On criticism in bio-medical research – A tribute to Uffe Ravnskov

Abstract

The great importance of criticism in science – and its ups-and-downs due to human prejudices and emotions – is discussed in a historical perspective. Towards such a background, attempts are made to evaluate present controversies concerning the widely assumed cause-effect relations between diet-adipositas per se and disorders, like diabetes 2 and atherosclerosis. Seen from a physiological angle, it appears that the real culprits are to a great extent of a different nature, though easily overlooked in e.g. mass screenings. Thus, the human brain reacts to the many mental challenges of modern hectic-competitive life with the same protective response patterns as seen in all mammals, i.e. with defeat- and/or defence-reactions. Here the hypothalamic-hypophyseal-glucocorticoid axis, respectively the hypothalamic-sympatho-adrenomedullary one, serves to support the associated behavioural expressions. Experiments in group-living mammals show how mentally induced prolonged engagements of these neuro-endocrine links end up in serious metabolic and organ-system disturbances, also if factors like diet are kept unchanged. To this comes that in ‘civilized’ man the respective behavioural expressions are commonly suppressed, whereby most ‘inside’ neuro-hormonally induced changes occur in vain. An aggravating component is inherent in generally dwindling physical activity, implying that the many bodily and mental advantages of regular exercise are much reduced. Towards such a background, it appears strange that ‘The metabolic syndrome’ and its sequalae are not even more common today.

According to the great Austrian-British philosopher Karl Popper, ‘the unknown’ should be exposed to Un-ended Quest (also the title of his autobiography) and ‘established concepts’ to scrutinizing scepticism. However, scientists do not always live up to these ideals – and mainly so because the human mind has also an emotional facet. For example, when unexpected new findings turn ‘established truths’ upside down, the reaction is not seldom intense and stubborn resistance. Or, when somebody's cherished hypothesis is challenged, this may – instead of inviting to constructive exchange – end up in stone-wall animosity … Thus, contrary to common belief, scientists are not throughout ‘cool-detached-experts’ but, rather, passionately engaged in their work – which is, in fact, often necessary to get things done in a tough and often frustrating occupation.

The history of science amply illustrates the consequences of these per se very human characteristics. For example, William Harvey's classical experimental discovery of the circulation of blood – which he taught his students already in 1617 – was published first in 1628 (De Motu Cordis) with the support of King James I. A major reason for this delay was that Galenos’ almost canonized theses were demolished by his results – and were thus by no means enthusiastically accepted by contemporary medical authorities. Instead he was for decades bitterly criticized, and finally he lost his patience, retorting something like ‘… why not repeat my experiments and trust your own eyes …’

Further, two centuries later Semmelweis’ all-important – and equally straight forward – discovery was for long met with such vicious resistance and ridicule that his mental health suffered badly. Again, simple control tests could have rapidly convinced anyone.

And to turn to present time: Barbara McClinton's outstanding contribution to genetics was for a long time disregarded and ‘pooh-poohed’ by colleagues, until she – to their disgrace – was awarded the Nobel Prize (and neither situation seems to have disturbed her peace-of-mind …'if you know you are right, it doesn't matter …’)

Another, and more sinister today variant: Scientists have lost their grants, and even positions, for criticizing ‘accepted truths’ and particularly so if this ‘rocks the boat’ for self appointed gurus – or/and threatens profits e.g. for pharmaceutical industries. Again human emotions: ‘Holy-cows-should-remain-sacred’ (and particularly so if they yield plenty of milk …).

Present situation

Uffe Ravnskov was awarded the 2007 ‘Leo Prize for independent thinking’, to honour his penetrating and fearless criticism of the current ‘adipositas-cholesterol-atherosclerosis-concept’. Despite strictly applying Popper's widely accepted ‘rules-in-science’, he has experienced much rebuke and/or ridicule for his in many respects indeed well-founded criticism. For example, it is rumoured that his interesting book ‘The cholesterol myths was not so long ago ‘publicly burnt’ at some scientific conference – which almost smells of dark-medieval-times …

Towards such a background it is not strange that emotions are much involved when it comes to such common, complex and serious ‘disorders of civilisation’ as the metabolic syndrome (MS) and primary (essential) hypertension (PH). I have, with six-decades-involvement in cardiovascular physiology and patho-physiology, for natural reasons followed these research fields and – with that – Ravnskov's scrutiny of MS-related problems and controversies. Below some aspects will be discussed, with references mainly restricted to reviews and books.

Despite the obviously multi-factorial background of both MS and PH – to which come their partly overlapping natures and expressions – it sometimes appears as if still ‘the-one-and-only-cause’ is searched, presumably reflecting Pasteur's EUREKA discovery that started bacteriology: ‘One bug one disease’. Thus, concerning MS ‘cholesterol’ seems to be a cherished culprit and, concerning PH ‘salt’ – even though both disorders harbour varying interactions between 1 Predisposing gene constellations 2 Environmental factors (psychosocial as well as material) and 3 Reinforcing biochemical and/or structural adjustments to 1+2 1, 2.

First some examples from PH, though partly relevant for MS as well: In PH an intensified, environmental-dependent sympatho-adrenal engagement is of major importance 1–4 – but this involves via nervous links the renin-angiotensin-aldosteron axis as well, and hence the handling of NaCl. However, quite-a-few experts consider present NaCl intakes as the major culprit. True enough, a minority of people are more ‘salt-sensitive’ than others, though they are not necessarily dominating the ‘PH-population’ 1–4. Further, in a recent meta-analysis by Graudal et al. 5, 6 covering no less than 56 extensive studies of substantial salt-restrictions in normotensives, a mere 0.6 mm Hg average reduction of mean arterial pressure (MAP) was achieved – and in hypertensives a modest 3 mm Hg. However, considerable reflex increases of sympathetic as well as of renin-angiotensin activities ensued, and usually of heart rate too, effects that can imply considerable drawbacks 5, 6.

In contrast, Korner's group in Melbourne 7 found that resting MAP was reduced 6 – 7 mm Hg in normotensives merely by three 40 min periods of exercise per week, and in hypertensives about as much as what conventional anti-hypertensive drugs can accomplish. To this comes, however, that exercise has other health-improving effects that no drug can achieve (– and which for tens of thousands Homo sapiens generations has been a matter-of-survival, though being almost eliminated concerning today's ‘Homo sedentaris’). It strengthens heart, skeletal muscles, tendons and skeleton, increases insulin sensitivity, improves intermediate metabolism, stimulates the immune system, enhances endorphin release in the brain, thereby reducing mental strain, sympathetic tonic activity etc. 8, 9. In fact, concerning MS these many advantages are, if anything, even more important.

And thus over to MS, being so often intertwined with PH in today's hectic-competitive society – and often combined with material affluence and dwindling physical activity, with its many advantages 2, 4, 8, 9. With such a perspective it can, along with Ravnskov, be questioned whether such ‘assumed culprits’, as fat and cholesterol intakes/levels and/or adipositas-in-general, really are the key elements behind such serious disorders as diabetes 2 and atherosclerosis, or instead fairly ‘innocent co-travellers’ to other overlooked factors. Thus, the intense interest concentrated on e.g. mentioned intakes easily overshadows what e.g. psychosocially induced mental strain can accomplish by means of associated, CNS-directed neuro-endocrine influences – which latter affect all tissues and organ-systems 1, 2, 4, 8, 9.

After all, life in the present ‘Brave-new-world’ is – as indicated above – in so many respects ‘biologically artificial’, compared with the hunter-gatherer-life that our species by means of tough ‘survival-of-the-fittest’ selections, is designed for – both physically and mentally. To paraphrase my colleague in human physiology, PO Åstrand: If one compares our species’ struggles – from the time when the ‘first-few tools were produced millions-of-years ago’, up to today's type-of-life – with a 42 195 m Marathon run, the perspective is: 7 – 8 millenniums of agriculture is like the last 150 meters of the run, the machine-age like the last few meters and present computer-email-life like the last few decimetres … But, genetically we are designed for a hunter-gatherer-small-group-life. And when challenged we induce the same protective, emotionally charged response patterns as all other animals 2, 4, 8, 9.

It is now well-documented how psychosocial challenges can per se elicit a variety of pre-formed neuroendocrine-and behavioural response patterns, designed for coping with different environmental situations 2, 4, 8, 9. In the present context the defence reaction, mainly engaging the sympatho-adrenomedullary axis, and the defeat reaction, mainly engaging the hypothalamo-hypophyseal-adrenocortical axis, are of paramount importance. Further, when persistently engaged, they can, by means of their autonomic-nerve and hormonal links, induce largely the same physical stigmata in animal models as seen in man's PH and MS, respectively.

Here the pioneer studies by Henry et al. in mice colonies, and those of Kaplan, Clarkson, Manuck et al on primate monkeys 2, 4, 8, 9 have been, and are, of greatest principal importance. With respect to man, the work of Björntorp's group concerning MS 4, 8, 9 is of particular interest. In about one third of 51-year-old men in Göteborg, the for MS typical changes were observed, like apple-shape adipositas, raised blood pressure, insulin resistance/diabetes 2, etc. Further, this sub-group showed largely the same disturbances of e.g. glucocorticoid secretion as seen in defeat reactions while, on the mental side, frustration and even depression were common.

It is highly worthwhile to ‘go-back-in-time’, e.g. to the early 1930's, when Harvey Cushing described what is now called Cushing's syndrome: Glucocorticoid hyper-secretion (e.g. via hypophyseal or adrenocortical tumours) led to apple-shape adipositas, diabetes 2, raised blood pressure, atherosclerosis, etc. Further, around the same time Benhardo Houssay in Argentina demonstrated how experimental diabetes was much attenuated when hypophysectomy was performed, and mainly so because of a markedly reduced glucocorticoid secretion – and for this Houssay was in 1947 awarded the Nobel prize. Finally, German medicine used still earlier the expression ‘Kummer-Speck’ (as in my own text-book in the early1940's), largely: ‘anxiety-frustration-related adipositas’. This condition was at least partly ascribed to the frequent ‘small-eating’, commonly used to relieve such mental states, but defeat reaction-related glucocorticoid hypersecretion was in all likelihood involved as well.

Concluding remarks

Towards such a background, it is hardly justified to throughout consider adipositas-in-general or/and lipid-cholesterol intakes/levels as the dominant health risks (except, of course, if excessive – just like definitely excessive salt intakes are not healthy: ‘Too much and too little spoils everything’). After all, quite-a-few authorities consider pear-shape adipositas as fairly innocent – except, again, when so marked as to indicate serious disturbances of e.g. the hypothalamic regulation of appetite. To exemplify: In recent extensive intervention studies by Berglund's group in Sweden 10, where intakes of both total fat and saturated fat were over long periods considerably reduced, this had no significant influence on cardiovascular disorders. They summarized these, and similar results of quoted studies, in the Swedish ‘Läkartidningen’ (LT) 2007 11 under the title “Fat intake and cardiovascular health-are we completely misinformed?”

After all, mankind has – thanks to an omnivorous constitution – during eons-of-time managed to thrive on strikingly different diets, like Eskimos or Australian Aborigines, and has – moreover – become adapted to cope with drastic shifts between food abundance and starvation. Thus, in primitive life an ability to rapidly fill-up fat depots in times-of-plenty must during starvation periods have contributed to ‘survival-of-the-fittest’. It may well be such genetically linked abilities that nowadays can, in a sense, ‘backfire’, when food is abundant while physical activity dwindles. Nevertheless, both these elements per se may be relatively innocent, though the ‘exercise-component’ certainly less so, for reasons given above.

Thus, concerning the assumed risks of ‘adipositas-cholesterol-fat’, such factors may alone be relatively innocent ‘co-travellers’ in present-life situations. The real culprits may instead be linked to the mentioned, centrally induced neuro-endocrine disturbances associated to prolonged defeat reactions, as more-or-less intertwined with those associated to prolonged defence reactions. This is strikingly illustrated in the above-mentioned animal models, where e.g. MS like disturbances of health were induced merely by prolonged and overwhelming psychosocial challenges 2, 8, 9.

However, when it comes to man and man's complex society, with a multitude of variables and a much longer time-axis, tools like statistics, correlation coefficients and-the-like must be used to separate true ‘culprit-victim’ relations from more-or-less innocent co-travellers. Undoubtedly this implies even greater difficulties than when per se complicated studies in animal-group models are analyzed. Naturally this also invites to interpretation divergences where, considering human mind, conflicts and other troubles ensue.

In any case, on the basis of such considerations, as seen from a physiologist's angle, it appears that Ravnskov's criticism of the assumed risks connected to the ‘adipositas-cholesterol-fat-complex’ has been highly justified and to-the-point. It also serves as a good example of how important Kars Popper's ‘rules’ really are in science. First then can divergences concerning result-interpretations be solved, and premature generalisations avoided – which otherwise can end up in misdirected or/and unnecessary pharmacological interventions. To a considerable extent this seems to have been the case concerning the here actual problem. This, of course, by no means denies the enormous value of the thousands of individual studies, which must be at hand in this type of world-wide health problem for real progress and final solutions.