The recent outbreak of Zika virus in Central and South America correlates with a spike in birth defects, the first and foremost being microcephaly, a severe impairment of brain development. In Brazil, 1,113 cases of microcephaly have been confirmed, with 3,836 more suspected (as of April 12th, according to the Brazilian Health Ministry). The World Health Organization has declared this spike in microcephaly and other defects to be a global health emergency. The White House has asked Congress for $1.9 billion and has already transferred $510 million previously earmarked for an Ebola response.
Emergencies like this prompt the scientific community to act quickly and effectively. But we also rely on investigators not to sacrifice their rigor or the innate skepticism that enables good science to happen. As annoying people like to say, “correlation is not causation.” There will never be $1.9 billion to investigate the correlation between GMOs and autism, likely because the chemtrails have diminished us to nodding automatons.
A brief history of Zika and microcephaly
Neither microcephaly nor Zika virus are novel offenders. Zika was first identified in 1947, and was shown to infect the central nervous system of mice in 1972. In adult humans, however, Zika does not seem to be that harmful. 80% of infected adults are asymptomatic. The other 20% show mild symptoms, with fevers far more mollified than the bone-crushing variety associated with infections of dengue and chikungunya, two cousin viruses of Zika.
Microcephaly has long been known to be a consequence of unfortunate genetic mutations. Microcephaly can also be caused by infections like meningitis, toxins like lead, and malnutrition. Whether Zika can cause microcephaly in an unborn infant is the current topic of debate, and UCSF researchers have contributed to filling in the causative links between the virus and the birth defects.
The lab of Dr. Arnold Kriegstein has identified cells in the developing brain that may be more susceptible to Zika infection and has investigated these cells for proteins that could allow Zika to gain access to the cell. Their results not only add to the growing body of evidence that Zika causes microcephaly, but also contribute a testable hypothesis for how this occurs.
From mosquito to neonate
The primary Zika vector is the mosquito Aedes aegypti, a species whose dominion spread with the slave trade. Female mosquitoes require a vertebrate blood meal to complete their life cycle, and in doing so pass on Zika (and a host of other arboviruses [lit. ARthropdBOrne]) to the human bloodstream. Then, frighteningly, Zika shows the ability to cross the fetal-placental barrier. This recent finding was a key step toward understanding the causative chain between Zika infection and birth defects.
Like all viruses, Zika requires the cooperation of host cells to first envelop the virus and then to replicate the virus, churning out viral daughters until the cell bursts open and releases the viral daughters back into circulation.
To infect cells, viruses must dock onto specific proteins (and often specific sugar residues attached to these proteins) on the surface of cells. Different viruses look for different loading docks, and different cells express different suites of proteins on their outer surfaces. This is largely why most viruses can infect some species but not others.
We do not have systematic knowledge of which proteins serve as Zika access points, but four have been discovered (DC-SIGN, TIM1, TYRO3, and AXL) that can turn a non-infectable cell into an infectable cell when any one of them is added to that cell’s surface.
The AXL of evil
As reported previously in this column, UCSF’s Kriegstein Lab has a pretty solid handle on the cells that make up a developing brain, and were thus well poised to look at which cell types might contain these Zika access points.
Tomasz Nowakowski and Alex Pollen -- who previously identified the signature of the outer radial glia, the stem cells responsible for generating most of the 16 billion neurons of the human cortex -- are back at it again, co-leading the recent effort into analyzing brain cells for Zika docking proteins. The paper is scheduled to appear in print in the May 5th issue of Cell Stem Cell, but was uploaded online on March 30th.
Nowakowski and Pollen saw that AXL, but not the other possible docking proteins, was expressed at high levels in the radial glia, the cells that generate neurons in a developing brain. Notably, AXL was not found in the mature neurons themselves. This may help explain why adult brains are not disrupted by Zika to the same extent as growing fetal brains. Other cell types, including astrocytes, microglia, and the endothelial cells that line the capillaries that feed the brain, were also shown to express AXL.
What’s next?
We knew that Zika could cross the fetal-placental barrier and we knew that Zika could use AXL as an access point to infect a cell. Showing that AXL is present specifically on the radial glia brings into focus how Zika infection might create severe problems in brain development.
This paper does not confirm this mechanism, but suggests it for further testing. The research also suggests model systems that may be useful for studying this mechanism, as they show that AXL is also present in radial glia in the developing mouse and ferret brains, as well as in brain-like “organoids” derived from pluripotent stem cells.
Yet even if AXL is the primary docking protein responsible for Zika-caused microcephaly, it is unclear how to proceed in terms of treatment or prevention of microcephaly. Blocking AXL with a drug might cause more harm than good, as AXL function is normally required for the survival of radial glia, as well as maintaining the blood-brain barrier.
How researchers respond to global health emergencies
Aside from the important links made between Zika and microcephaly, this research also ties into a discussion of how the scientific community can change its modus operandi when faced with a global health emergency. Many prominent critics have blamed the current state of science publishing for stagnating research and prohibiting open sharing of results.
The Zika outbreak, in addition to mobilizing researchers to study the virus and its link to developmental disorders, has motivated many to appraise how scientific publishing procedures can and ought to change in order to expedite an effective medical response.
In a commentary in the New England Journal of Medicine, David Heymann and others say this about the recent Ebola epidemic: “in general, collaboration was suboptimal; in too many cases, West Africa became a playground for researchers allegedly appropriating and transporting specimens and data to their home laboratories, sometimes without the knowledge or permission of the countries in which they were collected.”
Such “parachute research,” where foreign research teams descend on an area, collect data, and leave, is often motivated by the competition to publish their findings in a prestigious journal, with little regard for actual public health benefits that would be expedited by open sharing of data and specimens.
The work of Kriegstein’s team follows in the wake of this call for rapid, open dissemination of Zika research. The paper is short – just a few findings – with the goal of publishing their results quickly rather than waiting to develop a more thorough story -- efficiency over vanity.
It remains to be seen how seriously these calls for open publishing will be heard in the long run. Many would argue that if the Zika outbreak is reason enough to change publishing principles, why shouldn’t other areas of research, such as cancer research, be treated the same?
