ЧИ НЕ ВТРАЧАЄТЬСЯ ПРЕСТИЖ НОБЕЛІВСЬКОЇ ПРЕМІЇ?

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In 2000, in what is perhaps the most famous specialist journal in the world, the American «Science», we read with great surprise about an open letter from 269 scientists protesting that the Nobel Prize for Physiology and Medicine had not been awarded to Oleh Hornykiewicz.¹At the time we were sceptical about this protest because it seemed improbable to us that the Nobel Prizes – the greatest scientific honours in the world – could be unjustly awarded.

However, later a news item perplexed us. In January 2004 Geir Lundestad, director of the Norwegian Nobel Institute, announced that the American President George W. Bush and the British Prime Minister Tony Blair had been nominated for the Nobel Peace Prize.²At first we thought this was a joke. A legitimate question – what for then? For the Iraq War, which the two politicians had begun with the help of bogus evidence? People throughout the world were against this war. The Iraq War was the first war in the history of humanity to be preceded by protest demonstrations before it had begun, and millions of people took part in the demonstrations. On 15 February 2003 approximately 9 million people worldwide participated in the biggest peace demonstration in history.³The protests were particularly strong in the USA, where people demonstrated daily against the planned war. International inspectors had found no weapons of mass destruction in Iraq. The UN had passed no resolution for military action in Iraq. The large majority of the world community was against this war and almost all European governments had rejected military intervention. This war had no ethical or judicial grounds and no justification under international law. However, all the protests did not help. The invasion of Iraq began on 20 March 2003. By the time Bush and Blair were nominated for the Nobel Peace Prize ten months had passed and Iraq already lay in ruins. Since the beginning of the war at least 100,000 Iraqi civilians have died as a result of violence.⁴At the same time there are approximately 2.5 million internally displaced persons in Iraq, 1 million of them from before the war, the others since 2003 with a dramatic increase since February 2006 with around 1.3 million internally displaced persons. Added to this there are more than 2 million refugees outside Iraq.⁵On 8 September 2004 the number of American fatalities passed the psychologically critical mark of 1,000. Until now a total of 4,792 coalition soldiers have been killed, 4,474 of them American.⁶ In addition more than 8,000 Americans have been severely wounded. The total number of wounded US soldiers amounts to 32,159.

And Bush and Blair were nominated for the Nobel Peace Prize for these deeds? What does this have to do with Alfred Nobel’s will?

We take the liberty of quoting the conditions for the award of the Nobel Peace Prize from Alfred Nobel's will: «… one part to the person who shall have done the most or the best work for fraternity between nations, for the abolition or reduction of standing armies and for the holding and promotion of peace congresses.» ⁷

The Nobel Peace Prize was awarded to personalities like Mother Theresa and organisations like Médecins Sans Frontières completely on merit.

The award of the Nobel Peace Prize to President Obama in 2009 leaves many open questions. The fact that he had been nominated was kept quiet until the last minute and the award was a surprise for everyone. The award itself could only be seen as being given in advance and as a signal – the president should end the war. However, the war is still going on.

These events have compelled us to see the Hornykiewicz story from another angle. «269 renowned scientists at prestigious universities in Brazil, China, Germany, England, Finland, France, Great Britain, Guam, Hawaii, India, Ireland, Italy, Japan, Canada, New Zeeland, Holland, Austria, Saudi Arabia, Spain, Taiwan, Turkey, Ukraine, Hungary and the USA, in fact all over the world, cannot all be wrong at the same time,» we then thought. We are not experts in the field of Parkinson's disease and cannot judge whose research is more important in this area. But these people are not journalists or similar laymen in medicine, they are specialists in this field. They use Hornykiewicz's discoveries in their research and most certainly know that he deserved the Nobel Prize.

We asked the publishers of the journal «Parkinsonism and Related Disorders» for permission to publish the letter from the 269 scientists. On 23 August 2011 we received permission and are very grateful to the publishers. This letter will certainly help readers to assess the importance of Hornykiewicz's research. The people who signed the letter see the benefit of Hornykiewicz's discoveries in their daily work. And they write that it was precisely in his work that the decisive link between dopamine and the development mechanisms of brain disease in humans was determined. However, what appears no less important is that his observations were the basis for the modern treatment of Parkinson’s disease, which is of the greatest significance for millions of people. However, this is not all: his research gave the impulse for countless similar studies of many other neurological and psychiatric disorders.

It clearly emerges from the scientists' open letter that Oleh Hornykiewicz made a decisive contribution to decoding the development mechanisms of Parkinson's disease as well as the establishment of the modern treatment of this widespread neurological disorder. The fact that despite being nominated around ten times he was not awarded the Nobel Prize does seem questionable, is not consistent with Alfred Nobel’s will and represents a dangerous precedent.

From these examples it can be seen that the social tendencies in today's world have taken an ominous course which must finally be stopped.

We have given much thought to why Professor Hornykiewicz did not receive the fully deserved Nobel Prize but have found no satisfactory answer. We live in a time when all people have the same rights irrespective of skin colour, religion or gender. The Nobel Prize Committee should explain why the prize was not awarded to the Viennese pharmacologist.

It would in any case make sense to examine where and when these questionable tendencies have their origin, how many people have undeservedly been awarded the Nobel Prize and who has not received it despite deserving it. Perhaps a group does in fact exist – so-called lobbyists who present second-rate discoveries to society as first-rate and honour certain scientists with the Nobel Prize. At the same time some first-rate discoveries disappear from history and outstanding scientists are left empty handed. Such a tendency is destructive and must be stopped because it disrupts the development of society.

It is incomprehensible why of all Parkinson’s disease researchers the Nobel Prize was awarded to Arvid Carlson. He did not completely understand the importance of dopamine and even wrote in 1965, «…it is not possible to draw any conclusions about the relative importance of dopamine and noradrenaline for the central effects [incl. parkinsonism?] of reserpine.»⁸.

Dopamine was synthesised for the first time in 1910 by George Barger and James Ewens at the Wellcome Laboratories in Herne Hill, London. In the same year, and also in London, Henry Dale (later Sir Henry Dale) examined the biological effects of dopamine and defined them as a weak sympatomimetic effect. Many years later, in 1952, this same Henry Dale gave the name dopamine to the substance with the chemical designation 3,4dihydroxyphenelethylamine.

Levodopa, or L-Dopa is the natural L-isomer of the amino acid dihydroxyphenylalanine. Levodopa was first isolated from broad beans in 1910-1911 by the Italian physicist Torquato Torquati.⁹In 1913 Markus Guggenheim determined the chemical formula of this substance.¹⁰Over the next 30 years after the synthesis of dopamine nothing special happened in its history or the history of levodopa. Only in 1938 did the German pharmacologist Peter Holtz discover the enzyme dopa decarboxylase and showed that this enzyme produces dopamine from levodopa in the tissue homogenate of mammals.¹¹Based upon this discovery, in 1939 in Cambridge, Hermann Blaschko postulated the synthesis chain for catecholamines, which have still not lost their significance. At the time a modest role was reserved for dopamine as an intermediary product in the synthesis of adrenaline and noradrenaline. At the beginning of the 1950's reports appeared that dopamine is present in small quantities in many tissues: adrenal glands, heart and nerves among others. These findings in themselves brought nothing new but led Blaschko to an important idea which he expressed in a talk to the members of the Swiss Society of Physiology, Biochemistry and Pharmacology in autumn 1956: dopamine could have its own physiological role. At the same time Oleh Hornykiewicz was in Oxford, in Blaschko's laboratory at the Institute for Pharmacology. Blaschko suggested to Hornykiewicz that he should search for dopamine's distinct function. Hornykiewicz carried out a study on guinea pigs and showed that both dopamine and levodopa reduced blood pressure. This meant that their effect was contrary to that of noradrenaline. It was thus confirmed for the first time that dopamine has its own distinct function. A short report from the British scientist Kathleen Montagu, which appeared in Nature on 3 August 1957,¹²attracted Hornykiewicz's attention. She had discovered a new substance in the brain and suggested that it was dopamine. Around a month later Holtz reported on the central stimulating effect of levodopa in rodents and conjectured that dopamine could be an active metabolic product from levodopa in the brain.¹³Six months later in February 1958 Arvid Carlson reported that he had found the presence of dopamine in the brains of rabbits with the help of a new, more accurate method. Reserpine reduced the dopamine content in a similar way to the concentrations of noradrenaline and serotonine, and levodopa increased the reduced dopamine content and, to a lesser extent, that of noradrenaline. However, the neurological community regarded these findings exclusively in relation to the heated argument of the time: is the calming effect of reserpine to be attributed to its effect on noradrenaline or serotonine? Even Carlson wrote at the time: «Dopamine… in the high concentrations observed [in brain after L-dopa] may be able to function as noradrenaline.»¹⁴Hornykiewicz was carrying out research in a completely different direction. It was clear to him that the decisive step should be the transition from animal experiments to patients with functional disorders of the basal ganglia, especially Parkinson’s patients. Hornykiewicz began collecting brain tissue from dead patients with his colleague Herbert Ehringer. It should be mentioned that at the time this tissue was regarded as absolutely unsuitable for tests on such instable substances such as catecholamines. Many older colleagues advised him to waste no time on «such dirty material». Another problem was of a completely different nature: the laboratory did not have a sufficiently sensitive spectrometer, so Hornykiewicz had to adapt other methods for his experiments. After the first tests on his own control samples in April 1959 the first study of a Parkinson's patient's brain finally took place. The result was already clear before the analysis: no dopamine! The next step was the idea to restore the lost dopamine reserves in Parkinson's patients. Levodopa was an obvious candidate for this role – the natural precursor of dopamine. An important partner was won over after protracted and difficult negotiations – the well-known Viennese neurologist Walther Birkmayer declared himself ready to participate in the clinical study. In July 1961 levodopa was administered intravenously to Parkinson's patients for the first time. The effect was incredible: «The bed-ridden patients who could not sit up, the patients who could not stand up once they had sat down, and patients who could not walk when they were standing were easily able to carry out these activities after L-dopa administration. They walked again normally and were even able to run and jump.»¹⁵

Thus it was Oleh Hornykiewicz who demonstrated the decisive connection between dopamine and Parkinson's disease in humans and also established the basis for the modern treatment of this disorder, which had a direct effect on the lives of millions of patients. The huge significance of these discoveries was quickly recognised and Hornykiewicz was nominated for the Nobel Prize several times, for the first time at the beginning of the 1970s. Since then thousands of publications and daily medical practice have proved the extraordinary benefit of Hornykiewicz’s discoveries. The great importance of Hornykiewicz’s work is also emphasised by the 230 neurologists from all over the world in their letter to the Nobel Prize Committee. They see the benefit of these discoveries in their daily work. Hornykiewicz was also nominated together with Carlson for the Nobel Prize in 2000. Carlson received the prize. Why was Hornykiewicz not honoured with the Nobel Prize? This question has remained unanswered until now. We tried to find a satisfactory answer, talked to a number of people and heard a strange explanation: if Professor Hornykiewicz had carried out his studies in the USA or Israel, he would certainly have received the Nobel Prize. Incidentally, in Israel he was honoured with the highest scientific award in 1979 – the Wolf Foundation Award. We are living in a time when all people have the same rights, irrespective of skin colour, nationality, ethnic origin, religion or gender. The Nobel Prize Committee is now obliged to explain why the prize has not been awarded to the Viennese pharmacologist. The question arises: what is more important – the quality of the work or the place where it is done? The non-award of the prize to Hornykiewicz is similar to the situation with penicillin when the Nobel Prize was only awarded to Fleming while Florey and Chain were left empty-handed. Without the work of these two scientists the world would perhaps not have been able to correctly judge the benefit of penicillin until now. This is the reason why the scientific community was so outraged and why 269 scientists addressed the open letter of protest to the Nobel Prize Committee.

Another example. The 2004 Nobel Prize for Chemistry was awarded to Aaron Ciechanover, Avram Hershko and Irwin Rose, «for their research into the basis of the ubiquitin system at the beginning of the 1980s,» as the official statement puts it. What did Alfred Nobel in fact bequeath in his will? The prize is to go to the person who has made «the most important discovery or invention» in science.¹⁶Very quickly after its establishment the Nobel Prize became the most important scientific award and the Nobel Peace Prize became the most important political award. Its award represents the highest recognition of achievements and an extremely important signal for the further development of science. The significance of the Nobel Prize for further research can be seen from the example of ubiquitin. In the seven years after the award of the Nobel Prize to Rose, Ciechanover and Gerschko one and a half times so many publications appeared on the subject of ubiquitin than in the thirty years previously: the number of publications rose from around 400 to 2,500 per year. The story of ubiquitin is in any case rather strange. This protein had already been discovered and decoded by other scientists in the mid-1970s. Why just these three shared the Nobel Prize remains a mystery. The first publications of these authors on the subject of ubiquitin only go back to 1980.

For example, J.W. Hadden published an article about ubiquitin in 1975.¹⁷At the time when Gerschko and Ciechanover published their first article about ubiquitin there were already 154 articles on the subject by dozens of other authors, including in such renowned journals as Nature, Science and Journal of Immunology. At the time J.W. Hadden had already published 70 articles. Thousands of publications appeared about ubiquitin after the award but brought about no decisive breakthrough. This discovery did not result in any really great advances. In addition, no new medicament has been developed thanks to ubiquitin. This means that there was no justifiable reason to describe this work as «the most important discovery». Hundreds of new proteins are being discovered, or their functions decoded, all the time. Every dissertation contains something new but they still remain far away from meriting a Nobel Prize. With very few exceptions these research works remain of pure academic interest and have only little – if any – influence on medical practice. Why the 2004 Nobel Prize was awarded to and shared by these three scientists – Rose, Ciechanover and Gerschko – remains incomprehensible.

Another case is particularly shocking. The Nobel Peace Prize was awarded to a politician who is waging a war of occupation. Every country has the right to freedom and independence. Young patriots fight for their country and the politician who allows war to be waged against them is honoured with the Nobel Peace Prize.

Such tendencies lead to this high honour losing its prestige. They should be analysed and, if necessary, revised. Cases in Germany can be mentioned as an example, where, when it was proved that a doctoral thesis had been copied from others, the PhD title was revoked. Such a practice should also be applied to the Nobel Prize. We hope there are courageous investigative journalists who will concern themselves with this interesting and important subject. Because the awarding of the Nobel Prize is slowly becoming a farce.

It should be clarified whether these incomprehensible stories with the non-award of the Nobel Prize to Oleh Hornykiewicz, who fully merited it, and the award of the prize for a discovery that is of no special importance are individual cases or whether they already represent a dubious tendency. It would be most advisable also to investigate other awards.

However, since there is currently a 50-year obligation to secrecy with regard to information about the nominated and those nominating them as well as to opinions and investigations on the part of the Committee¹⁸(which seems rather questionable since it completely contradicts the spirit of Alfred Nobel's will) journalists can only research and reassess the award of the prize from its inception until 1961. It would in any case be worthwhile in order to discover where these unfavourable tendencies have their beginnings.

¹ An open letter to the Committee on The Nobel Prize in Medicine. Parkinsonism and Related Disorders, 7 (2001) 149–155.

⁸«… not possible to draw any conclusions about the relative importance of dopamine and noradrenaline for the central effects [incl. parkinsonism?] of reserpine». Carlsson A. Drugs which block the storage of 5-hydroxytryptamine and related amines. In: Eichler O, Farah A (eds). 5-Hydroxytryptamine and related indole alkylamines. Handbook of Experimental Pharmacology, vol. 19. Springer, Heidelberg, p. 529-592.

⁹Torquati T. Sulla presenza di una sostanza azotata nei germogli del semi di vicia faba. Arch Farmacol sper 1913, 15:213-223.

¹⁰Guggenheim M-Dioxyphenylalanin, eine neue Aminosäure aus Vicia faba. Hoppe-Seyler's Z Physiol Chem 1913, 88:276-284.

¹²Montagu KA. Catechol compounds in rat tissues and in brains of different animals. Nature 1957, 180:244–245.

¹³Holtz P, Balzer H, Westermann E, Wezler E. Beeinflussung der Evipannarkose durch Reserpin, Iproniazid und biogene Amine. Arch Exp Path Pharmak 1957, 131:333-348.

¹⁴ «Dopamine… in the high concentrations observed [in brain after L-dopa] may be able to function as noradrenaline». Seiden LS, Carlsson A. Brain and heart catecholamine levels after L-dopa administration in reserpine treated mice: correlation with a conditioned avoidance response. Psychopharmacologia (Berl) 1964, 5:178-181.

¹⁵ Birkmayer W, Hornykiewicz O. Der L-Dioxyphenylalanin (= DOPA)-Effekt bei der Parkinson-Akinese. Wien Klin Wschr 1961, 38:1236-1239.

¹⁷Hadden JW. Thymopoietin, ubiquitin and the differentiation of lymphocytes. Clin Bull 1975; 5(2):66–7.