Methanethiol: The Scent of Disease and Discovery

In a previous blog post, we discussed the role of SELENBP1 in nonosyndromic (monosymptomatic) halitosis. We learned that if this enzyme isn't functioning correctly, it can lead to the release of more Methanethiol, a volatile and rather unpleasant-smelling gas often associated with the aroma of rotten cabbage. 

However, Selenium binding protein 1 (SELENBP1) isn't just a casual bystander in our biological processes. It has been linked to various health conditions and diseases. These include:

Hypermethioninemia: A rare condition that can sometimes come with learning disabilities and neurological issues.

Schizophrenia: a complex mental disorder that challenges our understanding of the human mind

Hypertension and Ischemic Heart Conditions, conditions such as Guillain-Barré syndrome and Infectious Diseases: Dysregulation of SELENBP1 is associated with Zika virus (ZIKV) and dengue infections, as well as COVID-19.

SELENBP1's role in several types of cancer, including its downregulation at the onset of cancer and upregulation in later stages, is a subject of intense research.

Methanethiol contributes to the distinct scent signature linked to cancer, characterized by a combination of volatile organic compounds (VOCs). Researchers are increasingly exploring this intriguing scent profile as a potential tool for non-invasive early cancer diagnosis.

Methanethiol is a testament to the intricate connections between genetics, metabolism, and disease, reminding us that even the smelliest molecules can lead to groundbreaking discoveries.

Methanethiol also contributes to the distinct scent signature associated with cancer, characterized by a combination of volatile organic compounds (VOCs). This intriguing scent profile is increasingly being explored for non-invasive early cancer diagnosis.

In a recent paper titled "Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer,"  researchers unveiled new findings:

Tumor cells undergo metabolic adaptations to meet increased energy demands and enhance stress resilience. This includes dysregulation of sulfur metabolism and elevated levels of volatile sulfur compounds (VSCs) in cancer patients.

Methanethiol stands out as the predominant cancer-associated VSC and is being considered as a potential biomarker for non-invasive cancer diagnosis.

Within the gut microbiome of colorectal carcinoma (CRC) patients, gut bacteria, particularly methanethiol-producing strains like Fusobacterium nucleatum, are a significant source of exposure to methanethiol.

Selenium-binding protein 1 (SELENBP1) plays a crucial role in the rapid degradation of methanethiol through its methanethiol oxidase (MTO) activity.

Odor-based cancer screening methods, such as sniffer dogs and canine scent detection, even human feedback, have shown great promise in identifying lung and colorectal cancer patients, opening doors to non-invasive detection approaches.

The dysregulation of sulfur metabolism and the potential use of methanethiol as a biomarker, coupled with the innovative odor-based cancer screening methods, offer not just promising but transformative avenues for non-invasive cancer detection and cutting-edge research.

REFERENCE

Philipp TM, Scheller AS, Krafczyk N, Klotz LO, Steinbrenner H. Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer. Antioxidants (Basel). 2023 Sep 19;12(9):1780. doi: 10.3390/antiox12091780. PMID: 37760083; PMCID: PMC10525899.

Seeing Through the Skin

by AURAMETRIX

​Human skin emits light (albeit the glow is extremely weak) and a wide variety of small molecules that may be sometimes "sniffed" by dogs or even other humans. These chemicals tell a story about our health and wellness, things we eat and drink, touch and breathe. Mosquitoes use such emissions to assess our "attractiveness" from indicators such as Indoles (unpleasantly smelling but healthy "inner soil" biomarker) or carbon dioxide (amount of which correlates with the size of the person producing it) in the air.  Sampling air for health indicators is much less invasive than drawing blood and could be an invaluable diagnostic tool. Many applications of gas sensors have been proposed over decades ranging from sweat patches to sensorized garments. Where are we now? What is the 2016 state of the art? Last month, BACtrack won 1st Prize in “Wearable Alcohol Sensor Challenge” Issued by National Institutes of Health. Milo Sensors, employing a different approach to identify ethanol molecules diffusing through the skin, won 2nd prize. BACtrack Skyn will be available in limited quantities later this year, marking an important step from bulky alcohol-monitoring ankle bracelets remotely monitoring offenders to inconspicuous devices. Perhaps, one day, drug patches, too, won't require sending them to a lab for analysis. Human skin is a super-highway of many small molecules reflecting our health and wellbeing. Various devices capable of "seeing" through our skin were announced in the past several years. Some of them - like AIRO watch claiming to detect metabolites in your bloodstream as they are released during and after meals - turned out to be vaporware. The jury is still out on many others like HealbeGobe. And the remaining ones are still in prototyping stages.  EU-funded Biotex textiles and Perspiration Detective patch development at the University of Cincinnati started from detecting sodium ions in sweat as indicators of hydration levels. A tattoo-like electronic sweat sensor built by a team in UCSD demonstrated that measuring a change in lactate might be sufficient to find when an athlete is about to “hit the wall.” Startup Electrozyme, later renamed to Biolinq, was formed to commercialize this technology. The picture shows their prototype of a skin-applied electrochemical sensor that analyses body fluids to provide actionable health information. The goal is to develop temporary tattoo biosensors providing blood level info without accessing blood. Halo Wearables will launch their non-invasive hydration monitoring wearable in early 2016. It is tailored specifically for elite athletes.  Halo's optical sensors track sodium and potassium levels in the user's blood. ​ Researchers from the University of California, Berkeley, Stanford and Lawrence Berkeley National Laboratory have also developed a wearable sensor that can monitor sodium, potassium and lactate levels in sweat. A paper with their findings was published in Nature earlier this year. ​ Startup Xsensio, accepted this year in Mass Challenge accelerator, works on “intelligent stamps” the size of a credit card (Lab-on-Skin wearables) including a unique low-power sensor for sweat analysis. ECHO smart patch from Kenzen aims to "silently follow your health and notify you only when it's most important". It analyzes sodium and potassium in sweat to monitor hydration, lactic acid and glucose analysis energy expenditure.  Existing technologies can detect a general increase or decrease in metabolites rather exact concentrations. So using sweat to accurately monitor clinically important variables such as glucose levels, is still out of reach. But developers are employing innovative approaches to make it possible. A team from Seoul National University, University of Texas and a Massachusetts-based company MC10 are developing a flexible patch that senses glucose in people with diabetes and administers drugs, all in a single device. And there may be easier ways to display all the information collected from various sensors -  perhaps even directly on the body - as the team from the University of Tokyo demonstrated with device measuring oxygen saturation levels in blood. ​We've come a long way from bulky and invasive medical equipment that required the patient to remain in the hospital for monitoring. We have made a lot of progress from the times when all symptoms and signs were recorded with a pencil and paper. There is still a lot more to do before real-time self-managing noninvasive diagnostics reaches a breakthrough, but we are so much closer.

REFERENCES


Andreoni G, Standoli CE, & Perego P (2016). Defining Requirements and Related Methods for Designing Sensorized Garments. Sensors (Basel, Switzerland), 16 (6) PMID: 27240361

Gao W, Emaminejad S, Nyein HY, Challa S, Chen K, Peck A, Fahad HM, Ota H, Shiraki H, Kiriya D, Lien DH, Brooks GA, Davis RW, & Javey A (2016). Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature, 529 (7587), 509-14 PMID: 26819044

Imani S, Bandodkar AJ, Mohan AM, Kumar R, Yu S, Wang J, & Mercier PP (2016). A wearable chemical-electrophysiological hybrid biosensing system for real-time health and fitness monitoring. Nature communications, 7 PMID: 27212140

Lee H, Choi TK, Lee YB, Cho HR, Ghaffari R, Wang L, Choi HJ, Chung TD, Lu N, Hyeon T, Choi SH, & Kim DH (2016). A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy. Nature nanotechnology, 11 (6), 566-72 PMID: 26999482

Panneer Selvam A, Muthukumar S, Kamakoti V, & Prasad S (2016). A wearable biochemical sensor for monitoring alcohol consumption lifestyle through Ethyl glucuronide (EtG) detection in human sweat. Scientific reports, 6 PMID: 26996103
XXX

Yokota T, Zalar P, Kaltenbrunner M, Jinno H, Matsuhisa N, Kitanosako H, Tachibana Y, Yukita W, Koizumi M, & Someya T (2016). Ultraflexible organic photonic skin. Science advances, 2 (4) PMID: 27152354

Odors and Infections

Many illnesses are associated with distinct odors. Especially those caused by infectious or opportunistic microbes inside the body or on its surfaces.  Body odor of someone infected with C. difficile, for example, can appear "swampy", Rotavirus gives sharply sweet putrid smell that some people associate with wet dogs. H. pylori can create a range of foul odors, and pseudomonas infections can smell like grapes and bitter almonds. 

Infections like C. difficile are usually linked to a general imbalance of the intestinal microbiota, often referred to as dysbiosis. This means that the odors could be coming from several microbial species, hence could be different for different individuals. Does it mean odor-based diagnostics will never be enough specific?

Not according to a 2-year-old beagle from Netherland, named Cliff. After just a little over two months of training, the beagle learned to identify the C. diff toxin by sniffing people or their samples. During one test, he was able to identify 25 out of 30 infected patients and 265 of 270 non-infected individuals. He also correctly identified 50 of 50 C. diff positive stool samples and 47 of 50 samples from people that did not have this infection. That's sensitivity of 100% for samples and 83-93% for sniffing the air around the patients, and a specificity of 94-100%! And it took him less than 10 minutes to accurately perform 300 diagnostic tests.  

Dogs already do the dirty work with detecting molds. They can examine an office building with 200 rooms in just 8 hours, a task that would take us several days of measuring  moisture, probably without any result. Electronic noses would be of great help and many years of research are finally being translated into useful technologies - to be integrated with refrigerators and mobile phones. But until we are able to build smart devices to detect odors without labor-intensive dog training, perhaps we could train our own nozzles. Studies have shown we do get better with practice. 


REFERENCES

Bomers MK, van Agtmael MA, Luik H, van Veen MC, Vandenbroucke-Grauls CM, & Smulders YM (2012). Using a dog's superior olfactory sensitivity to identify Clostridium difficile in stools and patients: proof of principle study. BMJ (Clinical research ed.), 345 PMID: 23241268

Poulton J, Tarlow MJ. (1987) Diagnosis of rotavirus gastroenteritis by smell. Arch Dis Child. 1987 Aug;62(8):851-2. PMID: 3662595

Arnaud Tognetti, Megan N Williams, Nathalie Lybert, Mats Lekander, John Axelsson, Mats J Olsson, Humans can detect axillary odor cues of an acute respiratory infection in others, Evolution, Medicine, and Public Health, Volume 11, Issue 1, 2023, Pages 219–228, https://doi.org/10.1093/emph/eoad016