Wednesday, July 10, 2013

Call Off the Dogs

The space between the lost clinical art of olfactory diagnosis and Dr. McCoy’s tricorder of the future is filled with canine scent detection studies. These prove, ad nauseum, that a disease may have a distinctive scent signature. But to put this principle to work in a way that doesn’t involve teams of trained dogs we need a precise, chemically defined profile of each disease’s scent. Some new studies suggest we’re finally getting some traction on the problem.

My former Monell Center colleague George Preti, along with others at Monell and UPenn, has found a small set of volatile molecules that distinguish melanoma cells from normal melanocytes. The usual cautions apply—e.g., the volatiles were collected over cell cultures and not over the skin of actual patients—but the work is a significant step toward a device that can “smell” skin cancer. Preti et al. used sophisticated scent capture (solid-phase micro-extraction for GC-MS) supplemented by nanotubes coated with single-stranded DNA. Strictly speaking this isn’t an e-nose but an e-nose with nanosensors. The team then did a lot of heavy lifting to screen out volatiles not endogenous to the melanoma cells. (Earlier studies picked up traces of antiseptics and anesthetics from the hospital environs.)

The result: key differentiating compounds included isovaleric acid, 2-methylbutyric acid, and isoamyl alcohol, plus the sulfur containing compounds dimethylsulfone, dimethyldi- and trisulfide. None are exotic but the pattern allows discrimination of healthy and cancerous cells. Heightened production of these molecules is presumably to metabolic differences between the two cell types.

Meanwhile, researchers in the UK reported pilot data on detection of bladder cancer using a GC-sensor device that samples urine headspace. Using statistical algorithms the device correctly separates urine from cancer patients and that of healthy matched controls. Nice.

A leading member of the team is Professor Norman Ratcliffe, pictured below.

With necktie and fresh, unwrinkled lab coat he’s quite well dressed for an engineering professor. [Especially a British one!—Ed.] He appears to be holding a urine sample. Honestly, dude, glove up!

Prof. Ratcliffe presumably knows better than to bare-hand biofluids. He and his colleagues have previously done a lot of shitty work [Phrasing!—Ed.] using fecal volatiles to diagnose diarrhea, cholera, necrotizing enterocolitis, and irritable bowel syndrome.

From the Competing Interests statement of the PLoS ONE paper, it appears that team Ratcliffe has been granted one patent and has applied for another. To my inexpert eye, the granted patent seems rather broad—it covers the idea of a headspace collector and analyzer that can diagnose disease via odors. I don’t see how it would hold up in litigation, but then I’m not a patent attorney. [Or a patent troll.—Ed.] By publishing in PLoS ONE they certainly achieved plenty of free publicity for their patented device.

While human cancer studies make the headlines, olfactory diagnosis is advancing down on the farm. In Germany, a group of veterinarians and vet students was matched against an e-nose. The task: sniff post-partum vaginal discharge from a cow and judge whether or not the animal suffers from acute puerperal metritis. The humans performed adequately but they were completely dusted by the DiagNose device. The researchers note, however, that the e-nose is yet suitable for use in the field, er, barn.

The studies discussed here are “Volatile biomarkers from human melanoma cells,” by Jae Kwak, Michelle Gallagher, Mehmet H. Ozdener, Charles J. Wysocki, Brett R. Goldsmith, Amaka Isamah, Adam Faranda, Steven S. Fakharzadeh, Meenhard Herlyn, A.T. Charlie Johnson, and George Preti, published in Journal of Chromatography B 15:90-6, 2013,

A pilot study combining a GC-sensor device with a statistical model for the identification of bladder cancer from urine headspace,” by Tanzeela Khalid, Paul White, Ben De Lacy Costello, Raj Persad, Richard Ewen, Emmanuel Johnson, Chris S. Probert, & Norman Ratcliffe, published in PLoS One, 8(7):e69602, 2013,

An investigation of fecal volatile organic metabolites in irritable bowel syndrome,” by Iftikhar Ahmed, Rosemary Greenwood, Ben De Lacy Costello, Norman M. Ratcliffe, & Chris S. Probert, published in PLoS One, 8(3):e58204, 2013, and

Evaluation of odor from vaginal discharge of cows in the first 10 days after calving by olfactory cognition and an electronic device,” by I. Sannmann, O. Burfeind, V. Suthar, A. Bos, M. Bruins, & W. Heuwieser, published online in Journal of Dairy Science, June 27, 2013.

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