I’ve thought more about CRISPR and genome editing over the past year than ever before, ending up devoting a chapter to it in my upcoming popular science biophysics book. The ability to cut, paste, and edit strands of DNA inside living cells is truly amazing, an advance that deserves all the hype that it’s received in recent years. It was therefore great to see this morning’s announcement that this year’s Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for their groundbreaking CRISPR work [Link]. As noted in the Nobel summary, “In an epoch-making experiment, they [Charpentier’s and Doudna’s labs] then reprogrammed the genetic scissors. In their natural form, the scissors recognize DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.”
I mentioned this news in my biophysics class this morning, especially because of its importance but also because we’ll see CRISPR later on, near the end of the term. Gene editing isn’t commonly thought of as a biophysical topic, but I’ve covered it each time I’ve taught the course because (i) it’s amazing, and physicists often seem unaware of the past few decades’ revolutionary developments in the life sciences, and (ii) CRISPR is fascinating from a physical perspective. The Cas9 protein together with a piece of RNA finds a particular DNA sequence among a vast number of possible targets, grabs the DNA, pulls its two strands apart, and slices them. Understanding and then re-designing this system requires taking seriously the notion of biological components as physical entities, small-scale machines that perform concrete tasks. This isn’t a new perspective, of course, but it’s notable nonetheless, and it’s often missing from the vague and confusing discussions of genes in popular literature.
For a couple of wonderful CRISPR animations, the second of which is from Doudna’s group, see:
The Nobel announcement is, for me, tinged with one bit of sadness. Doudna’s and Charpentier’s landmark 2012 paper demonstrating programmable gene editing (Jinek et al, Science, 2012), was submitted to Science on June 8 and published online on June 28. A few months earlier (April 6), a group led by Virginijus Šikšnys at Vilnius University, Lithuania, submitted to Cell a paper that also demonstrated programmable DNA editing using CRISPR/Cas9, essentially the same method though using two RNA fragments rather than one as a guide. Šikšnys’ paper, like the Berkeley/France groups’, noted that the results “pave the way for engineering of universal programmable RNA-guided DNA endonucleases [i.e. cutting].” The manuscript was desk-rejected, not even sent for peer review. The authors sent the paper to PNAS, where it sat for a few months before being published in late September, three months after Doudna’s and Charpentier’s work.
In science, the prizes tend to go to those who were first, though in this case it’s hard to say what “first” means. Šikšnys has been called “the forgotten man of CRISPR” [Link], but this story is increasingly well known. In fact, Šikšnys was co-awarded the million-dollar Kavli Prize for Nanoscience in 2018. I was surprised, therefore, that he didn’t share the Nobel. Perhaps the distinction between two guide RNAs rather than one was considered crucial. Perhaps first-to-be-published was pivotal, regardless of the rest of the timetable. Perhaps there’s a disdain for those who aren’t at the top-tier places like UC Berkeley, especially if they’re off the beaten track in Lithuania. (As a non-top-tier person, and a former undergrad and postdoc at Berkeley, I can state that this suspicion is not unreasonable.) It’s fruitless to speculate, of course. And more importantly, it’s great to see that there is an abundance of wonderful work and wonderful scientists pushing the field forward.
Overall, this year’s CRISPR Nobel prize recognizes brilliant and even revolutionary work, and has been awarded to two scientists who richly deserve it.
A photo I took while working on a CRISPR illustration for my book. RNA is yellow/orange, DNA is blue, and the Cas9 protein is the blob behind them.
— Raghuveer Parthasarathy, October 7, 2020