The return of the MMR charlatan fits with our times | Nick Cohen

If you are unlucky, and all of us are unlucky in the end, you will visit a doctor in the confident expectation that they can fix any illness as a mechanic fixes a car and learn of the vast areas of ignorance on the map of medical science. If you are very unlucky, you will take an autistic child to a doctor and learn that “autism” is a vague and flabby label. There isn’t even agreement on what causes it, let alone on what, if anything, might alleviate or cure it.

Into the gap, between inexplicable suffering and the inability to relieve it, pour the conmen. Last week, Andrew Wakefield, the most contemptible of the charlatans, arrived in Britain to exploit the false hopes and fill the nightmares of his native land.

That he is a fraud has been established beyond reasonable doubt. The General Medical Council struck him off in 2010 after, in a superb example of journalism at its best, Brian Deer showed how Wakefield had manipulated research to make a non-existent link between the measles, mumps and rubella vaccine and autism.

Not content with lying, Wakefield exploited his voodoo science for financial gain. The money was not the worst of it. The MMR conspiracy theory sent vaccination rates below the level of herd immunity. As unvaccinated children become teenagers, we are yet to see whether they will pay a price in blood for Wakefield’s fraudulence. Given the threat to public health, the personal enrichment and the neglected fact that Wakefield’s malign fantasy has led parents who vaccinated autistic children needlessly blaming themselves, in my eyes he appears to be a criminal.

If you want to know what is wrong with a country, look at the criminals its courts cannot punish. Just as it was impossible to prosecute bankers after the crash of 2008, so it is impossible now to arrest Wakefield. Rob an old lady of her savings and you go to prison. Rob millions of children of protection against preventable illness and you are endorsed by the Trump administration, which has, inevitably, made its support for the MMR con explicit.

The one good thing Andrew Wakefield has done in his worthless life is show that sick societies are like sick people. They, too, face suffering without relief or prospect of a cure. They, too, are open to exploitation by every variety of crank and fanatic. Nowhere more so than in Trump’s America. At a personal level, Trump’s wife, Melania, promises to sue anyone who says their son, Barron, may be autistic. Her threat suggests the couple have feared, however fleetingly, that they might learn of the pain of the parents of autistic children and of autistic people themselves.

Whatever twinge of sympathy I felt, vanished, however, when I saw that at the political level Trump had said that “doctors lied” about vaccination and has given every indication of pursuing the Wakefield conspiracy theory in office. If he does, it will be a disaster for autistic people. In America, as in the UK, they fall over a cliff edge when they move from child to adulthood. So bad are the services, the US does not know how many autistic adults live in its borders.

Hillary Clinton, who actually talked to autistic people, something vaccination conspirators neglect to do, promised a census. She lost. And now, as Steve Silberman, the author of the magnificent Neurotribes tells me, the Trump administration can indulge in junk science, safe in the knowledge that its billionaire friends will never need public assistance to provide for their autistic children.

The “doctors lied” is the first link between MMR and so many other modern manias. Climate change deniers have to maintain that 97% or more of the world’s scientists are lying. It is easier to believe an unbelievable fiction than contemplate the vast and wrenching changes manmade climate change must bring to our lives. Rather than face them, say Trump and the Anglo-Saxon right, we can retreat into a surprisingly comfortable state of paranoid delusion.

Second, and this point needs emphasising when elements on the right claims to be the champions of the working class (and let us see how long that lasts) and elements on the left blame it for Trump’s victory: conspiracy theories always begin with pseudo-intellectuals.

Anyone who has looked at the work of Holocaust, 9/11 or climate change deniers, will see that it is stuffed with footnotes. It was not a tabloid catering for the “left behind” that began the MMR lie, but the learned medical journal, the Lancet. Its editors did not know they were victims of a fraud. But they ought to have seen that Wakefield’s original 1998 paper was “badly written and had no clear statement of its hypothesis or indeed of its conclusions”, as Ben Goldacre, the debunker of scientific fraud, put it.

Last week, Wakefield did not speak at a working men’s club, but at the supposedly reputable Regent’s University in London. To top that, he was invited to the European parliament, not by a neofascist know-nothing, but by an MEP from a Green party, which readers who have not been paying attention may think is filled with decent people.

Third, the MMR scandal rebuts the myth that we are living in a uniquely mendacious era of web-driven “fake news”. Mainstream national newspaper journalists (including here at the Observer, I am afraid) and BBC and Channel 4 broadcasters amplified Wakefield’s message in the last decade without making the most basic checks. There can be no “post-truth age” for the autistic, for they never had an age of truth to begin with. To put the disgrace of my trade as mildly as I can, if Wakefield were put on trial, there would be hundreds of journalists alongside him in the dock.

Finally, ask yourself why Andrew Wakefield does not recant, when every study of autism and vaccination has shown his original claim to be false. Asking that is like asking why Donald Trump does not cut his links with climate change deniers or Jeremy Corbyn cut his links with the Socialist Workers party. Wakefield would lose his support base. More to the point, as I suspect he, Trump and Corbyn know, the very fools he has encouraged would throw the accusations of corruption he has thrown at others back at him.

Whether you are dealing with climate change or MMR, the final lesson is this: you cannot rely on charlatans to expose themselves. You have tune up your bullshit detector and do the exposing yourself.

The return of the MMR charlatan fits with our times | Nick Cohen

Caloric Restriction: Understanding the Genetic Basis and How Alpha Lipoic Acid Fits the Picture.

Research on caloric restriction (CR) covers a span of 80 years and study results have fluctuated between negative, to sometimes positive, to consistently positive under the right conditions, and presently to positive but of little value beyond a normal caloric intake. Recent research, in addition to confirming the value of CR on health-span and possibly longevity, has identified the genetic pathways that are activated in CR, and opened the door to interventions such as alpha lipoic acid that might mimic the positive effects of CR, without the difficulty of adhering to a low calorie diet. The most recent research on CR has highlighted the importance of the macronutrient ratio in achieving positive health effects, particularly the ratio of protein to carbohydrate.

EARLY CR STUDIES:

The first study on CR was conducted in 1935, but was based on societal problems with malnutrition, and had nothing to do with possible beneficial effects on health and aging. To the contrary, the study demonstrated retarded growth during development, poor health and a shorter lifespan. Some years later, a study was performed in rats by McKay et. al., that only restricted calories, but still provided the vitamins, minerals and micronutrients required to maintain health. Like the earlier study, developmental growth was retarded, but the animals experienced a considerably longer lifespan. During this time period, researchers concluded that the beneficial effects of CR are the result of delayed developmental growth. This conclusion was a clue to the mechanism behind the health benefits of CR, but was later proven incorrect.

Studies in the 1950’s and 1960’s demonstrated that intermittent fasting was as effective as chronic CR, providing a more user-friendly way to achieve the health benefits of CR. Considerable research, with varying results continued for several decades, but the real breakthrough came in 1996 in research that was performed on simple animal models (worms and flies) that elucidated the molecular pathways involved in CR.

CR METABOLIC PATHWAYS:

It comes as no surprise that humans have a gene-based survival system to prolong survival during periods of prolonged famine, and that this system serves as a sensor for nutrient and energy levels, and a regulator of biomass formation. What is surprising is the fact that regulation of this system can have long-term beneficial effects on health and possibly on lifespan. The discovery of this system had it’s origins in an antifungal/immunosuppressant substance that was isolated from a soil sample from the Easter Islands (Rapa Nui). It was named Rapamycin in reference to the place it was discovered. Work on microorganism resistance to Rapamycin led to the later discovery in yeast that Rapamycin inhibits a gene that produces a serine/threonine protein called mTOR (mammalian target of rapamycin), and that like CR, Rapamycin extended lifespan.

The key regulator in this metabolic pathway is a complex of mTOR and co-factors that is identified as mTORC1. mTORC1 is a signaling hub that integrates nutrient and energy signaling with growth factor signaling. Generally mTORC1 stimulates protein synthesis and anabolic growth and inhibits autophagy. Conversely, CR and Rapamycin inhibit mTORC1 which reduces protein formation, and ATP formation, and increases autophagy.

mTORC1 is a complex system that stimulates numerous downstream processes including messenger RNA translation and the transcription factor C/EBPbeta-LIP. LIP is a protein that binds to DNA metabolic regulating sites. The LIP protein can be suppressed by removing an upstream regulatory element (uORF), which produces an effect equivalent to CR or Rapamycin. As is usually the case in this type of situation, developing a drug that inhibits uORF or another critical step in the mTORC1 pathway could theoretically lead to a drug to extend health-span and lifespan.

PHARMACOLOGIC INTERVENTION IN mTORC1 PATHWAY:

The scientific community and the media are conditioned to judge the value of a research finding by the possibility of developing a drug to achieve a therapeutic objective. History, while uniformly disregarded, has shown that drugs designed to block physiological processes rarely act on only the process being targeted. The result is an effective drug, with serious side effects that emerge during clinical trials or after the drug is marketed. To my amazement, society is becoming more accepting of these serious side effects as reflected in the marketing of most biologics. I believe that Rapamycin fits this description as a drug to combat aging. Rapamycin clearly inhibits mTORC1, but has many serious side effects that make it unsuitable for widespread chronic use. This hasn’t stopped the media from touting Rapamycin as the Fountain of Youth drug, and I sense that drug companies will eventually promote the drug for this use and attempt to justify the side effects as reasonable vs. the benefits.

There are many naturally-occurring substances that have epigenetic effects similar to the actions of more powerful drugs, and generally without the serious side effects. One such substance is the widely researched and less widely used alpha lipoic acid. In addition to its favorable effects on oxidative stress and diabetic neuropathy, more recent research has recognized the multi-functional properties of alpha lipoic acid, with particular emphasis on the stimulation of AMPk and the corresponding inhibition of mTORC1 activity. As described in the research reports referenced below, alpha lipoic acid, along with other energy restriction mimetics (resveratrol, rapamycin, metformin and spermidine) stimulates formation of kinase activated AMP, that in turn signals that the cell is in an energy restricted state, and mTORC1 is inhibited. The paper by Nikolai et.al. states that these CR mimetics can have serious side effects and have not been proven safe for long-term use. Contrary to this position it should be noted that alpha lipoic acid has been studied extensively for several decades and has been cited in almost 5000 scientific papers, the vast majority of which report beneficial effects. It is true that alpha lipoic acid has not been subjected to extensive controlled, double-blind studies in humans, but it is commonly used by many health conscious consumers, with no reports of adverse events. Because alpha lipoic acid is a naturally occurring substance that cannot be patented, it is unlikely that funding will be made available for controlled clinical studies or education of the public regarding its many benefits.

PROTEIN: The FINAL NAIL in the CR COFFIN:

Research on CR has focused attention on all of the factors in the design of studies that have had unexpected outcomes. One of these factors was the macronutrient composition used in the study, with particular attention to the ratio of protein to carbohydrate. Using a research tool designated the Geometric Framework nutritional modeling method, researchers Raubenheimer and Simpson (Sydney, Australia), found that diets that were low in protein and high in carbohydrates produced a health-span comparable to CR. A low protein diet was defined as <5% calories from protein, a moderate protein diet as 10% – 20%, and a high protein diet as >20%. Disease and mortality was surprisingly high for the high protein diet, but ameliorated by substituting plant protein for animal protein. This effect was observed in persons under age 65, but the reverse was true for people over age 65, who had higher disease and mortality with a low protein diet and better health and longevity with a high protein diet. The mechanism behind the negative effects of a high protein diet appear to be related to stimulation of the mTORC1 pathway by nutrient sensing of the high availability of amino acids in the cells. It isn’t clear why this protein effect reverses at age 65, but presumably has to do with the accelerated loss of muscle mass with aging, which would be exacerbated with inhibition of the mTORC1 pathway.

CONCLUSION:

It is well-established that under the right conditions, CR is an effective way to lose body mass, extend health-span and possibly extend lifespan. Research studies on CR have contributed to the discovery and understanding of the mTORC1 pathway, which is the major regulator of metabolic activity in humans. While CR is beneficial in itself in reducing chronic disease, it is a difficult regimen to follow and certainly not in sync with modern lifestyles. CR research has led to the discovery that equivalent beneficial effects can be realized with a normal diet, provided that the ratio of protein and carbohydrate are optimized for age. Elucidation of the mTORC1 pathway has also opened the door to user-friendly means of inhibiting the mTORC1 pathway through design of drugs that block or inhibit steps in the regulatory process, or preferentially the application of naturally-occurring molecules such as alpha lipoic acid that stimulate formation of AMPk and down-regulation of mTORC1.

REFERENCES:

1. The ratio of macro-nutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum fed mice.  Solon-Biet, SM  et. al., Cell Metab. 2014 Mar 4: 19 (3); 418-430.


2. Alpha-Lipoic Acid Supplementation Reduces mTORC1 Signaling in Skeletal Muscle from High Fat Fed, Obese Zucker Rats.  Zhuyun Li, Cory M. Dungan, Bradley Carrier, Todd C. Rideout, David L. Williamson.  Lipids. Dec 2014, Volume 49, Issue 12, pp 1193-1201.


3. Energy restriction and potential energy restriction mimetics.  Nikolai, S et. al., Nutr Res Rev. 2015 Dec;28(2):100-120. Epub 2015 Sep 22.

Caloric Restriction: Understanding the Genetic Basis and How Alpha Lipoic Acid Fits the Picture.