A Disobedient Mass of Cells


Current radiation-based methods for detecting and destroying tumors tend to themselves be potentially carcinogenic, because they use harsh and ionizing radiation. Microwaves, on the other hand, are much less harmful. Their use for imaging and therapy could change the way medical science deals with breast cancer.


A disobedient mass of cells – loosely called a cancer, or tumour – sits in the midst of healthy tissue. Evading the body’s immune system, and drawing sustenance from the blood vessels that it manages to recruit around itself, the rogue mass continues to grow – as cells within it divide, and divide again. As it works hard at performing this deadly exercise, the tumour cannot help but warm up and give off some heat. This heat radiates outwards and is ordinarily lost to surrounding spaces. Dr. Kavitha Arunachalam and her group at the Department of Engineering Design have been working on ways to detect this naturally-emitted heat reliably, using microwave radiometry. They also use externally-supplied heat to destroy the growing mass, using an approach known as hyperthermia.

When a microbe (a bacterium or a fungus) infects a human body, we manage to attack it with chemicals, such as antibiotics, which take advantage of the bacterium’s vulnerabilities; vulnerabilities that are not shared by our own cells. In contrast, a cancerous cell is like a healthy cell in almost every way, except that it somehow manages to divide uninhibitedly. A cancer generally does not announce its arrival in a hurry, and it cannot be made to leave without a sacrifice of some of the body’s healthy tissue.

(from left) Dr. Kavitha, Geetha, Rachana and Vidyalakshmi
(from left) Dr. Kavitha, Geetha, Rachana and Vidyalakshmi

In the specific context of breast cancer, which affects more than a million women every year, another unfortunate fact needs to be faced. Today, the most reliable method of detecting breast cancer is X-ray mammography; a technique which involves sending high-energy radiation through breast tissue. X-rays have enough energy to damage DNA, and create mutations. X-rays, therefore, can actually potentially cause cancer even as they are used to detect its presence. Thus, there is a dire need for alternative imaging methods.

Dr. Kavitha’s group works with low-energy, low-frequency, non-ionising electromagnetic radiation. The group works with microwaves (which have already given us tools such as radar, radio telescopes, GPS, mobile phones and microwave ovens). Microwave frequencies are lower than those of red and infrared light, and go down all the way to the frequency ranges of radio waves. Dr. Kavitha’s group believes that microwaves have potential for medical imaging and treatment which is only just beginning to be explored.

Microwaves, unlike X-rays, cause no mutations in DNA. Also, the heat that a tumour generates includes a component of microwave radiation. This makes microwaves ideal for use in both treatment and imaging, firstly because one does not need to introduce any external radiation to perform imaging, and secondly because much less harm is done when one does need to send some microwave radiation into cancerous tissue, to destroy it.

A microwave radiometer transmits nothing to the object that it images. It merely receives and measures the radiation generated by the object, making it completely safe for use with tissues. When used for cancer detection, the radiometer simply detects the heat that a tumour generates at microwave frequencies, and uses this information to find the tumour.

The heat radiated by a tumour, and by healthy parts of the breast, carries information about temperatures. This allows a radiometer-based device to create a three-dimensional temperature map of the breast. Going inwards, as the temperature rises, one encounters a series of isothermal (equal temperature) contours centred around a hotspot – the cancerous mass. How well the device is able to locate a tumour depends on its ability to measure differences in temperature. The tumour’s size at this stage is roughly five to ten millimetres across – making it large enough to be resolved from surrounding tissue through the use of micrometre wavelengths.

The temperature of an object tells us how energetically its atoms and molecules are moving around. Every object which is at any temperature above absolute zero (at which atomic motion ceases) radiates some energy. The object might make up for what it loses this way by absorbing radiation that falls on it, in order to maintain a steady temperature. This is a fundamental consequence of the restlessness of the charged particles inside it; the energy of that motion is converted to the energy of the radiation emitted. The nature of the radiation emitted by such an object depends on its temperature. This is how astronomers estimate the temperatures of stars. In the spectrum of light received from a star, a particular frequency has the maximum representation in terms of energy. The higher this peak frequency, the higher the temperature of its source. So blue stars are hotter than red ones.

If, instead of receiving and analysing the entire spectrum, we were to build a device focusing on a select group of frequencies – e.g., the microwave region of the spectrum – then the amount of energy that such a device would get from the radiating object would be directly related to its temperature. Of course, this is an oversimplification and only roughly true; but it holds for low frequencies. Microwave is low enough in frequency for this to hold true, making it a reasonable choice for the narrow band of frequencies that one chooses to detect in the case of cancers.

Another factor that determines this choice is how deep the technique allows us to look. The tumour emits heat at all frequencies, but as these waves make their way to the antenna at the surface of the breast, their energy gets absorbed by layers of muscle, fat and glandular tissue. It is possible to form a picture of breast tissue by measuring infrared emissions as well, but this picture would go less than a centimetre deep. This is because infrared emission, having much higher-energy, would die out much faster with distance. Microwaves, on the other hand, can bring information from as deep as three to four centimetres into the breast. As Dr. Kavitha explains, decent resolution and very good penetration are what make the microwave frequency range a good choice for such applications.

Note, however, that while these waves reach us with more of their initial energy intact than that of infrared, this says nothing about how much of that energy was there to begin with. Vidyalakshmi MR, the research scholar who designed and built the device circuitry, gives me an idea of just how weak the signal that they’re trying to catch is. As I enter the lab with her, she sits down with a sheet of paper and proceeds to explain with extreme efficiency everything I can understand about how the device works, despite her dismay at my lack of knowledge of anything but the very basics of field theory. I watch in awe as she lists out all the mobile, bluetooth and WiFi signals that are always zipping across everywhere around us, and shows me, in the middle of that chaos of frequency bands, the tiny signal that their device works with. It’s a signal, she tells me, as weak as what one would receive on the Earth’s surface from a satellite in orbit. A good quality call on a mobile network would generally use a signal about a hundred thousand times stronger than that, and such mobile signals would most likely be abundantly available to interfere with the detection device, anywhere that it might be used.

The problem, then, is not only to sort out the frequencies but to detect and deal with such a weak signal in the first place. It is a signal in picowatts, a trillion times weaker than the milliwatt scale at which most power sensors operate. Measuring a broader range of frequencies, which would have increased the detected power, is made impossible by the flanking communication bands. What’s more, every measurement device has random internal variations, called noise, that are usually too small to make much difference to the signal but can distort it beyond recognition if the signal itself is equally small.

To be able to detect the power without adding any noise, while also making sure that it was a signal only from the cells and not from the environment, the lab had to meet the challenge of designing a very good front-end for the instrument. A front-end is a component of every communication system that directly takes the signal collected by the antenna, processes it and passes it on. The front-end normally starts with what is called a band pass filter, which passes on the required frequency and gets rid of the rest. Following this, the output from the filter is amplified so that later stages in the circuit can work with a better signal. So at first, Vidyalakshmi tried placing the filter and amplifiers in this configuration. It didn’t work; what the filter received from the antenna was too weak for it to work with. The front-end that she finally developed now has three stages of amplifiers to get the strength up to a decent level before it reaches the filtering stage. At the end of each stage, there are isolators that act like valves or one-way gates, so that nothing happening in any part of the circuit feeds back to the stage before it, to affect it.

I ask her if she was apprehensive about choosing such a weak signal in such a crowded zone of the spectrum. She is surprised by the question; she did not ever doubt that it could be done. The device is now ready, complete with casing. With a heated water bath and a thermometer, she has been testing it to see how well it can measure temperatures. So far, the results have been rewarding.

The tabletop radiometer, needless to say, is more portable than any X-ray system used for recording mammograms. It does not involve shielding, isotope handling, or specially built units, and is almost a hundred times cheaper to manufacture. It runs on two AA batteries.

Measured properties of PVAL solutions can be compared with known tissue behaviour. Courtesy: Dr. Arunachalam
Measured properties of PVAL solutions can be compared with known tissue behaviour. Courtesy: Dr. Arunachalam

Along with the practical applications of microwave radiometry for imaging come a whole host of complexities. Rachana S Akki, also a research scholar in Dr. Kavitha’s group, is working to identify and model the factors that affect the quality of the scan and develop protocols that will ensure its reliability. Some factors, she explains, are beyond our control – the size and depth of the tumour, for instance, and the balance of fat and glands in the breast tissue. Because the amounts of power normally emitted from different patients’ breasts are different, the device must be able to tell whether a change in the measurement is because of the presence of a cancer, or merely due to diversity in the composition of the breast tissue.

The elimination of subjectivity, I realise from my conversations with Rachana and Dr. Kavitha, is the ideal that medical imaging of all sorts constantly tries to attain. A scan that can be carried out any number of times, by different people with different skill levels, and still look the same, is a scan that can be trusted. An ultrasound probe, for instance, with all its constant movement, offers no hope of obtaining such a scan reproducibly, even when the person operating it is skilled. In both X-ray mammography and radiometry, the chances of such disturbances are reduced by keeping the device steady and compressing the breast between two plates. This compression is necessary with X-ray so that large volumes of tissue do not absorb too much radiation. It also gives a better quality scan, since the healthy tissue is compressed more easily, bringing the tumour closer to the surface. But X-ray mammograms are painful, with the breast being compressed to half its size. Rachana emphasises that the microwave radiometer, on the other hand, can work with much, much lower levels of compression; about a quarter or even a fifth.

To model the breast, Rachana prepared solutions of a chemical called polyvinyl alcohol (PVAL) in water, changing the amount she added each time, to get gels with different properties. After making a wide range of gels, she studied their stiffness and other mechanical properties. Combining available data about how fatty, glandular and mixed breast tissues behave under compression with the results of her experiments on these PVAL `phantoms’, she was able to deduce which PVAL solution would mimic which kind of tissue. This allowed her to design and control computer simulations of the breast, and to extract information, for instance, about the power emitted by hotspots in fatty or glandular breasts, when compressed to different extents. One way in which this is relevant is that a more glandular composition leads to more discomfort under compression, and this has to be taken into consideration while deciding on imaging procedures. These studies also gave Vidyalakshmi an estimate of the power levels that the front-end must be designed to take, as input.

Developing protocols for imaging by studying all these factors will someday allow the device to be made suitable for use in clinics in urban as well as rural areas where, unlike in the lab, the environment is not controlled. That is why it is important to carefully look into which factors influence the measurement, their relative significance, how much they may vary, and the corresponding effects of such variations on the results. Researchers can then optimise the parameters that can be controlled, to give reliable results while minimising cost, pain and discomfort. “If a defined protocol is there, then the person who is handling the device will have a checklist,” says Dr. Kavitha. “That will give us greater confidence that a hotspot detected is from the tissue, and not from the influencing environment.”

The microwave radiometer is intended to become an alternative screening tool, one that can avoid unnecessary exposure to ionising X-radiation during regular screenings. If a cancerous growth is suspected, however, X-ray mammography would still remain the golden standard. Apart from preliminary scans, the microwave radiometer could also be used for intermediate screenings to check a patient’s response to treatment – currently done using infrared thermograms – and for follow-ups that check for recurrence, which may currently tend to combine ultrasound and X-ray examinations. Looking into how microwave can be used along with these techniques could help increase the scan depth while reducing the risk of exposure to harmful radiation.

Applicator placement on a healthy volunteer during preclinical pilot study Courtesy: Dr. Arunachalam
Applicator placement on a healthy volunteer during preclinical pilot study. Courtesy: Dr. Arunachalam

It turned out that most of the pieces of equipment that I saw in Dr. Kavitha’s lab had been built in-house; these include, amongst other things, a large variety of antennae. The antenna that Rachana has made for the radiometer is a small circular, nearly flat one, like a stethoscope disc. An antenna can cover either a wide angle up to a short distance, or a long distance in a specific direction – and this applies to both microwave transmitting and microwave receiving antennae. In this case, the antenna needs to collect radiation from as large a region as possible, and the source of this radiation is not too far away. So a wide angle antenna is best to use. In other applications, directionality becomes important. For microwaves can be used to not only detect cancers but treat them as well, and in this effort – with the location of the tumour becoming known – an irradiating antenna must transmit in a very specific direction.

Another of the PhD students, Geetha Chakaravarthi, is working on one such application, and the lab shelves are dotted with antennae and other devices she has prepared to investigate the use of microwaves to kill cancerous cells. This technique, called hyperthermia, works by heating up cancerous cells by focussing microwave radiation upon them. Hyperthermia supplements chemotherapy and radiotherapy as well, by differing mechanisms.

Prototype of the microwave radiometer
Prototype of the microwave radiometer

Radiotherapy, where cancer cells are killed with X-rays, works better in those parts of a tissue which are rich in oxygen. Thus, tumour cells are more sensitive to radiotherapy if they are located near a major blood vessel. Microwave therapy, on the other hand, works better where the blood supply is poor, because the blood is not able to effectively transport away the extra heat. It can thus reach areas of the tumour where radiotherapy fails. Together, radiotherapy and hyperthermia can defeat the tumour more effectively.

As a supplement to chemotherapy, microwave hyperthermia acts by improving the delivery of the drug to tumour cells. In chemotherapy, the blood carries a drug to destroy the tumour, the idea being that the higher metabolic activity of the cancer cells will lead them to take up more of the drug than healthy cells do. Heating the tumour with microwaves effectively forces the body to raise circulation in the heated region in an effort to regulate its temperature, and more circulation means better drug delivery. It is crucial that the heating be highly localised, so that there is as little damage as possible to healthy cells.

While it is known that microwave therapy can improve radiotherapy and chemotherapy results, effective devices have not yet been developed for this. The ongoing effort in Dr. Kavitha’s lab is to develop patient-friendly devices well-suited to treating both large and small tumours with very site-specific application of therapeutic microwaves. The ‘patch applicator’ which Geetha has developed is the smallest one currently available and its gently-concave surface, unlike the rigid ones of most of its predecessors, allows it to rest comfortably on the patient’s skin.

To get microwave to the tumour, a transmitting antenna sends radiation through a water bag placed on the skin (without the water bag, the antenna would burn the skin). Computer simulations as well as clinical measurements done by the group have shown that it is very important to get rid of air bubbles in the water if the microwave is to reach deep tumours. But ‘degassing’ systems for getting bubble-free water are expensive, either incorporating specialised bubble traps or filters, or degassing the entire liquid before use. And since less power reaches the target cells if bubbles are present, any inefficiency in removing bubbles makes higher doses of radiation necessary to achieve the same effect.

Geetha’s work has led to a new degassing system that is much cheaper than existing ones. In this setup, a pump circulates water through pipes while an electronic feedback system maintains the volume and temperature of water in the applicator. Equipped with sensors, the degassing system uses its control over flow rates to remove bubbles with a vacuum chamber. Because it can degas a circulating fluid efficiently and economically without disrupting the ongoing process, this invention has the potential to revolutionise a number of other medical procedures – dialysis being one case in point.

A cost effective Inline degassing system Courtesy: Dr. Arunachalam
A cost effective Inline degassing system
Courtesy: Dr. Arunachalam

Both medical imaging and therapy, as far as cancer is concerned, are fields dominated today by toxic chemicals and high-energy radiation. Technologies in both fields are far from ideal, but the goals are clear. Imaging needs to be as non-invasive as possible, with higher and higher degrees of accuracy. Therapy needs to be as specific as possible, with little or no effect on healthy parts of the patient’s body. In the battle against cells that can look just like their healthy sisters, and invite widespread destruction with every effort to kill them – but which cannot conceal their own heat footprint – there is little doubt that the future will see enormous contributions from microwave research.

 


 

KavithaDr. Kavitha Arunachalam is an Assistant Professor in the Department of Engineering Design at IIT Madras. She works on microwave antenna design, non-destructive testing of materials, and development of instrumentation for biomedical applications. Dr. Arunachalam obtained her B.E. in Electronics and Communication Engineering from the College of Engineering, Guindy, Anna University, and her PhD from the non-destructive evaluation laboratory at Michigan State University. Following postdoctoral research at the hyperthermia research laboratory, Duke University Medical Centre, she joined IIT Madras in 2010.


 

ShivaniShivani Guptasarma grew up in Chandigarh, where she attended school at the Sacred Heart Senior Secondary School for girls and developed interests in all areas that are currently classified under the STEM subjects. She joined IITM in 2014 for a B.Tech. in Engineering Design and an M.Tech. in Biomedical Design. She is excited about her courses because they allow her to continue to study biology, maths, electrical and mechanical engineering, with prospects of someday developing insights and tools to help human beings.

 


Cover image : Image of breast cancer cells, via Wikimedia Commons

Shivani Guptasarma

Shivani is in the third year of a B.Tech. in Engineering Design and an M.Tech in Biomedical Design. She is excited about her courses because they allow her to study maths, biology, design, electrical and mechanical engineering with prospects of someday developing tools and insights to help human beings.