Smelling cancer
By: Hadas Goshen
Dr. Hossam Haick, Head of the Laboratory of Nanomaterial-Based Devices,
the Faculty of Chemical Engineering at the Technion, and Prof. Abraham Kuten, Director of the Oncology Department, the Rambam Health Care Campus

Does cancer have an odor? Maybe; perhaps not in the common meaning of "odor," but it definitely
has special signs that can be identified by a nose with a well developed sense of smell ─ a dog's nose, for example. One of the battles in the war against cancer is the battle for early detection. Many efforts and resources are being invested in various, and sometimes surprising, directions, with the aim of reducing the time of early detection of cancer, thus increasing the chances of successful treatment of the disease. Studies have shown that dogs, for example, can detect breast or lung cancer in the early stages of the disease, with precision reaching up to 90%. (*)
The most famous reported case, which encouraged initiation of medical research for the detection of cancer by means of smell, described a dog that drew its owner's attention to melanoma, by constantly sniffing at the affected region.

Dr. Hossam Haick took this research field a few steps further, and developed an "electronic nose" for early and rapid detection of cancer, using an easy and non invasive method. This is actually an artificial olfactory system, based on nanomaterials that undergo changes similar to olfactory receptors.
The electronic nose of Dr. Haick, Head of the Laboratory of Nanomaterial-Based Devices, the Faculty of Chemical Engineering and the Russell Berrie Institute of Nanotechnology at the Technion, and the Marie Curie Center of Excellence in Artificial Olfactory Systems, approaches the sensitivity level of the canine olfactory system, without the disadvantages of the animal system – the system never gets tired, and is not affected by environmental interference or stimulation like dogs and other animals.

Dr. Haick's studies are highly regarded worldwide, and he has been awarded numerous awards for his pioneering research. He was recently awarded a 1.73 million euro grant for excellence by the European Union, for the development of the electronic nose. This is in fact the largest grant received by a single Israeli scientist from the European Union. The grant has been used to build the Laboratory of Nanomaterial-Based Devices, and to recruit an international team of 17 scientists for further development of the electronic nose.
Dr. Haick's system is composed of two parts, which together create the electronic nose. One of them is an array of sensors for adsorption of a substance or a mixture of substances that we want to detect. The second part is a template for substance identification, simulating activity in the human brain.
Following exposure to a given substance, the system learns how to "recognize" it and displays it in a unique graphic template. It "remembers" the substance, and will recognize this template in the future.
"The electronic nose can differentiate between different diseases, just as it can differentiate between Pepsi and Coca Cola," explains Dr. Haick. When a disease starts to develop in the body, certain organic substances are released into the bloodstream. Hundreds of organic substances characterizing malignant diseases are now known."

How do we smell a disease?
The major difficulty identifying the substances released by the tumor stems from their very low concentration – one part per billion, approximately – among all the particles floating in the exhaled air. "Most of the currently available technologies cannot achieve detection of one part per billion, but the dog can do it!", emphasizes Dr. Haick.
The solution to the problem was provided by nanotechnology. "This is a novel technology based on minimization," explains Dr. Haick. "Every sensor is minimized to the size of one billionth of a meter (1/100,000 of the diameter of a hair). A very large surface area is formed, enabling high and efficient adsorption."
"Imagine that I'm holding a gold bar of 1 kg in my left hand, and the same weight of gold nanoparticles in my right hand. The surface area of the gold in my right hand is 100,000 times larger than that of the gold bar in my left hand, and enables adsorption of much more particles, thus significantly increasing the chance of identification," Dr. Haick describes one of the applications of nanotechnology in a concrete manner.

When the nanomaterial meets a transistor
The system developed by Dr. Haick combines nano-metals produced in his laboratory with electrical devices (transistors). The combination between a nanomaterial and an electrical transistor induces a change in its electrical behavior upon exposure to the material being examined; that is, a change in its electrical properties. The change in its electrical behavior is translated into a computerized graphic signal.
The nanoparticles are designed to adsorb only substances originating from the malignant tumor, while other particles are not adsorbed to them.
The electronic nose is composed of an air pump, a filter for filtering external contaminants and an array of sensors. Each sensor transmits a signal according to the materials it "knows" how to identify. Thus, it is possible to characterize most of the substance families characteristic of a certain disease, and the same system is designed for differential diagnosis of different diseases.
How can we ensure that we don't miss any sign of the disease? The system is designed for lower recognition levels, that is, it can recognize a concentration that is 10 to 100 times lower than the concentration of the particles produced by the tumor.

When Dr. Haick met Prof. Kuten
Dr. Haick and his team members succeeded in showing, under laboratory conditions, that the system differentiates between the healthy and the diseased, and that these results were consistent and reproducible. Theoretically, 95% of malignant diseases can be identified by the electronic nose, under laboratory conditions. However, laboratory conditions are controlled and ideal. The major test of the electronic nose is in the field, during examination of patients, and in the evaluation of the degree of compatibility in the interface between engineering and medicine.
In 2006, during the Second Lebanon war, collaboration was initiated with the Department of Oncology at the Rambam Healthcare Campus, directed by Prof. Abraham Kuten,. The first clinical trial is about to begin, including patients with four of the most common malignant diseases – breast cancer, prostate cancer, lung and colon cancer. In the study, exhaled air samples of cancer patients will be examined and compared with those of healthy volunteers (control group).
The objective of the first studies will be to confirm the efficacy and reliability of the device in identifying known diseases, which were already diagnosed and characterized by the accepted methods – laboratory tests for tumor markers, biopsies and CT and MRI imaging.
"The patients will exhale air into air bags, which will be transferred to the Technion laboratory for testing. The laboratory findings will be compared with the clinical parameters of the patients who will be examined," explains Prof. Kuten. Going back to the beginning of the article, Prof. Kuten emphasizes that "Cancer has no odor!" He explains: "We are not talking about identification of "odor" with its customary meaning, but rather identification of molecules (particles) formed by the tumor, transferred to the lungs by the bloodstream and then – to the exhaled air."

Prof. Kuten warns against premature enthusiasm: "At present, we don't have all the tools for utilizing the information obtained using the electronic nose, but this is an important aspect of cancer research. At this stage, it is too early to make therapeutic decisions based on the findings, without referring the patient for additional scanning tests." Other studies currently performed in Dr. Haick's laboratory may provide the remaining tools required in the future.
Due to the high sensitivity of the device in identifying particles at almost trace concentrations in the air, it is important to determine the threshold value, above which further evaluation will be performed, emphasize Prof. Kuten and Dr. Haick. Prof. Kuten estimates that the first practical application of the artificial nose will be during the follow-up stage, rather than during the initial diagnosis of the disease: "Similarly to the tests for blood levels of tumor markers, if we determine the baseline level of the substances originating from the tumor, and they either disappear or their level increases in follow-up tests, it will be possible to evaluate disease progression or remission."
The electronic nose will be further subjected to its real test by blinded exposure to people with unknown medical conditions, and the big question is ─ will it be able to identify their disease and the disease stage?

Prof. Kuten: "One of the advantages of the electronic nose is that the test is very easy for the patient, and is not associated with painful invasive procedures or radiation, or with nerve-wracking waiting for the result, since the result is obtained immediately."
If the clinical study succeeds, the device will become an inseparable element in the future clinic, due to its low price and portability.
In parallel with the clinical studies, Dr. Haick and his team will continue characterizing the electronic nose and finding additional medical applications. A special effort will be dedicated to the reduction of its size." At present, the device resembles the cellular phones of the 90s, and the aim is to develop a device of the size of a contemporary cellular phone," Dr. Haick indicates the direction of development. "Every physician will be able to keep such a device on his desk in the clinic, in his medical bag or in his pocket.

* Published in the paper:
"Diagnostic accuracy of Canine Scent Detection in Early and Late Stage Lung and Breast Cancers," (March 2006 issue of the Journal of Integrative Cancer Therapies published by SAGE Publications)