by MERLIN CROSSLEY
I once heard the line – “the development of human societies has passed three thresholds: learning to speak, learning to write, and learning to write the genetic code”. The Nobel Prize in Chemistry has just been awarded to Emmanuelle Charpentier (Max Planck Unit for Pathogens) and Jennifer Doudna (Uni California) for their development of CRISPR gene editing, a technique by which one can modify the genetic code of potentially any species.
This prize is unusual because it has been a case of when, not if, CRISPR would win. There was a certain mystery about who would share in the prize. Charpentier and Doudna were clear favourites, but the Nobel Prize can go to up to three recipients, so there may have been a third. But there isn’t. That’s sometimes the way with prizes – some good people do miss out but as long as the recipients are worthy then the message gets through and the work of the prize is done. The whole scientific world is celebrating because there is no doubt these two are worthy.
So what is this CRISPR story?
Of course, it all began with the realisation that genetic inheritance depended on a fairly simple substance – DNA. It relies on a chemical and can be understood in rock-solid digital terms. Once the structure of DNA was discovered genetics had a foundation to build on that is as solid as mathematics. Since DNA is just a string of letters, ACGT etc, it really is a bit like a computer code, and it should be possible to read it and write it.
It was Rosalind Franklin, James Watson, Maurice Wilkins, Francis Crick and others, who solved the structure of DNA (the latter three sharing a Nobel Prize, with Franklin sadly having passed away due to ovarian cancer – we will never know if she would have shared in the prize had she lived, one hopes so but fears not).
Francis Crick subsequently largely led the charge to understand the principles by which DNA replicated and encoded the bits and pieces we are made off – different stretches (like sentences) serve almost like casts for specifying strings of different shaped pearls that fold up to make the bricks, poles, doors and windows of our bodies.
If you can alter the sentences, you can change the shape of the doors, windows or how many we have etc.
Soon molecular biologists knew how to extract DNA, separate it from other parts of an organism, purify it, and even to replicate it in a test tube. Research on the simplest viruses – those that infect single celled organisms, bacteria or germs, took us to the next level. Viruses are nothing more than tiny bags of DNA that encode just enough to make more virus. It turns out that bacteria have evolved to fight off viruses using scissors that cut viral DNA. The first age of recombinant DNA technology involved “restriction enzymes”, simple scissors that cut at short DNA sequences, like GAATCC for the E.coli restriction enzyme EcoRI, and joining enzymes discovered from studying DNA replication. Researchers were able to cut out little bits of DNA and join them together. A few more Nobel Prizes here.
What held us up was – the “little bits” part. We have miles of DNA in our body and the sequence GAATTC will occur by chance every few thousand residues. Researchers made a lot of recombinant organisms by adding single genes but it was very hard to change one gene within an organism.
The breakthrough was CRISPR. This was again discovered by examining how bacteria cut up invading viruses. It stands for Clustered Regularly Interspaced Short Palindromic Repeats because the bacteria took pieces of virus, put them in their own genome in a tidy array, and used them to identify new invading viruses the next time they attacked – bacteria had repeat sequences in their genomes arrayed in a regular pattern of mugshots. Charpentier and Doudna showed how this system could be used to direct a “cut and replace” system, a gene editing system, to any part of even the most massive genomes.
In some ways, CRISPR is a “Google search” or word processing “cut and replace” function for the genome. You can send it into the endless code and it will find the spot and edit it. You can efficiently change any chosen gene, and technical issues aside (i.e. it’s dangerous to work on a lion and hard to keep a blue whale in a test tube) you can modify any organisms because all life on earth uses DNA (except some viruses that use RNA).
The discovery shows how important fundamental, basic, pure, blue-sky research is. If you develop a technique that applies at the bottom of the tree of life you can use it to alter every branch and it may be relevant to the treatment of many, if not all, diseases.
If you work on one branch, you may fix that but your work may not be relevant to other branches on the tree. Scientists bang on about fundamental research because it is important but also because the government is really the only organisation big enough to support long term blue sky research. You can’t really expect the shareholders of a pharmaceutical company to do that.
CRISPR has revolutionised biology across the world and the work in my lab. We started using it around five years ago and have been able to do experiments we would never have dreamed of. It is efficient and the technique can be learnt in a few weeks. It is simple molecular biology, mixing tiny drops of liquid and adding them to cells in flasks or petri dishes. We have introduced naturally occurring beneficial mutations that boost globin output into cells, as a model for treating sickle cell anaemia. There are now several clinical trials of this approach.
But don’t fear the attack of the mutant clones any time soon. When I say we can modify the DNA of any organism, it is not as if one sprinkles CRISPR dust over a dog and turns it into a non-shedding spoodle or labradoodle. It may be possible to edit that hair gene but only in the next dog’s pups – you have to get the CRISPR into a fertilised egg so that the resulting organism carries the change in every cell in its body.
And one can only edit one gene or a few genes at a time. Researchers are cautious when talking about therapies as there is still a risk you could edit the wrong gene (that risk is diminishing as the technology advances) but there could still be surprising knock-on effects that emerge as the new mutant genes work together in the existing genetic background. Even if one succeeded, it would take years to breed up the new non-shedding dogs for the market. When it comes to humans such editing is illegal in many countries and the backlash when it was done in China a few years ago was so great and universal that I think we can be confident it is not happening at scale. A few rogue operators may still be injecting human eggs to make babies who lack the HIV receptor but society will continue to scrutinise and respond to any such developments. These matters are important but will not upturn society by surprise.
Other unimagined applications of the technique, of course, may. Doudna and others have adapted CRISPR to do other things, like detect tiny amounts of corona virus and that is another great contribution. Many others are working in this field and the technology keeps improving. All this work does truly represent a new age of biology – or chemistry, as this prize was in chemistry!
I was delighted to hear the news of this prize. The two winners are inspirational scientists and ideal role models with gravitas and flair. Their achievements, contributions, and professionalism are inspiring. Both have attended local conferences here in Australia and give generously to the community and help support science, science communication and education. One of my recent PhD students went to Doudna’s department to do CRISPR work, she thrived there, and loved it. I know of others who have also thrived in that department. All this adds up to something to celebrate.
Hooray for Doudna and Charpentier, hooray for all the others who contributed to this work, hooray for future students who will be able to identify with this discovery and be inspired by coming to know the people who developed the technology and their stories, hooray for fundamental research – long live CRISPR.
Prof. Merlin Crossley
Deputy Vice-Chancellor Academic