Biomedical scientists are often urged to check that their cell lines are not contaminated or mislabelled. But as a new study shows, any effort to authenticate a cell line is only as good as the reference standard against which the cells are compared. A cell line that is widely used to study brain cancer does not match the cells used to create the line nearly 50 years ago, or the tumour purported to be its source, researchers report on 31 August in Science Translational Medicine1. In fact, no one is quite sure of the true provenance of the cell line distributed by most cell repositories. “It is a good cautionary tale to say, ‘Question your assumptions and do as many appropriate controls as you can to make sure you really have what you think you have,’” says Jon Lorsch, director of the US National Institute of General Medical Sciences in Bethesda, Maryland. And because few cell lines are ever verified against their primary-source material, “this paper is probably just the tip of the iceberg”, says Christopher Korch, a geneticist at the University of Colorado Denver. Many groups are trying to tackle the problem of misidentified cell lines to improve the reproducibility of research findings. This year, the US National Institutes of Health started requiring grant applicants to describe how they will authenticate their cell lines. And journals such as Nature have recently begun to ask authors to check their cells against a database of 475 lines (and counting) that are known to be mixed up. But no organizations have called for the kind of archival sleuthing that produced the new study. “It’s hard enough to get people to do the standard authentication,” says Leonard Freedman, president of the Global Biological Standards Institute, a non-profit organization in Washington DC that has found that most life scientists never authenticate their cells2. “This is much more elaborate.” The cell line in question, U87, was established in 1966 at Uppsala University in Sweden, using tissue from a 44-year-old woman with an aggressive brain cancer known as glioblastoma. U87 has since become a workhorse of brain-cancer research, subject to countless investigations that have yielded around 2,000 scientific papers. The enthusiasm for U87 initially puzzled Bengt Westermark, a tumour biologist at Uppsala. “I couldn’t understand why people would work with such boring cells,” he says. As a graduate student in the 1970s, Westermark studied eight different brain-cancer cell lines. U87 was “hopeless to work with”, he says, because it grew so much more slowly than the others. Years later, Westermark got his hands on the version of U87 that is distributed by the American Type Culture Collection (ATCC), a cell repository in Manassas, Virginia, that houses the world’s largest collection of biological materials. He could see from the cells’ growth properties that this U87 was clearly different from the cells that had given him so much grief in graduate school. Westermark decided to do a formal comparison. Fortunately, Uppsala still had the preserved tumour tissue that spawned the original cell line. This enabled Westermark’s team to verify the identity of the archival U87 sample in their freezer. The researchers then used DNA-fingerprinting techniques to show that the ATCC’s U87 was different — and that it didn’t match any other cell lines created at Uppsala, either. According to Mindy Goldsborough, ATCC’s chief science and technology officer, the repository acquired its U87 line in 1982 from the Memorial Sloan KetteringCancer Center in New York City, which itself had received the cell line from Uppsala in 1973. And by the time it arrived at the ATCC, U87 had a Y chromosome — despite the fact that it was supposed to have come from a female patient. This suggests that the mix-up probably happened at Sloan Kettering or during one of the hand-offs. In light of the new revelations, the ATCC now plans to update the background details in its listing for U87, which it describes as male. But the origin of the U87 line remains a mystery. A comparison of gene-expression profiles conducted by Westermark's team suggests that the ATCC cell line probably came from a brain tumour. “It’s bad news that it’s not what it should be,” Westermark says, “but it’s good news that it’s probably a glioblastoma.” This means that studies of U87 still reflect brain-cancer biology and don’t need to be tossed out, he adds. Still, many cancer researchers think that it is time to move beyond U87 and other “classical” cell lines — regardless of where they came from — because the culture conditions historically used to grow the cells change their biological nature. Westermark and others now favour newer cell lines that have been propagated on the types of growth medium that ensure genetic and epigenetic stability. Through its Human Glioma Cell Culture biobank, Uppsala provides these sorts of cells to other researchers for a small processing fee. “There is an increasing understanding that what we’ve historically used is so poorly representative of the human disease,” says Howard Fine, a neuro-oncologist at the Weill Cornell Brain Tumor Center in New York City. “So, any time someone can shoot down the [U87] cell line, I’m happy.”
News Article | January 8, 2016
In a finding that further links dinosaurs and their modern bird descendants, paleontologists report some dinosaurs engaged in mating dances similar to those employed by today's birds. The evidence for such behavior lies in 100-million-year-old rocks that bear large scrape marks similar to what results from modern birds' "nest scrape displays" or "scrape ceremonies," researchers say. In such behaviors, males attempt to attract mates by showing off their ability to excavate pseudo nests for potential partners, they explain. The ancient dinosaur scrapings were found in western Colorado. "These are the first sites with evidence of dinosaur mating display rituals ever discovered, and the first physical evidence of courtship behavior," says Martin Lockley, a geology professor at the University of Colorado Denver. The new finding, along with previous discoveries of dinosaur head crests and colorful feathers, strengthens speculation that dinosaurs engaged in sophisticated mating displays, the researchers say in a study appearing in Scientific Reports. More than 50 of the dinosaur scrapings were discovered by Lockley, a noted expert on dinosaur footprints, in an area already known for foot tracks of both herbivorous and carnivorous dinosaurs. Large theropods, two-legged carnivorous dinosaurs, likely made the scrapes marks in Colorado, the researchers suggest. A leading candidate is Acrocanthosaurus, which could reach 38 feet in length and weigh close to 7 tons. Paleobiologists have long speculated that dinosaur mating rituals might resemble those of some modern bird descendants like ostriches and Atlantic puffins, both of which conduct energetic dancing displays. Breeding season would have been a time of great activity and even frenzy among the dinosaurs, Lockley says. "This is typical of some bird species," he explains. "The extensive scrape evidence suggests much high-energy activity. If small birds get excited when breeding, imagine what big theropods might have done!" Males would have been the primary dancers and scrapers, he argues, as males are the main "show-offs" in birds today. However, while some carnivorous dinosaurs evolved into bird descendants retaining display abilities, Lockley acknowledges, "there is no reason to suppose that all theropods developed this behavior, or that all descendants should have inherited it." Still, he says, the scrapings are strong evidence of dinosaur mating displays and the evolutionary power of "sexual selection," in which female dinosaurs may well have chosen the most impressive male performers as mating partners. "These huge scrape displays fill in a missing gap in our understanding of dinosaur behavior," he suggests. The scientists made molds of the scrapes and took layered photographs since the scrapes could not be removed without damaging the fossilized markings.
News Article | December 16, 2015
There's a common refrain sung out whenever new research emerges about potential dangers associated with vaping: it's still better than smoking. This may be true, but should that stop us from talking about the possible dangers of vaping? Last week, I reported on a Harvard study published in Environmental Health Perspectives, a peer-reviewed open access journal published by the National Institutes of Health. The study tested a selection of e-cigarette flavors (both cigalikes and individual juices) for diacetyl (and two similar chemicals), a flavoring chemical that gives food and beverage products a creamy, buttery taste. That study found at least one of the three chemicals in 47 of the 51 flavors tested, which is noteworthy because diacetyl has been linked to serious lung disease when inhaled by workers in factory settings. But a handful of readers were unhappy with the story, and wrote to tell me as much. There were two main concerns raised: the first was that I never mentioned how much worse cigarettes are compared to vaping (both in diacetyl concentrations and overall health risks); the other was that, since we don’t yet know the effects of vaping diacetyl, linking it to lung disease is premature. I called up experts, both from the vaping industry and the medical community, to get to the bottom of these concerns and clear the air (pun intended) on this sensitive issue. Concern #1: Cigarettes are still way worse than vaping This point, raised by several readers, is true. Just this past summer, the UK’s public health agency released a report that declared e-cigarettes to be 95 percent less harmful than cigarettes. This claim was based on a review of all of the published research to date, and while there’s still much more research to be done, the consensus so far is that e-cigarettes are significantly less dangerous than smoking. “It’s about harm reduction,” said Tony Mandarano, founder of ZampleBox, a vaping subscription start-up. “Over years and years of additional research, maybe we’ll find it’s 99 percent less harmful, maybe we’ll find it’s 50 percent less harmful, but the point is: right now the research shows such a large improvement between the two that we must keep going and we can’t create a hysteria about this.” Some readers also pointed out that even when it comes to diacetyl specifically, smoking is still the worse option. This is also true. One 2005 study found levels of diacetyl as high as 433 micrograms per cigarette. Most of the e-cigarette liquids tested in the Harvard study were far lower than this, with even the highest concentration at 238.9 microgram of diacetyl in one e-cigarette. If you’re looking at vaping as an alternative to smoking—a way for lifelong, two-packs-a-day smokers to kick their habit and replace it with something comparatively healthier—this distinction between vaping and smoking is pivotal information. Mandarano (and some readers) expressed concern that without this context, smokers who were on the fence could see these kind of reports, assume e-cigarettes are just as dangerous as their current habit, and not make any changes. But the fact that research so far shows e-cigarettes are much less dangerous than smoking is already pretty well known—so much so that I didn’t see the need to repeat it. What we don’t know is what negative health impacts vaping might have, and if the goal is harm reduction, shouldn’t the industry be trying to make e-cigarettes as harmless as possible? “If the bar that you’re setting is ‘better than smoking,’ then you’re setting the bar awfully low,” said Russ Wishtart, host of the vaping podcast Click Bang!. “That said, some of the media that picked up on this study sensationalized it. Ultimately the main concern is that people will read the headline and smokers that may have considered vaping will say ‘I’m damned if I do, I’m damned if I don’t, so I’ll just keep smoking.’” It’s true that smoking is more harmful than vaping, but if you’re switching to vaping to improve your health, don’t you want that choice to be as healthy as possible? The best way to ensure that is to know what’s in an e-cigarette and what effects it could potentially have. That brings us to the second concern. Concern #2: We don’t know what vaping diacetyl does to your body This point is also true (and one that I made in my initial story), but not knowing if a chemical has a negative effect is a long way from knowing that it’s safe, and given diacetyl’s history, it’s not unreasonable to be concerned about it. Diacetyl is linked to a serious lung disease called bronchiolitis obliterans in factory workers who inhaled the chemical. This is an incurable lung disease that severely restricts airflow and can even lead to death. It’s probably not something you want to gamble with. “It’s very clear that diacetyl and other similar flavoring chemicals can, in some workers, cause this severe, irreversible, untreatable lung disease,” said Dr. Cecile Rose, a lung disease expert at the University of Colorado Denver. “Why would we allow the possibility of that occurring and then wait until there’s some dead bodies to count before something’s done about this?” Despite the relatively high levels of diacetyl in cigarettes, bronchiolitis obliterans is not well documented among smokers—a point some readers raised as evidence that diacetyl might not be that dangerous to inhale afterall. But Rose told me that’s not exactly the case. “There’s absolutely no doubt that cigarette smokers are at risk for respiratory bronchiolitis, which is a different kind of bronchiolitis,” Rose told me over the phone. “Whether it’s from the diacetyl or a combination of all the other things in cigarettes, that’s hard to say.” Rose also pointed out that bronchiolitis obliterans is difficult to diagnose because it mimics the symptoms of other, more common lung ailments like asthma and emphysema, so it could be that smokers are just misdiagnosed. Still, that’s not to say that vaping e-liquids containing diacetyl will definitely cause bronchiolitis obliterans (as some headlines suggested), it’s just that there’s a potential risk. So why risk it? “You can’t control what’s in cigarette smoke hardly at all, but you can control what’s in an e-cigarette to some extent,” said James Pankow, a chemist at Portland State University who researches cancer risks related to smoking. “If the goal is harm reduction, why would you put in a chemical that’s know to be a workplace hazard?” That’s a decision that’s up to manufacturers and individual vapers, and the risk depends on a number of factors including the concentration in a particular flavoring and the habits of the vaper. But the only way to make an informed decision is to know that these chemicals are widely used in the first place and to insist on more transparency from manufacturers, which is why studies like the one out of Harvard are so important. Vaping is a topic rife with contention. Those who have kicked serious smoking habits by switching to e-cigarettes are understandably defensive against any negative attention being shed on what they believe is a potentially life-saving piece of technology. Especially with potentially crushing regulation looming early next year, many vapers are worried about information being misconstrued and misrepresented. And as Mandarano point out, there are powerful interests, like Big Tobacco, that would probably love to see the entire vaping industry extinguished outright. But knowledge is powerful too, and the best way to ensure a future where safe, responsible vaping can thrive is to continue to seek out the truth, wherever it may lead.
In 2014, Michael Burel completed an online workbook that asked about his scientific competencies and interests. When he indicated that he was skilled in statistical analysis and enjoyed presenting research to a non-scientific audience, the programme suggested that he work in public policy, a field that didn't interest him. He tossed the results aside. But last year, the doctoral student, who is studying stem cells at New York University, revisited the tool as part of a course on building career options. This time it led him to science writing, a path that resonated, and the instructor and guest speakers helped him to identify ways in which he could train for a career in the field. Since then, he has attended a science-writing seminar, talked to science journalists about how they trained for and landed their jobs and attended a science-writers conference. He now interns as a science writer for the Albert and Mary Lasker Foundation in New York City, which supports medical research. He says that the career workbook and related course have been some of the most useful aspects of his graduate education: together, they helped him to identify a viable career and guided him to the workshops, classes and internships that provided a starting point for his success. Burel's experience illustrates both the promise and problems of the career-development programmes known as individual development plans (IDPs) in the United States and researcher development frameworks (RDFs) in the United Kingdom and mainland Europe. The programmes, available in hard copy and online, aim to help trainees to identify what aspects of science they like best, match them with careers that incorporate their interests and skills and identify gaps in their competencies. Versions of the programmes can be as elaborate as the multi-question workbook that Burel initially turned to, or as simple as a short conversation with an adviser followed up by a written training plan. Either way, IDPs and RDFs can lead users in wrong directions and to dead ends when completed on their own or without follow-up. Junior scientists who hope to exploit the value of a career-development plan should complete them as part of a career-building course, discuss them with peers and an adviser and revisit them often (see 'Career planner'). Although IDPs are commonplace in the private sector, the scientific workforce has adopted them fairly recently. Vitae, a UK-based organization that trains and develops researchers around the world, developed an RDF in 2009. In 2013, the US National Institutes of Health (NIH) recommended that principal investigators (PIs) use them with their postdocs and graduate students. The Federation of American Societies for Experimental Biology (FASEB) later created a template for the hard-copy version, and the American Association for the Advancement of Science (AAAS) launched an online version called myIDP. Many institutions have developed their own version. Some trainees say that their institution's IDP programme is written to aim users towards academia. And, they warn, if a PI or adviser is not on board with other career choices, it can be tricky to get effective results from the programme. Gary McDowell, a postdoc at Tufts University in Medford, Massachusetts, completes an IDP every year and discusses it with his PI. He says that both the programme and his PI are academically oriented, so he tries to be realistic about the plan's empirical value. “It's helpful to figure out conferences to go to, papers to plan, skills I need to be developing,” he says. “Ultimately, I think any reflection on your career goals, identifying successes in the past year and planning what you need in the next year is helpful, regardless of how you feel about your career path. But people may fall through the cracks.” There is little formal incentive to complete an IDP or RDF. The NIH does not follow up on its recommendation, and not all institutions require trainees to use one. Nor is there a mandate for its use in any nation. Just 47% of the postdoctoral offices that participated in a survey by the US National Postdoctoral Association said that they require their postdocs to complete an IDP, according to a 2014 report (see go.nature.com/awsupm). And another 37% encourage their use, the report said. Ultimately, the trainee should not just create, but also follow through on their career-development plan, says Philip Clifford, associate dean for research at the University of Illinois at Chicago, who helped to develop both the FASEB and AAAS versions. The biggest mistake users make is to consider it an endpoint rather than a launch pad, he adds. He has run some 200 career-building courses and workshops that incorporate the plan and build on its use and results. Lina Dimberg, who participated in one of Clifford's courses, followed the instructions with care and found the programme fruitful. As a postdoc in cancer research at the University of Colorado Denver, she knew that she did not want to stay in academia but was unsure of her options. She completed an IDP with Clifford's guidance and immediately learned that her strongest skills — writing grant proposals and papers, reading the literature and discussing research — gave her a solid foundation for several science-related careers, one of which was medical writing. Clifford's curriculum required her to set up meetings with scientists in occupations that the IDP had pinpointed as career possibilities. One of those chats led to a job as a writer at a medical-device company after her postdoc ended; today, she works there as a senior scientist. Dimberg credits the IDP process and the workshop that supported it for helping her to define her career objectives and to develop the necessary confidence to market herself for the position. “The IDP opens your eyes to careers where you can combine your science interest with other interests and skills,” she says. Sometimes, the programme might identify a good direction, but the user might not be quite ready at that point in time. When Nathan Vanderford was a graduate student and postdoc, his PIs encouraged him to complete an IDP that highlighted a tenure-track position — even though he wasn't sure that was the right route. “I ended up with a plan that I felt was not true to my desired career path,” he says. He then spent years in other careers, including science communications and research operations. Today, he has come almost full circle and is now a faculty member at the University of Kentucky in Lexington, where he has a faculty-administrator post that his IDP results from so long ago did not quite predict. He teaches a career-development class that incorporates the programme's best principles. “The IDP I was forced to do has little to do with my current position,” he says. “I want to give students a mechanism that allows them to explore freely any career option they want to pursue.”
Researchers on social media have been split by the decision of academic librarian Jeffrey Beall to add the Frontiers journals to his ‘blacklist’ of “questionable publishers”. Beall, at the University of Colorado Denver, announced the move in a tweet: His website Scholarly Open Access maintains a list of journals that may be “predatory publishers" — a term Beall coined to cover publications that charge scientists fees to publish research papers, but that do not offer standard publishing services such as peer review or that make misleading claims about their journals on issues such as impact factors or indexing. Critics spoke out against Beall’s blacklisting of Frontiers, maintaining that the open-access publisher is legitimate and reputable and does offer proper peer review. Daniël Lakens, an experimental psychologist at the Eindhoven University of Technology in the Netherlands and an associate editor at Frontiers in Cognition, tweeted: Beall told Nature that he stands by his decision and that he has received dozens of e-mails from the scientific community outlining bad practices at Frontiers. Beall names some controversies that he says helped raise concerns about the Frontiers journals. These include a Frontiers in Psychology paper suggesting that conspiracy theorists do not believe in climate change and a Frontiers in Public Health paper raising questions about the link between HIV and AIDS. Both ignited Internet firestorms on publication. In a statement, Frontiers said that it was committed to serving the academic community, was a member of the Committee on Publication Ethics and was also on the ‘whitelist’ of legitimate publishers kept by the Directory of Open Access Journals. “Dubious actions as such by an individual with a long history of opposing Open Access publishing serve only to create confusion that slows down the development of Open Access publishing,” says the statement. Adding Frontiers to the blacklist may cause problems for researchers who have previously published in the journals, says Lakens. "It could be, the articles people have published in Frontiers are no longer judged based on their own quality, but are now seen as less valuable because Frontiers is on Beall’s list," he says. "Having a single influential individual cast doubt on such a huge journal feels very unfair.” Love it or hate it, Beall's blacklist is the only one out there, and it's providing an important service, says Neuroskeptic, a pseudonymous neuroscience blogger and researcher in the United Kingdom. Although he doesn’t agree with Beall’s decision, Neuroskeptic says that he sees the value and merit of the Scholarly Open Access website. "The grand majority of these publishers really are seriously dodgy, and someone needs to be calling them out," Neuroskeptic says. "The list has helped me — I think it’s important." The Holtzbrinck Group, based in Stuttgart, Germany, is a part owner of Frontiers and also owns a share of Nature’s parent company, Springer Nature. Frontiers says that “While generally operating as an independent business and publisher, Frontiers now collaborates with Holtzbrinck businesses including NPG on key initiatives to advance the cause of Open Science for the benefit of both the research community and the broader public.” Nature’s news team is editorially independent.