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Revision as of 08:47, 3 October 2018

IntegratedHP

Overview

Synthetic biology techniques as CRISPR-Cas9 have gained huge public interest for human enhancement and are becoming more and more accessible to the general public. In this light, we identified the need to promote responsible use of synthetic biology. The discussion on human enhancement takes a most prominent place in sports with the doping affairs and unites with synthetic biology in the phenomenon of gene doping, for which an implemented detection system lacked. Therefore, we decided to develop an efficient, reliable and versatile detection method for gene doping based on a thorough value sensitive design.
In the initial stages we presented our idea at the Bioengineering Institute Kickoff and immediately caught the interest of Clive Brown, Chief Technology Officer at Oxford Nanopore Technologies. Skype calls with the company ensued and drove us to switch our idea from a nanopore blocking to a pulling method.
Subsequently, we visited the VVBN conference on advances in doping to gain more insight in the field. Here, we met Dr. Dimeo, Professor in Sports Policy, who prompted us to extend our model to anticipate athletes’ choices in gene doping administration.
This idea to anticipate on future athlete behaviour also led us to organise the Hackathon at the Cyber Security Week. By letting engineers hack our detection method, we obtained additional variations for possible gene doping sequences, which were automatically added to our database.
Then, we presented our project for life science experts at the Delft Health Initiative where we discussed the impact of gene doping on the environment and future generations. This led us to involve a broader public through the organisation of the first Dutch Biotechnology Day characterised by debates we instigated on trains throughout The Netherlands.
However, we wanted to take it further and organised an expert discussion on the topic at the University of Stirling, Scotland’s University for Sporting Excellence. Here, we focussed on the differences between gene doping and more conventional doping in all aspects and how scientists should respond. Here, it became even more apparent how vulnerable athletes are to doping use and our approach to education was reinforced to close the loop for future responsible research.

Approach

As a team we highly value responsible research. Therefore, we wanted to make sure our project is responsible from the start till the end and beyond. This we made sure by passing our project through the phases that constitute Responsible Research and Innovation according to Stilgoe et al. (2013), i.e. anticipation, inclusion, reflection, and responsiveness.
The dimension of anticipation focuses on researchers investigating what is known, what is possible and what is likely in the field. This includes scenario building, making an assessment of their plausibility through interaction with experts as well as the general public, and the stimulation of an open and multidisciplinary collaboration. This we did through surveys, train debates, and through visiting conferences to learn about developments in the field and to make connections.
Subsequently, inclusion targets the process of open innovation and user-centered design. It focuses on transparency and collectively challenging regulations and standards. Grove-White et al. (2000) argue that the public conversation should stretch further to include the debate on future social worlds, while critically rethinking the ‘social constitutions’ inherent to the technological choices – that is, the ethical, political and social implications of the development. This we did during inclusion processes as the train debates and the expert discussion in Stirling.
Throughout the project, the process of reflectivity is continuously going on. We, as scientists, are used to professional self-reflexivity during the complete product development process. Our team continuously challenged our detection and we even had an inter-team detection method hacking challenge. However, as was stated by Wynne et al. in 1993, responsibility makes reflexivity also into a public matter. According to Stilgoe et al. (2013) reflexivity demands scientists to publically combine their scientific and moral responsibilities. This has been a prominent focus from the choice of our topic till our final design as can be seen from our interaction with the many stakeholders involved and the design requirements we derived from that.
Lastly, we responded to all stakeholder input by making a value sensitive design by which we managed to answer all needs and preferences of our stakeholders to come to an optimal method.

1. Anticipation

As a first stage in Responsible Research and Innovation we focussed on addressing the need for gene doping detection as well as on making an assessment of the challenges constituting gene doping with respect to future worlds.

1.1 Relevance of Gene Doping Detection

Gene doping caught our team’s interest at an early stage. Having often been confronted with the application of gene technology to humans and animals, we got fascinated by the concept of gene doping, its challenges and opportunities as well as its social relevance. Due to a lack of an implemented detection method it is hard to assess whether gene doping is currently happening. This is then of course always the first question people ask us. How relevant is your research? We can say it is a more eminent threat than you might have expected.

Let us start with the timeline in figure 1. Here some of the most prominent events in gene doping development are sorted in time and as it appears gene doping might already be happening.

Timeline Figure 1. Timeline of gene doping use and development in society.

2003: Genedoping

WADA puts gene doping on the list of prohibited substances.

>

2004: Marathon mice

Geneticists at Howard Highes Medical Institute engineered so-called marathon mice that could run twice as far as normal mice by changing only a single gene PPARdelta. (Wang et al. 2004)

2006: German Coach (Thomas Springstein) Suspected of Genetic Doping.

The conviction was partly based on e-mails sent and received by Springstein, a one-time coach of the German Athletics Association (DLV), which were aquired by the police during a raid on Springstein’s home. These e-mails brought up references to Repoxygen, a banned substance meant to be used in gene therapy to treat patients with anemia. Repoxygen helps to induce a controlled release of erythropoietin (EPO), a substance that stimulates the production of red blood cells, thereby increasing the amount of oxygen the blood can deliver to the muscles. It was under preclinical development by Oxford Biomedica as a possible treatment for anaemia but was abandoned in 2003. (Michael Reinsch, 28 January 2006).

2008: Chinese Doctor Offers Gene Doping to Athletes

A German television report was brought out on the availability of gene doping in China shortly before the Beijing Olympics. In this documentary produced by ARD television, a Chinese doctor offers stem-cell therapy to a reporter posing as an American swimming coach in return for $24,000, according to a translation provided by the ARD television. The documentary broadcast does not offer evidence that the hospital has provided gene doping to other athletes, but it does provide a shocking insight into the doping development scene. (NBC News 2008)

2010: Gene Doping Detection: Evaluation of Approach for Direct Detection of Gene Transfer using Erythropoietin as a Model System

In two mouse studies, blood was positive for a plasmid in some animals for 1–2 days and up to 1 or 4 weeks after intramuscular or intravenous administration. The sensitivity of PCR methods used in these studies was 100 or 1000 vector copies per mg of gDNA. In another study with mice injected rAAV intramuscularly, 12 whole blood samples from a high-dose group tested positive for viral DNA until day 28, but viral DNA in plasma was cleared within 3–4 days. The sensitivity of the method for vector detection in this study is comparable to that for the assays developed here. (Baoutina et al. 2010)

2016: Officials Fear Some Olympic Athletes Might Be Altering Their Genes To Cheat In Rio

Sarah Everts reported for Chemical and Engineering News that officials planned to test 2016 Rio athletes' tissue samples for markers of gene doping. The most likely subject of a genetic hack appears to be the gene that codes for EPO. Therefore, this gene became what the officials planned to test for. (Letzter et al. 2016)
Athletes at Rio Olympics Face Advanced Antidoping Technology
According to the International Olympic Committee’s medical and scientific director, Richard Budgett, samples collected in Rio will be tested for gene doping at some point after the games, even though the test hasn’t been run during the Olympics itself. (Sarah Everts, 2016)

2017: Doping Control Analysis at the Rio 2016 Olympic and Paralympic Games

The EPO gene is mostly expressed in renal cells, and only the EPO protein (not generally EPO DNA) is secreted into the bloodstream; therefore, the identification of any concentration of EPO DNA sequences in blood is considered a positive result for gene doping within current detection methods. Considering the growing concern over gene doping, as well as the EPO availability of new molecular biology tools, the LBCD implemented, improved, and validated 2 amplification assays for EPO cDNA using the real-time PCR instrument QuantStudio12K (Thermo Fisher, São Paulo, Brazil). All work was performed with WADA-certified reference material for EPO gene doping within a range of 1 to 4000 copies of reference material spikes and EPO gene-doping-positive samples. However, in view of the absence of interlaboratory tests among the laboratories accredited by WADA, the analysis was not performed on the Olympic samples; it was only performed on samples selected exclusively for research. (Pereira, H.M.G. et al. 2017)

2018: ADOPE

Our enthusiastic team set out to tackle gene doping to promote responsible use of synthetic biology. Read more about our project here.