hypothetical moral dilemma for a doctor


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1 hour ago, jts said:

The probability of a rock from the sky hitting you is very small. Do you worry about that?

Ayn Rand smoked and got lung cancer as she deserved. (Greg the moralist probably would say.) If she had lived more rationally, the universe would have been more safe and benign to her.

Her smoking helped her be a writer. Nicotene helps the mind disregard extraneous noise. That's why old time newspaper rooms were filled with cigarette smoke. What she "deserved" was to be a great writer of great novels and not to be lectured about it through and to proxies like me. Smoking as a moral issue belongs primarily to the smoker, family and, maybe, some friends.


and times change context

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13 hours ago, jts said:

The probability of a rock from the sky hitting you is very small. Do you worry about that?

Ayn Rand smoked and got lung cancer as she deserved. (Greg the moralist probably would say.) If she had lived more rationally, the universe would have been more safe and benign to her.


No I don't.  For two reasons.

1. The chances of being hit by a palpable object falling from outer space is very small

2. Aside from living in a cave, the is no practical way of preventing such an improbable event from happening to me.

Therefore I do not concern myself with such low probability happenings which I cannot prevent in any case.  If it happens it happens.

The universe is not benign. The universe is not malicious.  The  universe (taken as a whole) is not a conscious entity therefore it cannot have -intentions-  benign, malicious or otherwise.  We are all children of chance and happenstance.  Each and every one of us is an accident. 

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On 1/30/2017 at 1:16 PM, jts said:

Mayfield says on average the medical profession makes about one million dollars per cancer patient. Multiply that by the number of cancer patients. About one third or so of the population will get cancer in a lifetime, so I'm told. In a population of 300 million, perhaps a million per year. That works out to a lot of money for the cancer industry, a million times a million per year.

Mayfield seems to have said a lot of things about medicine, from the 'natural' point of view, but there are errors in reasoning here, if Jerry has accurately paraphrased him.

First, the  'miliion dollars per cancer patient.'  That is unverifiable, a guess, an estimate, and we don't know which of the hundred-odd videos contains his estimate. 

Second,  multiply a million by a million.  A million cancer patients a year, Jerry estimates. 

One million times one million is ... 1,000,000,000,000. One trillion dollars a year for the "cancer industry."  And what is the estimated entire health-care expenditures for the United States?  I estimate it at or above 3 trillion dollars per year.



Now imagine you are a doctor in the cancer industry

Sure. Although I don't accept the presumptions of Jerry, that all medicine is quackery, and that only Hygiene can serve human health. And although I don't accept his claims that all cancer treatments are based on returns or profits to an 'industry' that means only harm to its patients.

I am going to imagine myself as a specialist cancer doctor, and I am going to imagine myself as the kind of doctor that does research. In other words, I am a cancer industry  innovator as well as a physician. I count myself in this imaginary state as a scientist.


and imagine you are an ass hole

This is a bit confusing, perhaps by ironic design. An 'asshole' in Bizarro World is someone who bucks the trend of punishing patients. This kind of asshole is actually seeking to provide the best, most evidentially-supported treatment for childhood leukemia.


and you come up with a way to completely reverse cancer

Along with colleagues, I have researched and developed a treatment protocol for common childhood leukemia. I do not proclaim anything like that our protocol 'completely reverses' the leukemias we study and treat.  My claims are less categorical, and are supported by the common kind of statistics on cancer mortality.  

In other words, the treatment protocols we developed and tested and put into practice claim only that our treatment is superior in terms of 'remission' to any other treatment (or non-treatment).  Our studies have shown that our protocols extend the 'survival rate' at five years, ten years, and so on.  What we specialize in is acute lymphoblastic leukemia. As other cancer industry types understand, this was -- until the work of our lab and international colleagues beginning in the 70s -- a particularly cruel disorder.  It was -- until the work noted -- almost invariable fatal. By 1997 our efforts at the research hospital helped to bring down the mortality level from near 100% to 30%.  

Today the long-term survival rate for ALL is around 90%.  What was once a death sentence ...

 Colleagues, of course, are not standing still. This month our team was much encouraged by a study in Cell, which speaks to genetic causes of mixed lineage leukemia**.  And we continue to involve ourselves with the scientific work of understanding the disease process, most notably in the newest subfields of treatment,  immunotherapy, notably using Chimeric Antigen Receptors.  Also promising is stem-cell transplantation.



for ten thousand dollars per cancer patient.

There is a difference between the price, the cost and the value.  At our imaginary Cancer Institute, no child who is ill is turned away because of inability to pay.  What price does one put on an effective 'cure' for your child's otherwise fatal illness?


We will assume this is real and not quackery and your cancer patients are restored to health. Now you find yourself impaled upon a serious moral dilemma.

Well, we have to carefully remove your ironic/Bizarro frame of view.  The reduction of death is real (not imaginary) and the children are indeed restored to health.  There is no dilemma for me and the team and my colleague and the research labs and the treatment hospitals. We are ordinary human beings with ordinary motives. We seek to reduce to zero the mortality rate for those childhood cancers we specialize in. 

One can either accept that we all have base commercial motives (what is good for cancer is good for us) or that we are generally as we say we are: interested in remission and a future permanent 'cure.'

Does this set us aside from a hundred-odd videos from a naturopath and expert in Oriental Medicine? I think not, but mileage may vary according to psycho-epistemology and investigation.



"Mixed lineage leukemia is caused when an errant chromosome 11 on the MLL gene breaks and attaches to other chromosomes such as chromosome 19, where it doesn't belong," said Liang, the paper's first author. "The mutation produces a protein that drives the pathogenesis of leukemia."

Most research related to this cancer has focused on the errant version of chromosome 11. But there are two copies of chromosome 11, and the Shilatifard group wanted to investigate the wild-type version. Shilatifard's laboratory discovered that individual cells with the pediatric leukemia had extremely low levels of a protein produced by the wild-type MLL gene. Shilatifard and Liang reasoned if they could beef up the levels of the wild-type MLL protein, it would displace the mutated version that drives cancer, and it could cure leukemia.

Through their detailed molecular and biochemical screens, Shilatifard's lab identified a compound that stabilized the wild-type MLL and interfered with the mutant protein driving leukemia. To test its effectiveness, in collaboration with John Crispino's lab of Northwestern University and his fellow Andrew Volk, they grew mixed lineage leukemia cells in a culture and transplanted them into mice. They then injected the therapeutic compound into the mice. The result: the wild-type MLL bounced back to healthy levels, and the leukemic cells were not able to grow as rapidly.

Northwestern scientists are now synthesizing better compounds and hope to eventually launch a Phase I trial to test these compounds in Chicago.

Edited by william.scherk
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I thought I expressed the question clearly but maybe I did not.

By 'restoration to full health' I do not mean the growth of the cancer slows down. I do not mean even merely that the cancer stops growing. I mean the cancer is totally reversed so there is no cancer, and more than that. I mean complete reversal of both the cancer and the underlying condition that gave rise to the cancer. And to be clear, if that is not clear enough, I do not mean it's about management of a disease or an underlying condition. I mean as I said, restoration to full health, and nothing more is required except to live a healthy lifestyle to stay that way.

When I postulate 10 thousand dollars, I do not mean per month for the rest of the patient's life. I was reading about someone paying $9000/month for gleevec and another person paying $6000//month for gleevec. This is not what I mean. I postulate $10,000, a one time deal, nothing more, full restoration of health as above described.

Spending thousands of dollars per month every month for perhaps the rest of one's life, and without reversing underlying causes, is not my idea of shutting down the cancer industry or reducing the size of the cancer industry and is not my idea of full restoration of health.

Obviously any doctor who would successfully help a cancer patient to achieve full restoration of health as above described would be an ass hole. Look at what he would be doing to the cancer industry. You probably would call him a bunch more things.

But he would be doing more than helping people to go from cancer to full health; he would educate people on how to not get cancer or other diseases. That's really scary. Look at how many people in the cancer industry would lose their job. And not just the cancer industry.

Do you see the ethical dilemma?


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2 hours ago, jts said:

I mean the cancer is totally reversed so there is no cancer, and more than that. I mean complete reversal of both the cancer and the underlying condition that gave rise to the cancer.

Long may you live, Jerry. I think you will be most interested in the next twenty years of advancement in two promising areas -- genetic therapies and the products to come from the present CRISPR revolution. These both give signs they may very well deliver complete reversals, by repairing at the DNA level, error syndromes that lead to cancer.

I don't see research and treatment in these areas as driven by bizarre and evil motives. That is the Hygiene delusion, to my mind, ideological and unsound.  

In an earlier discussion I invited you to explore these areas outside the paradigm of cut, poison, burn. Between now and a hundred years from now some of these destructive syndromes will be CRISPRed out of existence. Exactly what you hope for. The perfect is enemy of the good.

The basic underlying error or bizarre conclusion of Hygiene is I think the presumption of purity, a state of grace. That without pollution and bad living, no diseases could have a chance to root themselves in the human. Support can be given to this notion by "lifestyle diseases" and much statistical proof of dis-health imputed to a standard diet. But one also has to look at the other counter-evidence and the crazy notions about germs, vaccines and 'toxins.' Here it is clearly rational to understand some disease processes as 'un-luck' or mutation that escape error-removal in a genome, or as infections, as physical processes worthy of concerted study.  It isn't helpful to research to presume each of these syndromes as the fault of un-natural living.

Hygiene blots out the entire edifice of medicine as a curse, a parasite, a quasi-demonic force against Natural nature. After a certain point of repetition these seem like cult doctrines, immovable and incorrigible. That sounds rude, but they do not move an inch. The medical system is rotten quackery top to bottom, discipline by discipline, rotten rotten and crazy with malice. That's been a line for all this time. No exceptions.

I don't think anyone will convince Jerry that even one tiny corner of medicine outside bonesetting and warm blankets is the better choice than an idyllic and somewhat magical Hygiene.  It is difficult for to find community here on these issues because central positions on medicine seem contrary to reason.

Anyway, the hypothetical is too contrived and based on errant assumptions. It cannot deliver a lesson.  The ethical dilemmas of medicine do not consist of evil rapacious industry versus pure sweet nature versus cancer which is all your own fault. Hygiene in the Shelton sense is a non-starter when speaking of scientific medicine in this area.  It stopped making any sense in 1943.

When you find yet another Youtube 'doctor' dead or alive, or other remaining outpost of Hygiene belief in the world, I hope you bring it up. I really enjoyed researching the guy who administers water fasts down in the jungle. A self-imposed Auschwitz without hard labour. Skinny people going for weeks of water cleanse and turning out as full-on Angeline Jolie photoshop have a fucking sandwich.  Sad.  There is a strange poignancy in this attachment to pure nature.  There aren't that many full Hygienists like that in the world, and it might be by magic an aspect sticks to Randian forums. 



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Will genetic therapy cause people to have no effects from nutritional deficiencies, poison excesses, sleep deficiency, insufficient exercise, and so on? Will genetic therapy make healthful living irrelevant? I don't think so. Give it another 10 or 20 or 30 years and we will see how it develops.

Let's say the damage to DNA is corrected by editing it. Will the patient go back to the lifestyle that caused the damage to the DNA and expect the DNA to not be damaged again? Is editing the DNA really getting at the root causes? If not, you can expect the effects to happen again.

About hygiene. Let's start with a definition. Hygiene is the science of health. Hygiene is not a body of doctrine. Hygiene is not Sheltonism. Hygiene is not fasting. Hygiene is the science of health. As the science of health, it includes nutrition as part of it. And physiology and digestion and exercise and sleep and everything else to do with the science of health. To be opposed to hygiene is to be opposed to the science of health. What would you suggest as an alternative to the science of health as a way to restore and preserve health?

About deaths during a fast. This is exceptional. Why is it that when a death happens at a fasting place, the doctor gets blamed; but when a death happens in a regular hospital, the doctor does not get blamed? Did you never hear of diseases and deaths caused by legit government approved doctors. Double standard.

At TrueNorth, Dr. Alan Goldhamer's place, the last I heard they had supervised 15,000 fasts (fifteen thousand) without a single fatality.

There are dangers to fasting. There may be worse dangers to not fasting if the patient's health requires a fast. There are dangers to many things -- guns, knives, cars, fire, electricity. But if you are aware of the dangers and take the necessary precautions, you can handle these things safely. With ignorance there is danger, with knowledge there is safety, as much safety as the patient's health permits, in some cases he was going to die anyway.

 Fasting is not starving. The difference between fasting and starving is during a fast the body lives on expendable tissue such as fat; and during starving the body has run out of expendable tissue and is consuming nonexpendable tissue such as muscle. Fasting is not starving, and starving is not fasting. Consuming fat and consuming muscle are 2 very different events with very different effects.

We have fat for a reason. Obviously there is such a thing as too much fat (obesity) but fat serves a survival function, we can go without food for weeks without harm to health if we do it right.

I'll tell you what. If you don't trust Doug Graham because he is dishonest or whatever, and you don't trust Loren Lockman because he is self taught and he didn't learn it right and he is too much of a risk taker, and you don't trust Alan Goldhamer because he is not enough of a risk taker because maybe he is afraid of lawsuits, you have another fasting option. You do it all by your lonesome on your own responsibility if you know what you are doing. Maybe some emphasis should be put on that last part -- 'if you know what you are doing'.

Do not wish me long life; you might regret it.

In April 2000, they diagnosed me with ALS and according to stats I had 90% chance of dying within 5 years of diagnosis. I learned all I could about ALS and I didn't believe them when they said the cause is unknown. ALS can be produced in lab animals at will by a clearly understand process. I asked the doctor a question or 2 and it was obvious he didn't know anything. Then I lectured him and to my surprise he listened to me. Later I learned from another doctor that he was impressed by my knowledge. The doctors should have been ashamed of themselves. They were supposed to lecture me.

In April 2006, they changed the diagnosis. It was not ALS. The tip off was I had no symptoms above the neck. It was a a tumor on the spinal cord in the neck, causing symptoms similar to the symptoms of ALS but only below the neck. Surgery was not an option. By this time I had developed changes in eating habits applicable to both ALS and tumor. My rate of deterioration had slowed down. 

In April 2009, a bump on my left foot vanished during a fast. Right idea, wrong tumor. I was trying to get the spinal cord tumor to go away, I didn't give a rat's butt about the bump on the foot. But it was a nice sign that it might yet happen. Prior to that fast I was eating what I call an anti-tumor diet. This consisted of minimizing pro-tumor things and maximizing anti-tumor things.

I did a few more fasts over the years and an anti-tumor diet. All the fasts were without supervision, most short, the longest 22 days, which is medium length. I was unwilling to do a long fast without supervision and I was hoping a series of short fasts would equal a long fast. But it doesn't seem to work that way. I learned from Shelton that some problems can't be solved by a series of short fasts but require a long fast. I learned from Loren Lockman that the relationship between the length of a fast and the value of the fast is not a straight line but a curve. Doubling the length of a fast more than doubles the value of the fast. I figured I needed to do a fast of more serious length.

I learned from Alan Goldhamer that during a fast, changes happen in the body and these changes can persist after the fast and presumably accumulate from fast to fast. I learned from Dr. Moser that if you do a series of fasts, that the body adapts to fasting and it becomes easier.

My most recent fast was shortly before winter 2016. I had not done any serious fasting since 2012, the 22 day fast. I had some concern that maybe I was out of practise.  I figured it was time to give it another go, I was putting it off for a bunch of reasons. I did not expect anything to happen unless it was a fast of more serious length than any previous fast and it had to be without supervision. I lasted only 15 days. I know from experience that during a fast I must be warm and this is not optional, being cold during a fast can destroy the fast, speaking for myself. For me, sleep is important during a fast, a fast is a good fast or a bad fast depending on sleep in my experience, but cold disturbs sleep. The result is energy deficiency, both from cold and from sleep deficiency. During a fast, the metabolism slows down, tending to reduce body heat. In addition, one of the effects of the spinal cord tumor is reduced body heat. The loss of muscle mass caused by the tumor over the years probably didn't help to produce body heat. In spite being cold, I was okay the first 14 days, no symptoms, no weakness. The 15th day I collapsed. My safety policy always was if anything went wrong and it didn't get corrected in a day or so, I would terminate the fast. On the morning of the 15th day, I started to get up, my head off the pillow. I'm not quite sure what happened, the next thing I remember was I was dizzy and wondering where I was. It seemed like I momentarily lost consciousness. I was so weak that day that I figured I can't handle this weakness and the next day I took the electric scooter out and bought some nicely ripe tomatoes and broke the fast.

Perhaps of some relevance is the following from Shelton in the Science and Fine Art of Fasting:

Fasting patients should not be permitted to remain cold. They are inclined to chill easily and if nurse or doctor is careless, such patients can freeze to death even in July or August; and they certainly will freeze to death in the winter time unless they are carefully attended to.  

But that is not the end of the story. I noticed 2 effects after the fast, a slightly negative effect and a positive effect. On the negative, for a few weeks I had brief mild dizzy spells. Nothing serious or problematic, just puzzling. A dizzy spell was mild and lasted maybe 2 or 5 or 10 seconds. But that is completely gone now.

The positive effect took me by surprise. I wasn't expecting it. I wasn't expecting anything to happen in a fast so short as 15 days, and a poor fast at that. For the first time in a long time, I could lift my left foot off the floor when walking. Previously it was always dragging, either heavily or lightly depending on sleep. I thought maybe this was a temporary effect but it persists to this day. I noticed that even when sleep deficient, I can lift my left foot off the floor. Unless there is something I'm not understanding, this is the first unmistakable sign that the spinal cord tumor is starting to reverse. Obviously it is hard to be sure what happened to the tumor because it is in a place where I can't see it; all I know or can guess about what is happening to the tumor is from the symptoms it produces. An interesting question -- how is it possible for a poor 15 day fast to accomplish something that was not accomplished by a good 22 day fast? Perhaps one of the mysteries of life. But I tend to think -- accumulative effects of the stuff I've been doing between then and now.

When I saw that I could lift my left foot off the floor and continued to be able to do so, I figured I absolutely must do another fast to finish the job that began during this fast. I found myself being eager to begin the next fast, which is unusual for me. But not yet. Winter is not a good time. The next fast I want to be warm and do it right.


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Some people will always do unhealthy things.  Before the Stupidity of Man  even the Gods are powerless.

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13 hours ago, jts said:

ALS can be produced in lab animals at will by a clearly understand process.

There is a mice model:



Scientists create mice with a major genetic cause of ALS and FTD

NIH-funded study provides new platform for testing treatments for several neurodegenerative disorders.

Scientists at Mayo Clinic, Jacksonville, Florida created a novel mouse that exhibits the symptoms and neurodegeneration associated with the most common genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), both of which are caused by a mutation in the a gene called C9ORF72. The study was partially funded by the National Institutes of Health and published in the journal Science.

More than 12,000 Americans may live with ALS, which destroys nerves that control essential movements, including speaking, walking, breathing and swallowing. After Alzheimer’s disease, FTD is the most common form of early onset dementia. It is characterized by changes in personality, behavior and language due to loss of neurons in the brain’s frontal and temporal lobes. Patients with mutations in the chromosome 9 open reading frame 72 (C9ORF72) gene have all or some symptoms associated with both disorders.

“Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with theC9ORF72 mutation,” said the study’s lead author, Leonard Petrucelli, Ph.D., chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and a senior author of the study. “These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments.”

To create the model, Ms. Jeannie Chew, a Mayo Graduate School student and member of Dr. Petrucelli’s team, injected the brains of newborn mice with a disease-causing version of the C9ORF72 gene. As the mice aged, they became hyperactive, anxious, and antisocial, in addition to having problems with movement that mirrored patient symptoms. The brains of the mice were smaller than normal and had fewer neurons in areas that controlled the affected behaviors. The scientists also found that the mouse brains had key hallmarks of the disorders, including toxic clusters of ribonucleic acids (RNA) and TDP-43, a protein that has long been known to go awry in the majority of ALS and FTD cases.

“This is a significant advancement for the field. Scientists have been trying to create mice that accurately mimic the pathologies associated with these forms of ALS and FTD,” said Margaret Sutherland, Ph.D., program director, the National Institute of Neurological Disorders and Stroke, part of NIH. “This mouse model will be a valuable tool for developing therapies for these devastating disorders.”

The C9ORF72 gene is encoded by repeating strings of six DNA molecules. Disease-causing C9ORF72mutations make the strings excessively long which leads to the accumulation of RNA that either cluster into structures, called foci, or cause the production of abnormal c9RAN proteins in the brain and spinal cord of patients. The scientists found both in the brains of the mice. They also found clumps, or inclusions, of TDP-43 protein which is another pathological hallmark found in patients with the C9ORF72 mutation.

“Finding TDP-43 in these mice was unexpected” Dr. Petrucelli said. “We don’t yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities, but with our new animal model, we now have a way to find out.”

Dr. Petrucelli and his team think these results are an important step in the development of therapies for these forms of ALS and FTD and other neurodegenerative disorders.



To the allied notion that if an ALS-simulacra can be induced in mice, then the same induction causes all ALS -- that is an unwarranted conclusion.  But the mice model does allow testing of new approaches to halting ALS progression:



New therapy halts progression of Lou Gehrig’s disease in mice

Researchers at Oregon State University announced today that they have essentially stopped the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, for nearly two years in one type of mouse model used to study the disease – allowing the mice to approach their normal lifespan.

The findings, scientists indicate, are some of the most compelling ever produced in the search for a therapy for ALS, a debilitating and fatal disease, and were just published in Neurobiology of Disease.

“We are shocked at how well this treatment can stop the progression of ALS,” said Joseph Beckman, lead author on this study, a distinguished professor of biochemistry and biophysics in the College of Science at Oregon State University, and principal investigator and holder of the Burgess and Elizabeth Jamieson Chair in OSU’s Linus Pauling Institute.

In decades of work, no treatment has been discovered for ALS that can do anything but prolong human survival less than a month. The mouse model used in this study is one that scientists believe may more closely resemble the human reaction to this treatment, which consists of a compound called copper-ATSM.

It’s not yet known if humans will have the same response, but researchers are moving as quickly as possible toward human clinical trials, testing first for safety and then efficacy of the new approach.

ALS was identified as a progressive and fatal neurodegenerative disease in the late 1800s, and gained international recognition in 1939 when it was diagnosed in American baseball legend Lou Gehrig. It’s known to be caused by the death and deterioration of motor neurons in the spinal cord, which in turn has been linked to mutations in copper, zinc superoxide dismutase.

Copper-ATSM is a known compound that helps deliver copper specifically to cells with damaged mitochondria, and reaches the spinal cord where it’s needed to treat ALS. This compound has low toxicity, easily penetrates the blood-brain barrier, is already used in human medicine at much lower doses for some purposes, and is well tolerated in laboratory animals at far higher levels. Any copper not needed after use of copper-ATSM is quickly flushed out of the body.

Experts caution, however, that this approach is not as simple as taking a nutritional supplement of copper, which can be toxic at even moderate doses. Such supplements would be of no value to people with ALS, they said.

The new findings were reported by scientists from OSU; the University of Melbourne in Australia; University of Texas Southwestern; University of Central Florida; and the Pasteur Institute of Montevideo in Uruguay. The study is available as open access in Neurobiology of Disease.

Using the new treatment, researchers were able to stop the progression of ALS in one type of transgenic mouse model, which ordinarily would die within two weeks without treatment. Some of these mice have survived for more than 650 days, 500 days longer than any previous research has been able to achieve.

In some experiments, the treatment was begun, and then withheld. In this circumstance the mice began to show ALS symptoms within two months after treatment was stopped, and would die within another month. But if treatment was resumed, the mice gained weight, progression of the disease once again was stopped, and the mice lived another 6-12 months.

In 2012, Beckman was recognized as the leading medical researcher in Oregon, with the Discovery Award from the Medical Research Foundation of Oregon. He is also director of OSU’s Environmental Health Sciences Center, funded by the National Institutes of Health to support research on the role of the environment in causing disease.

“We have a solid understanding of why the treatment works in the mice, and we predict it should work in both familial and possibly sporadic human patients,” Beckman said. “But we won’t know until we try.”

Familial ALS patients are those with more of a family history of the disease, while sporadic patients reflect the larger general population.

“We want people to understand that we are moving to human trials as quickly as we can,” Beckman said. “In humans who develop ALS, the average time from onset to death is only three to four years.”

The advances are based on substantial scientific progress in understanding the disease processes of ALS and basic research in biochemistry. The transgenic mice used in these studies have been engineered to carry the human gene for “copper chaperone for superoxide dismutase,” or CCS gene. CCS inserts copper into superoxide dismustase, or SOD, and transgenic mice carrying these human genes die rapidly without treatment.

After years of research, scientists have developed an approach to treating ALS that’s based on bringing copper into specific cells in the spinal cord and mitochondria weakened by copper deficiency. Copper is a metal that helps to stabilize SOD, an antioxidant protein whose proper function is essential to life. But when it lacks its metal co-factors, SOD can “unfold” and become toxic, leading to the death of motor neurons.

There’s some evidence that this approach, which works in part by improving mitochondrial function, may also have value in Parkinson’s disease and other conditions, researchers said. Research is progressing on those topics as well. 

The treatment is unlikely to allow significant recovery from neuronal loss already caused by ALS, the scientists said, but could slow further disease progression when started after diagnosis. It could also potentially treat carriers of SOD mutant genes that cause ALS.


This shows me that the practice and research underlying medical practice shows new fruit, gets us closer to dealing out ALS from the human deck.  To the contrary of this growth of understanding and power, Hygiene is still fixed in 1943, immobile. 

13 hours ago, jts said:
18 hours ago, william.scherk said:

Hygiene blots out the entire edifice of medicine as a curse, a parasite, a quasi-demonic force against Natural nature. After a certain point of repetition these seem like cult doctrines, immovable and incorrigible. 

Hygiene is the science of health. Hygiene is not a body of doctrine. Hygiene is not Sheltonism. Hygiene is not fasting. Hygiene is the science of health.  [...] To be opposed to hygiene is to be opposed to the science of health.


In my opinion, Hygiene is incorrigible doctrine. It is fixed and self-exiled from any correction or update. 


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1 hour ago, jts said:
3 hours ago, william.scherk said:
17 hours ago, jts said:
22 hours ago, william.scherk said:

Hygiene blots out the entire edifice of medicine as a curse, a parasite, a quasi-demonic force against Natural nature. After a certain point of repetition these seem like cult doctrines, immovable and incorrigible. 

Hygiene is the science of health. Hygiene is not a body of doctrine. Hygiene is not Sheltonism. Hygiene is not fasting. Hygiene is the science of health.  [...] To be opposed to hygiene is to be opposed to the science of health.


In my opinion, Hygiene is incorrigible doctrine. It is fixed and self-exiled from any correction or update. 

You don't know the history of hygiene.

Wrong.  But other folks on the forum might be entirely ignorant.  When did it start? Who wrote its major works? What brought it forth on the world? At what time did Hygienic approaches to wellness hit a 'peak'?  When were its major works of research published, and by whom? Which doctrines have remained intact in the world of Hygiene, and which have been set aside? Who teaches Hygiene in the world today?

Most compelling is the question: What makes it 'science'? -- I mean by what actual definition of science?


If I state "Hygiene is the Science of Health,"  and I am asked what was the last scientific update to Hygiene, I know enough of its history to answer honestly that it isn't able be corrected by input from allied sciences.  It is self-sealed in a way that geology is not sealed from advances in more basic physics, or that archaeology is not sealed apart from geography.

In other words, the only 'scientific allies' Hygiene has are outgrowths of an original Vitalism, themselves unable to be corrected and updated.  Medicine got rid of bloodletting and mercury for syphilis and burning out cancers with caustic salves, and has come closer to an evidence-based modality every decade of the post-war era.

The enemy of Hygiene, the anti-Science, the Medical Cartel, has banished smallpox, removed the death sentence of many common fatal diseases of the original Hygiene hey-day ... but on the Hygiene side not one single advancement  in treatment or understanding of disease processes has emerged. Not one correction. Not since 1943.

To de-personalize it ...

This pair of charlatans in the Central America jungle promise effective cures to a vast range of modern problems. But when confronted with simple medical supervision (as with Type I diabetes), they fuck up every time, because they have zero medical training. They cannot recognize danger signs of fasting going wrong. That was what fucked up Loren Lockman and his business in the USA. He botched the care of more than one person, presented his practice as quasi-medical, allowed his staff to act as medical technicians, and basically ran a clinic that killed a patient through stupidity.

The warning stories out of the jungles are three-fold. That extreme fasting is a now a cult led by exploitative and self-interested gurus. That extreme fasting is not medically supervised, which puts vulnerable people in danger. That extreme fasting is 'prescribed' by the 'supervisor' slash guru without any basic expertise in physiology.

These marks of malpractice are on the jungle gurus, who assume superior knowledge of human physiology, not on their patients/clients. What disgusts me further about Loren Lockman is that he is a dissembler, and has never accepted responsibility for the least error of his prescriptions. At any time he could have educated himself and his jungle clients about what really went wrong back home -- and what safeguards are now in place to prevent a like malpractice to that in Maryland.

It disgusts me that he lies to camera about what made him flee accountability. He didn't even have the guts to show up for his adjudication and defend himself, unlike his employee. He lies about what his errors were and blames his clients for any issue that has come to bite him. That basic unethical stance is beyond reason.  That is why I dismiss Lockman as an unethical quack.


Look, Jerry, my heart is with you, rather that with the chilly concept of Medical Sciences. I care more about you than I do an abstraction. I wish there was a solution to the inoperable condition of the spinal tumour that disables some activity.  That you lock yourself away with distilled water for a couple of weeks, taking to your bed, in the hopes of improvement or a cure,  and that you will one season go on a Lockman-length (33+) H-Block fast is disturbing to me in a way that damage to cult clients in the jungle is not. 

Ask yourself what could possibly change your mind about the truth or effectiveness of Natural Hygiene (and/or extreme fasts)?  If there is nothing brought to mind, then your adherence to Hygiene could be incorrigible.

That's why I think Reason and I are your friends where Shelton and the latter-day gurus of Hygiene are not. I am not in it to tear you down along with the false constructs you entertain. Coming out from your spell would benefit you, from my point of view. 

The terrible end of the H-Block strikers after forty-odd day fasts is what I remember. I remember reading the forecasts, which bodily systems would become damaged in what order on a water-only fast, which signs were initial, which effects were irreversible, which symptoms indicated death's final approach. 

Speaking of death's final approach, I like to think of Stephen Hawking, struck down young with fatal motor neurone disease, ALS.  He is the one in a hundred million  -- who ate a standard diet of stodge, lived in the toxic hell of England, and could yet survive the assault of ALS with his cortex intact.  Making those words and signs appear on a screen, to be heard. To explain the cosmos through the medium of a small twitch on his left cheek.

There is something uncanny about the tribe of folks attracted to Water-fasts in the Jungle.  I looked deeply into the stories that Lockman covers up or denies or dissembles about.  These folks already had bought into his Hygiene delusion that fasting was pan-curative, and they were indeed damaged.  There is something self-punitive and unbalanced about the forces that drive the believers into the charlatan's lairs. It is psychologically interesting how a body of belief can overrule reason, and how a person can best come out of a spell in thrall to such a body. 

Jerry up, Gurus down! Up Jerry, up Hawking, down the cult of starving oneself to life!


Edited by william.scherk
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This is the theory. My theory, so nobody else gets the blame. I will try to explain it clearly and slowly. I don't need to prove the theory to justify acting on it.

1.  During a fast, the body consumes expendable body tissue such as fat. It does not consume nonexpendable tissue such as muscle to any great degree until the expendable tissue runs out. When the fat runs out, it is no longer fasting but starving.

2.  Sometimes tumors autolyze during a fast, sometimes not. We can ask what makes the difference.

3.  My theory is whether a tumor is autolyzed during a fast depends on whether the tumor is expendable or nonexpendable. If it is expendable, it will autolyze. If not, then not. It may be possible for a nonexpendable tumor to become expendable during a fast. We can ask what makes a tumor expendable or nonexpendable?

4.  The tumor was made by the body. I do not expect the body to make the tumor and at the same moment to consider it expendable. To change a tumor from nonexpendable to expendable, we want to remove all justifications for its existence. That means remove all excesses, deficiencies, imbalances that justify or tend to justify its existence. How is this done?

5.  The purpose of the anti-tumor diet (as I call it) is to convert the tumor from nonexpendable to expendable. In the best case scenario this might be enough by itself to get rid of the tumor. There are stories where this seems to have happened. But it's probably a poor bet.

6.  The purpose of converting the tumor from nonexpendable to expendable is to prepare it for demolition during the fast.

7.  If the tumor is expendable, during a fast it will get consumed as a food source along with fat. When this happens it is called autolysis of the tumor.

(edit:  I forgot to mention that I'm talking about only a non-cancer tumor, not a cancer tumor.)


My purpose in fasting is autolysis. I have evidence that it has begun, even if to a small degree. I take this as evidence that the tumor has become expendable.


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3 hours ago, jts said:

This is the theory. My theory, so nobody else gets the blame. I will try to explain it clearly and slowly. I don't need to prove the theory to justify acting on it.

1.  During a fast, the body consumes expendable body tissue such as fat. It does not consume nonexpendable tissue such as muscle to any great degree until the expendable tissue runs out. When the fat runs out, it is no longer fasting but starving.

2.  Sometimes tumors autolyze during a fast, sometimes not. We can ask what makes the difference.

3.  My theory is whether a tumor is autolyzed during a fast depends on whether the tumor is expendable or nonexpendable. If it is expendable, it will autolyze. If not, then not. It may be possible for a nonexpendable tumor to become expendable during a fast. We can ask what makes a tumor expendable or nonexpendable?

4.  The tumor was made by the body. I do not expect the body to make the tumor and at the same moment to consider it expendable. To change a tumor from nonexpendable to expendable, we want to remove all justifications for its existence. That means remove all excesses, deficiencies, imbalances that justify or tend to justify its existence. How is this done?

5.  The purpose of the anti-tumor diet (as I call it) is to convert the tumor from nonexpendable to expendable. In the best case scenario this might be enough by itself to get rid of the tumor. There are stories where this seems to have happened. But it's probably a poor bet.

6.  The purpose of converting the tumor from nonexpendable to expendable is to prepare it for demolition during the fast.

7.  If the tumor is expendable, during a fast it will get consumed as a food source along with fat. When this happens it is called autolysis of the tumor.


My purpose in fasting is autolysis. I have evidence that it has begun, even if to a small degree. I take this as evidence that the tumor has become expendable.


A mutated cell might  appear to be a foreign body to the immune system and therefore could be attacked. 

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Gleason, the movie, is on Amazon Prime. His inevitable decline with ALS from diagnosis to present is chronicled in an "ode" to his son and the father he couldn't be. He played pro ball for 7 yrs. and safety for the Saints.

Keep on keeping on Jerry! I wrestled with your pretzle logic. It took awhile to sink in. You've supplied the context, finally. :rolleyes:  And what I see is a person engaged in a full on conscious fight to save their life. I admire you for that.

This is a tribute to you, from a story I'm writing.  

Swearing a silent oath he carved an arc overhead and as the downward stroke split the wind, a scream, held in its wake, rose above the turbulence below, a reminder of what the blade joined to a man, with a purpose, could do. He recoiled from the emotion and what he was made to do. Armed with his vision, he stepped towards those values..... 




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On 2/3/2017 at 1:42 PM, william.scherk said:
On 2/2/2017 at 11:55 PM, jts said:

ALS can be produced in lab animals at will by a clearly understand process.

There is a mice model:

I note that my two excerpts of articles featuring advances in understanding ALS and other neurodegenerative disorders are but a thimbleful of the work underway. I think in some ways we are within the era of a new medical revolution, though its products of knowledge are by no means complete. 

As Jerry himself notes, human physiology is at some corners and to some level a combination of 'clearly understood process.'

What I find most exciting about the recent researches and occasionally over-promoted "Breakthrough!" is the human knowledge is accumulative and combinatory. This is evident where medical research gets to the molecular-atomic-quantum level, how much some new vaults of understanding are built that combine chemistry, physics, microbiology and genetics.  It isn't that 'all is known or suspected,' but that the shadows of ignorance shrink as we go along.

What is poignant about "The Science of Health" propounded by latter-day Hygienists is the disconnect from the March of Science. Science has nothing to offer the committed Hygienist, not the least of which is its mode of inquiry. 

In other words, all the works of Hygiene are complete, self-sealing and not subject to error.  

On 2/3/2017 at 1:42 PM, william.scherk said:

New therapy halts progression of Lou Gehrig’s disease in mice

By way of contrast, there is no mice model in Hygiene. There are no laboratories in Hygiene. There are no clinical records or studies.  There are no research agendas.  



Anyway, until the next starvation-vacation in Costa Rica is featured, I'll just add some links that ALS-interested people may find intriguing, if not glamorous. Most of these stories I came upon by searching Science-Daily for the key word "ALS".

First up, extended knowledge on the pathology of toxoplasmosis (which can engender later neurodegeneration):


"We have shown for the first time the direct disruption of a major neurotransmitter in the brain resulting from this infection," Wilson said. "More direct and mechanistic research needs to be performed to understand the realities of this very common pathogen."

Next, Wilson and her colleagues will research what initiates the downregulation of GLT-1 during chronic Toxoplasma infection.

"Despite the importance of this transporter to maintaining glutamate homeostasis, there is little understanding of the mechanism that governs its expression," Wilson said. "We'd like to know how cells, including peripheral immune cells, control the parasite in the brain. Toxoplasma infection results in the lifelong presence of parasitic cysts within the neurons in the brain. We'd like to further develop a project focused on killing the cysts, which is where the parasite hides from the immune response for the rest of the infected person's life. Getting rid of the cyst removes the threat of reactivation of the parasite and the risk of encephalitis while also allowing us to minimize chronic inflammation in the brain."

Next, a connection between gut biomes and ALS, and a possible therapeutic avenue.


Researchers at the University of Illinois at Chicago College of Medicine report that in a mouse model of ALS, the compound butyrate helped correct a gut microbiome imbalance and reduced gut leakiness -- both symptoms of ALS. The treated mice lived also longer compared to mice that weren't given butyrate.

The finding is reported in Clinical Therapeutics.

ALS, also known as Lou Gehrig's disease, slowly destroys the motor neurons that control movement. Patients gradually lose the ability to walk, speak and swallow -- and eventually, to breathe. Conventional treatments include physical therapy and medications, but researchers have recently started looking to the gut as a new target for intervention.

"The brain and the gut are linked, so it's not too surprising that the health of the gut can impact the functioning of neurons," says Jun Sun, associate professor of gastroenterology and hepatology at UIC and corresponding author of the paper. In March, she and her coworkers were the first to identify a gut component to ALS progression.

The gut microbiome -- the myriad bacteria, viruses and other microbes that make the gut their home -- when in balance, helps maintain health, starting with the gut lining. Leaky gut in ALS may lead to increased inflammation. Reducing this gut-associated inflammation has been a goal of clinicians and researchers, and rebalancing the gut microbiome has shown promise in small-animal studies.

Sun and her colleagues studied transgenic mice that were engineered to carry human genes known to contribute to certain forms of ALS. The mice were found to have an abnormal microbiome, along with damaged junctions between the cells of the intestinal lining. Poorly functioning junctions can cause the tissue to become leaky, and have been found to be associated with the onset of ALS in humans.

When the researchers fed the ALS-prone mice butyrate in their water, starting when the mice were 35 to 42 days old, the mice showed a restored gut microbiome profile and improved gut integrity. Butyrate-treated mice also showed improved neuromuscular function and delayed onset of ALS symptoms. Treated mice showed symptoms at 150 days old compared to control mice at about 110 days. Treated mice also lived an average 38 days longer than mice not given butyrate.

"There is only one approved drug to treat ALS, so we need additional treatments," Sun said. "Butyrate is a bacterial by-product, and already available over the counter as a supplement. Studies are needed to see its effects on ALS in humans, but our preliminary results in mice are very promising."

-- a molecular discovery and process insight:


Researchers at the Virginia Tech Carilion Research Institute have identified a naturally occurring molecule that has the potential for preserving sites of communication between nerves and muscles in amyotrophic lateral sclerosis (ALS) and over the course of aging -- as well as a molecule that interferes with this helpful process.

The discovery in mice has implications for patients with ALS, also known as Lou Gehrig's disease.

Published in The Journal of Neuroscience, the research team, led by Gregorio Valdez, an assistant professor at the Virginia Tech Carilion Research Institute and in the Department of Biological Sciences at Virginia Tech, describes a growth factor called FGFBP1, which is secreted by muscle fibers and maintains neuromuscular junctions -- a critical type of synapse that allows the spinal cord to communicate with muscles, sending signals from the central nervous system to create movements.

ALS strikes approximately 6,000 people in the U.S. each year, according to the ALS Association.

In mouse models of ALS, a growth factor associated with the immune system, called TGF-beta, emerges and prevents muscles from secreting factors needed to maintain their connections with neurons.

"TGF-beta is upregulated in ALS and in turn blocks expression of FGFBP1, which is released by muscle fibers to preserve the integrity of the neuromuscular junction," Valdez said. "The body is trying to help itself by generating more TGF-beta. Unfortunately, TGF-beta accumulates at the synapse where it blocks expression of FGFBP1, accelerating degeneration of the neuromuscular junction."

FGFBP1 also gradually decreases during aging, but more precipitously in ALS, because of TGF-beta accumulates at the synapse, according to Thomas Taetzsch, a postdoctoral fellow in the Valdez lab and a co-first author of the study.

-- a tie-in with diet, specifically nutrients rich in anti-oxidents and carotenoids ...


New research at Columbia University's Mailman School of Public Health reveals that foods like fruits and vegetables that are high in antioxidant nutrients and carotenoids are associated with better function in amyotrophic lateral sclerosis (ALS) patients around the time of diagnosis. This is among the first studies to evaluate diet in association with ALS function and the first to show that healthy nutrients and antioxidants are associated with better ALS functioning. The findings are published online in JAMA Neurology.

"Our cross-sectional study relied on a food questionnaire and those may not always represent a true daily diet," cautioned Dr. Nieves. "However, those responsible for nutritional care of the patient with ALS should consider promoting fruits and vegetables since they are high in antioxidants and carotenes. Future studies will look at follow-up-data on both dietary intake and progression of ALS."

-- insight into cellular messaging process and systems of significance for hereditary ALS:


Although only 10 percent of amyotrophic lateral sclerosis (ALS) cases are hereditary, a significant number of them are caused by mutations that affect proteins that bind RNA, a type of genetic material. University of California San Diego School of Medicine researchers studied several ALS cases with a mutation in a RNA-binding protein known as hnRNP A2/B1. In the study, published October 20 by Neuron, they describe how damage to this protein contributes to ALS by scrambling crucial cellular messaging systems.

"Our findings are a significant step forward in validating RNA-based therapy as a treatment for ALS," said senior author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.


Yeo's team studies RNA-binding proteins and their ability to control how, when and if cells make certain proteins. To unravel the role RNA-binding proteins play in ALS, Yeo's team gathered skin cells from four patients with the disease -- three with mutations in the hnRNP A2/B1 gene, one with a mutation in a different gene -- and two healthy volunteers as controls. The researchers coaxed these skin cells into becoming a special kind of stem cell called induced pluripotent stem cells (iPSCs) and ultimately turned these patient-specific stem cells into motor neurons. This technique provided them with personalized models of each patient's disease, in a laboratory dish, where it's easy to do experiments.

To determine the effects of the mutant hnRNP A2/B1 proteins in these samples, the researchers then measured the activity of thousands of genes in each of the ALS and healthy motor neuron samples. In the ALS patient samples, Yeo and team found that the hnRNP A2/B1 mutation these patients had didn't merely disable the protein. Instead, the mutation gave the protein new toxic properties that scrambled RNA processing, and ultimately led to the death of motor neurons.

Yeo said these findings may have important implications for their collaborators and others who are developing therapeutics that aim to treat disease by targeting RNA."These RNA-targeting therapies can eliminate toxic proteins and treat disease," said first author Fernando Martinez, a graduate student in Yeo's laboratory. "But this strategy is only viable if the proteins have gained new toxic functions through mutation, as we found here for hnRNP A2/B1 in these ALS cases."


-- leveraging endogenous protective mechanisms to prevent toxic 'clumping' of proteins:



In the quest to understand the driving forces behind neurodegenerative diseases, researchers in recent years have zeroed in on clumps of malfunctioning proteins thought to kill neurons in the brain and spinal cord by jamming their cellular machinery. In a new study published in the journal Structure, researchers at the UNC School of Medicine announced the first evidence that stabilizing a protein called SOD1 can help reverse this process in the types of neurons affected by the fatal neurodegenerative condition Amyotrophic Lateral Sclerosis (ALS). Also known as Lou Gehrig's disease, ALS has no cure and its causes remain largely mysterious.

In addition to showing that stabilizing SOD1 is protective for motor neuron-like cells, the new study is also the first to demonstrate a way to mutate disease-associated SOD1 in order to stabilize it, offering exciting new leads for finding drugs that could potentially prevent the disease or slow its progression.

"The identified mutation mimics a natural process called phosphorylation, thus suggesting that there may be a natural, or endogenous, mechanism to stabilize SOD1 in cells and prevent the protein from forming toxic oligomers in people without disease," said senior author Nikolay Dokholyan, PhD, the Michael Hooker Distinguished Professor of Biochemistry and Biophysics at UNC. "Understanding the cellular mechanisms resulting in SOD1 phosphorylation not only offers insights about how cells respond to toxic SOD1 clumps, but will potentially offer insights into new pharmaceutical strategies aimed at promoting SOD1 phosphorylation. That is our immediate goal."


The findings offer two new avenues for identifying possible drug targets for treating ALS. One is to find ways to promote phosphorylation of SOD1 in a patient's motor neurons. The other is to look for other ways to stabilize SOD1 where it tends to clump.

"We can now see a way forward," Fay said. "We know that this mutation stabilizes SOD1, and the hope is that we can find a drug that makes the protein act in this way. By slowly piecing together the larger story of how SOD1 acts, hopefully that can be useful in drug studies to try to get a handle on how to affect the behavior of this protein in a planned way."

The findings also may provide clues about why some people get ALS while others do not. If phosphorylation of SOD1 is found to be common in people without ALS, it could indicate that defects leading to reduced phosphorylation play a role in destabilizing SOD1, even in people without detrimental SOD1 mutations.

-- identification of recessive mutation ...



A research team led by Prof. Koji Yamanaka (Nagoya University) found that collapse of the MAM is a common pathological hallmark to two distinct inherited forms of ALS: SOD1- and SIGMAR1- linked ALS. The research findings were reported in EMBO Molecular Medicine on November 7th, 2016.

The researchers focused on the mitochondria-associated membrane (MAM), which is a contacting site of mitochondria and endoplasmic reticulum (ER). Recent studies have revealed that the MAM plays a key role in cellular homeostasis, such as lipid synthesis, protein degradation, and energy metabolism. Intriguingly, a recessive mutation in SIGMAR1 gene, which encodes sigma 1 receptor (Sig1R), a chaperone enriched in the MAM, is causative for a juvenile ALS. In this study, the researchers identified a novel ALS-linked SIGMAR1 mutation, c.283dupC/p.L95fs in a juvenile-onset ALS case. Moreover, ALS-linked Sig1R mutant proteins were unstable and non-functional, indicating a loss-of function mechanism in SIGMAR1-linked ALS.

A loss of Sig1R function induced MAM disruption in neurons. However, it was still unknown whether the MAM alternation was also involved in the other ALS cases. To address this question, the researchers cross-bred SIGMAR1 deficient mice with the other inherited ALS mice which overexpress a mutant form of SOD1 gene. SIGMAR1 deficiency accelerated disease onset of SOD1-ALS mice by more than 20 %. In those mice, inositol triphosphate receptor type-3 (IP3R3), a MAM-enriched calcium ion (Ca2+) channel on ER, was disappeared from the MAM. The loss of proper localization of IP3R3 led to Ca2+ dysregulation to exacerbate the neurodegeneration. The researchers also found that IP3R3 was selectively enriched in motor neurons, suggesting that integrity of the MAM is crucial for the selective vulnerability in ALS.

These results provide us with new perspectives regarding future therapeutics, especially focused on preventing the MAM disruption for ALS patients. Together with the research from other groups, collapse of the MAM is widely observed in the other genetic causes of ALS, and therefore it may be applicable to sporadic ALS patients.


-- atomic-level understanding of mechanics of protein-disruption via mutation:



In amyotrophic lateral sclerosis, aggregates of the protein TDP-43 are almost always found in afflicted neurons and glial cells. Meanwhile, about 50 ALS-linked mutations are known to affect a particular region of TDP-43. Yet scientists have never understood how those two associations connect. A new study in the journal Structure shows how ALS mutations disrupt the protein at the atomic level, preventing it from executing its proper function and instead leading to those aggregates.

"We knew that part of TDP-43 builds up in aggregates and that there are 50 mutations in that domain, but we didn't know the job of that domain, how it goes wrong and why it aggregates," said study corresponding author Nicolas Fawzi, assistant professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University.

In general, TDP-43 acts like a chaperone for RNA in a cell, binding to it, guiding its processing, transporting it to where it needs to go and regulating it, so that other proteins can be expressed properly. Using nuclear magnetic resonance, computer simulations and microscopy, Fawzi, Brown graduate student Alexander Conicella and colleagues at Lehigh University were able to show that under normal circumstances, TDP-43 molecules concentrate into little droplets, a process called "liquid-liquid phase separation." It's within these droplets that they could process and ferry RNA.

The team's focus was on a particular region of TDP-43, called the "C-terminal domain," which appeared to be crucial in the concentration of molecules that leads to phase separation.

"We were looking for a functional role for this part of the protein," Fawzi said "Its job can't just be to do nothing and then aggregate in disease."

The observations showed that the interactions and resulting concentration of TDP-43 molecules depend on a small corkscrew-shaped part of the protein's C-terminal domain termed a helix. The same sequence of DNA specifying that corkscrew shape has been exactly preserved by evolution in many vertebrate animals suggesting it has an important biological function.

What Fawzi and his teams observed is that as one TDP-43 molecule meets another, the corkscrews stabilize and lengthen, promoting a bond between them.

Finally, the team shows in the paper that the various ALS mutations disrupt this process, either by upsetting the formation of the corkscrews or their ability to lengthen and stabilize.

"Mutations in this [corkscrew] region blow that interaction up," Fawzi said.

The result is that the concentration and phase separation does not occur. Instead the proteins can combine in a more potentially harmful way -- in the aggregates seen in diseased neurons.

By ferreting out this mechanistic connection between the mutations, the loss of protein's proper phase separation behavior and how it frees molecules up to aggregate, the team shows how the mutations could lead to disease, Fawzi said.

"That might be one mechanism by which ALS mutation cause ALS -- by disrupting TDP-43's normal function," he said.

The paper further emphasizes the urgency of an overarching question in ALS. Only about 10 percent of ALS cases are traceable to a genetic cause. It remains unclear what's happening to disrupt TDP-43 in many cases when a known mutation is not the cause.

But now scientists have new a new set of data and an explanation of how TDP-43 appears to work and what can make it fail.

That's also important, Fawzi noted, because TDP-43 is implicated in other degenerative neural diseases as well.

"Given the recent evidence that TDP-43 also accumulates in Alzheimer's disease, understanding the role of TDP-43 is all the more urgent," he said.


Fabulous, he said.

Here, Scientists keep a molecule from moving inside nerve cells to prevent cell death
Findings may have implications for Lou Gehrig's, Alzheimer's, Parkinson's and Huntington's diseases

August 3, 2016



A groundbreaking scientific study published in Nature Medicine has found one way an RNA binding protein may contribute to ALS disease progression. Cells make RNA to carry instructions for making proteins from DNA to protein-constructing machinery.

The culprit protein, TDP-43, normally binds to small pieces of newly read RNA and helps shuttle the fragments around inside nerve cell nuclei. The study describes for the first time the molecular consequences of misplaced TDP-43 inside nerve cells, and demonstrates that correcting its location can restore nerve cell function. Misplacement of TDP-43 in nerve cells is a hallmark of ALS and other neurological disorders including frontotemporal dementia (FTD), Alzheimer's, Parkinson's, and Huntington's diseases. Studies that characterize common mechanisms behind these diseases could have widespread implications and may also accelerate development of broad-based therapies.

To find the misplaced TDP-43, the researchers viewed nerve cells donated by people who died from ALS or FTD under high powered microscopes. They discovered TDP-43 accumulates in nerve cell mitochondria, critical structures responsible for generating the enormous amount of energy nerve cells require. By physically isolating the affected mitochondria the researchers were able to pinpoint TDP-43's exact location inside the subcellular structures. They were also able to characterize variations of the protein most likely to get misplaced.

This important work was led by Xinglong Wang, PhD, from the department of pathology at Case Western Reserve University School of Medicine and a team of scientists from his laboratory.

"By multiple approaches, we have identified the mitochondrial inner membrane facing matrix as the major site for mitochondrial TDP-43," explained Wang. "Mitochondria might be major accumulation sites of TDP-43 in dying neurons in various major neurodegenerative diseases."

The researchers discovered that once inside the mitochondria, TDP-43 resumes its RNA binding role and attaches itself to mitochondrial genetic material. This disrupts the mitochondria's ability to generate energy for the cell. Wang's team was able to precisely identify the RNA in mitochondria that was bound by TDP-43 and observe the resultant disassembly of mitochondrial protein complexes. This finding provides much needed clarity on the consequences of TDP-43 misplacement inside nerve cells and opens the door for deeper studies involving a range of neurological disorders. Although the study focused on ALS and FTD, according to Wang "mislocalization of TDP-43 represents a key pathological feature correlating strongly with symptoms in more than half of Alzheimer's disease patients."

Mutations in the gene encoding TDP-43 have long been linked to neurodegenerative diseases like ALS and FTD. Wang's team found that disease-associated mutations in TDP-43 enhance its misplacement inside nerve cells. The researchers also identified sections of TDP-43 that are recognized by mitochondria and serve as signals to let it inside. These sections could serve as therapeutic targets, as the study found blocking them prevents TDP-43 from localizing inside mitochondria. Importantly, Wang's team was able to keep TDP-43 out of nerve cell mitochondria in mice using small proteins which "almost completely" prevented nerve cell toxicity and disease progression.

"We, for the first time, provide the novel concept that the inhibition of TDP-43 mitochondrial localization is sufficient to prevent TDP-43-linked neurodegeneration," said Wang. "Targeting mitochondrial TDP-43 could be a novel therapeutic approach for ALS, FTD and other TDP-43-linked neurodegenerative diseases."

Wang has begun to develop small proteins that prevent TDP-43 from reaching mitochondria in human nerve cells, and has a patent pending for the therapeutic molecule used in the study.


--  unexpected findings that provide crucial insight into inflammatory versus protective response, at the molecular level.



Research into amyotrophic lateral sclerosis (ALS) conducted by VIB-KU Leuven has led to interesting and unexpected conclusions. When scientists were investigating the relevance of the higher expression of the IP3R2 protein in blood of ALS patients, the general expectation was that lowering the expression of this protein would have a protective effect on the affected motor neurons. But the exact opposite was true: IP3R2 turned out to be a protector against the negative effects of inflammation during ALS. Even more, the same mechanism may also apply to other diseases, such as stroke and multiple sclerosis.

This research was conducted in the VIB Laboratory of Neurobiology, led by professors Ludo Van Den Bosch and Wim Robberecht (VIB-KU Leuven). Other laboratories involved include Adrian Liston's Translational Immunology laboratory (VIB-KU Leuven), Jo Van Ginderachter's Inflammation Research Center (VIB-Vrije Universiteit Brussel), UZ Leuven and the Brain Science Institute RIKEN in Japan. The study's remarkable conclusions are published in the scientific journal Human Molecular Genetics.

Protective receptor

ALS is a fatal and currently incurable neurodegenerative disease caused by the progressive loss of motor neurons and denervation of muscle fibers, resulting in muscle weakness and paralysis. In Europe, 2.7 out of every 100,000 people are diagnosed with ALS on a yearly basis. Around 10% of all cases are hereditary, 20% of which are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). For this type of ALS, mouse models have been developed and were used in this VIB research project.

Prof. Ludo Van Den Bosch (VIB-KU Leuven): "In blood of sporadic ALS patients, as well as in models of chronic and acute neurodegeneration, there is a significantly higher expression of the intracellular receptor IP3R2. When we removed the gene encoding IP3R2, the ALS mice didn't just die quicker, we also saw systemic inflammation and increased expression of certain cytokines, proteins that plays an important role in the immune system. As a consequence, we conclude that doing the opposite, which is increasing the amount of IP3R2, is a protective response. Not only for ALS, but also for other neurogenerative diseases."

An unexpected twist

The research process is a prime example of good science, where no hypothesis whatsoever pre-determines the outcome. Although the scientists expected that deleting the gene encoding IP3R2 which is responsible for the release of calcium from intracellular calcium stores would have a positive effect on the survival of motor neurons, the study proved the opposite: IP3R2 deletion had a negative effect on the survival of the ALS mouse model.

Prof. Ludo Van Den Bosch (VIB-KU Leuven): "The negative effects of IP3R2 removal in other cell types seem to outweigh the potential benefits of removing IP3R2 in motor neurons. In the case of unexpected findings like this, a researcher has two options: to stop the project, or to dig deeper into the problem. The last strategy is the most challenging one, as the outcome is uncertain. But, in this case, it has yielded interesting new insights, supported by our data."

Next steps

The VIB lab is currently involved in a new ALS study in collaboration with the Stem Cell Institute Leuven (SCIL) and supported by the Belgian ALS Liga. Focusing on different cell types derived from skin fibroblasts of ALS patients, scientists are looking for aberrations in their calcium metabolism. The research into the role of the IP3R2 can serve as an important foundation, as it helps to strengthen the scientific community's understanding of the mechanisms that may protect motor neurons.

Prof. Ludo Van Den Bosch (VIB-KU Leuven): "We have now proven that some aspects of inflammation could play an important role in the disease, which could eventually open new therapeutic options for patients. But if we really want to cure ALS, we need to understand all the ins and outs of ALS on the patient's cellular level. Studies like ours are crucial pieces of this complex puzzle that we need to solve before we can develop a successful therapy."


-- in search of genetic vulnerabilities and protective factors.



Because ALS and frontotemporal dementia belong to a genetically complex disease spectrum that isn't easily studied in humans, the mouse models will enable researchers to tease apart exactly how the gene mutation causes disease. The C9orf72 gene produces at least eight different mutant products. Having the mouse model will help researchers understand which ones are the most important in terms of causing disease. It should also allow them to learn more about what takes place in a particular region of the brain where healthy cells exist next to ones that have died.

"I am excited because one of the two mutant RNAs produced by the mutation accumulates in neurons that are vulnerable to the disease and die. This gives us an important clue for future studies aimed at developing therapies for people," Liu said.

Likewise, Ranum is intrigued by the 20 percent of the mice that have the mutated gene but do not develop ALS or frontotemporal dementia. Similarly, a subset of people who carry the C9orf72 mutation do not develop the disease. This suggests there is some protective element at work that, if understood, could be exploited to prevent disease onset, she said.

Ranum said her group is already making use of the new mouse model. That includes collaborations with private industry on research aimed at reversing or preventing the disease.


Here, below, I highlight in yellow the research project of the association that instructs in Hygiene. Click to enter the project space.



Edited by william.scherk
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