Croatia swastika: Hosts apologise for Nazi pitch symbol

 The Croatian Football Federation has apologised after a swastika symbol was marked on to the pitch ahead of their Euro 2016 home qualifier against Italy.

 "This is sabotage and a felony," said Tomislav Pacak, a Croatian Football Federation (HNS) spokesman. "We expect police to identify the perpetrators.

 "This is a disgrace not just for the HNS but for the whole of Croatia."

 The game was played behind closed doors after Croatia were punished for racist chants by fans against Norway in March.

 Pacak added that Uefa had been told about the incident, which overshadowed the 1-1 draw between the two sides who are vying for top spot in Group H.

 The swastika - widely recognised as the symbol of Nazi Germany - was seen during the first half and although ground staff at the stadium in Split tried to cover it up at half-time they were not successful.

 It is unknown whether the symbol was mowed or painted into the grass, or who is responsible.

 "As far as we have learned, the symbol was imprinted into the pitch between 24 and 48 hours before the match so that it could be visible during the game," added Pacak.

 "We apologise to all fans watching the game on television, to both teams and to our guests from Italy for the Nazi symbol."

 November's reverse fixture in Milan was stopped twice for crowd trouble, with riot police involved.

 Croatia were forced to close part of their stadium for March's game against Norway as a punishment for their fans' behaviour at the San Siro.

 But the supporters who did attend the Norway game caused more problems, leading to the Italy game to be played in an empty stadium.

 "It's one of our problems and we are working to fix it,'' said Davor Suker, the president of the Croatian football association. "We'll speak about it on Saturday, but I'm very angry." ||||| ?

 A Brentwood homeowners association that threatened to sue a family over their wheelchair ramp has apologized.

 Last summer, Michael Broadnax, a popular Nashville pastor, suffered a debilitating stroke. A few months later, his family learned he could come home for rehabilitation, but they would need to install a wheelchair ramp in a few days before rehab officials would clear the move.

 The family hired a legal contractor and had the ramp installed at the front of their home at the Woodlands at Copperstone in Brentwood. For the last several months, they thought everything was fine. But last week, their homeowners association threatened to sue if they didn't remove the ramp because the family didn't get permission and approval first.

 Charlotte Broadnax, Michael Broadnax's wife, said since Channel 4's story first aired on Monday, she has received dozens of calls and letters expressing support for her and her husband.

 "I've had several people come to my door in support," Charlotte Broadnax said.

 Wednesday, Michael Broadnax came out of intensive care after his latest brain surgery. His wife has continued to battle her homeowners association, which mailed two letters demanding the wheelchair ramp be removed.

 "I called to let them know I am trying to work this out," Charlotte Broadnax said. "I am trying to work with them and I want them to work with me."

 After making several calls Wednesday to Ghertner and Company, which manages the HOA, Charlotte Broadnax received a hand-delivered letter of apology from the Woodlands at Copperstone Homeowners Association and its attorney, Alvin Harris.

 "Please accept the apologies from my previous letter, which should not have been sent," said Charlotte Broadnax, reading from the letter. "It was not approved by all board members of the association and did not contain all the information that the board had previously discussed."

 The letter explained the board's original intent was to bring to the Broadnaxes attention the ramp required a permit from the city of Brentwood and needed approval by the homeowners association's architectural review committee.

 The homeowners association manager Elecia Lewis explained that board members noticed a lot of visitors on Sundays and thought the ramp might be for guests.

 "She said, 'we did not know the owner of the house was the one that was in need,'" Charlotte Broadnax said. "I asked, 'Why didn't you come to the house and ask why the ramp was up instead of waiting seven and a half months?'"

 The Federal Housing Act "makes it unlawful for any person to refuse to permit at the disabled person's expense, reasonable modifications of existing premises or to be occupied by a person if such modifications may be necessary to afford that person full enjoyment of the premises."

 Beverly Watts, director of the Tennessee Human Rights Commission, reached out to make sure the family was protected legally.

 "The homeowners association is responsible for contacting the individuals," Watts said. "The letter was a bit harsh, in our opinion. So they had already made a decision that there was no need to interact, that there was no need to talk with the homeowner about an accommodation. And that's what we were concerned about because that, in and of itself, is a violation of the law."

 Tracey McCartney with the Tennessee Fair Housing Council said in an emailed statement: "Homeowners or renters who are trying to modify their unit for the use of a person with a disability and who are running into roadblocks are welcome to call the Tennessee Fair Housing Council at 615-874-2344.”

 Charlotte Broadnax said she will be filling out the proper paperwork for the ramp. For now, her top priority is her husband's recovery.

 "My focus is on [going] from the hospital to rehab and from rehab back home," she said.

 The Broadnaxes no longer have a two-week deadline and will be working with the Brentwood Codes Department to make sure the ramp is in compliance.

 The Tennessee Human Rights Commission and Tennessee Fair Housing can both assist people with disabilities work are seeking legal or anti-discrimination help. Both services are free.

 For more information on housing modifications for disabled persons, click here.

 Copyright 2015 WSMV (Meredith Corporation). All rights reserved. |||||

 Tim Hunt, winner of the Nobel Prize for Medicine, made troubling comments at the World Conference of Science Journalists in South Korea. (AP Photo/Alastair Grant, File)

 Earlier this week at the World Conference of Science Journalists in Seoul, Nobel Prize-winning scientist Tim Hunt laid this on the audience during his remarks: “Three things happen when they are in the lab.... You fall in love with them, they fall in love with you, and when you criticize them, they cry."

 Hunt, who won the 2001 Nobel Prize in medicine for his work on cell division and now works for Cancer Research UK, wasn't talking about whiny, distracting lab puppies. He was talking about women.

 He went on to say that he thought people should work in gender-segregated labs but that he hoped such sentiment wouldn't "stand in the way of women."

 The reaction in the science and science journalism community has been, well, about what you'd expect. I'm not going to embed any tweets, but my favorite lighthearted takes on the subject have been to the effect of well to be fair, most female scientists have a 'no Tim Hunt' policy in their labs and but where will we get that male co-author we're supposed to have if the lab is all female?!

 [Sexism in science: Peer editor tells female researchers their study needs a male author]

 Outside the Twittersphere, the Royal Society distanced itself from Hunt's remarks, reiterating its commitment to help women succeed in the sciences.

 And why are Hunt's feelings so troubling? Well, there's this problem we've got where women are underrepresented in the sciences, math, technology and engineering. In fact, in Britain (Hunt's home country) only 13 percent of people working in STEM are women. In science academia, 84 percent of full-time professors in the field are men. The situation in the United States is perhaps a bit better, with women getting a share of science doctorates that hovers just above 25 percent. One recent study claimed the problem had been solved, but other scientists were quick to dismantle the flaws in its methodology and cast doubt on its conclusions.

 [Gender gap: Women welcome in ‘hard working’ fields, but ‘genius’ fields are male-dominated, study finds]

 This isn't to say that Hunt is the first Nobel laureate to use his elevated status to share some problematic remarks. James Watson is known for having some real zingers (of the racist and sexist variety) up his sleeve. What punishment did the politically correct hordes inflict on that soul? Well, he sold his Nobel Prize for $4 million, then had it returned to him by the Russian billionaire who'd bought it, as a gift. Rough, I know.

 Hunt has since apologized via the BBC, but he seems to be as much in need of a lesson on proper apologies as he is on one in gender equality. From the BBC:

 Speaking to BBC Radio 4's Today program, he said he was "really sorry that I said what I said," adding it was "a very stupid thing to do in the presence of all those journalists." The British biochemist, who became a Royal Society fellow in 1991, said the remarks were "intended as a light-hearted, ironic comment" but had been "interpreted deadly seriously by my audience." He went on to say he stood by some of the remarks. "I did mean the part about having trouble with girls," he said. "It is true that people -- I have fallen in love with people in the lab and people in the lab have fallen in love with me and it's very disruptive to the science because it's terribly important that in a lab people are on a level playing field. I found that these emotional entanglements made life very difficult. I'm really, really sorry I caused any offense, that's awful. I certainly didn't mean that. I just meant to be honest, actually." On his remarks about women crying, he said: "It's terribly important that you can criticize people's ideas without criticizing them and if they burst into tears, it means that you tend to hold back from getting at the absolute truth. "Science is about nothing but getting at the truth and anything that gets in the way of that diminishes, in my experience, the science."

 Honesty is obviously important, but -- really? These remarks were only troublesome because journalists were there to be offended by them? Obviously no one can force Hunt to be repentant for his personal belief that women are emotional time bombs, but a non-apology is never the answer. What's a non-apology? Here's a good summary from Pacific Standard Magazine:

 The term “non-apology” first appeared in 1971, but it wasn’t commonly used until the late '90s and then on into today. It’s when you apologize ... if you’ve offended anyone. “I’m sorry ... if you felt this way.” Or when you say you’re sorry because you didn’t mean to do whatever terrible thing you ended up doing. It’s a conditional apology. It’s an apology, plus more some words that make it into something that’s not an apology.

 As the PS Mag piece goes on to explain, a non-apology is the aggressive version of an apology. To not apologize is passive, but to come out with one of these non-apologies shows an active refusal to admit your wrongdoing.

 I've come under fire for being like "nah, that's sexist," before, so I decided to check my facts this time.

 So, okay: Hunt is revealing that he has trouble dealing with women. There are probably a lot of older male scientists who feel this way. I know, I know, we ladies totally crashed the party! We're so cheeky.

 If Hunt said he wanted single-sex labs because he couldn't help falling in love with female lab scientists -- well, that's kind of icky, too. But it's his insistence -- even in his apology -- that women, as a group, cry to get what they want that really sticks the landing.

 [Science columnist tells student bothered by breast-ogling prof: ‘Put up with it’]

 Maybe Hunt is guilty of hiring the wrong people all-around, if it's just inter-lab affairs and the howling lamentations of women in there 24/7. If Hunt has an HR problem, he should go ahead and fix it -- not use it as the basis for proposing that labs be segregated. (Also, how would that even work? Where would people outside the gender binary go? Would labs full of non-heterosexuals descend into the same weepy, chaotic interpersonal jumble that Hunt fears? I HAVE QUESTIONS.)

 But let's call this what it really is: Just the inescapable truth for countless women working in science. They have colleagues -- bosses in position of great power, even, with globally recognized accolades -- who seem to genuinely believe they just can't help but cry when they're criticized. They can't help it, mind, it's a lady problem. And that's no way to do science now, is it?

 [Sexism often comes with a smile, study finds]

 When men believe women are inherently less capable of handling the rigors of science and working professionally without falling over themselves to date their colleagues, they're not going to be considered for the jobs they should be considered for. They're not going to perform as well in those labs. They're not even going to make it to those labs, because someone earlier in their career pipeline has already hit them with this roadblock.

 No one expects another apology from Hunt: He's at peace with what he said. And that's the problem. Hunt's views are not outside the norm. They will not have him booted from his institution. No one wants his head on a platter. They just really really wish he could stop having these views, because they're incredibly harmful to women in a field that's already making women run up the down escalator.

 In some ways, Hunt is right in apologizing only for saying these things in front of an audience that took offense. If he said them in his lab, it's safe to say, none of the women under fire would disagree with him. That would just be a bad career move.

 Read More:

 Men (on the Internet) don’t believe sexism is a problem in science, even when they see evidence

 Cards Against Humanity releases science-themed expansion to benefit women in STEM

 Can science make you less sexist while you sleep?

 Sexism often comes with a smile, study finds

 Sexism in science: Peer editor tells female researchers their study needs a male author ||||| Follow @marymitchellcst

 Sen. Mark Kirk, 55, is a good example of why it never pays to try to keep up with the younger generation.

 Instead of looking cool, you wind up saying stupid stuff that makes you look lame.

 Kirk was caught on a live microphone Thursday referring to his Republican colleague and presidential hopeful Lindsey Graham as a “bro with no ho.”

 I didn’t even know what that meant. My adult son had to fill me in.

 “It just means he’s a single man,” my son explained.

 OPINION

 Follow @marymitchellcst

 In my day, a “bro” was a black man with a ‘fro. As for “ho,” well, the definition of that slur hasn’t changed. Coming from the senator, the “bro with no ho” comment is an embarrassment.

 But what was especially offensive was Kirk also saying, “That’s what we’d say on the South Side.”

 Wait a minute. Since when did Kirk become a South Sider?

 You can’t just proclaim yourself a South Sider. You’ve got to pay your dues by riding those overcrowded buses and trains, living in food deserts, traveling impossible distances to shop and navigating dangerous neighborhoods.

 Kirk is from Highland Park — the land of plenty.

 I know some people falsely claim to be from this side or that side of Chicago, when you’re really from the suburbs. That’s OK.

 But Kirk has repeatedly pretended to have a grasp on what’s going on in these communities.

 In 2013, he clashed with U.S. Rep. Bobby L. Rush, D-Illinois, when he called for the mass arrests of the Gangster Disciples, a gang he said numbered 18,000.

 Rush called Kirk’s proposal “a middle-class, elitist white-boy solution to a problem he knows nothing about.”

 The senator put his foot in his mouth again in an interview about economic development when he declared that black neighborhoods are the ones that people driver through faster.

 I have no doubt that some white people are afraid to drive through black neighborhoods. But there are a lot of white people who work, live and play in black neighborhoods, and I would argue that they are safer in those neighborhoods than the young black males who live there.

 A spokesman for Kirk dismissed his boss’ comments Thursday as a joke.

 Maybe he should have added that was a joke that was in poor taste and which could prove costly.

 The senator was engaging in the kind of bawdy banter some “bros” engage in when women aren’t a part of the conversation. That shows he really doesn’t get it.

 Kirk is up for re-election. And two fierce women — U.S. Rep. Tammy Duckworth, D-Illinois, and Andrea Zopp, the former head of the Chicago Urban League — are seeking the Democratic nomination to face him.

 Either one of these accomplished women could benefit from Kirk’s gaffe. I can’t wait to see how the “bro with no ho” soundbite ends up being used in campaign commercials.

 Meantime, Kirk owes the South Side an apology.

 While some African-American aldermen are still making an ugly fuss over New York filmmaker Spike Lee calling a movie he’s making in the city “Chiraq,” what Kirk’s doing is worse.

 He’s stereotyping the black community, casting it in a negative light and then crowing about it.

 Follow Mary Mitchell on Twitter: @MaryMitchellCST ||||| Diane Rehm, a Washington radio host whose show is widely syndicated on National Public Radio, apologized Wednesday for saying presidential candidate Bernie Sanders has Israeli citizenship, which Sanders repeatedly denied.

 "On today’s show, I made a mistake," read "An Apology From Diane" on the episode's website. "Rather than asking Senator and Presidential Candidate Bernie Sanders whether he had dual U.S./Israeli citizenship, as I had read in a comment on Facebook, I stated it as fact."

 "I want to apologize as well to all our listeners for having made an erroneous statement. I am sorry for the mistake. However, I am glad to play a role in putting this rumor to rest."

 “I am glad to play a role in putting this rumor to rest.” Diane Rehm

 Sanders, an independent Vermont senator who is running for the Democratic nomination for president, had talked about a variety of topics on Rehm's Wednesday's show, including foreign policy, when she declared, "Senator, you have dual citizenship with Israel."

 Sanders, who was raised Jewish, interrupted her.

 Sanders: No I do not have dual citizenship with Israel. I'm an American. That’s—I don't know where that question came from. I am an American citizen, and I have visited Israel on a couple of occasions. No, I'm an American citizen, period. Rehm: I understand from a list we have gotten that you were on that list. Forgive me if that is… Sanders: No, that’s some of the nonsense that goes on in the internet— Rehm: Interesting... Sanders: But that is not something that’s true. Rehm: Are there members of Congress that do have dual citizenship, or is that part of the fable? Sanders: I honestly don't know.

 Sanders then said he was "offended a little bit by that comment," and said, "I do not have any dual citizenship."

 Rehm apologized on the show again on Thursday, saying she had "made an erroneous statement," according to Poynter.org, a media blog.

 "This is an issue that has come up over the years in American politics," she said, according to Poynter. "One of our listeners suggested by Facebook that I ask Senator Sanders about Internet speculation that he has dual citizenship with Israel. But instead of asking it as a question I stated it as fact and that was wrong."

Summary: – Public apologies making headlines this week include a scientist and a senator trying to show how funny they are: Prize winner: "I'm really, really sorry I caused any offense, that's awful. I certainly didn't mean that. I just meant to be honest, actually."—Tim Hunt, Nobel-winning scientist, after he made light of "girls" working in labs. He added that it was a "stupid" thing to say in front of journalists, which is partly why a writer at the Washington Post calls this the "non-apology of the year." New name, please: "We are sorry that wording which could be considered offensive has been used, as this has not been our intention at all."—Lego, after it described a strange-looking new Lego model as a "window-licker," a derogatory term for people with learning disabilities. If it's on Facebook, it must be true: "I want to apologize as well to all our listeners for having made an erroneous statement. I am sorry for the mistake. However, I am glad to play a role in putting this rumor to rest."—Diane Rehm of NPR, after she informed Bernie Sanders that he had Israeli citizenship during an interview. He doesn't. She had seen it on Facebook. Unsportsmanslike: "We apologize to all fans watching the game on television, to both teams and to our guests from Italy for the Nazi symbol."—Tomislav Pacak, a Croatian Football Federation spokesman, referring to the faint but unmistakable imprint of a large swastika on a soccer field. He's a what? "(He) was joking with his colleague and immediately apologized to anyone offended by his remark."—Spokesperson for Sen. Mark Kirk, after he described his bachelor colleague Lindsey Graham as a "bro with no ho." (A Sun-Times columnist thinks he owes a specific apology to residents of Chicago's South Side.) All business: "Please accept the apologies from my previous letter, which should not have been sent."—Homeowners association in Brentwood, Tenn., after threatening to sue a family for putting up a wheelchair ramp. The homeowner, a pastor, just had brain surgery. The HOA had second thoughts when the story went public.


Story highlights Lego tower in Budapest confirmed as world's tallest by Guinness World Records

 Tower reaches 34 meters over city's St. Stephen's Basilica

 Local school children helped build the structure, which was topped by a Rubik's cube -- a Hungarian invention

 Imagine the size of the box this one came in -- a Lego tower stretching 36 meters into the sky above the Hungarian capital Budapest.

 The 34.76- meter (114 feet) tower, which was completed on Sunday, has been certified as the world's tallest toy brick structure by Guinness World Records.

 It beat the previous record holder, a 34.4-meter structure constructed last year with the help of U.S. students from a school in Delaware.

 A spokesman for Guinness World Records confirmed that the tower qualified as the "tallest structure built with interlocking plastic bricks."

 He said the record was officially registered to Lego Store Budapest on May 25.

 The Budapest tower, topped by a Rubik's cube -- a Hungarian invention -- was also built with the help of Hungarian primary school children, according to local news websites.

 The structure, built in front of the city's St. Stephen's Basilica, used hundreds of thousands of blocks.

 MORE: Budapest's escape games go global ||||| Hungarian enthusiasts set a new Guinness world record for the world's tallest Lego tower. Standing at 36 metres, the tower was constructed in front of Saint Stephen's basilica in Budapest. School children helped to build the structure, and the mayor of the city's fifth district put the final block in place. The previous record was 34.43 metres

Summary: – Lego lovers will be stoked by this news: Budapest, Hungary, is now home to a 114-foot-tall Lego tower to rival the city’s most picturesque architecture, CNN reports. The Guinness Book of World Records has put its official stamp on the project, declaring the multi-colored structure—which features a profile of Pac-Man and is topped by a Rubik’s cube (Hungary's contribution to pop culture)—the "tallest structure built with interlocking plastic bricks." The Lego Store Budapest will be listed as the record holder. And for a too-cute spin on the story, the Guardian reports that school kids helped snap together some of the hundreds of thousands of blocks needed to build the tower. Sadly, somewhere in Delaware a bunch of students may be weeping—they held the previous record of nearly 113 feet, CNN notes. (More quirky Lego news: Lego people will outnumber real people by 2019.)


Citation: Lipsitch M, Galvani AP (2014) Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens. PLoS Med 11(5): e1001646. doi:10.1371/journal.pmed.1001646 Published: May 20, 2014 Copyright: © 2014 Lipsitch, Galvani. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by awards from the National Institute of General Medical Sciences, number 5U54GM088558 to ML and U01 GM087719 to AG. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: ML reports consulting income or honoraria from the following sources within the past five years: Novartis, Pfizer (pharmaceutical companies); AIR Worldwide, i3 Innovus, and Outcome Sciences (risk assessment and consulting companies). None of these relationships is ongoing. He has research grants with Pfizer (active) and PATH Vaccine Solutions (pending). AG reports consulting income from Vitality (a health insurer) and AIR Worldwide (a risk assessment company). ML is a member of the Editorial Board of PLOS Medicine. Abbreviations: BSL, biosafety level; DURC, dual use research of concern; HHS, US Department of Health and Human Services; PPP, potential pandemic pathogen Provenance: Not commissioned; externally peer reviewed.

 Summary Points “Gain of function” experiments involving the creation and manipulation of novel potential pandemic pathogens (PPPs) deserve ethical scrutiny regarding the acceptability of the risks of accidental or deliberate release and global spread.

 The Nuremberg Code, a seminal statement of clinical research ethics, mandates that experiments that pose a risk to human life should be undertaken only if they provide humanitarian benefits that sufficiently offset the risks and if these benefits are unachievable by safer means.

 A novel PPP research program of moderate size would pose substantial risks to human life, even optimistically assuming a low probability that a pandemic would ensue from a laboratory accident.

 Alternative approaches would not only be safer but would also be more effective at improving surveillance and vaccine design, the two purported benefits of gain-of-function experiments to create novel, mammalian-transmissible influenza strains.

 A rigorous, quantitative, impartial risk–benefit assessment should precede further novel PPP experimentation. In the case of influenza, we anticipate that such a risk assessment will show that the risks are unjustifiable. Given the risk of a global pandemic posed by such experiments, this risk assessment should be part of a broader international discussion involving multiple stakeholders and not dominated by those with an interest in performing or funding such research.

 Two recent publications reporting the creation of ferret-transmissible influenza A/H5N1 viruses [1],[2] are controversial examples of research that aims to produce, sequence and characterize “potential pandemic pathogens” (PPPs) [3], novel infectious agents with known or likely efficient transmission among humans, with significant virulence, and for which there is limited population immunity. There is a quantifiable possibility that these novel pathogens could be accidentally or deliberately released. Exacerbating the immunological vulnerability of human populations to PPPs is the potential for rapid global dissemination via ever-increasing human mobility. The dangers are not just hypothetical. The H1N1 influenza strain responsible for significant morbidity and mortality around the world from 1977 to 2009 is thought to have originated from a laboratory accident [4]. Risk evaluations surrounding biomedical research have not kept pace with scientific innovations in methodology and application. This gap is particularly disconcerting when research involves the construction of PPPs that pose risks of accidental release and global spread. We argue here that accepted principles of biomedical research ethics present a high bar to PPP experiments, requiring that risks arising from such experiments be compensated by benefits to public health not achievable by safer approaches. Focusing on influenza, the object of most current PPP experimentation, we further argue that there are safer experimental approaches that are both more scientifically informative and more straightforward to translate into improved public health through enhanced surveillance, prevention, and treatment of influenza.

 Influenza “Gain of Function” Experiments: Prototypical Examples of Potential Pandemic Pathogen Studies Although several pathogens may be categorized as PPPs (see Box 1), “gain of function” experiments involving influenza strains modified to be PPPs are expanding [5]–[7] (Box 2), and hence of immediate concern. In addition to the two controversial studies recently published, studies with H5N1 [8], H7N9 [9], and H7N1 [10] have used similar ferret passage protocols, while still others have created mammalian-transmissible strains in vitro, followed by in vivo analysis [11],[12]. Related studies have genetically combined less pathogenic zoonotic avian viruses, such as H9N2, with human seasonal influenza viruses to generate strains that exhibit enhanced transmissibility, and to which humans would be immunologically susceptible [13]–[15]. Box 1. Scope for Heightened Ethical Scrutiny of Potential Pandemic Pathogen Experiments This article describes the responsible ethical scrutiny that should be applied to experimental studies creating or employing PPPs. We define PPPs as infectious agents with four characteristics: Having known or likely efficient transmission among humans Significantly virulent Unmitigated by preexisting population immunity Genetically distinct from pathogens currently circulating These criteria define pathogens on which experimentation would pose a risk of sparking a pandemic, placing the human population at risk of morbidity or mortality, over and above the background risk of a naturally occurring pandemic. The paradigm case is the creation of variants of influenza A/H5N1 that are readily transmissible between ferrets, a model for human transmission. Such criteria would likely be applicable to experimentation with human isolates of smallpox or SARS, since these pathogens are no longer known to be circulating naturally. In the future, the list may expand [57]. We do not advocate the necessity of heightened scrutiny for isolation and characterization of naturally occurring pathogens, such as wild-type H5N1 or H7N9, consistent with the HHS framework for evaluating gain-of-function studies of H5N1 viruses, which exempts characterization of naturally occurring viruses [33]. Box 2. Gain of Function: What's in a Name? The recent ferret transmission experiments with influenza A viruses have been termed “gain of function” experiments because they involve engineering viruses that gain transmissibility in ferrets. Gain of function is a common and important approach in biological experimentation, and is not by itself cause for concern [58]. However, the elevated concern over these experiments arises from the particular function that is gained. Ferret transmission is thought to be a good [59],[60] (albeit imperfect [61],[62]) model for human-to-human transmission. Consequently, strains resulting from selection for heightened ferret transmission are likely to be similarly transmissible by humans via respiratory droplets, a prerequisite for pandemic spread. In combination with demonstrated virulence for humans, this particular gain of function presents unique risks and raises special ethical issues. These studies have typically been conducted in biosafety level (BSL) 3 or 3+ containment facilities. Laboratory-associated infections in BSL3 facilities are conservatively estimated to occur at a rate of two per 1,000 laboratory-years [3],[16] in the United States, where protocols and enforcement are relatively stringent. Globally, high-containment laboratories have variable standards and enforcement [17]. Experimentation in less-regulated or unregulated laboratories, with the attendant risks of accidental or deliberate release, is facilitated by the publication of sequence and functional data on PPPs, even if the original research was conducted with state-of-the-art safety and security [18]. From the conservative estimate of the rate of laboratory-associated infections of two per 1,000 laboratory-years [3],[16], it follows that a moderate research program of ten laboratories at US BSL3 standards for a decade would run a nearly 20% risk of resulting in at least one laboratory-acquired infection, which, in turn, may initiate a chain of transmission. The probability that a laboratory-acquired influenza infection would lead to extensive spread has been estimated to be at least 10% [19]. Simple branching process models suggest a probability of an outbreak arising from an accidental influenza infection in the range of 5% to 60% [20],[21]. Such probabilities cannot be ignored when multiplied by the potential devastation of an influenza pandemic [22],[23], even if the resulting strain were substantially attenuated from the observed virulence of highly pathogenic influenza A/H5N1 [24], the subject of much of the published PPP work to date. We advocate a dispassionate review of pertinent evidence and calculations of the probabilities and magnitudes of potential risks parameterized for specific PPP research programs.

 Ethical Frameworks for Novel Potential Pandemic Pathogens Thus far, experiments with novel PPPs have been assessed in the context of “dual use research of concern” (DURC), a designation for “research that could be used for good or bad purposes” [25]. Within the broader category of DURC, PPP experimentation raises ethical issues that deserve more extensive evaluation than other DURC, because the scale of risk posed by PPPs is much greater. While DURC by definition presents a risk of malevolent use, the impact of the accidental release of many agents involved in DURC—anthrax, hemorrhagic fever viruses, and, most recently, a novel Clostridium botulinum toxin [26],[27] –is constrained by transmission mode or limited host susceptibility. The magnitude of accidental risk for a novel PPP is much greater. The Nuremberg Code, a seminal document in clinical research ethics, specifies that in research conducted on human participants, “the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.” More broadly, 74 national academies of science have stated: “Scientists have an obligation to do no harm. They should always take into consideration the reasonably foreseeable consequences of their own activities” [28]. The ethical principles underlying both guidelines would seem to apply a fortiori to research that imposes far-reaching risk to the public [29]. Given the global nature of influenza transmission, and thus implications beyond a country's borders, international agreement regarding acceptable risks is needed. Ethical constructs and risk evaluations must be tailored to scientific advances in methodology and application. Limited attention has been paid to the ethics of scientific experiments that pose risks beyond identified human participants [30]–[32]. On a practical level, however, the spirit of the Nuremberg Code's “humanitarian importance” criterion is embodied in the recent frameworks for evaluating PPP experiments from the US Department of Health and Human Services (HHS), the primary sponsor of such experiments to date. The HHS frameworks for studies anticipated to create mammalian-transmissible H5N1 [33] and H7N9 [34],[35] viruses specify that the risks and benefits should be weighed. The Nuremberg Code's second point states: “The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.” When projecting the benefits of experiments that put human life at risk, therefore, it is critical to compare against alternatives. What unique public health benefits do PPP experiments offer relative to the benefits of investing equivalent resources in alternative research strategies? If there are unique benefits to novel PPP experiments, do they justify the risks entailed? This concept, too, is partially incorporated in the HHS frameworks, which permit funding of H5N1 [33] or H7N9 [34],[35] transmissibility gain-of-function experiments only if “there are no feasible alternative methods to address the same scientific question in a manner that poses less risk than does the proposed approach” [33]. The Nuremberg Code suggests a broader criterion: that PPP experiments should be performed if the public health benefits envisaged cannot be obtained by safer methods. We argue that alternative scientific approaches are not only less risky, but also more likely to generate results that can be readily translated into public health benefits.

 Challenges in Translating Understanding of Influenza Transmission into Public Health Practice Proponents of PPP experimentation cite two main benefits of such studies: improving our interpretation of surveillance data to detect dangerous viruses and facilitating vaccine development against future natural pandemics. Both claims have been disputed. The vaccine claim has been denied by vaccine developers, who note that many, if not all, vaccines have been developed without a detailed molecular understanding of transmission [36]. Advocates of PPP experimentation further argue that creating potentially pandemic strains of a particular virus, e.g., A/H5N1, could facilitate the production and stockpiling of vaccines against that variant. However, given that PPP experiments inevitably consider only a few possible genetic pathways to transmissibility, and that the precise correspondence between transmissibility in the ferret model and human transmissibility remains uncertain, we can never know whether PPP experimentation would hit upon the antigenic composition of the next pandemic strain that will emerge from nature. Indeed, as described below, it is clear that there is no one-to-one mapping between a few genetic changes in a virus and its transmissibility. By contrast, universal influenza vaccines currently in preclinical and clinical trials [37] may, with further development, prove to be more worthwhile to stockpile for the purposes of pandemic preparedness than an assortment of vaccines targeting antigenic variants manufactured via PPP experimentation. Current surveillance is likely inadequate to detect an emerging pandemic strain before it is too late [29],[38], regardless of any warnings that PPP experimentation might generate about potentially worrisome mutations. Between 2008 and 2013, over 1,580 highly pathogenic avian influenza (almost all H5N1) outbreaks, involving over 5 million birds, were reported to the World Organisation for Animal Health [39]. The US National Center for Biotechnology Information Influenza Virus Resource [40] received about 1,400 complete or partial avian H5N1 virus sequences over this period [41]. Most of these sequences were over eight months old by the time they were publicly available in the Influenza Virus Resource. Similar considerations apply to GISAID's EpiFlu Database, the other major influenza virus sequence database [42]. Given that birds [43], like humans [44], harbor a genetically diverse quasispecies of influenza variants, it is highly unlikely that such limited surveillance could detect a pandemic viral sequence and, furthermore, spur effective mitigation actions, before the worrisome variant was already widespread in birds. As an example of the limited public health response even when a dangerous virus has been observed, consider the global response to H7N9 avian influenza, which has proven zoonotic potential and has probably been repeatedly transmitted from human to human [45]. Isolates from human cases reveal efficient binding to human sialic acid receptors and airborne transmission in ferrets [9] and guinea pigs [46]. These indicators of pandemic potential are much stronger than sequence comparisons with engineered viruses could provide, yet most live bird markets in China remain open, and human cases continue to emerge [47]. Given these realities, it is difficult to envision how a surveillance signal alone would prompt swifter actions than these existing warning signs for H7N9 have. In short, the benefits for public health of the scientific findings from PPP experimentation are speculative at best.

 Alternative Approaches: Safer and More Promising The prominent role of epistasis in influenza biology suggests that alternative approaches to studying the phenotypic impact of mutations on mammalian transmissibility would be not only less risky, but also more informative. In vivo replication and transmission of influenza in humans depend on myriad interdependent factors, including the binding affinity between hemagglutinin and human sialic acids, the ability of the virion to fuse with the endosomal membrane at the appropriate pH and temperature, as well as the stability of various viral proteins [11],[51],[53],[54]. Each of these traits, in turn, is not simply determined by the presence or absence of individual amino acids at particular sites, but by biophysical properties arising from the interaction of many sites within and between proteins [50],[51]. Consequently, the challenge of predicting transmissibility hinges on understanding the genetic determinants of each trait, coupled with the interactions of the traits from which the higher-level phenotype of transmissibility arises. An array of safer approaches (Table 2) to studying influenza pathogenesis and transmission focus on dissecting these interactions. Some approaches start with sequence analysis and molecular dynamics modeling, which are intrinsically safe. The experimental evaluation of hypotheses raised by such studies may use viral components rather than the entire infectious virus, making these experiments simultaneously safer and more precise and mechanistic than engineering PPPs. Furthermore, these approaches are typically less costly than PPP experimentation, facilitating phenotypic evaluation of a greater diversity and abundance of genetic variants. Ultimately, studies with intact viruses will be necessary for a full understanding of human transmissibility, a phenotype of a whole virus. Elucidating the evolutionary trajectory through which existing seasonal (former pandemic) viruses became transmissible from avian precursors is safer than PPP experimentation, given that there is preexisting population immunity to seasonal strains, the products of such evolution. PPT PowerPoint slide

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 larger image ( ) TIFF original image ( ) Download: Table 2. Safer approaches to studying human adaptation of influenza A viruses, and more generally to improving vaccines and therapeutics. doi:10.1371/journal.pmed.1001646.t002 More generally, it should be remembered that the public health goal is to curtail influenza pandemics and seasonal transmission [55],[56]. Exploring basic biology is just one scientific means to this end. Other approaches, such as developing universal influenza vaccines and novel antiviral drugs and strategies to enhance host responses, as well as improving technologies for rapid vaccine manufacture, are being pursued without risks of PPP release (Table 2).

 Paths Forward We urge that proposals for any future experiments on PPPs be evaluated according to quantitative risk–benefit analysis guided by the principles of the Nuremberg Code. Indeed, HHS frameworks require a risk–benefit analysis to approve gain-of-function experimentation on H5N1 and H7N9 [33]–[35] viruses, yet no such analysis has been made public, if it has been conducted. Other funding and regulatory agencies, which have not yet called for a risk–benefit analysis, should require one as well. In biomedical grant review processes, proposals compete for limited funding, and most proposals that could advance science are never supported, because of budget constraints or because funding agencies conclude that there are more promising, safer, more humane, or otherwise superior ways to achieve scientific goals. PPP experimentation poses a significant risk to public health, arguably the highest level of risk posed by any biomedical research. Such experiments should be assessed on the basis of their marginal benefits, compared to those of safer approaches. In the case of influenza, given the higher throughput and lower cost of alternatives, we believe the benefits of alternative approaches will be greater than those of novel PPP experimentation, yet without the risks–thereby negating the justification for taking such risks. Similarly, careful consideration should be given to analyses of novel PPP experiments beyond the study of influenza, as these are proposed. Funders and regulators should evaluate the balance of risks and benefits before further novel PPP experiments are undertaken.

 Acknowledgments The authors thank Ilaria Capua, Sarah Cobey, Norman Daniels, Dylan George, Yonatan Grad, James Hammitt, Meira Levinson, Katrina Lythgoe, Richard Malley, Daniel Markovits, Jonathan Moreno, Michael Osterholm, Steven Riley, and Colin Russell for helpful discussions and comments on earlier drafts. ||||| Public health experts have warned that controversial experiments on mutant viruses could put human lives in danger by unleashing an accidental pandemic.

 Several groups of scientists around the world are creating and altering viruses to understand how natural strains might evolve into more lethal forms that spread easily among humans.

 But in a report published on Tuesday, researchers at Harvard and Yale universities in the US argue that the benefits of the work are outweighed by the risk of pathogenic strains escaping from laboratories and spreading around the world.

 They calculate that if 10 high-containment labs in the US performed such experiments for 10 years, the chance of at least one person becoming infected was nearly 20%. If an infected person left the laboratory, the virus might then spread more widely.

 "We are not saying this is going to happen, but when the potential is a pandemic, even a small chance is something you have to weigh very heavily," said Marc Lipsitch, an epidemiologist at Harvard School of Public Health, who wrote the report with Alison Galvani, an epidemiologist at Yale.

 The report threatens to reignite a crisis in science that erupted in 2012 when a US biosecurity panel ruled that two separate studies on mutant bird flu were too dangerous to publish. They described the creation of new mutant strains that spread among ferrets – a proxy for humans – held in neighbouring cages. One fear was that the recipe for the pathogens might fall into the hands of bioterrorists.

 Those studies, led by Ron Fouchier at Erasmus medical centre in Rotterdam, and Yoshihiro Kawaoka at the University of Wisconsin-Madison respectively, were eventually published after months of delays. Other researchers have now begun similar experiments.

 Both Fouchier and Kawaoka criticised the latest report, published in Plos Medicine, and said their work had full ethical, safety and security approval, with the risks and benefits taken into account.

 Last year, the US government, which funds most of the controversial work, revised its guidelines for "dual-use research of concern", or DURC. Under the new rules, work can be funded if the potential benefits are substantial and the risks considered to be manageable.

 But Lipsitch said there was no evidence that the risks and benefits had been weighed up properly. "To my knowledge, no such thing has been done, but funding for these experiments continues," he said.

 Lipsitch said that the US government and other funding bodies must commission comprehensive risk assessments from independent experts before deciding which studies to support.

 Lipsitch and Galvani are most concerned about what are called gain-of-function studies, which aim to create highly virulent strains of viruses in secure laboratories so their genetic codes can be studied. Mutations that make a respiratory virus lodge in the throat, for example, can make the virus more transmissible through coughing.

 The rational for gain-of-function studies is twofold. If scientists can work out which mutations make a virus more dangerous to people, they can improve surveillance by looking out for those mutations in natural strains. The work might also help to steer vaccine development. But Lipsitch argues that neither justification stands up: surveillance is not good enough to use the information, and vaccine developers can do without it, he says.

 Rather than creating dangerous viruses in high-containment laboratories, Lipsitch and Galvani urge scientists to pursue alternative routes, for example, comparisons of seasonal human flu strains and other respiratory viruses that have jumped from animals into humans. These are not only safer, the authors claim, but the studies are scientifically sound, because they do not rely on small numbers of animals.

 The report was roundly rejected by Fouchier and Kawaoka, two of the leading scientists in gain-of-function studies. Fouchier said the authors were wrong on both points they made – that alternative experiments could provide answers about the transmissibility of viruses, and that the risk of an outbreak or pandemic was high.

 "The research agenda they propose is important and currently ongoing, but alone will never lead to solid conclusions about mammalian adaptation and transmission: the proof of the pudding will need to come from gain-of-function studies using infectious viruses. This is why the department of health and human services has approved our research, taking into account all ethical, safety and security issues, and weighing the risks of the research against the benefits," Fouchier said.

 He said the authors had misinterpreted published data to arrive at their risk of someone picking up a virus in the laboratory. "The truth is that scientific research has never triggered a virus pandemic." Lipsitch and Galvani point out that a flu strain that spread around the world from 1977 to 2009 was probably released in a laboratory accident.

 Kawaoka was similarly unimpressed with the report. "The authors imply that gain-of-function studies are going on without proper reviews. This is not so and suggests they do not understand how highly regulated this work is and the approvals and planning required to conduct this research," he said. "This commentary lists many experiments they think we should be doing. We are doing many of those experiments already."

 Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, said that scientists working on the controversial virus studies should be less defensive. "There are times when we have to open up and face our critics. Marc is articulating what many of us feel is obvious," he said.

Summary: – Scientific testing is great—except when it has the potential to unleash a global pandemic. That's the word from a new study that warns experiments on mutant viruses could do more harm than good. Scientists around the world are creating new viruses or changing existing ones to better understand how strains evolve and spread, but that's a big problem, say Harvard and Yale researchers. If 10 labs in the US performed high-containment experiments for 10 years, they estimate about a 20% chance that at least one person would become infected and a 1% chance that it would escape the lab, USA Today reports. "We are not saying this is going to happen, but when the potential is a pandemic, even a small chance is something you have to weigh very heavily," says a Harvard epidemiologist as quoted in the Guardian. Scientists who study bird flu immediately criticized the study, saying their research provides insights that would be otherwise impossible. Two of those quoted created an airborne strain of avian flu in 2012 that was transmissible to mammals, a controversial feat whose details were published only after much debate.