On Writing a History of Crispr-Cas9




DERRICK ROSSI HAS stylish jet-black hair, wears a Dr. Seuss watch and, sometimes, ironic eyeglasses with chunky black frames. In the winter of 2013, I worked in his lab on the ground floor in the white marble quadrangle at Harvard Medical School, where I used a computer station with a chair that had the legend “Rajewsky” written on the back in marker. Rossi had recently co-founded a company called Moderna Therapeutics, which uses customized RNA to alter the level of proteins in a cell, an exciting new route to drug therapy. But now he was looking deeper, seeking to alter the DNA code itself as a means to develop new drugs. That January, five papers had dropped in journals describing Crispr-Cas9, a new genome-editing technology, which was poised to change life as we know it.

Rossi was on telephone conference calls with Harvard synthetic biologist George Church and UC Berkeley biochemist Jennifer Doudna, among other scientists, who were in a tizzy over the founding of companies using Crispr-Cas9. Eric Lander, director of the Broad Institute, also wanted in on the action. Along with Church and others, Feng Zhang would go on to found Editas Medicine, while Rossi ended up as a founder of Intellia Therapeutics, along with Erik Sontheimer from UMass Medical School, Doudna, and others. Alliances were quickly shifting around the patent portfolios, which would become the subject of litigation running to tens of millions of dollars, and fierce public attacks over the right to claim Crispr-Cas9 as an invention. But all of this was only beginning when I met Derrick Rossi.

On a sunny day in 2013, Rossi was descending a hill on his bicycle when a car door opened in his path. He broke his collarbone and seven ribs, and splintered bones nearly nicked major arteries. Boston is marked with “ghost bikes” — bicycles spray-painted white and chained to the sites of bicyclists’ deaths as a reminder to all commuters. Luckily, Rossi’s bike was never painted. What impressed me, strolling into his office, was how his brush with death only intensified Rossi’s enthusiasm to get back into the lab. He had only missed work for a couple of weeks.

It was about this time that I began to take a deep dive into writing a book on the drama that was unfolding around the development of Crispr-Cas9, which became Modern Prometheus: Editing the Human Genome with Crispr-Cas9, which will be released this month. Among the first people I contacted was Doudna, who rattled a few emails back to me. It wasn’t long before our correspondence broke down. One reason may have been that I was affiliated with the Broad Institute at that time, and she and colleague Emmanuelle Charpentier — who I would meet a couple of times — were in the midst of a developing patent fight with the Broad. I also realized that Doudna, along with her protégé Sam Sternberg, was writing her own book, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, which will be released in June 2017.

I have a sense that readers may come to think of my book as an “East Coast” and Doudna’s as a “West Coast” history of Cripsr-Cas9. This is true insofar that I primarily interviewed scientists in the Boston area, but I do not take a side in the patent fight. If anything, my book is sympathetic to Charpentier, since her technical work is a threshold through which any development of Crispr-Cas9 must pass. Doudna did have a look at my final draft before it was sent to press, and although she and I may disagree on emphasis, I don’t believe either of our books will be biased one way or another. In fact, when I met Sternberg, Doudna’s co-author, along with Jonathan Moreno and some other writers at a summit on genome editing at the National Academy of Sciences a year ago, I felt a writerly kinship with them. Sternberg and I talked about the historical sources we found useful, and which we tossed away. I had been probing the collections in the Institute Archives and Special Collections at MIT, and he had been scrolling through the archives at UC Berkeley. Both of us had picked up Donald S. Fredrickson’s The Recombinant DNA Controversy: A Memoir: Science, Politics, and the Public Interest, 1974-1981 (2001).

One of the things Sternberg impressed upon me was that the Crispr-Cas9 story did not begin in 2012–’13 but developed over years of incremental discoveries and mounting tension. You can connect Crispr-Cas9 with a number of previous innovations, such as the ability to culture cells in a lab or the emergence of DNA repair machinery. Sternberg is also a scientist, one of the “unsung heroes” of the Crispr-Cas9 story — along with Prashant Mali and Krzysztof Chylinski. When Lander wrote his own history of Crispr-Cas9 for the journal Cell, he was chided by historian Nathaniel Comfort for producing a narrative that celebrates the most famous scientists while marginalizing or ignoring other contributors. I can’t say that I’m sure I succeeded in writing a “people’s history” of science, and I am almost certainly guilty of similar slights. In fact, I sent my manuscript to Lander several years before he wrote “The Heroes of CRISPR,” and I was certainly the first person to connect Greek mythology to the Crispr story — an approach Comfort assails as “melodramatic.” Lander denies ever seeing my manuscript.

It is a truism that people enter scientific fields because of their commitment to free inquiry and their scant tolerance for the status quo. We do science to get at the truth, not to reinforce social positions — though of course such motivations as ambition and envy cannot be discounted. That’s why I was cautious in presenting the charged atmosphere — professional, legal, and financial — surrounding Crispr-Cas9. Elite scientists must be aware how large a role contingency plays in their accomplishments, how any achievement is not so much a stroke of individual genius as the culmination of a complex collective history.

In the 1980s, Richard C. Mulligan at Harvard, and other scientists around the world, had learned to use viruses as tiny pilots to install genes into a human cell — so-called “gene trapping,” which would drop a new gene as cargo at a random site in a random chromosome. By contrast, Mario Capecchi and colleagues soon invented “gene targeting,” showing that organisms could be created by introducing a new gene into a cell; often, the genome would magically swap out its original gene for the new gene introduced at a very precise target. In fact, the feat worked about 0.01 percent of the time, and it had to be performed in mouse cells that could be selected for and picked out of an in-vitro plate in the lab. The process was by no means efficient, but the implications were obvious. At about the same time, the “Cre-Lox recombination” system was invented. In this technique, scientists deploy the Cre enzyme to snip out the genetic region in between two sites in a mammalian cell. Scientists quickly learned that they could invert or organize two “Lox sequences” in many series in order to knock out genes or rearrange genomes to order. The German scientist Klaus Rajewsky advanced the system to a whole new level by introducing it into embryonic stem cells, in a process called “conditional gene targeting.” In effect, Rajewsky used engineering tricks to get the Cre enzyme to be expressed only in some cells in mice — for instance, only in liver cells under the control of an external stimulus such as interferon.

In many ways, gene-targeting technology was the forerunner of genome editing. In 1994, Maria Jasin, a molecular biologist at Memorial Sloan Kettering, performed an elegant experiment to show that by instigating breaks in a plasmid (a circular vector that included a new gene to introduce to the cell), with an endonuclease called I-SceI, she could dramatically increase the frequency of recombination at those places. In fact, Jasin and colleagues showed that causing a double-strand break in the plasmid actually increases recombination events 100-fold, suggesting that initiating such breaks was a critical step for gene engineering. By doing this, she vastly improved upon Capecchi’s 0.01 percent rate of recombination. Keith Joung, a founder of Editas Medicine and a physician-scientist at Massachusetts General Hospital, pointed out to me that while fights have emerged over whether to grant Charpentier, Doudna, or Zhang a Nobel Prize, you could just as easily point to the seminal work of Maria Jasin.

This is how science moves, through layers of history, through what phenomenologists call the “lifeworld.” The great scientist Benno Müller-Hill famously described the “two faces” of molecular biology. “In the textbooks, almost everything is solved and clear,” he wrote. “Most claims are so self-evident that no proofs are given. Old, classical experiments disappear.” In a sense, the first face is taken as a given. “The other face of molecular biology is seen at scientific conferences or read in recent issues or Nature, Science or Cell,” at the cutting edge of the field, where knowledge struggles with ignorance. Robert Pogue Harrison has suggested the metaphor of “two angels,” drawing on Paul Klee’s painting — made famous in Walter Benjamin’s “Theses on the Philosophy of History” — that depicts an “angel of history is borne upward through the air on outspread wings, facing backward.” In Benjamin’s vision, all the angel sees are “the accumulated ruins of the has-been.” Harrison goes on to suggest that

science flies on the wing of another kind of angel — the angel of neoteny — who weaves in and out of enfolded spaces, forever turning a corner or rounding a bend, entering or exiting a crease of the cosmos, such that his expectant, forward-looking gaze sees anew a world it has been seen countless times before, always as if for the first time.

The prefix “histrio-” means actor, and we all know histrionic personalities who must be the centers of attention, absorbed in history. To be hysterical means to be incapable of being an object or objectified, to exclude oneself from history. A more dire condition is psychosis, which is the inability to historicize. It would be nice if there were a gene for psychosis. If so, we could just edit or snip it out with a pair of tiny molecular scissors such as Crispr-Cas9. In fact, there are perhaps thousands of genetic risk variants for psychiatric disorders scattered over the human genome. And we know that “epigenetic” markers that we acquire during times of stress can dampen the expression of genes that are key to learning — such as GRIN1, a gene that builds an NMDA receptor, which is used to create new memories. The dynamic nature of human experience means that genetic engineers will never replace the hard work of psychology.

The creation of history is an active process, even more important if you take it, as I do, that nature is memoryless. There is no singular event in nature, and history is encoded as a singular event only in our experience. Science is embodied by its living scientists. History must be shouldered through effort, carried forth, fought for, appropriated. At the National Academy of Sciences, when I was talking to the other writers, I glanced to one side and saw an old blue-eyed German fellow with a name tag that said “Rajewsky.” “You’ll never believe this,” I said. “There is an abandoned chair at Harvard, and it says ‘Rajewsky’ on the back in marker.” Rajewsky looked at me wryly, with some irony. He had moved back to Germany. The chair was empty, open for the future, waiting for someone to start anew.

¤

Jim Kozubek is the author of Modern Prometheus: Editing the Human Genome with Crispr-Cas9.


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