The CRISPR Nobel: back to basics

Streptococcus pyogenes under siege from siphoviridae copy.jpg
“Streptococcus pyogenes bacteria under attack from Siphoviridae” by Mark Palfreyman

At last – the least surprising Nobel in recent memory finally got awarded. But despite its inevitability, the prize for CRISPR is still worth celebrating.

The Nobel prizes always have an element of drama, thriving beforehand on the perennial guessing game of who’s going to get it, and afterwards (cattily) on whether or not they deserved it. In this respect, 2020 was the definition of anticlimax. There are few discoveries or inventions in science that genuinely deserve the “revolutionary” tag but CRISPR indisputably does, making it the clearest recipient for at least the last 20 years.

Given the ongoing controversy over the patent rights to CRISPR technology, it’s significant too that the prize was awarded to just the two women – Emmanuelle Charpentier and Jennifer Doudna – who converted CRISPR-Cas9, a bacterial anti-virus defence, into an all-purpose genome editing tool. Feng Zhang of the Broad Institute, who optimised CRISPR for use in mammalian cells and who has been a major beneficiary in the patent court cases, was not selected.

Charpentier and Doudna’s breakthrough was twofold, and like many masterstrokes, it seems so obvious with hindsight that it’s hard to credit the creativity and lateral thinking required at the time. The Cas9 endonuclease relies on two RNAs – called a crRNA and a trRNA – for its activity. Charpentier and Doudna’s elegantly simple trick was to show that those two RNAs could be fused together to make a single guide RNA, and by altering the sequence of this guide RNA the endonuclease could be programmed to target any specific DNA sequence for editing.

CRISPR is not the only genome editing tool out there, with TALENs and the zinc finger nucleases being prominent and programmable alternatives. But what has made CRISPR pre-eminent is the ease of the programming – all it requires is a single guide RNA – and (which never could have been anticipated) how broad its utility is. From single-celled microbes to multicellular organisms, it seems to function in every organism into which it is introduced. It makes gene editing possible, and easy, seemingly anywhere. None of its competitors have that same combination of attributes.

That the Nobel prize was deserved is therefore not challenged, but what makes it especially noteworthy, despite its inevitability, is the way it highlights a prominent flaw in the incentive structure of scientific research.

Turn the clock back to 2008, when Emmanuelle Charpentier was a junior group leader at what was then called the Max F. Perutz Laboratories (MFPL) in Vienna, Austria, and it’s fair to say that few if any saw value in her work. Would you have paid attention to the role of small RNAs in bacterial? Would the question of how bacteria defend themselves against viruses sound like a potentially world-changing topic for research? Commercial interest came from the mighty yoghurt industry – hardly the global health priority that cancer, or cardiovascular disease, or AIDS are, with their attendant pharmaceutical companies and charitable foundations. 

Not only was this work of limited health benefit (unless you’re seriously into your probiotics and dairy), it was also far from being fashionable. The function of small RNAs in bacteria (not even eukaryotes!) was most definitely not in the spotlight. It wasn’t epigenetics, or autophagy, or exosomes, or any of the topics that perpetually form and swell like soap bubbles all iridescent and shining and then, having achieved maximum size, simply pop as the interest and the money moves on to the next big thing

These two points – that Charpentier and Doudna discovered how Cas9 could easily be programmed, and made that discovery in a field that wasn’t fashionable – are significant. They are significant because they underline the importance of basic, blue-skies research, and how the Nobels – for all their flaws, not least their appalling track record on diversity – do one thing right. 

The reason is that the current incentive structure in science doesn’t really reward this kind of work. To get funded these days, you maximise your chances if you’re doing something fashionable, and that usually means doing something well-established*. The pioneer work needs to have been done in advance.

This cosy relationship between science funding and science fashion has led to the formation of many, many research institutes and medical schools whose sole aim is to churn out papers for publication in prestige journals. It is undoubtedly a very successful system in terms of attracting funds, but it is one that ultimately does not reward real risk. It’s work like Zhang’s. Take something that’s already showing promise and mine it.

That the future significance of Charpentier’s work wasn’t appreciated in 2008 is easily demonstrated by the fact that when she decided to leave for a specialist microbiology institute in Umeå, Sweden, none of the other research institutes at the Vienna BioCenter campus fought to acquire her services. She left without fanfare, with some of her group remaining behind at MFPL and receiving continued support. In 2008, CRISPR wasn’t fashionable.

And herein lies the problem. If an institute or medical school is predicated on doing research that is publishable in prestige journals, then it has to chase after the latest fashions**, but chasing what’s fashionable means that the discovery has already been made. And The Nobels reward discovery.

To compete for Nobels, you have to go into the unknown, and that will probably not be fashionable. It generally means doing research in its purest sense, following nothing other than your interests and your curiosity. And yet what riches those inclinations have yielded! Who would have anticipated that mixing a control sense-RNA with an experimental antisense-RNA in nematode worms would lead to the discovery of a whole pathway for regulating gene expression? Who would have anticipated that studying how jellyfish glow would deliver a tool for live-cell imaging and a revolution in fluorescence microscopy? Who would have anticipated that investigating why corn kernels come in different colours would yield the insight that there are mobile DNA elements? And who would have anticipated that questioning why fruit flies hatch when they do would uncover molecular clocks that tell subjective time? All those discoveries stemmed solely from the compulsion to venture into the unknown, and ask why.

In that vein, it’s worth noting that while CRISPR-Cas9 won the Nobel prize, the technology wasn’t the question that was funded. There wasn’t a Millennium Goal for genome editing, and you can bet that Charpentier wasn’t writing grants promising to design and deliver such an outcome. The universal genome engineering tool was the answer, but it wasn’t the question. The basic question posed in grants was almost certainly something to the effect of, “How do Streptococcus bacteria resist Siphoviridae infections?”***

Feng Zhang, conversely, got loads of funding and loads of press for studying the answer. But he didn’t win the Nobel prize.

And this is what makes the CRISPR prize both well-deserved and incredibly valuable. The Noble committee took a stand (a different one than a lot of funding agencies and high profile institutes) in celebrating the people who studied the question. It’s a prize for basic research, for doing weird stuff that doesn’t seem interesting to anybody else, but doing it well and finding something novel. Something novel that might change the world.

Acknowledgement:
This posting co-authored with Mark Palfreyman.

Disclosure:
Brooke Morriswood was a postdoc at the Max F. Perutz Laboratories from 2008-2014; Mark Palfreyman was a postdoc at the Institute for Molecular Pathology, one of the other three research institutes on the Vienna Biocenter campus, from 2009-2013.

 

*One example:Mario Capecchi had his proposals for generating gene knockout mice rejected each time he applied, because it was felt that the chance of success was too low. He ultimately repurposed the money from other grants to the project that eventually won him a Nobel prize.
**For a current example, look at the ongoing and rather indecent rush to do phase separation work.
*** It’s beyond the scope of this posting, but the fact that the CRISPR systems of bacteria and Archaea represents a genuine adaptive immune system**** is a mind-blowing insight into the basic biology of unicellular organisms.
*** And on that point, it’s worth remembering that restriction enzymes – the foundation of recombinant DNA technology – are themselves a kind of innate immune system that operates in bacteria as an anti-viral defence, and were first discovered by looking at the interaction between gut bacteria (E. coli) and lambda phage.

4 thoughts on “The CRISPR Nobel: back to basics

  1. I see that you’re making a clear case for basic science over translational and popular “trendy” science. I think you missed an important scientist in this discussion…Virginijus Siksnys… His paper was rejected from Cell, and then delayed in PNAS… Submitted before Doudna’s whose paper was fast tracked for reasons???

    Liked by 1 person

    1. Agreed – he’s one of several obvious absentees; Francisco Mojica would be another, for doing some of the real pioneer work. Quite why the Siksnys paper was delayed so long might well be due to snobbery/Matthew Effect issues related to address lines, but I wouldn’t want to speculate further than that.

      It’s a personal opinion, but for me, the fusion of the crRNA and the trRNA in the Doudna/Charpentier paper is the masterstroke, and that’s something that only appears in that publication (neither Siksnys nor Zhang made the same jump). Demonstrating that Cas9 was programmable was a logical extension once its activity had been characterised, but realising that the system could be simplified even further requires both a profound knowledge of the relevant RNA biology and structural biology, and some outside-the-box thinking.

      Anyhows, I’m sure this will be a fun topic for pub discussions in years to come..! 🙂

      Like

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