Lately I've been thinking a lot about the Grinch. You know, the one who stole Christmas by taking away everything fun and good? (Shades of 2020, anyone?) The story goes that the Grinch's heart grew three sizes when the inhabitants of Whoville showed him the true meaning of the holiday. (Hint: it is love for one another in the face of adversity.)
Although it didn't happen in a matter of moments, humans and other large primates saw a similarly dramatic increase in heart size as they evolved from smaller primates. It's thought that the increased blood pumping ability may have contributed to our relatively larger body size.
Now, Stanford Medicine pathology instructor Kitchener Wilson, PhD, together with cardiologist Joseph Wu, MD, PhD, graduate student Mohamed Ameen and instructor Hongchao Guo, PhD, have come up with a reason for this Grinch-like transformation. They recently published their findings in Developmental Cell.
Endogenous retroviruses
The culprit looks to be a remnant of an ancient viral infection in the form of a DNA sequence called BANCR that has piggybacked in our genomes for millions of years.
These viral fossils aren't rare. As Wilson explained:
About 10% of our genome is made up of these remains of viral infections in the form of pieces of DNA known as endogenous retroviruses. In fact, these viral sequences make up about five times more of our DNA than the genes that encode for actual proteins.
Normally, retroviruses insert their genetic material into the genomes of their host cells and just coast there until it's time to pop out and make new virus particles. Every time the host cell replicates its own genome, it also copies the stealthy invader and passes it along to the daughter cells. Occasionally these viruses infect egg or sperm cells. After fertilization, the developing embryo carries the inserted viral sequence in all of its cells.
DNA hitchhikers
For many years, it was thought that these DNA hitchhikers were just that -- freeloaders that didn't have much to do with the host cell's development or function. But more recently, it's become clear that some of these sequences are important in the expression of nearby genes, particularly in developing or cancerous cells.
As Wilson explained:
We became interested in an endogenous retroviral sequence called BANCR, which other than in some cancers, is active only in developing heart muscle cells in humans and larger primates like gorillas. Because the original viral infection occurred in a small primate ancestor, BANCR is not found in mice or other non-primates. We used induced pluripotent stem cell technology to study the effect of BANCR expression in developing heart muscle cells from humans, chimpanzees, gorillas and rhesus macaques, and found that it likely plays a role in cell migration during development.
There are intriguing hints that this effect on cell migration affects heart size. When Wilson artificially introduced BANCR in embryonic mice, the animals developed hearts with larger-than-normal left ventricles. Injecting a virus expressing BANCR into rat hearts also caused the heart to dilate under certain experimental conditions.
Finally, children with a rare condition called dilated cardiomyopathy, in which the heart is abnormally large and functions poorly, express higher-than-normal levels of BANCR. The researchers are cautiously hopeful that their findings may someday lead to future therapies for the life-threatening condition.
"Now we have a number of pieces of evidence that this retroviral sequence specifically affects heart size and function," said Wilson. "We've seen this ancient viral infection occurred in our primate ancestors, and subsequently all primates with this sequence have gotten larger. It's a provocative idea."
Photo by Debra
