Cancer Hydrogen Isotopes May Reveal Atomic Fingerprints

Cancer is the world’s second-leading cause of death, responsible for over 10 million deaths annually.

However, many cancers can be cured when they are detected early and treated successfully. Cancer’s often subtle nature is a major obstacle.

New research suggests it may be possible to spot cancer’s ‘fingerprints’ at the atomic scale, using an approach more usually associated with geology than medicine.

The finding could create new opportunities to study how cancers develop and may eventually support earlier detection.

“This study adds a whole new layer to medicine, giving us the chance to look at cancer at the atomic level,” says lead author Ashley Maloney, a biogeochemist at the University of Colorado Boulder.

Hydrogen isotopes and cancer’s atomic fingerprints

Maloney and collaborators in the US and Switzerland examined naturally occurring differences in how hydrogen isotopes are distributed. Isotopes are versions of the same element whose atoms contain the same number of protons but different numbers of neutrons.

Deuterium, the heavier of hydrogen’s two stable isotopes, has one additional neutron compared with ordinary hydrogen. It is relatively scarce on Earth: hydrogen atoms outnumber deuterium atoms by around 6,000 to one.

In Earth science, the pattern of these isotopes can reveal information about subjects such as ancient rocks and ice sheets.

Hydrogen atoms are distributed in varying patterns within the human body too. Inspired by her father’s work as a dermatologist, Maloney set out to determine whether these isotopes could reveal anything about cancer.

“He takes skin cancer cells off people all the time,” Maloney says. “I wondered how the metabolism of those cells might be different from the cells growing next to them.”

In laboratory tests, the team cultivated yeast cultures and mouse liver cells before analysing their hydrogen isotopes. They discovered that rapidly growing cells, such as cancer cells, display a markedly different hydrogen-to-deuterium ratio.

Maloney and her colleagues stress that the work remains preliminary. There are still many unanswered questions about whether, and how, hydrogen isotopes could signal the presence of cancer in the human body.

Nevertheless, the possibility of saving lives through earlier diagnosis makes the subject worth further investigation, says co-author Sebastian Kopf, a geological scientist at the University of Colorado Boulder.

“Your chances of survival are so much higher if you catch cancer early on,” Kopf says. “If this isotopic signal is strong enough that you could detect it through something like a blood test, that could give you an important hint that something is off.”

How cancer cells use fermentation

Yeast and mouse cells generally produce energy through cellular respiration, absorbing oxygen and releasing carbon dioxide. When oxygen is not readily available, though, most cells can temporarily switch to fermentation, breaking down sugars to generate energy instead.

“In humans, if an athlete performs beyond their aerobic limit, their muscles will also start fermenting, which doesn't use oxygen,” Kopf says. “That gives you a quick energy boost.”

Many cancers similarly power their growth through fermentation, a feature of the Warburg effect. Scientists have therefore long searched for ways to monitor metabolic irregularities that might indicate cancer cells in patients.

For the new study, Maloney and her team investigated whether these metabolic shifts could be followed through hydrogen isotope analysis.

Cells receive hydrogen atoms from an enzyme known as nicotinamide adenine dinucleotide phosphate (NADPH). Although it performs several roles, one of NADPH’s functions is to deliver hydrogen atoms to particular molecules during fatty-acid production.

Depending on the actions of other enzymes within a cell, NADPH can assemble differing proportions of hydrogen and deuterium atoms.

Because cancer can reshape a cell’s metabolism, the researchers wanted to find out whether it also alters how cells acquire hydrogen, consequently affecting their atomic make-up.

Testing hydrogen isotope ratios in cells

The experiments used yeast colonies, which are frequently employed as cancer research models, alongside colonies of healthy and cancerous mouse liver cells.

The scientists collected fatty acids from the colonies and used a mass spectrometer to determine the ratio of hydrogen isotopes in every sample.

​​“When we started the study, I thought, 'Ooh, we have a chance to see something cool,” Maloney says. “It ended up creating a huge signal, which I didn't expect.”

The study found that fermenting yeast cells, used as stand-ins for cancer cells, contained roughly 50 percent fewer deuterium atoms than normal yeast cells. Cancerous mouse cells showed a comparable, although less marked, reduction in deuterium.

“Cancer, and other illnesses, are unfortunately a huge theme in many people's lives. Seeing Ashley's data was a special, profound moment,” says co-author Xinning Zhang, an environmental microbiologist at Princeton University.

“It meant that a tool used to track planetary health might also be applied to track health and disease in lifeforms, hopefully one day in humans. Growing up in a family challenged by cancer, I hope to see this area expand.”

The study was published in the Proceedings of the National Academy of Sciences.