Science publishing has a Zika problem

Zika virusScience publishing has a problem. I agree with Nobel Laureate Randy Schekman, who wrote that prestigious science journals like Cell, Nature, and Science – which he calls ‘luxury journals’ – are damaging science.  The succession of articles on Zika virus nicely illustrates this problem.

The big three in science publishing – Science, Nature, and Cell – have published many papers on Zika virus since the beginning of 2016. Many of these have had a turnaround time of a week or two – the time between when the papers were submitted, and when they were published online. A rapid turnaround time is unusual, and not compatible with proper peer review of the work. Indeed, many of the papers have been clearly rushed into print, and lack proper controls and clear explanations of what has been done.

The recent publication in Cell Host & Microbe of a description of an infectious DNA clone of Zika virus is a perfect illustration of the problem with luxury journals. Infectious DNA clones of viral genomes are nothing new – the first were described the late 1970s and 1980s. They are important reagents, allowing manipulation of the viral genome to study replication and pathogenesis. But publishing a reagent has never been enough to get into a high profile journal.

As a postdoctoral fellow with David Baltimore in 1981, I was fortunate to publish the first report of an infectious DNA clone of an animal virus – poliovirus – in Science (At the time there were no luxury journals. Years later Nobel Laureate Paul Berg asked why we chose to publish in such a lowly journal). A few years later, I submitted a paper to the Journal of Virology describing the construction of an infectious DNA clone of a different serotype of poliovirus which had the unique ability to infect mice. The paper was rejected because, I was told, it didn’t contain any new results.

The first infectious DNA clone of a calicivirus – the family that includes noroviruses, agents of human gastroenteritis – was published in 1995 in Virology. The senior author told me the paper was rejected from the Journal of Virology because an infectious clone is ‘just a tool’.

The Journal of Virology is a solid journal that publishes many important articles in the field. But no one would mistake it as a luxury journal.

Some infectious DNA clones of viruses have been published in prominent journals – for example, Ebolavirus and influenza virus in Science (2000 and 2001). Zika virus is a flavivirus, and the first infectious DNA of a member of this virus family was for yellow fever virus, published 27 years ago in PNAS. Subsequently there have been many reports of infectious DNA clones of other flaviviruses, notably, West Nile virus, published in Virology in 2001. This virus, which entered the United States, gained quite a bit of attention in the press.

Technically, there is nothing novel about making an infectious DNA clone of Zika virus. It is an important reagent, just as infectious DNA clones are important for the study of all viruses. But the paper reports no experimental results using the Zika virus infectious DNA that advance the field. In my opinion, the infectious DNA clone of Zika virus should not have been published in a high profile journal.

Clearly the paper was published because Zika virus is hot and it will garner the journal a great deal of publicity, a consideration that should not determine whether an article should be published or not. It is the science that should drive publication – and the luxury journals have lost track of this fact.

Schekman points out that the reputations of luxury journals reputations as the “epitome of quality” is only “partly warranted”: they don’t always publish outstanding work, and they are not the only journals to publish great science. He feels that they “aggressively curate their brands, in ways more conducive to selling subscriptions than to stimulating the most important research”. They are driven by impact factor, which Schekman and others, including myself, think is wrong. Highly cited papers are not necessarily correct; they might be “eye-catching, provocative or wrong”. He says that editors accept papers that will ‘make waves’ and therefore influence, inappropriately, the direction of science. He favors open-access journals that are edited by scientists, and so do I.

In my view there are two main forces that have corrupted science publishing. The first is one that Schekman notes: that these journals are in the business of selling subscriptions. The Cell and Nature journals are owned by for-profit publishing companies. This situation is problematic because the drive for profit is not necessarily compatible with the need to publish high quality science. Editors know that controversial or prominent (e.g., Zika) papers will drive advertising revenue, but this should not even be a consideration when deciding what to publish. The publication of scientific data should not be a for profit enterprise. Unfortunately, Science magazine, which is published by the non-profit AAAS, seems to be driven by the same corrupting influences.

A second problem is that decisions at the luxury journals are typically not made by working scientists, but by full-time editors. A professional editor cannot possibly know the field as well as a working scientist, who spends his or her days in the trenches of science: designing experiments, interpreting data, guiding students and postdoctoral fellows, reviewing manuscripts, writing grants, going to meetings, and much more. The result is that the working scientist is fully immersed in science every day, all year, and is in the best position to know what work is significant, advances the field, and should be considered for publication.

These two factors control what kinds of papers are published. The luxury journals want high-impact papers that are of broad interest. But the problem is that it’s not always clear exactly where a paper fits in. Many of us have had the experience of submitting a paper to Cell, Science, or Nature, only to be told ‘it’s not of sufficient interest’. But the real reason is that the paper won’t sell advertising, or subscriptions; or perhaps the editor who made the decision simply doesn’t sufficiently understand the field.

A paper on an infectious Zika virus DNA clone will help Cell Host & Microbe get more advertising. A year ago, the journal would not even have reviewed the paper.

It’s no secret that publishing controls our scientific careers. Decisions about important things like hiring, promotion, tenure, and grant funding revolve around what you have published and where. I’ve been on many tenure or grant review committees, and it’s common to count the number of Cell, Nature, and Science publications as a metric of quality. The same occurs when examining job candidates for professorial positions.

In other words, the luxury journals are controlling the careers of scientists. Journals motivated by profit, run by professional editors who are not scientists, are deciding who is hired, promoted, tenured, and who gets grant money.

Unfortunately it is a system that scientists have created and nurtured until it has become an absurd and untenable situation, and it has to change. The PLoS journals and eLife are helping to do that, but what is also needed is to diminish the importance of the luxury journals to the careers of scientists. That is a much harder goal to achieve, as all my colleagues who are sending their Zika virus papers to luxury journals, will admit.

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  • Hannah 19 May 2016, 9:00 pm

    Your point is well taken, but I think you’re overly hard on the infectious Zika clone paper (no I was not involved in said paper in any way, but I did read it):

    1) Cell Host & MIcrobe is not Cell. (We can talk about the issue of the big three journals milking their brand by publishing a bunch of other journals another day) It’s an important journal, but nowhere near as high profile as Cell.
    2) This paper was published as a “Resource” article, not a research article. This articles “highlight significant technical advances and/or major informational databases.” So it’s fair to complain that the Zika infectious close is insufficiently significant of a technological advance, or that it’s not appropriate for journals to publish this type of article, but it’s important to note that the journal is not putting the paper out there for its results. Generally speaking, I think there is value to the scientific community in sharing important tools and wells as findings with one another. And as a result of this specific publication, the world now knows from whom they can potentially obtain an important reagent.
    3) It’s valuable to know how the phenotype of the recombinant virus compares to the parental one. While the two are generally similar, the authors note that the recombinant is less virulent in vivo than the parental strain. While this phenomenon is certainly not unheard of for a recombinant virus, this is still useful information for other groups who may have similar results and wonder if there’s something wrong with their clone. Furthermore, I think it’s important to note cases when recombinant and parental viruses behave differently. I’ve seen a number of papers where researchers minimize such findings or only hint at them so that they can go on and describe the results of mutagenesis experiments. This just makes it harder for science to solve the puzzle (one that may give us valuable insights) of what’s responsible for the differences.

    In the end, I think the issue is less the behavior of the big journals and more the fact that we use publication in them as a metric of researchers’ ability to do good science. The fact is, lots of people do want to read Zika papers right now, so it’s appropriate for journals that target a wide audience to publish them. The part that’s not fair is when we ooooh and aaah over very basic studies that get published in eg Nature and pooh-pooh much more elegant studies with, for example, non-pathogens that get published in the “lesser” journals.

  • Nahal 19 May 2016, 10:28 pm

    Thank you so much for sharing your comments Hannah, they were very insightful.

    During the first meeting of the Emergency Committee convened by the Director-General under the International Health Regulations regarding clusters of microcephaly cases and other neurological disorders in some areas affected by Zika virus was held by teleconference on 1 February 2016, from 13:10 to 16:55 Central European
    Time.” (http://www.who.int/mediacentre/news/statements/2016/1st-emergency-committee-zika/en/)In the notes, they made a specific point about data sharing, attached below:

    Data sharing
    -National authorities should ensure the rapid and timely reporting and sharing of information of public health importance relevant to this PHEIC.
    -Clinical, virologic and epidemiologic data related to the increased rates of microcephaly and/or GBS, and Zika virus transmission, should be rapidly shared with WHO to facilitate international understanding of the these events, to guide international support for control efforts, and to prioritize further research and product development.

    I agree with your views on these major articles only publishing flashy exciting findings and skewing the reality. Having even made the connection between the words ‘luxury’ and ‘science’ is quite indicative of the state we are currently practising science. How far from the truth we are collectively in our understanding of the independent investigation of truth. How any scientific paper gets rejected is beyond my comprehension. Sure, it needs to be good, sure it should be scientifically rigorous, but we are discovering things about this earth, and since when have we decided that there is a hierarchy of knowledge that we will allow through the gates?

  • Brian Hanley 20 May 2016, 11:52 am

    Yes, we have a problem in science publishing, although it is my observation that PLoS journals have already slid off into nearly the same realm as Nature and Cell. Just look at the price lists for these. Cell charges $5,000 for open publishing. The core problem is that cliques form and act as, well, cliques. We have replaced the editor politics of 25 years ago with new editor politics. That politics is what motivated young scientists to create the open publishing movement. I agree with Hannah that Cell Host and Microbe published the article as a resource which is appropriate. (And note that they probably paid $5,000 to open source it — unless Cell Press gave them a waiver, which is plausible.)

    That said, my frustration (and outrage really) with the Zika outbreak and vaccinologists in general is that we know how to protect people from this infection using DNA vaccines that are very safe. No, they will not be sterilizing, but there is every reason to think they will be protective, and that they will do no harm. So why are we condemning tens, perhaps hundreds of thousands of infants to microcephaly in order to dot the i’s and cross the t’s on the classical vaccines? Seriously. What the hell are we doing? Yes, we need those down the line as they come through the system. But in the meantime we CAN deal with this in a matter of months. We can just do it.

    I will also note that since Zika is carried by mosquitoes, and per serological studies in Africa has a broad spectrum of animal hosts, there is little reason to believe that mass vaccination with classical vaccines will create better protection for populations than would DNA vaccine methods. DNA vaccines act to create strong cellular immunity priming, which is good enough. Yes, classical vaccine production is cheaper per dose, but we can easily afford to vaccinate every pregnant woman or every woman of child-bearing age.

    Could it be that the science establishment prefers to see the governments of the world motivated to a fever pitch by the mass media in order to increase budgets? What the science establishment is doing with Zika and what it did with the Ebola outbreak is consonant with that. The behavior of “5-Star Aid” NGOs has long been all about the money and benefits the 5-Star Aid agencies can accrue for themselves. (See: Collision and Collusion: The Strange Case of Western Aid to Eastern Europe, by Janine R. Wedel.)

    That, Vincent, is the real corruption in my opinion. It is corruption at the heart of the profession, which is to make it all about the money and about “my career” and “my budget” not saving lives and averting disease disasters.

  • NuclearReceptor 20 May 2016, 2:13 pm

    Are you confident DNA vaccination won’t lead to antibody-dependent enhancement with Dengue virus?

  • Fernando Aleman 23 May 2016, 3:01 pm

    To my knowledge, DNA vaccines work great in rodents but not in humans or primates.

  • Brian Hanley 24 May 2016, 3:10 pm

    They work differently. In primates DNA vaccines don’t raise high titers of antibodies. This is sometimes called the “primate barrier”. But DNA vaccines do raise a good and effective T-cell response, CD8’s and CD4’s that recognize the antigen are produced. B-cell response is muted. Since viral diseases are not cleared by antibodies, but require T-cells to clear the body of infected cells, this makes DNA vaccines quite effective for protection.

    In monkey trials, in adult monkeys, DNA measles vaccine prevented symptoms after challenge. In infant monkeys, DNA vaccination prevented about half from any symptoms, and the other half got short-term, mild symptoms with low grade viremia. Controls for both have severe disease.

    That is good enough for protection. Also, there is no other way to vaccinate neonates in the presence of maternal antibody. Note that infants are the ones who most commonly develop the worst complications of measles (e.g. pneumonia, encephalitis, death).

    The assays we inherited from yesteryear (along with false assumptions about the role of antibodies in clearance, as opposed to prevention of infection) use antibody titers as surrogate endpoints for effective protection. T-cell assays are harder to do, and not many are familiar with how to perform these assays.

    Epidemiological evidence indicates that with current influenza vaccines, as much as 30% of people vaccinated against influenza still get infected, get a light case they barely perceive and transmit the disease to others. So reality is that the old-school antibody titer exclusive vaccination assays are not as good as they are supposed to be in predicting “sterilizing immunity”. In reality, we already use “protective vaccines” as a very effective public health tool. The vaccine world is stuck in the past using the easy surrogate endpoint that we know doesn’t mean what it’s supposed to mean.

  • Fernando Aleman 24 May 2016, 5:59 pm

    In my opinion, the word “protection” is very misleading. Sovaldi (Sofosbuvir) may “protect” individuals that recently got infected with HCV from disease progression, and neutralizing antibody cocktails have been proven effective “protecting” from several pathogen challenges. Still none of those provide protection for future challenges, the main and only goal of any true vaccine.

    In this sense, since DNA “vaccines” don’t induce the humoral antibody response, they don’t protect for future challenges and are not useful as a traditional vaccination strategy in public health. They might be useful as treatment (the same as an antibody cocktail) to “prevent” disease symptoms or disease evolution, like you mentioned with the monkeys example. But that’s not the function of a vaccine, but a treatment/cure.

    Please correct me if I’m wrong.

    (BTW, I didn’t understand your point in the last paragraph).

  • angela offer hotmailcom 27 May 2016, 1:38 am

    This is for the other zika article, as it is getting moderated, I know the comment will be removed, so I try again here. Yes, internet and especially D is qus ting, is that corrupt. Few dates wrong in the above. Women were vaccinated from May, 2015, with T dap vaccine. G SK brand made under licence in Brazil, they got it as early as 20 weeks gestation, the babies were born disabled 20 weeks later in OCTOBER 2015. They are the facts, trying to twist them any other way, is just manipulation, trying to blame a mossie. 5,000 of 5,000 babies damaged were ALL D tap vaccinted, 4 (FOUR) had zika virus. Bit weird how the worlds scientists think the link is blindingly obiously vaccine damage, EXCEPT FOR CDC? Usa has had a corresponding rise, after vaccinting babies in utero with D tap from 400, to 25,000 (2014). Again CDC seem to miss this horrific rise, corresponding exactly to vaccinating babies in utero. USA has more microcephalic births than Brazil, and not a zika mossie in sight

  • angelaoffer hotmailcom 27 May 2016, 1:43 am

    Called money, imagine if everyone knew how useless D tap vaccine actually is, the whole truth was known in Australia since 2010. Instead of banning the vaccine, as it is causing the ONLY non stop epidemic of who oping cou gh Oz has ever known, and if they banned it no more asymptomatic carriers anymore, they vaccinate more? The fraud is just so blatant, it is vomitous.

  • angelaoffer hotmailcom 27 May 2016, 1:47 am

    Are you kidding me? 5.000 of 5.000 microcephalic babies in Brazil, had Tdap given in utero from 20 weeks, and you are saying because 4 had zika, zika done it? OMG the blatant fraud in all these posts is appalling!

  • Brian Hanley 27 May 2016, 2:15 pm

    Sofosbuvir is a drug that acts while it is present. It is not a vaccine.

    DNA vaccines contain genes from viruses and produce viral proteins in cells after injection. Those viral proteins are recognized as foreign and generate an immune response. Once established, like any other vaccine, that immune memory remains for most of a practical lifetime. Specific antibody levels will drop at varying rates. Slifka published some work monitoring Ab levels after various vaccinations.

    DNA vaccines are vaccines and do generate a humoral response, but it isn’t as strong as a conventional vaccine. You are making the mistake of thinking that humoral response is primary for protection and it isn’t. What clears a virus is cellular response and that is what DNA vaccines generally produce strongly.

    A DNA vaccine, like any other vaccine, is not particularly useful for treatment of illness once it develops. It is only useful for prevention. A vaccine can be helpful if given at the same time as probable exposure to a disease, because in some cases the vaccine will get the immune system working faster than the real disease will. This is why possible rabies infection is treated with vaccination. The latency of rabies is longer than the vaccine takes to get the immune system activated.

    The basic point of my last paragraph is that there are two types of immunity produced by vaccination. Humoral response (antibodies from B cells) and cellular response (T-cells). CD8 T-cells create antibody-like proteins that are just as specific to the antigen as antibodies are. But CD8 T-cells have a different job. The job of a CD8 T-cell is to recognize that any cell in the body is infected by detecting viral proteins on that cell. When it does, it kills that cell. This is what clears a viral infection by destroying the cells in the body that are used to manufacture the virus. In tests in mice, if cellular response is suppressed, it doesn’t matter how high the antibody levels are, the mouse will die.

  • Brian Hanley 27 May 2016, 2:41 pm

    Yes, exactly. Tetanus, diptheria and pertussis vaccines have been licensed since 1949. Generations have used them. Tdap is the tetanus and diptheria vaccine with acellular pertussis. Acellular means that they didn’t use complete pertussis cells, just minimal antigen. The “wp” designation means whole pertussis and is sometimes used, but mostly the “ap” designation distinguishes this newer, lighter-weight version. The Tdap vaccine has less immune system stimulation, and it does not protect as well because of that. As a result, pregnant mothers have lower pertussis antibodies, and their babies are not as well protected, so mothers are recommended to get a booster to raise their antibody levels. A baby will be born with Ab levels approximately 1.6 times the antibody levels of the mother. On average, those maternal antibodies have a half-life of 40 days. So if a baby starts with specific Ab levels of say, 800 to pertussis, 40 days later they will have 400. After 80 days, 200. After 120 days, 200. Etc.

    Tdap, this somewhat less immune-stimulating version of the tetanus-diptheria-whole_pertussis vaccines given to billions of people since 1949, was licensed in 2005. Over 100 million doses of Tdap have been administered since 2005. If Tdap was a cause of the microcephaly plague, then you would have to see microcephaly happening first in the USA and Europe. It would follow the pattern of introduction of that vaccine. But we don’t see that. You can validate this yourself. There is not an epidemic of microcephaly in the USA.

    The microcephaly plague in Brazil is new. Microcephaly has been verified in animal model from the mutated Zika found in Brazil.

    The numbers you posted are made up.

  • Fernando Aleman 7 June 2016, 5:03 pm

    “Sofosbuvir is a drug that acts while it is present. It is not a vaccine”. Agreed. Hence my comment about how misleading the word “protection” is. You can still say Sofosbuvir protects you from hepatitis disease progression/development and also protects infected individuals from the associated morbidity such as liver cancer. I think prevent and protect are misleading or at the very least, misused.

    “Once established, like any other vaccine, that immune memory remains for most of a practical lifetime” Any reference for a DNA vaccine that created immune memory in primates? Because my point is, even though the cellular response is the ultimate response that would clear the pathogen, there will be no lasting response if Abs (humoral response) are not properly activated as well. It will work as a temporal treatment like the mentioned drug (or your rabies example), but won’t create an immune system ready for a future second pathogen exposure.

    “You are making the mistake of thinking that humoral response is primary for
    protection”. I don’t think it’s primary, I think it is necessary. Without a proper Ab response I think you can’t get protection. But I can be wrong. Please, could you share a reference or two. Thanks.

    “In tests in mice, if cellular response is suppressed, it doesn’t matter how high the antibody levels are, the mouse will die.” Is the opposite also true? If you suppress the humoral response in mice, would they also die? I think so, but I don’t have any reference.

    Thanks.