The fine-tuning of CRISPR-Cas has begun

The debate over the dangers of gene editing with CRISPR-Cas1 has died down, but the question of who will profit from it remains very much alive. Microbiologist John van der Oost is committed to ensuring that gene editing benefits people, society and the environment.

‘Evolution is the result of genetic modification – every biologist knows that. In that light, I found the debates about the safety of CRISPR-Cas techniques and the need for labelling rather overblown. We all eat tomatoes that descend from a wild tomato in which thousands of years of breeding and mutagenesis have changed around fifteen million of the billion base pairs. We consider that safe, yet according to plant geneticists you can achieve roughly the same result by making six knockouts in a wild-type tomato using CRISPR-Cas, changing just fifteen base pairs. And that tomato would supposedly be risky. I simply cannot get my head around that’, says microbiologist John van der Oost (1958). He received the M.W. Beijerinck Virology Prize of €35,000 on 21 March for his pioneering work on CRISPR-Cas technology, and on 27 June he will give his farewell lecture in Wageningen, exactly thirty years after his appointment as group leader of bacterial genetics.

Ramped up
According to Van der Oost, the fading of the debate about the dangers of CRISPR-Cas is partly thanks to consistent public communication and technical improvements. ‘With Cas9 there were concerns about unintended off-target effects, but that problem has been resolved through modifications to the guide RNA, and with Cas12 the efficiency has been ramped up’, Van der Oost notes. ‘Over the past few years I have visited almost every lecture hall in the Netherlands to explain this patiently, time and again.’ Gene editing with CRISPR-Cas is now embraced in virtually every field of research, and an increasing number of successful applications are also emerging. ‘Think of the ten patients with a hereditary swelling disorder whom Amsterdam UMC reported last year had been permanently relieved of their symptoms thanks to a single CRISPR-Cas transfusion. Or the study published last week in which American doctors corrected a mutation in liver cells in a baby with a rare metabolic disorder using targeted CRISPR-Cas editing. The fine-tuning of CRISPR-Cas has begun, and the future belongs to gene editing’, Van der Oost believes.

‘The question of who will profit from it remains very much alive’

‘Specific applications are still very costly at the moment, and there is a minefield of patents surrounding them. The question of who will profit from it remains very much alive’, he acknowledges. He himself is now working on his fortieth patent. One of his earliest patents on Cas12 has been pooled in a portfolio with patents from the Broad Institute–MIT in Boston belonging to biochemist and CRISPR-Cas pioneer Feng Zhang. That institute also holds foundational patents on medical applications of Cas9, which are still being contested in court by UC Berkeley, home of biochemist and Nobel laureate Jennifer Doudna. ‘Filing a patent is little more than speculation’, Van der Oost believes. ‘Politically I sit on the left of the spectrum, and I’m not particularly keen on revenue models – and certainly not on Monsanto-style monopolies.’ He also dismisses the use of CRISPR-Cas to resurrect the extinct dire wolf or mammoth as nonsense. ‘I embrace the Norwegian model, which holds that gene editing is only permissible if it is safe and beneficial to people, society and the environment. That is why in 2021 we decided to make licences on five of our Thermo-Cas9 patents freely available to NGOs seeking to improve global food security on a non-profit basis.

Compost heap
‘That idea bubbled up when I watched a television report in which WUR colleague and plant physiologist Christa Testerink spoke about her research on salt-tolerant and drought-resistant crops in collaboration with the International Rice Research Institute (IRRI) in the Philippines’, Van der Oost recalls. ‘We are now working together on this in the SurpRICE project, developing a stable Thermo-Cas9 system that was isolated here by students from a thermophilic bacterium in a compost heap. We are combining knowledge from Arabidopsis, tomato and rice to optimise our Thermo-Cas9 for genetic modification of rice varieties with improved resistance to salinity and drought. We have already made considerable progress, and we hope to gain enough room to manoeuvre – in terms of both patents and regulatory approval – to bring such new rice varieties to market together with the IRRI. If not, Bionieuws and the New York Times will be the first I call to expose that.’

Highlight
Now that his retirement is drawing closer, Van der Oost looks back on his career with satisfaction, with the highlight being the Science publication in 2008 – together with microbiologist Stan Brouns, now at TU Delft, and American genome biologist Eugene Koonin – on the Cascade complex and the Cas3 gene in E. coli. ‘That was really the first publication to convincingly show how prokaryotes defend themselves against viruses by using the CRISPR archive and cutting out pieces of the viral genome. We were also the first to design a CRISPR, three years before others showed that you could use it to edit genomes in a programmable way. We have made an important contribution to the development of knowledge, and I have no regrets.’ Looking back, he is grateful to NWO and his then supervisor, microbiologist Willem de Vos, for giving him the freedom to use the Vici grant he received in 2004 in an entirely different direction. ‘Because Koonin pointed out to us that there were CRISPR genes in our E. coli, I decided to shift the focus of my research entirely onto that. In hindsight, that was a crucial turning point. I am glad I did not miss it.’

¹ Van der Oost’s request to retain the scientifically correct spellings CRISPR-Cas and RNA was overruled during final editing.

See also:
–CRISPR-Cas pioneer John van der Oost: ‘My scientific career was held together by coincidences‘ – Wageningen World, 2025

–CRISPR-Cas: already an indispensable genetic toolkit – Bionieuws, 24 February 2018