Zika And The Mystery Of Microcephaly
Zika has become a viral epidemic. In general, a virus is a single-celled, arguably non-living, microbe that needs to infect a living cell in order to reproduce.
Without a cure or vaccine for Zika, our biggest concern is that it causes microcephaly, a birth defect where a baby’s head and brain are smaller than average.
Dr. Debra Silver, assistant professor of molecular genetics and microbiology at the Duke University School of Medicine, is co-author of a study recently published in PLOS Genetics investigating genetic, non-viral causes of microcephaly.
We have a long way to go in terms of understanding how Zika virus actually causes microcephaly.
My strong feeling is that we need to step back and understand the basic rules of how stem cells can influence production of these critical cell types in the brain. And so that’s where our study comes in.
Using custom mouse models, Silver’s lab isolated three separate genes which are known to be related in terms of brain function.
What we essentially discovered in this study is that mutation of any one of these three genes, that are known to work together in other contexts, results in similar outcomes in terms of how the brain develops.
A mutation in any one of these individual genes caused microcephaly in the mice. But why?
We not only discovered that these genes cause microcephaly, but they also do so by regulating a critical gene called P53.
They discovered that a reduction of any of the three genes caused an accumulation of P53. This lead to the hypothesis that this accumulation could cause developing brain stem cells to die.
These are cells that are absolutely critical for the brain to develop properly. They are cells that produce the neurons of our cerebral cortex, and, if they don’t function properly, you don’t get enough neurons made. Or, in some cases, you might get neurons made, but the wrong types of neurons made. In the case of a disorder like microcephaly, it’s thought that the stem cell, their ability to produce a sufficient number of neurons is impaired.
To test that, the lab blocked the development of the P53 protein in developing mouse brains that already had the gene mutation. This caused a partial or full recovery to normal brain size.
But this discovery doesn’t cure microcephaly or vaccinate against Zika. So what’s the point?
What we gained from the research that this particular paper was on is a basic understanding of what are the types of genes and what are the types of processes that, when disrupted, will cause microcephaly? And what that does is it starts to give us clues of things we can evaluate to see if Zika virus infection perturbs those same pathways.
Silver’s study found one genetic pathway that can cause microcephaly in a mouse’s brain. But the trick is to find out if Zika virus causes the same genes to mutate or the same accumulation of the P53 protein.
This is research which may be vital groundwork for a treatment for microcephaly.
We've identified genes that we know are important in the pathology of microcephaly. If you can identify drugs that would alter defects that had arisen due to the viral infection, I think that would be the most likely outcome to come out of our understanding of these types of genetic causes of microcephaly.
And, as with all research, there may be unforeseen discoveries with great benefits.
One of the genes that we’ve been studying is a gene called RMB8A, and we know that mutations of RMB8A can be associated with Autism spectrum disorder, as well as microcephaly. We actually understand very little about how this gene works. We are interested in understanding the link between this gene and autism; I don’t think it’s going to be a simple answer, but it is something we are working on in the lab.