The Smell of Stress and Fear

Can we recognize if people around us are stressed, anxious or fearful without observing their facial expressions, body language and actions or hearing their voice and messages? Can we understand if we are stressed ourselves without assessing our heart rate, blood pressure, noticing dry throat, sweating, drops or surges in energy? Yes, we can - by using our nose - as humans, too, recognize and transmit their emotions through chemical senses.

When we are stressed or panic we become more sensitive to odors (Buróna et al., 2015), ranking neutral odors as unpleasant (Krusemark et al, 2013). Chronic stress will actually dull the senses (Yuan & Slotnick, 2013), but that's another story.

When other people are stressed, we can feel it without seeing or hearing them. Numerous experiments showed that we can recognize emotions from sweat alone. We might not be able to tell why, but experience sympathy by smelling odors of those taking exams vs just exercising on a bike (Prehn-Kristensen et al 2009), become more cooperative when smelling hard work, more submissive when detecting that other people's health status prioritizes their needs, more fearful when detecting chemical clues coming from people watching horror movies (Zhou and Chen, 2009, de Groot et al., 2012) and exhibit risk taking behavior when detecting other people's anxieties (Haegler et al, 2010).

What is the exact chemistry of stress, anxiety and fear? We are getting close to deciphering it. Stress, for example, might be recognized by six biomarkers, including indole and 2-methyl-pentadecane (Turner et al, 2013) that are also indicators of COPD (Martinez-Lozano Sinues et al, 2014) and heart disease. 

Correlating chemicals to health and wellness conditions is not easy. Acetone in breath, for example, has attracted the interest of clinical researchers for more than 60 years. Several dozen independent studies using various techniques and methods showed that much more complex analysis is required with long-term measurements of various health and environmental indicators including diet, treatments and prior medical history (Dowlaty, Yoon, and Galassetti, 2013). Aurametrix provides an integrated platform for such analysis, but until we sift through all the data, if you are stressed out, just take a deep breath and relax. Inhale confidence, exhale doubt.

REFERENCES

Haegler, K., Zernecke, R., Kleemann, A., Albrecht, J., Pollatos, O., Brückmann, H., & Wiesmann, M. (2010). No fear no risk! Human risk behavior is affected by chemosensory anxiety signals Neuropsychologia, 48 (13), 3901-3908 DOI: 10.1016/j.neuropsychologia.2010.09.019

Prehn-Kristensen A, Wiesner C, Bergmann TO, Wolff S, Jansen O, Mehdorn HM, Ferstl R, & Pause BM (2009). Induction of empathy by the smell of anxiety. PloS one, 4 (6) PMID: 19551135

Dowlaty N, Yoon A, & Galassetti P (2013). Monitoring states of altered carbohydrate metabolism via breath analysis: are times ripe for transition from potential to reality? Current opinion in clinical nutrition and metabolic care, 16 (4), 466-72 PMID: 23739629

de Groot JH, Smeets MA, Kaldewaij A, Duijndam MJ, & Semin GR (2012). Chemosignals communicate human emotions. Psychological science, 23 (11), 1417-24 PMID: 23019141

Krusemark EA, Novak L, Gitelman D, Li W. (2013) When the sense of smell meets emotion: Anxiety-state-dependent olfactory processing and neural circuitry adaptation. Journal of Neuroscience. 33(39):15324 –15332.

Martinez-Lozano Sinues P, Meier L, Berchtold C, Ivanov M, Sievi N, Camen G, Kohler M, Zenobi R Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. Respiration; International Review of Thoracic Diseases [2014, 87(4):301-310] PMID: 25545545

Yuan TF, Slotnick BM. Roles of olfactory system dysfunction in depression. (2014) Prog Neuropsychopharmacol Biol Psychiatry. 54:26-30. doi: 10.1016/j.pnpbp.2014.05.013. 

I Know What You Ate This Summer

Despite active foodstagramming and foodteresting, and eagerness to show pictures of meals and diet reports to friends on social media, we don't really want others to know everything we eat. But they might know anyway.

Why worry about NSA, when Google, Facebook, Amazon and many others know what we might be eating. Cameras record our ways to groceries and restaurants, credit cards record our purchases, food chains know our weaknesses, clothes shops know how, as a result, our pant sizes change over time. One day phones will know what we ate too.  As both short- and long-term diets change our breath-prints - creating signature metabolites in exhaled breath.

A recent Dutch study actually looked at what gluten-free eating does to our breath. Just 4 week of dieting lead to remarkable - though reversible -  differences. (As detected in 20 healthy individuals by gas chromatography coupled with mass spectrometry (TD-GC-tof-MS) in combination with chemometric analysis ). A set of twelve volatile compounds that distinguish gluten-free eaters along with information from Aurametrix knowledgebase is listed in the table below.

Compound	Odor	Notes
2-butanol	strong alcoholic	1-Butanol smells like permanent marker (Sharpie)
octane	Gasoline-like, car exhaust	octyl chloride smells faintly of oranges
2-propyl-1 pentanol	green banana	1-Pentanol smells like paint thinner
nonanal	strong fruity or floral	attracts mosquitoes
dihydro-4-methyl-2(3H)-furanone	strong coconut aroma	5-butyl-4-methyloxolan-2-one is known as "whisky lactone"
nonanoic acid	rancid beer, old cooking oil	armpits of males over 30
dodecanal	Soapy, waxy, aldehydic, citrus, orange rindy with floral nuances	Pure, synthetic qualities of this fatty aldehyde are used in traces in perfumery for "fresh laundry"-like effects.

Reference

Baranska A, Tigchelaar E, Smolinska A, Dallinga JW, Moonen EJ, Dekens JA, Wijmenga C, Zhernakova A, & van Schooten FJ (2013). Profile of volatile organic compounds in exhaled breath changes as a result of gluten-free diet. Journal of breath research, 7 (3) PMID: 23774130

Come out smelling like a rose

You are what you eat. And you smell like your food. Well, it's actually a bit more complicated - as we emit complex combinations of volatile chemicals produced from food by our own metabolic system as well as microbes that call us home. Same foods can be translated into a wide range of odors, depending on the individual. People exhibit a large variety of smells, much more diverse than animals or plants. Thanks to variations in our digestive enzymes, diets, supplements, medicines, perfumes, detergents, clothes, cars and a lot of other chemicals we are exposed to via different routes. And there are many ways to smell of a rose - for example, by putting a few petals in the pocket, wearing Sa Majeste La Rose or drinking rose oil.

As confirmed by gas-chromatograph mass spectrometry using a thermo desorption system and a selective ion mode (Akiyama et al., 2006), linalool, citronellol and geraniol, which are the main components of rose essential oil, are emitted from our palms after an oral intake of rose oil. The aroma starts to increase 30 minutes after ingestion and reaches its peak within an hour, then slowly decreases, wearing off more than 100 times in the next 6 hours. Citronellol seems to evaporate the fastest, and linalool lingers a little longer than the other two compounds, but, of course, this may very well differ for different individuals.

A new "functional food" - Deo Perfume Candy  - is an attempt to take the sciences of smells and foods to a whole new level by creating a sweet treat intended to make you smell good. The main active ingredient of this candies is Geraniol. It is extracted from rose oil, which in its turn is extracted from real rose petals - one gram of oil per two thousand petals. Small amounts of citric acid and tangerine oil are added for more flavor. An healthy food company Beneo partnered with Bulgarian candy maker, Alpi, to develop this nutricosmetics  treat. At present it is sold exclusively on Amazon and has already collected 5 reviews - ranging from a praise of the observed fresh-just-showered smell to complaints of the need to eat a buck load of candies to see some kind of effect. Does it really work? It might for some of us. With the right chemistry and metabolism, and the right combination of everything else. You can enter it in Aurametrix as Deo Perfume Candy and check back later to see how it worked for others. Or just log what you normally eat and wear to find how your body could react to Geraniol.

You might want to compare it with “Fuwarinka” or Otoko Kaoru's chewing gum - despite a name that translates to "man smell" it also contains rose-flavored geraniol. Although one tester reported to smell like an apple-flavored soap after chewing it.  You can also experiment with the "coming soon" edible perfume from Netherlands, and its mystery ingredient (transformed by the body enzymes and excreted through the skin’s surface through perspiration). There will be more to come.

The possibilities are endless and so are the human odor outcomes.

REFERENCES

AKIYAMA, A., IMAI, K., ISHIDA, S., ITO, K., KOBAYASHI, T., NAKAMURA, H., NOSE, K., & TSUDA, T. (2006). Determination of Aromatic Compounds in Exhalated from Human Skin by Solid-Phase Micro Extraction and GC/MS with Thermo Desorption System BUNSEKI KAGAKU, 55 (10), 787-792 DOI: 10.2116/bunsekikagaku.55.787

Colonoscopy for everyone! ..or Gonna Buy Me A Dog

New research from Japan brings good news: dogs can be almost as accurate as a colonoscopy exam.

In patients with colorectal cancer (CRC) and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99.

The sensitivity of canine scent detection of watery stool samples was 0.97 and the specificity was 0.99.

The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease.  

As simple as that: exhaling 100-200 ml into a breath sampling bag and storing it in a Ziploc bag at 4°C until a trained dog has a change to sniff it can be enough for diagnostics. Just one breath sample! And it was almost as good as a watery stool sample obtained during colonoscopy or this joyous examination itself.

There have been many research studies that dogs, rats and even moth can detect scents pertaining to human disease. Ordinary household dogs can be trained to distinguish breath odors (McCulloch et al 2006). For some cancers, sensitivity can be as high as 100% (Horvath et al 2008).

Unfortunately, sophisticated mass-spectrometry, gas chromatography and software tools interpreting the signals are still not as good as our four-legged friends that are never getting lost in the noise of disease-unrelated flavors.
But we are getting better in identifying specific chemicals responsible for various conditions - from alkanes  - such as pentane in breath of IBD patients and polystyrene foam or aromatic components of petroleum in cancer breath to blends of fatty acids like oleic and linoleic acids forming the smell of death.

Perhaps pet rats will find their use as pocket doctors before men-made sensors are developed to cope with infections, medical conditions, even fear and anxiety that also have a distinctive odor signature. In any case, Dr. Sonoda and his colleagues bring us a reassuring word that not every frequent visitor to the GI doctor's office will have to experience the joys of a colonoscopy.


Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, Morita M, Watanabe A, Morita M, Kakeji Y, Inoue F, & Maehara Y (2011). Colorectal cancer screening with odour material by canine scent detection. Gut PMID: 21282130


Other published literature on olfactory signatures in gastrointestinal disease:

Cheu HW, Brown DR, Rowe MI (1989) Breath hydrogen excretion as a screening test for the early diagnosis of necrotizing enterocolitis. Am J Dis Child 1989;143:156–9.

Pelli MA, Trovarelli G,, Capodicasa E, Breath alkanes determination in ulcerative colitis and Crohn's disease. Dis Colon Rectum 1999;42:71–6.

Pelton NS, Tivey DR, Howarth GS, A novel breath test for the non-invasive assessment of small intestinal mucosal injury following methotrexate administration in the rat. Scand J Gastroenterol 2004;9:1015–16.

Tibble JA, Sigthorsson G, Foster R, Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123:450–60.

Of blood and breath: metabolite-based diagnosis of ovarian cancer

Physicians always knew that breath contains clues to diseases. Chemicals in breath often correlate with chemicals in saliva and blood - be it alcohol, anaesthetics or other metabolites (see, for example, this study by Dr Andreas Hengstenberg).

As one of my interests is breath-based detection of ovarian cancer, I took note of the recent paper claiming 99% to 100% accuracy of detecting ovarian cancer by metabolites in blood.
The authors used customized functional support vector machine-based machine-learning algorithms to classify thousands of metabolites measured by mass spectrometry (JEOL AccuTOF™ DART® that allowed to forego conventional liquid chromatography as sufficient resolution was achieved without separation) in peripheral blood. 

100% sensitivity and 100% specificity was achieved with 64-30 split validation technique, while 100% sensitivity and 98% specificity was the accuracy of leave-one-out-cross-validation. Very large number of metabolites, from 2,000 to 3,000 features, contributed to such discriminatory power (see the list of 14,000+ in supplemental material) 
 

Set of 25 canonical metabolic pathways relevant to the uploaded elemental
formulae ranked according to their p-values (hypergeometric distribution).

Histamine, amino acid, fructose and glucose metabolism were among the most prominent processes discriminating cancer and healthy blood.
It's that simple: sugar feeds cancer. Scientists have long found that cancer cells slurp fructose, and that fructose intake can be linked to some cancers. Histamine/polyamine interplay in cancers is also known. Histamine may be involved in inhibition of the local immune response against cancer. Is amino acid metabolism also linked to cancer? Well, what is not.   




Metabolomic biomarkers were always known to have diagnostic potential - cholesterol and glucose are among the oldest and most widely performed diagnostic tests. Yet, most bleeding edge cancer detection platforms are genomic or proteomic in nature.  Of the thousands of known biomarkers, only a handful have made it into the clinic. Existing ovarian cancer tests mostly rely on detecting a protein -  carbohydrate antigen 125. Vermillion's OVA1 and HealthLinx OvPlex tests use five proteins. This may be extended to 7.

Metabolites represent the end products of the genome and proteome, thus metabolomics-based diagnostics  holds the promise of providing powerful diagnostics,  allowing for differentiation of increased and decreased levels of chemicals with low process coefficient of variation.


Metabolomic tests were used for medical diagnostics starting with Hippocrates and Lavoisier. They continue to be explored by modern scientists. Dr Michael Phillips, for example, developed HeartsBreath Test, approved by the US Food and Drug Agency for early diagnosis of heart transplant rejection. Research proved the potential of inexpensive breath tests in discriminating lung, breast, colon and prostate cancers. Let's hope the new article  - along with others - will lead to novel consumer products, not only more academic research and peer-reviewed publications.



Zhou M, Guan W, Walker LD, Mezencev R, Benigno BB, Gray A, Fernández FM, & McDonald JF (2010). Rapid Mass Spectrometric Metabolic Profiling of Blood Sera Detects Ovarian Cancer with High Accuracy. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699376