Walter Isaacson on CRISPR and the People Behind the Revolution

Walter Isaacson on CRISPR and the People Behind the Revolution

; Abraham Verghese, MD; Walter Isaacson, MA

Disclosures

June 18, 2021

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This transcript has been edited for clarity.

Eric J. Topol, MD: Hello. This is Eric Topol for Medscape's Medicine and the Machine, with my co-host, Abraham Verghese. We're especially delighted today to welcome Walter Isaacson, one of the great biographers of our time. His most recent book is The Codebreaker, which is about CRISPR and genome editing. Walter, welcome.

Walter Isaacson, MA: Thank you so much, Eric. I'm a big fan of both of you. It's an honor to be on your show.

Topol: We are thrilled to have you. I thought I'd set the stage because the medical community — our Medscape audience — certainly knows a bit about CRISPR. It's a true life sciences breakthrough. We don't use that term lightly. I wanted to read two passages in your book that are striking to set the stage. They are like "A.C." and "B.C.," where "C" is CRISPR. You captured it. You're a man of words, of course. Here's the first one I wanted to highlight.

The issue is one of the most profound we humans have ever faced. For the first time in the evolution of life on this planet, a species has developed the capacity to edit its own genetic makeup. That offers the potential of wondrous benefits, including the elimination of many deadly diseases and debilitating abnormalities.

And the other passage, from the book's introduction, is also telling. You wrote:

There was a sense that we had crossed the threshold into a whole new age, perhaps a brave new world, like when Adam and Eve bit into the apple or Prometheus snatched fire from the gods.

These are pretty profound statements. Can you give us an overview, because you really delved into this. You're not a genomicist. You're not a hard-core scientist. Yet you actually did CRISPR in the lab. You did a deep dive.

More Consequential Than the Computer?

Isaacson: I do think that we've seen certain revolutions in our time in the early 20th century — the physics revolution, much of which came out of the work of Einstein and others at the very beginning of the century. And likewise, in the second half of the century, we saw the computer, the microchip, and the internet combine to create a digital revolution.

Now we're on the verge of what I think is going to be a far more consequential revolution, one in the life sciences and biotechnology. It has many components and it begins to some extent with the sequencing of the human genome at the turn of this century, but also with genetic engineering and recombinant DNA.

CRISPR takes us into an entire new league because we can not only read the human genome and try to engineer things, we can actually make ever more precise edits to human or, for that matter, the DNA of any organism.

Just out of curiosity, I think people should want to know this, but also because they'll probably have to wrestle over the next 10 or 20 years with some of the implications of this. And by the way, it's just beautifully exciting to understand how something works, especially when that something is ourselves. I want to thank you, but also all the graduate students and various labs in Berkeley and the Broad Institute and other places that went through the process with me of understanding exactly what the tracer RNA and the guide RNA do, and how you engineer a single guide, and all the things that I try to make exciting in this book.

The Cast of CRISPR Characters

Abraham Verghese, MD: I want to echo what Eric said. It's just a tremendous book and a very compelling read — it almost read like a mystery — it just seemed to evolve on the page, which was wonderful. My question is, as a writer and biographer, when you approached this, you must have had an infinite number of choices as to how you would tell the story. I'm curious to hear how you arrived at the particular structure that you used.

Isaacson: That's a great question, Abraham, because I did spend a lot of time trying to sort through the process of the best way to tell the story. I have a natural proclivity to biographical narrative. I don't think that's anything new; I mean, that's how the Bible tells interesting stories and makes moral points. It's got a great lead sentence, which is "In the beginning (comma)."

So I tend to try to write chronological narratives with main characters that help bring it along. Biographers sometimes can distort history by making it seem like a guy or a gal goes into a garage or a garret and has a light-bulb moment and innovation happens, when we know that it's a collaborative effort, a team sport. I've written a couple of books, including one called The Innovators. That was about a whole group of people without a main central character. I thought of doing that here.

And there have been many good books on CRISPR. Kevin Davies has one called Editing Humanity. Hank Greely has a great one called CRISPR People that brings you through all the people involved in this revolution. I spoke to a lot of people who could have been central characters, including George Church, Feng Zhang, and Jennifer Doudna. I flew to Berlin to spend time with Emmanuelle Charpentier and Francisco Mojica. Many people, like Rodolphe Barrangou, were involved in this story. As my writing and thinking evolved, it seemed that as a narrative writer, it's often useful to have a driving central character. And secondly, writing through Jennifer Doudna as a central character had certain advantages, especially because she began her career, so to speak, in middle school when she read The Double Helix and became absolutely fascinated with the notion that the structure of a molecule is a key and a clue to figuring out what it can do.

She wanted to become a scientist but a guidance counselor said no, girls don't do science. She was inspired by a character named Rosalind Franklin in the book. And then she spent the 1990s under Jack Szostak and, to some extent, Tom Cech, doing the structure of various types of RNA, including self-replicating introns that answer the big questions, because Szostak had taught her to always ask the big question. She said, "What's the big question?" And he answered, "How did life begin?"

While a lot of the other scientists in the field (especially the men) were chasing the Human Genome Project and sequencing DNA, a lot of women, including Jennifer Doudna, Jillian Banfield, and Emmanuelle Charpentier, were focusing on RNA, which turned out, at least in our time, to be a more interesting molecule. It actually does work. It becomes a messenger to tell ourselves which proteins to build, and that's why we have the vaccines we now have. It became a guide that can take an enzyme and cut in a specified place, and hence we have CRISPR.

Telling the story through Jennifer offered the advantage of having a narrative that brings us through the history. She then turned her attention to the ethical and moral issues, and along with David Baltimore and others who led the Asilomar conference in the 1970s, she used a similar process to figure out what to do with gene editing. Then, as you'll see if anybody gets to the end of the book, she pivoted to get groups of people in the Bay Area to take on coronavirus using both CRISPR and other forms of molecular biology. And so she became a very good narrative thread.

As you flip through the book, even just looking at the pictures and certainly reading the chapters, you'll see pictures of many of the graduate students and young investigators and researchers. You'll see Virginijus Šikšnys, Martin Jinek, Prashant Mali, and Jennifer Hamilton. I wanted not only to get the stars of the CRISPR story to be main characters, meaning Feng Zhang, George Church, Emmanuelle Charpentier, and Jack Szostak, but all the principal investigators, because I wanted to show that creativity is a team sport when it comes to science.

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