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The Code Breaker

Book cover

This is a book about the history of CRISPR, the discovery that allows for gene editing. Isaacson tells this history through one of its main protagonists, Jennifer Doudna.

Doudna’s Biography Summary

Doudna’s trajectory can be summarized as follows: she was born and raised in Hilo in Hawaii. She got interested in science at early age and eventually did her PhD at Harvard and then became a professor of chemistry at UC Berkeley.

Her research was around RNA interference. People studying CRISPR thought it worked via RNA interference, ahd that’s how she got looped in. In 2009 she met Emmanuelle Charpentier at a conference and they started collaborating which led to the discovery of how CRISPR works and eventually doing DNA editing in a bacteria, followed by a seminal paper in 2012.

The next step would be to make CRISPR work in mamalian cells. Feng Zhang was able to obtain better results and patented the discovery which led to ongoing legal battles between them. While the debate about who deserved credit for making CRISP work in human cells hasn’t settled, Charpentier and Doudna received a join Nobel prize in 2023, but Feng wasn’t included in the award.

The path to CRISPR

The book covers some of the events and discoveries that led to the discovery of CRISPR.

On CRISPR itself:

Ethics

Many chapters are dedicated to the ethics of gene editing. Should it be allowed at all? In what circumstances? Who should decide it: scientists, politicians, the people?

The basic dichotomy is between gene editing to cure diseases vs. enhance traits. The problem is that it’s hard to draw a line that separates these.

A more clear cut case is Huntington’s disease: it only appears after middle age and manifests as the death of brain cells and leads to suffering. It arises from an abonormal repetition of letters in DNA, so it’s easily editable. There’s virtually no evolutionary advantage of Huntington’s disease. It just that it only manifests after childbearing age, so there’s also no evolutionary pressure to get rid of it either.

Sickle cell anemia causes a lot of pain and suffering but differently from Huntington’s, it has an evolutionary purpose: it makes people more resistant to malaria. However nowadays there are treatment for malaria, so one can claim this genetic trait is undesirable. It becomes philosophical though, because disease might be part of someone’s personality.

He cites the famous jazz player Miles Davis, who had sickle cell anemia. It’s believed that his pain led him to drinking and drugs - but also likely contributed to his creativity - if he didn’t have the disease he wouldn’t be him. In general, the author claims that many famous artists have some form of mental illness. A more explicit example is from a deaf lesbian couple that chose a sperm donor who was also deaf so their kid would be deaf, because they thought it was a cultural identity.

Another complication is what do we consider as a disability or negative trait. Some are only so due to culture and society, such as sexual orientation and skin color. Some positive traits are only so in a relative way, for example height. There’s not much advantage of being tall in absolute terms, but being taller than other people is usually positive. If parents started selecting for height, it would be a arms race and we’ll end up with a society of giants. An absolute positive trait is memory: it benefits the individual irrespective to whether others do too.

The book also retells the case of He Jiankui who didn’t wait for consensus and went ahead with editing the genes of two babies from parents with HIV, to make them more resistant to it. He was in jail for 3 years and banned for life on doing gene editing research.

The scientific method

Another pervasive theme throughout the book is the practice of science. On whether academia (theory) or industry (practice) drives innovation, Isaacson claims it’s a “dance” between the two.

The book provides a glimpse on how lab leaders contribute to research:

Although she [Doudna] takes a hands-off approach during the early stages of a researcher’s project, as it gets close to fruition she engages intensely.

Competition in science:

Healthy rivalries have fueled many of humankind’s greatest discoveries.

and:

Scientists are mainly motivated by the joy that comes from understanding nature, but most will admit that they are also driven by the rewards, both psychic and substantive, of being the first to make a discovery.

Still on the topic of competition, Doudna’s advisor, Szostak, switched from studying DNA to RNA, in part because the field studying DNA was too crowded:

Never do something that a thousand people are doing.

Role models and inspiration. Doudna read the book The Double Helix by Watson and had a serendipitous encounter with Barbara McClintock, the Nobel prize winner in 1983 in Medicine for her discovery of transposons. To which she said:

She was what I wanted to be.

Quotes by Emmanuelle Charpentier:

There were lessons from the arts, she would discover, that applied to science. “Methodology is important in both,” she says. “You also must know the basics and master the methods. That requires persistence— repeating experiments and repeating them again (…). It’s part of the training, just like the hard work of a ballet dancer, repeating all day long the same moves and methods.” Also like the arts, once a scientist masters the basic routine, she has to combine it with creativity. “You have to be rigorous and disciplined,” Charpentier explains, “but also know when to let yourself loose and blend in a creative approach. I found in biological research the right combination of persistence and creativity.”

Politics and science. as of 2025, we can see firsthand that the person who is in power can influence the overall trajectory of science. Another fascinating example is that of Linus Pauling at Caltech. He was using X-ray crystallography and was pretty close to figuring out the structure of DNA and is believed that if he attended a conference in England, he might have made the leap ahead of Watson and Crick. According to Isaacson:

Fortunately, the U.S. State Department came to the rescue. In the weirdness engendered by red-baiting and McCarthyism, Pauling was stopped at the airport in New York and had his passport confiscated because he had been spouting enough pacifist opinions that the FBI thought he might be a threat to the country if allowed to travel. So he never got the chance to discuss the crystallography work done in England, thus helping the U.S. lose the race to figure out DNA.

Commercialization

The practical application of biological methods is demonstrated by the amount of companies that are founded on them. The book covers several of them, not only those related to CRISPR:

Company Technology Founders Year
Genentech Recombinant DNA Herbert Boyer 1976
Caribou Cas6 (viral detection) Doudna and Rachel Haurwitz 2011
Editas medicine CRISPR (gene editing, gene therapy) Doudna, Zhang, et al 2013
Intellia Therapeutics CRISPR (gene editing, gene therapy) Doudna, Haurwitz, Barrangou et al 2014
Mammoth Biosciences CRISPR, Cas12a (diagnostic tests) Doudna, Janice Chen, et al 2017
Sherlock Biosciences CRISPR, Cast13 (diagnostic tests) Zhang et al 2019

Other Topics

Bio-weapons

As CRISPR becomes a possibility, scientists started worrying that it could be used for terrorist purposes. The Defense Advanced Research Projects Agency (DARPA) started financing research projects aiming to counter these risks.

One such line of research are anti-CRISPRs: proteins that can disable CRISPR enzymes such as Cas9. It’s produced by virus that became resistant to the bacteria defenses and was first noticed in 2012, by Joe Bondy-Denomy.

Another research supported by DARPA is finding genes that could protect humans from nuclear radiation.

Anti-virals

This book was finished or edited after the COVID-19 pandemic started. One application of CRISPR is antivirals, in fact CRISPR is literally an antiviral mechanism used by bacteria. Interestingly I never heard of it being used in practice and I was wondering why.

Apparently because of safety concerns (it chopping DNA other than the intended target, immune response to Cas proteins), difficulty in delivering it to cells, speed (virus replicate very fast) and ethical considerations (it’s considered a gene-editing tool so the regulations are more strict).

Conclusion

Isaacson is a master storyteller. He built a narrative around individuals, with Doudna as protagonist, Feng Zhang and the Broad Institute as antagonists, and He Jiankui as the outcast, and highlighted the drama involving them.

Perhaps in order to build a cohesive and engaging story, Isaacson might have been more generous towards Doudna and less so to Zhang. Reality is usually a lot more nuanced than stories (see Story Bias in The Art of Thinking Clearly).

I also learned quite a bit about Doudna’s life, the history of CRISPR and the ethics around gene editing. I also liked the coverage of the scientific method. Other random Things I learned:

Some books referenced in this one that might be an interesting read:

Notes