Guest Post: Crispr Craze and Crispr Cares

Written by Robert Ranisch, Institute for Ethics and History of Medicine, University of Tuebingen

@RobRanisch

Newly discovered tools for the targeted editing of the genome have been generating talk of a revolution in gene technology for the last five years. The CRISPR/Cas9-method draws most of the attention by enabling a more simple and precise, cheaper and quicker modification of genes in a hitherto unknown measure. Since these so-called molecular scissors can be set to work in just about all organisms, hardly a week goes by without headlines regarding the latest scientific research: Genome editing could keep vegetables looking fresh, eliminate malaria from disease-carrying mosquitoes, replace antibiotics or bring mammoths back to life.

Naturally, the greatest hopes are put into its potential for various medical applications. Despite the media hype, there are no ready-to-use CRISPR gene therapies. However, the first clinical studies are under way in China and have been approved in the USA. Future therapy methods might allow eradicating hereditary illnesses, conquering cancer, or even cure HIV/AIDS. Just this May, results from experiments on mice gave reason to hope for this. In a similar vein, germline intervention is being reconsidered as a realistic option now, although it had long been considered taboo because of how its (side)effects are passed down the generations.

The developmental history of genome editing reveals itself as a recalibration of ethical standards in research. Two years ago, the first-time use of these new tools on (non-viable) embryos in China led to a solid scandal; in retrospect, it is not clear anymore whether the outrage was triggered by ethical concerns or by the circumstance that this (perceived) taboo was broken by China of all countries. Just a few months later, laboratories in the UK and Sweden followed with similar experiments. Since then the US National Academy of Sciences and National Academy of Medicine have adopted a somewhat permissive stance on heritable germline interventions. Even in Germany, where the use of embryos for research is heavily restricted, the Academy of Sciences Leopoldina recently published a discussion paper in which the authors advocated rethinking the strict laws to allow research on germline cells and embryos. For many the promises of CRISPR and co. now seem too big to maintain a prohibitive stance on embryo research.

Two weeks ago, a short contribution by an US-American team of researchers joined the flood of academic publications about genome editing that broke into the hype surrounding CRISPR/Cas9. The one-page correspondence was printed in the current edition of the scientific journal Nature Methods. The actual research – the successful restoration of eyesight for mice – was barely mentioned. Rather the scientists reported a disturbing discovery.

After having treated the rodents with the CRISPR-method, they sequenced the whole genome and found an unexpectedly high number of mutations. This did not only occur in loci of the genome that where expected according to the usual predictive algorithms. The molecular scissors seemed to have an effect where it hadn‘t been foreseen. These so-called off-target effects in relation to genome editing are a known phenomenon and one of the central challenges of applying CRISPR/Cas9. But the report of more than 1000 changes that were identified in the genome of the mice caused quite a stir.

This news-bite was taken up quickly by the international media and even led some commentators to dismiss the hopes put into CRISPR so far. “Genome surgery” is a term people like to apply to these methods; in the light of these results the methods seem to be far less precise than a scalpel and rather more akin to a lawn-mower. For humans, the results indicate that the promised future gene therapies could also lead to unwanted mutations – facilitating the growth of tumours, for example. What critics of genome editing have long suspected seemed to be confirmed: This all-purpose tool has unforeseeable side-effects.

While the prophecies of doom regarding the failure of CRISPR almost outstripped each other, some scientists tried to give an assessment of the published results in real time. The study was deemed to be deficient; the interpretation of the data was questioned and fault was found with the experimental set-up as well as the molecular DNA-scissors used. The risk of off-target effects was confirmed while the high number of off-target mutations doesn‘t  match up with other research. In addition, some of the off-target-mutations that were identified might not have been off-target but on-target after all, or couldn’t be traced back to the genome-editing. The main criticism was aimed at the conspicuously small number of only two test animals and one control to base findings on, especially since the relationship between the mice was unclear.

The data of the US-American research team must be replicated and validated by further studies to show how reliable it is. After all, what is striking is not so much the dispute within the scientific community – which simply is a motor for new discoveries – but the insight which this specific controversy allows into the ongoing debate about genome-editing.

It is a case in point of how changeable the public perception is, of how the belief in a genetic revolution can suddenly turn into unbelief. Within very few years, genome surgery acquired the reputation of up-ending science as we know it. What Uber is for taxi companies, CRISPR and other new tools of genome editing is believed to be for the genomics industry: a disruptive innovation. Because clinical trials spanning several years must precede the routine application of genome-editing, the advances in science cannot catch up with these high expectations. And expectations react accordingly: That a single publication – albeit with a limited explanatory power – could make such a splash testifies to the manifold insecurities about the question whether the hopes can ever be fulfilled. The first gene therapies for humans already began in the early 1990s. After a phase of euphoria, the realisation followed quickly that only a fraction of these could be applied in a clinical context.

How fragile the confidence in these applications is, can be illustrated best with economic key indicators at hand. The technologies of gene-editing, with CRISPR in the lead, are treated as the next billion-dollar industry by analysts. The World Economic Forum in Davos held a special panel on the potentials of genome editing, and its founder, Klaus Schwab, outlines a  vision of the first gene-modified human being as a deep shift on the way to the fourth industrial revolution. Basically, all the big companies in the life-science sector are trying to win a piece of the CRISPR-cake, for example, by investing in genome editing start-ups. Currently, the market reacts just as strongly as leading CRISPR-researchers do when the promises generated by the technology are in doubt. Two mice were sufficient to make stock prices fall. Companies specialising in CRISPR, such as Editas Medicine or Intellia Therapeutics, were hit with the strongest stock market losses and published their own critical statements in response to the study shortly after, calling its conclusions “inappropriate”.

The commotion surrounding the study also highlights the heightened nervousness in the ongoing race for developing successful gene therapies with the CRISPR-method, which has been descripted as “Sputnik 2.0” already. China is momentarily in the lead with the first clinical studies, and it seems that some have a premonition: the boundaries delineated by ethical standards could be pushed further out systematically to win this race. This impression is confirmed by the enormous attention that a one-page correspondence perceives, by pointing out (alleged) shortcomings of genome-editing, especially regarding the precision of this hope-infused method. The noticeable acceleration of research certainly makes some in the scientific community expect a big bang.

 

Robert Ranisch (@RobRanisch) is head of the research unit “Ethics of Genome Editing” (@GenomeEdit) at the Institute for Ethics and History of Medicine, University of Tuebingen and Director of the Global Applied Ethics Institute (@GAEI_org). Robert is a member of the tt30 of the Club of Rome, Germany.

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