014 the exact date hasnt yet been determined academics will need to cough up some cash, too. We will ensure that the subscription price is easily affordable for academic scientists, teachers and students, and we will allow a limited degree of data access for those who are unable to pay, the TAIR team reassures. How did TAIR end up in such a financial mess? The US-based National Science Foundation, NSF, initially funded the project with $1.6 million but only to develop and optimise the database. They phased out their financial support after a few years, starting in 2009. In August 2013, the last pennies were transferred and now the governmental source of capital is dry. Although, they tried hard, TAIR couldnt find any suitable alternative way to keep the cash flowing. But money is needed as curating all the valuable data that has accumulated over the years and updating it is expensive. Already in 2010, ten years after TAIRs inception, jobs had to be cut and more followed, Well be cutting back further to the point where new information is added only if its submitted to us by researchers directly, said Huala back then. At the moment, gene product function data is, according to the website, updated every two weeks, while the latest information on gene structures is updated one to two times per year using computational and manual methods. But will scientists really pay for access to TAIR and thus, keep the database going?

TAIR would need to be massively improved in format and speed to make its customers ready to pay for it, Wilhelm Gruissem, plant geneticist from the Swiss Federal Institute of Technology in Zrich, tells Nature. The TAIR team is aware of their shortcomings and is currently working on improvements. It remains to be seen whether their new funding model will pay out for them.

Wrong cells cause paper retraction

Culture Infiltration
News about the retraction of an academic paper reaches the scientifically-inclined reader almost every day. Usually, they are the result of misconduct but, occasionally, a paper is retracted due to honest errors, too. Those cases, however, cause far less stir in the media than fraudulent subreption of a publication. Recently, Nature Methods had to pull through one such retraction; its very first, by the way. Involved were scientists from Switzerland, from the Universities of Geneva and Lausanne. At the beginning of 2013, corresponding author, Ivan Radovanovic became Assistant Professor of Surgery at the University of Toronto, Canada. In their publication from 2010, the scientists developed a method to identify and isolate glioma-initiating cells (GIC) from human glioma or glioma cultures solely based on their intrinsic autofluorescence and distinct morphology. Our data propose an alternative approach to investigate

tumor-initiating potential in gliomas and to advance the development of new therapies and diagnostics, the authors wrote optimistically. Their protocol also impressed colleagues. Wolfgang Wick, director of the National Center for Tumor Disease in Heidelberg, Germany, for example, recommended the article on F1000Prime. Their findings are important as within the glioma hierarchy, GICs are thought to be on top and therefore are responsible for resistance to radiochemotherapy and recurrence,

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Lab Times

6-2013

News

he wrote. To-date, the article has been cited over 30 times, according to Web of Science. There was only one problem, as it has now turned out. The cells, the Swiss scientists thought were glioma cells, were, in fact, GFP-expressing (thats where the mysterious autofluorescence probably came from) HEK cells, a transfection favourite, originally derived from human embryonic kidney cells. The researchers got on to the track of the contaminators, when they tried to verify the identity of their cell lines using short-tandem-repeat profiling. Thorough analysing revealed that the HEK cells had stealthily sneaked into their glioma cultures, derived from primary tumours, over time. Early passages were clear of them. Even though, the problem of cell line contamination has long been recognised (also see Lab Times 3-2011, pp 20-23), not enough is apparently done, yet. But the International Cell Line Authentication Committee (ICLAC), formed in 2012, is there to provide first aid. It aims to make cell line misidentification more visible and to promote awareness and authentication testing as effective ways to combat it. So, before starting a new project, they advise, The simplest way of checking the cell lines that you propose to use is to look in the Database of Cross-Contaminated or Misidentified Cell Lines. The PDF document is linked on the ICLAC website.

Austrian crowdfunding project

Injecting Money
Money makes the world go round, especially the scientific one. But, as we all know, less and less money is provided by the public sector. Hence, crowdfunding, raising money from private donors, is the new magic word. Austria recently opened its first crowdfunding portal called Inject Power (www.injectpower.at/en). The rapidly rising costs of basic research have not been matched by a corresponding increase in government budgets for R&D and the financial situation has become very difficult for many research workers. Our objective is to neutralise this negative trend by recruiting private sponsors for R&D, says project initiator Rdiger Schweigreiter, neurobiochemist at the Innsbruck Medical University. Currently, the portal has four partners: the Ludwig Boltzmann Gesellschaft (a private sponsor of research establishments in Austria), the Natural History Museum in Vienna, the Austrian Archaeological Insti-

tute, the Institute of Molecular Biotechnology (IMBA) and Debra Austria, a patient organisation helping children suffering from the hereditary skin disorder Epidermolysis bullosa. Using the Inject Power portal comes with many advantages for both researchers and generous sponsors. Sponsors can pick their personal favourite project from a well-structured, easy-to-understand database; donations are, at least for Austrian citizens, tax-deductible and the sponsor can remain anonymous, if he or she wishes to do so. Researchers, intending to raise money via Inject Power, need to be affiliated with an institution that is a partner of the portal. If this prerequisite is met, researchers can look forward to fresh funds from private sources; they are offered a platform to present their research to the public, do not need to pay income tax or VAT on donations and, last but not least, can polish up their conviction and advertising skills. Donations can be made by credit card or online banking. The money goes directly to a dedicated bank account, opened by the sponsored researchers. Inject Power deducts a commission of 6.5% to cover the operators costs and finance the further development of the sponsoring portal. At the moment, 11 projects are listed in the database. Arabella Meixner, head of the Stem Cell Centre Gene Targeting at IMBA, for example, collects money to advance novel cell therapies for the treatment of Epidermolysis bullosa. At the time of going to press, the project had raised 110.

reportingguidelines). As experts in their field, many authors assume they already know the best way to report their research findings, but this is not always true, write Amy Ross and Laureen Connell, associate and associated editor, respectively, at PLoS Medicine). For example, a recent survey found that most of the 271 randomly chosen papers in animal research did not report using randomisation (87%) or blinding (86%) to reduce bias in animal selection and outcome assessment Only 70% of the publications that used statistical methods fully described them. In 2010, PLoS Biology, hence, published the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines a checklist of 20 items describing the minimum information that all scientific publications reporting research using animals should include. These guidelines, along with recommendations for the reporting of randomised clinical trials (CONSORT), systematic reviews and meta-analyses (PRISMA) as well as epidemiological studies (STROBE), are part of the PLoS Reporting Guidelines Collection.
Photo: www.publicdomainpictures.net/Charles Rondeau

Reporting guidelines published

Better Writing
Obviously, writing a good scientific paper is not a piece of cake. As many journals provide no or only little guidance, its up to the authors themselves to decide what information is important and what not. That this is not always working out to the best of science is evident from the recent wave of guidelines and tips on how to improve the quality of research reporting. Towards the end of September, for example, the Malta Institute for Medical Education organised the three-day conference How to Write a Scientific Paper. Also PLoS wants to maximise the impact of research. They recently announced the launch of a collection of previously published articles that all deal with reminding authors what to include in their papers (www.ploscollections.org/

Another recently published study takes the same line (PeerJ 1:e148, see also LT editorial on page 3). Here, Melissa Haendel, developmental neurobio logist at Oregon Health & Science University and colleagues, lament the lack of information regarding research resources. When working at the Zebrafish model organism database (ZFIN), I was frustrated at my inability to identify the precise organisms, probes, antibodies and other scientific materials that underpinned genotype-phenotype assertions in the literature. My curator colleagues and I spent enormous amounts of time tracking down specifics that should have been in the publications, even going so far as to call the authors, she said in an interview with PeerJ. In her recent study, scrutinising 240 articles from more than 80 biology journals, she and her colleagues found that 54% of resources are not uniquely identifiable

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Lab Times

6-2013

News

in publications, regardless of domain, journal impact factor, or reporting requirements. So, they put together their own Reporting Guidelines for Life Science Resources: www.force11.org/node/4433. Last but not least, Rowena Murray, professor in education at the University of the West of Scotland, also has a few tips for paper writers, which were recently published by The Guardian. Especially, tip number 10 should be taken to heart: Take care of yourself. Writing for academic journals is highly competitive. It can be extremely stressful. And there are health risks in sitting for long periods, so try not to sit writing for more than an hour at a time. Finally, be sure to celebrate thoroughly when your article is accepted.

Nepalese eye research honoured

Making Blind See


Cataracts, clouding of the lens inside the eye, are the leading cause for blindness

around the world. In countries such as Nepal, incidence of cataract-caused blindness is even higher, nobody knows why. But it is common knowledge that eyesight can easily be restored by surgery. Four Nepalese institutions have distinguished themselves through their efforts to find solutions to the ophthalmologic problems affecting the population of Nepal found the Portuguese Champalimaud Foundation and recently awarded their annual Antnio Champalimaud Vision Award, endowed with 1 million, to the Tilganga Institute of Ophthalmology, the Nepal Netra Jyoti Sangh, the Eastern Regional Eye Care Programme involving the Sagarmatha Choudhary and Biratnagar Eye Hospitals, and the Lumbini Eye Institute. Over the past twenty years, the Foundation explained, the institutions have helped to bring cataract surgery to even the poorest people in Nepal and to those living in the most remote, mountainous areas. At the beginning of the 1980s, only 1000 rudimentary surgeries were carried out per year;

now, that number has increased to a quarter of a million high quality interventions. One of the awarded institutions, the Tilganga Institute of Ophthalmology, located in Kathmandu, is not only a clinic but also has an education and training department, as well as an ophthalmologic bank, storing corneas for transplantation, and a research unit. Its founder and director, Sanduk Ruit, who, together with his colleagues, received the Vision Award from the hands of Portuguese president, Anibal Cavaco Silva, is one of the experts in cataract surgery, known well beyond the countrys borders. Together with Utah-based ophthalmologist, Geoffrey Tabin, who the Dalai Lama has dubbed an Unsung Hero of Compassion for his service to society, Ruit initiated the highly successful Himalayan Cataract Project in 1994. Until now, the two have been doing more than their fair share to dispel the clouds in thousands of Nepalese peoples eyes and, with the Portuguese financial backing, will continue to do so. -KG-

Genetic Congregation
UK scientists watch live as genes come together to be silenced.

hen its getting cold outside, it can be a good idea to cuddle up with your nearest and dearest to warm one another. Caroline Dean and colleagues from the John Innes Centre in Norwich, UK, observed with her own eyes that genes do the same, albeit for a totally different reason. What the scientists study is a process called vernalisation. Certain plants need a period of cold temperatures (like in winter) to prepare themselves for flowering in the spring. The molecular sequence of events is well-described and involves the FLOWERING LOCUS C (FLC) protein, which when expressed represses flowering. When the days get colder, the cell progressively silences the FLC gene through a Polycombmediated epigenetic mechanism. But what exactly is happening inside the nucleus when its getting cold outside? To monitor nuclear organisation and dynamics of FLC during vernalisation, Stefanie Rosa et al. constructed a FLC-lacO transgene and inserted it into Arabidopsis thaliana plants. Then they looked a little closer at the plants root epidermis cells as these cells are easily imaged, strongly express FLC and show cold-induced epigenetic silencing. When the plants were kept at ambient temperatures, the scientists saw many (six or more) dots or FLC-lacO foci lighting up under the microscope. The foci were not localised to any special area of the nucleus, Sometimes (they are) found at one pole in the nucleus of the elongating cells, sometimes in the center, they write.

But when plants were exposed to a chilly 5C for two weeks, the FLC-lacO foci had clustered into one or two foci. These dots were also much bigger than those observed before, suggesting a physical clustering of the FLC-lacO alleles (Genes & Dev, 27(17):1845-50). Still, the dots had no favourite location in the nucleus. Why do the genes get together? It could have something to do with the way they are silenced as Polycomb proteins are known to aggregate into so-called Polycomb bodies, dynamic nuclear structures that bind to specific DNA regions in target genes to repress their transcription. Dean and co. are convinced that physical repositioning in the nucleus may be a common feature of Polycomb-mediated epigenetic silencing in general, not only in plants. What is remarkable about this finding is that we saw genes move in response to changes in the environment, and that this movement seems to be involved in genetic control, says study co-author Joshua Mylne in a press release. What we want to know now is what is happening at these sites where the genes are congregating. () What takes them there and how do the chromosomes move and let the genes congregate? How many other genes congregate like this when they get turned off? Questions that will probably be answered soon.
www.publicdomainpictures.net/George Hodan

-KG-

(More research results from European labs on pp. 28-33)

Opinion

6-2013

Lab Times

page 13

Research Letter from: England

The Wisdom of the Beasts


By our corresponding author, Hoarse Whisper

n England, its become something of an obsession to rank all things educational, from infant school through to university. But apparently, some researchers have now extended this measure of relative abilities to Britains animals. In Spatial cognition and perseveration by horses, donkeys and mules, Britta Osthaus claims that mules and donkeys rank higher than dogs and horses (Animal Cognition vol. 16: 301-5). Osthaus, from Canterbury Christ Church University, says her experiment shows the problem-solving abilities of different species. In this case, donkeys and mules are more flexible in their learning than horses and even dogs. This means there is a lot going on between those long ears. They are not stubborn: they stop and think. The experiment is fairly straightforward. Animals start from the midpoint at one end of a 7 metre wide, 14 metre long arena. They then have to walk unaccompanied to the target at the other end (= a person with a feed bucket). But halfway along, theres a fence blocking the way. To get to the food, the animals have to work out theres a gap to one side of the barrier that they can get through. Animals deal with this set-up between one and four times, then the gap is moved to the other side and they all get four tries at this new configuration. How long will it take the animals to work out that the gap has moved? In total, 36 equids were compared: 12 horses (Equus caballus), 12 donkeys (E. asinus) and 12 mules (the offspring of a female horse and a male donkey), and their results, in turn, compared to a previous study of domestic dogs (Canis familiaris). Two measures of performance were recorded. First, the accuracy rate if they found the gap, they got a point, but if they strayed into the wrong side of the arena, away from the gap, they got zero. Second, their solution times were measured as the time taken to move from the starting point to the gap, ending when the shoulders of the animal passed through.
4bPhoto iStockphoto

Similarly, in their first trial after the gap has been shifted, were told that horses and dogs perform significantly below chance level because only 2 out of 12 were accurate compared to the slightly better 3/12 for mules and donkeys. In effect, it appears that the whole species ranking rests on the shoulders of a single individual one error and they all lose. What about solution times? Donkeys generally worked at a slow walking speed, mules at a faster walk and horses sometimes even at a trot; yet the mules still had the fastest solution times. Mules were significantly faster than horses and donkeys in the first trials. When the gap was shifted, the mules completed the new trial in a mean of 16.75 s, much faster than the horses (44.67 s) and donkeys (56.75 s). This seems like quite a difference but Osthaus now says this is not statistically significant due to the large variation. Yet, she still believes that differences in solution times reflect genuine cognitive differences rather than the physical or possibly motivational differences of the species. But what about their life histories? At an average age of 26 years, the mules were older (and possibly wiser?) than the horses (18) and donkeys (17). Meanwhile, the 12 dogs used had an average age of just two years old. Their data was not even included in solution times due to differences in body size. Only their accuracy rate was compared to the equids. But why did Osthaus use results from just 12 dogs when she had data from a total of 50 in her dog paper (Minding the gap: spatial perseveration error in dogs, Animal Cognition vol. 6: 881-5)? We are informed that the 12 dogs used in the latest study were randomly selected from the previous dataset. Overall, however, the 50 dogs had an average age of 3.8 years. It takes some doing to randomly half the age of your experimental subjects!

Osthaus performed statistical analyses using two-tailed binomial tests on the accuracy rates of the four (single-tailed) species. Mules and dogs performed significantly above chance level in the first trial. But when you look at the data (Table 1), you find this means 10 individuals out of 12 were accurate. By contrast, only 9 out of 12 donkeys and horses were accurate but, for Osthaus, 9/12 is a non-significant result.

Accurate stats

So what are we to conclude from all of these animal rankings? Osthaus states that the general spatial, problem-solving abilities were surprisingly similar in dogs (predators) and in equids (a prey species). It takes quite a leap to compare pet dogs with stabled horses and then arrive at predator-prey analogies! Why not test other large herbivores, like cows or sheep? Or is there a problem with using animals not trained to interact closely with humans? Could training be a key factor to performance? For example, horses that are ridden versus mules that are not. Osthaus concludes that horses, mules and donkeys are used in recreation and sport. Therefore, knowing more about their cognitive abilities, especially their spatial learning and their flexibility, will improve their welfare through adapted expectations by their trainers. Why? Mankind has had a statistically significant association with these animal species for over 6,000 years. Will this new educational ranking really affect the basics?

Predator-prey?

page 14

Lab Times

6-2013

Opinion

Observations of the Owl (46)

hhh, this was a great sumYes, thats true, I agreed, but what about software? Today, mer! After years of just staythey help a lot in filtering out good from bad data and, thus, ing in my cosy little forest finally seeing the truth. For example, several visual attributes can during the warmer months, this now be measured in a cold, unbiased fashion by automated image year the time was ripe to spread my analysis: is X bigger or smaller than Y? Is A brighter or dimmer wings and turn my beak towards a than B? And I am sure its also possible to write a software that, long holiday far from home. on a photo or video, automatically and reliably recognises water After weeks of unstressed surface patterns specifically caused by fish movements, in conflight, I finally ended up in a dense trast to curls and waves due to current, wind or rain alone. jungle on a huge tropical island full I am not sure, Buffy replied. Obviously, algorithms still of strange and sometimes scary anarent very good at textures and patterns. In fact, a very clever imals. And right in the thick of it, postdoc here in my jungle lab had a crack at exactly such a water my old friend Prof. Buffy Fish Owl. It was still dark when I arrived movement video but wasnt able to see the fishes. On the video, but he immediately caught us two big carps from the river... his image analysis software only picked up one of seven fishes I What, me eating fish, you are wondering? Yes, yes owls like could actually see with the naked eye. me do eat fish. I mean, in principle. The point, however, is that we Okay, so eyes are still better than computers, I murmured. normally just dont get any in our landlubber lives. Even if there Yes. I am convinced that in a lot of cases our owl eyes still do are fish-bearing creeks and ponds in our forests, I have to admit a better job than any software. Let me give you another examthat we simply cant catch them. Small mammals from the forest ple. Last year, further down the river, quite a number of fellow floor at night okay. But fish from the water... in the dark? No way! owls had died from infection with a new virus. Back then, we susFor Buffy, however, this was no problem at all. He took off pected that the virus was transmitted by devouring a certain barb from his branch, I heard a short splash in the darkness below subspecies. To confirm this, we collected as many owl pellets as and back he came with a fat carp in his claws. Less than two minpossible from that region, to check whether the local owls had, utes later he had caught the second one. indeed, predominately fed on that distinct barb at the time. Hey Buffy, I said admiringly. I can spot every mouse scutAnd what did you find? I curiously asked. tling around the forest floor at night but Id never ever see any A lot of fish bones, of course. However, the bones of related fish below the water surface in the dark. How can you? fish species resemble each other much more closely than say Well, what shall I say? he replied. Ultithe bones of different dogs. So how were we to The software only picked up 100% reliably distinguish the jaws, vertebrae or mately, its a matter of your eyes, of course... And, indeed! Have you ever seen the eyes of one of seven fishes I could actu- pelvic bones of different barb species? a Buffy Fish Owl? They truly have the most inWell, I suppose scanning the bones with ally see with the naked eye. tensely staring eyes that even I have ever seen. some software was not a possibility, I considMy own owl eyes certainly do appear rather pale in comparison. ered. Perhaps PCR? Just Google a picture of them and check for yourself. The material in the pellets was too highly contaminated to Buffy, however, ponderingly continued, And you have to yield unambiguous PCR results, Buffy replied. No. The only recognise and trust what you see, of course. You just see a faint clue, therefore, was inspection by eye. But not of the bones! The movement on the water, you immediately infer that its a fish, fish scales proved to provide much better material. Again, their you trust your conclusion and take action. You see its like in scishapes were, in fact, almost indistinguishable between barb speence, somehow... cies to computers and owl eyes alike. However, our hope was: Hmm, I mumbled, not sure where his thoughts were going. texture! So, we caught a couple of different barbs and collected Sometimes you are wrong, of course. For example, when the scales. And indeed, when illuwind and rain churn up the water surface you are easily deceived minating them from a certain angle by what you see. Which movement really is a fish and which not? and inspecting them from another, Dyou know what I mean? the specific texture suddenly gave Not quite, I had to admit. only the scales of the barb subspeWell, its like finding the really true results in a sea of data cies in question the exact look of a noise after a series of big experiments, for example. You look at smiling smiley emoticon. the whole huge data set and you know there must be some truth Crazy! I hooted. in it because, well... its certainly in the nature of correctly perYes, totally, Buffy said. But formed experiments to reveal truths. In most cases, however, the in this way, we were finally able to truth is intricately hidden in the bulk of data or the numerous quickly ascertain that the deadly vipictures weve finally collected. The problem, therefore, is recogrus indeed came from that certain nising the truth when we see it in the oceans of data and more barb. Because we trusted our own importantly, realising when, despite the perfect appearance, we eyes. actually dont. Comments: owl@lab-times.org

Seeing The Truth A

Opinion

6-2013

Lab Times

page 15

Deadline Daze N
ero,

My office or Chez Cubbyhole is not a place to be stressed in. It concentrates the outputs of the bodys more visceral responses. Yes, the downside of a state-of-the-art working place is the overload in olfactory or auditory sensory cues. There has been a lingering essence in my office. This is a consequence of the production of the flight and fight response. My circulation has been replete in catecholamine, thus raising heart rate and sebaceous secretions. All triggered by what, you might ask? Well, if I hinted that it related to the annual deadline associated with mobility and movement of those with game-changing potential around Europe, I suspect you might imagine I was referring to a last-min-

Over the Line?

Dispatches Dispatches from from the the borderlands of science borderlands of science
ute, extra-time, dash to compete for a Mary Curry Fellowship Programme. This would be a reasonable conclusion based on two aspects of such submissions. Firstly, there is the stress-inducing sequelae of a late summer, forgotten deadline. However, this difficulty is minor, relative to having to cope with writing a grant in the unfathomable language of Eurospeak. The repetition and banality of documentation makes interacting with a traffic warden seem like fun. These schemes are virtuous, allowing free transfer of young talent across the great continent. However, they are so alien to your average Research Scientist that they now require the background support of a veritable industry of grant support administrators. These are agents that understand or convincingly pretend to understand what needs to be said, so that the grant receivers are satiated. My suspicion is that the grant support teams have been hired from pools of grant receivers and vice-versa. This is a closed shop to rival the French Air Traffic controllers. Dealing with this combination certainly raises the pulse and has potential to sully my microenvironment but is not the reason for my heightened sympathetic tone. My deadline stress rather reflects a distinct but more lucrative exercise in Trans-European Human Mobility. Namely, the movement of elite footballers! Legislation allows players contracted at one club to move to another, during fixed periods of

the year. There is a small window of opportunity after Christmas but the main market runs from the end of the football season until the end of the summer. The open Transfer Window ensures a high wind of press speculation blowing through the summer. This holds us on tenterhooks; as it did this year, well, at least after it was clear that we were going to stuff the Australians at cricket. At the extreme, this speculation can run right up to the deadline day. Indeed, there are deals cut, which make the supporting documentation and accreditations of a Mary Curry award look trivial. So complex are football transfers that they require highly trained Agents: an unusual breed of multilingual, second/thirdhand car salesmen. The big deal this summer was the will-he-wont-he move of Gareth Hail from Totteringontheham to Reel em in Madrid. The club from the country with only 30% youth employment scratched together 100 million euros to secure the services and limited talent of a 24 year old. This all eventually happened on deadline day and the excitement was too much. So, it came to pass that the end of summer was officially marked by a young man, who became the most expensive footballer ever entering a Madrid car park to meet the player that was formerly the most expensive player in the world. Of course Mr Hail arrived and was pictured with his toiletry bag, the most important tool of his trade (http://goo.gl/1J1al9). Not to be outdone, Christine Ronald was waiting with two toiletry bags. Between them they had enough hair gel to lubricate most, if not all, of all Europes Universities greasy poles.

The Transfer window, falling at the end of summer, marks an important and busy time for the car parks of the Ruddy Redbrick. It is the time of year, when the new influx of undergraduates is delivered by their parents to the UK universities. The financial exchange that fosters this may not be on the scale of a 100 million transfer fee. However, the young hopefuls make a substantive contribution in fees, now upward of 10,000 per year. Such money would have only bought you a modest right back when I first started watching football. You would have to go way back to 1928, to find a time when such a fee would break a transfer record when the Arse bought David Jack from Bolt-on. Anyway, this education transaction sees cars aliened with the young hopefuls on the move, as parents transport their offspring to their new academic institutions. The cars display cases, dried food stuffs, tins, pots and pans, duvets and collapsed bicycles; essentials for a successful stay at university. Toiletries are usually hidden but the judicious parent of the budding engineer will insist on copious amounts of underarm deodorant. However, the unifying, common and more obtrusive essential seems to be the giant multi-packs of toilet rolls. As Mum and Dad drive off, the message it seems is clear: That will keep you going till Christmas. I will certainly be in need of some then because that is when the transfer window re-opens and the stress is bound to play havoc with my colonic tone. FintaNOToole

Toilet rolls til Christmas

page 16

Lab Times

6-2013

Analysis

Research with geneticallymodified plants

A European Phoenix?

The bad reputation of genetically modified crops has culminated in the destruction of several field trials. This slows down progress and makes the corresponding research expensive. But perhaps there is still hope for a change in attitude.

8 goj888 /doma : Fotolia Picture

Analysis

6-2013

Lab Times

page 17

he debate about genetic modifications, in Germany as well as in Europe, is blocked and thus actually resolved, said Wolfgang van den Daele in a video statement for the web platform Pflanzen-Forschung-Ethik (Plants ResearchEthics). With this statement, the retired professor of sociology at the Freie Universitt Berlin implies that the opponents of genetically modified (GM) plants have finally won over public opinion. However, is European plant biotechnology really dead? When talking to people conducting field trials you will definitely get this impression. An extreme example occurred in 2008 at the Hochschule fr Wirtschaft und Umwelt Nrtingen-Geislingen. In the town close to Stuttgart, Andreas Schier, professor for applied plant biotechnology, wanted to conduct a field trial with the maize variety MON810 from the agrobiotech company Monsanto, which was genetically engineered to produce the insecticidal Cry1Ab protein from Bacillus thuriengensis, on the Universitys own farm. He had done similar field trials in previous years. And as always, Schier had all the permissions and was ready to proceed.

One day, however, some protesters occupied the field and blackmailed the university to stop the trial. The university administration gave in and, according to their own press statement, strongly recommended Schier to stop his trial. The vicechancellor of the university even ordered a ban on GM-field trials during his term that from then on lasted another five years. The mood on the matter in the local press and politics was so bad that a proud university, once founded as an applied agricultural research institution, gave up its own freedom of research. Protest from 160 of its students did not change anything. The local press hailed the victory. Many people at the University were pleased that this was over, Schier says laconically. Only the national press was more critical: The Frankfurter Allgemeine headlined Geopferte Forschungsfreiheit (Sac rificed Freedom of Research on 22 April, 2008 and Zeit Online called it a Gene Scandal (20 April, 2008). The mood has become even less favourable for GM plant research with the new green government in our state Baden-Wrttemberg, Schier bemoans. Now, in 2013, Schier would be allowed to conduct field trials but he is not motivated to get into trouble again for the

University yields to protesters

ban was just the surface of it all. Schier received abusive e-mails some even stating that he should be hanged. Only five out of his 13 trials in the previous years were not destroyed. Across the whole of Germany, a total of 23 sites were destroyed in 2006 alone. Between 1996 and 2006 it was an average of ten per year. In a trial near Munich, waste oil spilt on the field showed that the motivation for GM plant opposition cannot only be the protection of the environment. Researchers from other European countries suffered from similar actions. In Switzerland, only two field trials were conducted at all after 1992 with wheat resistant against the fungal diseases common bunt and powdery mildew. One field was highly besieged by Greenpeace activists; the other one was finally destroyed by unidentified vandals. In the Netherlands, only three out of 24 field trials were destroyed between 2008 and 2013. Protecting the sites is very costly for the researchers as well as for the police. For the Swiss wheat trial in 2008, for each euro spent on the research, 78 cents had to be spent for the unsuccessful protection against vandalism, 17 cents for the supervision and 31 cents for biosafety measures demanded by environmental authorities (and deemed unnecessary by the scientists). In the most cases, the vandals cannot be identified and when they can, judges only declare low money sentences. This is in no relation to the time and effort demanded from the scientists to estimate the loss. As a consequence, the demand for field trials in Europe has constantly dropped from over 100 in 2009 to just 20 in 2013. In Germany, not a single one is planned for 2013.

ruses, genetic engineering in medicine and air pollution by cars. This harsh rejection has left plant bio technologists clueless. Central to the opposition is certainly the belief that GM plants are unnatural. Along the same lines, the consumption of potatoes was initially seen as a sin when they entered Europe in the 16th century. Or take the case of Liechtenstein that opposed the adoption of hybrid maize in 1952. This kind of religious emphasis toward food can still be found today for example, when the British smoothie producer innocent places a halo above the face on their logo, or when the Swiss restaurant chain not guilty puts angels wings around theirs. This seems particularly strange in societies as supposedly enlightened as those in Europe. And thats mainly why most experts agree, it cannot be just the mere lack of information that has led to the great degree of opposition to GM crops. They believe another deep root lies in a common lack of trust in the respective scientists, who are believed to be dependent on the industry. The social scientist Monika Kurath, for example, showed in her PhD thesis at the University of St. Gallen in 2005 that the timing of bringing scientists into the risk debate was crucial. Today, however, Kurath is less convinced of her own conclusion and rather states that there is no single, most important reason why the perception of scientists and the public is that different.

Interestingly, citizens largely accept application of gene technology for medical use. But GM food somehow seems to instantaneously conjure up the vision of Frankensteins monster. In the 2010 Eurobaro meter studies, for example, only 23 percent wanted to promote research into GM foods, whereas 61 percent voted against it. Similar results have been repeated in other studies over and over to-date. A survey from August 2013, conducted by the sociologist Andreas Diekmann of the ETH Zurich, revealed that 53 percent of the Swiss considered the cultivation of GM-crops very or extremely dangerous. Cultivation of GM crops came in third position on the list of global threats, behind nuclear power and terrorism and ahead of climate change, new types of vi-

Religious opposition

One reason, of course, is that there is a rift going through science itself. Many scientists working on biodiversity topics are opposed to or, at least, very sceptical about the cultivation of GM crops. Primarily, however, this opposition turns against the nonsustainable agricultural practice obviously promoted by the most widely-used GM varieties. And in addition, scepticism often also comes from the political sciences where small-scale subsistence farming is seen as the better solution to feed the world than large-surface industrialised farming, where GM plants are mostly employed today. These questions, however, have nothing to do with genetic modification itself. In fact, most academic GM researchers probably see themselves as actually working and developing towards a sustainable development. New plant varieties are desperately needed if we are to feed an estimated nine billion people at affordable prices in 2050, write, for example, Peter Stamp, retired professor of agronomy at the ETH

Conflict within science

page 18

Lab Times

6-2013

Analysis

Zrich, and Richard Visser, head of the Plant Breeding Laboratory at Wageningen University. Altogether, they list seven constraints that make it hard to achieve this goal: climate change, loss of arable land, use of land for biofuel production, scarcity of water and phosphor, increasing demand for meat in Asia, industrial interest limited in a few crops and food preferences limited to a few crops (Euphytica, 186: 585-91).

Some individuals, however, in academia play a strange game when conducting risk studies. The (in)famous recent GM-fedrat-study of Gilles-Eric Sralini et al. is only the tip of the iceberg, despite being a very ugly one. Sralinis team were using rats with a high propensity to develop cancer, so that toxic effects of chemicals are quickly revealed. Nevertheless, they fed the rats GM maize resistant against the herbicide RoundUp together with the herbicide itself in a two-year, long-term study. In the end, Sralini and co-workers shocked their audience with photographs of such rats that had developed ping-pong-ball sized tumours. However, by basically using ridiculously low numbers of control animals and, moreover, not conducting any statistics on general rat mortality or tumour appearance, the Sralini group was finally able to cherry-pick the most dangerous-looking flukes (Food Chem Toxicol, 50:422131). In addition, Sralini refused to publish the detailed diet of the rats. To top it all, he finally broke the press embargo and was thus able to launch a successful media coup, even before their study was officially published. If you look more closely, the stories of the scientific consensus reached on genetic engineering and of the one on climate change are remarkably similar just from opposite camps. In climate science, the consensus is that the climate is dangerously warming and a few scientists continue to present unimpressive data to question the whole consensus. Thus, the fossil fuel industry happily quotes outliers and confuses the public. In genetic engineering, the consensus is that there is no inherent danger in altering the DNA content of organisms and, more specifically, that it would be irresponsible not to use the technique to assist plant breeding. Here, however, special interest groups for the environment, like Greenpeace, for small scale farmers and for development aid happily quote the work of outlier Sralini and the like. In a letter to the editor of Nature Bio technology titled When bad science makes

Unfair risk studies

Frightens crows away from a maize field but not the anti-GMO activists...

good headlines: Bt maize and regulatory bans, the Swiss biosafety researcher Jrg Romeis and two US-American co-authors denounce these poorly designed studies. They write, Despite a preponderance of evidence, a few outlier studies claiming adverse effects of Cry1Ab to non-lepidopteran species have been the subject of persistent media coverage and often undue consideration by regulators. In the majority of cases, the wrong or no controls at all are used in those studies, or the test substances are not characterised for their activity. But even if the study conclusions do hold true, claim Romeis et al., authorities should check whether the reported effect is new and whether it is a real danger for the receiving environment (Nature Biotechnol, 5: 386-7). Since mid 2013, for example, the European Commission has been asking for mandatory rodent feeding studies, irrespective of the type of GM plant used meaning that data about this aspect must abound.

While the rest of the world, mainly the USA, Argentina, Brazil, India, China and Canada, steadily increase their surfaces to grow GM crops, Europe is continuing to debate unlikely risks. The Swiss, for example, in 2005 cautiously voted for a fiveyear ban (moratorium) on the cultivation of GM plants and the parliament has since prolonged it twice, until the end of 2017. The situation in the EU is more confusing but equally GM-unfriendly. Between 1998 and 2004, no new GM plants were given access to the EU import market or EU fields.

Europe in a bad mood

This de-facto-moratorium was finally lifted under pressure from the USA, arguing that this was an unfair trade barrier and, therefore, violates free trade treaties. Today, the European Commission still does not process GM plants cultivation authorisations from biotech crop industry, as EU member states cannot agree on either allowing or banning GM plants completely. Apart from Switzerland with its ban on any cultivation, many other European countries have imposed a ban of cultivation on certain products, which, in fact, are authorised in the EU. Most noteworthy is Switzerlands neighbour Austria, who banned GM plants more or less completely. But also France, Germany, Poland, Hungary, Luxembourg, Greece and Italy have banned cultivation of the otherwise EU-approved Btmaize MON810. Only Spain and Portugal show a considerable cultivation of MON810 maize. This legal situation in Europe leads to confusing or rather amusing events. In September 2011, the European Court of Justice ruled that pollen is an ingredient of honey. This means that honey containing more than 0.9 percent of GM pollen of an unapproved GM plant in Europe cannot be imported but this is currently impossible to measure. It would also mean that pollen should also be added to the list of ingredients on the honey packaging. Another situation emerges when a GM plant is not (yet) approved for import into the EU but trace amounts are detected on the bottom of shipments. In these cases, the whole shipload has to be sent back, result-

Photo: Fotolia/onepony

Analysis

6-2013

Lab Times

page 19

ing in peak rises of prices for livestock feeding material and the loss of millions to the shipment company. A related problem is Europes increasing dependence on protein-rich soya imports to feed its livestock. As more than 80 percent of the worlds soya production comes from GM plants, feeding livestock becomes more and more expensive in Europe. Furthermore, most consumers of meat are completely unaware of this. In April, British retailers Tescos, Sainsburys, Marks & Spencer and the Co-op announced that they are now permitting GM food for their poultry, after having banned it for more than ten years.

Altogether, the ever-tightening rules, the constantly shifting goal posts, the outright bans, the lack of consumer acceptance and the destruction of field trials certainly make Europe a bad place for the biotech crop industry. Add the bureaucracy! The European Food Safety Authority (EFSA), a panel of scientists, checks the

Agroindustry is giving up

safety of GM crops for authorisation and hands its opinion over to the European Commission. Here, a proposal for the authorisation decision is made to the Standing Committee on the Food Chain and Animal Health, which must accept or reject the decision with a qualified majority (corresponding to two-thirds of European voters). The Council of Ministers for agriculture and fisheries then has to adopt or reject the decision. At each step the whole process can come to a halt, mostly meaning that no decision is taken, what practically comes down to a rejection. In this confusing situation, even court rulings in favour of the biotech crop industry usually dont have any real world effect. Not least because of these complications, BASF abandoned their programme on starch-accumulating GM potatoes (Amflora) for the paper industry in Europe and, in January 2012, moved their centre for plant science to the USA. Monsanto announced in July 2013 they are to stop all their market approval applications in Europe except

for the reapplication of MON810. Syngenta had moved their GM research to the USA as early as 2004. Monsanto and Syngenta, nevertheless, continue to sell agrochemicals in Europe. Usually it is seen with benevolence when universities perform research that leads to applications in industry. In GM research, however, working together with the industry is exclusively seen as a threat to academic independence. For PhD students who do not want to stay in academia this can constitute a big problem. For someone who wants a job with a direct link to plant biotechnology the choice in Switzerland is limited, says Christian Hardtke, professor for molecular plant biology in Lausanne. Most of them have to leave Switzerland and, presumably, Europe as well.

So, it does indeed look like plant bio technology is slowly dying in Europe. In Rothamsted Research, an agricultural research centre 20 kilometres north of Lon-

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page 20

Lab Times

6-2013

Analysis

don, the conflict between protesters and scientists took a surprising new twist in 2012. Toby Bruce, senior scientist at Rothamsted, and others tested a new va riety of GM wheat containing three enzymes, to produce the sesquiterpene E-farnesene. Many years earlier this substance was shown to repel aphids and attract aphid predators in potatoes also at Rothamsted, which claims to be the oldest agricultural research station in the world. Around the beginning of April 2012 some anonymous protesters with the name Take the flour back announced on a website, on Twitter and on YouTube (http:// youtu.be/u5_5dF9Fw8k) that they were planning to decontaminate the site. They called for mass action on Sunday, 27 May 2012. Despite a long tradition of destructive protest against GM field trials Bruce was not really expecting threats of crop destruction. We considered our approach as a more environmentally friendly approach than using insecticides to control pests and therefore were quite surprised that some environmentalists were against it. The researchers tried to contact them via e-mail and the social media. We would be pleased to provide some space for you and a platform where representatives from your group and Rothamsted could present their perspectives on this issue, they wrote. As they did not receive a response the scientist recorded a very personal video plea urging the protesters to come in the spirit of openness and dialogue. They said: We know we cannot stop you, but please reconsider before its too late and before several years of work, to which we have been devoting our lives will be destroyed forever. (http://youtu.be/I9scGtf5E3I)

This kind of destructive protester repellent seems to have worked fairly well. The British charity Sense About Science launched a petition named Dont Destroy Research; they collected over 6,000 signatures from academics and many other people as well. The mass media were really talking about the destruction of valuable science rather than only repeating the arguments of the three decades-old debate. In the end, only around 200 protesters with mostly confusing arguments appeared and thanks to a strong police presence, they were unable to do any damage to the wheat field. Maybe this success in the defence of a scientific experiment marks a turning point in European attitudes towards GM crops.

...of indomitable scientists

In a survey commissioned by the British 1990s, and thereby assisted in demonising Science Association the number of people an important technological option, which very concerned and fairly concerned can be used to benefit the environment. by genetically modified food fell by five Lynas explained how facing climate change percent to 46 percent between 2003 and denialists forced him to become more sci2012. At the same time, the number of peoence literate, what finally caused a probple not very concerned and not at all conlem for him: For me, this anti-science encerned rose by eight percent to 25 percent. vironmentalism became increasingly inconThis is also roughly the number of people sistent with my pro-science environmental(27 percent) that agree or totally agree that genetically modified food Quo vadis, GM plant research? should be encouraged. These numbers might be very theoretical but they correspond to the results of a Swiss study performed in 2008 during a national research programme on the risks and benefits of releasing GM plants into the field (NFP 59). In a real world experiment, real market stands sold real maize bread. Customers did not know that it was an experiment and were presented with three real choices: bread from conventionally-farmed maize, organic maize or GM maize (Bt11 maize, legally imported from Spain). All information was clearly indicated. A total of 23 percent bought at least one loaf of GM bread. Even when the price was as high as for organic bread, 20 percent were still buying it. Sales increased by 30 percent ism with regard to climate change (http:// when GM bread was present on the stands. vimeo.com/56745320). Of course, curiosity might have played There seems to be hope that others will an important part but, apparently, most follow. The challenges that humankind people do not care at all about the prehas to face in the future are enormous. But sumed danger of GM food in supermarkets. solely developing GM crops will not solve In fact, voting behaviour in the moratorium all food problems either. Like most plant was barely linked to the consumer choice biotechnologists today, Toby Bruce from in the experiment (Food Policy, 36:830-8). Rothamsted is modest about their potential: The green side of life We see GM technology as part of the mix Another encouraging fact is that some of potential solutions. However, Bruce and environmentalists are gradually becoming all other biotechnologists want to develop alienated by the irrational anti-science becutting-edge technology together with the haviour of their fellow activists. The most rest of the world. The current political situfamous example is Mark Lynas. The author ation in Europe makes it difficult and frusand environmental activist apologised at trating for them. They all, like Bruce, hope the Oxford Farming Conference in January that the debate is becoming more rational 2013 for having spent several years ripping and based on good scientific information. up GM crops and that he helped to start the anti-GM movement back in the mid Florian Fisch
Photo: Fotolia/Edler von Rabenstein

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Biocuration an emerging field

The Future of Big Biological Data


Data explodes in the post-omics era in biological databases and literature. Computer and Life Scientists are in a semantic cold war. Biocuration emerges as a new resort for the data and the scientists.

re you a bioinformatician holding this magazine to get to know thy neighbours? Or, are you contemplating leaving the field but, before quitting, have accidentally found this article and want to see what all this fuss is about? Whatever the reason, welcome! You are certainly not the first one to ponder, Should I leave bioinformatics? A few months ago, I happened to come across a polemic rant by former bioinformatician, Fred Ross. I am not sure, if its a pseudonym. However, he vented to the world that he was about to kiss goodbye to bioinformatics, to work in the software industry (http://madhadron.com/a-farewellto-bioinformatics). There were, and probably still are, some vehement responses to his outburst. Although he calls the public opinions a group monkey dance, if you read his words of fury, whether as a bioin-

formatician or a biologist, you may think, this guy might have a point (http://madhadron.com/public-comments-consideredharmful). Really? Well, yes and no! Whatever; the bee-hive that Ross had disturbed must calm down sooner or later. I would like to represent, on behalf of some of the concerned voices for bioinformatics.

The problem is neither with the biologists nor the bioinformaticians. Since they are used to their schools of thought, as naturally as breathing, we can only blame the language used by either groups of scientists. You might have read of our Lab Times Owls concern about this misunderstanding, from Goshawks story (Lab Times, 2-2013:16). But how serious is the problem? Quite serious! With evolution in experimental techniques, from microscopy to spectroscopy

Big-data and the semantic war

and sequencing, biologists, with little foresight, began accumulating data. When there was too much data for them to handle, they sought the help of computer scientists to make space for the data, and thus the era of biological databases and bioinformatics began. Furthermore, they asked for their expertise to automate the mathematical processes to find meanings from the big-data. This data deluge is a problem for not only biologists but also physicists and chemists. The physicists, however, do not seem to have as great a language problem as the biologists, and to an extent also the chemists. Why is it so serious for biologists, though? Are they poor in communicating what they want? Or, are computational scientists too stringent in their strategies and methods? Or could it be the other way around? The answer is yes to all the questions.

Andy Picture: Fotolia/ Dreaming

Analysis

6-2013

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Any science is stochastic and especially biology is, in addition, complex too, with several natural sub-systems at work for life to begin or carry on its journey. Mathematically it takes a lot of time, effort and energy to correlate and corroborate the meanings of the data, to reach a conclusion. At the same time, it is only possible to think of new ideas or to form new theories if we can analyse and understand the big-data. Computer scientists might not be intuitively aware of that nor might biologists have the inclination to explain this to them, in their relentless journey towards a different strategy or method. Computer scientists, in return, might have intimidated the biologists with their numbers, equations and their precious, unnatural programme codes. Somewhere, this must have stirred up a distasteful concoction for the two. The result is a mistrust or aversion towards each others fields.

Realising that the problem is due to the accumulated big-data, the databases, the networking caveats and the data redundancy, biologists and computational biologists started their congregated work on manual and automated curation of databases (Nature, 455:47-50); in the same way that the museums were curated decades ago. Curation does not only mean collection, storage (or preservation), and collating authentic information about the specimens or the data. The job is also to maintain the museums, i.e., the databases, by annotating, tagging, verifying and showcasing the information, by default or when queried. Just imagine all these activities with the super computing power and the internet! This plethora of activities makes biocuration, a promising field that writes the future of biological data and the discoveries thereof (www. biocurator.org/what.shtml). Then, how does the future look for biocurators?

Cube Biotech

In fact, with the borrowed words of our wise Owl, it is time to realise that bioinformatics and bioinformaticians can make real discoveries. Although there was an initial language problem between the two schools, thanks to the scientific temperament, neither of the groups ceased to work on the solution. And the result is the currently emerging, new face of bioinformatics: biocuration! The International Society for Biocuration (ISB) is an asylum for it (www.biocurator.org/mission.shtml)! It is quite depressive to think that we are spending millions in grants for people to perform experiments, produce new knowledge, hide this knowledge in an often badly written text and then spend some more millions trying to second guess what the authors really did and found. These words of Amos Bairoch, a biocurator and an eminent bioinformatician in Europe, clearly express his concern over the fate of the biological data and databases (Nature Proceedings, 2009). However, to define the purpose of the field, I will adopt the words of Alex Bateman, from the Wellcome Trust Sanger Institute, Cambridge, UK, who is also an ISB board member: Biocuration [is] the transformation of biological data into an organized form. It is only achieved through the combined efforts of the experimental community who generate the data, the biocurators who organize the data, and the software and database developers who make the data available for all to use (Bioinformatics, 2010; 26:991).

Depressive second guessing

As asked at the beginning of this article, if you are intending to shift your career from wet bench to electronic bench, to hold mouse and keyboards instead of pipettes, and yet be connected to both biology and computers, then biocuration is the field for you (Database, bar059). Now let us hear from some of the rare breeds of biologists, who are already finding alternative pleasures from life science and computers, alike, curating electronic museums. In 2011, they told Nature their stories (470:295-6). Klemens Pichler is a biocurator at the European Bioinformatics Institute (EBI) in Hinxton, UK. After a PhD in Virology and a brief period of postdoc experience, he stepped into this field. As a bookworm, he says, he finds the desk job of writing programmes for curation exciting. Judy Blake, a principal investigator of the Mouse Genome Informatics project at the Jackson Laboratory in Bar Harbor, Maine, says that if you want to be a generalist in life sciences and computers, then you could make a good biocurator, because, according to her, there is no stress on publications or funding in this field. Sandra Orchard, a senior biocurator at EBI, points out that you mainly need to have prior experience in laboratory research because you shall most often have to talk to the scientists when you are working on databases or their entries that exist, thanks to their research and publications. If you are curious to keep up with the progress in this field, you may want to start with the PLoS (Computational Biology) Col-

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lections on biocuration. In addition, it is worth browsing through the pages of the dedicated journal, Database: The Journal of Biological Databases and Curation. The journal publishes novel ideas in database research surrounding biological information,

I was searching for a particular gene or protein in the relevant databases, I used to get results with discrepancies. The sequences remain the same but the identities are different. Also, I used to find papers from different groups on the same gene. Nowadays,

informaticians, we can understand that: biocurators have to mine the different types of data from various databases online; using text mining strategies, and of course with their computer programmes, they also mine the scholarly literature relevant to dif-

it provides a platform for the description of novel advances in the field of biocuration, and promotes the use of information from biological databases to assist in the planning and design of original research projects (http://database.oxfordjournals.org). You may also browse through the virtual issues on the proceedings of ISB conferences (www.oxfordjournals.org/our_journals/databa/biocuration_virtual_issue.html).

If you are an ardent pursuer of an alternative life science career, this might encourage you: the field is gaining attention, not only in the universities but also as a business in industry. There are companies like the California-based Ingenuity Systems (www.ingenuity.com) and the Cambridge, UK-based Genestack (www.genestack.com/ about). But wait! Better get to know the cats inside the bag! While having a casual chat about biocuration with a life science researcher friend, who often uses bioinformatics for her work, I got this statement: not long ago, when

Cats in the bag

this seems to be reduced. I didnt know then what was happening but was wondering about it. So, is this what biocurators do?... Quite a helpful job for us and our geeky chat continued. But I was somewhere else in my thoughts, wondering; it would be nice if the biocurators would release a generic handbook about the field, with a detailed glossary. Curious folks often hear several keywords on biocuration, such as annotation, core attributes, workflows, ontologies, semantics, etc. Although one could make literal and contextual guesses at the words, and what they could mean, it does not hurt to make sure that what we guessed is correct. After all, through the ages, language problems have been fundamentally solved by good old dictionaries. So, why should we not have one for biocuration? Until such time, we shall have to make do with important keywords that form the pillars of biocuration data mining, text mining, ontology development and semantic integration. Since we have been handling these words for quite a while, along with the bio-

ferent database entities, such as protein or nucleic acid sequences, micro array data, microscopic images, whole genome and proteome data, and so on; if they are not sure of whether there are discrepancies between the database entries and the literature, then they have to contact the concerned scientists and sometimes have to work with them, to write computer programmes. Using these programmes, the computers look for discrepancies, with the help of various internet agents (again programmes). Then, in turn, the biocurators have to write programmes to develop ontologies (definitions) seman tically. If these all sound abstract, you may have to wait until we discuss some examples from the literature library of the Biocurators.

But for now, it is important to know that biocuration will not be successful if there are no ecosystem or community activities among all the groups of experts involved in the problem of (biological) big-

Community curation

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data. Networking through specific biocurating activity portals like EBI, or community web services like Wikis, or public professional networking sites like LinkedIn, is one of the ways to encourage the participation and interaction of the experts, on

BioCreAtIve is a community web service for any interested individual to participate and extract information from biological scholarly literature by text mining, thereby contributing to biocuration (Database, bas037; www.biocreative.org).
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the Web. B ioSharing is a group of 31 communities, so far (www.biosharing.org), including curators (e.g. ISB), publishers (e.g. BioMedCentral), websites of literature da tabases and portals (e.g. Europe PubMedCentral), Web Services (e.g. BioCatalogue), Creative Commons for Science, and so on. Each of these communities have their respective roles in contributing to curation of biological data through data-publishing, data-annotation, semantic and syntactic annotation of literature, literature curation, and community web servicing where scientists, curators and developers can search, interact and curate. The underlying theme of these community activities are data sharing, upon trust, for better tagging and annotation of data with the literature and the respective databases. BioDBCore is an initiative by ISB to define standard categories, strategies and methods to curate databases for better interoperability, thus paving the way for curated data annotation and integration (Nucleic Acids Res, 1-4; http://biodbcore.org).

BioCatalogue hosts all sorts of web activities and services for life science researchers, bringing the relevant web service providers and their world users together (Nucleic Acids Res, W689-W694; www.biocatalogue.org). Tadashi Imanishi, a curator at the Biomedicinal Information Research Center in Tokyo, says that as of 2011, there were some 100 biocurators from Japan, thanks to the joining of curating communities worldwide by ISB (Nature, 470:295-6). These are just a few examples to mention, of the community initiatives for biocuration (http://colleagues.biocurator.org/affiliations).

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ferent experts in each step of the work flow (Database, bas036). For instance, a bioinformatics research group may provide annotation tools for databases or literature and another group or a company may provide semantic tools with different ontologies for specified databases. WebApollo, for example, is a web- based community tool for visualising and editing sequence annotations, developed collaboratively by experts from different groups in the Lawrence Berkeley National Laboratory, University of California, Berkeley, and University of Missouri (www.gmod. org/wiki/WebApollo). Attila Csordas and colleagues at the EBI, Cambridge, UK, have provided workflows for the PRoteomics IDEntifications (PRIDE) database for data quality control and integration with primary databases like UniProt (Database, bas004).

Cambridge and University College London, UK, have provided FYPO, the fission yeast phenotype ontology, to computationally describe the phenotype data of yeast (Bioinformatics, btt266). For better biomedical discoveries, a comprehensive taxonomy of diseases, their taxonomic rationale, integrating this information with the data and literature, and suitably annotating them become vital. Hence, developers design data mining architectures to integrate such data and the relevant information. Take, for example, the work of Allen Davis, with his folks from the Mount Desert Island Biological Laboratory, Salisbury Cove, USA. They have contributed to the biocuration community with a practical disease vocabulary, MEDIC, at the Comparative Toxicogenomics Database (CTD) (Database, bar065).

Picture: Cambridge University Library

Long gone are the times, when a simple lab notebook was enough to store all your hypotheses and experimental data as Darwin (see above) did.

trometry data for proteomics, or micro array gene expression data for systems biology. If we look beneath the fabric, we shall be overwhelmed with the varied strategies and methods the biocurators adopt, with the data type they curate. If you are curious, browse through the issues of Database and you may be amazed. Let us go through a few examples. Since it is a language problem among the experts, one of their primary duties is to bring on their specific workflows for curation. Workflows can be compared with the lab protocols for experiments. Every time the protocol fails, the flows are modified; and when it works, certainly the work shall be repeated for concordance. For biocurators, contribution comes from difPhoto: www.publicdomainpictures.net/ Petr Kratochvil

Modern biology encompasses mutation studies on model organisms, from recombinant expression of desired proteins or metabolites to creating disease models. Describing the resultant phenotypic changes upon varied degrees of mutations is indeed challenging. And the resultant descriptions may certainly have semantic and ontological discrepancies. Based on the phenotypic data and the information, for better curation through computation, developers bring out specific phenotype descriptions. For instance, Midori Harris and team from the University of

A disease vocabulary

Literature annotation and curation are indispensable for biocuration, for better data-literature integration. Using several semantic web and publication approaches, experts work on various annotation tools or schemata. For example, Karin Verspoor and her interdisciplinary research team from the University of Melbourne, RMIT University and the Royal Melbourne Hospital, all in Australia, have brought about a Variation Annotation Schema to conveniently catalogue and interpret human genetic variations and their relationships to diseases, with reference to the relevant literature (Database, bat019). It is common in biology to use data from different experimental methods, such as microscopy and sequencing. In such cases, the data shall certainly be deposited in respective databases. To integrate such data, an important criterion in biocuration is database interoperability. Developers work on devising tools for, for instance, community annotations to link such data. If you click on the work by Andrew Oberlin et al. at the Miami University, USA, you shall be a wit-

Linking databases

Important Internet Links


The International Society for Biocuration www.biocurator.org Database journal http://database.oxfordjournals.org Biosharing www.biosharing.org BioDBcore http://biodbcore.org BioCreAtIve www.biocreative.org BioCatalogue www.biocatalogue.org

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ness for their BioDIG, a community annotation tool to link databases with images and genomic data (Database, bat016). You might also want to take a look at one such image database at www.cellimagelibrary. org. Although often drawn into the light of ethics and logical controversies, animal models are used a great deal, to relate disease phenotypes with those of humans. In those cases, scientists have to rely on such translated results from the data on the animal mutational (disease) models. Developers also write programmes to semantically annotate, integrate and link different data, like gene sequences related to human and animal diseases, and link the phenotypic information suitably. One such example is PhenoDigm, developed by Damian Smedley and his international team of colleagues from Wellcome Trust Sanger Institute, Cambridge, UK; Universittsklinikum Charit, Berlin, Germany; University of Oregon, USA; and Lawrence Berkeley National Laboratory, Berkeley, USA. The tool, mathematically automates the data integration from varied model animals that support gene candidates for human genetic diseases (Database, bat025).

tinue for many more years, biocurators, the modern bioinformaticians, who came together and formed this new discipline, are finally able to put their skills to good use on a mega scale. They can convince us that this field is trying to settle the language problems between the concerned experts. Unfortunately, biocuration is reportedly reliant on volunteering services from the academics and still needs recognition by the funding agencies. Contradicting Judy Blakes point about stress on funding, Owen White, a bioinformatician at the University of Maryland School of Medicine in Baltimore, opines that biocuration longs for a better recognition from funders. He says that the agencies should consider the curation costs for the projects funded (Nature, 470:295-6).

One step and youre done.

Biocuration activities are certainly not new. Ever since the dawn of computation of data accumulation, storage and analysis in biology, scientists have been doing this on a small scale. Since there has been a data explosion in recent decades, which will con-

The future for biocuration

Some commercial enterprises also attend the biocurators but anyone can guess that there is only a slight distance between their commercial monopolies and the community activities for the betterment of bio logical discoveries. Thus, life scientists, computationists and funding agencies have the levers of biocuration, so that may govern the speed of development of the field and the direction in which it paces. We have no other option but to wait and watch, besides continually working towards the resolution of this big-data and language issues.

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Bioarchaeology in Vienna, Austria

Where History Meets Biology


For hundreds of years, mummies in the Capuchin Catacombs of Palermo have been resting in peace preserved for eternity. But during recent times, microbes have been giving them a hard time. Can life scientists like Guadalupe Piar help curators stop the mummies decay?
un-swept serene beaches, awe-inspiring architecture, the delicious cuisine and a rich historical heritage attract thousands of visitors to Palermo in Sicily every year. At first glance, this would be the perfect summer destination for any tourist, so what would a team of Austrian and Italian biologists be searching for in this Italian city? The Capuchin Catacombs of Palermo or Le Catacombe dei Cappuccini house a collection of more than 1,800 mummified bodies hailing from the 16th to 20th centuries AD. The relics here include notable members of the clergy, military and nobility, and provide a glimpse into history, into how people lived back then. Sadly, the very survival of this collection is in peril, as time and the forces of nature have taken their toll on the mummies. Katja Sterflingers research group at the for all molecular analyses the project particVIBT-Department of Biotechnology,Univeripants performed for this study. sityofNatural Resourcesand Life Sciences, What is now behind the mummy deinVienna(Austria) and the European Acadcay? A first assessment of the catacombs emy of Bozen (EURAC) Institute for Mummies and the Iceman, inBolzaMolecular biologists and mummy preservationists: no(Italy) took up the task at hand. Katja Sterflinger (left) and Guadalupe Piar (right) We aimed at investigating the biodeterioration of these remains, given the strong evidence of rising deterioration in the Capuchin Catacombs of Palermo, describes Guadalupe Piar from the Sterflinger group and lead author of the groups latest paper, the goal of their research (FEMS Microbiol Ecol, 2013 Jun 16, Epub ahead of print). With their results, they could thus help curators and restorers to come up with optimal preservation measures. Piar shares her experiences of working on this unique project Biologists shake hands with curators with Lab Times. revealed that diverse factors are contributUnderstanding the factors causing this ing to the problem at hand. Piar lists the Various culprits unfortunate degradation is vital to the surmost noticeable ones observable within the The project was first conceptualised tovival of this unique collection. Thus, a reunderground chambers of the catacombs. wards the end of 2010, within the framesearch team consisting of scientists from The poor indoor air quality was unlikely work of the Sicily Mummy Project. to be suitable for the safe conservation of Piar explains, The Sicily Mummy the human remains and could also pose a Project, established in 2007, is an onhealth risk to visitors. In addition, the walls going research project aimed at docuof the catacombs, and some other materimenting and studying these and othals, showed an intriguing extensive rosy diser Sicilian remains. Scientific studies colouration, that was possibly biological in have been performed on many Sicilorigin. Thirdly, the environmental condiian mummy collections and informations in the catacombs allowed the formation has been gathered on their biotion of salt deposits over the walls, produccultural context, focusing on funerary ing salt cracks that detached and contamiarchaeology, paleopathology, paleonated the surfaces of other materials. Finalbotany and paleonutrition. Some ly, theres the mouldy appearance of many of these results are summarised in a mummies, especially those located in cor2012 report by Dario Piombino-Masridors with higher humidity, and the prescali et al. (Antrocom, 2012, 8(2):341ence of insects, deteriorating coffins and 52). Generously, the Austrian Science clothes. Obviously, besides unfavourable Dario Piombino-Mascali (right) and Albert Zink (left) Fund (FWF) supported Piar and paid environmental conditions, clearly also some sampling some naturally mummified bodies in Sicily

Photos (3): EURAC, Sterflinger group

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biological agents were at play and thus, the team investigated whether specialised microorganisms, with potential degradation activities, were present on and inside the mummy materials.

Unlike regular experiments in the field or in the laboratory, the team had to proceed very cautiously at every step as they were working with extremely sensitive material. Piar explains, The big challenge always, when working with objects of cultural heritage, is the use of non-invasive sampling techniques or minimally invasive sampling. In this case, sampling occurred under the restricted permission of the curator, Dario Piombino-Mascali, on different materials, such as skin, muscle, bone, hair, clothes, stuffing materials and surrounding walls using forceps and scalpels. We were only allowed to use this destructive method on fragments that could not undergo conservation. The team carefully adapted their approach of sampling, analysis and microbial cultivation techniques to accommodate this special situation. All techniques were adjusted on a case-by-case basis to best suit the materials and conditions at hand. For the microbial investigations, we applied conventional culture-dependent as well as culture-independent techniques, comprising direct DNA extraction from sample material, PCR amplification using universal and species-specific primers for the detection of specific groups of microorganisms, fingerprinting by denaturing gradient gel electrophoresis of amplified DNA and sequencing, elaborates Piar. After all this careful analysing, Piar et al. concluded that one of the reasons the human remains in the Catacombs suffer so much is the very high concentration of fungal spores in the air, exceeding 2,000 spores per m3. In addition, these levels pose a potential health risk to visitors and hence need to be dealt with swiftly. What about the rosy discolouration on the walls? Piar and co. linked it to the growth of halophilic microorganisms that are specialised to thrive under these environmental conditions. Another problem the researcher initially identified had to do with salt depositions on the Catacombs walls. This contamination, the researchers found, invited even more halophilic microorganisms to settle on these materials, further encouraging their deterioration. Finally, on and inside mummy materials, such as skin, muscle and hair, the mum-

Handle with care

my researchers identified gene sequences indicating the presence of highly-specialised bacteria and fungi, well-known for their proteolytic and keratinolytic activities. On cellulose-containing materials like clothes, cellulolytic microorganisms had, apparently, found themselves a new home. All of the above observations strongly suggest that specialised microorganisms that dont care much about preservation had indeed conquered the mummies. Over time, the environment within the catacombs, as well as the microbial sub-populations inhabiting different surfaces had jointly contributed to the degradation of the mummified remains.

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In order to combat these forces, Piar suggests very modest, yet very effective means. Simple measures such as the creation of an optimal ventilation system, the cleaning of dust and detached salt, and the installation of insect traps, will help to stabilise the conservation of the remains. Future restorers need to decide whether they want to apply further disinfectant treatments to combat mould formation and growth. Our results will be used to establish, together with the restorers of the Capuchin Catacombs and other responsible persons, a monitoring of the abiotic and biotic agents responsible for the deterioration of the objects and furthermore, to develop a concept to maintain these agents under controlled conditions, she states. The most important factors for prevention of biological damage on objects of cultural heritage are climate control, frequent cleaning and phenomenological monitoring, she mentions. She believes that scientists can play a major role in getting this message across to those responsible for preservation, Microbiologists have to increase the awareness for those prevention measures by consulting and teaching restorers, preservationists and museum curators.

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Cancer biology in London, UK

Picture: Fotolia/ Iryna Melnyk

The Shape Shifters


Chris Bakal has been conducting research in the area of cell shape regulation over the last 14 years, since embarking on his PhD at the University of Toronto. Chris says he got into the field as he is just fascinated by the fact cells can adopt such a range of shapes whilst having exactly the same genetic code in each cellfrom flattened skin cells, to elongated muscle cells, to lengthy neurons. After his PhD, Chris went on to do postdocs at Harvard Medical School and then MIT in the USA, before setting up his lab in London where he is a Wellcome Trust Research Career Development Fellow. least a further six acknowledged individuals, who contributed assistance and advice, many months to complete. The study involved the use of Drosophila cells, human and mouse melanoma cells and some in vivo mouse work, coupled with a vast array of techniques. Bakal and co. identified PTEN, a tumour suppressor mutated in many cancers, as a key regulator, ubiquitously involved in cell shape switching across mouse, human and fly cells. Unfortunately, Chris tells me PTEN is not drug-targetable. The team did, however, identify a number of other genes, which could potentially be bettersuited for pharmacological purposes, such as kinases, which could be drug targeted if they were found to be mutated. The genes were identified by using RNAi screens, firstly on Drosophila cells, later on mouse and human cells, along with the knockdown of identified genes, such as Rho kinase, and immunoblotting, immunohistochemistry, image acquisition and image analysis.
Photo: Bakal group

Rounded, elongated or with ruffled edges cells can come in different shapes and sizes. What regulates cell shape changes and can that knowledge one day be used to prevent metastasis? Chris Bakal and his team are eager to find answers.
ts not always a case of too many cooks spoiling the broth in science, collaborations are the nuts and bolts of a successful project. Combining expertise from many corners of the world will bring new, never-thought-of ideas to the table and enable experiments that one research group alone would not be able to perform or it would take them a very long time. In the war against cancer, though, time is of the essence Thats why Chris Bakal, working at the Institute of Cancer Research based in London, UK, teamed up with colleagues in the US, at the Weill Cornell Medical College in Texas and at Harvard Medical School, Boston. Together, they have identified key genetic regulators of cell shape changes and published their results in Nature Cell Biology (15, 86071). I hope that the identification of genes or pathways, which can be drug-targeted will hopefully allow for prevention of cancer progression and metastasis, Bakal states his ultimate research goal.

Chris Bakals lab is focused on signalling that regulates cell shape, such as phosphatases, kinases and a family of proteins called RhoGTPases and he is most interested in cancer cells, or more specifically, melanoma cells. The research, published in his latest paper, took 13 authors and at

Thirteen authors and six more experts

Chris Bakal (back row, far left) and his team study cell shapes to wipe out cancer.

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Homogenisers
Many people will look at the cells under a microscope and think they have an endless array of possible shapes. However, Bakal, his team and collaborators show this is just not true, and what we are seeing is thousands of slight variations of only a few distinct cell shapes. Bakal tells me that using robotic microscopes we were able to collect around 200,000 images a day of single cells in tissue culture. He went on to say that a specific computer programme, similar to face recognition software, then automatically makes hundreds of different measurements of each cell, such as the number and size of projections and the cell area, before statistical analysis is applied to identify the number of discrete shapes that are found within the population. The computer programme used to quantify cell shape was, by the way, both developed and implemented by Bakals group. postdocs in the group to obtain their own funding to support a fellowship. The other major funding problem he has encountered is the lack of funding available for infrastructure and equipment. In particular, he points out, CRUK have stopped their Project Grants, meaning that Young Researchers have nowhere to turn for money to buy expensive equipment. Perhaps surprisingly, Chris believes, Getting fellowships and money for equipment is much easier in other countries, for example the USA, where more options are available.

It depends on the mixture

What did the programme tell Bakal and his team mates? Interestingly, Drosophila cells can adopt only five distinct cell shapes, which can obviously have many slight variations since no two cells will ever be completely identical. Most fruit fly cells in their study were of the normal type, being rounded with smooth borders of cortical actin. In addition, they identified four more discrete shapes: the L-shape elongated, bipolar, spindle-shaped cells; the Cshape large cells with smooth edges; the T-shape small, partially polarised teardrop-shaped cells and finally, the R-shape very large flat cells with ruffled edges. The team then turned their attention to cancer cells. They found that human melanoma cells grown in 3D collagen gels only have two distinct shapes being either spindleshaped or rounded, similar to what is seen in vivo. Conversely, the authors saw that the same human melanoma cells grown in 2D on tissue culture plastic adopted only one shape, which Bakal suggests is likely due to the stiffness of the plastic compared with both collagen gels and the in vivo soft tissue environment. Bakals research group receives the majority of their funding from the Wellcome Trust but they also rely on funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Cancer Research UK (CRUK). The laboratory has been running for four years now and typically hosts between ten and fourteen researchers at any one time. Chris is a little frustrated regarding his funding situation as he says, It is particularly difficult for

Cell shapes are not limitless!

As for now, the group are continuing work in the field, which Bakal describes as the interface between cytoskeletal bio logy and computational biology. Unlike the huge number of people involved in the greater field of cytoskeletal biology, there are far fewer researchers in this specific niche, with only a handful of scientists doing anything remotely similar, such as Lucas Pelkmans in Zrich, Switzerland. Meanwhile, Bakals group is busy doing more RNAi screens in the hope of identifying further regulators of cell shape changes and better understanding the pathways involved. They are also undertaking the massive challenge of trying better to understand the connection between the in vitro findings and the melanoma in vivo. Firstly, they need to perform genetic manipulations on mouse models, and secondly, and most difficult, perform in vivo imaging of single cells, something which is seldom done at present due to the challenging nature of the technique. Moving forward, Chris Bakals group is also starting to investigate genes, which control shapes of organelles within cells, of which almost nothing is currently known. The importance of understanding control of organelle shape is that, for example, the mitochondria shape differs between melanoma cells and normal skin cells, and it is thought that the shape of the mitochondria might influence the metabolism of these cells. Another organelle of interest to Bakal is the Endoplasmic Reticulum (ER), which he tells me is known to change shape due to ER stress, which becomes chronic in obese people, and this may be linked to some forms of cancer and also other diseases such as type II diabetes. So, although Chris Bakal is primarily working towards a treatment for melanoma, his research may well benefit many other diseases along the way. Nicola Hunt

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page 32

Lab Times

6-2013

Cardiovascular disease research in Stockholm, Sweden

Journal Club

Too Cold for Comfort


For the healthy, swimming in an ice-cold lake or shovelling snow in the dead of winter comes with many benefits it boosts circulation and metabolism. But for those predisposed to certain metabolic conditions, exposure to Arctic conditions might be life-threatening. Yihai Cao and his team found out whats behind CV-related death in the cold.

n the small picturesque village of Spaa, Poland, there is a chamber dubbed the evil sauna by Welsh rugby player Sam Warburton. No larger than a service elevator, willing participants don thick socks, gloves and a bathing costume, protect their ears, nose and mouth and march into temperatures that hover around minus 110C for three long minutes. The aftermath of these undoubtedly cold minutes, where the core body temperature remains largely unchanged, sees the release of those happy hormones called endorphins that lift the mood, soothe existing pains, decrease inflammation, accelerate tissue repair and may even help shed those extra pounds. The benefits of full-body exposure to extreme cold temperatures are well known. Ice swimming is, after all, an age-old winter pastime in many parts of the world. However, in spite of the many benefits there is a dark side. Hypothermia, depression and frequent bouts of the flu are almost commonplace during winter months. More ominously, colder temperatures are blamed for deaths due to stroke, heart attacks and other cardiovascular-related diseases. Overexertion from snow shovelling has been blamed but the underlying cause has nevertheless remained a mystery. This mystery intrigued vascular biologist, Yihai Cao, who, together with scientists at his home lab at the Karolinska Institute in Stockholm and several labs spread throughout China, proposed a mechanism in an elegant study published in Cell Metabolism (18, 118-29).

Currently a professor in the Department of Microbiology, Tumor and Cell Biology, Cao began his illustrious career studying medicine at Shandong University in China. After further training in Beijing, he travelled far west to Bern and then to Karolinska for his PhD. He continued westward to Harvard Medical School for a postdoc and

A return trip to Stockholm

For their model, the group used a mouse lacking apolipoprotein E (ApoE), which spontaneously develops atherosclerotic lesions, even when fed regular chow. ApoE is a key component of very low-denKeeping warm sity lipoproteins (VLDL). It directly binds Like all mammals, we have fat in one of fats such as cholesterol, which are then two forms brown adipose tissue (BAT) or transported through the blood to the livwhite adipose tissue (WAT). BAT is abuner for processing. Therefore, it is no surdant in small mammals and babies, who inprise that alteration in ApoE is associated terestingly cannot shiver when cold to genwith heart disease. To confirm cold activation of the adipose tissue, the mice were pre-fed a high fat diet, then switched to a normal diet and exposed to either 30C or 4C for eight weeks. Cold decreased the weight of the various fat depots throughout the body (subcutaneous, inguinal and epididynd Yihai Cao (front row, 2 from left) and his team: not exposed to cold. mal WAT and the interscapular BAT), in erate heat. They make up for this deficienaddition to decreasing number and area of cy by firing up a process called non-shiverthe adipocytes good news for those intering thermogenesis that is based on the actiested in weight loss. vation and subsequent upregulation of unActivation of BAT was confirmed by incoupling protein 1 (UCP1) in the BAT micreased UCP1 expression. The expression of tochondria. WAT is a major energy store in endothelial markers CD31 and endomucin adults and just as cold activates BAT, it also also went up, suggesting new blood vessel converts WAT to BRITE (brown-like adipose formation. Elevation of O2 consumption and CO2 production also pointed to increased tissue), characterised by increased UCP1 metabolic rates in ApoE-deficient mice exexpression in mitochondria. Cold activation posed to cold. Other important changes incan be good because it increases metaboPhoto: Cao lab

then returned to Karolinska in 1996. Caos main research interest is angiogenesis growth of new blood vessels from pre-existing ones but always with disease in mind, be it cancer, obesity, diabetes, ocular disease, and, of course, cardiovascular disease (CVD). Our goal is to carry out meaningful and clinically relevant research by translating our laboratory findings into clinical implication and by taking clinically unresolved problems to the laboratory. In this case, the clinically unresolved question centres around CV-related deaths associated with exposure to cold.

lism and processes, such as angiogenesis, to provide oxygen to our more active cells. Cao believes that in healthy persons higher metabolic rates are beneficial but the resulting metabolic changes may exacerbate underlying metabolic diseases in predisposed individuals the hypothesis tested in the present study.

Eight weeks in the cold

Journal Club

6-2013

Lab Times

page 33

cluded increased breakdown of fats (lipolysis), expression of lipolysis-related genes, increased levels of blood cholesterol, and LDL-cholesterol, including VLDL and LDL remnants, which make up atherosclerotic plaques. All these changes in metabolism could not be caused by the initial fatty diet because similar observations were made in mice fed a normal diet. On the other hand, wild type healthy mice also lost adipose weight in the cold, but unlike the ApoE-deficient mice, their plasma cholesterol underwent a healthy decrease rather than increase. In fact, ApoE levels went up in the control mice, most likely to facilitate the removal of cholesterol, supporting the theory that cold can be beneficial to the healthy. To exclude that the results were ApoE-specific and that cholesterol synthesis was more critical than its clearance, all experiments were confirmed in a mouse lacking low density lipoprotein receptor (Ldlr), which binds and endocytoses LDL-cholesterol, thus removing cholesterol from the blood. When there is too much cholesterol in the blood, it accumulates with triglycerides, immune cells, collagen and actin in the arteries to form atherosclerotic plaques. Collagen and actin form a fibrous cap that holds the lipids and cells in place. Plaque build-up blocks blood flow, increasing the risk of heart attack and stroke. However, in addition to size, plaque stability is also critical and is quantified by an instability index = (content of macrophages + lipid)/(content of actin + type I collagen).

exhausting of the study; but it was worth it. Loss of UCP1 in the ApoE-deficient mice protected them from all the detrimental effects caused by exposure to the cold. Could this be clinically relevant? The scientists looked to already available drugs for answers acipimox, which inhibits lipolysis, and simvastatin, a cholesterol synthesis inhibitor. Although not complete, both drugs decreased LDL-cholesterol, plaque area and instability in the ApoE-deficient mice. To get deeper into the mechanism, they investigated the small molecules that run communication between adipocytes, socalled adipokines. First author, Mei Dong, described how they finally settled on one particular adipokine, adiponectin. We found that adiponectin not only showed a persistent change under different time length of cold exposure but also a close relationship with atherosclerosis and lipolysis. Like the drugs, systemic administration of adiponectin to the ApoE-deficient mice at 4C decreased total and LDL-cholesterol, plaque area and instability back to the levels seen in mice at 30C. Adiponectin also decreased UCP1 expression in the different fat depots, suggesting that adiponectin, by some unknown mechanism decreases UCP1-induced lipolysis and atherosclerotic lesions.

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Exposure to cold led to more and faster-growing plaques in the arteries of the ApoE-deficient mice. More critically, these plaques were more unstable, as determined by immunohistochemical analysis of actin and collagen I. Cao warns, The stability of the plaque is quite critical to CVD. A smaller but unstable plaque is much more dangerous than a bigger but stable one. A stable plaque is a risk factor but, usually, the body could still get enough blood supply. But, once the plaque becomes unstable, it could rupture at any time; a thrombus will be formed immediately, the blood flow will be completely blocked and the heart will have an acute cardiovascular event. The results, so far, were good but they still failed to address why cold caused the observed metabolic changes. Cao chose to focus on UCP1 but to do so it was necessary to get rid of it in the ApoE-deficient mice, a task which Cao admits was one of the most

Small and unstable is worst

Never losing focus of their central goal of clinical relevance, it was time to test the relevance of their results in humans. For this, they needed subjects, which would prove to be a challenge. It was unsurprisingly difficult to find participants willing to hang out for a couple of hours in the cold in a semi-nude state of dress. Out of only 14 individuals, five were chosen due to their high LDLs, admittedly too few to make any dramatic conclusions. However, after two hours each day for two days, the five subjects had elevated LDL-cholesterol and adiponectin plasma levels. (Levels did return to normal after four hours at ambient temperatures). There are plans for a larger, more complete study, once willing candidates are found. For Cao and Dong, they believe that their data can eventually be used as a warning for people suffering from diseases like hypercholesterolemia. Essentially, they should bundle up and stay warm during the winter. And those who are planning to lose weight through cold exposure should have a second thought before they jump into the cold room. Rosemarie Marchan

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Publication Analysis 2005-2011

Immunology
Image: F. Hoffmann-La Roche Ltd.

Measured by the unusually high number of research papers and an even higher number of citations, immunology research seems to be one of the biggest topics in Europe. Most remarkably, not less than four women scientists are among our top 30 most-cited immunologists.

he red-beard sponge, Microciona prolifera, dwells in the Northwest Atlantic, where it attaches to rocks and feeds on plankton. You may be wondering: Why start an article about Immunology with a sponge? But even the most primitive multicellular organism is already able to distinguish between self and non-self, which is the very basic requirement for a functional immune system. Transplantation experiments have shown that sponges happily accept grafts taken from their own kind but reject those of other species. In most sponges this immune response is realised through certain receptors at the sponge cell surface, not unlike those of vertebrates, but M. prolifera and certain other marine sponges have come up with something extraordinary they entrusted specialised cells, called gray cells, with the job. These sponge immunocytes are huge, highly motile and they quickly accumulate at the contact site of xenogeneic grafts and initiate the rejection reaction. With life getting more and more complex, the immune system had to meet increasingly diverse demands. At some point, one type of immune cell simply wasnt enough. Thats how the mammalian immune system ended up with that bewildering variety of cells in charge of keeping foreigners out and natives in. And whenever scientists think they have finally caught all immune cells, new ones pop up somewhere. One of the more recent additions is a new type of T helper cell called Th9, which produces the cytokine interleukin-9 and might be involved in pathogen immunity and immune-mediated disease (Immunol Rev, 252(1):10415).

As vast as the number of cells involved with immunological processes, is the number of immunologists in Europe. The disciplines high popularity forced us to make a tiny modification for the nations ranking, which is, by the way, based on expert journals filed under the subject category Immunology in Thomson Reuters Web of Knowledge database. In contrast to some of the most recently published rankings (LT 6-2012 LT 5-2013), in which we included any type of publication, we, this time, had to restrict our query to articles, reviews and proceedings papers. The exclusion of those publication types, however, resulted in a slightly higher citation per article value. All in all, European immunologists published more than 60,000 articles, reviews and proceedings papers between 2005 and 2011 most of them (7.5%) in the Journal of Immunology. The top three Immunology journals, according to the Impact Factor, are the Annual Review of Immunology (IF: 36.56), Nature Reviews Immunology (IF: 33.13) and Nature Immunology (IF: 26.2).

A vast number of immune cells and immunologists

Comparing our latest publication analysis in Immunology to the one we did six years ago (LT 4-2007) revealed quite little movement in the nations ranking. The top six kept their positions, with England firmly holding on to its Immunology crown. In hot pursuit are Germany, France, Italy, the Netherlands and Switzerland. Switzerland also shines with the highest citation per article ratio (27.3) among all contenders; similarly well-cited articles were written in Ireland (25.8) and, surprisingly, Iceland (25.0), placing only 25th according to total citations. Incidentally, the Icelandic paper collecting the most citations (316 out of 3076) is about Innate Immunity of Fish, written by Bergljt Magnadttir from the University of Iceland in Reykjavik. As we have observed with many publication analyses before, also with this ranking European immunologists authored more articles than their US peers but couldnt achieve more total citations and citations per article. Both Europe and the US collected over one million citations. Japan and Canada also did their part to contribute to advances in Immunology. In Japan, Shizuo Akira from Osaka University, is the expert when it comes to pattern recognition receptors, of which the famous Toll-like receptors are an example. These receptors recognise certain microbial molecules like bacterial lipopolysaccharide and kick-start the immunological response. Akira was once the worlds most-cited scientist. Had he been working in Europe between 2005 and 2011, he would have been the uncontested number one in our ranking. His almost 500 papers gathered a staggering amount of 36,000 citations.

But who is the number one of our top 30 most-cited immunologists? For us, recognising real immunologist (self) from a scientist with an interest in some aspects of immunology (non-self) wasnt as easy as it is for dendritic cells. But we, nevertheless, attempted to devise a few exclusion criteria. Whenever a researcher mostly published papers that dealt with the treatment (guidelines, clinical trials) or the genetic risk factors of a disorder that involves the immune system like arthritis, asthma or HIV, we decided to leave them out. Was it his or her major intention to characterise the pathomechanisms of such a disease, we considered him or her fit for the ranking. To be counted as one of Europes most-cited immunologists, at least 5,000 citations needed to be collected within the sevenyear time frame. This is much more than compared to most other rankings and is evidence of the importance of this discipline in the life sciences. Besides the high citation numbers, another num-

A minimum of 5,000 citations needed

Ranking

6-2013

Lab Times

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ber increased significantly, too: the amount of women among the top 30. Not one, not two but four female scientists Laurence Zitvogel (7th), Erika von Mutius (17th), Maria Roncarolo (26th) and Fiona Powrie (28th) mix with the usual all-male club at the top. Looking at institute affiliations reveals that the UK hosts the most (seven) highly-cited immunologists (including one in Wales and another in Scotland). Immunological research is also of high priority in the Netherlands and France both countries have five researchers placed in our top 30. France can even pride itself with the fact that our top-cited scientist, Guido Kroemer (1st), works at one of the countrys institutes, the Institut Gustave Roussy. The Institut specialises in research on and the treatment of all types of cancer and thats conveniently also the expertise of Kroemer and colleague Zitvogel. Both work on the role of the immune system in cancer and anticancer treatment. Inflammation, which can be caused by various factors, such as burns, pathogens, radiation, stress or damaged cells, is, scientifically, of interest for a subset of other researchers. Among them is Josef Penninger (10th). One of his projects deals with the question on how malnutrition leads to disorders of the immune system, diarrhoea and intestinal inflammation. Fiona Powrie is also highly fascinated with the gut. By dissecting the interaction between T-cells and dendritic cells and the cytokine network, she wants to understand how the host manages to keep good bacteria alive but kill the bad ones and, like Markus Neurath (27th), what goes wrong in inflammatory bowel disease.

Europe...
Country 1. England 2. Germany 3. France 4. Italy 5. Netherlands 6. Switzerland 7. Spain 8. Sweden 9. Belgium 10. Denmark 11. Austria 12. Scotland 13. Israel 14. Finland 15. Norway 16. Ireland 17. Poland 18. Greece 19. Hungary 20. Turkey Citations 261,289 235,786 181,604 144,345 114,436 100,809 90,473 71,301 56,583 42,683 40,922 38,392 33,308 27,127 26,354 23,858 21,710 15,198 12,800 12,384 Articles 10,971 10,657 8,077 7,880 4,991 3,693 5,667 3,698 2,573 1,978 1,691 1,597 1,682 1,309 1,325 925 1,963 918 785 1,340 Cit./Art. 23.8 22.1 22.5 18.3 22.9 27.3 16.0 19.3 22.0 21.6 24.2 24.0 19.8 20.7 19.9 25.8 11.1 16.6 16.3 9.2

Since the discovery of Toll-like receptors expressed by cells of the innate immune system, it seems that cells of the acquired immune system have lost a bit of their popularity among scientists. Thus, scientists studying T-cells or B-cells like David Price (20th), Maria Roncarolo and Antonio Lanzavecchia (29th) are few and far between in our top 30. All the higher is the number of innate immunologists, determined to find out exactly how macrophages, dendritic cells or natural killer cells recognise and eliminate bacterial, viral or fungal invaders. Among them, the late Jrg Tschopp (2nd), Siamon Gordon (7th), Mihai Netea (9th), Luke ONeill (14th), Tom van der Poll (18th), Gordon Brown (21st) and Steffen Jung (25th), who even has one paper together with the discoverer of the dendritic cells, Ralph Steinman. Yet a few other researchers, Jean-Laurent Casanova (11th), who has a double affiliation with Rockefeller University in New York, and Alain Fischer (12th), turned their attention to primary immune deficiencies. These conditions can be traced back to inborn errors of genes important for immune function, giving carriers a much higher likelihood of contracting an infection. Also among our top 30 is Nico von Rooijen (4th), who still reaps the rewards of having developed a system in the late 1980s that depletes tissues of macrophages and which is still used by many immunologists around the world. The immune system, innate and acquired, still leaves a lot of room for researchers to indulge their wildest (scientific) fantasies. Who knows what new cell type or signalling pathway are only waiting to be discovered. As a final remark because, just like space, the immunology field is so vastly, hugely, mind-bogglingly big, it is very well possible that we might have overlooked one or the other immunologist. So, if you think youve got what it takes to make the top 30 (and you dont see your name there yet), we encourage you to step forward and give us your citation numbers. Kathleen Gransalke Thank you.

Innate immunity beats acquired immunity research

Articles appearing between 2005 and 2011 in immunology journals as listed by SCImago and Thomson Reuters Web of Science. The citation numbers are accurate as of July 2013. A countrys 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 Europe USA Japan Canada Australia China South Korea 1,130,647 1,352,059 174,383 137,830 110,395 82,505 36,767 Articles 60,620 54,558 9,860 6,538 4,960 7,790 2,940 Cit./Art. 18.7 24.8 17.7 21.1 22.3 10.6 12.5

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Lab Times

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Ranking

Publication Analysis 2005-2011 Immunology

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 Jrg Tschopp, Univ Lausanne ( 22.03.2011) Alberto Mantovani, Clin & Res Inst Humanitas, Milan Nico von Rooijen, Mol Cell Biol, VU Amsterdam Yehuda Shoenfeld, Ctr Autoimmu Dis, Sheba Med Ctr, Tel Hashomer Adrian V. S. Hill, Jenner Inst Lab, Univ Oxford Siamon Gordon, Univ Oxford (emerit.) Laurence Zitvogel, Inst Gustave Roussy, Villejuif Mihai G. Netea, Med, Radboud Univ Nijmegen Med Ctr Josef Penninger, Inst Mol Biotechnol Austr Acad Sci, Vienna Jean-Laurent Casanova, Hum Genet Infect Dis, Paris Descartes Univ Alain Fischer, Immunol & Haematol, Necker Child Hosp, Paris Bart J. Kullberg, Med, Radboud Univ Nijmegen Med Ctr Luke A. J. ONeill, Sch Biochem & Immunol, Trinity Coll Dublin Veit Hornung, Clin Chem & Pharmacol, Univ Bonn Rino Rappuoli, Novartis Vacc & Diagnost, Siena Erika von Mutius, Asthma & Allergy, Univ Childrens Hosp Munich Tom van der Poll, Ctr Infect & Immun, Acad Med Ctr, Amsterdam Caetano Reis e Sousa, Immunobiol Lab, Cancer Res UK, London David A. Price, Inst Infect & Immunity, Cardiff Univ Gordon D. Brown, Med Sci, Univ Aberdeen Gurdyal S. Besra, Scho Biosci, Univ Birmingham Peter Vandenabeele, Mol Biomed Res, Univ Ghent Jos W. M. van der Meer, Med, Radboud Univ Nijmegen Med Ctr Steffen Jung, Immunol, Weizmann Inst Sci, Rehovot Maria G. Roncarolo, Vita-Salute San Raffaele Univ, Milan Markus F. Neurath, Intern Med, Univ Erlangen-Nuremberg, Erlangen Fiona Powrie, Sir William Dunn Sch Pathol, Univ Oxford Antonio Lanzavecchia, Inst Res Biomed, Bellinzona Francois Ghiringhelli, Med, Univ Bourgogne, Dijon 22,990 11,767 11,618 11,470 9,531 8,793 7,636 7,598 6,917 6,669 6,648 6,549 6,537 6,499 6,264 6,124 5,929 5,925 5,925 5,924 5,850 5,708 5,575 5,504 5,466 5,425 5,346 5,343 5,252 5,199 264 100 191 317 375 150 106 111 200 156 173 161 135 83 38 143 129 231 31 115 77 203 91 178 69 98 163 41 61 66

Guido Kroemer (1.)

Alberto Mantovani (3.)

Laurence Zitvogel (8.)

Alain Fischer (12.)

Erika von Mutius (17.)

Jos van der Meer (24.)

Maria Roncarolo (26.)

Fiona Powrie (28.)

... and Papers

Citations of articles published between 2005 and 2011 were recorded up until July 2013 using the Web of Science database from Thomson Reuters. The most-cited papers had correspondence addresses in Europe or Israel.

1. Veldhoen, M; Hocking, RJ; Atkins, CJ; Locksley, RM; Stockinger, B TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. IMMUNITY 24(2): 179-189 FEB 2006 2. Mantovani, A; Allavena, P; Sica, A; Balkwill, F Cancer-related inflammation. NATURE 454(7203): 436-444 JUL 24 2008 3. Gordon, S; Taylor, PR Monocyte and macrophage heterogeneity. NATURE REVIEWS IMMUNOLOGY 5(12): 953-964 DEC 2005 4. Martinon, F; Petrilli, V; Mayor, A; Tardivel, A; Tschopp, J Gout-associated uric acid crystals activate the NALP3 inflammasome. NATURE 440(7081): 237-241 MAR 9 2006 5. Korn, T; Bettelli, E; Oukka, M; Kuchroo, VK IL-17 and Th17 cells. ANNUAL REVIEW OF IMMUNOLOGY 27:485-517 Published: 2009

Citations 1,758 1,457 1,285 1,061 1,044

Opinion

6-2013

Lab Times

page 39

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Whats behind paper retractions? (19)

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In praise of researchers who correct the scientific record at personal cost.
effery Kelly, of the Scripps Research Institute in La Jolla, California, USA, realised after publishing two papers in Protein Science in 2009 and 2010 that his lab had made a mistake in those studies. My laboratory, in the process of trying to isolate and identify a protein(s) exhibiting disaggregase activity, realised that too many candidates were active which led us to realise that the interpretation of our previous data was incorrect, Kelly told us recently for a Retraction Watch post. It took us almost a year of effort to figure this out and convince my trainees who actually did the initial experiments that we misinterpreted our data.

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A lot of researchers would have just shrugged, or have published a new paper without noting the issues. Science corrects itself over time, right? But not Kelly. In a paper recently published in Protein Science, he and his team wrote: Based on the results described in this paper, we conclude that our interpretation of the kinetic fibril disaggregation assay data previously reported in Protein Sci. 2009, 18, 22312241 and Protein Sci. 2010, 19, 836-846 is invalid when used as evidence for a disaggregase activity. Thus, we retract the two prior publications reporting that worm or mammalian cell extracts disaggregate A amyloid fibrils in vitro at 37C. We apologize for misinterpreting our previous data and for any confounding experimental efforts this may have caused. It turns out that the journals editor thought the retractions should actually be corrections, and that the version we quote above was published in error. Some Retraction Watch commenters agreed that retraction wasnt appropriate. Regardless of how Kelly et al.s move is categorised, however, the intent publicly admitting error, something which unfortunately still comes with a professional price tag is clear. Kelly joins other scientists in taking the high road. Pamela Ronald, of the Universi-

Admitting an error publicly

ty of California, Davis, did the same thing with a PLoS ONE paper. About a year after publishing a study on quorum sensing, Ronald and her colleagues discovered critical errors, which they noted in a comment on the paper. When they tried to replicate the original findings, they couldnt, so they retracted. And the authors of a 2006 Journal of Immunology paper retracted it in early 2011 when they realised they had ordered the wrong mice. Compare this model behaviour to what we too often see: Obfuscation, euphemisms and ignoring whistleblowers. When you run a blog about retractions, its easy to get into a rut of criticising scientists and publishers for a lack of transparency. Thats why, at the suggestion of a reader, weve created a Doing the Right Thing category on Retraction Watch. The hope is that highlighting and praising such behaviour will remove some of the unfortunate stigma thats now attached to correcting the scientific record transparently, because so many retractions are, in fact, due to misconduct.

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As University of California, Berkeley biologist Michael Eisen wrote last year in response to a retraction that many questioned: When a word means something in the community, it doesnt matter what a dictionary or some unknown committee says. Retractions are viewed by scientists and the public as marks of shame. What if we could change that? To be sure, were not advocating that every paper proved incorrect should be retracted. But researchers who fall on a grenade to protect their fellow scientists from folly are doing the field a commendable service. Perhaps its time more people began acknowledging the sacrifice. Adam Marcus and Ivan Oransky (The authors run the blog Retraction Watch: http://retractionwatch.com)

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Lab Times

6-2013

Biobusiness

BASF acquires enzyme hunter Verenium

Catalysts Wanted
Photo: Verenium

in bio fuel production, grain processing and the animal health and the nutrition industry. The monetary potential of the industrial use of modified enzymes is huge. To retain their leading place as one of the worlds major chemical groups, BASF must also keep the ball in green and white (bio)technologies hoping that the Verenium acquisition will give them a better position in the enzyme growth market. -wk-

ed in 2002, has developed four automated patch clamp instruments so far. Recently, they released their latest (and most sophisPatch 384. If ticated) device, the Syncro this grey plastic hutch is even half as tricky as its manufacturers from Bavaria proudly maintain, it should be every electrophysiologists dream. Developed for, automated patch clamp-based ion channel drug

In 2008, Verenium opened up this first de mon stration-scale cellulosic ethanol plant.

The German chemical group, BASF, is strengthening its white biotechnology business by acquiring the Californian enzyme hunter Verenium for 48 million (3 per share). That is almost the same as Vereniums entire annual sales in 2012, and a 56 percent premium on the US companys average share price in the six months prior to the announcement of the transaction. Verenium originated in 2007 out of a merger of two industrial biotech companies, Diversa and Celunol, to create a leader in the emerging cellulosic ethanol industry. The company currently employs 130 people who design tailored enzymes that are more cost-effective for industrial purposes (primarily enzymes that split cellulose to make sugar). To gain access to those enzymes, they first extract microbial DNA directly from collected samples, often from extremophile microorganisms. Then they use highthroughput screening technologies to identify unique enzymes and further optimise and refine them for commercial use, for example

Nanions automated patch clamp robot

Giga Seal Machine


Have you ever performed patch clamp experiments in your scientific life? Your Lab Times reporter did, more than 15 years ago, and found it fascinating on the one hand, but very arduous on the other. To record the currents of single ion channels in cells, as Nobel prize winners Erwin Neher and Bert Sakmann did in the late 1970s and early 1980s, you have to be patient as a saint. You must manually tinker with a range of fine glass micropipettes with extremely fine tips (just a micrometer in diameter), then accurately fill them with a ionic solution and finally dock your cell surface smoothly to your pipette, to form a high resistance (giga) seal with its membrane. In short, its a lot of meticulous experimental work that tends to end too often with no usable result. Finally, however, the 21st century has reached patch clamping. Munich-based device producer Nanion Technologies, foundPhoto: Nanion

This tricky device will relieve you of a lot of arduous work, and, well, money.

screening, the SynchroPatch is equipped with 384 patch clamp amplifiers and an advanced 384 channel liquid handling robot. According to Nanions CEO, Niels Fertig, the device allows up to 20,000 data points per day, recording 384 to even 768 cells in parallel (if using two devices and integrating them into one liquid handling robot). Given its specified success rates of over 85%, even the pioneers of patch clamping, Neher and Sakmann, are surely impressed by Nanions gadget and by its purchase price of around 500,000. -wk-

Ch ies i ( I TA ) & A c ti va e ro ( G E R) c o mb i n e tec h n ologies, while G alap agos (B E L ) targets m ain m utat i o ns
Image: University of Utah

Alleviating Cystic Fibrosis

he German lung disease specialist, Activaero (Gemnden), has developed a targeted drug deposition method that delivers the active agent in pre-defined regions of the lung by (according to them), highly efficacious and safe aerosol therapy. This ensures transportation of the maximum amount of aerosol drug to the targeted regions, improving the therapeutic safety of the drug as well as the exact reproducibility of a patients daily therapy requirement. So far, Lab Times has not been able to verify the companys advertising slogans. At least the Italian pharmaceutical group, Chiesi Farmaceutici (Parma), trusts Activaeros claims. Recently, the two companies announced a collaboration. They will combine their two respective technologies to treat cystic fibrosis (CF) in a better way than today, to create a highly mobile and effective treatment solution. While Activaero is to contribute their inhalation approach outlined above, Chiesi will add their proprietary tobramycin drug solution.

CF is caused by an inherited gene mutation that restricts the movement of chloride and sodium ions across epithelial membranes, resulting in the accumulation of thick, sticky mucus in the lung, frequent chest infections and shortness of breath. One in 2,000-3,000 newborns is affected by CF. Another worthwhile collaboration on CF started at the same time, between Belgiums Galapagos and Chicago-based pharmaceutical group, AbbVie. The huge deal, worth up to 300 million for Galapagos, targets the main genetic mutations in cystic fibrosis patients with the aim of correcting the defects using an oral (still experimental) drug. Early-stage clinical testing is to begin by -wkthe end of 2014, they announced.

Biobusiness

6-2013

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Fetal bovine serum (FBS) with unexpected ingredients

Unpleasant surprise inside...

Undeclared Extras
For years, the Austrian lab provider PAA Laboratories sold nutrient media without informing their customers about a secret admixture of ingredients.

n March 2013, a person (whose name is irrelevant in this case) informed Lab Times that PAA Laboratories, a supplier of cell culture media from Austria, supposedly had serious quality problems. We were told that these quality issues were behind PAAs alleged decision to put a worldwide delivery block on their fetal bovine serum (FBS) media. Some time later, another person (the head of a university research lab whose name is known to Lab Times) told us similar things about PAA and their culture media. The second caller was able to substantiate his allegations with hard facts and your Lab Times reporter started to investigate. Within just a few hours, it became obvious that these quality problems would grow into a huge scientific scandal, with serious consequences for thousands of medical and life science researchers. First, however, we have to introduce the main protagonist, PAA. So lets step back in time to the late 1980s.

Burian and Mladek decided to sell their company to the US group GE Healthcare, for an undisclosed sum. The trade name PAA was kept by the new parent group. Burian, now 58 and probably a multiple millionaire, explained that the offer from GE was, an opportunity to give the company into good hands, while GE was in good spirits, too. Everything seemed rosy. In colourful, stylish prospectuses, PAA/GE marketed their business and products with the slogans, Highest Quality, Consistency, Total Trust and Production Transparency.

At that time, an Austrian merchant, Rainer Burian, 35, bought a small regional laboratory in Mhlviertel, Upper Austria. Together with his business partner, Andreas Mladek, Burian gradually expanded it into a global player, PAA Laboratories, sometimes accompanied by hostile media reporting. In 1993, for example, a feature in the German news magazine Der Spiegel was headlined Total Gruesome Events. The article was about a slaughterhouse Mafia that controls the global procurement of FBS and their unsavoury business practices. PAA played a minor part in the Spiegel feature, but not a glorious one: The company was accused of selling FBS with false indications of source, to increase their profits. By August 2011, PAA had grown to become a big fish in the rough and competitive FBS waters. As one of the major suppliers of cell culture media, they controlled an estimated 25% of the worldwide FBS market of about 800,000 litres (some say it was even more), worth about 100 million in all, and employed more than 200 people, yielding a 39 million annual turnover. At this point,

A big fish with a shady past

Consistent they may well be, but the details have nothing to do with quality, trust and transparency. The objective facts a number of memorandums and product informations leaked to Lab Times in recent weeks sound even more outrageous. It started in April 2013 with an Important Product Information, sent by GE to a number of PAA customers. Here it is clearly stated that some PAA Laboratories FBS products may [...] be of different origins from stated, and further that allegedly pure FBS, as well as all other FBS products, may contain added adult Bovine Serum Albumin (BSA), water, and/or cell growth promoting additives. The warnings are followed by a long list of products (440 in total!) GE sent out more warnings and similar product informations in the following months. Interestingly, many customers that had used PAA sera for years didnt know that those media might be contaminated. Even in August 2013 when Lab Times contacted several cell culture researchers for more information, most were still unsuspecting. GE Healthcares spokesman in Germany, Christoph Habereder, confirmed to Lab Times in August that the PAA products, didnt meet GEs quality standards. Habereder also told us that they have launched an extensive investigation, to establish all the facts and to prevent anything similar from happening in the future. After all, the affected sera were produced between 2008 and 2013 a period of five years! This

Serious irregularities

suggests that there has been an unspecified number of undeclared, unknown substances in the culture flasks of hundreds of cell culture laboratories around the world for that length of time. Why is that a problem? Well, FBS is a substance that nearly each cell culture laboratory needs. The orange-brown liquid is one of the most important reagents in basic medical research and biotechnological drug production. FBS contains a variety of partly unknown factors, without which many cultured cells will grow only poorly or not at all.

So it was no surprise that another expert interviewed by Lab Times, a proven specialist in cell therapy and a plain speaker, reacted with angry words that we prefer not to repeat here. This brave scientist fell to earth with a bump when he heard about the PAA affair and that the FBS media he used for many months in his laboratory had been exchanged by 20% in volume without his knowledge with water, soybean extract and various other ingredients. What, he grumbled on the phone, if the stuff that was undetected in the medium causes an effect in our experiments? Then perhaps half a year or even years of hard work was a waste of time. He added, Sure, everyone knows that any FBS is poorly defined, and other providers give additives into the medium, too. But they inform their clients, and thus we know whats in it and can therefore handle it reasonably. A supposedly reputable manufacturer mixes a reagent with additives and does not inform its customers thats the worst case for customers as well as for the company. It looks as if GE Healthcare acquired a rotten egg in the shape of PAA when the takeover took place in 2011. Its up to them to repair the damage rapidly. Winfried Koeppelle

Hundreds of laboratories affected

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Biobusiness

Switzerlands Devirex fights an unusual fight against a common disease (Walchwil, Zug Canton)

Drug without Agent


Herpes is a common scourge of the human race. Three friends in Switzerland are addressing the viral disease with a surprisingly effective placebo drug that has unexpected qualities.

ts just an office. A lonely office in a half empty building on a busy road in the centre of Rotkreuz, Zug Canton, Switzerland. The only visble landmarks are a few futuristic buildings just across the road: Roche Diagnostics global HQ (see picture opposite), with more than 2,000 staffers. On this side of the road, we approach the rather dull office and enter Devirex, its administrative bureaux as well as its laboratory and storage rooms. All in a single office that is more than adequate for Devirex. The company consists of three friends (the founders and management), a secretary and an additional board member. Thats all and thats enough.

They are rarely in the office. The home of the operational director, Paul Scherer, a chemist with experience in the quality management of Pharma companies, is the real headquarters. The other two are also chemists and have long experience in pharmaceuticals. The general director, Peter Vitins, has managed several Pharma companies.

We are old hands, says Marcel Langenauer, Scientific Director of Devirex, confidently. These old hands founded Devirex in 2006 mainly because they could. Their product: a preventive gel

Old hands in a dull office

Marcel Langenauer, Devirex Chief Science Officer, operates from a single office in Walchwil, Switzerland.

Photo: Florian Fisch

Biobusiness

6-2013

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against Herpes labialis or cold sores. Their enWhatever the reason... Langenauer has anothdeavour almost failed, but today they still occuer idea. He is convinced that py the office in Rotkreuz. The Swiss Economic it is the drying effect on the Forum nearly funded them, choosing Devirex as lips of the hygroscopic PEG one of three finalists for its Pharma category. that makes the formulation. Herpes is a problem for some of our Roche Diagnostics futuristic So in addition to a patent apfriends, Langenauer explains. And then they headquarters in Rotkreuz, Zug Canton. plication in 2010 for the use had an idea. A wonder molecule called 2-hyof PEG compositions to treat droxypropyl-beta-cyclodextrin (HBBCD) was various types of Herpes infection, Devirex also filed a patent for shown to successfully inhibit the replication of viruses. It acts the use of hygroscopic substances in 2013. In fact, zinc sulphate against enveloped viruses like Herpes. The HBBCD ring molecule, is known to have a preventive effect against herpes and some composed of modified sugars, is cone shaped. It is hydrophilic on people even use toothpaste, though probably not on a regular bathe outside and hydrophobic on the inside, which gives it the casis. Anybody can sell PEGs and hygroscopic substances, but only pacity to solubilise fatty molecules like cholesterol. As cholesterDevirex may write on the package that it prevents herpes outol is a vital component of enveloped viruses, where it forms lipid breaks. The first patent on HBBCD turned out to be useless. rafts to assemble proteins, HBBCD successfully inhibited cell enBut Langenauer and Devirex do not really care why it works. try in vitro. Neither do their customers apparently. An inactive active substance We could hire hundreds of scientists to find out what exactly So why not try it against the Herpes simplex virus? Nobody happens. But we have a treatment and dont really need to know had done it before. The Devirex friends convinced a group of why it works and whether it is placebo, Langenauer explains. 25 people from their circle of aquaintances to become small inIt is getting even easier to gain market approval for a so called vestors in their company. The only problem was that HBBCD is medical device (getting a CE number for the European market) a large, hydrophilic molecule that is not easily absorbed by the that acts physically rather than for a medicinal product that body. So they created a formulation using a massive 20 percent acts pharmacologically, although post-market monitoring is two HBBCD in a polyethylene-glycol (PEG) gel that turned out to be to four times more frequent, Langenauer says. Langenauer talks a convenient formulation. With this in their hands they asked the of a relatively simple formulation, but at the same time exClinical Trial Center of the University Hospital in Zurich to test their wonder-gel. It was a nice randomised, placebo-controlled study involving nearly 40 participants who suffered from frequent Herpes relapsion es (at least eight per year). The gel with HBBCD was extremeNew suct Cpro H V t e s d han ly effective. It reduced the median of relapses in six months from five to two, a statistically speaking highly significant finding. But, to everyones surprise, the placebo gel, without HBBCD, was even more effective, reducing the median of relapses from six to zero. The authors do not discuss why placebo should be better than the same gel with an active ingredient (Dermatology (2013) 226:247252). Langenauer does not care.

My colleagues were a bit frustrated, but I quickly realised what this meant, Langenauer remembers. HBBCD proved safe, but not effective, the authors of the study write. Later on they continue, Such a profound reduction of relapses appears too high to be explained solely by a placebo effect. So HBBCD is probably not absorbed efficiently enough by the skin to replicate the in vitro studies. On the other hand, the gel has a highly preventive effect although to confirm this, another study would be required. Langenauer, who is responsible for product development, production and marketing at Devirex, and the researchers from the University Hospital Zurich tried to put some more flesh on the studys bones, but failed. This is, according to Langenauer, why it took two years from the end of the study to publication. At the Clinical Trials Centre they say that this is the normal time necessary for processing data and rather quick compared to other studies. The authors of the study speculate that the alcohol groups of PEG could have an effect on viral replication. It may also be the case that general lip care does the job.

Probably effective

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Photo: Roche

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Photo: Florian Fisch

Biobusiness

Cantonal Pharmacy Zurich. The University Hospital in Zurich conducted the trials. Product analysis was done in an Italian company. Samples for assessing the products stability are deposited at Interlabor near Bern. The ...it sells company C.P.M. near Munich does the proLipivir is already produced and sold in Switduction for the German market. Another Muzerland. It has been produced under license by Genich company, Kyberg, does the distribution. bro Pharma (Fieberbrunn, Austria) under its own The patent lawyers Mewburn Ellis are sitting Cremolan product line since May 2012. Now we in London. A lonely office in a half can issue invoices ourselves instead of just having What about China or India? Langenauer empty building in the to pay them, Langanauer jokingly and happily reshakes his head. They prefer short distanccentre of Rotkreuz... marks. But Switzerland is a small market and mares, good relations with people they already gins are rather low when out-licencing the product. know. It is their personal network. Here we Now Devirex has jumped to the, biggest and keep all the various strands together, the scihealthiest market in Europe: Germany. Instead of one million entific director explains. They have the legal responsibility, their Euros turnover per year, Devirex hopes to reach ten million Euaddress is on the packaging and they have to answer to the auros. German sales started in September. This time Devirex wants thorities. So it is also the three Devirex friends who perform the to walk on its own. Which means that they must enter into maraudits. And they started on a part-time basis. But now the Gerketing themselves. The result can be seen in the office: Small Liman adventure has begun, managers Vitins and Scherer are, alpivir samples are given out freely and are accompanied by a quesmost full time workers. tionnaire, which is going to be scientifically evaluated by German From labialis to genitalis Infectiologists. The clinical side is expanding, too. Devirex wants to extend The line between science and marketing is becoming blurred. the use of its PEG-formulation to Herpes genitalis the more And medicine and cosmetics are nearly indistinguishable in this painful version of Herpes. The team from University Hospital Zucase. The Lipivir and Devirex websites are mainly filled with large rich started to recruit patients in the spring. The PEG-formulation photographs of beautiful people with perfect smiles. The fact that will be studied on its own no placebo, no control group. This Herpes labialis looks unpleasant and that Lipivir is colourless is time, they will keep a diary to report on the six months before more important than whether it really works the old hands and the six months during the treatment, explains Langenauer. again. This is also a way to avoid the bias from patients trying to rememA pan-European enterprise ber their past outbreaks They will also test with PCR whether the Devirex has just finished the design of the packaging for the number of viruses produced in unnoticed outbreaks about every German market. A printout of the shiny-silvery box, like a paper fifth day can be reduced. cut-out (bastelbogen), lies on the table for a photograph to be What is the motivation behind all this? There is certainly a taken. A proper marketing photograph follows some days later monetary motivation. But I like to do something unconventionvia email. Design of website and packaging are outsourced along al instead of just following the mainstream, says Langenauer. with every other step as well. Pharma companies are not interested in prevention, he adds. The dull office is the control room of a pan-European enterSun protection and vaccination are the exceptions. Devirex wants prise. The Welsh Penn Pharm near Cardiff developed the formuto establish Lipivir firmly and maybe sell it, Those companies Florian Fisch lation. The samples for clinical studies were then produced by the prefer established brand names.

plains that the melting temperature, the look and feel are extremely important. The result is a colourless, perfumed PEG-gel with no active substance called Lipivir.

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Youll like it!

Biobusiness

6-2013

Lab Times

page 43

Stone age biotechnology in Oxfordshire: Selling sheep and their products at a fair in the early 1920s.

Oxfordshire Biotech Roundup

Recession? What recession?

fter all the post-2008 doom and gloom, the announcement this August that the Eurozone is edging out of recession was welcome news indeed. But talk to anyone in Oxfords biotechnology sector, and youd be wondering whether there was a recession at all. Indeed, the last two years have treated the regions biotechnologists pretty well. Look back over just the past few months, for instance. In June this year, privately owned Immunocore announced their first major partnership in developing their T-cell cancer therapy. And its a big one. Genentech, the fabled founder of the biotech industry themselves, have pledged initiation fees of between 8 and 15 million for each project and over 230 million per project in development and milestone payments. Immunocores approach is to use the ability of T-Cell receptors to identify cells that are undergoing changes that signal the onset of cancer. They claim that this means only the cancerous cells are killed, leaving healthy cells intact.

their selling point is that they provide all the building blocks for DNA technology in a single, integrated system. All those plasmids are built on the same core plasmid background the SnapFast technology that forms the core of their services (they call their technology with a wink Lego for DNA).
Photo: Samantha Decombel

Cherwell Innovation Centre, located just a few miles from Bicester on the site of the former RAF Heyford base

the two Oxfordshire towns of Abingdon and Didcot. A former stately home, it is now a mixture of lowly functional huts and the latest, high-tech glass & chrome buildings. Last year Genefirst, a Milton Park company that focuses on cheap PCR-based diagnostics, won a feasibility award from the Medical Research Council (MRC) and the Technology Strategy Boards joint Biomedical Catalyst. The Biomedical Catalyst, which was announced by Prime Minister David Cameron in December 2011, is managed jointly by the Medical Research Council and the Technology Strategy Board and is handing out more than 210 million in an integrated translational funding programme (not to Genefirst alone, of course). In any case, Genefirsts Luke Stephen Alphey and Guoliang Fu, who incorporated Genefirst in January 2011, are surely proud of this official acknowledgement.

If that wasnt enough to brighten the summer, in July the start-up company Oxford Genetics landed a 175,000 seed funding from Mercia Fund Management. Founded in 2011, the company develops plasmid expression vectors for biological research;

All the DNA building blocks

The fresh company is based at Oxfordshires Cherwell Innovation Centre, run by their founder and scientific mastermind, Ryan Cawood (see photo next page), a former PhD student, who worked as data analyst at the British Ministry of Defence before he entered the life sciences. Lets move a few steps further to Milton Park which spans the green space between

One of Genefirsts Milton Park neighbours has also benefited from the Biomedical Catalyst. Regular readers of Lab Times will remember that we featured Glide Pharma, who invented a way of injecting without needles more than ten years ago (see Lab Times 4/2010, page 50). Their technology presses a tiny solid pellet, incorporating the drug, through the skin. This February, Glide completed a 16 million investment

Milton Parks colourful mixture

Photo: historic

The Nasdaq biotechnology index has grown more than 40 percent over the last 12 months. What about the British sector? Is it edging out of recession or is recent success just a flash in the pan? Steven Buckingham takes a closer look at one of the UKs main biotech hubs, Oxfordshire.

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Biobusiness

How spiders make silk was once one of natures great mysteries. But in 2001 researchers at Oxford University were so sure they knew how to do it that they spun out Oxford Biomaterials, which develops spider silk-like fibres for the medical device industry. These fibres have many of the advantages you would expect from natural silk, along with a few pluses of their own. They are naturally absorbed by the body, are completely bio-compatible, and provide a perfect scaffold for colonisation by mammalian cells. Their Scientific Director, Fritz Vollrath, has been busy giving interviews on their silk technology on the BBC (no less) and other UK television stations this year. He conducted these interviews having just heard that their patent (Methods and Ap-

On the silk road

Oxford Genetics young founder and CEO, Ryan Cawood

Photo: Oxford Genetics

paratus for Enhanced Growth of Peripheral Nerves and Nervous Tissue) was granted in China. Silk is coming home. It will be thrilling to see how the Brits cross swords with their German counterpart, spider silk company Amsilk from Martinsried (near Munich). Amsilk is a brainchild of Thomas Scheibel, full professor at the Chair of Biomaterials at the University of Bayreuth, who once developed the Ger-

In 2011 we also featured Zyoxel, who are finding ways to build 3D human tissues in the lab for drug discovery (see Lab Times 5/2011, page 60). Zyoxels founder, Professor Zhanfeng Cui, told us then how he valued his links with his native China. It seems that link has paid off: this year Zyoxel has agreed a license deal with Tianjin Weikai of the Peoples Republic of China for the manufacture and distribution of their TissueFlex in China.

Linking with China

Back in the summer of 2010 we featured Peptcell, a fast-moving company focusing on better vaccines (see Lab Times 6/2010, page 64). Peptcell is Peptcell no longer: within months of our article being published they had already renamed themselves SEEK and moved to London last year. Their CSO, Wilson Caparrs-Wanderley, readily acknowledges the part played by the Oxford biotech community in Peptcells sorry, SEEKs success. We could not have reached our current situation if at

Fresh start in London

Photos: University of Oxford; Oxford Biomaterials

round, bringing their total investment up to some 29 million. Glides new CEO, Mark Carnegie-Brown, will be using the cash to scale up production of their injector (including the validation of an aseptic pilotscale production line for clinical testing), as well as for developing their research programmes, which include epinephrine and parathyroid hormone. Organox, located further south in the Oxford Science Park, is another company to benefit from the Biomedical Catalyst scheme. Their cash will go towards funding a Phase 2 clinical study.

mans spider silk technologies at the Technische Universitt Munich.

Oxford Immunotecs future brightened further this year when the medical diagnostics companys leadership heard that they had won a place in Red Herrings Top 100 Europe list for 2013. Fritz Vollrath (small photo above), the scientific master mind be The Red Herring list hind Oxford Biomaterials, investigates the evolution of spider is a showcase for the webbuilding behaviour and the properties of spider silk. most exciting startEarlier in the year, Zyoxel raised over ups in the technology and life science sec1.5 million from Maxford O Technologies tors, and was among the first to recognise to accelerate the further development of its the potential of companies such as Face3D tissue culture technology. And if Zyoxbook, Twitter, Google, Yahoo, Skype, Salesels success was not enough, to crown the force.com, YouTube, and eBay (and, surely, year Zhanfeng Cui was elected as a Fellow some third row companies that never realof the Royal Academy of Engineering. ly got into higher gears). Time will tell into In January this year we told you about which category Oxford Immunotec falls. PlayDNA, a company that combines art and This question no longer arises in the science, giving customers an insight into case of Oxford Nanopore Technologies (ONP). their genetic makeup. PlayDNA took their Last year, your Lab Times reporter interfirst big corporate order this year of 17 piecviewed Hagan Bayley, pioneer of the pore es of artwork. Founder Samantha Decomtechnology that gave rise to ONP. The combel tells me, Weve had a steady stream of pany is increasingly recognised as a leading custom from our exhibitions and through developer of nanopore sensing technology word-of-mouth. For us things are certainly for the analysis of DNA, RNA, proteins and looking good! other single molecules. ONP And PlayDNA have been doing a bit of expanded their empire further gene duplication of their own, by spinning this year with the completion of out a new company (MuscleGenes) in cola series of agreements with unilaboration with a medical doctor/PT and versities in Britain and the USA. nutritionist. Soon afterwards, ONPs We got chatting to these two guys at a co-founder and CEO, Gordon wedding, says Decombel, and they were Sanghera, announced that especially interested to hear about the they have raised another 38 DNA Sports portrait. We had a few more million in new funding via a meetings, registered the company and beprivate placement of ordinary gan selling last month. Networking at its shares in the company, bringfinest. ing the funding raised so far to 125 million.

Another Red Herring

Biobusiness
Photos (3): Begbroke Science Park

6-2013

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the start we had not had the support provided by the people and facilities at the Diagnox labs.

Indeed, at least one of the above-mentioned companies has reason to echo this optimism. OGT are on a roll this year with a series of launches, including a next-generation sequencing service (SureSeq) for profiling solid tumours. It screens for mutations in 58 genes implicated in breast, prostate, ovarian, lung and colorectal cancers. OGT claims to be the first commercial facility in the UK to offer this service. OGT are also starting up development of an auto-antibody biomarker panel for diagnosing systemic lupus erythematosus. The platform detects auto-antibodies, a class of proteins that show up several years before the clinical symptoms of the disease and distinguishes it from confounding diseases such as rheumatoid arthritis. This suggests that the enthusiasm of OGTs Director of Communications, Stephen Archibald, is genuine. In terms of the business climate, we have actually seen

OGTs series of product launches

To the south of the city of Oxford lies Oxford Science Park, whose business development manager, Ian Macpherson, admitted surprise when asked if there was a sense of gloom in the current economic climate. How can anyone be optimistic with Big Pharma pulling out of research? The closure of many major Big Pharma research centres obviously can have a devastating effect, says Macpherson. On the other hand, he even believes that, with the loss of in-house research, more Big Pharma companies are looking to the university research base and working

Devastating or beneficial?

Edwin Southern founded Oxford Gene Technology in 1995 to commercialise his work in microarrays. 18 years later, OGT are on a roll.

Photo: Jane Glitschier/PLOS Genetics

North of Milton Park, and North of Oxford itself, lies another biotech hot-spot, Begbroke Park. Begbroke is owned and managed by Oxford University and about half of its space is occupied by different university departments. The other half is occupied by start up and spin out companies. Caroline Livingstone, Begbrokes manager, says that, we are very proud of the achievement of all of our companies. I am happy to say that Begbroke Science Park and its companies are thriving despite the economic downturn. Indeed, we have remained full for the last few years now and are keen to expand and grow. Begbroke is definitely open for business! According to Livingstone, Open Innovation is the new buzz phrase the growing trend for large companies to look for their next big idea from the start-up community. She adds that, At Begbroke we have companies who have successfully navigated these potentially difficult waters and achieved good relationships with major players. We also have companies that are growing by their own endeavours and going from strength to strength. The Begbroke companies that spring to mind in the biotech arena are Oxford Gene Technologies (OGT), Prosensa and Midatech. All three are doing more or less well and have been featured in the press recently.

Another biotech hot spot, Begbroke

Academic Director, Peter Dobson, and park manager, Caroline Livingstone, manage Beg broke Science Park in the North of Oxford. Both are, very proud of their thriving compa nies achievements.

very strong growth during the last couple of years, Archibald told Lab Times. This is a result of a clear strategic focus on high growth markets such as cytogenetics research, the introduction of innovative new products and services, plus expansion into new territories. OGT recently opened their New York office which services the Americas region in November 2012, and the company has seen over 40% revenue growth over the last 12-month period with almost 80% of revenue from exports. Peter Dobson, Begbroke Parks Academic Director, is as upbeat as you would expect, emphasising that, Some of the University nanomedicine research could lift any gloom. There is a growing emphasis on new methods of drug delivery and enhancement of medical imaging using nanoparticles. There are also new protocols for developing antimicrobials using nanotechnology and there are opportunities in these areas for either new spin-offs or collaborations.

more closely with universities and outsourcing research, either via partnerships or licensing deals or acquisition. This appetite continues to attract additional early stage finance from the VC and Angel networks, who now understand the more complicated requirements of investing in the bioscience industry.

According to Macpherson,We have experienced the most successful 12 months since the start of the current economic downturn. The Magdalen Innovation Centre has seen occupancy of its variety of offices and laboratories increase by more than 23% during the year to March 31st 2013, adding, It has been great to see both existing companies expanding and new companies moving to our Park. Given the mostly promising news reported above, it seems that Oxfordshires biotech industry is flourishing. Lab Times will carry on watching the area and investigate whether this impression is true. Steven Buckingham

The most successful 12 months ever

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6-2013

Products

Lab Times
Founded 2006. Issue 6, 2013 Lab Times is published bimonthly ISSN: 1864-2381 Publisher: LJ-Verlag Herfort und Sailer Kai Herfort, Ralf Neumann Office: Alte Strae 1, 79249 Merzhausen, Germany Phone +49(0)761-286869; Fax +49(0)761-35738 Management: Kai Herfort, Tel: +49 (0)761-286869 Editors: Ralf Neumann (Editor-in-chief), Kathleen Gransalke, Kai Herfort, Winfried Koeppelle, Harald Zhringer, Phone +49(0)761-2925884, editors@lab-times.org Reporters: Latika Bhonsle, Steven Buckingham, Florian Fisch, Jeremy Garwood, Karin Hollricher, Madhuvanthi Kannan, Alejandra Manjarrez, Rosemarie Marchan, Ralf Schreck Graphics, Design and Production: Ulrich Sillmann (Art Director), Kathleen Gransalke, Kai Herfort, Winfried Koeppelle, Ralf Neumann, Harald Zhringer Cover Photo: iStockphoto, Editing: Kai Herfort Sales: Advertising Manager: Bernd Beutel Top-Ad Bernd Beutel, Schlossergchen 10, 69469 Weinheim, Germany Phone: +49(0)6201-29092-0 Fax: +49(0)6201-29092-20 info@top-ad-online.de Recruitment: Ulrich Sillmann, Phone +49 (0)761-2925885, jobs@lab-times.org Printed at: Strtz GmbH, Alfred-Nobel-Strae 33, 97080 Wrzburg, Germany Web: www.lab-times.org Webmaster: Carsten Rees, Tel.: +49 (0)761-1563461, webmaster@lab-times.org Prices & Subscription rates: - price per issue: 4.90 - research institutes/units: free of charge - annual subscriptions for companies and personal subscribers: 27.Subscribe at www.labtimes.org/kontakt/sub. html, or mail to: subscriptions@lab-times.org Bank Accounts: - Volksbank Freiburg KTO: 319 0 315; BLZ: 680 900 00; BIC: GENODE61FR1; IBAN: DE24 6809 0000 0003 1903 15

Product survey: Hand-held Dispensers

Step by Step
Repetitive or stepper pipettes are specialised micropipettes adapted for quick sequential dispension of liquids. Electronic steppers may even be an alternative to expensive liquid handling robots.
Though pipetting and liquid handling robots are commonplace in many labs, there is still a lot of manual pipetting left for PhD students, technicians and other lab workers. Setting up a pipetting robot makes sense for high throughput applications but starting a liquid handler to just fill a few microplates or prepare a serial dilution is not very economical. Its a much better idea in these cases to pipette by hand, however, not necessarily with a classical micropipette but rather a hand-held dispenser alias repetitive or stepper pipette. tronic display, electronic with manual tip removal and electronic with electronic tip rejection. At first sight, manual dispensers look similar to micropipettes; however, they significantly differ from their cousins in certain features. The most obvious is a syringe kind of tip locked into the tip holder via a bayonet lock that replaces the typical micropipette tip. Hand-held dispensers work according to the positive displacement principle in contrast to micropipettes, which are based on the air-displacement concept. Positive displacement tips used for hand-held dispensers are basically syringes, with a precision-moulded piston moving up or down the cylindrical barrel that comes in direct contact with the liquid. The liquid is drawn into the syringe with a constant aspiration force, which facilitates ac-

Different formats

Hand-held dispensers are special micropipettes, optimised to accurately dispense repetitive amounts of liquids at a remarkable speed. They are available in four different formats: manual, manual with elec-

Classical micropipettes are perfect for pipetting different amounts of liquids into a limited number of reaction tubes. Dispensing equal amounts of liquids into many reaction vessels, however, calls for handheld-dispensers or stepper pipettes.

Products

6-2013

Lab Times

page 47

curate aspiration and dispensing of viscous or volatile liquids. Positive displacement tips also come in handy to aspirate bigger volumes that, afterwards, can be dispensed in small repetitive steps. They are available in different sizes, ranging from 0.05 ml to 50 ml, with most manufacturers offering at least three volume sizes. The liquids are drawn into the syringe by shifting a filling lever, usually positioned at the lower end of the hand grip. Once the syringe is filled, the liquid may be dispensed by pushing a second lever at the opposite end of the grip or a button on its top. Before dispensing, however, the number of steps must be selected by turning a stroke-setting wheel to the respective position. Depending on syringe capacity and dispensed volume, different numbers of steps are possible. Usually, a table printed on the instrument shows the possible combinations, e.g., 49 steps of 20 l if a 1 ml syringe is used. After dispensing, the empty syringe is released by pushing an ejection key or lever and a new one may be locked in.

only difference that immediately catches the eye is the syringes used as positive displacement tips. All other features, such as grip design, arrangement of keyboard and operation buttons as well as the positioning of the display are pretty much the same as in electronic micropipettes.

L L I K

PILL

All steppers are ergonomic. Really?

Filling and dispensing lever as well as stroke wheel and ejecting key are essential parts of every manual stepper pipette. How these components are arranged and positioned, however, in the hand grip is quite different for every model and certainly has an impact on ergonomics. Of course, all manufacturers claim that their steppers are ergonomic; even the square-edged models with long heavy levers, whose design seems to date back to the nineteen-fifties! These models may be okay for dispensing a few drops but your Lab Times editor wont be too eager to perform extensive dispensing tasks with a stepper, whose grip is shaped like a rectangular stick! Some manual stepper pipettes are equipped with an electronic display that indicates the selected tip size and after choosing the number of steps, displays the dispensing volume. Messing up dispensing volumes should be almost impossible with this feature.

The operator may choose between several programmes, such as pipetting, diluting, multiple dispensing, multiple aspiration or sequential dispensing where aliquots of different volumes may be dispensed. Electronic dispensers use a slightly different tip system than mechanic instruments. The tips (syringes) of manual dispensers usually have a gradation of five and the smallest dispensed volume equals the tip content divided by 50. Most electronic steppers use a gradation of 20 and divide the tip content by 100. Hence, they offer more volume choices, provided that the locked-in tips are compatible with the stepper model and also allow dispensing of odd volumes. Overlooking the many numbers and symbols flickering on the displays of some steppers is not always easy. Some display every single instrument setting, from operation mode, volume, selected tip to aspiration/dispensing direction to battery status, in and out speed and the number of dispensed aliquots.

Different tip systems

deS SharP bLa uraI Sam createS no , PrecISIon y g o L o n h tec te Ledge crea and Know aSter the m
PoLytron Pt-da 2Xec-e116 dispersing aggregate. the master! Ultra-fast crushing of tablets or sugar-coated tablets Extraction of active pharmaceutical ingredients (APIs) Best basis for content analysis and quality control

Fully or semi-electronic

Electronic dispensing

The real dispensing fun, however, starts with electronic hand-held dispensers. No more clumsy filling and dispensing levers, no fiddling around with stroke wheels. Touching an operation button instead will do to start the desired dispensing programme automatically. Electronic handheld dispensers are almost indistinguishable from electronic micropipettes. The

Granted, electronic steppers are much more ergonomic than manual dispensers. Most instruments, however, are not completely electronic, since the tips still have to be removed manually: either by pushing a tip ejection lever or, even worse, by pulling out the tip from a locking mechanism. Thats not only inconvenient or time consuming, it also exposes the operator to a considerable risk if, for example, the tips were used to dispense infectious or radioactive liquids. Using an electronic dispenser with an electronic tip ejection mechanism eliminates this risk; it simultaneously increases the working speed and reduces the workload during extensive dispensing tasks. Electronic dispensers are more costly than mechanical steppers but they are still much cheaper than liquid handlers. Hence, buying a couple of high quality, electronic dispensers instead of a liquid handling robot could be an option for many labs and is certainly worth thinking about. Harald Zhringer

InformAtIons

www.KInematIca.ch/InFo

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Lab Times

6-2013

Products

Electronic Hand-held Dispensers (Table 1)

Company/Distributor Name of Product


Biozym Scientific
Dispenser eLine

Volume range / Number of steps Miscellaneous, Specialities, Generally


1 to 50,000 l 0.05 ml up to 50 ml (12 tip sizes) / Number of steps depending on tip and set volume 1 to 50,000 l 0.05 ml up to 50 ml (12 tip sizes) / Number of steps depending on tip and set volume 1 to 50,000 l 0.05 ml up to 50 ml (12 tip sizes) / Number of steps depending on tip and set volume Volume range: 1 l to 50 ml / Up to 100 dispensing steps n.a.

Price [EUR]
750.-

Hess. Oldendorf, Germany www.biozym.com Contact: Helmut Prechel support@biozym.com Phone +49 5152 9020

Dispenser eLine lite

n.a.

518.-

Ripette genX

n.a.

499.-

Brand

HandyStep electronic

Wertheim, Germany www.brand.de Contact: Kathrin Kraft Phone +49 9342 8080 info@brand.de

Electronic repetitive pipette for positive displacement tips | Automatic tip-size recognition with Brand PD-Tips | Open system accepts most third-party dispenser tips | Modes: Dispensing (DISP) / Auto-Dispensing (Auto-DISP, learn function) / Pipetting (PIP) | Separate speed adjustment for filling and dispensing, independently adjustable Multi-dispensing | Sequential dispensing | Up to 9 protocols | High accuracy | Long lasting lithium batteries

553.(without recharging base and AC-adapter 470.-) On request

Dunn Labortechnik

CappTronic

Asbach, Germany www.dunnlab.de Contact: info@dunnlab.de Phone +49 2683 43094 Capp (Manufacturer)

Single- or 8-channel electronic dispenser / pipettes Single-channel volumes: 2 to 20 l, max. 66 steps; 10 to 100 l, max. 66 steps; 100 to 1,000 l, max. 66 steps 8-channel volumes: 2 to 20 l, max. 66 steps; 10 to 100 l, max. 66 steps; 100 to 1,200 l, approx. 66 steps 1 l to 50 ml / 100 steps 1 step

Eppendorf

Multipette stream

Hamburg, Germany Contact: www.eppendorf.com Phone +49 2232 4180

3 different modes (dispensing, automatic dispensing, pipetting) | 990 different volume settings per Combitip size (9 Combitips in total) | Automatic Combitip recognition and volume calculation via integrated Combitip sensor

On request

Multipette Xstream

1 l to 50 ml / 100 steps 1 step

6 different Modes (dispensing, automatic dispensing, On request pipetting; sequential dispensing; aspiration; titration) | 990 different volume settings per Combitip size (9 Combitips in total) | Automatic Combitip recognition and volume calculation via integrated Combitip sensor Automatic tip size identification to make the pipette easier and faster to use | Intuitive menu-driven operation to enable quick and simple set-up | Large LCD screen so that all operating information is clearly displayed. On request

Gilson

Repetman

Middleton (WI), USA www.gilson.com Contact: sales@gilson.com Phone +1 800 445 7661

1 l to 50 ml (with 8 sizes of Repet-tips)

Mettler Toledo

AutoRep E

Aliquot volume from 1 l to 50 ml

Giessen, Germany Contact: Phone +49 641 5070 www.mt.com

Micro-processor controlled | For highly precise repeat pipetting with negligible user pipetting forces | Dispensing, Auto-Dispensing and Pipetting modes and a Learn function | AutoRep E model reads the volume of each Encode syringe tip

On request

Ritter

Ripette Pro

Schwabmnchen, Germany www.ritter-online.de/en Contact: Phone +49 8232 50030 info@ritter-online.de


Ripette GenX

1 l to 5,000 l / 48 steps

12 tip sizes, 10 volume adjustments and 120 programme On request steps | Due to its low weight most-suitable for long dispensing series | Ergonomic design allows an onehand-operation of volume selection, loading and dispensing of liquids | The dosing table shows all dosing possibilities at a glance for choosing the most-suitable tip for your application Self-controlled tip-selection | Smooth change of the consumables due to electronic tip ejection | The speed adjustment allows to manage the working-process efficiently Unique TipGuide for automatic tip selection | Easy programming, quick and simple to operate | Speed adjustment for aspiration and dispensing | Electronic tip ejection reduces the risk of RSI (repetitive strain injury) Electronic tip ejection reduces the risk of RSI (repetitive strain injury) | Unique TipGuide for automatic tip selection | Comprehensive range of liquid handling protocols with easy programming On request

1 l to 50,000 l

Sartorius

eLine Lite Dispenser

1 l to 50 ml

On request

Gttingen, Germany www.sartorius.com Contact: Phone +49 551 3080 info@sartorius.com

eLine Pro Dispenser

1 l to 50 ml

On request

STARWATCH
Artificial Intelligence made by Hamilton

Increase safety of your automated processes Hamiltons sustainable STARwatch software enables pro-active system service due to a long-term error tracking.
*Elephants are a symbol of wisdom in Asian cultures and are famed for their memory and intelligence.

For more information visit: www.hamiltonrobotics.com

2012 Hamilton Robotics GmbH. All rights reserved.

page 50

Lab Times

6-2013

Products

Manual Hand-held Dispensers (Table 2)

Company/Distributor Name of Product


Biozym Scientific
Ripette

Volume range / Number of steps Miscellaneous, Specialities, Generally


0.05 ml up tp 50 ml (12 tip sizes) / 8 up to 48 steps depending on tip and set volume step 0.05 ml up to 50 ml (12 tip sizes) / 8 up to 48 steps depending on tip and set volume 5 volume adjustments

Price [EUR]
199.-

Hess. Oldendorf, Germany www.biozym.com Contact: Helmut Prechel support@biozym.com Phone +49 5152 9020

Ripette pro

10 volume adjustments

259.-

Brand

HandyStep S

Wertheim, Germany www.brand.de Contact: Kathrin Kraft Phone +49 9342 8080 info@brand.de

Volume range: 2 l to 5 ml / Repetitive pipette for positive displacement tips | Up to 59 different dispensing volumes / One-handed volume adjustment for right- and left-handed Up to 49 dispensing steps operators | Ergonomic eject button for contact-free, safe tip ejection | Easy tip mounting tip simply inserted from below | Open system accepts most third-party dispenser tips 25 l syringes, 50 steps 50 l syringes, 50 steps 100 l syringes, 50 steps 250 l syringes, 50 steps 500 l syringes, 50 steps See above 50 l syringe, 50 steps 100 l syringe, 50 steps 250 l syringe, 50 steps 500 l syringe, 50 steps 80 l cell syringe, 50 steps Designed for serological tests | Precision glass syringes | Repeating dispensing mechanism | Less than 1% variation between the single syringes | PTFE tips

189.(with shelf/ rack mount)

Dunn Labortechnik

Asbach, Germany www.dunnlab.de Contact: info@dunnlab.de Phone +49 2683 43094 Art Robbins Instruments (Manufacturer)

Hand-held 6-syringe dispenser

On request

Hand-held 8-syringes dispenser Tissue typing single microsyringe repeating dispensers

See above Narrow or wide bore syringes | Precision glass syringes | Repeating dispensing mechanism | PTFE tips

On request On request

Cell microsyringe repeating dispenser Lipidic Cubic Phase (LCP) Hand Held Multi Volume Dispenser

For tissue typing plate with 60 or 72 wells | Narrow or wide bore syringes | Precision glass syringes | Repeating dispensing mechanism | PTFE tips For dispensing of viscous solutions | Precision glass syringes | Repeating dispensing mechanism | PTFE tips High precision repeater | Light weight | Robust design | Variety of syringes Integrated step counter | Central Combitip ejector | 20 different volume settings per Combitip size (9 Combitips in total) | Automatic Combitip recognition and volume calculation via integrated Combitip sensor

On request

10 l or 100 l LCP syringe, max. 200 steps 0.1 ml to 50 ml, max. 48 steps 1 l to 10 ml / 100 steps 5 steps

On request

Capp (Manufacturer)

Capp Rhythm Multipette M4

On request On request

Eppendorf

Hamburg, Germany Contact: www.eppendorf.com Phone +49 2232 4180

Gilson

Distriman

Middleton (WI), USA www.gilson.com Contact: sales@gilson.com Phone +1 800 445 7661

3 syringes to cover aliquot volumes ranging from 1 l to 1.25 ml / Up to 125

Control button for volume selection | Distritips syringes available in standard and sterilised versions | Only 3 syringes to cover aliquot volumes ranging from 1 l to 1.25 ml

On request

Labnet International

Labpette R Repeating Pipette

Edison, NJ, USA www.labnetinternational.com Contact: Phone +1 732 417 0700

1 l and 5000 l / 48 pipetting steps

Looks and feels like a standard pipette | Convenient tip selection chart located on body of pipette | Maintenance free | Use with Labnet BioFree dispenser syringe tips

On request

Mettler Toledo

AutoRep S

Giessen, Germany www.mt.com Contact: Phone +49 641 5070

Aliquot range 2 l to 5 ml / Up to 49 steps

Lightweight ergonomic manual version | Easy volume On request setting using the supplied volume setting card | Comfortable and simple to use for up to 49 pipetting steps/ doses without refilling

Peqlab Biotechnologie

hand dispenser Erlangen, Germany www.peqlab.com Contact: info@peqlab.de Phone +49 9131 6107020

peqSTEPPER, mechanical

Dispensing volumes from 1 to 5,000 l / Adjusting wheel with 5 positions to set the dosage volume On request Up to 48 dispensing steps per tip volume | Uses standard commercially available repeating pipette tips | Ergonomic design enables simple single-handed volume selection, loading and dispensing | Chart of dosage volumes can be found at the instrument for selection of the right tip | Supplied with adapter for 25 and 50 ml tips Dispensing volumes from 1 to 5,000 l Lightweight (105 g) | Low maintenance requirements | Ergonomic design and positioning of the dosage button in the upper part of the device | Choose between the highest precision or a maximum of repetitions of your desired dosage volume On request

Ritter

Ripette

Schwabmnchen, Germany www.ritter-online.de/en Contact: Phone +49 8232 50030 info@ritter-online.de

Products

6-2013

Lab Times

page 51

Manual Hand-held Dispensers (Table 2)

Company/Distributor Name of Product


Sartorius
Mechanical Stepper

Volume range / Number of steps Miscellaneous, Specialities, Generally


1 l to 5,000 l / 48 steps Lightweight (105 g) yet robust construction | Maintenance-free design | Compatible with a wide range of dispenser tips | Ideal for dispensing aqueous and viscous liquids

Price [EUR]
On request

Gttingen, Germany www.sartorius.com Contact: info@sartorius.com Phone +49 551 3080

Socorex Isba

Stepper 411

Ecublens, Switzerland www.socorex.com Contact: socorex@socorex.com Phone +41 21 651 6000

10 to 100 l, 50 to 500 l, 500 to 5,000 l / Up to 73 dosing step per volume 5 to 50 l, 20 to 200 l, 100 to 1,000 l / Unlimited number of steps

4-finger activation | Setting knobs bear clear indication of volumes and number of aliquots | Selection of over fifty different volumes | Three positive displacement syringes, colour coded | Self-locking mechanism Microdispensing pipette with three way valve system | Continuous filling and dispensing | Precise volume setting in the l range | Versatile feeding through bottle, tubing or syringe | No need for consumables or tips | Autoclavable fully assembled | Easy In-lab calibration

228.-

Acura manual 865

269.246.231.-

Starlab International

RepeatOne Dispenser

Hamburg, Germany www.starlabgroup.com Contact: Phone +49 40 675 99 390

10 l to 5 ml / Up to 48 dispenses from the same sample

Locking clamp holds the dispenser tip securely in place | On request Conforms to EN ISO 8655 Piston-Operated Volumetric Apparatus | Conforms to ASTM E1154-89 (2003) Standard | Specification for Piston or Plunger Operated Volumetric Apparatus | Conforms to 98/79/EEC In Vitro Diagnostic Medical Devices | 2-year warranty Positive displacement design ensures accurate results, even for viscous, volatile, or other problematic liquids | Lightweight, ergonomic handle and wide finger rest minimise operator hand strain | Operation is simple just attach the appropriate tip size, fill and prime the tip, and dial the selected volume On request

Thermo Fisher Scientific

Finnpipette Stepper Pipetter

n.a.

www.thermoscientific.com Contact: See local website

PCR products from BRAND.


Reliable and reproducible results with high quality PCR plates in standard and low profile version. n Low profile PCR plates reduce evaporation losses and reagent costs n Blue alphanumeric code and cut corner marking n White PCR plates maximise the fluorescence signals of qPCR n Extra-thin wall thickness to provide the optimal thermal transfer and short cycle times Get the new catalog GC 900 at www.brand.de BRAND GMBH + CO KG 97861 Wertheim (Germany) Tel.: +49 9342 808-0 www.brand.de info@brand.de

Always the right plate!

! W E

page 52

Lab Times

6-2013

Methods

Bench philosophy (47): Digital PCR

All or None
Everybody knows digital is (most often) better than analogue. This holds true not only for computers but also for some biological applications.

t didnt take long after PCR burst onto the scene for it to dawn on biologists that quantifying the PCR technique would open up a whole host of new possibilities. After all, plain old vanilla PCR just tells you what sequence is present in your sample, but not how much. At best, the only clue as to how much is there comes from looking at the size of the smear on the gel a crude measure at best. Then along came quantitative (real-time) PCR. Dilute your sample to an appropriate level, run PCR as per the instructions on the packet but stop the reaction every so often and see if you get any detectable product. This tells you when the product reached a threshold, providing in turn a relative measure of how much product you started off with. This is fine and works well in many situations. But it falls down when the amount of the target sequence is very low. And as for being quantitative, well, it only gives you a relative measure, not an absolute one, raising the need for some sort of external calibration. But there is another problem, which arises from the very power of the PCR reaction itself: because it is a chain reaction, it not only amplifies your target but also low levels of near-miss sequences as well. That doesnt happen if you have a lot of your target to start off with, because the target amplification simply out-competes the junk. But when target and junk start from a level playing field, you are just as likely to amplify primer dimers or pseudogenes, for example.

Tiny droplets are used as reaction chambers in droplet digital PCR.

A single target molecule

So, if your target is rare, what you would ideally want is to find some way of increasing its relative concentration. That sounds like putting the cart before the horse but a little bit of lateral thinking shows how it can be done: by decreasing the volume of the reaction. If you take the reaction volume right down, you might, just by chance, get

a reaction mix with one, perhaps two, molecules of your target, along with much less of the junk. This, in essence, is the idea behind digital PCR (dPCR). Split the reaction into thousands of tiny reactions (partitions) until stochastic statistics kick in. You dilute the reaction mix to start with and if you get the dilution just right you will, by the laws of statistics, end up with one molecule of target in some, but not all, reactions. Then you do your PCR amplification and just count the partitions that have a product. The logic is simple: if at least one molecule of target is present, there will be a reaction product, otherwise there will be none. All or none; one or zero. Hence digital. Sometimes, of course, there will be more than one molecule of target in a reaction wont that skew the results? At such low levels, assuming you have got the dilution more or less right, the number of molecules in individual partitions follows a Poisson distribution. There is a simple sta tistical trick called the Poisson correction that can take account of this. There are several advantages of digital PCR over traditional qPCR. Some are typical advantages of digital over analogue: the relative insensitivity to noise, for example. Digital is clean: you just decide whether something is there or not, yes or no. The PCR chain reaction, like a bi-stable switch, lends itself to just this sort of approach. dPCR also gives you the absolute levels of the target the proportion of droplets with product, divided by the total number of reactions, gives you the absolute concentration of target molecules. So, no need for calibration curves. It is also less liable to off-target false positives, because you are dealing with such small volumes, which mean lower

concentrations of pseudogenes etc. dPCR is also robust against another bug-bear of qPCR the destructive effects of inhibitors. So what is the best way of getting the small volumes? Forget buying in thousands of 386-well plates, you need to deal with thousands, if not millions, of micro- or even pico-litre reactions here. In practice, there are two ways you can achieve this: chips or droplets. Chips physically divide up the reactions into tiny chambers, which are then analysed in parallel. But there are only so many miniature chambers you can fit onto a reasonably-sized chip and this effectively reduces the dynamic range of the assay.

Enter microfluidics: use oil to separate your reactions into an emulsion of tiny droplets. The advantages of droplets over chips are obvious you can do more, and faster. The microfluidics cupboard is stocked full of tricks and techniques to make uniformly-sized aqueous droplets and move them about, merge them, split them, heat them and measure them. You also run less risk of contamination a major issue when you are dealing with single molecules because your reaction mix never sees the same chamber twice! So much for the theory is there actually any evidence that dPCR out-performs good ol qPCR? Surprisingly, this question has been given scant empirical evidence, until recently. This year, Chris Hindson and his colleagues gave an answer to the question in a Nature Methods paper (doi:10.1038/nmeth.2633). The group did the obvious test: take some RNA sequences and prepare your own gold standard material, and see who does best at detecting and measuring it a dPCR/qPCR head-tohead.

Droplets or chips?

Methods

6-2013

Lab Times

page 53

The team took six human microRNAs and performed nested, serial dilutions, which were then put through droplet dPCR and a standard qPCR. They used synthetic oligos, so they knew what they were probing for and ran the experiment in two conditions: one in which the oligos were diluted in pure water and another where they were diluted in plasma RNA from a healthy human donor. They found that while dPCR was no more sensitive than qPCR, it was very much cleaner the coefficient of variation between the reported concentrations of target and the actual values was some 80% less for digital. This advantage held, regardless of whether plasma or water was used as the diluent. They then ran the two methods head-to-head on sera from people suffering advanced prostate cancer compared to healthy controls. This is because advanced prostate cancer is signalled by the presence of one of the microRNAs in the blood. Digital PCR achieved a p-value of less than 0.005, compared to more than 0.1 for qPCR. Admittedly, Hindson works for BioRad, a manufacturer of a droplet dPCR device. But the general consensus is that dPCR is, indeed, cleaner and more reliable than real-time PCR when you are trying to detect small levels, where it is emerging as the method of choice. Keith Jerome, for example, of The Vaccine and Infectious Disease Institute at the Fred Hutchinson Cancer Research Center, Seattle, WA, reported that when they tested samples they had deliberately seeded with inhibitors, they found droplet dPCR much more robust than qPCR (www.clinchem.org/content/early/2013/08/28/clinchem.2013.211045.full. pdf).

But as with all new techniques, several notes of caution need to be sounded. dPCR may solve a lot of qPCRs problems but it doesnt solve them all. For instance, there is nothing to stop sequences similar to the target occasionally still being amplified, such as pseudogenes, resulting in false positives. There is also a lower limit to the rarity of the sequence that can be detected: if a sequence is only present at one molecule per 100 microlitres, you may not pick it up unless you run your dPCR on at least that volume. You also have to get the dilution factor right too much or too little and you lose accuracy.

4t Matthes + Traut Darmstadt

Stain it.
the non-toxic answer: Say Yes to No.

DNA staining with DNA-Dye NonTox

DNA-Dye NonTox

Things to consider

Detecting rare copies

And there is no lack of applications in this area crying out for better methods of detecting rare copies. Take HIV, for one example. Earlier this year, Matthew Strain and others reported in PLoS ONE that the very features we have talked about make it an attractive approach for measuring HIV in clinical DNA samples (PLoS One 2013; 8(4):e55943). In another application, Dany Morriset and colleagues showed how the selling points of dPCR can help to detect something sniffy in our food in this case, markers for genetically-modified organisms (GMOs). They claim that it was cheaper and more reliable in detecting GMOs in the complex, dirty matrices we find in tins on supermarket shelves. Any horsemeat in there, I wonder?

And of course there are the usual dangers when you work on quantal numbers for instance, if the target molecule drops out of your reactions, you will critically underestimate its abundance. Finally, things can also get a bit complicated if it is DNA you are after rather than RNA, because complementary strands of denatured DNA might partition into more than one reaction. Indeed, the dangers of overconfidence in the technique have provoked the recent publication of a set of guidelines for the minimum information for publication of dPCR papers (Hugget et al., 2013, Clinical Chemistry 59:6). If you are unsure of whether to leave the qPCR comfort zone and launch out into the uncharted waters of dPCR, fear not. Manufacturers of dPCR devices are aware of this anxiety and their trend so far has been to market devices capable of both qPCR and dPCR. The four main players in dPCR technology are Life Technologies, Fluidigm, BioRad and RainDance. The first three offer chip-based devices, whereas BioRad and RainDance take the droplet approach. So, should I go for chips or droplets? You may be tempted by the price: any dPCR machine will set you back about 75.000 to 150.000 but chip-based devices are around 50 % more expensive. Droplet devices have considerably higher throughput, while manufacturers of chip devices claim their approach has higher accuracy. Steven Buckingham

No mutagenicity No toxic waste No effect on DNA structure and integrity No loss of functional DNA after gel extraction No complex application Replace Ethidium bromide for bright signal with the safer dye! Sensitive like Ethidium bromide only better!

Fancy composing an installment of Bench Philosophy?


Contact Lab Times E-mail: editors@lab-times.org
There is another top address in Darmstadt: AppliChem GmbH Phone +49 6151 93 57-0 service@de.applichem.com www.applichem.com

page 54

Lab Times

6-2013

Methods

Tips and tricks of the trade

The pitiable sight of a messy bench is not only discouraging when starting the workday. Working in a disorganised lab may also cost you time and money.
Lab Hin t hen I started grad school, the word organisation was synonymous with time spent not invested in research. With time, however, I learned that through organisation, I could actually save both money (for my PI) and time (for myself). This is simply because being organised means being efficient and efficiency means using fewer resources to reach the same goal. That simple! Through trial-and-error and lots of reading on the web, I have developed a systematic way to organise my bench, store samples and document experiments, all to be easily searched and identified. Is a messy bench the sign of a busy scientist or a disorganised one? Though it requires a bit of planning and some upkeep, a smartly organised bench can lower stress, reduce errors and is the simplest way to increase your efficiency. Consider seven starting tips: Keep all your pipettes and tools on the side of your dominant hand. Place the trash bin on the same side. Set frequently used solutions on the other side of the bench. Store stock solutions and less commonly-used solutions or devices on the upper shelves. Keep the number of stands and tip boxes to a minimum so that the centre of your bench is an empty workspace. Lay your lab notebook as far as possible from the experimentation area and potential chemical spills. Retain your own scissors, labelling tape, paraffin, Kimwipes and marker. Doing so, eliminates frequent walks around the lab and encourages good labelling habits at the bench. (Its not a bad idea to write your name on these items, too.) A group of more than 400 researchers answered a recent survey on the lab ordering process, conducted by the makers of the research and lab management software, Labguru (www.labguru.com). The results painted a worrisome picture. Although PIs or lab managers approved most orders, approximately half of the respondents reported that their lab wastes money each month on duplicate orders, resulting in an estimated yearly cost of at least 1,800 ($2,400). Three-quarters of the respondents reported finding their stocks unexpectedly depleted each month, which delayed most respondents experiments by approximately six weeks per year. Thats a lot of time wasted simply due to a lack of organisation. In the lab of Raz Zarivach at the Ben Gurion University of the Negev in Israel, where I conducted my PhD studies, there is a strict rule only the lab manager can place orders, not even the PI himself has access to the ordering system! This solution eliminates any order duplication and requires lab members to raise a flag when a reagent or a chemical is close to depletion. The result: our lab has never wasted money on duplicated samples. planned an experiment during my two-hour commute to the lab and consulted with my PI about the protocol once I arrived. Then I would run my experiments, collecting the data as digital images. On my way back home I would organise all the data, results and conclusions. If time allowed, I planned and reviewed the follow-up experiments. Ive continued in this manner for the rest of graduate school but with fewer check-ins with my PI, since Im no longer a novice.

Digital lab organisers

Identify weak spots

Reward yourself

One way to encourage good habits is to subject yourself to operant conditioning. Try the Martini Method: reward yourself when you have had a productive week or one, in which you were well organised.

Another method to increase efficiency and reduce experimental error is Good Research Practice (GRP), the sibling of the biotech industrys Good Laboratory practice (GLP). The goal is to identify weak spots and required controls before you encounter them in real-time and have to repeat the experiment. According to GRP, one should take the following measures before conducting an experiment: plan and allocate materials and resources, think through the physical motions of performing the experiment, identify potential pitfalls in the protocol and have your PI or lab manager approve a documented experimental plan, if possible. While it might sound tedious and elaborate, GRP can eventually become second nature. In fact, this was my method of work in the first and crucial year of my PhD, when I learned the ropes of protein expression, purification and crystallization. Each day, I

As the size of a lab grows, it is increasingly difficult to coordinate lab meetings or any other lab event. Moreover, a lab can have several instruments that if not scheduled or maintained properly can produce bottlenecks and throw a wrench into experiment plans. If your lab still uses a whiteboard or pen and paper, stop! Advocate for a research management web app or Google Calendar for booking instrument time or lab chores. This has the added benefit of providing an overview of everyones workload, too. You can also try apps like Doodle for finding a good meeting time for a big group. Cant be bothered to implement these tips? Consider this point: In that same Labguru survey, researchers were asked if they felt their lab was efficient. Nearly 80% of respondents said no. Thats four days out of a five-day work-week. Now extrapolate the data: How many weeks or months does inefficiency delay a graduate students defence or the submission of a manuscript? As I see it, academic labs are not doomed to this fate. It is the responsibility of all lab members students, lab managers and PIs alike to proactively develop more professional habits to get the most of their resources and to do more good science. Chen Guttman

Do you have any useful tips? Contact us at:


editors@lab-times.org

Photo: Labguru

Cure for Bench Chaos

New Products

6-2013

Lab Times

page 55

New Products
3D Localization Microscopy ELISA
mators with high blocking efficiency and high f-number (increased transmission) for filter-less measurements of absorbance and fluorescence. For utmost sensitivity in luminescence, a third specially selected and extremely noisereduced detector is engaged in the HiSens position which is used for Alpha and BRET readings, too. Up to 4 reagent complete the unit. The injector tips are located in reading position enabling the accurate measurement of very fast reactions. A new feature is the reagent compartment at the front which keeps the reagents within easy reach and which can be filled with ice to keep them cooled. Advantages: Mithras offers the possibility to use optical filters for luminescence measurements (of course, for all fluorescence and absorbance readings, too) enabling the sensitive measurement of BRET (e.g. functional assays in GPCR research) and multi-coloured luciferases (reporter gene assays). Each individual filter is coded with an RFID tag and can be positively identified. More Information: www.licor.com

Product: Super-resolution microscope Name & Manufacturer: SR GSD 3D from Leica Microsystems Technology: Based on GSD (Ground State Depletion) or dSTORM technology, the widefield fluorescence microscope attains resolutions of down to 20 nm in the lateral and 50 nm in the axial direction. It is equipped with a 160x highperformance objective specifically developed for super-resolution microscopy. Its design is optimised for high-power laser emissions. Advantages: The instrument is based on a fully automated TIRF system (Total Internal Reflection Fluo rescence), allowing super-resolution to be combined with TIRF microscopy. The system can also be used for a wide variety of applications in all fields of live cell or advanced fluorescence microscopy. More Information: www.leica-microsystems.com

Product: ELISA Kits Name & Manufacturer: SimpleStep von Abcam Technology: SimpleStep ELISA kits are single wash, colorimetric sandwich ELISAs which retain the familiar process and data outputs of a traditional ELISA kit. The kits require no specialised training or instrumentation and, in contrast to standard ELISA, achieve increased accuracy due to reduced sample handling steps. Additionally, a more efficient in-solution binding process provides superior sensitivity and specificity. Advantages: The new kits have a greatly simplified protocol when compared to standard multistep ELISAs, providing significant time savings and ease of use. More Information: www.abcam.com/SimpleStep

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Product: Microplate Reader Name & Manufacturer: Mithras2 from Berthold Technologies Technology: The optical concept ONE-4-ALL is employed for sensitive luminescence, fluorescence and absorbance measurements with performances as in dedicated instruments for filter-based reading. Additionally, the instrument is equipped with two double monochro-

Product: Imaging system Name & Manufacturer: ImageXpress Micro XLS from Molecular Devices Technology: The system includes environmental control, on-board liquid handling, and brightfield capabilities for label-free cellular monitoring over time-lapse experiments. A variety of light engines is available at time of purchase. Advantages: With a screening capability of >50,000 wells per day, the system allows for faster characterization of highly heterogeneous samples from large, diverse populations, and identification of rare sub-populations. More Information: www.moleculardevices.com/hc

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Book Review

Book review: Genome-Wide Association Studies and Genomic Prediction

A Guide to Genome Glancing


Genomes, big data and new age medicine. Whats the connection? Another new specimen from the popular Methods in Molecular Biology series joins the dots. Laymen, however, should stay away.
enome sequencing and advanced computing technologies play a large role in understanding the complex ity of living systems. Genome Wide Association Studies and Genomic Prediction (Methods in Molecular Biology, vol. 1019) is a prac tical guide for experts to obtain, qualify, and statistically analyse data on ge nomes and to support geno type-phenotype information. In a growing field, this is the first hands-on book for experts in a relatively new discipline. Biologists and computer ex perts are working out how to better use expertise from each field. One recent attempt is to statistically scan the genom es based on Single Nucleotide Polymorphism (SNP) markers, for differenc es in their frequencies and numbers, and to associate them with complex traits or dis eases. This shift from identifying a candi date gene to candidate genomic regions attempts to pave the way towards finely tuned agriculture, personalised medicine and a better understanding of basic biolog ical complexity. The number of such Ge nome-Wide Association Studies (GWAS) have grown rapidly since the first study al most a decade ago. Thus this discipline is indeed thirsty for good textbooks both for beginners and experts. How suitable is this book for an enthusiast in the field?
Image: Soberve/iStockphoto

ty of New England (New South Wales) and Ben Hayes from the department of Primary Industries, Victoria, Australia. Experts, beginners and enthusiastic readers will all look for a good introduc tion to the field, whether to brush up on basic knowledge or to hear differing view points on the subject. GWAS is a complicated topic that re quires an initial investment of time. When it comes to speci fic terms like linkage disequilib rium, odds ratios and so on, it would be nice to have an intro ductory chapter and a thorough glossary at the end of the book. Your reviewer was disappoint ed to find the introduction lim ited to a preface and searched in vain for a glossary. Another issue is chapter organisation. After scanning through the book for some time, one can only guess at what the ran dom chapters tell you about statistical pro gram packages, databases and how to use them to design, carry out and make use of GWAS.

lyse genomic data is ample and clear. The practical implication of vali dating a GWAS is meticulously detailed in a separate chapter.

The 26-chapter tome was edited by three Australian scientists: Cedric Gondo and Julius van der Werf from the Universi Er rat u m

The discipline longs for good books

In the last issue of Lab Times, we inadvertently attributed the wrong cover to Exploring Personal Genomics (page 56, Hold on to Your Genome!). This is the correct image. Were sorry.

Otherwise, the book is too good to ig nore once you start reading and pick up in formation along the way. This is in fact a reference book for your genomics lab that you cannot whizz through in one go. There is good information about using the opensource statistical program Suite R in the first chapter. Other chapters cover, along with R coding scripts, how one can use modules of R for various GWAS purposes. Another good thing about the book is the clear picture that it gives of GWAS design and how to enhance its pow er (for instance by a clever choice of samples, managing their data before and after the experiments for decent anal ysis). The information on the significance of data quality control, and methods to ana

The significance of data quality control

The field of GWAS is also useful in plant and animal sciences. However, the book covers this application of the subject in only a few chapters. Otherwise, it is rich ly packed with statistical tools and notes to identify genomic regions for selected phe notypes and to predict their associations (in different sample sizes or with prior knowl edge of the phenotypes). The readers hopes are naturally high as the book comes from a popular se ries and is written by scientists from var ious walks of life. As expected, the book does not disappoint the reader outright, but would have been better without the above dents. One hopes that the next edi tion will fill existing gaps. But if you are new to the field, this book will certainly extend you a warm welcome to the tricky world of GWAS. Vijay Shankar

Richly packed with statistical tools

Genome-Wide Association Studies and Genomic Prediction, by Cedric Gondro, Julius van der Werf and Ben Hayes (Eds.). Methods in Molecular Biology Series, Vol. 1019. Springer Protocols / Humana Press, 2013. 566 pages, 134.

Careers

6-2013

Lab Times

page 57

Career strategies for young European scientists (XLV)

Observations of a Frustrated Scientist


You may know him from our One Fine Day in the Lab cartoons, but Leonid Schneider is concerned about the world of science in text form, too. Here are two short essays about modern scientists daily struggles.

...MUst Publish in Nature...

A Postdocs Short Guide to Publishing High

mpact factor is everything. If you do not publish high enough as a postdoc, then hopefully your boss still has a job for you. On the other hand chin up, there are many alternative opportunities. Why not open a caf, for example? In order to publish high, however, there are a couple of things you need to concentrate on. Of course, if you are very smart and prepared to work a lot and take initiative, you may eventually get lucky. But even this is in no way guaranteed. There are a lot of very smart, hardworking ex-postdocs out there who are wishing they had enough money to make a fresh start, right now. Host lab: It all starts with a lab to go to for your postdoc. Well, it starts with your PhD lab really, as you need to convince your prospective employers not to delete your application e-mail right away. But your postdoc lab is decisive. By definition, only well-equipped labs run by Principal Investigators (PIs) with their own high-impact publishing record can participate in the high-impact publishing game. Technology and budget are, therefore, the main aspects but the PI him/herself is certainly another. Principal Investigator (PI): There are various reasons how successful PIs became what they are now. Mould your scientific personality to that of your prospective employer, unless you are really keen on finding out who wins the argument on being the better scientist. Most successful PIs follow a theory-based approach: they use their experience, intelligence and knowledge of what is hot in the field to develop an exciting scientific theory, which is guaranteed to get published high and to bring lots of grant money. Remember the thumb rule: big PIs also publish big. When you work in their lab, listen and learn e.g. how they sweet-talk the editor or discredit a referee. Project organisation: Your goal is to publish and this means you need data at best, data that experimentally supports your PIs theory. Thus, get your PIs favourite project of interest assigned to you or at least convince your PI that your project is the most interesting and promising. Show intelligence in anticipating your PIs ideas, applaud them and enjoy together refuting external critics as incompetent and inferior. Remember the addendum to the thumb rule: big PIs also publish big but not everyone in their lab does publish. It is sad when some people are not capable of producing sufficiently convincing data needed to support their PIs theory. Experiments: Hence, do your best to produce the results you and your PI agreed to be necessary for a high-impact publication.

Do not become discouraged by experimental outcomes, which do not fit the exciting theory that you and your PI had initially developed. Usually, they come about due to technical difficulties. Normally, if you repeat an experiment often enough you will finally see the predicted result (or a close approximation, at least). Work towards a simple, streamlined but incredibly sexy story, just as your experienced PI desires. One gene alone (the one your lab is working on) is responsible for cancer, you get the idea? Collaboration: Delegate as much work as possible. There are a lot of skilled and capable people out there who would do everything to rescue their failing career by getting on your high-impact paper. Use their hard work and their technologies to produce the key data for your paper. They should always be aware, which experimental data you expect from them if they want an authorship. Moreover, when collaborating yourself on their projects, dont forget to generously share a key reagent with them and, when the time comes, remind them on it in terms of authorship, of course. Authorships are not assigned according to who worked how much on the project but according to the individuals importance. If you have dealt smart, you will become first author without actually having produced much of the data. On the other hand, you need to abide some senior PIs to authorships on your paper to help it get published or because they are powerful enough to demand this. Revision: This is when you should quench the last of the socalled science ethics. You were told which theory you exactly needed to experimentally prove in order to get your paper accepted. The perspective that your career is now ready to skyrocket should motivate you high enough, shouldnt it? No need to explain more When your paper is finally accepted by the publishing olymp, you are ready to join the gods yourself. You can start your own lab and write your own grants. Remember what you learned from your PI and promise to cure pharma-relevant diseases by pursuing whatever is hot in your field now just to get the third-party money rolling. And note that your impact factor is now your greatest argument: it definitely helps the referees to save time when deciding on your application or your grant proposal I wish I had this guide when I was doing my PhD

Leonid Schneider

Cartoons (2): Leonid Schneider

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Careers

Careers in academia

The Hierarchy of Science

g! n i d n u More f me! a More F ry! lo g e r o M

t the end of studying life sciences at university, you are likely to be excited and eager to join the scientific community. You admire the all-knowing but detached professors, your highly intelligent and capable postdoc tutors (who you probably expect to become professors any moment) and even the PhD students, who are already doing great science although they are nearly your age. You decide to do a PhD as well and march through the ranks to become a great scientist yourself. This text is to stop you right in your tracks. A PhD is a great thing to put before or after your name. It signifies someone is highly intelligent and has produced previously undiscovered knowledge through his/her own scientific work. Or so it is said. Never mind the reasons for young graduates to pursue a PhD, what is in it for the professors and group leaders? Science is not a charity; it is a race for survival with evolutionary pressure for the best scientists to get to the top (whatever best means). So why invest your time and energy tutoring PhD students, many of whom are more interested in getting a PhD rather than in being a scientist? Because a principal investigator, the PI, whose job it is to obtain money to design research projects to obtain more money to design more research projects, still needs someone to actually work in the lab. Someone who will do as they are told, yet still works without the need for excessive guidance, even late in the evenings and on weekends. And PhD students are ridiculously cheap and cannot leave for several years, until their PhD defence is approved. No other academic professional outside of life sciences would work for this petty money, not even for the prospects of a PhD title. A PhD student is the poor PIs laboratory tool. And when you used the PhD students

work to progress to a higher financing level, you progress to more advanced technology: postdocs. Postdocs are wonderful and versatile tools to have in the lab, from a PIs point of view. They are highly educated, have many years of research experience, can work independently and are still humble employees with little claim to anything. The PI still decides where their research goes and if or when it will get published. Good postdocs even have really smart ideas and can drive the entire project all by themselves, but the PI gets all the official credit as the last and corresponding author. You can delegate teaching and organisational work onto postdocs, plus they can be made responsible for the performance of PhD students on the projects you assigned. Yet one of the best things is that postdocs still cost little; in fact, often enough, you dont even have to pay their social insurance or even their salary, as they live off their own fellowships. The whole idea behind postdoc fellowships is very clever. Their purpose is to help aspiring young scientists finance their own research ideas in a lab of their choice. Or so it is said. In practice, only at the PI level are you qualified enough to develop and pursue your own projects (and employ postdocs for this purpose). Now, the real idea of fellowships is to provide the PI with a smart source of thirdparty funding. Unfortunately, one still needs to put forward a postdoc to submit it, as a formality, as indeed why would anyone be interested in reading the immature fantasies of a lab member? So, for a postdoc fellowship proposal to have a realistic chance, it is designed by a qualified PI in advance, who then goes on to recruit

Science is a race for survival

Careers

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Lab Times

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Careers in academia
a suitable postdoc to submit it. The good thing is that there are so many of them squabbling for a job out there, as you and your colleagues kept producing so many job-seeking PhDs during your leaner years. Some scientists (real ones, with their own groups) seriously suggest postdoc-ing should become a proper profession. There are, however, certain flaws to this idea. Of course, while everyone can command a bunch of young students or technicians, doing so to senior scientists around the age of forty is certainly good for the PIs ego. Yet, the postdocs age could become a problem: the older they get, the lazier they become. Some even start leaving before 7.00 p.m. and stop working weekends. But not only workload-wise, eventually they cant be bothered with moving institutes, countries or continents. Furthermore, the postdoctoral age often coincides with reproductive activity so far, you have given them their chance but you really have to let them go if this happens. In the end, you need to reach a certain impact factor to become a PI and the road there is paved by the hard work during your postdoc-time, as every Professor and PI will tell you. Thus, old postdocs are more of a nuisance. They spend their day worrying about the threat of unemployment and lack of pension benefits instead of working. The criteria for advancing your career to the junior group leader position and beyond are somewhat obscure. As a junior PI or assistant professor you can officially boast of being independent, just never forget whose bread you are eating. Indeed junior group leaders are likewise a smart source of third-party funding to powerful professors and directors above them. The young PIs do not get recruited for having excitingly interesting ideas but because the institutes senior directors need someone of certain skills to develop their narrowly defined research interests. As these people decide your professional fate, you better be loyal and useful for them. Also, a PI without tenure is constantly under pressure to obtain money to design research projects to obtain more money to design more research projects, and is therefore even more anxious than a postdoc. The age is often more advanced and the financial status is scarier to lose. The tenure is the ultimate goal. From the point of financial security, not much can threaten you now. But sometimes still, your ambition to get even higher and to become more influential eats at you. Now, it is the small incompetent people in your lab, who are apparently conspiring to deliberately obstruct your success and recognition as the leading scientist in your field. You get annoyed at their arrogance of thinking their ideas are as good as or even better than yours. Remembering how hard you had to work to get where you are, you wonder how they plan to get anywhere at all with their attitude. You notice you are not really popular as their boss and begin to get slightly paranoid, looking for a loyal and career-oriented lab member to help you keep this incompetent treacherous lot under control. But again, science is not a charity, and the institutional selection will take care of the fit and unfit, at some point. Do you feel fit enough?
Leonid Schneider

Young PIs are not recruited for having exciting ideas

The article first appeared at www.labtimes.org on July 19th, 2013.

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Job Appointments

I N T E R N AT I O N A L RA M M E Ph D PR OG MAINZ, GERMANY
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Bild: pkchai, shutterstock.com

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D Bioinformatics & Systems Biology B
PROGRAMME THEMES: Epigenetics, Transcriptional Control & Dynamics, RNA Biology, DNA Damage & Repair, Chromatin Biology,
This programme is supported by the Boehringer Ingelheim Foundation

For further Information, please see www.imb-mainz.de/PhD or contact us at PhD@imb-mainz.de. Apply by 25th November 2013.

INTERNATIONAL PhD
So you work in Life Science Research in a North or Eastern European country and want to try Freelance Writing? Contact editors@lab-times.org
Affiliated with the University of Basel

PROGRAM
IN BASEL, SWITZERLAND Application information: www.fmi.ch/training/phd Application deadline: November 30, 2013 Next deadline: May, 2014

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.

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Conferences

6-2013

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Calendar
2013
19-24/10 San Feliu de Guixols (ES) EMBO Conference on Comparative Genomics of Eukaryotic Microorganisms: Patterns of Complexity in Eukaryotic Genomes, Info: www.fems-microbiology.org 20/10-24/10 Stresa (IT) ESF-EMBO Symposium on the Neurobiology of Action, Info: www.esf.org/conferences/13426 21/10-22/10 Luxembourg (LU) From Systems Biology to Systems Medicine: 2nd International Systems Biomedicine Symposium, Info: sysbiomed2013.uni.lu 22/10 Frankfurt (DE) International Symposium on Membrane Kinesis Shaping and Transport of Cell Membranes, Info: www 2.uni-frankfurt.de/46363756/merz 22/10-24/10 London (UK) Translational CNS Summit: New Strategies, Imaging, Biomarkers, Animal Models, Info: translationalcns-london.com 23/10 London (UK) Abcam Cell Cycle Club, Info: www.abcam.com 23/10-24/10 Tuebingen (DE) 1st International mRNA Health Conference, Info: www.mrna-conference.com 23/10-25/10 Leipzig (DE) World Conference on Regenerative Medicine, Info: www.wcrm-leipzig.com 23/10-25/10 Reims (FR) 23rd European Tissue Repair Society Meeting: Stem Cells and Regenerative Medicine, Info: www.alphavisa.com/etrs/2013 23/10-25/10 Torino (IT) 2nd International Conference on Microbial Diversity: Microbial Interactions in Complex Ecosystems, Info: www.biotagr.unipd.it/md2013 24/10-25/10 Schluchsee (DE) International Symposium on Nanoscale Membrane Organisation, Info: www.bioss. uni-freiburg.de/cms/binep-meeting 28/10-30/10 Bielefeld (DE) 8th CeBiTec Symposium: The Genomics Revolution and its Impact on Future Biotechnology, Info: www.cebitec.uni-bielefeld.de 28/10-30/10 Cambridge (UK) Phenotypic Drug Discovery Meeting Maximizing Information in Early Drug Discovery for Better Target and Drug Selection, Info: www.fastcongress.com/ Phenotypic-Drug-Discovery 30/10-1/11 Cambridge (UK) Wellcome Trust Conference on Regenerative Medicine: From Biology to Therapy, Info: www.hinxton.wellcome.ac.uk 31/10 London (UK) Abcam Conference: Cardiac Failure Epigenetics, MicroRNA, Mitochondria, Info: www.abcam.com 31/10-2/11 Berlin (DE) Insulin Club: From Basic Science to Clinical Practice, Info: www.comtecmed.com/insulinclub 31/10-3/11 Luebeck (DE) From Infection to Therapy: Trends in Virology 8th Students Biomedical Symposium, Info: www.lifescience-symposium.de 1/11 Amsterdam (NL) Trippenhuis Meeting: From Stem Cells to Aging, Info: www.cell-biology.nl 1/11-2/11 Vienna (AT) Mind the Gap 4: Bridging the Gap Between Theoretical and Empirical Population Genetics, Info: www.popgen-vienna.at 1/11-3/11 Groningen (NL) International Conference on Individual Differences: 20th Royal Dutch Zoological Society Zoology Conference, Info: www.rug.nl/fwn/indiv 2/11-6/11 Roscoff (FR) Jacques Monod Conference on Ecological and Evolutionary Perspectives in Cancer, Info: www. cnrs.fr/insb/cjm/cjmprog_e.html 3/11-5/11 Heidelberg (DE) EMBL Conference: Cancer Genomics, Info: www.embl.de/training/events 4/11-5/11 Cambridge (UK) 8th International MicroRNAs Meeting & 3rd Single Molecule/ HT Biology Europe Meeting, Info: expressgenes.com/ micrornai2013/main.html 4/11-5/11 London (UK) Stem Cell Congress 2013, Info: www.stemcell-congress.com 4/11-5/11 London (UK) 2nd Annual Cell Culture & Bioprocessing Congress 2013, Info: www.cellculture-congress.com 4/11-6/11 Weimar (DE) 17th STS Meeting: Signal Transduction Receptors, Mediators and Genes, Info: www.sigtrans.de/events/rmg2013 7/11 London (UK) Recent Advances in Molecular and Cellular Pathology, Info: www.regonline.co.uk/Pathology13 7/11-8/11 Heidelberg (DE) 14th EMBO-EMBL Science and Society Conference: Public and Private Health Genomics, Medicine and Society, Info: www.embl.de/training/events 7/11-8/11 Wien (AT) Vienna Biocenter (VBC) PhD Symposium 2013: Time How Nature Sets the Clock, Info: www.vbc-phd-symposium.at 7/11-10/11 Cambridge (UK) Wellcome Trust Conference on Epigenomics of Common Diseases, Info: www.hinxton.wellcome.ac.uk
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11/11-12/11 Granada (ES) 2nd Neuron Bio Symposium: Discovery Platforms for Alzheimer Disease, Info: www.symposiumneuronbio.com 11/11-13/11 Geneva (CH) European Antibody Congress 2013 Where Global mAb, ADC and Biosimilar Stakeholders Meet to Do Business, Info: www.terrapinn.com/2013/ european-antibody-congress 12/11-13/11 Geneva (CH) World Biosimilar Congress 2013, Info: www.terrapinn.com/2013/ biosimilars-congress 12/11-13/11 Muenster (DE) 10th Mnster Conference on Single Cell and Molecule Analysis Progress in Research and Technology, Info: http://campus. uni-muenster.de/ifg_sica.html 12/11-15/11 Avignon (FR) International Conference on Development & Genetics, Info: www.sfbd.fr/meeting 15/11 Muenster (DE) 4th Mnster Immunology Meeting, Info: www.cim-imprs.de 14/11-15/11 Geneva (CH) World Orphan Drug Congress 2013, Info: www.terrapinn.com/ 2013/world-orphan-drug-congress 14/11-15/11 Heidelberg (DE) EMBL Conference: Genome Editing Using Zinc Finger Nucleases, Info: www.embl.de/training/events 17/11-20/11 Ringberg (DE) International Symposium on Giant Virus Biology, Info: www.mpimf-heidelberg. mpg.de/11304027/ Symposium-Giant-Virus-Biology 18/11-19/11 London (UK) 5th Annual Next Generation Sequencing Congress, Info: www.nextgenerationsequencingcongress.com

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6-2013

Conferences

19/11-20/11 Manchester (UK) Advances in Recombinant Protein Technology, Info: www.elrig.org 21/11-22/11 Barcelona (ES) Barcelona Conference on Epigenetics and Cancer, Info: www.imppc.org/congress/bcec1 21/11-23/11 Cambridge (UK) Wellcome Trust Conference on Functional Genomics and Systems Biology, Info: www.hinxton.wellcome.ac.uk 21/11-23/11 Heidelberg (DE) 15th EMBL PhD Symposium: Competition in Biology Race for Survival from Molecules to Systems, Info: www.embl.de/training/events 21/11-24/11 Antalya (TR) 2nd Anticancer Agents Congress: Targeting Cancer Stem Cell, Info: www.cancerresearch2013.org 23/11 Duesseldorf (DE) BMFZ Meeting 2013: New Insights in Epigenetics: From Gene Regulation to Clinical Application, Info: www.bmfz.de 24/11-26/11 Wittenberg (DE) 24th Joint Glycobiology Meeting, Info: www.glycobiology2013.net 25-26/11 Egmond aan Zee (NL) Systems Biology Symposium: From Molecular Networks to Phenotypes, Info: www.ncsb.nl/sbnl2013 25/11-27/11 Malaga (ES) 2nd Applied Synthetic Biology in Europe, Info: www.efb-central.org/ index.php/syntheticbiology 26/11-27/11 Munich (DE) 3rd Munich Biomarker Conference, Info: www.m4.de/mbc 27/11 London (UK) Towards Artificial Cells: Novel Advances in Bottom-Up Cell Design and Construction, Info: www.eventsforce.net/iop/417 27/11-29/11 Warwick (UK) Glyoxalase Centennial: 100 Years of Glyoxalase Research & Emergence of Dicarbonyl Stress, Info: www.biochemistry.org/Conferences

28/11-30/11 Berlin (DE) 2nd European Congress on Endometriosis, Info: www.eel-congress.de 2/12 Paris (FR) Brain Crosstalk in Puberty and Adolescence, Info: www.ipsen. com/en/brain-crosstalk-pubertyand-adolescence 2/12-3/12 Amsterdam (NL) BrainModes Symposium 2013: Criticality, Connectivity, and Neural Masses, Info: www.brainmodes.org 2/12-3/12 Brigg/Lincolnshire (UK) Positive Plant Microbial Interactions: Their Role in Maintaining Sustainable and Natural Ecosystems, Info: www.aab.org.uk 3/12-4/12 Nottingham (UK) Functional Proteomics: From Proteins to Organisms Scientific Meeting of the British Society for Proteome Research (BSPR), Info: www.bspr.org/2013meeting 4/12-6/12 Berlin (DE) 4th BSRT PhD Symposium: Regeneration is Communication Fireside Chats between Cells and Matrices, Info: www.bsrt-phdsymposium.de 4/12-6/12 Estoril (PT) International Clinical Genomics & Informatics Conference, Info: www. clinicalgenomicsinformatics.com 5/12 London (UK) Molecular Mechanisms of Targeted Cancer Treatments, Info: www. royalmarsden.nhs.uk/molecular 5/12-7/12 Leipzig (DE) 13th Lipid Meeting Leipzig, Info: www.lipidmeeting.de 6/12 London (UK) Recent Advances in Molecular and Cellular Pathology, Info: www.regonline.co.uk/Pathology13 7/12-11/12 Roscoff (FR) Jacques Monod Conference on Bacterial-Fungal Interactions: A Federative Field for Fundamental & Applied Microbiology, Info: www. cnrs.fr/insb/cjm/cjmprog_e.html

9/12 London (UK) Targeting Cyclic AMP Signalling to Combat Cardiovascular Diseases, Info: www.biochemistry.org/Conferences 11/12-13/12 Braunschweig (DE) 2nd International Thnen Symposium on Soil Metagenomics, Info: www.soil-metagenomics.org 11/12-13/12 Dublin (IE) Epithelia and Smooth Muscle Interactions in Health and Disease (Joint Physiological Society Themed Meeting in Epithelia & Membrane Transport and Vascular & Smooth Muscle Physiology), Info: www.physoc.org/emvs13 11/12-13/12 Macclesfield (UK) Annual Symposium on Biochemical Determinants of Tissue Regeneration, Info: www.biochemistry.org/Conferences 12/12 London (UK) Trends in Drug Discovery Meeting of the Society for Medicines Research, Info: www.smr.org.uk

30/1-31/1 Geneva (CH) Angiogenesis and Leukocytes in Atherosclerosis, Info: www.abcam.com 30/1-2/12 Utrecht (NL) Applied Neuroscience Conference 2014, Info: appliedneuroscience.org/san2014 5/2-7/2 Cambridge (UK) Wellcome Trust Conference on Mouse Models of Disease: Using Pathology Techniques to Enhance Phenotyping Outcomes, Info: www.hinxton.wellcome.ac.uk 13/2-14/2 Cologne (DE) 5th International Symposium on Crossroads in Biology, Info: crossroads.uni-koeln.de 16/2-20/2 Zurich (CH) Mechanics of Biological Membranes, Info: www.csf.ethz.ch/conferences 17/2-19/2 London (UK) Biobanking 2014: Experiences and Challenges of Setting up Biobanks and Biobanking Networks / Biobanking Sample and Data Management: Automation and Best Practice / Sample Processing After Biobanking: Molecular and Non-Molecular, Info: biobanking2014.com 18/2-19/2 Barcelona (ES) 4th International Conference of the Flow Chemistry Society / 7th Annual ADME & Predictive Toxicology Congress / 10th Annual Discovery Chemistry Congress, Info: www.selectbiosciences.com 18/2-20/2 London (UK) Behaviour Meets Biochemistry: Animals Making Sense of Molecules Making Scents, Info: www.biochemistry.org/ Conferences 22/2-28/2 Lucca/Barga (IT) Gordon Research Seminar & Conference: Biology of Acute Respiratory Infection Host-Pathogen Interaction in the Lung, Info: www.grc.org

2014
5/1-7/1 Cambridge (UK) Signalling and Acquired Resistance to Targeted Cancer Therapeutics, Info: www.biochemistry.org/Conferences 14/1-17/1 Cambridge (UK) Wellcome Trust Conference on Fundamentals of Clinical Genomics, Info: www.hinxton.wellcome.ac.uk 22/1-24/1 London (UK) The Impact of Pesticides on Bee Health, Info: www.biochemistry. org/Conferences 23/1 Cambridge (UK) Exploiting Bacteriophages for Bioscience, Biotechnology and Medicine, Info: www.regonline. co.uk/bacteriophage2014 23/1-25/1 Torino (IT) 2nd International Symposium on Peripheral Nerve Regeneration, Info: https://sites.google.com/ site/ispnr2014

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24/2-26/2 London (UK) The 2014 Ageing Summit: The Immunology of Ageing / Biomarkers and Ageing / Establishing Anti-Ageing Medicines, Info: ageingsummit2014.com 25/2-27/2 Munich (DE) Cell Culture World Congress 2014, Info: www.terrapinn.com/ conference/cell-culture 1/3-7/3 Lucca/Barga (IT) Gordon Research Seminar and Conference: Angiotensin New Developments in the Renin-Angiotensin System, from Bench to Bedside, Info: www.grc.org 3/3-6/3 Angers (FR) 5th International Conference on Bioinformatics Models, Methods and Algorithms, Info: www.bioinformatics.biostec.org 3/3-6/3 London (UK) Forensic Forums 2014: Crime Scene Analysis and Victim Identification Forum / 3rd Forum for Disaster Victim Identification / Research in Forensic Mass Grave Victim Identification / Location of the Missing Using Archaeological and Forensic Sciences, Info: www.terrapinn.com/ conference/biopharmabigdata 4/3-5/3 London (UK) World BioPharma Big Data Congress 2014, Info: www.terrapinn.com/conference/ biopharmabigdata 4/3-7/3 Heidelberg (DE) EMBO Conference: Visualizing Biological Data (VizBi), Info: www.embo.org/events 8/3-11/3 Kloster Seeon (DE) 1st International Kloster Seeon Meeting on Mouse Models of Human Cancer, Info: www.vwfb.de 8/3-14/3 Lucca/Barga (IT) Gordon Research Seminar and Conference: Molecular Mechanisms in Lymphatic Function and Disease, Info: www.grc.org

10/3-11/3 Berlin (DE) Lab-on-a-Chip Congress / Advances in Biodetection & Biosensors/ Advances in Microarray Technology / Single Cell Analysis Europe, Info: www.selectbiosciences.com 10/3-22/3 Cambridge (UK) Genetic Engineering of Mammalian Stem Cells, Info: www.wellcome.ac.uk 13/3-15/3 Munich (DE) The Power of Programming: International Conference on Developmental Origins of Adiposity & LongTerm Health, Info: munich2014. project-earlynutrition.eu 15/3-21/3 Lucca/Barga (IT) Gordon Research Seminar and Conference: Autophagy in Stress, Development and Disease The Focus on Selective Autophagy, Info: www.grc.org 19/3-21/3 Edinburgh (UK) Redox Regulation in Health & Disease: A Celebration of 50 Years of the Keilin Memorial Lecture, Info: www.biochemistry.org/Conferences 19/3-24/3 Dublin (IE) Keystone Symposia on Lipid Pathways in Biology and Disease, Info: www.keystonesymposia.org 20/3-21/3 London (UK) Coenzyme A and its Derivatives in Cellular Metabolism and Disease, Info: www.biochemistry.org/Conferences 22/3-28/3 Lucca/Barga (IT) Gordon Research Seminar and Conference: Antibody Biology and Engineering: From Biology to Therapeutics, Info: www.grc.org 23/3-27/3 Sevilla (ES) 12th European Conference on Fungal Genetics, Info: www.ecfg12.com

23/3-28/3 Oberstdorf (DE) Keystone Meeting on Chromatin Mechanisms and Cell Physiology, Info: www.keystonesymposia.org 24/3-25/3 Chester (UK) Quantitative Proteomics, Info: www.biochemistry.org/Conferences 26/3-27/3 Edinburgh (UK) Nanomedicine 2014, Info: www.selectbiosciences.com 26/3-29/3 Heidelberg (DE) EMBL Conference: Microglia Sculptors of the Brain, Info: www.embl.de/training/events 26/3-30/3 Nice (FR) 9th International Congress on Autoimmunity, Info: www2.kenes.com/autoimmunity 27/3-29/3 Cambridge (UK) Wellcome Trust Conference on Alzheimers Disease in Down Syndrome: From Molecules to Cognition, Info: www.hinxton. wellcome.ac.uk 27/3-30/3 Mosbach (DE) 65th Mosbach Kolloquium: Cellular Protein Quality Control in Health, Aging and Disease, Info: www.gbm-online.de/ gbm-tagungen.html 29/3-4/4 Lucca/Barga (IT) Gordon Research Seminar and Conference: Craniofacial Morphogenesis and Tissue Regeneration, Info: www.grc.org 30/3-3/4 Marburg (DE) Stalked alpha-Proteobacteria and Relatives: from Genes to Structure, Info: www.fems-microbiology.org 31/3-3/4 Jena (DE) MiCom 2014 4th International Student Conference on Microbial Communication, Info: www1.uni-jena.de/cms

1/4-3/4 London (UK) The 2014 Obesity Summit: Biomarker Discovery / GeneEnvironment Interactions in Obesity /Anti-Obesity Drug Discovery and Development, Info: obesitysummit2014.com 1/4-4/4 Munich (DE) Analytica 2014: International Trade Fair for Laboratory Technology, Analysis, Biotechnology and Analytica Conference, Info: www.analytica.de/en 5/4-11/4 Lucca/Barga (IT) Gordon Research Seminar and Conference: Photosensory Receptors and Signal Transduction, Info: www.grc.org 6/4-9/4 Osnabrueck (DE) Metabolism Meets Virulence: 2nd International Symposium on Metabolism and Bacterial Pathogenesis, Info: www. metabolism-meets-virulence.org 9/4-11/4 London (UK) 6th European Spores Conference, Info: sporesconference.com 9/4-12/4 Soelden (AT) 15th International Neuroscience Winter Conference, Info: www.nwg-info.de/de/node/14 9/4-12/4 Magdeburg (DE) 8th Symposium on Neuroprotection and Neurorepair, Info: www.neurorepair-2014.de 10/4-12/4 Valencia (ES) 2nd Biomarker Meeting in Personalized Reproductive Medicine, Info: www.comtecmed.com/biomarker 26/4-2/5 Lucca/Barga (IT) Gordon Research Seminar and Conference: Molecular and Ionic Clusters, Info: www.grc.org 28/4-29/4 Leicester (UK) 5th British Pharmacological Society Focused Meeting on Cell Signalling, Info: www.bps.ac.uk/ meetings/139a131cf49

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28/4-29/4 London (UK) Astrocytes in Health & Neurodegenerative Disease A Joint Biochemical Society / British Neuroscience Association Conference, Info: www.biochemistry.org/Conferences 30/4-2/5 Cambridge (UK) Conference on Chromatin: From Nucleosomes to Chromosomes, Info: www.hinxton.wellcome.ac.uk 30/4-3/5 Heidelberg (DE) EMBO-EMBL Symposium on Translating Diabetes, Info: www.embo-embl-symposia.org 5/5-8/5 Abruzzo (IT) Membrane, Morphology and Function, Info: www. biochemistry.org/Conferences 7/5-10/5 Heidelberg (DE) EMBO-EMBL Symposium on Tumour Microenvironment and Signalling, Info: www.embo-embl-symposia.org 10/5-16/5 Lucca/Barga (IT) Gordon Research Seminar and Conference: Environmental Endocrine Disruptors, Info: www.grc.org 12/5-14/5 Heidelberg (DE) 10th Annual BioMalPar/EVIMalaR Conference: Biology and Pathology of the Malaria Parasite, Info: www.embl.de/training/events 12/5-14/5 London (UK) Controlling Cancer Summit: Advances in Screening & Prevention Research / Cancer Biomarker Discovery & Assay Development / Anti-Cancer Therapeutics, Info: controllingcancersummit2014.com 12/5-17/5 Stockholm (SE) Keystone Meeting on Adult Neurogenesis, Info: www.keystonesymposia.org 13/5-15/5 Barcelona (ES) European Lab Automation / Advances in Cellular Assays & Cell Culture / 3rd Annual Advances in Automation & Robotics /11th High Content Analysis / 4th Annual Advances in Next-Gen Sequencing & Big Data / 5th Advances in qPCR, Info: www.selectbiosciences.com

14/5-16/5 Berlin (DE) CRISPR 2014 The Prokaryotic Immune System CRISPR / CAS, Info: www.crispr2014.de 14/5-16/5 Zurich (CH) 33rd New Phytologist Symposium Networks of Power and Influence: Ecology and Evolution of Symbioses Between Plants and Mycorrhizal Fungi, Info: www. newphytologist.org/symposiums 14/5-17/5 Kiel (DE) Interleukin 6: BiologyPathophysiology-Therapy MidTerm Conference of the International Cytokine and Interferon Society (ICIS), Info: www.kielcytokines2014.com 14/5-18/5 Acaya-Lecce (IT) EMBO Conference on Molecular Biology of Muscle Development and Regeneration, Info: events.embo.org/14-myogenesis 15/5-19/5 Amsterdam (NL) 9th International Conference on Cryptococcus and Cryptococcosis, Info: www.iccc2014.org 16/5-19/5 St. Petersburg (RU) 21st Annual International Stress and Behavior Neuroscience and Biopsychiatry Conference, Info: www.stressandbehavior.com 17/5-20/5 Prague (CZ) 41st European Calcified Tissue Society Congress (ECTS 2014), Info: www.ectscongress.org 17/5-21/5 Bertinoro (IT) EMBO Conference on Lymphocyte Signalling, Info: www.embo-embl-symposia.org 17/5-23/5 Lucca/Barga (IT) Gordon Research Seminar and Conference: Nox Family NADPH Oxidases, Info: www.grc.org 18/5-21/5 Heidelberg (DE) EMBO-EMBL Symposium on Molecular Machines: Lessons From Integrating Structure, Biophysics and Chemistry, Info: www.embo.org/events

18/5-22/5 Stuttgart (DE) 20th International Symposium on Microsomes and Drug Oxidations (MDO), Info: www.mdo2014.de 19/5-23/5 Alicante (ES) Mechanisms of Recombination: 50th Anniversary Meeting of the Holliday Model, Info: www. abcam.com/recombination2014 20/5-22/5 London (UK) 9th World Stem Cells and Regenerative Medicine Congress, Info: www.terrapinn.com/ conference/stem-cells 23/5-27/5 Cavtat (HR) EMBO-EMBL Symposium on Cellular Signalling & Cancer Therapy, Info: www.embo.org/events 24/5-30/5 Lucca/Barga (IT) Gordon Research Seminar and Conference: Visual System Development Building and Maintaining Eyes, Info: www.grc.org 28/5-31/5 Heidelberg (DE) EMBO Conference on Microtubules Structure, Regulation and Functions, Info: www.embo.org/events 1/6-4/6 Manchester (UK) EMBO Conference on Enzyme Mechanisms by Biological Systems, Info: www.embo.org/events 2/6-4/6 London (UK) The 2014 Tissue Engineering Congress: Stem Cell Reprogramming / Stem Cells and BioProcessing / Novel Biomaterials and Technology, Info: tissueengineeringcongress2014.com 7/6-13/6 Lucca/Barga (IT) Gordon Research Seminar and Conference: Mammary Gland Biology, Info: www.grc.org 14/6-17/6 Cambridge (UK) Wellcome Trust Conference on Evolutionary Biology of Caenorhabditis and other Nematodes, Info: www.hinxton.wellcome.ac.uk

14-19/6 San Feliu de Guixols (ES) EMBO Conference on Gene Transcription in Yeast: From Regulatory Networks to Mechanisms, Info: www.embo.org/events 14/6-20/6 Lucca/Barga (IT) Gordon Research Seminar and Conference: Biointerface Science, Info: www.grc.org 15/6-18/6 Uppsala (SE) Biocontrol of Plant Diseases: From the Field to the Laboratory and Back Again, Info: www.iobc-wprs.org/events 15/6-20/6 Girona (ES) Gordon Research Conference: Mutagenesis Changes to the Genetic Landscape, from Single Nucleotides to Entire Genomes, Info: www.grc.org 21/6-27/6 Lucca/Barga (IT) Gordon Research Seminar and Conference: Proteolytic Enzymes and Their Inhibitors, Info: www.grc.org 22/6-27/6 Girona (ES) Gordon Research Seminar and Conference: Three Dimensional Electron Microscopy, Info: www.grc.org 22/6-28/6 Kolymbari (GR) EMBO Conference on the Molecular and Developmental Biology of Drosophila, Info: www.embo.org/events 24/6-27/6 Paris (FR) Genomes 2014 EMBO Conference on Microbiology after the Genomics Revolution, Info: www.genomes-2014.org 23/6-25/6 London (UK) The 2014 Alzheimers Disease Congress: Biomarker Discovery and Assay Development / Vaccine Development / Drug Discovery and Development, Info: alzheimersdiseasecongress2014.com 25/6-27/6 Freiburg (DE) 3D Cell Culture Advanced Model Systems, Applications & Enabling Technologies, Info: events.dechema.de/tagungen

More events at www.labtimes.org/labtimes/calendar

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25/6-27/6 Montpellier (FR) 11th International Symposium on Aeromonas & Plesiomonas (ISAP), Info: www.ecosym.univ-montp2.fr 29/6-2/7 Munich (DE) 30th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Info: www.eshre.eu/ annual_meeting/page.aspx/11 29/6-4/7 Girona (ES) Gordon Research Conference: Biogenic Hydrocarbons & the Atmosphere Interactions in a Changing World, Info: www.grc.org 29/6-4/7 Lucca/Barga (IT) Gordon Research Conference: Transglutaminases in Human Disease Processes Molecular Dissection of Human Diseases Pathogenesis, Info: www.grc.org 30/6-2/7 London (UK) Physiology 2014, Info: www.physoc.org/physiology2014 1/7-3/7 London (UK) Beating Malaria: Malaria Vector Control Research, Economics & Policy/Malaria Immunology & Vaccination/Malaria Drug Development & Resistance Control, Info: beatingmalarialondon2014.com

5/7-9/7 Milan (IT) 9th Federation of European Neuroscience Societies) Forum, Info: fens2014.neurosciences.asso.fr 5/7-11/7 Girona (ES) Gordon Research Seminar and Conference: Endothelial Cell Phenotypes in Health and Disease, Info: www.grc.org 6/7-11/7 Lucca/Barga (IT) Gordon Research Conference: Mitochondria and Chloroplasts, Info: www.grc.org 12/7-18/7 Lucca/Barga (IT) Gordon Research Seminar and Conference: Single Molecule Approaches to Biology, Info: www.grc.org 12/7-24/7 St. Petersburg (RU) World Congress on the Frontiers in Intelligent Data and Signal Analysis, Info: www.worldcongressdsa.com 13/7-16/7 Edinburgh (UK) 16th European Congress on Biotechnology, Info: www.ecb16.com 17/7-19/7 York (UK) Signalling 2013: From Structure to Function, Info: www. biochemistry.org/Conferences

19/7-25/7 Girona (ES) Gordon Research Seminar and Conference: Thiol-Based Redox Regulation and Signaling, Info: www.grc.org 23/7-26/7 Heidelberg (DE) EMBL Conference: Microfluidics, Info: www.embl.de/training/events 26/7-1/8 Girona (ES) Gordon Research Seminar and Conference: Neurobiology of Brain Disorders, Info: www.grc.org 29/7-30/7 London (UK) The Biological and Biomedical Consequences of Protein Moonlighting, Info: www. biochemistry.org/Conferences 3/8-8/8 York (UK) 10th European Congress of Entomology, Info: www.royensoc.co.uk/meetings 10/8-15/8 Potsdam (DE) 8th International Congress of Dipterology, Info: www.icd8.org 20/8-23/8 Heidelberg (DE) EMBO Conference on Chemical Biology, Info: www.embo.org/events

23/8-27/8 Heidelberg (DE) 11th EMBL Conference: Transcription and Chromatin, Info: www.embl.de/training/events 27/8-30/8 Heidelberg (DE) EMBO-EMBL Symposium on Epithelial Biology, Info: www.embo.org/events 30/8-4/9 San Feliu de Guixols (ES) Synthetic Biology of Antibiotic Production II, Info: syntheticbio.esf.org 30/8-4/9 Paris (FR) FEBSEMBO 2014: Joint Conference of the Federation of European Biochemical Societies, the European Molecular Biology Organization & the French Society for Biochemistry & Molecular Biology, Info: www.febs-embo2014.org 31/8-4/9 Egmond aan Zee (NL) 11th Symposium on Lactic Acid Bacteria, Info: www.lab11.org 1/9-5/9 Cambridge (UK) Harden Conference: Total Transcription, Info: www.biochemistry.org/Conferences 1/9-6/9 Hydra (GR) Molecular and Cellular Biology of Helminth Parasites VII, Info: hydra. bio.ed.ac.uk/content/hydra-2012

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Humour

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