The Viruses That Make Cancer Cells, and the Story of SV40

This document was translated by Gemini 2.5 Pro. Read the original Korean post here.

Viruses That Create Cancer Cells?!

The causes of cancer are diverse, but one of the most intriguing is none other than the virus. Of course, we are well aware of viruses causing cancer in our daily lives; we just don’t pay much attention. A prime example is the alpha-Human Papillomavirus (α-HPV), which causes cervical cancer. Additionally, it has recently been discovered that beta-HPV, similar to its alpha cousin, directly contributes to skin cancer, particularly Cutaneous squamous-cell carcinoma (SCC).¹ And that’s not all. Viruses like Epstein-Barr virus (EBV), Human T-cell lymphotropic virus type 1 (HTLV-1), and Kaposi's sarcoma-associated herpesvirus (KSHV) can also directly cause cancer. These viruses have, quite obviously, only been identified in humans, and the academic world refers to these cancer-causing viruses specifically as Oncoviruses. The prefix Onco- is used in academia to mean cancer-inducing. As a bit of trivia, an Oncogene is a cancer-inducing gene, and an Oncoprotein is a protein that contributes to cancer development. Similarly, the prefix carcino- has the same meaning.

So, How Dangerous Are These Cancer-Causing Viruses?

How dangerous are Oncoviruses really? If you get infected, will you just get cancer everywhere? How much do these cancer-causing viruses contribute to the overall cancer burden? The textbook Oncogenic Viruses, 2023 states that globally, about 15-20% of all human cancers are caused by oncoviruses.²

A Century’s Discovery or the Start of a Disaster: The Unwanted Guest in the Polio Vaccine

The legendary SV40 virus is one of the incredible pillars that drove the dazzling advancement of modern life sciences. To understand why this cancer-causing virus contributed to science, we need to understand the background of its discovery.

The story takes us back to the 1950s, a time when humanity was battling the terror of polio. The development of a polio vaccine was in full swing. To create this vaccine, it was essential to culture the virus. Here lies the problem. A virus is something between living and non-living, incapable of multiplying on its own. One of a virus’s key characteristics is that it needs a host cell to reproduce. To develop a vaccine, scientists had to obtain cells that could be infected by the polio-causing virus and then forcibly infect them to produce the material needed for the vaccine.

Here, scientists faced a dilemma. Although immortal human cancer cells (HeLa cells) were available, there was a great fear that a vaccine made from cancer cells might transmit cancer. The alternative they chose was to use primary cells freshly harvested from animals. Since the host of the polio virus was primates, the most reliable culture cells were undoubtedly monkey cells. Kidneys, being rich in cells and actively dividing, were easy to culture, so rhesus monkey kidney cells were ultimately chosen as the virus farm.

Uh Oh, Doctor… I Think We’re Screwed.

Isn’t it a bit odd to suddenly talk about the polio vaccine when the topic is the cancer-causing virus, SV40? But don’t worry, we’ve reached the climax. At the time, a scientist at the US National Institutes of Health (NIH), Bernice Eddy, was an expert in cancer-causing viruses. She was the protagonist of a legendary incident at the NIH, where she exposed that some of the supposedly attenuated virus vaccines being distributed still contained viruses that retained their infectious ability.

While conducting various experiments to test vaccine safety, she realized there was a problem with the cell extracts made from grinding up the monkey kidney cells used to create the polio vaccine. When she injected these cell extracts into hamsters, 109 out of 154 of them developed cancer³. Sends shivers down your spine… This was a powerful signal that there was something in these monkey kidney cells that caused cancer.

Eddy persistently warned of this danger, but it received little attention at the time. Why on earth did no one pay attention? Then, while Maurice Hilleman and Benjamin Sweet’s team at the Merck Institute were replicating Eddy’s research, they finally identified the cancer-causing agent. It was a new virus lurking in the monkey cells: SV40.

The cancer-causing agent Bernice Eddy had discovered was the SV40 virus, and the terrible truth was revealed that this virus had been mixed into the polio vaccine and administered to millions. This incident sent a massive shockwave through the scientific community, and SV40 instantly became the hottest topic in cancer research. How could this tiny virus turn a normal cell into a cancerous one?

The Hijacker That Seizes the Cell’s Steering Wheel: ‘Large T-antigen’

The protein that enables SV40 to cause cancer was named Large T-antigen. Here, T stands for Tumor. This protein is just a clever little guy that unwinds SV40’s twisted DNA after the virus invades a cell. The fact that it causes cancer might be purely coincidental! We have a similar protein called Helicase.

For DNA to be replicated, its double helix must be unwound into single strands, and this is where these two proteins come into play. The one on the left is structured specifically for the SV40 virus’s DNA, while the one on the right is the human equivalent. A striking similarity is that both are composed of six peptides working together. Coincidentally, this protein happens to interact strangely with a vertebrate protein called p53, which is why it was identified as the cause of carcinogenicity.

p53 is a protein that functions as a transcription factor. Normally, it binds to DNA and regulates the production of various proteins. The proteins that p53 is widely known to produce by binding to DNA are mostly related to DNA repair, especially a protein called p21. In turn, the p21 protein can be considered a direct manager that oversees a system preventing our cells from dividing recklessly. Now, let’s imagine a scenario:

1. Large T-antigen binds to p53.
2. p53’s normal role of binding to DNA is interrupted.
3. The DNA protection and repair proteins and p21 that p53 used to induce are no longer produced.
4. Without p21, cell division doesn’t stop.
5. Cell division doesn’t stop? It has become a cancer cell.

That’s how it works. Isn’t it fascinating? A virus that caused no cancer whatsoever in its original host, the monkey kidney cell, suddenly causes cancer when it enters a different host.

This Is Why Cross-Species Infection Is Dangerous

It’s a baffling situation. Why didn’t SV40 cause cancer in monkey kidney cells? The difference lies in whether the virus replication process completed or not. What does that mean? Viruses are picky creatures; once they’ve chosen a host cell, they rarely infect other species. Avian flu, for instance, is highly infectious among birds but has a drastically lower probability of transmitting to humans. Just as the monkey kidney cell is SV40’s home, it doesn’t easily infect other species. But the story changes when humans inject it. These viruses, introduced via injection, beat the incredible odds and succeed in a cross-species infection. They manage to successfully break into a home that wasn’t their original target.

But it’s unfamiliar. It’s someone else's house. The virus tries to use the tools inside the house it has broken into to self-replicate, but the tools it knows are not there! This means it can’t self-replicate.

According to the laws of nature, SV40 should replicate itself into hundreds or thousands of copies, tear the cell apart, and be released outside. That was its destiny, but in someone else's house, it can’t replicate, and the cell doesn’t burst to let it out. It just stays inside, quietly. Meanwhile, it clumsily uses the unfamiliar tools to continuously produce just one thing: Large T-antigen. And then, the 1-5 steps described earlier are set in motion.

SV40’s Unexpected Gift: Immortal Cells and the Dawn of Cancer Treatment

The study of SV40 went beyond just revealing how a virus causes cancer. This research bestowed an invaluable gift upon modern life sciences.

The most representative gift is the ‘immortalized cell line’. Normal cells, after a few divisions in a lab setting, age and die. This made long-term research nearly impossible. But scientists discovered that by inserting the SV40 Large T-antigen gene into a cell, the cell gains the ability to divide forever, becoming ‘immortal’. In fact, a quick check on Cellosaurus, a site that manages information on cell lines, reveals that there are 4183 cell lines that have been immortalized from normal cells using SV40.⁴

Furthermore, it was largely thanks to SV40 research that the world learned that p53 and p21 are key players in cancer development. The small, unwanted guest in the polio vaccine had, paradoxically, opened the most important door to conquering cancer.

Similarly, in another cancer-causing virus, HPV, proteins called E6 and E7 disable our cells’ key defense systems, p53 and Rb, to cause cancer. The Epstein-Barr virus (EBV) uniquely uses miRNA or a protein called LMP1 that acts like a continuously active ECAR to create furiously proliferating tumors. While this is more of a tumor, when EBV invades B cells, it immortalizes them, turning them into cancer cells.

Thus, cancer-causing viruses, or Oncoviruses, use different methods to attack cells and cause cancer. Some directly break the cell’s defense systems (HPV, SV40), while others induce DNA errors through a cycle of chronic inflammation and regeneration (HBV/HCV, hepatitis viruses).

And all these methods can be used to create immortalized cell lines, which in turn become the foundation for scientific progress!

Conclusion: The Giant World Opened by a Tiny Virus

The story of SV40, which began as an unwelcome guest in the polio vaccine, drew a decisive map that brought humanity one step closer to the summit of the colossal mountain that is cancer. Although SV40 itself did not conquer human cancer, this tiny virus provided us with clues to the most fundamental principles of cell life, death, and how a state of uncontrollability is created.

Great scientific progress often begins with such unpredictable coincidences and unexpected discoveries. SV40 is the most dramatic example of this, and the knowledge left by this tiny giant will continue to illuminate humanity’s journey to unravel the secrets of life and conquer disease.