Monday, March 2, 2015
Extinction Edge: a new thriller on how epigenetic changes induced by viruses could kill us all
Today my friend Nicholas Sansbury Smith releases Extinction Edge, the sequel to Extinction Horizon, a sci-fi thriller where humanity is driven to extinction by a lethal virus. I posted an interview with Nick for the release of his first book, but today I wanted to talk about the science behind his premise: can a virus induce epigenetic changes?
In a way, Nick's premise is similar to the premise I used in Chimeras: a large part of our DNA is made of pseudogenes, which are ancient genes that are no longer coding for proteins. They are "fossils" in a way, remnants of our evolutionary history. In very layman terms: new species evolve from old ones not because old genes are replaced, rather, new gene copies arise, then mutations accumulate and differentiate the new genes from the old ones, until the old genes are silenced and the new ones take over.
The part that tickles a writer's imagination is the following: if we still have all these ancient genes that once made our ancestors predators and hunters, could we possibly activate them and have people regress back to those ancient states?
If you've read Chimeras, you know how I made it happen in my detective Track Presius, and if you've read Extinction Horizon you know how Nick answered the question in his book. We both use a virus, though not the same one. A virus that "awakens" non-coding genes... is that completely far-fetched?
Turns out, it's not. Of course, it highly depends on what genes we want to awaken.
Epigenetics studies the mechanisms that turn genes "on" and "off" (i.e. expressed or not), how they are affected by the environment, and how they can be inherited from one generation to the next without being encoded in the DNA itself. One of such mechanisms that alters gene expression is DNA methylation, the addition of a methyl group to one of the A or C nucleotides in the DNA. Several studies have looked at how viruses can alter our epigenome, some in a permanent way.
Viruses insert their genes inside the host cell and hijack the cell's own proteins in order to replicate. The cell, on the other hand, defends itself by trying to silence the viral genes through a series of epigenetic mechanisms. So of course viral infections and epigenetic changes go hand in hand. I'm sure that these virally induced epigenetic changes can affect us in many subtle ways, and the vast majority of these changes leave us unharmed. However, when you search the literature, you find mostly studies that have looked at viruses that are associated with tumorigenesis because clearly that's of great interest to the medical field: viruses are much easier to detect early than tumors, and if we can understand the mechanisms they use to trigger cancer, then we can also prevent them from establishing the disease.
For example, the Epstein-Barr virus causes mononucleosis but it's also associated to some types of cancers, especially in immuno-suppressed individuals such as AIDS patients. As it turns out, the virus alters genome-wide gene expression in infected cells and these alterations can be pre-cancerous  (meaning the affected cells have a higher chance to accumulate tumorigenic mutations). Another virus that induces pre-cancerous epigenetic changes in liver cells is hepatitis, both the B and C kind [2, 3], which lead to liver carcinoma in about 10% of the infected individuals.
Epigenetic changes have been studied in HIV infected cells, too. People infected with HIV have to take a cocktail of antiretroviral medications for life and, despite the regimen, they never completely get rid of the virus. This is because the virus inserts its genome inside cells and then some of these cells become latently infected. They do not produce virions for months, sometimes years. However, as soon as the patient stops the antiretroviral therapy, the virus suddenly "awakens" and starts spreading throughout the body. These latently infected cells form a "reservoir" and how to get rid of it has been the focus of many studies lately as it is one of the major obstacles preventing us from finding a cure for AIDS. In this review , Mbonye and Karn explain how provirions (the HIV genes inserted inside the host cell genome) become latent through epigenetic mechanisms that silence them.
Studying epigenetic changes induced by viral infections is a relatively new field, but one that is very promising because contrary to genetic changes, epigenetic alterations are reversible. So, if we can find the viral triggers that lead to pathogenesis we have a potential preventive therapy by reversing those mechanisms.
Extinction Edge by Nicholas Sansbury Smith: Survivors call them Variants. Irreversible epigenetic changes have transformed them into predators unlike any the human race has ever seen. And they are evolving. A bioweapon designed to save the world, a scientific discovery that will alter human history, and a new threat that will bring humanity to the edge of extinction.
Chimeras by E.E. Giorgi: Haunted by the girl he couldn't save in his youth, and the murder he committed to avenge her, Detective Track Presius has a unique gift: the vision and sense of smell of a predator. When a series of apparently unrelated murders reel him into the depths of genetic research, Track feels more than a call to duty. For Track, saving the innocent becomes a quest for redemption. The only way he can come to terms with his dark past is to understand his true nature.
 Birdwell CE, Queen KJ, Kilgore PC, Rollyson P, Trutschl M, Cvek U, & Scott RS (2014). Genome-wide DNA methylation as an epigenetic consequence of Epstein-Barr virus infection of immortalized keratinocytes. Journal of virology, 88 (19), 11442-58 PMID: 25056883
 Tian Y, Yang W, Song J, Wu Y, & Ni B (2013). Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis. Molecular and cellular biology, 33 (15), 2810-6 PMID: 23716588
 Rongrui L, Na H, Zongfang L, Fanpu J, & Shiwen J (2014). Epigenetic mechanism involved in the HBV/HCV-related hepatocellular carcinoma tumorigenesis. Current pharmaceutical design, 20 (11), 1715-25 PMID: 23888939
Mbonye U, & Karn J (2011). Control of HIV latency by epigenetic and non-epigenetic mechanisms. Current HIV research, 9 (8), 554-67 PMID: 22211660