Like bloodthirsty hunters, worms sniff out human cancers

Strange as it may sound, worms could one day play a key role in fighting cancer. How?

Lung cancer cells seem to smell delicious of one type of small worm. Now, scientists are using that attraction to create a new twisted cancer detection tool. Researchers hope that this new device “worm on a chip” will one day provide a simple, painless way to detect early disease.

This video shows wiggly C. elegans choosing the sides on this tool for diagnosing cancer “worm on a chip”. We first see the center of the chip, where the worms settle. The video is then scanned from one side to the other. This shows that the left has more worms than the right. The video is recorded through a microscope.

The cancer-seeking worm in question is a common roundworm, Caenorhabditis elegans. At just about one millimeter (0.04 inch), C. elegans easily mounted on a handheld chip. To build that chip system, the researchers made something that looks like a microscope slide. It has three large depressions, ie wells. Healthy human cells are placed in a well at one end. Lung cancer cells enter the well at the other end. The worms go to the central well. From there I can smell the stations at both ends. In the experiments, the hungry worms twisted toward the end containing the diseased cells.

“It has been reported that dogs can smell people who have lung cancer,” says Paul Bunn. He is a cancer researcher at the University of Colorado at Aurora who was not involved in the work. “This study,” he says, “is another step in the same direction.”

Each chip employs about 50 worms. “About 70 percent of worms move toward cancer,” says Shin Sik Choi. He is a biotechnologist who helped develop a worm system on a chip at Myongji University in Seoul, South Korea. By training, Choi suspects that the worm’s ability to smell cancer can increase.

The Seoul-based team debuted with its new worm-on-a-chip on March 20 at the Spring Meeting of the American Chemical Society. It was held in San Diego, California.

a photograph of a hand in a blue glove holding a slide
This “worm on a chip” slide works by setting up C. elegans worms in the center. When lung cancer cells are placed at one end of the slider and healthy cells at the other, the worms move to one side to give their voice at which end they hold the diseased cells.Nari Yang

Hot super sniffers

No one can read a C. elegans worm’s mind. So, it is impossible to say with certainty why these little creatures find cancer cells attractive. But Choi thinks the smell is a pretty safe bet. “In nature,” he explains, “a rotten apple on earth is the best place we can find worms.” And cancer cells release many molecules of the same odor as that rotten apple.

C. elegans has a rather refined flair, says Viola Folly. He is studying neuroscience at the Sapienza University in Rome, Italy. Like the Korean team, she is researching C. elegans‘the art of sniffing cancer. And use what he has learned to develop hand screening sensors. Although these worms cannot see or hear, Folly notes, they can smell just as good as dogs. Actually, C. elegans it has about the same number of genes for chemical sense as mammals known for their excellent sense of smell, such as dogs or mice.

That’s pretty impressive, considering C. elegans there are only 302 nerve cells in the whole body – while the human brain alone has about 86 billion.

The simplicity of the worm has even allowed scientists to pinpoint a nerve cell that responds to the aromas of cancer cells. Enrico Lanza, a physicist who studies neuroscience with Folly, did this by genetically tuning some of the wigglers so that when a particular neuron is activated, it lights up. He then exposed the worms to diseased cells and examined them under a microscope, looking for cells that glow in the dark.

C. elegans is transparent, ”says Lanza. “So if something lights up inside [it]”You can detect it from the outside.” And something lit up — one, glowing neuron at one end C. elegans. Lanza took a picture.

image showing a glowing neuron in the C. elegans worm
This image shows a luminous neuron ua C. elegans a worm that responds to the smell of breast cancer in the urine. The scale bar is 10 micrometers long (394 millionths of an inch).E. Lanza

But what do odors that spread from cancer cells C. elegans‘nerve cells glow like this? Choi thinks his team may have identified some of the compounds responsible. These chemicals are known as volatile organic compounds or VOCs emitted by cancer cells. One that could attract C. elegans is a floral-scented VOC known as 2-ethyl-1-hexanol.

To test this idea, Choi’s team used a special type C. elegans. These worms were genetically adapted to lack receptors for 2-ethyl-1-hexanol odor molecules. While normal C. elegans preferred cancer cells over healthy, genetically modified worms are not. This suggested that 2-ethyl-1-hexanol played a key role in attracting worms to diseased cells.

This finding “makes perfect sense because we know that cancer creates VOC signatures,” says Michael Phillips. He did not participate in the research. But he is developing cancer screening tests at Menssana Research in Fort Lee, NJ. Some recent Phillips research has shown that VOCs in the breath can help predict breast cancer risk. That study appeared in Breast cancer research and treatment in 2018.

Cancer Scouting

C. elegansThe ability to detect cancerous cells in the current system of the worm on the chip is a good start. But now, Choi wants to see if these worms can smell cancer when they are not directly exposed to diseased cells. Maybe worms in saliva, blood or urine could pick up a whiff of VOC emitting cancer. Physicians could use such a test to check for lung cancer without the need to sample cells from the patient.

Phillips research on VOCs associated with respiratory cancer suggests that this idea is promising. Folly’s research too. This was reported by her team last year C. elegans preferred the urine of breast cancer patients over the urine of healthy people. This research appeared in Scientific reports.

Such non-invasive tests could give doctors an advantage in fighting cancer. Many patients with lung cancer, for example, are not diagnosed before their disease spreads and becomes difficult to treat. Some screening tools – especially CT – can detect lung cancer early. But X-rays of the scan bring new problems. “The more CT scans you get,” Bunn says, “the more radiation you get.” And that radiation alone can lead to cancer. That’s why doctors don’t want to do these tests unless they suspect a disease.

A safer alternative could be to test for worms on a chip or urine. “Wouldn’t it be nice to have [such] screening test? “Bunn says.” Even if it’s not as accurate as CT? “At the very least, it could indicate who might benefit most from these CT scans.

Phillips agrees. He uses his breath analyzer – BreathX – in the UK to check for cancer. He says different cancer cells release a different blend of VOCs. Each pattern is like a fingerprint. Some other diseases also release VOCs. Using exhaled breath, “We see completely different fingerprints for breast cancer compared to tuberculosis,” Phillips says. The fingerprint of VOC, he says, changes with each disease.

Neither BreathX nor the on-chip worm device is intended to diagnose cancer. “I would never tell a woman she has breast cancer based on breath results,” Phillips says. Or, he adds, a test of worms on a chip. The value of this technology, he believes, is to provide a harmless, inexpensive way to screen people at high risk for disease. These tools could help in the early detection of cancer, when it can still be completely removed or effectively treated.

This is one in a series that presents news on technology and innovation, made possible with the generous support of the Lemelson Foundation.

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