CRISPR’s Inventor(s) and Headscratchers: a review of Walter Isaacson’s “The Code Breaker”

Walter Isaacson is famous for his biographies of geniuses including Leonardo da Vinci, Benjamin Franklin, Albert Einstein and Steve Jobs. In his latest book, he set out to biographize 2020 Nobel Prize winner Jennifer Doudna as the definitive hero of a new age of biology.

The covid pandemic suddenly threw recent advances in biology into global public consciousness. Magazine covers, newspaper editorials and television news are filled with gushing coverage of the heroic scientists who rushed out new vaccines. Social media is agog with technical discussions about RNA.

Isaacson though was clearly already a fanatical convert before anyone had heard of covid. In this book, he gushes with enthusiasm about biology as the new frontier. Doudna is the poster-child of explorers of this new frontier: clever, articulate and wise.

Jennifer Doudna’s Story

Doudna is by now famous as the Nobel prize winning biochemist who worked in the path-breaking area of CRISPR. Her story is well known, not least because she actually wrote her own autobiographical story just a few years before Isaacson got his own book out.

During her childhood in Hawaii, Doudna was fascinated by the book “The Double Helix” written by James Watson, the co-discoverer of the structure of DNA. She decided to pursue a career in science and became a biochemist who decided on a risky area of focus — the structure of RNA. She gained recognition for her work and was well ensconced as a professor with her own lab at Berkeley. Doudna’s knowledge of biochemical structures led other scientists to connect and tap into her expertise. One of her Berkeley colleagues Jillian Banfield contacted her for help with unraveling the structure and function of a then mysterious part of the chromosome that had been acronymized as CRISPR. Later, she met French scientist Emmanuelle Charpentier at a conference in Puerto Rico and the two agreed to collaborate on CRISPR, bonding while strolling together around San Juan.

Doudna was not only a sharp scientist, she was also known to have a keen sense for seeing what is coming around the corner. Doudna clearly recognized that CRISPR had the potential to be a major scientific advance. Together with her own lab team and in collaboration with Charpentier’s team, Doudna threw herself into the CRISPR challenge with gusto and cracked open its structure and function. Going beyond the pure scientific discovery, Doudna and her colleagues honed CRISPR into a simpler and more elegant gene-editing technology, in the process replacing older and (to some) clumsier techniques. These triumphs triggered excitement and ferment: an a-ha moment for science where biologists felt they had created easy tools with which to edit the very code of life. And, in turn, set off an astonishing wave of CRISPR related research, pushing forward both the basic science and practical applications.

Doudna had at one stage left Berkeley to join Genentech, only to find corporate life uncomfortable and to return to Berkeley within a couple of months. Notwithstanding that stumble, Doudna became (eventually) an eager co-founder of biotech companies, having played a role in the creation or early conceptualization of companies such as Caribou Biosciences, Editas Medicine, CRISPR Therapeutics and Mammoth Bio.

Widely lauded for her scientific work on CRISPR, Doudna also took on the role of raising awareness about CRISPR and addressing public concerns. Doudna took center-stage in policy debates about the ethical aspects of editing the human code — what should be considered legitimate applications and, in particular, whether the world at large was ready for edits that could be passed down the germline.

In October 2020, just a short few years after their initial paper, Doudna and Charpentier won the Nobel Prize in Chemistry cementing how seminal their work in CRISPR had been.

The Wrangling Among CRISPR’s Inventors

Isaacson wrote this book apparently in close cooperation with Doudna. Quite naturally, therefore, he places her at the center of the story and of his own sympathies.

However, the fact that Doudna had already written her own autobiographical book seems to have allowed Isaacson to also wander through the wider cast of characters who inhabit or travel through CRISPR-land. He writes in detail about the rivalries that played out within this cast of characters.

Indeed, one senses that as he dug deeper into his subject, Isaacson reluctantly realized what others before him did — that Doudna was only one among a number of key contributors to CRISPR. Isaacson takes considerable pains to highlight the contributions of Feng Zhang and George Church of the Broad Institute in Boston who went head-to-head against Doudna’s team in the early years of CRISPR research and then continued to match wits over the years.

While writing this book, Isaacson met Eric Lander, a senior MIT biologist (now slated to be President Biden’s cabinet-level science advisor) who had written a provocative article trying to set right what in the latter’s view was the correct apportionment of credit for the early work on CRISPR. Although Isaacson seems to be unimpressed by Lander’s overall approach to defending his own (Zhang and Church were associated with MIT affiliated Broad Institute), he does allow that Zhang and Church may have played very critical roles.

What is more, just from reading Isaacson’s book, one cannot but help feeling that it was Zhang who first clearly validated CRISPR gene editing within human cells, something that Doudna’s lab had struggled with. As Zhang disparagingly remarks when interviewed by Isaacson: “Theirs [Doudna and Charpentier’s] was not a gene editing paper. It was a biochemistry experiment in a test tube”.

Isaacson finds that even once-close collaborator and fellow Nobel Prize winner Charpentier is now somewhat cool to Doudna, seemingly underwhelmed by the latter’s hyper-competitiveness and knack for publicity.

It is obviously difficult for those outside the charmed circle to know what exactly transpired and who should genuinely have received credit for what. However, Isaacson’s account savors and delights in the intense and sharp-elbowed battles for priority and patents. And, almost as an act of exculpation for having to play on Doudna’s side, Isaacson expresses the hope that Zhang and Church will in future receive the Nobel for Medicine (Doudna and Charpentier received the Nobel for Chemistry).

And, in any case, whatever the real story behind all the wrangling (which may ultimately never really be known), science may have at least partly been a winner of this competition of the best minds.

Broader Scientific Dimensions

Speaking of science as a winner, it perhaps wasn’t the aim of his book but Isaacson seems to have under-emphasized (although admittedly not completely ignored) some further or related winning scientific advances.

First, Isaacson’s book focuses on CRISPR and somewhat downplays RNA — the other hot (but of course related) subject in biology of late. RNA was, after all, the subject where Doudna earned her early spurs. It is also apparently the area where Doudna’s current academic research is again focused, in particular RNA interference and translational control by way of microRNA. It is a pity that Isaacson’s book misses the chance to dwell in detail on this aspect of her work. Thanks to mRNA covid vaccines, RNA is now splashed all over even in the popular media. It would have been interesting to know more about how the research of Doudna — ever the scientist who can look ahead — traces to today’s covid vaccines.

Second, going back to CRISPR, earlier work by Doudna and her collaborators and rivals has long since paved the way for many further leaps in the science of gene editing. Most importantly perhaps, David Liu at Broad has developed base editing i.e. efficiently converting one base pair to a different base pair without inducing double-stranded DNA breaks or extensive insertions and deletions. This can correct more than 60% of human pathogenic point mutations. Liu followed this up in late 2019 with a highly versatile technique called prime editing in which edited DNA sequences can be copied into a specified target site from an extended guide RNA without requiring double-stranded DNA breaks or donor DNA templates. If CRISPR is understood as a pair of scissors, then base editing is meant to work like a pencil and prime editing akin to word processing. Other than Liu’s work on base and prime editors, there is a constant stream of improvements and mini-breakthroughs e.g. the so-called “CRISPRoff” which can be used to control gene expression with high specificity, while leaving the sequence of the DNA unchanged. In short, the science is progressing rapidly enough for gene editing to become simpler, nimbler, more versatile and therefore an even more widely accessible technology in the coming years.

Third, Isaacson has very little to say about the progress that CRISPR based medicines are making in the real world. For all the buzz about CRISPR, the most advanced treatments are as yet still only in preclinical or early clinical development. It is not covered in the book but it is nevertheless heartening to note from recent updates that the very companies at the forefront — CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics — are still the ones that were founded by or had early involvement from Doudna and the other heroes of CRISPR-land that Isaacson describes in his book. What would have made Isaacson’s book more useful and interesting would have been a review of the issues and challenges in taking CRISPR from breakthrough technology to real-life medicine.

The Bioethical Dimension

Isaacson may have over-emphasized interpersonal rivalries and under-emphasized the scientific and medical advances. However, he very convincingly and deeply explores the ethics of CRISPR and gene editing. In fact, this is one of the best parts of his book. Isaacson makes clear that the issues involve deep moral philosophy. Views often line up along where one ultimately stands on personal liberty versus social control over important decisions. In any case, after much deliberation, most of the scientific community appears to have steered to a seemingly sensible middle path — that germline editing shouldn’t be ruled out over the medium term but should be deferred (and some believe a moratorium be placed) for the immediate future.

The (Inevitable) Economic Dimension

While Isaacson consumes many pages over the moral debate about germline editing, he pays very little attention to another moral (and economic) dilemma that will inevitably come to surround CRISPR, RNA and indeed all other advances in medical biology: who is to pay for these expensive treatments? Economists Andrew Lo, Jonathan Gruber, Rena Conti and their co-authors have run some simulations. Even with pretty conservative assumptions — such as only a linear rather than exponential growth in new treatments — cell and gene therapies will involve additional US health spending of over $ 300 billion over the next 15 years. The concerns around germline editing are of course profound and deeply philosophical. However, given already stretched public and health insurer budgets in wealthy countries to say nothing of sheer fiscal incapacity of poorer nations, the moral questions about affordability are far more practical and urgent.

Summing Up

While researching, writing and releasing this book, Isaacson seems to have been ambushed or upstaged on multiple fronts.

He sought to make the world aware of biology as the new technological frontier. But the covid pandemic beat him to it.

He set out to write a biography of Doudna as the definitive hero of a new age of biology because of her breakthrough work on CRISPR. However, he seems to have somewhere realized that Doudna — though clever, articulate and wise — was only one among a number of key contributors to CRISPR.

He set out to explain the excitement and science of CRISPR to a general audience. But the early developments were quite lucidly explained by Doudna’s own 2017 autobiographical book. And, in the bargain, Isaacson probably missed out on fully detailing the fast-paced and quantum scientific and clinical leaps that have taken place since in the world of gene editing.

The author set out to lionize CRISPR as the key new technology breakthrough. In the process, he may have ended up downplaying Doudna’s other significant contributions in the (related) field of RNA. Thanks to the covid mRNA vaccines that are already being injected into millions across the world, RNA is now “hotter” than ever.

Finally, he set out to detail the complex bioethics of germline editing. However, he has paid far less attention to the challenge of how all these medical advances will be paid for: an even more urgent and — to some tastes — perhaps an even more important ethical issue.

These limitations notwithstanding, Isaacson’s tale of scientific rivalries and moral debates remains interesting and readable. It is recommended for anyone with more than a cursory interest in the emerging world of new biomedical technologies.

References

American Society of Gene + Cell Therapy (2021) “Gene, Cell & RNA Therapy Landscape: Q1 2021 Quarterly Report” https://www.asgct.org/research/news/april-2021/gene-cell-rna-therapy-landscape-q1-2021

Anzalone, Randolph, Davis, Sousa, Koblan, Levy, Chen, Wilson, Newby, Raguram and Liu (2019) “Search-and-replace genome editing without double-strand breaks or donor DNA”, Nature Vol 576 Dec 5

Doudna and Sternberg (2017) “A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution”, Houghton Mifflin Harcourt

Economist (2021) “A new phaRNAcopoeia” in issue on “Bright side of the moonshot: Science after the pandemic”, March 27

Isaacson (2021) “The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race”, Simon & Schuster

Jinek and Doudna (2009) “A three dimensional view of the molecular machinery of RNA interference”, Nature Vol 457/22, January

Lander (2016) “The Heroes of CRISPR”, Cell, Vol 164, January 14

Nunez, Chen, Pommier, Hovestadt, Gilbert and Weissman (2021) “Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing”, Cell, April 9 https://doi.org/10.1016/j.cell.2021.03.025

Shaffer (2020) “Gene Editing Startups Cut Fine Figures”, Genetic Engineering & Biotechnology News, December 3

Terry (2021) “Jennifer Doudna’s Second Act: Covid-19 and beyond”, BioSpace March 10

Wong, Li, Wang, Gruber, Conti and Lo (2021) “Estimating the Financial Impact of Gene Therapy in the US”, NBER Working Paper 28628

Founder and Chairman of HitchinRock Advisors. Specialist in biomedical M&A, BD&L and investments. London, New York, Singapore

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