When Viruses Give Back – How BANCR Helps Hearts Develop | Stanford Cardiovascular Institute

When Viruses Give Back – How BANCR Helps Hearts Develop

by Adrienne Mueller, PhD
August 7, 2020

Our Viral Genome

Not all viruses are harmful. Endogenous retroviruses (ERVs) are viruses that incorporated themselves into our genome so long ago that our systems now consider them part of us. Approximately 10% of our genome is actually composed of endogenous retroviruses, but how they impact our biology remains very unclear. Almost all of the research we perform is on the 2% of our genome that is made up of protein-coding DNA, not the 98% of our genome that is comprised of non-coding DNA, including ERVs. From what we do know, ERVs can often be harmful—studies have linked them to cancer, schizophrenia, diabetes, and multiple sclerosis. They can also be neutral, having no effect either positive or negative on our biology. But sometimes ERVs are integrated to such an extent that our cells are now using them as part of their own machinery.

Joining this latter group of co-opted viruses is one that entered our genome tens of millions of years ago. BANCR is a long non-coding RNA that is produced by an ERV that only exists in primates. We think BANCR originated from a retrovirus infection that occurred in our common primate ancestor with marmosets, 45-60 million years ago. For reference, hominids appeared in our evolutionary tree only about 20-15 million years ago, and Homo sapiens less than a million years ago. Over the intervening tens of millennia, BANCR has evolved to be a useful part of our biology. A group of Stanford Cardiovascular Institute-affiliated scientists led by first authors Kitchener D. Wilson, MD, PhD, Mohamed Ameen and Hongchao Guo, PhD, and senior author Joseph C. Wu, MD, PhD recently demonstrated how endogenous retrovirus-derived BANCR contributes to primate heart development.

BANCR boosts migration of human cardiomyocyte stem cells.

Evolution and Development of Primate Hearts

In their recent report in Developmental Cell, Wilson et al first showed that retrovirus-derived BANCR is specifically present in human fetal heart muscle cells (cardiomyocytes), as well as the cardiomyocytes of other large non-human primate species’ such as gorilla, chimpanzee and rhesus macaques. Cardiomyocytes are heart cells that do not regenerate and their concerted contraction is what causes our hearts to beat. The fact that BANCR was specifically present in fetal heart muscle cells suggested that it was important for heart development. Wilson et al then went on to show two specific ways that BANCR contributes to heart development. First, they used human stem cell-derived heart muscle cells and a unique bioengineered cell culture system to show that BANCR actually helps heart muscle cells to move and migrate across a petri dish (Figure). Cell migration is a critical component of heart development but has not been well studied in cardiomyocytes, so these findings were surprising. Second, they introduced BANCR into mice and rats that do not normally have this gene and found that it enlarges and dilates their hearts. These results, combined with their findings that children with enlarged (dilated) hearts have high expression of BANCR, and also the fact that only larger but not smaller primate species have BANCR, led the authors to hypothesize that BANCR promoted increased heart size during primate evolution. As Dr. Wilson states, "What we’ve uncovered in this study is evidence that an ancient viral infection in our primate ancestors changed the course of human evolution and allowed our species to grow larger hearts and bodies. Given that as much as 10% of our genomes are filled with the remnants of past viral infections, which is 5 times larger than the portion that codes for proteins, it is likely that many more examples of viruses impacting evolution are yet to be discovered. Recent technologies such as iPSCs and genomics will help us understand just what exactly this 'viral' genome is doing in human health and disease."

As Dr. Wu, director of Stanford Cardiovascular Institute, explains: "Similar to how mammals have evolved to live symbiotically with microorganisms in our gut microbiomes, our genomes have likewise evolved to co-exist with continuous viral DNA invasions. In most cases, these are benign, but in some cases they lead to disease, and in others—as with BANCR—it is a net benefit. Viruses are certainly dangerous as we are seeing with COVID-19, but it is also important to remember that some have helped shape who we are as humans."

This study shows that we have been able to exploit a virus that attacked us 45-60 million years ago to help our hearts develop and grow larger, which in turn allowed for larger body sizes in humans and other primates. Perhaps in the future we will be able to use this information to understand the role other retroviruses play in our genomes and to exploit ERVs even further to help treat sick or poorly-developing hearts.

Other Stanford Cardiovascular Institute-affiliated authors include Oscar J. Abilez, Lei Tian, Maxwell R. Mumbach, Sebastian Diecke, Xulei Qin, Yonggang Liu, Huaxiao Yang, Ning Ma, Sadhana Gaddam, Nathan J. Cunningham, Mingxia Gu, Evgenios Neofytou, Maricela Prado, Thomas B. Hildebrandt, Ioannis Karakikes and Howard Y. Chang.