HORMESIS AND OTHER MATTERS 3

Hormesis – what is it? First I will tell you what it is not. It has nothing to do with homeopathy which is a method of treating disease by giving highly diluted doses of drugs to patients such that the same drugs given to healthy people in much more concentrated form would cause the same symptoms as the disease. Sometimes these doses given to patients are less than one part in one billion. The idea is to theoretically simulate the symptoms of a disease rather than attacking the cause. Yet with such a diluted dose the patient would in effect be given a placebo. Not only is the idea nuts, but the method makes even less sense.

Hormesis also is not scientology which is a screwball philosophy/religion/cult based on the inane rants of a pulp and science fiction writer named L. (Lafayette) Ron Hubbard (1911-1976). Hubbard attended George Washington University where he received poor grades, was on academic probation, and dropped out after two years. He took a course called Atomic and Molecular Physics. Based on this he later claimed he was a nuclear physicist. He received an F in the course. His military record in WWII and domestic life is a sorry story which, if interested, I invite you to consult on the internet. Scientology does affect people though – it can cause a person to dementedly jump up and down on a couch in front of television cameras and to undertake a mission impossible by dispensing medical advice to women even if one does not know any more about medicine than a frog.

In his book The Politically Incorrect Guide to Science Tom Bethell explains that hormesis is the theory that whereas large amounts of certain substances are toxic and even deadly, small amounts of these same substances are not only not harmful, but actually beneficial. This is not only true, but reasonable and demonstrable when you think about it. Consider alcohol. When taken in large amounts over years you would likely need to go shopping for a new liver, yet the public has been inundated in the past few years with reports from the news media that alcohol taken in small amounts daily, say a 12 oz. bottle of beer; a mixed drink; or a 5 or 6 oz. glass of wine will keep a person healthy, if not happy and wise.

Hormesis contradicts the widely held assumption in public health that large doses of toxic substances continue to be toxic in smaller and smaller doses - this is called the linear, no threshold theory. When plotted with “harm” and “dose” on the ordinate and abscissa, respectively, a straight line intersects the origin. Another theory is called the linear, threshold theory. In this case the straight line intersects the “dose” axis short of the origin and plots as a horizon line along the “dose” axis back to the origin. A third theory is hormesis which plots as a curved line again intersecting the “dose” axis short of the origin, but in this case goes below the “harm” line into what is labeled the “benefit” area, then plots back to the origin at the zero dose amount.

So frequently has hormesis been observed that, quod erat demonstrandum, it is not difficult to find substances that are beneficial at low doses. Consider vitamin and mineral supplements. The ingredients include boron, chromium, copper, iodine, magnesium, molybdenum, nickel, phosphorous, potassium, selenium, vanadium, and zinc – all toxic at high doses. The widespread use of multi-vitamins shows that people do not subscribe to the linear, no threshold theory when it comes to ingested substances. How about externally applied substances and processes? Is long time exposure to x-rays and radiation bad and short time exposure still detriment, only less so? Many people would say so, but what is the evidence?

The unfortunate people at the center of the nuclear bomb sites in Hiroshima and Nagasaki naturally were incinerated. In fact the blast was so powerful and bright that permanent shadows of objects were cast on concrete structures which were not completely destroyed. The people further away from the blast later died in great numbers of various cancers. As expected as the distance from the center of the blast increased fewer and fewer people died from cancer. However, then an unexpected phenomenon happened. At increasing distances from the central blast site, where people still received some radiation, but only small amounts, the later incidence of cancer was less that for people further away who had not been subjected to any radiation. Interesting to say the least, is it not?

Anti-nuclear zealots assert, ipse dixit, or seemingly deliberately misstate the dangers of long half-life radioactive materials from nuclear power plants citing that these sites will be rendered uninhabitable for thousands of years. This is completely backwards. It is the radioactive materials with short half-lives that are dangerous. Author Tom Bethell quotes a former acting Secretary of Energy posing the question: “Would you rather sit on a box of firecrackers if half will go off in the next week or a box in which half will go off in the next 24,000 years?”

Plutonium is deadly because it can be used to make atomic bombs. It is not injurious to handle because its half-life is 24,000 years. Bernard Cohen of the University of Pittsburgh once offered to eat some plutonium if Ralph Nader would eat a like amount of caffeine. Nader refused. Plutonium is not to be confused with Polonium – 210 which was discovered in 1898 by double Nobel Prize winner Marie Curie and her husband, single Nobel Prize winner, Pierre Curie. Polonium - 210 has a half-life of 138 days and is so rare that only about 100 grams/yr. are made, mostly as a byproduct of nuclear reactions in power plants. It is thought to be the substance that was used to poison ex-KGB and vehement critic of Russian President Vladimir Putin, Alexander Litvinenko, in London recently. Milligrams or even micrograms of the stuff, if ingested, would be enough to fatally destroy internal organs.

A congressional resolution declared in 1970 that,”The conquest of cancer is a national crusade to be accomplished by 1976.” In 1971 when the National Cancer Act became law, 330,000 American died of cancer. In 2004 about 560,000 Americans died of cancer. Even when adjusted for an aging population, the percentage of Americans dying of cancer is about the same as in 1970 and in 1950 as well. In contrast age-adjusted deaths for heart disease have declined by 59% and by 69% for stroke.

A decline in lung cancer in recent years is attributable to a decline in cigarette smoking for men. Lung cancer for women has increase as a proportion of total lung cancers for both men and women. When the stigma of cigarette smoking for women abated many years ago little did they realize what a pyrrhic victory it would become - another unintended consequence of an otherwise admirable equality goal. Cures for some types of leukemia (the four main types are acute lymphocytic leukemia [most common for children], acute myclogenous leukemia, chronic lymphocytic leukemia, and chronic myclogenous leukemia) and testicular cancer have met with striking success. Improvement in five year cancer survival rates are a function of better surveillance and earlier diagnosis, when surgery and chemotherapy have a better chance of success. Survival gains for the most common forms of cancer are measured in additional months of life, not years. Compared to cure rates of infectious diseases, especially through most of the 20th century, the record of cancer has been woefully lagging.

In part, the answer to the slow progress in curing and successfully treating cancer may be linked to its cause. What does cause cancer? In the 1920’s researchers bombarded fruit flies, Drosophila melanogaster (the black-bodied dew-lover) with x-rays, resulting in mutant flies. Humans exposed to large doses of x-rays proved to be at high risk for skin cancer and leukemia. Therefore it was clearly shown that x-rays produced both mutations and cancers.

In the 1960’s researchers at the National Institutes of Health used fast growing bacteria to detect the mutagenic properties of various substances. Some carcinogens proved to be mutagenic, advancing the gene-mutation theory of cancer. In the 1970’s Dr. Robert Weinberg at an MIT cancer research lab concluded that carcinogens act by damaging DNA (deoxyribonucleic acid), thereby creating mutations in genes of the targeted cells. Radiation is an example of a carcinogen which is a mutagen, others are not. Tar found in cigarettes and asbestos are carcinogens, but are not mutagenic – that is they do not affect DNA.

Viruses were once thought to play an important role in causing cancer, however since only a couple types of cancer are definitely connected to viruses it is now thought that viruses play a minor role in cancer. In 1970 two researchers at the NIH, Robert Heubner and George Todaro put forth the “oncogene hypothesis” which attributed all cancer to the activation of certain genes that are intrinsic to cells – not transported there by viruses. These hypothetical cancer genes, called proto-oncogenes, are activated by being mutated.

The oncogene theory at the outset posited that a single gene mutation was enough to turn a normal cell into a cancer cell. Although a few types of cancer are now considered to be caused by a single gene mutation these are the exceptions. It was always unlikely that a single gene mutation was a major factor because mutations occur at a predictable rate in the body and as the number of cells in the body number in the tens, if not hundreds, of trillions, we would all have cancer if a single hit was sufficient to transform a cell in many cancers. In time it was proposed that two genes, then six or seven genes would have to mutate in the same cell during its lifetime to make it cancerous. That was just guesswork based on gene mutation theory. Researchers have never been able to show that any gene, whether or not mutated, except in a few isolated cases, could transform a normal cell into a cancer cell, nor could it start a tumor in any animal. Further, they have never been able to show that any combination of genes taken from a cancer cell can transform normal cells, whether tested in vitro or in the lab. The theory has not been confirmed by any functional test. These mutated genes can be transported into test cells, but when these genes are integrated into the cell’s DNA the recipient cells do not turn into cancer cells, and if injected into experimental animals, they do not cause tumors. Genetically engineered mice have mutated oncogenes in every cell of their bodies so one would think they would die immediately of cancer. In fact offspring grow up and live long enough to pass on their supposedly deadly genes to the next generation.

Cells divide in the course of life, sometimes frequently as in the gut or skin, and sometimes infrequently, as in bone or muscle. This cell division is called mitosis (from Greek mitos, meaning thread). The chromosomes (from Greek chrōma color plus sōma body) double up, and then separate, and after mitosis a full compliment of chromosomes ends up in both of the resultant cells. Normal cells in the body divide only a certain number of times called the Hayflick limit which is roughly 50, before expiring. It is thought to be a cause or concomitant of aging.

Normal mouse cells have 40 chromosomes, humans have 46 – 23 from each parent. Such cells are called diploid because they have two of each chromosome. Genes are segments of DNA strung along these chromosomes. The largest chromosomes incorporate several thousand genes each. It may not be flattering to the male ego, but by far the “Y” chromosome, which defines a male, is the smallest of all the human chromosomes.

Sometimes there is an error in the anaphase or telophase stages of cell division such that the chromosomes do not divide properly, but end up unequally in the daughter cells. One cell could come up a chromosome short while another cell would have an extra one. Such pathological cells will usually die and then there would not be a problem. But sometimes the error persists, more likely in the cell with an extra chromosome. The cell just keeps on dividing, ignoring the Hayflick limit with its control mechanisms. This is dangerous because a tumor forms in that part of the body and that is cancer.

This abnormality of the number of chromosomes in the cells is called aneuploidy. Some human cancer cells may have as many as 80 chromosomes instead of the normal 46 which could give them double the right number of genes. It is not just that a cell has two or three genes that malfunction. It is far worst than that. And the more aneuploid they become, the more likely they are to metastasize.

A leading cancer researcher, Bert Vogelstein of Johns Hopkins, a few years ago accepted that “at least 90% of human cancer cells are aneuploid.” More recently his laboratory reported aneuploidy “is consistently shown in virtually all cancers.” More and more researches accept that cancer cells are aneuploid. Some insist that this is a consequence, not a cause of cancer, but others are beginning to say that perhaps both gene mutation and aneuploidy play a role in cancer. Christoph Lengauer, a researcher in the famed Vogelstein/Kinzler lab at Johns Hopkins University, said that “with our experiments, we found that aneuploidy is a very early event in tumorigenesis.”

What is the answer then? Does aneuploidy have no connection with cancer; is it the main cause of cancer; or is it a cause in addition to gene mutation? At this point the last possibility seems to be the most likely.