Originally published 2022-03-16.
Researchers at Northwestern University in Chicago, led by cancer biologist Marcus Peter, have described what they call a built-in "kill switch" for cancer cells: tiny RNA molecules carrying a specific six-letter genetic code that make cancer cells destroy themselves by shutting down many survival genes at once. The work, published mainly between 2017 and 2018, is promising laboratory and animal research. It is not a cure and not yet a treatment for people, and although the story kept circulating years later, the key findings are several years older than many headlines implied.
An artist's 3D illustration of nanoparticles delivering a cell-death-inducing treatment to a tumour cell (Kateryna Kon/Shutterstock). In Northwestern's mouse experiments, nanoparticles were the vehicle used to carry the toxic RNA molecules into tumours.
What the Northwestern team found
Peter's group at the Feinberg School of Medicine spent around eight years studying a strange observation. Small interfering RNAs (siRNAs), short RNA molecules that scientists use as tools to silence one gene at a time, sometimes killed cancer cells regardless of which gene they were designed to target. Something in their sequence was toxic in its own right.
The team traced the effect to a short stretch at the start of the molecule known as the "seed", just six nucleotides long. Certain six-letter seeds, when loaded into the cell's gene-silencing machinery, switch off a whole set of genes that cancer cells need to survive. The researchers named the process DISE, short for "death induced by survival gene elimination". Because many survival genes are hit at the same time, several cell-death pathways are triggered together.
The findings appeared in a series of papers. In October 2017 the group reported the mechanism in the journal eLife, with companion studies in Oncotarget and Cell Cycle. In October 2018 two further papers, in Nature Communications and eLife, described the most toxic seed sequences and showed how the body itself can produce such molecules.
The "kill code" and the CD95L connection
To find the most lethal sequences, Peter's team tested all 4,096 possible combinations of six nucleotides. The deadliest seeds turned out to be rich in guanine, one of the four letters of the genetic code. Peter later called this the "kill code".
A key question was whether this was only a laboratory trick or something the body uses naturally. The 2018 work suggested the latter. The group reported that cells can cut the messenger RNA of a gene called CD95L, also known as Fas ligand, into small fragments that act like toxic microRNAs. More broadly, they estimated that about 3% of protein-coding RNAs in the genome could be processed into small RNAs with this kind of toxicity.
MicroRNAs are the body's own small regulatory RNAs. Each one fine-tunes the activity of many genes. Peter's argument is that some of them, and fragments of larger RNAs, carry toxic seeds that act as a safety net against cells that start to behave like cancer.
An ancient defence against cancer?
The most eye-catching idea in the research is evolutionary. The adaptive immune system, which includes the T cells and antibodies that can recognise tumours, is thought to be around 500 million years old. Multicellular life is older than that, so early animals must have had other ways to deal with cells that grew out of control.
Peter proposed that DISE could be one of them. "We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system," he said in a 2017 Northwestern press release. He described it as a fail-safe that may be active in every cell. This remains a hypothesis: it fits the data from his lab, but it has not been proven that the mechanism protects people from cancer in everyday life.
The mouse study and nanoparticle delivery
Laboratory dishes are one thing; living animals are another. In the Oncotarget study, Peter worked with urologist and nanotechnology researcher Shad Thaxton to package the toxic RNA molecules into nanoparticles. Mice carrying human ovarian cancer tumours were treated with them. Tumour growth was strongly reduced, no toxicity was reported, and the tumours did not become resistant.
The lack of resistance is one of the most interesting findings. Cancers often survive treatment because a few cells carry mutations that let them escape a drug aimed at a single target. Since DISE removes many survival genes at once, the cells have no easy escape route. Peter put it vividly: "It's like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time."
The team also said the toxic RNAs seemed to affect cancer cells more than normal cells, which is essential for any future therapy. Peter has said his group hopes to design artificial microRNAs even more powerful than natural ones.
What this research does not mean yet
Headlines about a "kill switch that could end disease" go far beyond the evidence. Several points are worth keeping in mind:
- It is early-stage. The published results come from cell cultures and mice. Northwestern itself said that any therapy would be many years away, and the releases describing the work did not report human trials.
- Delivery is hard. Getting RNA molecules safely into tumours, and not into healthy tissue, is one of the biggest challenges in RNA medicine. Nanoparticles help, but they are not a solved problem for every cancer type.
- Cancer is many diseases. A mechanism that works against ovarian cancer cells in mice may behave differently in other tumours or in people.
- "Kill switch" is a metaphor. It describes a biological process, not a button that can be pressed to cure cancer.
Anyone facing cancer decisions should talk to their doctor or oncology team about proven treatments and suitable clinical trials, rather than relying on news about laboratory discoveries.
Why it still matters
Even with those caveats, the work is a good example of how basic research changes the way scientists think. A side effect that many labs had seen as a nuisance, the "off-target" toxicity of siRNA tools, turned out to point to a possible natural defence system and a new kind of anti-cancer strategy. RNA-based medicines in general have moved from theory to approved treatments for some diseases in recent years, which makes the idea of an RNA drug against cancer more realistic than it once seemed.
Cancer survival has improved greatly over recent decades thanks to earlier detection, better surgery, radiotherapy, targeted drugs and immunotherapy, but many cancers remain hard to treat. Approaches that attack many weak points at once, as DISE does, are one of the ways researchers hope to get ahead of resistance. Whether this particular kill code becomes a therapy will depend on years of further testing.
Sources: Northwestern University via EurekAlert!: cancer kill switch press release (October 2017); Northwestern University via EurekAlert!: "kill code" press release (October 2018); IFLScience: A cancer kill switch has been found in the body (November 2018).
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