A viral fossil that our cells put to work
Human endogenous retroviruses, or HERVs, are the molecular residue of infections that occurred long ago, when viruses inserted their genetic material into the human genome. These sequences can no longer infect anyone. George Kassiotis, who leads the Retroviral Immunology Laboratory at the Francis Crick Institute, explains that such stretches of DNA tend to persist across evolutionary time only when our cells have found some other use for them. His team suspected that was precisely what had happened with one particular family of these sequences, known as HERVH, which acts as a switch for the gene that produces a calcium-binding protein called calbindin.
That suspicion was worth testing, because the same switch had already been spotted in cells that make up the early embryo. Its presence there hinted that it might matter during a critical window of human development—not merely as a curiosity of tumour biology, but as part of the normal machinery of life's first days.
Why a cancer survival trick puzzled the lab
Three years ago, Kassiotis and his colleagues made an unexpected finding: a specific way of producing calbindin helped cancer cells survive by preventing them from aging. The result raised an awkward question. Why would a mechanism that boosts tumour growth exist in the first place?
The biology of calcium offers a clue. In high amounts, calcium becomes toxic to cells, so levels must be held within narrow limits. Calbindin removes calcium from the cell, and it is normally found in the brain and the kidney—two tissues where calcium concentrations need to be tightly controlled. Yet the team found that a certain form of calbindin was present in lung cancer cells, and that it had been switched on by a remnant of viral DNA embedded in our genome.
That finding framed the puzzle the researchers have now followed into embryonic development. If HERVH-driven calbindin is useful enough to be preserved, perhaps its original purpose lies in the embryo rather than in a tumour.
Testing the switch in human embryonic stem cells
To investigate, Judith Pape, then a postdoctoral researcher in Kassiotis' team, joined forces with Kathy Niakan's group. Niakan's laboratory pioneered genetic editing in human embryos, work it began at the Crick and continues at the University of Cambridge. That expertise gave the collaboration the tools to ask a direct question: what happens when you take away calbindin, or the HERVH sequence that drives it, specifically in human embryonic stem cells?
The results are published in the journal Science Advances. Together, the experiments connect a viral remnant to the cellular housekeeping that keeps early human development on track. The work was carried out at the Francis Crick Institute and involved researchers whose specialties span retroviral immunology and human embryo genetics—a combination that made it possible to move between cancer models and stem cell systems.
Amnioids and blastocysts as living models
A central part of the evidence comes from stem cell models that mimic the development of the amniotic sac, known as post-gastrulation amnioids. When the key calcium-buffering gene and its accompanying viral switch are intact, these structures form as expected. When the gene and its switch are missing, the amnioids fail to form properly. The contrast offers a visual demonstration that the HERVH–calbindin circuit is not incidental to these early structures.
The researchers also examined human blastocysts developing from embryos with and without HERVH-calbindin. Comparing embryos that retain the switch against those that lack it gives a window into how the circuit influences the earliest stages of development, when cells are dividing rapidly and fate decisions are being made.
Two faces of the same circuit
Put together, the findings describe a genetic switch with a double life. In the embryo, it appears to support the growth and organisation of cells that will form the amniotic sac and other early structures. In lung cancer, that same circuit is repurposed to keep malignant cells alive by blocking the ageing process that would otherwise end their run.
That duality is a familiar pattern in cancer biology: tumours often reactivate programmes that belong to developing tissues, borrowing the growth and survival signals of embryonic life. What makes this case distinctive is the source of the switch. It is not a gene our ancestors evolved from scratch, but a piece of viral DNA that was absorbed into the human genome and later repurposed.
- HERVH is a human endogenous retrovirus—a non-infectious viral remnant retained in the genome.
- The HERVH sequence drives production of calbindin, a protein that removes calcium from cells.
- Calbindin is normally found in the brain and kidney, where calcium must be tightly controlled.
- A specific form of calbindin had already been linked to lung cancer cell survival and resistance to ageing.
- Removing calbindin, or the HERVH switch that controls it, disrupts human embryonic stem cell models.
- Amnioids, which mimic amniotic sac development, fail to form as expected without the gene and its switch.
What the work could mean
The study adds to a growing picture of endogenous retroviruses as functional parts of the human genome rather than inert junk. Over evolutionary time, the sequences that survive appear to be the ones that earned their place, and HERVH now looks like a clear example of a viral relic recruited into normal biology.
The cancer angle is equally important. If tumours depend on a switch that embryos also use, then understanding how that switch is flipped—and how calcium buffering protects cells from stress and ageing—could eventually inform strategies for disrupting it in disease. Any such application remains a long way off, and the research so far focuses on fundamental mechanisms rather than treatments.
The work also highlights how fragile early development can be. A single control element, inherited from an ancient infection, appears to influence whether model structures assemble correctly. That connection between viral history and human fertility biology is likely to be explored further, particularly as stem cell models such as amnioids become more refined and allow researchers to study stages of development that are otherwise difficult to observe.
For now, the message is a striking one: a scrap of ancient viral DNA, harmless and long past its infectious days, has been co-opted to help build the human embryo—and cancer has learned to exploit the very same circuit.
This article is based on reporting by Medical Xpress. Read the original article.
Originally published on medicalxpress.com
