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Using nematodes to sniff out cancer

Imagine being able to test for 15 types of cancer from just a drop of urine at a high sensitivity. That’s what a primary cancer-screening test based on nematodes offers.

The test, using the soil-dwelling nematode Caenorhabditis elegans, is based on the research of Takaaki Hirotsu, founder and CEO of the Japanese startup company, Hirotsu Bio Science. While investigating the sense of smell, or olfaction, of C. elegans, Hirotsu discovered that their olfaction is highly sensitive, surpassing that of dogs, for example. It occurred to him that just as some dogs can sniff out cancer in people, it may be possible to use the millimetre-long worm to detect cancer from body fluids.

About a millimetre long, the nematode Caenorhabditis elegans has a sensitivity to certain compounds that exceeds that of state-of-the-art analytic techniques. In particular, they can detect trace amounts of compounds produced by various cancers. Credit: Heiti Paves/Shutterstock

The biology of cancer is very different from that of healthy cells. Since the output of body fluids such as urine is a reflection of our body condition, Hirotsu speculated that it might be possible to use C. elegans to sense the smell of cancer. And it turned out that nematodes such as C. elegans are amazingly good as a biosensor that can detect the smell of cancer in urine. Subsequent studies revealed that they detect and respond to this change in urine composition by showing a distinct chemotaxis response relative to that for urine from a healthy person.

According to Eric di Luccio, head of the Shonan R&D Center at Hirotsu Bio Science, the sensitivity of C. elegans’ olfaction to certain compounds exceeds that of state-of-the-art analytical techniques such as mass spectrometry and chromatography. Its diminutive size belies its powerful biological ability.

Simple and sensitive

The test could hardly be simpler — just add a drop of urine to a container with wild-type nematodes. If they crawl towards the urine, there is a high probability that the person has one of 15 types of cancer, including lung, breast, stomach, colorectal and uterine cancers. The nematodes detect some compounds produced by cancer and are attracted to them. In contrast, they will crawl away from urine from a healthy person. To determine the specific type of cancer, follow-up tests using conventional methods are needed. The simplicity of Hirotsu’s method has the potential to revolutionize cancer screening. “People often don’t get tested for cancer because it takes time and costs money; they have to have a blood test or go into a machine,” says di Luccio. “But a test based on a urine sample is very easy and non-invasive.”

Nematodes (Caenorhabditis elegans; white flecks) are attracted to urine from a person with cancer (left), they keep away from urine from a healthy person. In both cases, urine is placed on the two dark spots on the left side of the dish.

In Japan, people can even order a test online and have a kit delivered. They use it to collect a urine sample, which is then collected and taken to the testing centre. This improves screening access, an important consideration in an ageing society such as Japan where many people find it difficult to visit a clinic, especially under the conditions created by the COVID-19 pandemic.

The technique exhibits impressive sensitivities for 15 types of cancer, detecting early-stage cancers (stages 0 and I) with a similar sensitivity to late-stage cancers (stages III and IV). In contrast, tests involving other cancer markers, such as carcinoembryonic antigen and carbohydrate antigen 19-9, generally cannot reach the high sensitivity needed for catching early-stage cancers. Using C. elegans will help detect cancers earlier, when they are still more responsive to treatment. “This is a totally new approach to cancer screening,” comments di Luccio.

President of Hirotsu Bio Science, Takaaki Hirotsu (left), and Eric di Luccio (right), head of the Shonan R&D at a press conference announcing a genetically modified Caenorhabditis elegans that can detect pancreatic cancer. The announcement received a lot of media attention.

Comparison with other techniques

While many other methods are being developed for detecting cancer based on emerging technologies, most of them are more invasive. In particular, methods such as those based on micro-RNA technology and those that detect tumour cells circulating in the blood require blood samples. In contrast, urine is so much easier to collect. It is very inexpensive compared to a comprehensive systemic examination using other cancer-screening methods. This modest cost combined with its ease of administration lowers the barriers for people being tested for cancer, which will help increase screening rates and help catch cancer while it is still in the early stages.

Detecting a silent, deadly cancer

Of the 15 cancers that the screening test detects, pancreatic cancer is probably the worst one to be diagnosed with. It has a low five-year survival rate of 9% because there are no symptoms in the early stages, and the pancreas’ position deep in the body makes it hard to check using conventional methods.

Researchers at Hirotsu Bio Science have now genetically engineered a version of C. elegans that is sensitive to trace amounts of substances produced by pancreatic cancer at its early stages, while there is still time to potentially treat it. “This really is a big deal,” says di Luccio. “It’s a breakthrough to finally be able to detect pancreatic cancer early and thereby significantly improve its prognosis.” The company plans to commercialize this test in 2022, and it is currently developing other nematodes specific to other types of cancer.

A coloured scanning electron micrograph of pancreatic cancer cells. Pancreatic cancer often causes no symptoms until it is well established and untreatable, but a genetically modified strain of Caenorhabditis elegans can now detect it in the early stages from urine samples. Credit: Science Photo Library - STEVE GSCHMEISSNER/Brand X Pictures/Getty Images

A potentially life-saving test

The screening test for 15 types of cancer has only been available to the public since 2020, but it has already been well received. “We receive many testimonies from customers saying they took a test that was positive and when they went to hospital, it turned out that they had an early stage of a cancer,” says di Luccio. “It’s a real game changer — a very different way of cancer screening that will save lives.”

To view a list of recent peer-review publications on using C. elegans to screen for cancer, see this timeline.


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