Astronomers and physicists have long used a laser-based sensor called an “optical frequency comb” to study the material composition of the cosmos and make timekeeping more accurate. But the covid pandemic has propelled this versatile tool from the world of space and physics into healthcare.
Optical frequency combs are lasers that fire pulses of light at multiple frequencies simultaneously. Because these ultra-fast pulses are precisely spaced along the light spectrum – from infrared through visible colors to ultraviolet – they form a series of peaks on a frequency graph that resemble the teeth of a comb. . This “comb” can be used in different ways. For example, different types of molecules absorb different colors of light; by detecting which colors of light are absorbed near specific frequencies, the comb can identify specific molecules in an air sample. In a recent study, scientists have proven that this tool can detect COVID from breathalyzer type tests in which subjects simply blow into a tube, potentially paving the way for rapid, non-invasive diagnostic tests for a host of diseases.
Every time humans exhale, we expel over 1,000 types of trace molecules called volatile organic compounds, or VOCs. “Changes in VOC profiles may be linked to specific health conditions,” says Cristina Davis, associate vice chancellor for interdisciplinary research and strategic initiatives at the University of California, Davis. Researchers have known for millennia that certain breath odors are associated with clinical diseases or disorders. References in ancient Greek and Chinese medical literature indicate that doctors used the nose as a diagnostic tool, Davis says. More recently, dogs have been trained to identify certain diseases in humans, and laser comb detectors also need training, says physicist Jun Ye, co-author of the new study. “We train our frequency comb nose using machine learning, and once it is trained, it becomes an electronic dog, with much greater sensitivity,” Ye explains.
This powerful artificial nose has the advantage of being able to detect disease in a rapid and non-invasive way, says the study’s lead author, Qizhong Liang, a graduate student at the University of Colorado at Boulder. For maximum accuracy, adds Liang, positive COVID test results from the new technology should be followed up with a more reliable PCR test. But for a quick test at airports, concert halls or hospitals, it could beat other methods, such as body temperature scans, which are used to assess potential COVID infection without requiring an invasive nasal swab.
Frequency combs can do more than identify molecules. They were originally developed in the 1990s to make more accurate optical atomic clocks, for which the inventors won the 2005 Nobel Prize in Physics. Combs can measure the natural oscillation of atoms with such precision that they have become an indispensable part of atomic clocks, which keep time incredibly well by counting these oscillations. In astronomy, researchers use optical frequency combs to measure the frequencies of light from distant stars; disturbances may indicate that a star has an exoplanet. In atmospheric science, they have been used to study greenhouse gases. And in 2008, Ye and his colleagues at JILA (a joint institute of the National Institute of Standards and Technology and the University of Colorado at Boulder) first proved that the technology could be used as a breath test for disease biomarkers. They put that discovery aside, but world events suddenly gave them a very good reason to relaunch the work in April 2020. “The use of respiration as a diagnostic tool has been around for a while,” Davis says, “ but I think it took a pandemic to get the research interest really really advanced.
Shortly after the onset of the COVID pandemic, Ye received a call from his colleagues at the National Academies of Science, Engineering and Medicine and the Air Force Office of Scientific Research. They wanted to know if his early research on the “Breathealyser” frequency comb could help develop a non-invasive COVID test.
Ye and his team started by updating their technology from 2008. The researchers extended the frequency range of the laser comb from the near-infrared region of the spectrum to the mid-infrared part, where molecules absorb light two to three times more. strongly. This signal amplification allowed the researchers to improve the detection sensitivity of the tool by 1,000 times, allowing them to identify molecules at extremely low concentrations on the scale of hundreds of parts per trillion.
Next, Ye’s team collected breath samples from 170 students and staff at the University of Colorado Boulder from May 2021 to January 2022. Each participant received conventional PCR nasal swab COVID tests, and about half were positive. The researchers then used the frequency comb to analyze light absorption patterns among molecules in the participants’ breath. By applying machine learning to frequency comb data, combined with already known PCR data on who was positive or negative, they found six “discriminant molecules” that indicated COVID infection. The work was described in an article published in April in the Breath Research Journal.
Liang says the AI was key to the project’s success because of the vast amount of information the frequency comb collects when analyzing breath. “Machine learning can analyze all of this data simultaneously and automatically find the best way to use all of this discriminating information to build a prediction model,” he says.
Frequency combs aren’t the only way to test human breath for COVID or other illnesses. Other methods include gas chromatography/mass spectrometry systems such as the InspectIR test, which received Emergency Use Authorization from the United States Food and Drug Administration in April 2022. In these chemistry-based techniques, gas molecules to be analyzed are separated by an inert gas, broken down into fragments then measured. Davis calls these types of tests the “gold standard,” but they require time, specialized training, and bulky equipment that limits their use in the lab. Davis worked on a smaller, portable type of test, an ion mobility spectrometer, which identifies substances based on the mobility of their molecules in an electric field. Other options use chemicals that bind to VOCs to isolate and test them. “There are over 15 companies working on a variety of these types of tests,” Davis says.
Frequency comb technology is different, Liang says, because it uses laser spectroscopy and therefore “detects molecules in the breath non-destructively.” By this, he means that the comb does not cause a sample to degrade or create unwanted by-products like breath tests that rely on chemical reactions can. Frequency comb technology also has the potential to be very, very fast: it could potentially deliver results in seconds, compared to minutes of other breath tests.
That said, you probably won’t see laser combs the next time you take a flight. “Respiratory testing, in general, hasn’t reached prime time yet,” says Wilbur Lam, a COVID testing expert, pediatrician, and biomedical engineer at Emory University and the Georgia Institute of Technology. With the frequency comb method, he says, “you get an optical signal, and you really have to prove whether that optical signal is really indicative of a COVID infection. Right now they’re showing some correlation. But how does that does it correlate with other types of conditions that might affect breathing?”
If frequency-comb “breathalyzers” prove successful in new research, they could make a huge difference in many clinical settings beyond rapid tests for COVID. Study co-author Kristen Bjorkman, director of interdisciplinary research at the BioFrontiers Institute, suggests that this technology could one day be used to detect chronic obstructive pulmonary disease, kidney failure, lung cancers and pancreas and even Alzheimer’s disease. Several early studies have provided preliminary evidence that the contents of exhaled breaths can be used for these diagnoses.
Breathalyzer-type tests could also be ideal for diagnosing children, and Ye says some pediatricians have already approached him about a frequency comb test for asthma in children. When a child presents sick to the emergency room, Ye explains, many invasive tests are needed to determine whether the symptoms are caused by a bacterial or viral illness or by asthma. He says a Denver-based pediatrician told him, “’Imagine you could do breath analysis on children, which is totally non-invasive. Children won’t cry if they just have to breathe.