If you have ever heard p53 (a protein encoded by the TP53 gene) called “the guardian of the genome,” you might picture a wise molecular sentry that patrols DNA, stops cell cycles, and flips apoptosis switches like a seasoned air-traffic controller. But p53 didn’t make its debut as a heroic gene. p53, actually, began as a mysterious band on a gel as a stubborn ~53 kDa shadow that kept showing up whenever scientists poked at cancer-causing viruses. And for years, the field argued about what it meant; because the tools of the time could show you something was there, but not what it really was.

This is the story of how p53 went from being a molecular hitchhiker to an accidental “oncogene” then to the most famous tumor suppressor on Earth; and how a few very human scientific decisions (and missteps) shaped everything that followed.

p53 story timeline

A fishing expedition in 1979

In London, 1979, a cancer virus called SV40 was the hot object. Researchers were trying to understand how viral proteins hijack cells. One of those researchers was Sir David Lane, the co-discoverer who later coined the phrase “guardian of the genome” and was knighted in 2000 for contributions to cancer research. He also co-edited the bench-classic Antibodies: A Laboratory Manual with Ed Harlow—one of those books that ends up permanently warped from humidity on lab shelves.

Sir Lane and his colleauge, Lionel Crawford, weren’t looking for p53 per se; they were doing what the field often does best: following the weird thing that refuses to go away. Using immunoprecipitation with anti–T-antigen antibodies (Lane later called it essentially a “fishing expedition”), they pulled down SV40 large T antigen, and with it, a mysterious ~53 kDa host protein that seemed to bind T antigen over and over again.

Even in that first moment, there’s something delightful: Lane and Crawford reasoned the protein had to be host-derived, because SV40’s tiny genome couldn’t encode for the gene behind that extra big band. And in their first Nature paper, they floated a bold idea that this host protein might normally regulate growth control. That band would become one of the most consequential in modern biology.

Meanwhile in Princeton: another gel, another band, same ghost

A few months later, another group sees the same kind of thing. This group of researchers was led by Arnold J. Levine who was born in Brooklyn (1939). Levine, later, became the president of Rockefeller University. Rockefeller’s own announcement notes he became its 8th president in 1998, after years building molecular biology at Princeton. He would act as one of the central characters in the p53 saga.

Daniel Linzer, a graduate student in Levine’s group, isolated a 54 kDa protein in SV40-transformed cells using sera from tumor-bearing animals. Peptide mapping suggested it was distinct from viral antigens, reinforcing that this too was a host protein induced during transformation. After graduating with a seminal thesis that included the discovery of p53, Dan Linzer later became a major academic leader and research administrator.

At roughly the same time, multiple other teams detected similar ~53–55 kDa proteins in transformed cells. By late 1979, it was clear: different groups, different assays, same molecular “something.” . That “something” was later named as p53 (for its apparent molecular weight), thanks to Lloyd Old’s immunology group. Beside being a legendary tumor immunologist, Lloyd Old had a deep love of music and he was often described as an accomplished violinist. In that sense, he is not unique: many of the scientists who built modern cancer biology had entire parallel lives that involved music, art, and languages.

Toolbox check: what 1979 could (and couldn’t) do

To appreciate why p53’s story gets messy, it helps to remember a few things. In 1979, p53 was basically a recurring band on SDS-PAGE. Back then, scientists could detect peptides by immunoprecipitation and gels; they could compare peptide maps to confirm it’s the same protein that is seen by others; you could infer it’s host-encoded or not; but, you couldn’t easily clone/sequence it on demand, or do fast mutational surveys across tumors.

So, early p53 was characterized biochemically and immunologically, long before anyone knew its DNA sequence or true function. This matters, because when the gene finally was cloned, the versions that are easiest to clone are often not the “normal” ones.

The great misunderstanding (early–mid 1980s)

By the early 1980s, scientists started asking: When does p53 show up in normal cells? Reich and Levine showed p53 levels rise when quiescent cells were stimulated to re-enter the cell cycle, which was supporting an early interpretation of p53 as a growth-linked regulator. Even more dramatic was that Mercer and colleagues microinjected anti-p53 antibodies and found cells could fail to enter S-phase, which was another nudge toward the “p53 helps proliferation” story.

And then came the cloning race.

The cloning grind (and a near-abandonment moment)

Cloning TP53 in the early ’80s was laborious, failure-prone, and brutally slow. Moshe Oren, who was a key figure who initially helped push p53 into the “oncogene” narrative, then later helped overturn it with data. His arc is basically the plot twist in human form. Oren recalled repeated failures so discouraging that Levine briefly considered abandoning p53 around 1981.

Eventually, cloning succeeded but there was still a catch: Tumor cells often overexpress p53. Those are the samples that jump out at you. Those are the samples you build libraries from. Those are the samples that give you clones. And (as the field would learn the hard way) many of those clones encoded mutant p53. So, p53 was labeled a proto-oncogene not because scientists were careless; but because they were doing the best possible science with the most available material and tools.

1989: the year the story flips

By the late 1980s, the cracks in the “p53 is an oncogene” story were getting impossible to ignore.

Finlay, Hinds, and Levine noticed that a p53 cDNA from a normalish context (e.g., F9 embryonal carcinoma) didn’t behave like the tumor-derived clones in transformation assays. Phil Hinds discovered that many cloned p53 sequences differed by single amino acid substitutions. These were first thought to be polymorphisms but then soon recognized as mutations. That realization is one of my favorite scientific moments: not flashy, not cinematic. It was just the slow dawning that the “same gene” everybody has been studying wasn’t actually the same gene in everybody’s experiments.

Then two kinds of evidence arrive like a one-two punch:

  1. Functional proof that wild-type p53 suppresses transformation: Finlay et al. (Cell) showed wild-type p53 could suppress oncogene-driven transformation. Eliyahu et al. (PNAS) then confirmed similar suppression and even early hints of growth arrest.
  2. Genetic proof that p53 is mutated in human tumors: Baker, Fearon, Vogelstein, and others sequenced colorectal tumors and found frequent TP53 mutations often paired with 17p loss, which was the classic tumor suppressor “two-hit” logic.

It is worth mentioning that Bert Vogelstein, another key figure in the p53 story, was a math major who also won an undergraduate award for Semitic languages and literature at Penn (yes, really). His genetic “sleuthing” approach helped shift p53 from cell-culture argument to human-cancer fact. So, he was yet another scientist who had diverse interests spanning more than the biology field.

Within about a year after all these happened, p53 went from “maybe an oncogene” to “the most commonly mutated gene in cancer,” and the field’s collective interpretation snapped into a new shape.

When p53 becomes personal (Li-Fraumeni, 1990)

If the tumor data convinced the scientists, Li-Fraumeni syndrome convinced everyone else. Two groups found germline TP53 mutations in Li-Fraumeni families, which suddenly connected the molecular story to a human one: families haunted by sarcomas, breast cancers, brain tumors, and early-onset malignancies…

At this point, debates about p53 were not about assays but the whole narrative became a disease story.

Overview of the p53 story

1992 - “Guardian of the genome” (and the knockout mice that sealed it)

1992 delivered two milestone breakthroughs:

  1. Knockout mice: the brutal clarity of genetics: Donehower, Jacks, and others created p53 knockout mice. They developed normally, but were highly prone to spontaneous tumors early in life (often by 4–6 months). That finding is one of those rare science results that feels like a gavel strike: case closed.
  2. The phrase that stuck: “guardian of the genome”: Lane wrote a short Nature commentary titled “p53, guardian of the genome,” crystallizing the idea of p53 as a sentinel that halts the cell cycle or triggers cell death in response to DNA damage. The 1992 paper is a tiny one-page piece with an outsized cultural footprint.

With genetics and language finally aligned, p53’s role as a tumor suppressor was no longer a matter of debate but of detail. What followed was not a search for whether p53 mattered, but a deeper reckoning with how it worked and why cancer seemed so determined to disable it.

1993 - superstardom (and the uneasy next chapter)

By 1993, p53’s reputation exploded. Science dubbed it the “Molecule of the Year.” And then, as if the story needed one more twist, the field began to absorb a deeper complexity: mutant p53 wasn’t merely “loss of function”. Some mutants seemed to acquire gain-of-function behavior, a theme Levine and others pushed into the open by the early 1990s.

The gene didn’t just have a heroic form and a broken form. It had multiple identities that are all context- and mutation-dependent. p53 was like a character whose motives changed depending on which chapter the reader was going through.

Epilogue: p53, understood at last

What we now call TP53 encodes a transcription factor that acts less like a single-purpose brake and more like a cellular decision-maker. In healthy cells, p53 is kept low and fleeting; it is powerful enough that the cell actively restrains it. When genuine danger appears (e.g. DNA damage, oncogene activation, replication stress), p53 stabilizes and turns on gene programs that pause the cell cycle, enforce permanent arrest, or trigger cell death. Which outcome occurs depends on context: cell type, stress intensity, and the surrounding regulatory circuitry. The early confusion around p53 was not just technical. It was conceptual. Scientists were looking for one function, while p53’s biology is inherently conditional.

Cancer’s relationship with p53 explains both its fame and its early mislabeling. TP53 is the most frequently mutated gene in human cancer, and most of those mutations are missense changes that produce a stable, altered protein rather than a simple loss. These mutants can disable normal p53 function, interfere with any remaining wild-type protein, and sometimes acquire new, tumor-promoting behaviors. In retrospect, it’s easy to see why p53 looked oncogenic in early assays: the field was unknowingly studying mutant versions while assuming they represented the gene’s true nature.

Today, p53 stands as both a solved mystery and an ongoing challenge. We understand its structure, regulation, and role in tumor suppression with extraordinary depth, yet translating that knowledge into universal therapies remains difficult precisely because p53 is so context-dependent. The gene that began as a stubborn band on a gel ultimately taught the field something broader: biology rarely reveals its meaning all at once. Sometimes it takes a decade (sprinkled with wrong turns) for a gene to be fully understood.

References

  1. International Agency for Research on Cancer (IARC). Professor Sir David Lane. Available at: https://www.iarc.who.int/friends-of-iarc/professor-sir-david-lane/
  2. Harlow E, Lane D (eds.). Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory Press, New York; 1988. Available at: https://www.cambridge.org/core/journals/genetics-research/article/antibodies-a-laboratory-manual-edited-by-ed-harlow-and-david-lane-cold-spring-harbor-cold-spring-harbor-laboratory-new-york-1988-726-pages-paper-5000-isbn-0-87969-314-2/4DCD2ECC6484BBE46541208D52F324CE
  3. The Rockefeller University. Arnold J. Levine Named President of Rockefeller University. Available at: https://www.rockefeller.edu/news/4415-arnold-j-levine-named-president-of-rockefeller-university/
  4. The Rockefeller University. Arnold J. Levine Becomes Eighth President of The Rockefeller University. Available at: https://www.rockefeller.edu/news/4399-arnold-j-levine-becomes-eighth-president-of-the-rockefeller-university
  5. University of Arizona, College of Science. Dr. Dan Linzer. Available at: https://science.arizona.edu/person/dr-dan-linzer
  6. Old LJ. Lloyd J. Old — a scientific concertmaster. Proc Natl Acad Sci U S A. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC3337005/
  7. Johns Hopkins Technology Ventures. Bert Vogelstein, MD. Available at: https://ventures.jhu.edu/jhtv-events/celebration-of-innovation-in-medicine-2025/bert-vogelstein-md/
  8. Lane DP. p53, guardian of the genome. Nature. 1992;358:15–16. Available at: https://www.nature.com/articles/358015a0
  9. Wikipedia contributors. Lionel Crawford. Wikipedia. Available at: https://en.wikipedia.org/wiki/Lionel_Crawford