Jan van Aken

Prospects and Limits of Pharmacogenetics The Thiopurine Methyl Transferase (TPMT) Experience

Thiopurine drug metabolism is a quintessential case of pharmacogenetics. A wealth of experimental and clinical data on polymorphisms in the thiopurine metabolizing enzyme thiopurine methyl transferase (TPMT) has been generated in the past decade. Pharmacogenetic testing prior to thiopurine treatment is already being practiced to some extent in the clinical context, and it is likely that it will be among the first pharmacogenetic tests applied on a regular basis.We analyzed the published TPMT data and identified some lessons to be learned for the future implementation of pharmacogenetics for thiopurines as well as in other fields. These include the need for comprehensive and unbiased data on allele frequencies relevant to a broad range of populations worldwide. The nature and frequency of TPMT gene polymorphisms in some ethnic groups is still a matter of speculation, as the vast majority of studies on TPMT allele distribution are limited to only a small subset of alleles and populations. Secondly, an appreciation of the limits of pharmacogenetics is warranted, as pharmacogenetic testing can help in avoiding some, but by far not all adverse effects of drug therapy. An analysis of six clinical studies correlating adverse thiopurine effects and TPMT genotype revealed that an average of 78% of adverse drug reactions were not associated with TPMT polymorphisms. Pharmacogenetic testing will thus not eliminate the need for careful clinical monitoring of adverse drug reactions. Finally, a careful approach toward dose increases for patients with high enzyme activity is necessary, as TPMT-mediated methylation of thiopurines generates a possibly hepatotoxic byproduct.

Individualized Pharmacogenetic Therapy: A Critical Analysis

Objective: Individualized, or personalized, therapy is highlighted as the declared goal of pharmacogenetics. In this paper, the content and significance of the individualization concept are analyzed. Method: Our analysis is based on a systematic reading of the current literature pertinent to pharmacogenetics. Results: This analysis reveals that the pharmacogenetic understanding of individualization is based on a biomechanistic paradigm. In contrast to a notion of individualized therapy based on a biopsychosocial paradigm, this biomechanistic concept does not provide for individualization in psychosocial terms, but instead leads to the stratification and classification of patient populations. This finding does not necessarily cast doubt on the efficacy of pharmacogenetics, but does call its underlying ideology into question. Conclusion: The term ‘individualization of therapy’ does not reflect the real potential of pharmacogenetics, but instead represents a widely used and theoretically unjustified publicity slogan.

Pharmacogenetics, Adverse Drug Reactions and Public Health

Adverse drug reactions (ADRs) are a major public health problem. Pharmacogenetic testing prior to drug treatment is supposed to considerably alleviate this problem. The state of pharmacogenetic development was assessed by a systematic literature review, supplemented by expert interviews. Analysis of three case examples revealed that – with the exception of thiopurine methyltransferase (TPMT) – studies are lacking which unambiguously prove the clinical value of pharmacogenetic testing. Testing can prevent some, but by far not all ADRs. Since it does not compensate for clinical monitoring, pharmacogenetics can be regarded as add-on technology, applied in addition to established methods. A non-representative, explorative survey conducted amongst members of the German Society of Laboratory Medicine revealed that the demand for testing is limited and has not increased much, although a certain increase is expected in the future.

When risk outweighs benefit Dual-use research needs a scientifically sound risk-benefit analysis and legally binding biosecurity measures

In October 2005, a team of US scientists, headed by Jeffery Taubenberger from the US Armed Forces Institute of Pathology (Rockville, MD, USA), published the full sequence of the highly virulent strain of influenza virus that caused the Spanish influenza pandemic in the winter of 1918– 1919 and killed up to 50 million people worldwide (Taubenberger et al, 2005). Further work based on the sequence led to the synthesis of an influenza strain containing all eight gene segments from the 1918 pandemic virus, which showed a high virulence and mortality rate when tested in mice (Tumpey et al, 2005). Both the sequencing and the reconstruction of the Spanish influenza virus are paradigmatic proof that recent developments in genetics, genomics and other areas of the biomedical sciences might create new possibilities for biological warfare. The resurrected 1918 virus has been described as “perhaps the most effective bioweapons agent now known” (von Bubnoff, 2005), and, given the availability of its full genome sequence on the Internet, its reconstruction by rogue scientists is now a real possibility.

Genetic engineering and biological weapons

Rapid developments in biotechnology, genetics and genomics are undoubtedly creating a variety of environmental, ethical, political and social challenges for advanced societies. But they also have severe implications for international peace and security because they open up tremendous avenues for the creation of new biological weapons. The genetically engineered ‘superbug’—highly lethal and resistant to environmental influence or any medical treatment—is only a small part of this story. Much more alarming, from an arms‐control perspective, are the possibilities of developing completely novel weapons on the basis of knowledge provided by biomedical research—developments that are already taking place. Such weapons, designed for new types of conflicts and warfare scenarios, secret operations or sabotage activities, are not mere science fiction, but are increasingly becoming a reality that we have to face. Here, we provide a systematic overview of the possible impact of biotechnology on the development of biological weapons. The history of biological warfare is nearly as old as the history of warfare itself. In ancient times, warring parties poisoned wells or used arrowheads with natural toxins. Mongol invaders catapulted plague victims into besieged cities, probably causing the first great plague epidemic in Europe, and British settlers distributed smallpox‐infected blankets to native Americans. Indeed, the insights into the nature of infectious diseases gained by Louis Pasteur and Robert Koch in the nineteenth century did not actually represent a great breakthrough in the use of infectious organisms as biological weapons. Similarly, the development of a bioweapon does not necessarily require genetic engineering—smallpox, plague and anthrax are deadly enough in their natural states. But the revolution in biotechnology, namely the new tools for analysing and specifically changing an organisms genetic material, has led to an increased risk of biowarfare due to several factors. First, the expansion of modern biotechnology in medical and pharmaceutical research and …

When risk outweighs benefit

In October 2005, a team of US scientists, headed by Jeffery Taubenberger from the US Armed Forces Institute of Pathology (Rockville, MD, USA), published the full sequence of the highly virulent strain of influenza virus that caused the Spanish influenza pandemic in the winter of 1918– 1919 and killed up to 50 million people worldwide (Taubenberger et al, 2005). Further work based on the sequence led to the synthesis of an influenza strain containing all eight gene segments from the 1918 pandemic virus, which showed a high virulence and mortality rate when tested in mice (Tumpey et al, 2005). Both the sequencing and the reconstruction of the Spanish influenza virus are paradigmatic proof that recent developments in genetics, genomics and other areas of the biomedical sciences might create new possibilities for biological warfare. The resurrected 1918 virus has been described as “perhaps the most effective bioweapons agent now known” (von Bubnoff, 2005), and, given the availability of its full genome sequence on the Internet, its reconstruction by rogue scientists is now a real possibility.

Gentechnik und die neue Qualität der Biowaffen

Die biologische Rustungskontrolle befindet sich gegenwartig in einer ihrer schwersten Krisen seit Unterzeichnung des Biowaffen-Ubereinkommens im Jahre 1972. Verhandlungen fur ein Verifikationsprotokoll des Abkommens sind 2001 am Widerstand der US-Regierung gescheitert,1 wahrend parallel in den USA die biologische Abwehrforschung immer starker ausgebaut wird und erste Ansatze fur die Entwicklung neuartiger biologischer Waffen in den USA zu beobachten sind.2