Fukushima Radiophobia Revisited

In his op-ed contribution to The New York Times with the title "Fear vs. Radiation: The Mismatch" published Oct. 21, 2013, Harvard lecturer David Ropeik weighs the potential threats posed by the Fukushima nuclear reactor disaster to public health in Japan and the ramifications for radiological emergency planning. His arguments may be misused to broadly label people with legitimate fears after a radiological incident as suffering from irrational fears of radiation.

The Fukushima Daiichi Nuclear Power Station is located on the east coast of Honshu about 120 miles north of Tokyo. In the wake of the Tōhoku Earthquake and Tsunami, Mar. 11, 2011, three of the station’s six reactors lost cooling and incurred fuel meltdowns. Powerful hydrogen explosions led to vast releases of hazardous radioactive material, rivaled only by the 1986 Chernobyl reactor accident in the Ukraine. More than 100,000 people were evacuated. Despite decontamination efforts, radiation doses in parts of the government-imposed exclusion zone around the stricken station are still considered unsafe for habitation. Roughly 70,000 former residents are not allowed to return home permanently.

On a day visit back home in the exclusion zone, 2013 (source: Die Welt).

No particular cancer can be causally linked to ionizing radiation. Statistical correlations between cancer rates and exposure must be used to provide probabilistic estimates for the radiation impact. Ropeik cites research on Hiroshima and Nagasaki atomic bomb survivors showing that within 6 miles off ground zero only 1 in 20 cancer deaths might be attributable to radiation. Furthermore, he notes that after the Chernobyl disaster “an exaggerated sense of the dangers to health of exposure to radiation”, known as radiophobia, exceeded recognized radiation-related illnesses. The author concludes that in present-day Japan radiophobia may pose a greater health threat to the public than the actual exposure to ionizing radiation emitted from the stricken Fukushima power station.

How realistic such inferences are remains to be seen. The situation in the former Soviet Union, also known as USSR, was distinctly different from Japan’s. The USSR had kept accidents in its nuclear effort secret. The protagonists of nuclear power had proclaimed the Socialist graphite-moderated RBMK reactors absolutely fail safe and superior to US reactors, particularly after one suffered a partial fuel meltdown at Three Mile Island in 1979.

We had passionate debates at my West German alma mater over the risks RBMKs might pose. The Communists were incessantly spinning how wonderfully accident-proof the design was. The reactors had to be safe, because they were designed by Socialist engineers who were not driven by profit thinking. The design was deemed so safe, they insisted, that the reactors did not need the protective containments Capitalist reactors in the West required. We remained unconvinced.

By contrast, citizens in the USSR more readily embraced the achievements of megalomanic Soviet technology. The horrible accident at Chernobyl would erode this trust deeply, particularly because the Soviet leadership did not acknowledge that it happened for several days. Confidence in the Soviet Union had been on the decline for some time. The inner resolve of the USSR was unraveling in face of the grinding war in Afghanistan. Loss of confidence in the authorities and lack of information may have exacerbated radiophobia around Chernobyl. Culture and political circumstance were unique. The Chernobyl experience may not be easily extrapolated to radiological disasters in other countries.

Moreover, irrational fears may be inseparable from rational fears of an uncertain future that the continuing emergency holds. Fukushima evacuees must worry about jobs, homes, farms, and fisheries. In a small country with a high population density like Japan starting over elsewhere is not trivial. Livelihoods are ruined. Parents fear for the health of their children.

In response to the crisis, Fukushima Prefecture invited families to enroll the children in periodic medical checkups. Enrollees have presented with thyroid nodules, that is abnormal growths with cancer potential. The authorities have not disclosed outcome in detail. The program remains opaque to patients and public alike. Assurances not to worry because the odds of developing cancer caused by the radiation are minuscule must seem callous and irrelevant to the parents.

So far, no one in Fukushima is known to have died acutely of high radiation doses. Tokyo Electric Power Company, the operator of the stricken power station, has reported only one suspicious case of a cleanup worker who suddenly perished of leukemia. Some types of leukemia can be radiation-induced.

By contrast, a greater concern for public health in Fukushima poses chronic exposure to low doses of radiation externally and, through incorporation, internally. The variability of the effects of such exposure is high, the predictability of outcome low, and variations in circumstance hamper comparisons with other radiological incidents.

For example, the atomic bombs unleashed radioactive fallout in a single blast, whereas the stricken Fukushima power station has continued to emanate radioactive material into air and sea since the accident two and a half years ago. The public health risks associated with the ongoing contamination in Fukushima may thus not be estimable using atomic bomb data.

In addition to the known health effects of the exposure to ionizing radiation, hitherto unrecognized effects may yet be discovered. For example, domestic animals left behind in Fukushima's exclusion zone have presented with infectious diseases at alarming rate, suggesting a weakened immune response. Comparisons with unexposed feral animals are needed to test this hypothesis.

The temporal signature of radioactive emissions from the stricken power station may be more compatible with that of Chernobyl, where thyroid cancers began to increase in children three years after the accident (see my post with the title "Fukushima Radiophobia & The Mind" published Feb. 22, 2013). It is too early to predict at this time how Fukushima children will fare.

Ropeik concludes his op-ed with the idea that sheltering in place may protect public health more effectively in a radiological emergency than evacuation. MIT professor Jacquelyn Yanch suggested the same in a recent interview about her latest findings with MITnews (see my post with the title "Science, Media & The Mind" published Apr. 28, 2013).

However, sheltering in place may deliver only limited reprieve. Fukushima’s most immediate health threat emerged from early fallout of radioactive gases and dust. Gases permeate human dwellings. Dust penetrates cracks in walls, windows and doors. Residents in the plume’s path must evacuate as soon as permissible, using accurate and timely fallout forecasts. Ropeik’s proposal to change existing US regulation must be regarded with utmost skepticism.

According to TEPCO accident reports, no evidence could be found to date suggesting that ground shaking severely damaged the Fukushima reactors. Rather, the reactors incurred fuel meltdowns because power distribution panels and emergency diesel generators were flooded, disabling emergency core cooling systems.

About two dozen nuclear reactors of the Fukushima type are currently operating in the US. A number are sited in flood-prone areas. Oyster Creek Nuclear Generating Station in Forked River, New Jersey, 50 miles from downtown New York City and Philadelphia, resembles most closely in design and age Fukushima Daiichi Unit 1. Engineered by General Electric and completed in 1971, Unit 1 was the first commercial nuclear power reactor of this type in Japan and the first to melt down, taking less than a day.

A similar accident could be equally catastrophic in the U.S. The most recent large-scale industrial disaster in this country was the 2010 Deep Water Horizon oil spill in the Gulf of Mexico. British Petroleum had to set aside 42 billion dollars for mitigation and compensation, and that amount needn’t cover losses and damages from permanent evacuations. According to Shigeru Sato, Tsuyoshi Inajima, Monami Yui and Emi Urabe's report with the title "Japan Mulls Plan for One Operator to Run All Reactors: Energy" published online by Bloomberg Oct. 22, 2013, the total cost of the Fukushima reactor disaster is currently estimated at 112 billion dollars, roughly equaling two Hurricane Sandies.

People touched by radiological disasters like Fukushima manifest legitimate, existential fears with little resemblance to radiophobia. These fears will not be dispelled merely because experts claim that the radiation doses are “relatively harmless” and Japanese officials fault “false rumor.” The Prime Minister of Japan’s demonstrative sampling of local foods on His Exellency’s recent visit to the region won’t help either. Only thorough radiation monitoring, health care, and effective cleanup will make a difference. Make no mistake, Fukushima fears aren’t all in the mind.

Related Post

• Fukushima Radiophobia & The Mind
• Science, Media & The Mind

Acknowledgement
The information used in this post was provided by simpyinfo.org.

Science & Fortuity

The historical account below is published with the author's permission. I annotated two typographical errors. The document is best read with fullscreen view. The reader may find this option at the right-hand corner of the task bar at the bottom of the text window or may open a new window, using this link. 

The lecture revisits the development of the fluorodeoxyglucose method for the imaging of the brain's metabolic activity. The author, whose contribution was instrumental in the endeavor, presented the lecture via video at Brookhaven National Laboratory (BNL) Oct. 19, 2012. The occasion was a symposium convened to celebrate the designation of BNL's chemistry department by the American Chemical Society as a historical site in recognition of its pivotal role in the adaptation of the method to the non-invasive use in humans.

The history of the fluorodeoxyglucose method represents a striking example for the value of basic research. It demonstrates that the translation of discoveries from bench to bedside involves unrelenting dedication and, at times, serendipity. Furthermore, this example shows that the process may require decades of continued funding, before the investment eventually comes to fruition. None of the investigators who embarked on this endeavor in the 1940s fathomed that their efforts would lead one day to the most widely used diagnostic tool for the staging of cancer anywhere in the body.

Lou Sokoloff BNL FDG Symp Lecture 2012

The Human Genome: A False Promise?

Genomic medicine, also known as personalized medicine, has become a universal buzz word, perhaps to attract more dollars to biomedical research. Only two months ago the new Director of the National Institutes of Health and former Director of the National Human Genome Research Institute Francis Collins announced the age of personalized medicine in the national media. In short, the sequencing of a person's genome will become less costly and available to everyone in the near future. Based on our genetic makeup, doctors will be able to treat prospective illnesses before they have a chance to afflict us. This country's biomedical research establishment invested billions of dollars in this idea.

Then, three weeks ago the new Director of the National Cancer Institute, scientific adviser to the president, and former Director of the National Institutes of Health Harold Varmus stated in the news that human genomic research is only useful to science at present. Nicholas Wade's article entitled "A Decade Later, Genetic Map Yields Few New Cures" and Andrew Pollack's article entitled "Awaiting the Genome Payoff" were published in The New York Times on Jun. 12 and 14, 2010, respectively, in the wake of what must seem like an about-face at the highest level of leadership in U.S. biomedical research. In both articles, the short-term prospects of personalized medicine seemed less certain.

Alas, understanding the human genome in health and disease is doubtlessly spawning important progress on numerous fronts in medicine. The discovery of modified genes in cancer cells and the proteins they encode is being used to develop novel chemotherapies. In particular, drugs for targeted therapies are currently being tested that may counteract the averse effects of modifications in genes KRAS and BRAF in a variety of cancers. In yet another advance, we may be able to adapt our diet to our personal genetic makeup with a better promise of controlling our weight, diminishing our risk for cardiovascular disease.

By contrast, uncovering the genetic bases of mental disorders like autism and schizophrenia has proved difficult. The findings to date suggest that such disorders are the result of highly complex interactions of a multitude of molecular signaling pathways involving many genes. Whether genomic research can benefit therapies to treat such mental disorders remains to be seen.

Addenda

• Recent studies uncovered a mutation of the gene ALK in tumor tissue of people with non-small cell lung cancer. ALK encodes the enzyme anaplastic lymphoma receptor tyrosine kinase. The fusion of this gene with the gene EML4 renders a tyrosine kinase persistently active that prevents programmed cell death from curtailing neoplastic growth.  Aaron Saenz describes a potential drug treatment using this important finding in his post entitled "Crizotinib Targets Gene To Stop Lung Cancer Tumors in 90% of Treated Patients" on Singularity Hub dated Jun. 9, 2010. No doubt, the development of drugs specifically targeting such cellular malfunction is highly desirable. However, less than four percent of lung cancer patients carry the EML4-ALK fusion, and the drugs tested to date only slow the progress of the disease. Personalized medicine definitely needs more research, time and money to come to fruition (08/05/10).
• Peter J. Boyer wrote an informative essay with the title "The Covenant" about Francis Collins and his goals as the new Director of the National Institutes of Health. The essay was published online Sep. 6, 2010, in The New Yorker (09/10/10).
• Because targeted therapies are expensive and may produce varying results, we may be confronted with difficult choices. This conversation between Paul Raeburn and Leonard Fleck entitled "Looking at the Ethics of Personalized Medicine" broadcast yesterday on NPR's Science Friday informs us about the dilemma inherent in this issue (09/25/10).
• Julie Steenhuysen's report with the title "Gene tests inadvertently exposing cases of incest" posted yesterday on Reuters provides a striking example for personalized medicine's potential of uncovering information that raises ethical questions (02/11/11).
• According to Sharon Begley's article on Reuters with the title "DNA pioneer James Watson takes aim at 'cancer establishments'" published online today, the co-discoverer of the molecular structure of DNA, Nobel-laureate, and eminent proponent for the human genome project J.D. Watson now believes that our greatest hope for fighting cancer is the use of antioxidants. That is, boosting antioxidants may help prevent cancer and blocking their actions in tumor cells may help with a cure. His voice lends credence to those who cautioned against excessive expectations in the promise of personalized genomic cancer medicine (01/09/2013).

Related Posts

• Academic Institutions & Profitability
• Schrödinger's Cat: Probability, Science & Medicine
• Reduced Calorie Diet & Body Mass Index
• Autism & Genes, Revisited

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Schrödinger's Cat: Probability, Science & Medicine

Prologue
Atoms with unstable nuclei decay, emitting ionizing radiation, known as radioactivity. We cannot feel ionizing radiation. Small amounts can be detected with devices such as the fabled Geiger-Müller counter. Radioactive atoms are called radionuclides. Numerous radionuclides have been found. They are listed in the table of nuclides. With most types of radioactive decay, the nucleus transforms into another element with new physical and chemical properties. Since we cannot predict when precisely a radionuclide decays, we are left with probabilistic assessments. According to the law of radioactivity (1), the nuclei decay exponentially. The period of time in which half of the nuclei in a sample decay is constant and characteristic for the radionuclide. This period is known as half-life.

(1) N(t_exam) = N(t₀) x 2^-t_exam/τ,

where N(t_exam) is the number of radionuclides left at time of examination t_exam. N(t₀) is the number of radionuclides at time t₀ when we started our test. τ is the half-life.

After ten half-lives, the chance of finding a nucleus still undecayed has become fleetingly small. Only about one in a thousand nuclei is still left in its original form. We may consider the material decayed. However, when half-lives measure tens of thousands of years and the radiation is detrimental to our health, ten half-lives add up to a serious threat for generations to come. That is why the proponents of nuclear power show intense interest in Yucca Mountain.

Applying the law of radioactivity on just one atomic nucleus, our odds of finding this nucleus decayed after one half-live are 1/2 or 50%. That is, we are equally likely to find the nucleus decayed or in its original form. After seven half-lives, the odds to still detect the original nucleus are less than 1/100. We would call this find a rare event. After ten half-lives the odds diminish to roughly 1/1000. We would find the atom undecayed merely once in a thousand tests and perceive this observation as extremely extraordinary. Try it yourself:

half-lives:

odds: 1/

Schrödinger's Thought Experiment

The Austrian physicist and Nobel Prize-laureate Erwin Schrödinger always insisted that his was only a thought experiment. He never contemplated carrying it out in practice. Its design was the following:

Method: A Geiger-Müller counter is set up in front of a radionuclide. The radiation emitted when the radionuclide decays produces a voltage spike in the counter. The spike is used to trigger a hammer installed inside an opaque box, housing a cat. The hammer will smash a vial with poison gas, killing the cat.

Question: Is the cat already dead or still alive once one half-life has passed?

Answer: According to the law of radioactivity discussed above, the chances of finding the cat in either condition are equal. We will only know for sure, when we open the box and look.

Discussion: With this experiment, Schrödinger intended to explain the implications of the wave function, he derived to determine the energetic state of electrons in the shells around the atomic nucleus. In analogy to the solutions for his function, the cat could theoretically exist in both possible states alike. That is, the cat could be dead and alive simultaneously, until checking the box resolves the ambivalence.

Schrödinger's contention, though accurate, is difficult for us to comprehend. We like to live in certainty. Einstein believed that uncertainty was the result of our shortcoming in making the correct predictions. In response to the idea that uncertainty naturally exists, he supposedly exclaimed mildly dismayed: "God does not role dice!"

Our ambivalent feelings toward chance become crystal clear, when we are confronted with a diagnosis of cancer and options for treatment. To the question,"Doc, will I live?" the answer may be, "well, the prognosis in cases like yours is not outright brilliant. But, half of the people in your situation are still alive after two years." Analogous to Schrödinger's thought experiment, this means that in two-years time our odds are 1/2.

With bewilderment, we respond, "but, Doctor, I did not ask how many people on average will still be alive when. I wish to know, whether I shall be alive!" The honest physician will conclude, "I cannot answer this question. But experience tells us that your chances are much improved, if you want to live and remain hopeful."

This uncertain answer fully reveals the dilemma of the medical profession. The physician is asked to divine the faring of a patient based on statistical probabilities derived from groups of patients. As often with cancer, the precise causes of the disease may not be known. Only intensive fundamental research will provide us with a more effective grasp on such complex diseases. Only deepening our knowledge of the molecular signaling mechanisms that trigger tumorous tissue growth will permit us to predict accurately, how the cells will grow and what needs to be particularly done to stop them.

For example, researchers using proteomics may be able to uncover differences in the proteins synthesized in cancerous cells. With this knowledge, physicians may be able to decide which group of patients will benefit the most from a particular type of therapy, and further research will unravel the functions of the proteins.

As to Schrödinger's cat, the experiments at CERN's Hadron supercollider will drastically enhance our understanding of subnuclear particles and their interactions. The findings at CERN may perhaps permit us one day to predict the decay of an unstable nucleus, erasing the uncertainty in Schrödinger's thoughts. The experiments may as well prove this goal elusive or even impossible to attain. In any case, the results of the research at CERN will deeply influence how we reckon with the odds in our lives.

It is regrettable that the U.S. partake only on the sidelines in the pivotal experiments. In the late 1980's, the construction of an even larger collider than Hadron, known as the Superconducting Super Collider, was begun in Texas. After hundreds of millions of dollars spent on digging tunnels, the project was aborted. Another several hundred million dollars were spent to fill in the holes already dug.

Addenda

• An example for the use of proteomics to reliably predict therapy outcome in lung cancer is in press here: Stuart Salmon and others (2009) Classification by Mass Spectrometry Can Accurately and Reliably Predict Outcome in Patients with Non-small Cell Lung Cancer Treated With Erlotinib-Containing Regimen. Journal of Thoracic Oncology 4 (6) (04/20/09).
• Cells of some tumors have been found to contain salient genetic mutations. Notably, deletions at the BRAF gene and substitution at the KRAS gene have been found to promote neoplastic growth. Therapeutics are being developed that may compensate for the defects caused by the mutations, arresting tumor growth. Amy Harmon posted an extensive series of articles for the New York Times on the experimental drug PLX4032 used to stop melanoma in people with BRAF mutations. Her first article in this series with the title "A Roller Coaster Chase for a Cure" appeared Feb. 21, 2010. Today, Ron Winslow reports in his post for The Wall Street Journal with the title "Using Biomarkers to Tailor Cancer Treatment" on the preliminary success of similar strategies in targeting lung cancer. Notably, the drug Nexavar was beneficial to people with KRAS mutations. While the use of these drugs has only succeeded in arresting further tumor growth to date, they hold the promise of profoundly improving the odds (04/18/2010).
• Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).

Cell Phones & Brain Cancer

Remember Jon Krakauer's account of tragedy on Mt. Everest? We have an irrational perception of acceptable risk. For sheer enjoyment, we frequently are willing to expose ourselves knowingly to the possibility of severe injury. Just three weeks ago about a dozen climbers succombed to an ice fall on K2. In any good summer, roughly 100 people perish in mountaineering accidents in the Swiss Alps alone. V. Lischke and others report 462 fatalities for 1997 Europe-wide. According to the U.S. Dept. of Transportation, 4,810 Americans perished on motor bikes in 2005, translating into 73 riders per 100,000 bike registrations. The fatalities continue to rise. Last year 5,154 Americans died on their bike.

By contrast, according to wrongdiagnosis.com every year fewer than 50 in 100,000 Americans battle glioblastoma multiforme, that is the most aggressive and fatal type of brain cancer. Recent research studies link brain cancer with electromagnetic radiation from cell phones. A discussion of some studies can be found here. The debate has become ever more intense since Senator Edward Kennedy was diagnosed with malignant glioma, probably a glioblastoma multiforme. I discussed this type of brain cancer in my post dated June 3, 2008.

Prudence is advised in the debate on a possible association between cell phone-related electromagnetic radiation and brain cancer. The energy of electromagnetic waves is directly proportional to their frequency. The spectrum of the frequencies ranges from meter-long radio waves via the nanometer-long waves of visible light to atom-sized gamma rays. The shorter the wave length, the higher the frequency and the greater the energy that potentially can harm our genes. DNA may be altered directly through the absorption of radiation energy or indirectly through radiation-produced free radicals that may react chemically with the DNA. Even low amounts of energy can damage DNA and may theoretically result in uncontrolled cancerous cell proliferation. However, our cells are provided with DNA repair mechanisms. Commonly many hits are needed to overcome the defenses and cause noticeable damage. Alas, the defenses appear to wear out with advancing age and we may become more susceptible to cancer.

To determine thresholds for harm from electromagnetic radiation, epidemiological studies are conducted that compare the health records of people with known exposure to those of people who match this group in all aspects, except the exposure. Professionals with job-related extraordinarily high exposure are frequently enrolled in the group of the potentially affected to improve the chances of discovery. Hardell and others (2005) observed that Swedish long-term users of analogue mobile (NMT) phones like the now obsolete car phones developed a significantly higher risk for auditory nerve tumors (acoustic neuromas) on the side of phone use. Digital mobile (GSM) phones like our modern cell and cordless phones did not increase this risk consistent with findings in Denmark (Christensen and others, 2004). The prevalence of acoustic neuroma in the U.S. is low. Less than 1 in 1000 Americans is affected. According to ctia.org, roughly 264 million wireless subscriptions are active at present.

Though the results of such studies provide important leads on the type of the potential harm to our health and may be instrumental for safety considerations at the work place, they cannot be easily extrapolated to regular phone users. The amount of radiation energy deposited in the auditory nerve can only be estimated. Moreover, the effects cannot be ascertained with the data collected at higher doses because of the non-linearity of the relationship between dose and effect and the increasing scatter of the observations at progressively lower doses. The concerned may opt to use plug-in extensions for ear and mouth pieces or voice-activation as precaution.

Addenda

• National Public Radio's All Things Considered ran an interesting update on this issue today. You may wish to read the report and listen to the podcast by Allison Aubrey entitled "Doctors Urge Research On Cell Phone-Cancer Issue" (09/25/08).
  
• On Aug. 24, an ice fall swept away a party of twelve on the Mont Blanc du Tacul, a smaller brother of the White Lady. Eight are missing. I once stood on this mountain at a different time in the year. I was fortunate to have a friend as guide who understood risk well (10/21/08).
• Maggie Fox reports in her post with the title "U.S. senator promises look into cellphone-cancer link" published online on Reuters today that Senator Tom Harkin, chairman of the Committee for Health, Education, Labor and Pensions, plans to encourage more research to examine whether the use of cellphones may cause cancer. The fear persists (09/14/09)!
• The environmental working group lists the head-absorbed power [W/kg] of the radio waves emitted from a number of cell phones in this table (06/16/2010).
• Volkow and others (2011) report in this week's issue of the Journal of the American Medical Association that cell phone radiation is statistically significantly associated with an acute increase of glucose metabolism in the temporal and frontal lobes of the cerebral cortex by, on average, 7.2 percent on the side the active, but muted, phone was held for 50 minutes. The researchers used the [¹⁸F]fluorodeoxyglucose method and positron emission tomography (PET) to determine regional cerebral glucose utilization rates in 47 healthy volunteers. They conclude in the abstract of their communication that “this finding is of unknown clinical significance.” Indeed, the finding does not provide any insight into the cellular mechanisms underlying the observed increase. Under healthy physiological conditions, brain glucose metabolism does not rise to levels posing a health hazard. I have written on this topic in my post with the title "Good News for Brain Energy Use" published Sep. 12, 2009. If the sole aim of this study had been to investigate the potential influence of modern-day cell phone radiation on brain energy metabolism, the study could have been conducted with mice at lower cost, sparing the participants unnecessary exposure to ionizing radiation from PET (02/24/11).
• Epidemiologists have recently come to discrepant conclusions on the risk of cancer associated with cell phone use. According to Scott Hensley's report with the title "Cellphone Use May Be A Cancer Risk After All" on National Public Radio's All Things Considered today, a recent World Health Organization review conducted by 31 experts from 14 countries found sufficient evidence that may support a correlation between cellphone use and gliomas and acoustic neuromas. The study will be published in the July issue of the journal The Lancet Oncology. By contrast, a comprehensive case–control study with 2708 glioma and 2409 meningioma cases and matched controls from 13 countries published last year by The INTERPHONE Study Group (2010) could not establish any elevated risks with mobile phone use with certainty (05/31/10).

References

• Christensen HC, Schüz J, Kosteljanetz M, Poulsen HS, Thomsen J, Johansen C (2004) Cellular telephone use and risk of acoustic neuroma. Am J Epidemiol 159: 277-283.
• Hardell L, Carlberg M, Hansson Mild K (2005) Case-control study on cellular and cordless telephones and the risk for acoustic neuroma or meningioma in patients diagnosed 2000–2003. Neuroepidemiology 25: 120-128.
• The INTERPHONE Study Group (2010) Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case–control study. Int J Epidemiol 39: 675-694.
• Volkow ND, Tomasi D, Gene-Jack Wang G-J, Vaska P, Fowler JS, Telang F, Alexoff D, Logan J, Wong C (2011) Effects of cell phone radiofrequency signal exposure on brain glucose metabolism. JAMA 305: 808-813.

As the eminent film director Werner Herzog so aptly documents in his recent public service announcement video below with the title "‪From One Second To The Next‬", cell phone use may pose other, more prevalent effects proven to be absolutely devastating to our health (08/20/2013):

Glioblastoma multiforme: The Octopus in the Brain

Cancer is a life-changing experience. Senator Edward Kennedy has been diagnosed with brain cancer. The ensuing media attention to this horrible disease has touched on a number of fundamental issues. However, the reporting has remained often vague. The vagueness is the inevitable result of the uncertainties involved.

To begin with, uncertainty is an integral part of any cancer. Prognoses of outcome for cancer therapies are probabilistic, diametrically opposed to our craving for definitive answers. We are challenged to beat odds. Yet, we only feel safe, when we know for sure what is going to happen to us. With cancer therapy there can be no assurance of success, only indications from prior experience that the therapy may prolong our lives and hope.

Senator Kennedy's tumor was located in the parietal lobe of the cerebral cortex. This area is large. Nerve cells on its borders process sensory information of mainly one modality. Nerve cells in its interior process multi-modal input, integrating information across multiple senses. The cortical regions that truly fit the idea of the center for a particular function are few. Primary sensory areas may fulfill this requirement best. They receive the most direct input from a particular sense organ and process predominantly information of this sense's modality. For example, a stroke in the primary somatic sensory area at the forward border of the parietal lobe predictably impairs the sense of touch. Therefore, this area may be designated a cortical center for touch. By contrast, injuries in the large swath of parietal cortex stretching backward from the primary somatic sensory area may only lead to subtle loss of sensory function. Attention, speech comprehension and short-term memory may be affected, dependent on the location of the damage. Hence, the uncertainty in the prognosis of the tumor's impact on brain function is rooted in our incomplete understanding of parietal lobe function. More research is needed in this area.

Even less is known about the nature of Senator Kennedy's tumor. Nerve cells and glia represent the most prevalent cell types in brain tissue. Nerve cells multiply at high rate only in the developing brain. In the mature brain, nerve cell proliferation is much reduced and restricted to a small number of regions. In contrast, glia retain the ability to multiply throughout life. The glia in the brain's gray matter essentially consist of astrocytes and microglia.

Astrocytes play vital roles in support of nerve cell function. For example, astrocytes remove the excitatory neurotransmitter glutamate from the space between cells. Neurotransmitters are substances that mediate the transfer of information between nerve cells. Too much glutamate in the extracellular space triggers a program in nerve cells leading to their death (apoptosis). Microglia support the brain's immune response.

After an insult to the brain, astrocytes and microglia increase in number at the site of the injury, owing to cell division and migration. Astrocytes form a glial scar encapsulating the damaged tissue. Microglia are known to incorporate debris of severed nerve cell connections (axons). The glial reaction extends from the site of the injury, following the tracts of severed connections. If the glial reaction progresses normal, the debris is digested and the tissue heals. The glia cease dividing and decrease in number.

At times, however, glia begin to proliferate abnormally without any known reason and the cells do not stop dividing. Aggressive, fast growth of a tumor ensues. Astrocytes develop the most malignant tumors known as glioblastoma multiforme, or GBM for short. Once the tumor reaches a certain size, the blood-brain-barrier is breached. Fluid invades the brain tissue, forming an edema. Nerve cell function is severely impaired, leading to seizures and often hemiparesis. Glia hitherto uninvolved in neoplastic growth react to the injury. The glial reaction possibly recruits abnormal glia and fans out along the disrupted nerve cell connections, infiltrating healthy brain tissue.

At this juncture, the steps to be taken for Senator Kennedy seem straight to the point. The tumor's bulk has been excised. The edema has been addressed. Now, the remaining abnormal astrocytes have to be stopped from dividing. Ionizing radiation will be used to damage the DNA of the cells dividing in the margins of the tumor, arresting the cycle of cell division. Cytostatic chemotherapeutics will be administered to stop astrocytic division in regions outside the focus of radiation. In addition, the growth of blood vessels into cancerous tissue may be slowed with drugs that inhibit angiogenesis (but see addendum, dated Apr. 10, 2009).

I lost my father and two good friends to glioblastoma multiforme and sincerely wish that this regimen will benefit Senator Kennedy in the best possible ways. However, as scientist I know that this vicious disease will only be defeated, once we identify the molecules that signal glial proliferation and devise a method that permits us to specifically inhibit the proliferation of astrocytes.

Addenda

• Most likely, the molecule signaling glial proliferation is epidermal growth factor (EGF) and the EGF tyrosine kinase receptor needs to be inhibited (8/30/08).
• Perhaps, the phosphorylated protein is Annexin/Lipocortin 1 (Melzer and others, 1998) (10/02/08).
• Glioblastoma multiforme is a rapidly growing tumor, showing regional differences from normal brain tissue in its metabolism of sugar as a source of energy. F.M. Santandreu and others (2008) provide a comprehensive description of such metabolic aspects in Cellular Physiology and Biochemistry 22:757-768. Since the tumor cells can store little sugar, the resource has to be delivered constantly with the bloodstream. The fast tumor growth induces growth of blood vessels. Therefore, anti-angiogenic drugs that inhibit vessel growth may help to shrink the tumor (02/18/09).
• Hai Yan and others (2009) report somatic mutations of the mitochondrial enzyme isocitric acid dehydrogenase crucial for sugar metabolism in 70% of astrocytomas and oligodendrogliomas as well as glioblastomas that developed from these tumors (New England Journal of Medicine 360:765-773). The mutations are discussed as potential predispositions for tumorigenesis (02/19/09).
• Microglia reactive to nerve cell injury are shown in my post dated Oct. 17, 2008 (03/04/09).
• To date, there is no compelling evidence that the use of contemporary cell phones causes glioblastoma multiforme. See my post dated Aug. 21, 2008 (03/05/09).
• You may be interested in reckoning with the odds in my post dated Mar. 5, 2009 (03/06/09).
• Erika Check Hayden summarizes the latest insights into the effectiveness and pitfalls of angiogenesis inhibitors in this weeks issue of the journal Nature, vol. 458: 686-687 (04/10/09).
• Using RNA interference (RNAi), Australian scientists developed a method with which the expression of tyrosine kinase receptors can be blocked, making tumor cells more vulnerable to chemotherapeutics and diminishing the tumor cells' ability of developing resistance against the drugs (MacDiarmid and others, 2009). Michael Perry reported on this progress in his post with the title "Scientists kill cancer cells with 'trojan horse'" published online on Reuters yesterday (06/30/09).
• Senator Kennedy passed away yesterday (08/26/09).
• Last Tuesday, Sep. 7, 2009, National Public Radio's Talk of the Nation aired an interview by Neil Conan with the British neurosurgeon Henry Marsh on his charity work in the Ukraine and general aspects of his profession. National Public Television's POV showed a movie on his work that evening. The movie, "The English Surgeon", will available on DVD Nov. 3. Particularly towards the interview's end, Dr. Marsh highlights in striking clarity the importance of finding an experienced neurosurgeon for the successful removal of a glioblastoma (09/10/09).
• A recent clinical study by Sampson and others (2010) reported promising results in the treatment of glioblastoma multiforme (GBM), using vaccines that target epidermal growth factor receptor variant III, or EGFRvIII for short. The receptor is extraordinarily prevalent on the surface of the most-aggressively growing GBM cells, owing to a genetic mutation. Thirty-five patients with GBM were enrolled in the phase II clinical trial; all underwent surgery, radiation therapy and chemotherapy with temozolomide. In addition, 18 were inoculated with vaccines.  Adding vaccines almost doubled median survival time from 15 to 26 months, extending the progression-free period from 6.3 months to 14.2 months. The vaccination eliminated all cancer cells carrying EGFRvIII, except in one patient. Half of the patients showed an immune response. Six developed antibodies specific for the receptor and three showed a T-cell response, supporting the contention that the increased survival may be associated with the immune response. Nine of eleven patients, whose recurring tumors were examined, tested negative for EGFRvIII, indicating that the cells with this mutation had been persistently eradicated. Taken together, the findings suggest that vaccines may prove a promising new avenue of treatment, though not a cure, for glioblastoma muliforme. Celldex Therapeutics and Pfizer developed the currently tested vaccine known as rindopepimut or CDX-110 and PF-04948568, respectively (10/05/10).
• Listen to this interview with Gordon Murray by Robert Siegel broadcast on National Public Radio's All Things Considered today and find words of strength and encouragement from a man with GBM who is making the best of his situation (12/17/10).
• Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).

• 

  Color-coded image of a transaxial FDG PET scan from a GBM patient with a recurrent tumor in the left cortical hemisphere.  High local cerebral metabolic rates for glucose starkly delineate the tumor (low rate - blue; high rate- white; courtesy L. Sokoloff). 

  The functional image above was acquired from a patient with a glioblastoma multiforme in the left cerebral hemisphere. The initial primary tumor and had been surgically removed. The removal was incomplete. When symptoms suggested a recurrence of the tumor, the surgery had altered the anatomy of the cortical hemisphere to such extent that an evaluation of structural brain scans was impossible. However, a new tumor could be localized with positron emission tomography and the [¹⁸F]fluorodeoxyglucose (FDG) method (Di Chiro and others, 1982). This method allows us to image and measure the local glucose consumption of brain tissue. The rate of glucose utilization was highly increased in the core of the new tumor. Under normal physiological conditions, brain cells metabolize glucose to produce adenosine-triphosphate (ATP) in an oxygen-consuming metabolic pathway called aerobic glycolysis. ATP represents a ubiquitous high-energy molecule that cells need to maintain vital functions. Because glia possess only a small capacity of storing glucose and oxygen cannot be stored at all in the brain, the blood supply must continuously deliver both to the brain tissue. An increase in demand stimulates angiogenesis, that is blood vessel growth. However, in fast growing tumors angiogenesis cannot keep pace with demand. Moreover, the activity of certain types of key enzymes for glucose metabolism, known as mitochondria-associated hexokinases I and II, can be increased as much as 200-fold in tumor cells, leading to extremely high rates of aerobic glycolysis (Warburg effect) which compound the local oxygen shortage. Moreover, using tumor genome sequencing Yan and others (2009) identified a mutation that changes arginine 132 in the product of gene IDH1 isocitrate dehydrogenase. Isocitrate dehydrogenase is a key enzyme in the Krebs cycle providing substrates for aerobic glycolysis. This change in amino acid modifies the function of the enzyme such that the enzyme's substrate isocitric acid is turned into a novel product which cannot be used in the Krebs cycle, hampering the efficiency of aerobic glycolysis. More than 70 percent of 445 tested central nervous system tumors were astrocytomas, oligodendrogliomas and glioblastomas that had developed from lower-grade tumors. These rapidly-growing, malignant cancers possessed the mutation. As a consequence, glucose may be metabolized in the malignant tumor's core without the use of oxygen, though this anaerobic glycolysis is much less efficient in generating ATP than aerobic glycolysis. The observations may be taken to suggest the possibility of starving neoplastic astrocytes to death with a diet extremely low in carbohydrates. Alas, cells in other tissues of our body, e.g. muscles, routinely use vast amounts of glucose in anaerobic glycolysis to meet rapidly increasing energy demands while oxygen is in short supply. A no-carb diet is not going to be selective for the tumor and may rather weaken the body's overall resilience. By contrast, avoiding high-fructose corn syrup and sucrose used to sweeten countless foods and beverages may be beneficial, because the fructose in these sugars may stimulate insulin-like growth factors that promote neoplastic growth (see Gary Taubes' article with the title "Is Sugar Toxic?" published online in The New York Times on Apr. 13, 2011) (01/13/2012).
• Dang and others (2009) report that when IDH1 mutations turn arginine 132 into histidine, the gene's changed product isocitric acid dehydrogenase may catalyze the formation of R(-)-2-hydroxyglutarate known to be conducive to tumor growth (02/06/2012).
• The leader of the four-decade effort to develop the deoxyglucose method for the use in tumor imaging (see image above) Dr. Louis Sokoloff presented a historical lecture for the public with the title "Development of the [18F]Fluorodeoxyglucose Method: A Serendipitous Journey From Bench to Bedside" on the endeavor at Brookhaven National Laboratory Oct. 19, 2012, to celebrate the designation of its Chemistry Department by the American Chemical Society as a historical site for its role in this accomplishment (10/29/2012).
• Personal accounts of GBM patients describing their experience with treatment are rare. Two days ago (Sep. 23, 2013), the Washington Post published Fritz Anderson's post with the title "Surgery, radiation and chemo didn’t stop the tumor, but an experimental treatment did" published online. Dr. Anderson, a retired cardiologist, writes about his situation eloquently with great sensitivity and encouragement. After surgery, radiation therapy and chemotherapy his tumor regrew and he decided to participate in an experimental phase I trial of a therapeutic that consists of an altered polio virus (PVS-RIPO) that glioblastoma cells preferentially bind, infecting and destroying the cells. The trial is led by Prof. Matthias Gromeier at Duke University's Preston Robert Tisch Brain Tumor Center. The procedure is invasive, requiring a craniotomy, because the drug must be administered directly to the tumor tissue in one six-hour session. The therapy shrunk the tumor decisively, and Dr. Anderson continues to enjoy life. Four of five treated patients were blessed with success to date (Sep. 25, 2013).

References

• Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden M G, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739-744.
• Di Chiro G, DeLaPaz RL, Brooks RA, Sokoloff L, Kornblith PL, Smith BH, Patronas NJ, Kufta CV, Kessler RM, Johnston GS, Manning RG, Wolf AP (1982) Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography. Neurology 32:1323-1329.
• De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE,Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14:3098-3104.
• Check Hayden E (2009) Cutting off cancer's supply lines. Nature 458:686-687.
• MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM, Brahmbhatt H (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol 27:643-651.
• Melzer P, Savchenko V, McKanna JA (2001) Microglia, astrocytes, and macrophages react differentially to central and peripheral lesions in the developing and mature rat whisker-to-barrel pathway: a study using immunohistochemistry for lipocortin1, phosphotyrosine, s100 beta, and mannose receptors. Exp Neurol 68:63-77.
• Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon II JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic Escape After Prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol: doi: 10.1200/JCO.2010.28.6963.
• Santandreu FM, Brell M, Gene AH, Guevara R, Oliver1, Couce ME, Roca P (2008) Differences in mitochondrial function and anti- oxidant systems between regions of human glioma. Cell Physiol Biochem 22:757-768.
• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-773.

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• Fahrenheit -459.67
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Fahrenheit -459.67

Molecules need to be on the move to react with each other. Inspired by his observations on the thermodynamics of gas molecules, the Irish scientist Lord Kelvin conceived it useful to set to zero the temperature, at which molecular motion must come to a standstill. Today, his idea is recognized in the international system for measures, and units of temperature have been named in his honor. Extrapolation from experimental observation has pegged -459.67° Fahrenheit to zero degrees Kelvin. At this temperature, the molecules reach the state of lowest kinetic energy and greatest stability.

However, at higher temperature, molecules are in motion and chemical reactions occur. As a result, energy may be set free. Although this energy can be used to fuel other chemical reactions, some will dissipate unused. The loss is called entropy. Entropy commonly increases with the multitude and the complexity of the reactions, summarily advancing our universe toward Lord Kelvin's endpoint.

Life is an effort to stem this progress. In order to survive, living things need to preserve energy like surfers tirelessly weaving up and down the face of a wave. Every descend fuels the next ascend. Organisms as a whole as much as the cells they are built from have to meet this challenge. This is our lot in life.

In the battle against entropy, nothing lasts forever. The building blocks of living cells are subjected to wear and tear. They need to be continuously repaired or replaced. Even constant upkeep may not suffice. Most cells possess a limited lifespan. Primordial cells must continue proliferation to make up for the losses.

To satisfy these needs, cells rely on two essential tools. One tool is a repository of construction plans for the cellular components. The DNA in the cellular nucleus encodes these plans. The other tool is the machinery that reads the plans, can duplicate them and use the instructions to synthesize the proteins needed to build the cells' components and even entirely new cells. It is existential to protect the plans and keep the machinery functional in order to prevent the manufacture of faulty, useless, and even harmful products.

Free radicals, e.g. highly reactive forms of oxygen, constitute a major group of agents that may modify the construction plans and interfere with proper protein synthesis. Aromatic products of the incomplete combustion contained in barbecue and cigarette smoke, e.g. benzo[a]pyrene, are another group.

Cells possess quality control and repair mechanisms to contain the damage such agents cause, entering into a ceaseless contest between destruction and restoration. If vital functions cannot be repaired, either because of the magnitude of the damage or because the repair comes to a halt, the cells die.

In addition, cells may contain programs that are specifically in place to enact their death (apoptosis) and are used in regular development. For example, skin fuses our fingers together early in embryonic development. Eventually, programmed cell death separates the digits. When the programs for cell death are disabled and programs for cell proliferation are falsely engaged, the tissue may grow out of control, a condition known as cancer.

In the battle for renewal, the brain holds a special place among our organs. Nerve cells proliferate only in a few places in the mature brain, e.g. the olfactory bulbs and the hippocampus. Replacement is a scarce option. Much of the maintenance and repair is left to different cells called glia. The picture shows an early rendering of these cells in the work of Auguste Forel. He called them spider cells.

To date, the precise role of glia remains little understood. Early scientists believed that they constitute the glue that holds the brain together. We know now that one major type, astrocytes, plays an important role in keeping the environment viable for the nerve cells. They remove salts and molecules from the fluid in the extracellular space, preventing levels that would trigger cell death. In contrast to nerve cells, astrocytes multiply after brain injury inflicted by stroke and trauma, producing a gliosis. Astrocytes are also known to enter proliferation erronously. The most deleterious brain cancer, glioblastoma multiforme, is of astrocytic origin.

Microglia are the other major type of glia in the brain.  Their role is more mysterious than that of astrocytes. The difficulty mainly arises from the fact that these cells change considerably in appearance as part of their reaction to brain injury. In the absence of direct observation, it is hard to ascertain whether and how the various cell forms are related that scientists identify as microglia. Hence, it remains difficult to pinpoint their origin. A scientist I worked with had evidence to believe that the microglia accumulating at the site of injury are derived from cell populations resident in the brain. Others believe that they consist mainly of bone marrow-derived white blood cells that infiltrate the brain from the blood stream through a blood-brain-barrier rendered leaky by the injury. Recent findings support both contentions.

Irrespective of their provenance, microglia are supposed to provide the immune response of the brain. They are known to incorporate the debris left behind by dying nerve cells. They attain a plum shape in the process and some remain unchanged on location for many years, even decades, after the insult. We do not yet understand, why they reside there and what purpose they still serve. Regardless, I take it that they are good soldiers in our cosmic fight against entropy and see to it that we do not reach Fahrenheit -459.67 too quickly.

Addendum
I omitted to mention a formidable tool of living cells to stem entropy: enzymes. Enzymes are catalyzing proteins. That is, they facilitate chemical reactions that may happen only at random otherwise by bringing the components of the reaction together, accelerating the biochemical processes important to vital functions of living cells. Compartmentalization of enzymes, that is confining enzymes in distinct parts of the cell, helps organize the reactions into orderly sequences of separate processes, enabling meaningful signal transduction and the regulation of enzymic activity involved in cell anabolism and catabolism as well as in protein synthesis, replication and proliferation. The eminent biochemist Jaques Monod argued in his famed book "Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology" that the first biochemical process of life in its simplest form might have been an enzyme synthesizing nucleic acids containing the information needed to synthesize this enzyme, hence empowering the protein to replicate itself. Alas, enzymic reactions are profoundly temperature dependent and come to a halt far above zero degrees Kelvin.

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