Bio-inspired Lessons from CRISPR
Image credits: Sangharsh Lohakare via Unsplash.
The world recently celebrated the 10-year anniversary of the publication of a scientific paper that made the world sit up and take notice: an investigation by Dr. Jennifer Doudna, Dr. Emmanuelle Charpentier, and others of the CRISPR/Cas system. The story of CRISPR is a great example of the Bio-inspired mindset. Why? Because by unraveling a natural biological process, these scientists—and many others—have unlocked astonishing potential across innovation spaces.
What is CRISPR/Cas?
You can think of these systems as the adaptive immune system for single-celled bacteria and archaea. CRISPR/Cas is how these tiny living things recognize and neutralize threats from invading DNA, particularly viral DNA. The molecular details can be quite complex, but overall, CRISPR/Cas systems recognize foreign DNA, chop it up (that’s the “Cas” part), and then tuck some examples of that foreign DNA into the host’s genome (that’s the “CRISPR” part).* That way, if the bacterium runs into the same virus again, it “remembers” that virus, and can quickly and precisely attack the invading DNA. Over the course of millions of years, evolution has delivered a delightfully diverse set of CRISPR/Cas “flavors” that scientists are still discovering.
Dr. Jennifer A. Doudna receiving her Nobel Prize medal and diploma. Image credits:
© Nobel Prize Outreach. Photo: Brittany Hosea-Small.
💡 Here’s something important to note: Doudna and Charpentier weren’t the first scientists to notice the bacterial immune system. In fact, since the early 2000s, scientists in the dairy industry had been protecting yogurt supply chains by figuring out how bacteria protect themselves from viral infections—and then using the same system to add new immunity to their bacterial starter cultures.
That’s right. You’ve been eating CRISPR’d food for years!
“But wait,” you might be thinking, “I thought CRISPR was about changing DNA code! You haven’t said anything about that!”
Bacteria aren’t in the business of gene “editing” (changing a DNA sequence, for example from ATCG to AACG), but humans sure are. Prior to Doudna and Charpentier’s 2012 publication, we had several molecular tools for changing the information stored in the DNA double helix. I used some of these tools back when I was in grad school—and boy, were they painful! Slow, laborious, expensive, error-prone … basically everything you don’t want when you’re trying to solve a gnarly problem.
We needed something better.
Fast forward to 2012. The very last line of Doudna and Charpentier’s short research article shines as a classic example** of scientific understatement: “We propose an alternative methodology based on RNA-programmed Cas9 that could offer considerable potential for gene-targeting and genome-editing applications.”
“Considerable potential”! In other words, the complexity and variety of bacterial immune systems constituted a crucial jumping-off point for humans to engineer new ways to precisely and permanently change genetic code.
Dr. Emmanuelle Charpentier receiving her Nobel Prize medal and diploma. Image credits: © Nobel Prize Outreach. Photo: Bernhard Ludewig.
Early CRISPR-based gene editing relied on the basics of the CRISPR/Cas system, such as the “molecular scissors” of Cas and the DNA repeats of CRISPR. But then some very clever scientists had a billion-dollar realization. By splitting an aspect of the natural system into two parts, a human could guide those molecular scissors to a very specific place in the genome***, where the scissors would cut the DNA. Finally, the human would trick the cell into filling in the cut with a new DNA sequence determined by the scientist.
This development of a programmable guide was the magic leap that transformed CRISPR from a cool set of ancient microbial pathways into perhaps the most powerful tool that humans have ever developed.
It was a compelling solution to the painful gene editing systems that I’d used in grad school, as I discovered the first time I did CRISPR with my own hands. (Seriously. I wish I had a video of my face at the end of my first CRISPR experiment as I screeched, “That’s it????”)
💡 Thanks to this breakthrough, the question had changed from “how do we make better yogurt?” to “how do we make better everything?” And it was that leap to the big question—thanks to a Bio-inspired mindset—that garnered Doudna and Charpentier the 2020 Nobel Prize in Chemistry.
Today, our headlines are stuffed with stories about how gene-editing technologies like CRISPR are being further adapted for better efficiency and accuracy than the original engineered system (it turns out that getting rid of the cutting function really helps). Gene editing is poised to revolutionize basic research as well as innovations in health, agriculture, the fight against climate change, and more. The CRISPR patent battles continue to rage. In 2021 alone, more than a billion US dollars in venture capital were infused into companies pursuing gene-editing technologies for human health, agriculture, and more.
We are just at the beginning of the CRISPR revolution that was kicked off by evolution billions of years ago. Now we have to ask even bigger questions. What does “better” mean when we’re talking about the future of life? And who gets to decide?
Here are a few of my favorite resources to keep learning about how gene editing works and how people are using it to solve the world’s biggest problems:
CRISPR: A Guide To The Health Revolution That Will Define The 21st Century (BBC Science Focus)
Human Nature (Netflix; reviewed in Nature)
How Engineered Crops Can Fight Climate Change (World Economic Forum)
The Genesis Machine: Our Quest to Rewrite Life in the Age of Synthetic Biology (Amy Webb and Andrew Hessel; reviewed in Nature and by me)
The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race (Walter Isaacson; reviewed by NPR and The New York Times and by me)
In the fantastic book The Code Breaker, Doudna is reported to have drawn two important lessons from her grad student days.
💡 First, don’t work on what a thousand other people are working on. Second, ask big questions.
Inspiring, yes, but also terrifying! With a Bio-inspired mindset and these two lessons, we are empowered to draw from Nature’s 4 billion years of innovation through evolution in order to build the best possible future(s).
*As a molecular biologist, I feel compelled to point out that we’re ignoring a lot of really fascinating details here. If you’re feeling ambitious and want to learn more, here are some search terms that will lead you to some of these details: protospacer adjacent motif (PAM); tracRNA; R-loop formation; Cas9, CasX, Cas12, Cas13; homology-directed repair.
**Perhaps the most famous example of scientific understatement is the second-to-last sentence of Watson and Crick’s 1952 publication solving the structure of DNA: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” I always laugh as I read this line as, “Hey colleagues and rivals, we’ve just solved all the science that you’ve been working on for the last decade. You can thank us later.”
***Cas is a pair of molecular scissors, but DNA-cutting molecular scissors are quite dangerous to biological systems. In natural, bacterial CRISPR/Cas systems, that’s the whole point: Cas chops up viral DNA to crush the infection. Engineered CRISPR/Cas systems, on the other hand, need to cut at very specific DNA sequences—and only those sequences. This problem was solved by bioengineers who invented a separate “guide RNA” that could target Cas to just about any location in the genome that the scientist wants (with rules).
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Dr. Tiffany Vora speaks, writes, and advises on how to harness technology to build the best possible future(s). She is an expert in biotech, health, & innovation.
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