Reassessing whether low energy electromagnetic fields can have clinically relevant biological effects
It is with some trepidation that I write this, given that I realize this post might lead to charges that I’ve allowed myself to become so open-minded that my brains fell out, but I think the issues raised by what I’m about to discuss will make our readers think a bit—and perhaps spark some conversation. Because I’m in a bit of a contrarian mood, I’ll take that risk, although it’s possible I might end up with the proverbial egg on my face. As our regular readers know, the issue of the health effects of radiation from mobile phones has been a frequent topic of this blog. The reasons are obvious because fear mongering claims not based in science are frequently made in the lay press and in books (for example, Disconnect by Devra Davis) and, unfortunately, also by some physicians and scientists. Moreover, like homeopathy, the issue demands a discussion of prior probability and plausibility based on basic science alone, but the issues are a bit less clear-cut. Whereas the tenets of homeopathy clearly violate multiple laws of physics and chemistry, it is possible, albeit very unlikely, that radio waves might produce significant biological changes.
There’s also sometimes a maddening dogmatism on the part of some physicists that it’s “impossible” that long term exposure to radio waves could possibly cause cancer because such electromagnetic waves do not have anywhere near enough energy to cause ionization and thereby break chemical bonds. While it is certainly true that such radio waves can’t break chemical bonds and the likelihood that the radio waves from cell phones can cause cancer appears very low based solely on physics considerations, all too often the arguments made based on physics considerations alone use a simplistic understanding of cancer and carcinogenesis as their basis. It’s not for nothing that I have referred to such arguments as being based on a high school or freshman level of understanding about cancer—or just an outmoded understanding that prevailed a decade or two ago but today no longer does. Bernard Leikind, for instance, argued and famed skeptic Michael Shermer accepted that, because the radio waves used in cellular communications are too low energy to break chemical bonds and do not produce significant heating compared to other sources, “cell phones cannot damage living tissue or cause cancer.” Note the implicit assumption: That it is somehow necessary to “damage” living tissue in order to cause cancer. That’s an assumption that is arguably quite simplistic and ignores knowledge we’ve gained about epigenetics and how potential metabolic influences might cause cancer. Cancer is associated with characteristic cellular metabolic abnormalities, and determining which is responsible for the formation of cancer, metabolic abnormalities or gene mutations, has become a “chicken or the egg”-type of question.
I do not in any way believe that cell phone radiation actually is a cause of cancer because, unlike the case in homeopathy, where multiple well-established laws of physics would have to be overturned for homeopathy to work, I find the argument that a causation is “utterly impossible” far less persuasive than some physicists do when it comes to cell phone radiation and cancer. Even dismissing the “impossibility” argument, however, clearly such a link is at the very least incredibly implausible on physics considerations alone, as I have pointed out time and time again. Add to that the nearly completely negative epidemiological data in which only one group of researchers has been able to produce apparently “positive” studies, and my personal conclusion is that we probably already have enough data to reject a connection between radio waves and cancer and don’t need any more new large epidemiological studies; following up long term results on the ones already under way should be sufficient. That is not the same thing as arguing that radio waves have no significant biological effect, which is what, in essence, the argument from physics is based on. In fact, the inspiration for the rest of this post came from a meeting I had last week with a scientist and that scientist’s talk for our cancer center’s weekly Grand Rounds. What I learned did not demonstrate that cell phones cause cancer or even that they might cause cancer. Not even this scientist claimed his results were consistent with cell phone radiation causing cancer; in fact, he quite clearly stated they were not. However, what I learned from him cast some doubt (to me, at least) on the assumption that radio waves cannot have profound biological effects. In fact, ironically enough, this scientist is proposing the use of amplitude-modulated (AM) radio waves to treat cancer. I’m not yet convinced by any stretch of the imagination that this researcher is on to something, but his findings made me think about the perils and pitfalls of declaring something “impossible” solely on basic science considerations, because he has some very intriguing results that I can’t find a compelling reason to dismiss.
And, at least as of now, there’s no known physical mechanism that can explain his findings. Leaving aside the possibility of fraud or some sort of systematic bias that is not apparent in the methods sections of the papers I’m about to summarize, either he’s found something new and potentially promising, or he’s somehow very, very wrong.
Boris Pasche and low energy EMF as a treatment for cancer
A couple of weeks ago, a reader sent me a link to a story in The Guardian entitled Hopes rise for new cancer treatment after tests with electromagnetism. It described the use of low energy electromagnetic fields to treat cancer:
Scientists have used low-intensity electromagnetic fields to treat cancer patients in trials which they say could lead to the development of a new type of anti-tumour therapy.
Patients hold a spoon-shaped antenna in their mouths to deliver a very low-intensity electromagnetic field in their bodies. In trials of patients with advanced liver cancer, the therapy – given three times a day – resulted in long-term survival for a small number of those monitored, the team has reported in the British Journal of Cancer. Their tumours shrank, while healthy cells in surrounding tissue were unaffected.
However, the scientists – from the US, Brazil, France and Switzerland – also stressed that the technique was still in its infancy and would require several years for further trials to take place. “This is a truly novel technique,” said the team’s leader, Professor Boris Pasche of the University of Alabama, Birmingham. “It is innocuous, can be tolerated for long periods of time, and could be used in combination with other therapies.”
I responded that I was unfamiliar with this treatment modality. Consequently, I didn’t know what to think (although at the time I thought it sounded very fishy, like Royal Rife or radionics quackery, even) but replied that maybe I would look into it. As is so often the case, given my work from my day job and all the blogging that I do, I didn’t get around to it right away. Little did I realize that a mere two weeks later I would be meeting Dr. Pasche, who came to visit my institution last week, and that he would be speaking about these very results. I must admit, I was intrigued, particularly after reading this editorial in the British Journal of Cancer by Carl F. Blackman entitled Treating cancer with amplitude-modulated electromagnetic fields: a potential paradigm shift, again? that appeared the day before Dr. Pasche’s talk.
Basically, Dr. Pasche and his collaborators have developed a machine that administers very low level electromagnetic fields, modulating their amplitude at frequencies that appear to be specific for various cancers. The energy of these EMFs is considerably lower than that of even the radio waves used for cell phone communications—according to Dr. Pasche, between 100 and 1,000 times lower. I must also admit, the machine is actually rather funny-looking. In fact, I couldn’t help but get the uncomfortable image of a Scientology E-meter in my head when Dr. Pasche showed the audience one of his machines, and it didn’t help that the EMF was administered by having the patient hold a spoon-like device in his mouth for up to three hours at a time in order to receive the treatments at home. So odd is the device that I can’t resist providing you with a photo from one of the papers:
As you can see, the device does look rather low tech, but it’s designed to administer EMF through the buccal mucosa in the mouth. Beginning with a clinical trial in 2009 (Barbault et al) that built upon previous work that used similar electromagnetic frequencies as a treatment for insomnia that produced both subjective and objective measures of improvement, Pasche’s team used EMF with the following characteristics:
- Carrier output: 100 mW
- Carrier frequency: 27.12 MHz
- Amplitude modulation (sine wave) with at least one or several of the following frequencies: 1873.447 Hz, 2221.323 Hz, 3669.513 Hz, 4486.384 Hz, 5882.292 Hz, 6350.333 Hz, 8452.119 Hz, and 10456.383 Hz
Treating various cancers using tumor-specific AM frequencies produced the following results in a patient series in which compassionate use of this therapy was administered to 28 patients with advanced cancer who had limited therapeutic options. The results of the clinical trial were intriguing, but not incredibly impressive, as only thirteen of these patients were evaluable for response, with these observations:
One patient with hormone-refractory breast cancer metastatic to the adrenal gland and bones had a complete response lasting 11 months. One patient with hormone-refractory breast cancer metastatic to liver and bones had a partial response lasting 13.5 months. Four patients had stable disease lasting for +34.1 months (thyroid cancer metastatic to lung), 5.1 months (non-small cell lung cancer), 4.1 months (pancreatic cancer metastatic to liver) and 4.0 months (leiomyosarcoma metastatic to liver).
The interesting result from this paper, which was clearly preliminary, was that specific amplitude-modulated frequencies appeared to be quite specific for specific tumors. One of the most striking demonstrations of this was a patient with metastatic breast cancer whose breast metastases shrank. However, she also had a uterine tumor that grew while she was undergoing this therapy, which Dr. Pasche’s group dubbed Low Energy Emission Therapy (LEET). What was also very difficult for me to believe was how Pasche discovered and identified these tumor-specific frequencies. Basically, he used variations in the amplitude of the radial pulse as a biofeedback method whose presence during scanning indicated a response, as described:
Patients are lying on their back and are exposed to modulation frequencies generated by a frequency synthesizer as described below. Variations in the amplitude of the radial pulse were used as the primary method for frequency detection. They were defined as an increase in the amplitude of the pulse for one or more beats during scanning of frequencies from 0.1 to 114,000 Hz using increments of 100 Hz. Whenever a change in the amplitude of the pulse is observed, scanning is repeated using increasingly smaller steps, down to 10-3 Hz. Frequencies eliciting the best biofeedback responses, defined by the magnitude of increased amplitude and/or the number of beats with increased amplitude, were selected as tumor-specific frequencies.
With the following results:
A total of 1524 frequencies ranging from 0.1 to 114 kHz were identified during a total of 467 frequency detection sessions (Table 1). The number of frequencies identified in each tumor type ranges from two for thymoma to 278 for ovarian cancer. Overall, 1183 (77.6%) of these frequencies were tumor-specific, i.e. they were only identified in patients with the same tumor type. The proportion of tumor-specific frequencies ranged from 56.7% for neuroendocrine tumors to 91.7% for renal cell cancer. A total of 341 (22.4%) frequencies were common to at least two different tumor types.
A single study like this, of course, is not evidence of much of anything. For one thing, it’s a small study. For another thing, there’s no control group. Also, an alternate explanation for the patient whose breast cancer metastases regressed while her uterine cancer grew is that the uterine cancer might have produced something that suppressed the growth of breast cancer. (Angiostatin, perhaps?) Most glaringly, the method by which the tumor-specific frequencies were identified is highly implausible on many levels. Leaving aside the method by which these “tumor-specific” frequencies were identified, however, the result was nonetheless intriguing, because, as the authors pointed out, the objective responses observed in this study due to tumor-specific AM frequencies are evidence that this treatment might actually have efficacy. Certainly it’s safe (after all, it’s even lower energy than cell phone radiation and there were no reported side effects that were attributable to the therapy). And a follow-up study is what Pasche’s group did, in the form of a phase I/II study published in the British Journal of Cancer in 2011 (Costa et al).
Costa et al concentrated on advanced hepatocellular cancer (HCC). Patients were eligible if they had advanced HCC, were not eligible for surgical resection, or had disease progression after locoregional therapies and/or chemotherapy. To summarize the other inclusion criteria, basically, the subjects had to have reasonable liver function and couldn’t have been on chemotherapy for four weeks before entering the trial. They also couldn’t have brain metastases or have had a liver transplant. Treatments were administered three times a day using tumor-specific AM frequencies until their disease progressed or they died. Out of 267 patients assessed for eligibility, 43 were deemed eligible, and 41 underwent the therapy. In actuality, the results of this study, although they don’t sound impressive, were actually somewhat promising, as oncologists familiar with the usual results of phase I trials would recognize. Median progression-free survival was 4.4 months and median overall survival was 6.7 months, while 14 patients had stable disease for more than 6 months. More importantly, there were three partial responses and one near-complete response, a result that would be considered quite good in a phase I trial of a monotherapy with a new chemotherapeutic agent.
Still, although the results of this phase I/II trial were unlikely to be due to chance or other factors given that complete and near complete responses were observed, it certainly wasn’t anywhere near impossible that selection bias or random chance alone might have produced results like this, which are promising, but very preliminary. So Pasche’s group carried out another study, which was published in the British Journal of Cancer just recently (Zimmerman et al). This is the first study where Pasche starts to do some real science on this in the laboratory. He concentrated primarily on HCC and breast cancer, because those were the cancers in which he had observed a clinical response. Basically, Zimmerman et al was an attempt to start to figure out the biology, if any, of the effects observed in the previous two clinical trials. In order to test the effects of tumor-specific LEET, Pasche’s group designed a special incubator that can administer carefully controlled LEET at various AM frequencies and, according to Dr. Pasche during his talk, can do it in a blinded fashion, switching between the different chambers as needed. The design is illustrated in this figure from the paper below:
Basically, this was a very simple study, at least in design. Its findings are fairly easily summarized:
The growth of HCC and breast cancer cells was significantly decreased by HCC-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of HCC cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, HCC-specific modulation frequencies disrupted the mitotic spindle.
The effects, however, were quite modest, as this figure shows:
As you can see, growth inhibition of the various tumor cell lines is never greater than 50%, and most of the time it’s between 10% and 25%. This is not particularly impressive for cell culture experiments in cancer, but it appears to be real. Moreover, it has the required characteristics that suggest a real biological effect rather than nonspecific toxicity. First, the LEET only had an effect on malignant cells but not not on nonmalignant cells of the same tissue type. That indicates specificity, as does the observation that HCC-specific frequencies don’t affect breast cancer cells and breast cancer cell-specific frequencies don’t affect HCC. Second, there is an increasing response with increasing dose. In addition, there is a common biological effect observed, specifically mitotic spindle disruption. Finally, using RNAseq, a technique designed to look at all the messenger RNAs expressed in a cell, including noncoding RNAs, Pasche’s group found certain genes downregulated. In his talk, Dr. Pasche also pointed out that he has unpublished results that show that his treatment appears to be working against tumor xenografts in mouse models. For those unfamiliar with what a xenograft is, it’s human cells implanted in immunodeficient mice.
In brief, the combined evidence suggests that there might actually be something going on here, as implausible as it sounds. It’s preliminary and inconclusive, but it can’t be ignored. (At least, I can’t ignore it.) I’ve looked for holes in the studies (particularly the 2011 and 2012 studies), and I can’t find them. Barring a revelation of fraud, which I seriously doubt, the evidence appears to be generally decent quality. Preliminary and unconfirmed by other groups, but, as far as I can tell, of decent quality.
On the perils of concluding “impossibility”
I admit it. I wrote this post because I was in a bit of a contrarian mood, so much so that I was willing to risk taking a bit of flak. (Besides, what fun is blogging if you can’t explore ideas outside of your comfort zone that might provoke a bit of controversy?) More importantly, I wrote it because Dr. Pasche’s results challenged my preconceived notions. The conclusion that cell phone radiation cannot cause cancer is predicated on a combination of the scientifically sound observation that the energy is just too low to do anything more than inconsequential tissue heating and the simplistic idea that, biologically, carcinogenesis requires the breakage of chemical bonds. Dr. Pasche’s results do not demonstrate that it is plausible that cell phone radiation can cause cancer. In fact, he himself pointed that out when I met with him. However, Dr. Pasche’s results also suggest the perils of concluding on strictly physics-based analyses that an effect is “impossible.”
What do I mean?
If it is impossible on a strictly physics-based analysis that cell phone radiation can cause cancer, then exactly the same argument can be made that Dr. Pasche’s results should similarly be impossible. After all, if the radio waves used by cell phones are too low energy to have a significant biological effect, then the LEET used by Dr. Pasche, which is 100-1000 times lower in energy than cell phone radiation, should have even less chance of having a significant biological effects. Yet it appears to have measurable and significant effects, certainly in cell culture at least. True, it is only specific AM frequencies that appear to have a biological effect, but if we were to use the very same argument that Bernard Leikind makes to dismiss the possibility of a link between cell phones and cancer, then what Dr. Pasche has found in his research should be equally impossible. No, more than equally. Remember, the energy levels of the radio waves he uses are considerably lower than cell phone radiation. If anything, they should be less likely to have a biological effect, even taking into account the use of “tumor-specific” amplitude modulated frequencies. After all, whatever the amplitude modulation, it’s still the same energy level.
Yet, Dr. Pasche shows an effect. It’s half tempting to say, “Eppur si muove,” except that I’m not entirely sure, based on Dr. Pasche’s rather preliminary results, that it does indeed move, so to speak. Again, it could turn out that there’s some sort of systematic bias in the methods that isn’t apparent in the papers. As Richard Feynman once said, “The first principle is that you must not fool yourself—and you are the easiest person to fool.” It could well be that Dr. Pasche is fooling himself. Even so, I am still sure that, with very few exceptions, saying something like this is evidence of a bit too much certainty, at least in biology:
I argue strongly that there is no possible mechanism, known or unknown, by which cell phone radiation might cause cancer.
Saying that there is no possible mechanism, even a mechanism that is as yet unknown, is going too far, at least when it’s coupled to a poor understanding of cancer. Now compare the statement above to Dr. Novella’s more nuanced appraisal:
While electromagnetic radiation from cell phones is a physical mechanism that can potentially have an effect, it is generally too weak to have any plausible biological effect. This by itself is very reassuring, but still cannot rule out a possible effect from cell phones through some as yet undiscovered biological effect of cell phone radiation.
This is the more reasonable approach, to point out the extreme implausibility, but leave the door open to new evidence, which is what I’m trying to do in discussing Dr. Pasche’s work. After all, it is not always easy to determine what is and is not plausible in medicine based on basic science considerations alone. Homeopathy is an extreme example where it is possible to do so, largely because we understand the science involved much better than we understand the science involved in cancer biology and the interaction between electromagnetic radiation and living organisms. In any case, you believe some physicists, it might seem that the cell phone/cancer link should fall into the same category as homeopathy in terms of plausibility. Who knows? Maybe it does. However, as incredibly implausible as even I consider such a link, I can’t quite conclude yet that it does fall into that category of physical impossibility. Yes, it’s possible—likely, even—that Dr. Pasche could be completely wrong and that I’m far too impressed with his preliminary work and charismatic personality. Clearly, Dr. Pasche’s work needs replication by other groups, something that appears not to have happened yet. On the other hand, unless there’s a huge hole in Dr. Pasche’s methodology that I missed, particularly in the 2012 paper, which was the most convincing to me, I’m having a hard time dismissing his results that easily. Maybe someone can show me where I’m wrong, which, while possibly embarrassing to me, would contribute to my education and development as a skeptic. Or we could just wait and see what follows from the labs of Dr. Pasche and others. If we don’t see some followup xenograft studies within a couple of years, it’s a good bet that Dr. Pasche reached a dead end because his current implausible results either couldn’t be replicated or turned out to be, as many expect, wrong. Even if that happens, based on his cell culture studies alone, I consider Dr. Pasche justified in following his results to see where they lead.
- Zimmerman JW, MJ Pennison, I Brezovich, N Yi, CT Yang, R Ramaker, D Absher, RM Myers, N Kuster, FP Costa, A Barbault, and B Pasche (2012). Cancer cell proliferation is inhibited by specific modulation frequencies. Br J Cancer 106: 307-313. DOI: 10.1038/bjc.2011.523.
- Blackman CF (2012). Treating cancer with amplitude-modulated electromagnetic fields: a potential paradigm shift, again? Br J Cancer 106: 241-242. DOI: 10.1038/bjc.2011.576.
- Costa FP, AC de Oliveira, R Meirelles, MC Machado, T Zanesco, R Surjan, MC Chammas, M de Souza Rocha, D Morgan, A Cantor, J Zimmerman, I Brezovich, N Kuster, A Barbault, and B Pasche (2011). Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields. Br J Cancer 105: 640-648. DOI: 10.1038/bjc.2011.292.
- Barbault A, FP Costa, B Bottger, RF Munden, F Bomholt, N Kuster, and B Pasche (2009). Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach. J Exp Clin Cancer Res 28: 51. DOI: 10.1186/1756-9966-28-51.