A major new feature of the fourth edition of Principles of Virology is the inclusion of 26 video interviews with leading scientists who have made significant contributions to the field of virology. For the chapter on Synthesis of RNA from RNA templates, Vincent spoke with Karla Kirkegaard, PhD, of Stanford University School of Medicine, about her career and her work on picornaviruses.
Project Premonition, a Microsoft Research project that uses drones to capture mosquitoes and analyze them for pathogens, preprint servers, and three mouse models for Zika virus induced birth defects are the topics of episode #390 of the science show This Week in Virology.
You can find TWiV #390 at microbe.tv/twiv, or listen below.
Three papers have been published showing that Zika virus can cross the placenta in mice, replicate in the fetus, and cause microcephaly. In this video from Virus Watch I summarize these data and their implications.
Science 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.
A major new feature of the fourth edition of Principles of Virology is the inclusion of 26 video interviews with leading scientists who have made significant contributions to the field of virology. These in-depth interviews provide the background and thinking that went into the discoveries or observations connected to the concepts being taught in this text. Students will discover the personal stories and twists of fate that led the scientists to work with viruses and make their seminal discoveries.
For the chapter on The Infectious Cycle, Vincent spoke with Thomas Hope, PhD, of Northwestern University Feinberg School of Medicine, about his career and his work on using high resolution microscopy to study the cell biology of infection with HIV-1.
Vincent speaks with Stan Lemon about his career in virology, from early work on Epstein Barr virus, through making essential discoveries about hepatitis A virus, hepatitis C virus, and rhinoviruses, on episode #389 of the science show This Week in Virology.
You can find TWiV #389 at microbe.tv/twiv, or listen below.
I am convinced that Zika virus causes microcephaly in humans, but it would be valuable to have an animal model to study how the virus crosses the placenta and damages the fetus. As with many questions about Zika virus, answers are coming very rapidly, and three different groups have now provided substantial insight into this problem.
When a Samoan isolate of Zika virus was injected into the brain of embryonic day 13.5 mice, the virus replicated mainly in neural progenitor cells, but also in many other brain cells (link to paper). At 5 days after infection, brain size was markedly reduced compared with uninfected littermates. Infection of neural progenitor cells disrupted their normal differentiation program which leads to the production of mature neurons. Gene expression profiling of infected brains showed an increase in the production of cytokines, suggesting that these proteins might play a role in disease development. The expression of genes that have been previously associated with microcephaly was reduced. The authors conclude that “these effects are likely to account for microcephaly in human fetuses or newborn babies.”
In a different approach (link to paper), pregnant mice (not fetuses as in the previous study) were infected with a Brazilian Zika virus strain, and newborns were studied. Zika virus was detected in many tissues of newborns, especially in brain. Newborn mice displayed overall reduced growth, cortical malformations, and reduced cortical cell number and cortical layer thickness, all defects associated with microcephaly in humans. The infected mice also had ocular abnormalities similar to those that have been observed in babies with congenital Zika virus syndrome. Of note was the observation that the ability of Zika virus to cross the placenta was dependent on the strain of mouse used. I would not be surprised if the ability of viruses (or any microbe) to cross the human placenta is also determined in part by the genetics of the host.
The authors of this study suggest that human to human passage of Zika virus in humans for ~60 years led to a strain that can cross the placenta and infect the fetus. Consistent with their hypothesis, they show that replication of a Brazilian Zika virus strain in human brain organoids (three-dimensional models of the human brain produced from human pluripotent stem cells), greater morphological abnormalities and a reduction in size compared with effects cause by infection with an African strain of the virus. Furthermore, they find that a Brazilian Zika virus strain does not replicate in chimpanzee organoids, while the African strain does well. However, they do not address their hypothesis directly by determining in their mouse model whether an African strain of Zika virus can cross the placenta and infect the fetus.
A third report provides insight into how Zika virus might cross the placenta (paper link). This model consists of immunocompromised mice in which the type I interferon response has been ablated either genetically or by the administration of antibodies to the receptor for this cytokine. Pregnant mice are infected subcutaneously in the footpad with a French Polynesian Zika virus strain at embryonic days 6.5 and 7.5; embryos are then sacrificed 7 or 8 days later. No microcephaly was observed, but virus was detected in the head of the fetus. Replication was also detected in placenta and is accompanied by placental damage. Infected placentas are smaller, have damaged blood vessels, and display evidence of cell death and virus replication in various types of trophoblasts that make up placental tissues. In contrast, dengue virus did not replicate in the placenta or in the fetus.
These observations suggest that Zika virus can cross the placenta and move from the maternal blood into the fetus. The authors conclude that “The cellular and ultrastructural evidence of ZIKV infection in trophoblasts and fetal endothelium suggests that maternal viremia leads to compromise of the placental barrier by infecting fetal trophoblasts and entering the fetal circulation.”
Previously it was shown that term placentas are resistant to Zika virus infection due to the production of type III interferon (paper link). The authors of the mouse study described above suggest that Zika virus may cross the placenta early in pregnancy due to infection of extravillous trophoblasts. These cells are abundant early but not later in pregnancy.
These three reports provide conclusive evidence that Zika virus can cross the placenta and cause fetal defects in mice, and provide models to understand the biology and pathogenesis of infection.
I am astounded at the unprecedented, rapid and frequent publication of new research results on Zika virus biology and pathogenesis. This phenomenon reflects the willingness and ability of large and mature groups of investigators from diverse fields (virology, neurobiology, cell biology) to tackle a new problem and make rapid progress.
I predict that we will learn more about Zika virus in the next year than we have about any other microbe in a similar period of time.
The results of recent structural studies have given us the ability to display the structure of Zika virus and of the viral E protein bound to antibody. In this video from Virus Watch I explain how the Zika virus particle is built, and how it interacts with an antibody that blocks infection, in beautiful three dimensional imagery.
Preprint servers, the structure of an antibody bound to Zika virus, blocking Zika virus replication in mosquitoes with Wolbachia, and killing carp in Australia with a herpesvirus are topics of episode #388 of the science show This Week in Virology, hosted by Vincent, Dickson, Alan, and Kathy.
You can find TWiV #388 at microbe.tv/twiv, or listen below.
Have you always wanted to better understand viruses, but did not know where to start? I have the solution for you – my undergraduate virology course. The 2016 version has just ended, and all the lectures are available as videos, either on YouTube or here at virology blog (where you can also find lecture slides and study questions).
It will take some time for you to watch all the videos – each is about 70 minutes long – but the effort will be worth it. In the end you will know more virology than most of the world. With new viruses emerging annually, don’t you want to understand how they work? Go ahead, dive in.
Lecture 1: What is a virus?
Lecture 2: The infectious cycle
Lecture 3: Genomes and genetics
Lecture 4: Structure
Lecture 5: Attachment and entry
Lecture 6: RNA directed RNA synthesis
Lecture 7: Transcription and RNA processing
Lecture 8: DNA replication
Lecture 9: Reverse transcription and integration
Lecture 10: Translation
Lecture 11: Assembly
Lecture 12: Infection basics
Lecture 13: Intrinsic and innate defenses
Lecture 14: Adaptive immunity
Lecture 15: Mechanisms of pathogenesis
Lecture 16: Acute infections
Lecture 17: Persistent infections
Lecture 18: Transformation and oncogenesis
Lecture 19: Vaccines
Lecture 20: Antivirals
Lecture 21: Evolution
Lecture 22: Emerging viruses
Lecture 23: Unusual infectious agents
Lecture 24: HIV and AIDS
Lecture 25: Viral gene therapy