Contamination created controversial ‘acid-induced’ stem cells

Posted on 28 Dec 2014 by Heidi Ledford

Stem cells that were claimed to be created simply by exposing ordinary cells to stress were probably derived from embryonic stem cells, according to the latest investigation into an ongoing scientific scandal. How that contamination occurred, however, remains an open question.

The investigation was instigated by RIKEN, the Japanese research institution where the original claims were made, and carried out by a committee composed of seven outsiders.

The committee analyzed DNA samples and laboratory records from two teams behind the original papers describing STAP (‘stimulus-triggered acquisition of pluripotency’) cells. Those papers — published in Nature but later retracted — were once heralded as describing a shortcut to producing stem cells: rather than expressing specific genes or carefully transplanting a nucleus from one cell to another, researchers could, it seemed, create stem cells by exposing them to stress, including bathing the cells in acid.

The latest investigation suggests that the STAP findings were merely the result of contamination by embryonic stem cells. Investigators found signs of three separate embryonic stem cell lines. They noted that it is difficult to imagine how contamination by three distinct lines could be accidental, but that they could also not be certain that it was intentional.

“We cannot, therefore, conclude that there was research misconduct in this instance,” the committee wrote. It did, however, find evidence that lead investigator Haruko Obokata, formerly of the RIKEN Center for Developmental Biology in Kobe, had fabricated data for two figures in the original STAP publications.

The committee’s report, released on 26 December, is the latest in a series of damning revelations about the STAP cells originally described in two Nature papers in January 2014. The approach quickly came under scrutiny as other researchers failed to reproduce its results, and as suspicions grew that images in the original papers had been manipulated. In March, another RIKEN investigation found Obokata guilty of scientific misconduct; in July, the STAP papers were retracted and in August another co-author, Yoshiki Sasai, took his own life. Earlier this month, Obokata resigned her position at RIKEN.

White House suspends enhanced pathogen research

Posted on 17 Oct 2014 by Sara Reardon

Past research made the H5N1 virus transmissible in ferrets.

Past research has made the H5N1 virus transmissible in ferrets.{credit}Sara Reardon{/credit}

As the US public frets about the recent transmission of Ebola to two Texas health-care workers, the US government has turned an eye on dangerous viruses that could become much more widespread if they were to escape from the lab. On 17 October, the White House Office of Science and Technology Policy (OSTP) announced a mandatory moratorium on research aimed at making pathogens more deadly, known as gain-of-function research.

Under the moratorium, government agencies will not fund research that attempts to make natural pathogens more transmissible through the air or more deadly in the body. Researchers who have already been funded to do such projects are asked to voluntarily pause work while two non-regulatory bodies, the National Science Advisory Board for Biosecurity (NSABB) and the National Research Council, assess its risks. The ban specifically mentions research that would enhance influenza, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Other types of research on naturally occurring strains of these viruses would still be funded.

This is the second time that gain-of-function research has been suspended. In 2012, 39 scientists working on influenza agreed to a voluntary moratorium after the publication of two papers demonstrating that an enhanced H5N1 influenza virus could be transmitted between mammals through respiratory droplets. The publications drew a storm of controversy centred around the danger that they might give terrorists the ability to create highly effective bioweapons, or that the viruses might accidentally escape the lab. Research resumed after regulatory agencies and entities such as the World Health Organization laid out guidelines for ensuring the safety and security of flu research.

The OSTP’s moratorium, by contrast, is mandatory and affects a much broader array of viruses. “I think it’s really excellent news,” says Marc Lipsitch of Harvard University in Cambridge, Massachusetts, who has long called for more oversight of risky research. “I think it’s common sense to deliberate before you act.”

Virologist Yoshihiro Kawaoka of the University of Wisconsin–Madison, who conducted one of the controversial H5N1 gain-of-function studies in an effort to determine how the flu virus could evolve to become more transmissible in mammals, says that he plans to “comply with the government’s directives” on those experiments that are considered to be gain-of-function under OSTP’s order. “I hope that the issues can be discussed openly and constructively so that important research will not be delayed indefinitely,” he says.

The NSABB, which has not met since 2012, was called back into action in July, apparently in response to a set of lab accidents at the US Centers for Disease Control and Prevention in which lab workers were exposed to anthrax and inadvertently shipped H5N1 virus without proper safety precautions. The NSABB will spend most of its next meeting on 22 October discussing gain-of-function research, and the National Research Council plans to hold a workshop on a date that has not yet been set. Lipsitch, who will speak at the NSABB meeting, says that he plans to advocate for the use of an objective risk-assessment tool to weigh the potential benefits of each research project against the probability of a lab accident and the pathogen’s contagiousness, and to consider whether the knowledge gained by studying a risky pathogen could be gained in a safer way.

Correction: This post has been changed to specify that Yoshihiro Kawaoka’s 2012 gain-of-function research increased the transmissibility of H5N1.

US announces rules for potential bioterror agents

Posted on 24 Sep 2014 by Sara Reardon

A long-awaited US government policy on biological research that could be used for terrorism or other nefarious purposes is little changed from a draft released 19 months ago, despite receiving 38 comments from institutions and researchers concerned that it goes either too far or not far enough. The centrepiece of the policy, released on 24 September, is a set of guidelines for researchers working on 15 specific pathogens or toxins. But the rules do not regulate experiments that engineer pathogens not on the list to make them more deadly – so-called gain-of-function research. Officials from the White House and US National Institutes of Health (NIH) say the government will be addressing these concerns in coming weeks.

The White House released its first draft policy on dual-use research of concern, or DURC, in February 2013. The policy requires researchers at institutions that receive funding from the US government and are working with one of 15 specific pathogens or toxins to notify their institutions if there is potential that their work could be misused. The institutions will then assess whether or not the research qualifies as DURC. In parallel, the federal government will assess whether such research should receive funding. It will work with the institutions to plan how to manage concerns such as containment of listed pathogens and the public release of information that could allow them to be misused. Amy Patterson, director of the NIH Office of Science Policy, says that it is “incumbent upon investigators” to report projects that have become potentially dangerous since they were funded, such as the discovery of a new pathogen, at which point the institutions and government would review the project again. Institutions that do not comply will have their government funding withdrawn.

The rules apply only to labs that receive government funding. All institutions are required to register with the US Centers for Disease Control and Prevention (CDC) if they are using one of a longer list of “select agents” defined by the government. But experiments that would, for instance, make a pathogen not on the list more dangerous “would be outside the scope of the current framework,” Patterson says.

Such experiments would include the controversial creation of a mutant flu virus that is deadlier and more transmissible between animals.

Marc Lipsitch, an epidemiologist at the Harvard School of Public Health in Boston, thinks the policy may be of limited use for biosecurity. “I think any list of agents is a temptation, if you’re trying to get around it, to find another agent to do mischief with,” he says.

Patterson says the National Science Advisory Board for Biosecurity (NSABB), which monitors and advises on biological threats to the NIH and federal government, will discuss regulating gain-of-function research at an upcoming meeting on 22 October — its first meeting in two years. Possible dangers include not just misuse but unintentional releases of pathogens. In two recent incidents at the CDC, H5N1 virus was accidentally shipped to a lab instead of a harmless virus, and dozens of workers were potentially exposed to anthrax.

The 15 pathogens and toxins on the list include:

Avian influenza virus (highly pathogenic)
Bacillus anthracis
Botulinum neurotoxin6
Burkholderia mallei
Burkholderia pseudomallei
Ebola virus
Foot-and-mouth disease virus
Francisella tularensis
Marburg virus
Reconstructed 1918 influenza virus
Rinderpest virus
Toxin-producing strains of Clostridium botulinum
Variola major virus
Variola minor virus
Yersinia pestis

Clarification: The original version of this post failed to identify the source of the quote in the third paragraph. The post has been amended to add the source.

Balzan prizes honour plant ecologist and mathematician

Posted on 09 Sep 2014 by alison abbott

Plant ecologist G. David Tilman of the University of Minnesota in Saint Paul and mathematician Dennis Sullivan of the City University of New York are among the four winners of this year’s prestigious Balzan Prize. The announcement was made on 8 September.

The prize is awarded by the International Balzan Prize Foundation, based in Milan, Italy, and Zurich, Switzerland. Each year, the jury selects four different categories for the award. Each winner receives 750,000 Swiss francs (US$800,000) and must spend half of it on research projects carried out, preferably, by young scholars or scientists.

Tilman was recognized for contributions to theoretical and experimental plant ecology that have illuminated how plant communities are structured and interact with their environment.

Sullivan was recognized for his work in topology and the theory of dynamical systems, as well other fields of maths, including geometry, the theory of Kleinian groups, analysis and number theory.

The other 2014 winners were Mario Torelli of the University of Perugia, Italy, for classical archaeology, and Ian Hacking of the University of Toronto, Canada, for epistemology and philosophy of mind.

The categories for the 2015 prizes will be oceanography, astroparticle physics including neutrino and γ-ray observation, history of European art (1300–1700) and economic history.

Lasker Award goes to breast-cancer researcher

Posted on 08 Sep 2014 by Lauren Morello

Posted on behalf of Mark Zastrow.

The 2014 Albert Lasker Special Achievement Award has been awarded to the geneticist Mary-Claire King. King, of the University of Washington in Seattle, is the leader of the team that discovered the BRCA genes, mutations in which are linked to breast cancer. King’s team found that the 10% of women affected by such mutations have nearly an 80% chance of developing breast cancer. The rush to develop tests for the mutations triggered a legal dispute in the United States that ended with a US Supreme Court ruling prohibiting the patenting of naturally occurring genes.

King was also recognized for her contributions to human rights in developing DNA analysis to prove genetic relationships. These have have been used to find the ‘lost children’ of Argentina — who were kidnapped and separated from their biological families as infants — and to identify the remains of soldiers missing in action and of disaster victims.

Other winners of this year’s Lasker awards, often referred to as ‘the American Nobels’, include molecular biologists Kazutoshi Mori of Kyoto University in Japan and Peter Walter of the University of California in San Francisco, in the category of basic medical research. They independently uncovered how cells correct proteins that are improperly folded by activating the transcription of certain genes.

The winners for clinical medical research were neurologists Alim Louis Benabid of Joseph Fourier University in Grenoble, France, and Mahlon R. DeLong of the Emory University School of Medicine in Atlanta, Georgia, for their work in high-frequency deep-brain stimulation. By targeting an area of the brain involved in motor functions called the subthalamic nucleus, they found the technique could be used to treat those with Parkinson’s disease to alleviate tremors and motor problems.

NIH finds forgotten ricin during lab sweep

Posted on 06 Sep 2014 by Lauren Morello

A laboratory sweep at the US National Institutes of Health (NIH) has turned up forgotten stores of the toxin ricin and four pathogens, according to a 5 September agency memo.

The agency undertook the search after discovering improperly stored vials of deadly smallpox virus in a refrigerator at its Bethesda, Maryland, campus in July. That news came just weeks after the US Centers for Disease Control and Prevention (CDC) said that employees at one of its labs in Atlanta, Georgia, were potentially exposed to anthrax because they did not follow established safety guidelines. And in March, CDC employees shipped samples of the dangerous H5N1 influenza virus to another government laboratory without taking proper precautions.

The NIH says that its lab-safety sweeps revealed small amounts of improperly stored ricin and pathogens that cause tularemia, plague, botulism and the tropical disease melioidosis. All five substances are classified as ‘select agents’ — pathogens and toxins that the US government considers to pose a severe threat to public health and safety.

The ricin was discovered in a historical sample collection dating from 1914 and may be 85–100 years old, the agency memo says.

“All of the agents were found in sealed and intact containers and there were no personnel exposures associated with the storage or discovery of these vials or samples,” NIH director Francis Collins said in the memo. Collins added that the agents were reported to the CDC and destroyed.

Meanwhile, the US Food and Drug Administration said on 5 September that it had found improperly stored samples of Staphylococcus enterotoxin, a pathogen that can cause food poisoning. The discovery was first reported by the Associated Press.

Australian gene-patent case dismissed

Posted on 05 Sep 2014 by Heidi Ledford

An Australian federal court has thrown out a lawsuit challenging a patent on the cancer-associated gene BRCA1. The decision, issued 5 September, is the latest setback for patient advocates who argue that the patent limits genetic-testing options for Australian cancer patients.

The patent, held by Myriad Genetics of Salt Lake City, Utah, is used to protect a genetic test for mutations in BRCA1 that may enhance the risk of cancer, particularly breast and ovarian cancer.

The Australian case is an echo of a previous legal challenge to patents on BRCA1 and BRCA2 in the United States. That case culminated last year in a unanimous, landmark Supreme Court decision that overturned decades of practice by the US Patent and Trademark Office, invalidating all patents on naturally occurring human genes. The implications of that decision for other US patents on natural products are still being worked out.

The Australian case began in 2010, and was brought by breast-cancer survivor Yvonne D’Arcy and a patient advocacy group, Cancer Voices Australia. But a federal judge dismissed the case on 15 February 2013, arguing that the patent’s reference to isolated DNA was enough to establish that it claimed a “manner of manufacture”, rendering the patent valid under Australian patent law. D’Arcy filed an appeal, which culminated in a second dismissal yesterday.

But that action may not spell the end of the patent challenge. In the wake of the decision, the non-governmental organization Cancer Council Australia called for legislative changes to prevent monopolies on diagnostic tests.

And D’Arcy may yet appeal today’s ruling. “The judgment has significance for access to genetic testing, research and the development of treatments for diseases,” wrote Rebecca Gilsenan, principal lawyer at the firm Maurice Blackburn, which represented D’Arcy, in a statement. “We will look at appealing the decision once we have considered the judgment in detail.”

US government labs plan biohazard-safety sweep

Posted on 29 Aug 2014 by Sara Reardon

The discovery of smallpox in a refrigerator at the US National Institutes of Health (NIH) in Bethesda, Maryland, on 9 July has apparently sparked some soul searching in the US government. On 27 August, the NIH designated September as National Biosafety Stewardship Month, encouraging researchers to take inventory of their freezers for potentially dangerous agents such as pathogens and toxins, and review their biosafety protocols. The White House Office of Science and Technology Policy (OSTP) did the same in a memo released to the public on 28 August, suggesting “a government-wide ‘safety stand-down,’” and “strongly urging” both federal agencies and independent labs to complete these steps within the month.

Although the OSTP does not have the regulatory power to enforce inspections, documents obtained exclusively by Nature show that some government agencies are already starting strict surveillance of their labs. In July, the NIH began scouring its own facilities for any misplaced hazards. Its rigorous strategy, obtained through public-records request, requires laboratories at all of its campuses — whether they work with infectious diseases or not — to survey their vials and boxes for potentially dangerous pathogens, venoms, toxins and other agents. The scientific directors of each NIH institute have until 30 September to submit affidavits confirming that this has been completed by the laboratories in their institutes.

The protocols for this comprehensive sweep describe steps that the laboratory directors must take “including, but not limited to: a) randomly choosing several containers in the inventoried repository and confirming that their contents are as expected; b) if feasible, visually inspecting the contents of a substantial number of containers in the repository to be sure they hold vials of the expected type.” Anything unlabelled must be thrown away, and labs are instructed to pay specific attention not only to pathogens, but also to other hazardous materials such as poisons, venoms and explosive materials.

For extremely large collections with more than 10 million vials, such as the tissue sample repositories managed by the National Cancer Institute (NCI), researchers will not need to evaluate every single sample. Instead, they can apply a statistical algorithm to determine how many are likely to be misidentified. The NCI’s algorithm, for instance, would require examining 10,000 out of 10 million samples and matching them to existing electronic records of the inventory, and then extrapolating the rate of mismatches to the entire sample collection.

Other government agencies that work with infectious diseases are also beginning laboratory sweeps. In testimony to Congress on 16 July, Thomas Frieden, director of the US Centers of Disease Control and Prevention (CDC) promised a sweeping inventory of all CDC labs at the wake of a pair of incidents in which scientists were exposed to anthrax, and accidentally shipped flu virus to another lab.

On 25 August, the US Department of Veterans Affairs (VA) sent out a memo to its staff announcing that it would be complying with a “government-wide safety stand-down” while the agency makes sure that none of its labs have unregistered dangerous biological agents or toxins and reviews its security practices. VA scientists have until 24 September to submit affidavits that they have complied with this order.

Carrie Wolinetz, the associate vice-president for federal relations at the Association of American Universities in Washington DC, says that a number of scientists were initially concerned about that the vaguely worded VA requirement meant that research would be suspended for an unspecified amount of time. She sent out a memo to universities on 26 August, clarifying that the OSTP would not be enforcing any mandates. “It’s saying just take a day to take a look through your freezer,” she says. “It’s a good opportunity to do some reflection on what’s in your lab without it being burdensome or regulatory.”

But the lack of regulatory power is what worries epidemiologist Marc Lipsitch of the Harvard School of Public Health in Boston, Massachusetts. “Overall the White House memo is encouraging as the first, small step in a comprehensive approach to biosafety and biosecurity, but it will have little effect unless many other changes are put in place, which remain unspecified at this time,” he wrote in an e-mail to Nature.

Lipsitch is particularly concerned about regulation of experiments that make pathogens such as influenza virus more dangerous, and incidents such as those at the CDC. “The three incidents with [dangerous pathogens] in federal labs that spurred this action are among hundreds that happen each year in US laboratories,” Lipsitch writes. “Given the magnitude of the response that these three incidents have provoked, it is unsupportable to keep secret the details of [these] incidents in general. The poorly justified ‘security’ reason for keeping such incidents secret cannot outweigh the need to understand and learn from them.”

NIH advocates gear up for budget fight

Posted on 28 Jul 2014 by Sara Reardon

The US National Institutes of Health (NIH) would see its budget worries eased if a long-time political champion gets his way.

Senator Tom Harkin, the Iowa Democrat who leads the Senate panel that oversees the NIH, introduced legislation on 24 July that would ensure that the NIH’s budget never drops below its current US$29.9 billion. The bill also proposes that Congress increase the NIH’s budget by up to 10% for the next two years, and 5% each year for the next five years. By 2021, the agency’s budget would rise to $46.2 billion.

The legislation is unusual in that it sets a minimum level for NIH funding regardless of the government’s total budget for a given year. That approach could pit the NIH against other agencies when money is scarce, a scenario that some agency supporters worry is not so hypothetical. A 2011 law known as the Budget Control Act caps total government spending to 2021 (although the caps have since been relaxed for 2014 and 2015).

The Harkin bill would allow increases for NIH beyond this cap. Some advocacy groups say that NIH is not the only biomedical agency that is in need of a boost. “The painful effects of austerity span beyond NIH across the entire health continuum,” Emily Holubowich, senior vice-president of the Coalition for Health Funding wrote to Nature. “We support a balanced, comprehensive, permanent solution to end this era of austerity for all public health and core government functions.”

The legislation’s future is uncertain, however. Harkin is retiring at the end of this year, and Congress is working on a schedule shortened by the federal election in November. Lawmakers are not expected to finish work on a funding plan for the 2015 budget year — which begins on 1 October — until after the election.

Scripps president resigns after faculty revolt

Posted on 23 Jul 2014 by Erika Check Hayden

The president of the Scripps Research Institute intends to leave his post, according to a statement from Richard Gephardt, the chair of the institute’s board of trustees. The announcement came in the wake of a faculty rebellion against the president, Michael Marletta, who had attempted to broker a deal in which the research lab, in La Jolla, California, would be acquired by the Los Angeles-based University of Southern California (USC) for US$600 million.

In the statement, posted on 21 July, Gephardt said that Marletta “has indicated his desire to leave” Scripps and that the board “is working with Dr Marletta on a possible transition plan”.

Scripps Research Institute president Michael Marletta resigned after clashing with faculty over a proposed merger.{credit}Scripps Research Institute{/credit}

Scripps faculty members see Marletta’s departure as a victory. They had been angered by the terms of the USC deal, which was scrapped on 9 July, and by the fact that Marletta did not consult with faculty during his negotiations with USC. Faculty members told the Scripps board of trustees earlier this month that they had an almost unanimous consensus of no confidence in Marletta.

“I think we are more optimistic than we have been in many years, because we feel like we have some control over our own fate,” says Scripps biologist Jeanne Loring.

Loring said that at a meeting with a majority of Scripps faculty on 21 July, Gephardt indicated that the board had thought that Marletta was communicating with the faculty as he negotiated the USC deal. Gephardt also promised that faculty would involved in choosing Marletta’s successor.

Whoever replaces Marletta must find a way to close a projected $21-million budget gap this year left by the contraction of funding from the US National Institutes of Health (NIH) and by the virtual disappearance of support from pharmaceutical companies, who had provided major support for Scripps until 2011.

How Scripps solves its funding issue will be watched by other independent institutes, which have been hard hit by the contraction in NIH dollars. Scripps’ neighbour institutes have brought in hundreds of millions of dollars in philanthropy, and many involved see that as part of the solution for Scripps as well. But, Loring says, “the funding that other institutes have got from philanthropy is going to be a short-term solution, because even though it seems like an awful lot of money, they have to spend it, so they will eventually be facing the same issues.”

Follow Erika on Twitter: @Erika_Check.

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