The pharmacologically improved human. Performance-enhancing substances as a social challenge. Final Report

For some years now, in response to the rising challenges of global socioeconomic competition, both the scientific community and the public have been debating whether the improvement of individuals’ performance with the help of technical or biomedical interventions in the human body – termed enhancement – is a welcome, inevitable or undesirable vision of the future. The report on brain research by the Office of Technology Assessment at the German Bundestag (TAB) (Bundestagsdrucksache 16/7821) also presented evidence of a growing trend towards the use of pharmaceuticals and other medical interventions to specifically influence mental states and capacities. Following publication of the highly respected TAB report »Gene Doping«, an analysis of physical performance enhancement in sport, the Committee for Education, Research and Technology Assessment commissioned the TAB to undertake a technology assessment project on »pharmacological and technical interventions to improve performance – prospects for more widespread use in medicine and everyday life« (»Enhancement Project«). The TAB’s final report analyzes the areas of development and use with the greatest social and political relevance now and in the foreseeable future, i.e. current developments and plausible trends regarding the use of psychopharmaceuticals and other drugs to enhance performance in working and everyday life. It provides a comprehensive analysis of the current status of possibilities to influence human performance by pharmacological means and of the classification of those agents within the framework of laws regulating medicines, foods and healthcare. This will facilitate a realistic discussion of future developments that clearly stands out from previous hypothetical and visionary descriptions of enhancement. The report shows that the targeted development and use of pharmacological substances for nontherapeutic performance enhancement is incompatible with the current objectives of the medical innovation system and the remit of doctors. A change in this situation would require a far-reaching public and political opinion-forming process. At the same time, the systematic analysis of the scientific approach to the doping problem in elite and competitive sport undertaken in the TAB report points to the need for a thorough public debate on how to deal with growing demands for performance and innate differences in abilities among individuals. The report based on TAB report Nr. 143 »Pharmakologische Interventionen zur Leistungssteigerung als gesellschaftliche Herausforderung. Endbericht zum TA-Projekt« examines the options for action in the fields of research, regulation, healthcare consumer protection and prevention

Gene doping. Summary

Like a phantom, "gene doping" has been haunting the debates on the future of competitive sport for years. Such fantasies and visions often culminate in the image of super athletes whose genetic make-up has been permanently manipulated. But the expected application scenarios will be much more unspectacular, but at the same time more probable and closer. We will soon have to reckon with the use of new substances as well as gene and cell therapeutic methods for the targeted manipulation of gene activity. Their use promises highly efficient performance enhancement and will be difficult, if not impossible, to detect. This volume provides comprehensive answers to the key questions of further development: What scientific results could be used for possible gene doping, where will the gateways be in elite and popular sport, and how can we react to this with the help of prohibition and control structures? It is also asked which individual behavioural patterns of athletes and which social contexts will play a role in the expected career of gene doping

Gene Doping: Scientific Basis - Gateways - Monitoring

Like a phantom, "gene doping" has been haunting the debates on the future of competitive sport for years. Such fantasies and visions often culminate in the image of super athletes whose genetic make-up has been permanently manipulated. But the expected application scenarios will be much more unspectacular, but at the same time more probable and closer. We will soon have to reckon with the use of new substances as well as gene and cell therapeutic methods for the targeted manipulation of gene activity. Their use promises highly efficient performance enhancement and will be difficult, if not impossible, to detect. This volume provides comprehensive answers to the key questions of further development: What scientific results could be used for possible gene doping, where will the gateways be in elite and popular sport, and how can we react to this with the help of prohibition and control structures? It is also asked which individual behavioural patterns of athletes and which social contexts will play a role in the expected career of gene doping

Pharmakologische Interventionen zur Leistungssteigerung als gesellschaftliche Herausforderung. Endbericht zum TA-Projekt

Seit einigen Jahren wird die Einnahme pharmakologischer Substanzen als Strategie der mentalen Leistungssteigerung in Arbeits- und Alltagsumgebungen unter dem Begriff »Enhancement« diskutiert. Der TAB-Bericht »Pharmakologische Interventionen zur Leistungssteigerung als gesellschaftliche Herausforderung« stellt den Stand der Möglichkeiten, menschliche Leistung pharmakologisch zu beeinflussen, detailliert dar und nimmt eine arznei-, lebensmittel- und gesundheitsrechtliche Einordnung der entsprechenden Substanzen vor. Gezeigt wird, dass die existierenden medizinethischen Standards und Zulassungsverfahren für Arzneimittel gegenwärtig eine erhebliche Barriere für die Entwicklung von nicht-therapeutischen Enhancementmitteln darstellen. Trotz fehlender Wirksamkeitsnachweise und erheblichem Nebenwirkungspotenzial ist dennoch von einem relevanten Substanzgebrauch in der Bevölkerung auszugehen, dessen Ursachen und Bedingungen als die eigentliche gesellschaftliche Herausforderung erscheinen. Die Analyse der bioethischen und sozialwissenschaftlichen Debatte zur Thematik sowie insbesondere die Auswertung von Erkenntnissen aus der Erforschung der Dopingpraxis im Leistungs- und Breitensport liefern Hinweise auf die mögliche Dynamik von Enhancement im Kontext einer »Leistungssteigerungsgesellschaft«. INHALT ZUSAMMENFASSUNG 5 I. EINLEITUNG 31 1. Hintergrund und zentrale Aspekte des Themas 31 2. Beauftragung, Zielsetzung und Vorgehensweise 32 3. Kooperation mit Gutachterinnen und Gutachtern 35 4. Aufbau des Berichts 36 5. Zur Verwendung des Begriffs Enhancement 38 II. MENSCHLICHE LEISTUNG UND IHRE PHARMAKOLOGISCHE BEEINFLUSSUNG 41 1. Begriffe und biologische Grundlagen 42 1.1 Menschliche Leistungen 42 1.2 Menschliche Fähigkeiten 46 1.3 Möglichkeiten und Grenzen der Quantifizierung von Leistungen und Fähigkeiten 47 1.4 Biologische Grundlagen 51 2. Ansatzpunkte und Grenzen der Verbesserung menschlicher Fähigkeiten 55 3. Pharmakologisch wirksame Substanzen 58 3.1 Psychostimulanzien 59 3.2 Substanzen gegen Dopaminmangel 73 3.3 Antidepressiva 77 3.4 Antidementiva 79 3.5 Beta-Blocker 82 3.6 Mögliche zukünftige Neuroenhancer? 84 4. Andere Substanzen: pflanzliche Inhaltsstoffe 85 4.1 Substanzen aus dem Bereich Heilpflanzen und Naturmedizin 87 4.2 B-Vitamine 89 4.3 Ungesättigte Fettsäuren 93 4.4 Tyrosin 94 5. Kognitives Training und sonstige Methoden 94 5.1 Psychologisch fundierte Trainingsmaßnahmen 94 5.2 Nichtinvasive technische Mittel 96 6. Fazit 98 III. ENHANCEMENTSUBSTANZEN ALS LEBENS- ODER ARZNEIMITTEL? RECHTLICHE ABGRENZUNG, NORMATIVER UMGANG UND VERBREITUNGSWEGE 103 1. Substanzdefinition und Abgrenzung 104 2. Normativer Umgang mit Lebensmitteln 107 2.1 Missbrauchsprinzip 107 2.2 Unterkategorien, Verkehrsfähigkeit 108 2.3 Wirksamkeitsnachweis und Informationspflichten 111 2.4 Marktakteure: Einstellungen und Verhalten 114 3. Normativer Umgang mit Arzneimitteln 118 3.1 Verbotsprinzip mit Erlaubnisvorbehalt 119 3.2 Arzneimittelforschung: Standards für die Wissensgenerierung und Zulassung 120 3.3 Verkehrsfähigkeit 131 3.4 Information und Werbung 133 3.5 Apotheker und Ärzte: Schlüsselpersonen für das Inverkehrbringen und den Gebrauch 144 3.6 Kostenträger und Gesundheitsmärkte 155 4. Die Verbraucherseite: Befunde zum Arzneimitteleinsatz zur Leistungssteigerung 168 4.1 Empirische Befunde zur pharmakologischen Leistungssteigerung 169 4.2 Umgang mit möglichen Folgekosten durch die Einnahme von (Enhancement-)Substanzen 175 5. Fazit 177 IV. DIE DEBATTE ÜBER ENHANCEMENT IN ETHIK UND SOZIALWISSENSCHAFTEN 183 1. Die ethische Debatte über Enhancement 183 1.1 Definitions- und Abgrenzungsprobleme 184 1.2 Ethische Prinzipien nach Beauchamp und Childress 188 1.3 Sorgen um die Zukunft der menschlichen Natur 193 2. Perspektiven der Sozialwissenschaften: Enhancement als Teil eines Medikalisierungsprozesses 195 2.1 Grenzverschiebungen im engeren Bereich der Medizin: Krankheit, Gesundheit, Heilung, Verbesserung 197 2.2 Die Subjektebene: Aneignungsformen zwischen sozialem Druck und eigener Gestaltung 204 2.3 Sozioökonomische Entgrenzungen: vom Gesundheitswesen zum Gesundheitsmarkt 211 3. Fazit 213 V. LEISTUNGSSTEIGERNDE MITTEL DER ZUKUNFT – EIN ERWEITERUNGSSZENARIO 217 1. Entwicklung von leistungssteigernden Pharmaka im derzeitigen Forschungs- und Innovationssystem 219 1.1 Akteure der pharmakologischen Wirkstoffforschung und -entwicklung 220 1.2 Bisherige Entwicklungs- und Verbreitungspfade 228 2. Elemente und Implikationen eines Erweiterungsszenarios 232 2.1 Bisherige rechtliche Restriktionen – notwendige Veränderungen 234 2.2 Forschung und Entwicklung vor Marktzulassung 237 2.3 Anforderungen an eine Langzeitüberwachung 243 2.4 Mögliche Konsequenzen für das Gesundheitssystem 244 2.5 Rückwirkungen auf das Innovationssystem 248 2.6 Fazit: mögliche Auslösebedingungen des Erweiterungsszenarios 249 VI. DOPING UND ENHANCEMENT: GEMEINSAMKEITEN UND UNTERSCHIEDE ZWISCHEN SPORT UND BERUFSLEBEN 251 1. Zum Dopingdiskurs: Argumentationen und Rechtfertigungsmuster 252 2. Dopingspirale: Quantitätsgesetz und Drop-out 254 3. Pharmakologische Leistungssteigerung: abweichendes, aber angepasstes Verhalten? 256 4. Pathologische Aspekte der Hochleistung 261 5. Prävention: Strategien gegen eine weitere Medikalisierung? 264 6. Fazit 266 VII. RESÜMEE UND HANDLUNGSFELDER 269 LITERATUR 282 1. In Auftrag gegebene Gutachten 282 2. Weitere Literatur 282 ANHANG 302 1. Tabellenverzeichnis 302 2. Abbildungsverzeichnis 303 3. Abkürzungsverzeichnis 30

Gendoping. Wissenschaftliche Grundlagen - Einfallstore - Kontrolle

Wie ein Phantom geistert »Gendoping« seit Jahren durch die Debatten zur Zukunft des Leistungssports. Häufig gipfeln entsprechende Phantasien und Visionen im Bild von dauerhaft in ihrer genetischen Ausstattung manipulierten Superathleten. Doch die zu erwartenden Anwendungsszenarien werden viel unspektakulärer, zugleich aber wahrscheinlicher und näherliegend sein. Man wird schon bald mit einer Nutzung neuer Substanzen sowie gen- und zelltherapeutischer Verfahren zur gezielten Manipulation der Genaktivität rechnen müssen. Ihr Einsatz verspricht eine hocheffiziente Leistungssteigerung und wird sich, wenn überhaupt, nur schwer nachweisen lassen. Dieser Band beantwortet umfassend die Schlüsselfragen der weiteren Entwicklung: Welcher wissenschaftlichen Ergebnisse könnte sich ein mögliches Gendoping bedienen, wo werden Einfallstore im Spitzen- und Breitensport sein, und wie kann mithilfe von Verbots- und Kontrollstrukturen darauf reagiert werden? Gefragt wird auch danach, welche individuellen Verhaltensmuster von Athleten und welche gesellschaftlichen Kontexte eine Rolle bei der zu erwartenden Karriere von Gendoping spielen werden

Evaluating the Relationship Between Visual Acuity and Utilities in Patients With Diabetic Macular Edema Enrolled in Intravitreal Aflibercept Studies

PURPOSE. The purpose of this study was to explore the relationship between visual acuity and utility (health-related quality of life) in diabetic macular edema (DME) using intravitreal aflibercept data. METHODS. The relationship between visual acuity in the best-seeing eye (BSE) and worseseeing eye (WSE) and utility was explored using ordinary least squares (OLS) and randomeffects models adjusted for different covariates (age, age2 , sex, body mass index, smoking status, glycated hemoglobin, diabetes severity, comorbidities, and geographic region). Utility was measured using the EuroQoL-five dimensions questionnaire (EQ-5D) and Visual Functioning Questionnaire-Utility Index (VFQ-UI). For each model, coefficients (R2 ) were reported, and WSE/BSE was expressed as the ratio of coefficients (OLS models). Models were independent of treatment effects, and outcomes from all time points (up to week 100) were included where available. RESULTS. Data from 1320 patients with DME were analyzed. In all models, the association between visual acuity (BSE > WSE) was stronger with VFQ-UI– than EQ-5D–derived utilities. The estimated relationship between VFQ-UI and visual acuity in the BSE and WSE was robust, even with an increasing number of covariates. WSE/BSE coefficient ratios were similar across VFQ-UI OLS models (32%) compared with EQ-5D models (41%–48%). Actual (unadjusted) versus predicted data plots also showed a better fit with VFQ-UI– than EQ-5D–derived utilities. CONCLUSIONS. These analyses show that VFQ-UI was more sensitive than EQ-5D–derived utilities for measuring the impact of visual acuity in the BSE and WSE. Visual acuity in the BSE was a major contributor to utility, but WSE is also important though to a lesser degree as shown by the coefficient ratios. These new data will be useful for health technology assessments in DME, where utilities data are lacking. Keywords: diabetic macular edema, intravitreal aflibercept, utilit

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

SC was funded by fellowships from NIHR and Cancer Research UK. IK was funded by the UCLH Experimental Cancer Centre and UCLH NIHR Biomedical Research Centre. TP was funded by grants from Cancer Research UK (the Experimental Cancer Medicine Centre). MG was funded by grants from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Schottlander Research Charitable Trust, the Royal Marsden NIHR Biomedical Research Centre for Cancer and the Wellcome Trust (grant number: 105104/Z/14/Z

Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

BACKGROUND: In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance. METHODS: To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS-associated CET resistance. RESULTS: This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration (p < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (p < 0.001), ephrin-A1 stimulation (p < 0.001), dasatinib (p < 0.01), or anti-EPHA2 antibody treatment (p < 0.001), identifying it as an actionable target in mCRC with acquired CET resistance. CONCLUSION: These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies

Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

AbstractBackgroundCandidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated.ObjectiveTo validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising markers to guide biomarker optimisation.Design, setting, and participantsCancer-specific survival (CSS) for each of 28 identified genetic or transcriptomic biomarkers was assessed in 350 ccRCC patients. ITH was interrogated in a multiregion biopsy data set of 10 ccRCCs.Outcome measurements and statistical analysisBiomarker association with CSS was analysed by univariate and multivariate analyses.Results and limitationsA total of 17 of 28 biomarkers (TP53 mutations; amplifications of chromosomes 8q, 12, 20q11.21q13.32, and 20 and deletions of 4p, 9p, 9p21.3p24.1, and 22q; low EDNRB and TSPAN7 expression and six gene expression signatures) were validated as predictors of poor CSS in univariate analysis. Tumour stage and the ccB expression signature were the only independent predictors in multivariate analysis. ITH of the ccB signature was identified in 8 of 10 tumours. Several genetic alterations that were significant in univariate analysis were enriched, and chromosomal instability indices were increased in samples expressing the ccB signature. The study may be underpowered to validate low-prevalence biomarkers.ConclusionsThe ccB signature was the only independent prognostic biomarker. Enrichment of multiple poor prognosis genetic alterations in ccB samples indicated that several events may be required to establish this aggressive phenotype, catalysed in some tumours by chromosomal instability. Multiregion assessment may improve the precision of this biomarker.Patient summaryWe evaluated the ability of published biomarkers to predict the survival of patients with clear cell kidney cancer in an independent patient cohort. Only one molecular test adds prognostic information to routine clinical assessments. This marker showed good and poor prognosis results within most individual cancers. Future biomarkers need to consider variation within tumours to improve accuracy