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The Molecular Biology of Needing a Bit More Nookie
by Dr. Michael B. Barratt
Dr Barratt, a NSW pathologist, explains the research findings on RNase-L presented at the 1999 Second World Congress on CFS and Related Disorders.
"For decades, patients and the occasional sympathetic physicians who suspect a biological basis for the disease have been made to feel like the medical equivalent of the Queensland cane toad. All these people will be heartened by the molecular biology studies presented at the Brussels conference."
It was my privilege to attend the Second World Congress on Chronic Fatigue Syndrome and Related Disorders held in Brussels (Belgium) in September 1999 [1]. Since perhaps 20% of patients attending medical practice are suffering from some obscure, chronic illness that has defied clinical acumen and laboratory investigations, Dr. Ian Tait, editor of Private Doctors of Australia, has invited me to share some of the issues raised by this important conference.
Chronic Fatigue Syndrome is an illness of unknown aetiology (origin, cause), often associated with debilitating fatigue, low-grade fever, myalgia and neuro-cognitive dysfunction (jargon for deteriorating memory and IQ). It has a worldwide incidence. It has been called "the disease in search of a name" or "the disease with a thousand names". A patient recently suggested finding the Latin for "living-death disease", and calling it that!
To name a disease after one of its most subjective symptoms is obviously ridiculous. The term fatigue may equally apply to a nasty hangover, mere laziness, or Monday morning-itis. I remember a church notice board near Sydney University back in 1958 with the message, "It takes a truly honest person to know whether he is really tired or just plain lazy." C.S. Lewis in his book The Problem of Pain suggests that some pain may even be mildly pleasurable, such as the feeling of fatigue and soreness after a long walk in the country. The problem with fatigue is that it is neither specific, definable, or easily scientifically measurable. Fatigue is both a normal and pathological feature of everyday life. Every normal person gets fatigued. Fatigue is a common feature of much major psychiatric illness and major medical disease. But, for the moment we are stuck with this hopelessly inadequate name even though it trivialises the clinical severity of the illness and ignores the fact that CFS mainly involves the central nervous system (CNS), and less so the muscles of the body. Even those who believe that Chronic Fatigue Syndrome represents a major attack on the CNS by the chronic effects of a viral or other infection have scarcely begun to work out how CNS dysfunction causes mayhem in so many other systems in the body.
In the absence of an understanding of its pathogenesis, and the lack, hitherto, of diagnostic laboratory markers, medical ignorance has aggressively masqueraded as a virtue. Dismissive attitudes, gratuitous and fatuous psychological and psychiatric interpretations ["yuppie flu", "infectious hysterical disease", "somatoform disorders", "a proto-language rather than a disease", etc.] have meant that a general lack of awareness and compassion for seriously ill patients has prevailed. Alas, we as a profession have been very infra ordinary in dealing with this illness, as we have with most chronic medicine.
Modern medicine is brilliant in handling acute, "blood-bath" situations but is very poor in handling chronic, obscure illnesses that question our delusions of omnipotence.
In September 1966 Dr. Philip Lee, the US Assistant Secretary of Health neatly highlighted the key issues:
- CFS is a serious, legitimate disease.
- It is not some sort of psychological problem.
- The spectrum of disease extends to the wheel-chair bound.
- Recovery is slow and uncertain for many. [For the more severely ill only 4% improve over 10 years.]
- Scientists need to learn more about the reactivation of latent viruses, and molecular interactions between the brain and the immune system.
- CFS is devastating to those who have it.
Those who have felt uncomfortable with a psychiatric causation of this illness have been regarded in the same class as people who think they are poached eggs. For decades, patients and the occasional sympathetic physicians who suspect a biological basis for the disease have been made to feel like the medical equivalent of the Queensland cane toad. All these people will be heartened by the molecular biology studies presented at the Brussels conference.
The conference also spells bad news for those in the profession who impose prescriptive, clinical and psychiatric guidelines, including the removal of adolescents to the state and psychiatric "protection". Shakespeare says, "open thy mouth, that I may know thee", and every time some open their mouth we clearly know they have little or no understanding of patho-physiological processes.
An eminent Australian Queen's Counsel [*?] told the conference that the medical profession was "looking down the barrel of the greatest class action in history. Forget about silicone breast implants and IUCDs. These were petty-cash issues compared to the big one coming". Ignorance may be bliss ... but the medical liability insurance premiums will not be.
What evidence is there to support those who, in growing numbers, think it is now proven beyond any reasonable doubt that CFS is not a psychiatric illness?
Since 1957 it has been known that when a virus infests a cell the "interferon" pathway is activated to destroy the virus. Since then there has been an explosion of knowledge about the interferon pathway. At least 200 molecules are involved in this and other cytokine systems. Interferon is also now known to play a key role in cellular immunity, cellular differentiation [eg. why one cell becomes a part of our toe-nail and another cell from the same zygote becomes a neurone or a polymorph] and organ growth [eg. why our liver doesn't grow as large as a giant beach ball, and why our lungs don't stop growing when they are the size of billiard balls].
At the risk of oversimplifying an incredibly complicated area of molecular biology and earning the derision of those who know far more about it than I do, may I attempt to outline what seems to be happening when a virus enters a cell and the cell attempts to destroy the virus. You must keep in mind that antibodies are large protein molecules and probably cannot pursue viruses into a cell.
Basically, when the interferon pathway "scrambles" to repulse an invading virus it does so by activating an enzyme that destroys the Ribose Nucleic Acid [RNA] within the virus. This enzyme is called RNaseL. [The "L" refers to an isomer.] This enzyme is the key molecule in intra-cellular viral destruction.
RNaseL is inactive until it is "up-regulated", to use an Americanism popular at the conference. This occurs when another enzyme called 2'-5' Oligo-adenylate synthetase binds with RNaseL. Once the newly activated RNaseL has destroyed the viral RNA, it must "switch off" almost instantly. If it does not do so, for some reason, the normal, "native" RNA in the cell would be vulnerable to "friendly fire". This is also the reason that RNaseL is normally inactive in the cell until it links with 2'-5' Oligo-adenylate synthetase, a bit like the American safeguard of needing two keys to blast-off a nuclear missile.
The normal, inactive RNaseL molecule is known to have a molecular weight of 80,000 [or 80 kiloDaltons in the newer terminology]. However in Chronic Fatigue Syndrome the 80 kDa RNase L molecule may be partially or totally replaced by a different but defective RNaseL molecule, with a lower MW of 37 kDa. The more of the defective, low molecular weight 37 kDa RNaseL that is present, the more severe the CFS is clinically. Incidentally, this last sentence alone is enough to blow psychiatric theories of aetiology out of the water.
When the 2'-5' Oligo-adenylate synthesase molecule binds with the 37kDa RNaseL molecule a newly activated, "rogue" enzyme is let loose. This linked, abnormal molecule is extraordinarily active, more than 6 times that of the linked, 80 kDa RNaseL. It resists proteolytic denaturation and has a deadly property --- it does not switch off! It therefore lasts longer in the body and plays havoc with protein synthesis, enzyme production and cellular function. This abnormal, "loose cannon" molecule is a rapidly cycling enzyme that consumes adenosine triphosphate [ATP], the molecule that supplies energy to the cell, by the bucket-full. Someone has called it a "black hole" for ATP. It is estimated that up to 70% of the cell's energy production is consumed by this abnormal up-regulation of the interferon pathway. It's little wonder that patients are "fatigued". It's a wonder they survive at all! It's the equivalent of a biochemical bushfire, where ATP is the fuel instead of trees.
Surely, this has to be cyto-destruction rather than psycho-destruction!
The myriad of non-specific biochemical and immunological abnormalities that have been described in CFS are now thought to reflect "downstream" disturbances in cells, induced by dysfunction of RNaseL and probably of numerous other enzyme systems.
As a result of all this, there is profound disregulation of both cellular and humoral immunity, including mitogen response, diminished natural killer cell [NK] function, changes in intermediary metabolism and cell membrane function ["channelopathies"]. The new name for CFS may well become "RNase Enzyme Dysfunction Disease" [REDD]. In this instance, it will no longer be "better REDD than dead" because some people with REDD will also die.
This exiting, pioneering molecular biology on RNaseL dysfunction was done by Dr. Bob Suhadolnik and his co-workers in the Department of Biochemistry at Temple University, Philadelphia in the early 1990's. He has also described abnormalities in Protein Kinase pathways in CFS. His critically important discovery of an abnormal molecule that is not present in control samples of subjects with cancer, AIDS, multiple sclerosis, clinical depression, malingering, hypochondriasis or normal health has been confirmed subsequently by French molecular biologists under Professor LeBleu and the Belgians under Professor Kenny de Meirleir. All these men spoke at the Brussels conference [2].
Interestingly, most of the speakers at the conference had no interest in CFS until they, or someone close to them, were stricken by it. I am reminded of the old adage that "the most passionate advocates of a non-psychiatric cause for CFS are those medical people who once passionately believed it was a psychiatric disorder, until they went down with it themselves."
The Crown Prince of Belgium attended several talks at the conference. Given the odium aroused by CFS this was, in Sir Humphrey Appelby's (of Yes Minister, BBC Television) words, "very courageous, your Highness." I asked Professor De Meirleir why the Prince would lend his support to an allegedly rat-bag cause. You might have guessed it. His wife's best friend suffers from severe CFS, and he obviously thinks she has something more than a severe depressive episode.
A future article for Private Doctors of Australia will discuss the immense legal implications for the medical profession of the new insights into the molecular biology of CFS. It will take you into the dirty world of military biological warfare, of the usual government lies and cover-ups in the name of "security", the intrigues of insurance companies, the attempted assassination of a biochemical researcher, legally sanctioned child kidnappings, the hideous lies of Munchausen Syndrome by Proxy hunters, the fraudulent misappropriation of multimillion dollars of research grants and more. Who said molecular biology was boring?
Bernard Shaw spoke of the "murderous absurdities of the medical profession" and more recently an Adelaide Professor reflected on "the combined idiocies of the medical and judicial bureaucracies." The CFS debate illustrates many of these absurdities and idiocies and shows how close we are to Samuel Butler's 1872 Utopian novel, Erewhon. In Erewhon, [an anagram of "nowhere", but increasingly a society that is being found "everywhere"], criminals were treated in hospital and those with genuine illness were put into prison for their "crime".
When the molecular biologists convince all but the purblind that CFS is a seriously debilitating, neurological illness with unknown but possibly contagious origins, the view that psychoanalysis was the only answer to the problem will stand proudly in the Great Medical Museum in the Sky, along with other slick, therapeutic nostrums such as blood-letting, snake-pit treatment for schizophrenia, cattle-dung poultices for African trachoma, snake-oil panaceas, and psychotherapy for peptic ulceration. I suspect that some Cosmic Curator may even give it pride of place in that therapeutic Pantheon.
If, in the meantime, you have a patient who has a strongly positive, 2'-5' Oligo-adenylate synthesase activated, low MW 37kDa RNaseL assay - and if you, like the doctor in this true story, can't resist telling the patient that "it's all in your head", and on three occasions tell her "you are not getting enough nookie", then first check your medical insurance. The Empire is about to strike back!
Postscript
The controversy around CFS is now millennia long.
Claudios Galenos (Galen), one of the most distinguished physicians of antiquity and the founder of experimental physiology, worked in the Roman, (now Turkish), city of Pergamum, (the same mentioned in the "Letters to the Seven Churches" in the New Testament). In 154 AD this Greek physician described patients who had an illness that sounds suspiciously like modern day CFS. Though at the time writing a book on wound healing (he was, after all, the chief physician for the Roman gladiators in that part of Asia Minor), he took time to note that he had found a similar illness described in the papyri of ancient Egypt. He stated that the Egyptians believed that the illness was due either to insanity, or the curse of the Gods. Galen comments that, after careful thought, he was convinced that this strange disease was a genuine illness with an organic cause.
Oh that physicians for the next nineteen centuries had listened to Galen, and not followed the Egyptians!
Acknowledgments and references
(c) Dr. Michael M. Barratt MBBS [Sydney], FRCPA
20 October, 1999 (this version revised August 2000)Dr Barratt is a NSW pathologist. This article first appeared in the journal Private Doctors of Australia in a shorter form. This longer version is issued with the kind permission of Private Doctors of Australia and the author.
1. Australian researchers were among the keynote speakers at the Brussells Conference. For more information see Dr. Rosamund Vallings' Report on the Conference on the Co-Cure website.
2. More information on this research see these links.
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last revised 31 August 2002