What Is Motor Neuron Disease or Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig Disease: How to Treat It
Lou Gehrig signed an autograph for Frank Sinatra (photo from StumbleUpon. Sept. 19,2014)
Neurons revived by stem cell therapy
Cord blood collected from the umbilical cord (Photos derived from "Supercells," HBO Documentary films)
Catch free radicals to stop damage they inflict on nerves and muscles then rebuild them by stem cell therapy
Motor neuron disease (MND) or amyotrophic lateral sclerosis (ALS) is a rare disease. It is also called Lou Gehrig’s disease.
ALS “... progressively causes the degeneration of the nerve cells that control the muscles, paralyzing the body but sparing the mind....” (Swartz H.M. et al. “Free radicals and medicine.” Eaton, S.S. et al. editors. Biomedical EPR-Part A: Free Radicals, Metals, Medicine, and Physiology. 2005:25-74).
About 10% of the cases of ALS are heritable; the rest are caused by sporadic or environmental factors.
The heritable one, familial amyotrophic lateral sclerosis, (FALS) involves the mutation of the gene Sod 1 that controls the enzyme copper/zinc superoxide dismutase (Cu/Zn-SOD).
The mechanism of FALS development is that “FALS-linked mutants acquired a cytotoxic ‘gain-in-function’" which means exposure to causal agents.
“...The ‘gain-in-function’ of Sod 1 mutants had been postulated to arise from an increased peroxidase or hydroxyl radical activity....” (same source as above, emphasis mine).
The above three paragraphs lead to clues as to the causes of FALS or ALS and to their treatment. Cytotoxic simply means a toxin or poison that affects a cell.
Let's look more closely into gene, sclerosis, enzyme, mutants, mutation, hydroxyl radical, peroxidase or substance with a name containing 'peroxide' or 'peroxy.'
[Lou Gehrig, a baseball player of New York team (Yankees), was "one of the most durable players in American professional baseball and one of its great hitters" (Internet. Sept. 19.2014). He died in June 1941 of MND or ALS. Being a celebrity, his name has been also appended to this disease.]
Possible mechanism of development
Inheritance. The basis of inheritance is the chromosome. A chromosome is composed of genes. A gene comes in pairs, one fellow is called allele. In each cell of a human being there are 46 chromosomes in the nucleus and 37 chromosomes in the mitochondria. Both father and mother pass on chromosomes in the nucleus; only the mother passes on chromosomes in the mitochondria (Doug Wallace, Director of Center for Molecular and Mitochondrial Medicine and Genetics (Bellomo, M., The Stem Cell Divide. 2006:184-95). The reason is that the egg of the mother has plasma where the mitochondria resides; the father's "seed" has no plasma so it does not contribute mitochondria in fertilization. The genetics of the nuclear chromosomes are much more studied than that of the mitochondrial chromosomes. That is why there is a need to find out if the mutated Sod 1 is carried by mitochondrial chromosomes. However, it is clear that Cu/Zn-SOD protects the cell plasma or fluid and the manganese superoxide dismutase (Mn/SOD) protects the mitochondria. It is more likely that heritable mutation of Sod 1 is passed on by the mother and the father because Cu/Zn-SOD is assigned to protect the plasma.
Inherited or familial amyotrophic sclerosis (FALS). A person inherited a gene whose one allele, Sod 1, is mutated. That means that all her/his cells carry a mutated Sod 1. This mutation occurred in the development of the egg of the mother and of the "seed" of the father in a process called meiosis. This mutation is passed on to their sibling. However, this mutation in one allele is not enough for him/her to develop FALS. S/he will develop FALS only once the normal allele, partner of the mutated one, had been mutated likewise. This second mutation occurs in the mitotic or dividing cell now part of the sibling. When both alleles of Sod 1 in one cell had been mutated his/her Cu/Zn-SOD fails to work. That means this enzyme cannot catch superoxide and turn it into hydrogen peroxide which is dismantled by glutathione peroxidase into safe water. Mutation of the mitotic cell is caused by environmental factors like free radicals.
This is similar to what happens in a person who has a heritable breast cancer whose link is the gene BRCA1 and the heritable ovarian cancer whose link is gene BRCA2 (Cummings, M. Human Heritage, Principles and Issues. 2009).
Sporadic form. Mutation of the normal Sod 1 owing to “gain-in-function” involves sporadic or environmental factors like free radicals and ROS. No mutated allele of Sod 1 is inherited. Both alleles are normal. However, both alleles sustain changes or mutations due to environmental causes resulting in amyotrophic lateral sclerosis (ALS). Mutation of the sporadic form occurs in the mitotic or dividing cells of a human being. Mutation in mitosis is different from mutation in meiosis. Mutation in mitotic cell consist in shortening, or thickening, or gaps, or thinning of chromosome.
This can be seen in an ordinary microscope. You can try it. Get five drops of blood from a frog. Put them in a test tube with a nutritional medium or distilled water that keeps the blood alive. Then pour a little hydrogen peroxide, 3% grade, into the mixture. In a short while harvest by ferreting out some clot from the mixture and fix them in slides. Then look at the slides under a microscope. You can see gaps between chromatids (a chromosome is composed of two threads aligned side by side), breakage, loose separated chromatids, and condensed chromosome (if the normal length were 2 inches it is shortened to, say, 1.5 inch). This was a laboratory exercise I did when I took up a subject in genetics.
The procedure is called karyotyping. This is used in trials on the effect of plant extracts, say, banaba tree, or garlic on diabetes. It is done in the laboratory this way: Follow the method of Moorehead et al. (1960). Get five drops of blood (from a 21-year-old fellow if he is willing) and culture them on a chromosome medium (GIBCO BRL, New York, USA Cat. No. 41675). Use aqueous extract (juice from macerated or pounded garlic. Let the culture stand for 48 hours then harvest clots and fix them on slides. Look into the slides under a microscope (Alban, A.E. et al. Cytogenetic effect of selected plants known to treat diabetes on human leukocytes. Philippine Agricultural Scientist. 2002 vol. 85 No,1:20-21). You see mutations in the chromosomes of blood cells.
Two-hit model of development. In one way, a person inherited a mutated allele of Sod 1 in the the egg or "seed." - during meiosis. The mother contributes 23 chromosomes; the father contributes 23 chromosomes to the 46 chromosomes of their sibling, now a human being. This sibling now carries one mutated Sod 1 in all his/her cells. When the other normal Sod 1 in the same cell is also mutated by sporadic factors, Cu/Zn-SOD stops working. Given that one allele is already abnormal, it only takes a few mutations in the other normal allele to become abnormal as well.
Huber AliciaC says that when a mutated Sod 1 allele is cultured or grown in a medium containing a normal allele, the latter also becomes mutated. The mutated Sod 1 might induce mutation in the normal Sod 1 (Cummings, M. Human Heritage, Principles and Issues. 2009).
In the other way -- the sporadic form -- neither mother nor father contributed a mutated Sod 1. So, the sibling has normal alleles of Sod 1. However, when both alleles of Sod 1 in one mitotic cell of the sibling had sustained mutations due to sporadic factors, ALS develops. It takes a long time for mutations in two alleles to occur that is why ALS may occur late in life.
This two-hit model of development was proposed by Alfred Knudson and his colleagues for cancer, like heritable breast cancer, ovarian cancer and cancer of the lens of the eye (Cummings, M. Human Heredity, Principles and Issues. 2009:289). It might just as well work in FALS and ALS.
Inherited spontaneous mutation. This occurs in the development of the mother’s egg and the father's "seed" before they ever meet in the process of fertilization. A spontaneous mutation - during meiosis - consists in (1) a deletion (loss) of a nucleotide, or (2) substitution of a nucleotide, or (3) rearrangement of nucleotide sequence, or (4) frameshift mutation. Nucleotides make up a gene. The fetus that develops from the fertilized egg carries a mutated Sod 1. If the natural sequence were GTC but rearranged into TGC mutation results. (G means guanine; T means thymine; C means cytosine).
Sclerosis consists in degeneration or loss of axons or nerve cells and decay of the myelin sheath that protects the axons (Morales, Y. et al. “The Pathology of Multiple Sclerosis: Evidence for Heterogeneity.” Advances in Neurology. 2006.8:28).. The nerve cell is like a copper wire that carries electricity (message); myelin sheath is the insulator that also contributes to message transmission. They can be damaged by free radicals and reactive oxygen species (ROS). A free radical is any atom or molecule or fraction of a molecule with at least one unpaired electron like O2- (superoxide with 2 atoms of oxygen and one unpaired electron). That unpaired electron will grab another electron of a nearly molecule or tissue resulting in injury. A ROS acts like a free radical in that its unpaired electron will also grab an electron of another molecule.
There are cells or tissues of the body that replace themselves in a process called apoptosis or programmed cell death. For example, blood cells undergo apoptosis every 120 days; that is, the 120-day old blood cell is replaced by a new one. Even bone cells undergo apoptosis. However, there are cells that do not renew themselves, like cardiovascular cells (heart, artery, vein, capillary), brain cells and nerve cells. If nerve cells renewed themselves, the damage done on them would be thrown away by apoptosis. Apoptosis differs from cell death that involve inflammation. The nucleus of a cell that apoptose shrinks. The apoptosed cell is engulfed by neighboring healthy cells that dispose them of.
We are assured of the services of nerve cells by the fact that a lot of them are produced once only in the lifetime of man. However, not all of them are put to use; some of them are put aside as reserves. When those in use get damaged, the reserves take their place. These reserves can be damaged by free radicals and ROS. That is why it pays to protect the reserves.
(I have a Hub “A Supplement To Prevent and Treat Multiple Sclerosis (Destruction of Nerves”).
Free radicals and reactive oxygen species
Yesterday, I visited and talked with a family friend who is afflicted with ALS. I cheered her up, assuring her that she will recover as I am recovering myself from myocardial ischemia (with angina as symptom). Ischemia is caused by free radicals like superoxide and ROS like hydrogen peroxide, hydroxyl, lipid peroxide, and peroxynitrite.
Let’s review the meaning of some terms. This review also shows a chain reaction in the production of free radicals and ROS.
Mutation results from some changes in the chromosome, the inheritance material, like shortening, deletion, substitution, and thickening. Mutation causes changes in appearance and work of affected cells or tissues.
Gene is a part of chromosome. The gene is the location of the genetic code or information, Sod 1, that controls the work of the enzyme copper/zinc SOD (Swartz, et al.).
The reason for being of superoxide dismutase (SOD) is superoxide, indicated as O2-. The first to be discovered was SOD. So the reasoning went "There must be a reason for SOD to be there." Then O2- was discovered only in 1969. SOD neutralizes O2-, the master free radical.
Superoxide is a molecule with two atoms of oxygen bound together by six electrons with one free unpaired electron that makes it a free radical. It was formerly a molecular oxygen (O22-) that had grabbed one electron. O2- is paramagnetic that is why its grabbing is strong, like a magnet. To demonstrate: put a small piece of iron inside a toy balloon before inflating it. The balloon is like a cell. Then pass a magnet on the surface of the inflated balloon. The iron jumps to the magnet. When you move the iron away from the balloon the magnet and iron stuck together will prick the balloon open - that is like an injury in a cell. The magnet is like the unpaired electron; iron inside the balloon is like another electron. Injury consists in the pricking of the balloon and the change in the molecule inside it whose electron, the iron in this demonstration, had been grabbed.
Some sources of superoxide are: (1) Cyclooxygenase, (2) adenine dinucleotide dehydrogenase, an enzyme in the mitochondria, (3) xanthine oxidase, (4) nitric oxide synthase, and (5) cytotochrome P450 monooxygenase (Spieker, L. E. , A. J. Flammer and T. F. Luscher “The Vascular Endothelium in Hypertension.” The Vascular Endothelium II.2006.249-283).
Superoxide (O2-) reacts with nitric oxide (NO) resulting in peroxynitrite with one free unpaired electron. NO is released by the inner wall of the artery called endothelium. It is a messenger for the relaxation of artery to make the flow of blood easier.
Peroxynitrite (ONOO-) is a reactive oxygen species (ROS); it catches NO three times faster than superoxide does, reducing the supply of NO. More on the definition of free radical and ROS below.
O2- oxidizes (destroys) L-arginine, the precursor of NO resulting in reduced supply of NO that can lead to hypertension, angina, stroke and heart attack.
O2- causes damage by grabbing one electron from another molecule that belongs to a tissue resulting in injury. That injury results in mutation.
Superoxides react with each other, catalyzed by SOD, producing hydrogen peroxide.
Superoxides reacting with each other in the presence of iron results in hydroxyl radical which is more destructive than superoxide (Sharma, H., MD. Freedom From Disease. 1993).
O2- oxidizes low-density lipoprotein of fats into lipid peroxide, a ROS, that grabs a molecular oxygen with its two unpaired electrons intact resulting in another ROS.
O2- taking an electron away from hydrogen peroxide results in hydroxyl radical.
O2- in excess of the threshold of SOD results in singlet oxygen, another ROS (Cranton, E., MD and A. Brecher. Bypassing Bypass. 1984:200).
Ultra violet rays energizing water in the skin results in hydroxyl radical (Brown et al. Chemistry the Central Science. 2nd ed.). The energy is at least 1216kcal/mol.
Sources or causes of free radicals and ROS outside the body are: (1) ozone, from the atmosphere, (2) ultraviolet rays that energize molecular oxygen, the one that we breathe, into singlet oxygen, (3) lead 210 and polonium 210, radioactive materials found in tobacco and smoke; they decompose into lead 206 emitting X-rays and generating free radicals, (4) ultraviolet rays energizing water in the skin resulting in hydroxyl, (5) sparks of electrical gadgets that create ozone, (6) pollution, nitrous oxide (7) nitrobenzene, (8) nitrosamine, meat preservative, (9) carbon tetrachloride, (10) trichloromethyl, (11) uranium, that decomposes to polonium 210 and lead 210, (12) sun that radiates thorium that decays to polonium 210 and lead 210, (13) pesticides, including insecticides, herbicides, fungicides and molluscicide, (14) red tide in a species of mollusk, can be used as a biological weapon, (15) saccharin, an artificial sweetener used in soft drinks; a leading brand is now banned by 17 states of the United States; toluene had been found as by-product in saccharin production; toluene is a carcinogen, (16) hydrochlorous acid, "a brutally destructive combination of hydrogen peroxide and chlorine" (Sharma, H. MD. Freedom from Disease. 1993:47). Sharma listed more external sources. Inside the body, the super generator of free radicals and ROS is superoxide..
So, hydroxyl radical (OH•) is produced in three ways. Take note of its one unpaired electron, indicated by the superscript dot, ready to grab another electron. Hydroxyl radical is the "most destructive free radical" (Sharma, H. MD. Freedom from Disease. 1993:45). It can damage lipid (fat) membrane of the cell resulting in lipid peroxide. It inflicts damage on membranes, enzyme, vitamin C and DNA. The extra unpaired electron is like a basketball that passes from one player to another until it finds the ring. Everyone that it touches is a hydroxyl radical. It passes on at a great speed in its lifespan of 0.000000001 of a second. It is very unfortunate that hydroxyl radical is involved in FALS and ALS.
Hydroxyl radical is different from the plain hydroxyl indicated as OH-. Water ionizes (separates) into hydrogen and hydroxyl ions, as follows:
H2O reversible reaction H+ + OH- (hydroxyl)
Hydroxyl is involved in acidic or basic solutions. A solution with more hydrogen ions than hydroxyl ions is acidic (Tortora, J. G. and J.F. Becker. Life Science. 2nd edition. 1978:27).
Hydroxyl does not grab any electron from another molecule.
In one pathway, hydroxyl radical is formed as follows:
Sun's energy moving to higher state an electron of H2O forms H2O+
H2O+ + H2O form H3O+ (hydronium) + OH• (hydroxyl radical).
Superoxide dismutase (SOD)
SOD catches or neutralizes superoxide radicals to prevent them from doing damage. If both alleles of Sod 1 that control SOD are mutated, SOD will not work. SOD is very important because it neutralizes the master free radical superoxide. SOD attaches one proton to one electron of superoxide resulting in one hydrogen atom then attaches another hydrogen atom resulting in hydrogen peroxide, indicated as H2O2, a ROS. The equally destructive H2O2 is dismantled by glutathione peroxidase converting it to safe water.That means without the glutathione enzyme system (glutathione peroxidase, glutathione reductase, glutathione synthase), SOD neutralizes superoxide but produces hydrogen peroxide, in turn, a hazardous ROS. Glutathione peroxidase donates one electron to hydrogen peroxide that turns to safe water. Glutathione reductase donates one electron to glutathione peroxidase to replace that one electron it used to dismantle hydrogen peroxide, recycling it. Glutathione synthase makes glutathione (Sharma, H. MD. Freedom from Disease. 1993).
There are two kinds of SOD that differ in composition and area of assignment but work the same way. Cu/Zn-SOD protects the plasma of the cell; the manganese SOD (Mn-SOD) protects the mitochondria, a particle inside the cell responsible for production of energy or adenosine triphosphate (ATP). ATP drives reproduction, cell maintenance and growth.
What are my bases in cheering up our family friend?
As I said my angina is ultimately caused by free radicals and ROS. Angina occurs because the arteries conveying blood to heart muscles are narrowed such that heart muscles are starved for oxygen. Such narrowing is caused by free radicals and ROS. The usual counter to angina are medications, angioplasty and heart artery surgery. I was diagnosed as a candidate for heart surgery. I opted to go for infusion chelation therapy whose main active agent is EDTA (ethylene-diamine-tetra-acetate).
EDTA is an antioxidant that captures oxidants like free radicals and ROS, it also removes iron whose presence induces the formation of hydroxyl. As a counter to FALS and ALS, intravenous (IV) chelation therapy would catch extra superoxides, peroxides, hydroxyl and other ROS. The aim is to balance oxidants and antioxidants. Protection for nerves cells in use is, at the same time, protection for nerve cells in reserve.
A dramatic demonstration of the lack of antioxidant is the disease called progeria. This lack is almost equivalent to SOD not working. Progeria is a heritable lack of built-in antioxidant (SOD, glutathione peroxidase, glutathione reductase, catalase). The fellow, whose body looks similar to that of a victim of ALS, dies of biological old age when he is only about 10 years old by the calendar. Some cases of progeria had been treated by the infusion of peroxidase (Cranton, F. MD and A. Brecher. Bypassing Bypass. 1984).
When I started IV chelation therapy I was diagnosed as high risk for heart disease, hypertensive, and with frequent episodes of angina. After 34 sessions of IV chelation therapy (administered at 250 ml per session) I am diagnosed as: risk of heart attack is eliminated, hypertension is controlled, free from angina episode, and my plaque had been reduced by at least 30%. Before, my status was in treatment mode; now in maintenance mode which means I should have one IV chelation per 3 months. I am much stronger now. These results came from reduction of free radical and ROS overload, erosion of plaque, removal of catalysts of free radical and ROS production, healing of cell receptors and inner wall of artery with endothelium progenitor stem cells. I have supplemented my IV chelation with antioxidants, like vitamin C, coenzyme Q10, EPA flax, and brewer's yeast (chromium). I am also taking juice of noni (Morinda citrifolia L.) that contains several antioxidants (Fontanilla, C.D. Benefits Derived from PhilNONI. 2008). If I want to reduce my plaque faster down to almost 5% I must go for IV chelation at 2 sessions per week to complete 45 sessions in all. I will go for more sessions when my finances permit.
New entries as of April 8,2014. The Institutes of Health of USA has found chelation therapy as safe and effective. A double blind randomized with control study called "Trials to Assess Chelation Therapy" TACT was conducted in 2002 though to 2011. Results were presented at a meeting of the American Heart Association held on November 4,2012 held in Los Angeles, California.
(I have a Hub “USA (Institutes of Health) Has Announced Chelation Therapy as Safe and Effective”). End of new entries.
Stem cell therapy
The bone morrow produces stems cells that can be grown to repair damaged tissues. For example, hematopoietic stem cells, also obtainable from cord blood, can be grown to replace blood cells. That is why cryopreserved cord blood is used in the treatment of leukemia. Stem cells can regrow damaged liver or earlobe.
[Leukemia is cancer of white blood cells that overgrow in population, crowd out and suppress red blood cells which fail to carry oxygen] .
Produced by bone marrow, the endothelium progenitor cells (EPC), stem-cell-like cells circulating in the blood, repair the inside wall of an artery (Moreno, O.R. et al. “Promoting Mechanisms of Vascular Health.” Journal of the American College of Cardiology. 2009. vol. 53, 25:2315). Relief from IV chelation does not come immediately like from a treatment with antibiotics. One gets the full benefit from a prescribed program of IV chelation "90 days" after completion of therapy (Cranton, E., MD and A. Brecher, Bypassing Bypass, updated edition. 1984). EPCs had done their job in healing.
Unfortunately, stem cells can be damaged by free radicals and ROS. Fortunately, neutralization of free radicals and ROS also protects stem cells.
Hematopoietic cells to grow must be free of free radical damage, especially their chromosomes. They should not have been pre-aged, according to Doug Wallace, Director of Center for Molecular and Mitochondrial Medicine and Genetics (Bellomo, M., The Stem Cell Divide. 2006:184-95). Damaged chromosomes may result in tumor or cancer. Wallace said that Dolly, the cloned sheep, did not live long because old and damaged stem cells might have been used in cloning it.
“It (stem cell therapy) also offers the possible growing of whole organs to replace totally damaged organs using the patient’s own stem cells and thereby avoiding organ rejection” (Halos, S.C. Ph.D. Stem Cell Therapy, Significant Change Stories. 2007:97-98, parenthetical mine). Dr. Halos is a geneticist.
Stem cell therapy consists in growing stem cells that differentiate and replace damaged tissues or organs. To recall, a human being starts as one stem cell - the fertilized egg. Following an irreversible order, a human being starts as a totipotent stem cell; that differentiates into pluripotent stem cells; that differentiate into multipotent stem cells; that differentiate into unipotent stem cells; that differentiate into adult stem cells; that produce specialized cells like skin, bone, heart, nerve cell, arms, kidney, liver -- finally a man or a woman (Bellomo, M. The Stem Cell Divide. 2006).
Chelation therapy augments stem cell therapy that rebuilds muscles and nerves - the ultimate goal in countering motor neuron disease or amyotrophic lateral sclerosis (ALS).
New entries as of Feb. 13,2012
A suggested protocol in treating FALS or ALS consists of:
1. Protection of the victim from further damage by free radicals and ROS. Since the CU/Zn-SOD is almost no longer working, something must take its place. It is like the heart-lung machine that takes the place of the heart during coronary artery bypass surgery. Antioxidants, especially IV chelation therapy, must be administered.
Dr. Cranton reported of progeria having been treated with glutathione peroxidase that dismantles the hydrogen peroxide produced from superoxides. Glutathione is made by glutathione synthase out of glutamate, cysteine. cystine and co-factors selenium, zinc, and B-2 that are available from food, and lipoic acid which the body makes.
To recall, a lot of axons are produced once in the lifetime of man/woman. Some are put to use others are held in reserve. When those in use conk out, the reserves take their place. There is a good chance that the reserves are still healthy to take the place of the damaged ones.
2. In stem cell therapy, use of stem cells other than those from the same person suffering from FALS or ALS. The reason is that her/his stem stems might have been damaged by free radicals and ROS. Stem cells to use must come from healthy donors. Take it from blood transfusion: blood from one with hepatitis, or infection, or who had drunk alcohol, or with a tattoo cannot be used.
Cord blood can be used. Cord blood, rich in stem cells, can be harvested in two ways: One, when the umbilical cord had been cut and the placenta has not yet been ejected. There is an interval of seven to ten minutes to harvest. Two, cord blood can be harvested after the placenta had been delivered. Cord blood is cryopreserved in liquid nitrogen in cord blood banks (Bellomo, M. The Stem Cell Divide. 2006). It pays to deposit in a blood bank the cord blood of your baby for future use, in case s/he will be afflicted with leukemia, FALS, ALS, or other free radical diseases.
Recent development in stem cell therapy
Editing as of Sept. 5,2013. The adult cell can now be used in stem cell therapy. This is advantageous because a person who needs the therapy can have his adult cell grown in culture medium then administered on him. That way, there is no problem about rejection. An adult cell can now be reprogrammed into multipotent stem cell.
Dr. Arturo V. Estuita, MD, a Filipino internist and chelationist is now administering stem cell therapy. The active ingredient is plant-based.
Actually the function of the administered stem cell is to incite the native stem cells to undergo differentiation. This is along the stem cell-organism theory that I have propounded