Expert sommeliers can take a quick sniff of a glass of wine and tell you a lot about what’s in your pinot noir or cabernet sauvignon. Now, a team of physicists at CU Boulder and the National Institute of Standards and Technology (NIST) has developed a tool that performs a similar feat—but for a much wider range of substances.
Qizhong Liang in Jun Ye's lab at JILA on the CU Boulder campus. Image Credit: Patrick Campbell/CU Boulder
This new laser-based device can analyze a gas sample and identify an extensive variety of molecules within it. It’s highly sensitive, capable of detecting these molecules at concentrations as low as parts per trillion. Its straightforward design makes it a practical and cost-effective option for various applications, from diagnosing medical conditions to monitoring greenhouse gas emissions from industrial sites.
Even today I still find it unbelievable that the most capable sensing tool can be built with such simplicity, using only mature technical ingredients but tied together with a clever computation algorithm.
Qizhong Liang, Study Lead Author and Doctoral Student, JILA
To demonstrate its capabilities, Liang and his colleagues focused on a fundamental question in medicine: What’s in the air we exhale?
By analyzing real breath samples, the researchers were able to identify different bacteria living in participants' mouths. This technique has the potential to help doctors diagnose a range of conditions, including lung cancer, diabetes, and chronic obstructive pulmonary disease (COPD).
Physicist Jun Ye, senior author of the study, explained that the work builds on nearly 30 years of quantum physics research at CU Boulder and NIST—particularly on a specialized device called a frequency comb laser.
The Frequency comb laser was originally invented for optical atomic clocks, but very early on, we identified its powerful application for molecular sensing. Still, it took us 20 years to mature this technique, finally allowing universal applicability for molecular sensing.
Jun Ye, Study Senior Author, Fellow, and Professor Adjoint of Physics, CU Boulder, JILA
A Shaking Cavity
To understand how the technology works, it helps to consider that all gases—whether carbon dioxide or the compounds in human breath—carry a unique fingerprint. When exposed to a laser spanning multiple optical frequencies, different molecules absorb light at specific frequencies, much like a burglar leaving behind a fingerprint at a crime scene.
Frequency combs are particularly effective for this method because, unlike traditional lasers, they emit pulses of light in thousands to millions of colors simultaneously. (JILA’s Jan Hall was awarded the 2005 Nobel Prize in Physics for pioneering these lasers.)
However, for the technique to detect molecules at very low concentrations, the laser light needs to pass through the gas sample over long distances—typically miles. Scientists must replicate that distance within a small container that holds the sample.
“We enclose the gas sample with a pair of high-reflectivity mirrors, forming an ‘optical cavity. The comb light can now bounce between those mirrors several thousand times to effectively increase its absorption path length with the molecules,” stated Liang.
That’s the goal, at least. In practice, optical cavities are notoriously tricky to work with and will eject laser beams if they aren’t precisely matched to the cavity’s resonant modes. Because of this, scientists have historically been limited to using only a narrow range of comb light, which in turn restricted the variety of molecules they could detect in a single test.
In their new study, Liang and his colleagues tackled this challenge head-on. They introduced a technique called Modulated Ringdown Comb Interferometry, or MRCI (pronounced “mercy”). Instead of keeping the optical cavity fixed, the team periodically adjusted its size. This controlled “jiggling” allowed the cavity to accept a much broader spectrum of light. To make sense of the complex laser intensity patterns emerging from the cavity, they applied computational algorithms—ultimately revealing the chemical composition of their samples with far greater precision.
“We can now use mirrors with even larger reflectivity and send in comb light with even broader spectral coverage. But this is just the beginning. Even better sensing performance can be established using MRCI,” said Liang.
A Sensor for Breath
The research team is now focusing on applying MRCI technology to human breath analysis.
Exhaled breath is one of the most challenging gas samples to be measured, but characterizing its molecular compositions is highly important for its powerful potential for medical diagnostics.
Apoorva Bisht, Study Co-Author and Doctoral Student, Ye’s Lab
Bisht, Liang, and Ye are collaborating with researchers at CU Anschutz Medical Campus and Children’s Hospital Colorado to test whether MRCI can distinguish breath samples from children with pneumonia versus those with asthma. They are also studying the breath of lung cancer patients before and after tumor removal surgery and investigating the technology’s potential to detect early-stage COPD.
“It will be tremendously important to validate our approach on real-world human subjects. Through close collaboration with our medical colleagues at CU Anschutz, we are committed to developing the full potential of this technique for medical diagnosis,” concluded Ye.
Journal Reference:
Liang, Q., et al. (2025) Modulated ringdown comb interferometry for sensing of highly complex gases. Nature. doi.org/10.1038/s41586-024-08534-2