As public bickering between the factions degenerated into outright hostility, it threatened to tarnish the reputations of the project leaders, not to mention the purpose of the mission. The White House helped orchestrate a temporary ceasefire to facilitate a historic celebration.1 Clinton hailed the achievement as “the most important, most wondrous map ever produced by humankind… The language in which God created life.” GENETIC CODE OF HUMAN LIFE IS CRACKED BY SCIENTISTS was the banner headline on the front page of the New York Times.2
But who was the owner of said cracked code? The NIH consortium had collected DNA from dozens of anonymous volunteers who answered a March 1997 newspaper ad placed in the Buffalo News by molecular geneticist Pieter de Jong (the Master Chef of building DNA libraries). Years later, genetic analysis revealed that the largest single contributor, code-named RP11, was likely to be African American.3 Like everyone else, RP11 and the other DNA donors were mutants, each carrying hundreds or thousands of DNA variants predisposing to rare and common diseases, including type 1 diabetes and hypertension.4 Celera had selected DNA from five volunteers of diverse ethnic backgrounds; Venter later admitted he was one of the chosen few.
Reading the book of life—even if at this stage there were many pages missing or torn or out of order—was a monumental achievement. This was the moonshot of biology, arguably the biggest event since Crick and Watson assembled the double helix in 1953. We had become the first species to translate the instruction manual, even if we couldn’t describe how much of it works. Textbook chapters proclaiming that humans possess more than 100,000 genes were rendered obsolete as we were humbled to learn that our genome contains barely 20,000.
One of the biggest champions of the HGP was Sir John Maddox, the editor emeritus of Nature. In 1999, Maddox published an ambitious book few would dare undertake, entitled What Remains to Be Discovered. Maddox wrote:
It is likely that the deeper knowledge of the working of the human genome now being won will suggest ways in which the design of Homo sapiens provided by 4.5 million years of natural selection could be decisively improved upon by genetic manipulation. After all, people are now manipulating the genetic structure of genes so as to make plants resistant to infections. Why not manipulate the human genome to the same end? It is a reasonable guess that Homo sapiens will not always disclaim such opportunities.5
As he wrote those words, a band of scientists worlds away from the television cameras and presidential plaudits were taking the first steps toward developing a new technology that could tinker with the code we had just spent some $2 billion over a decade to spell out. It was the dawn of genome editing.
Editing is an essential step in creating works of literature, or music, or art. The fortunes of many blockbuster films might have been very different if producers had gone with their original titles. Alien was going to be called “Star Beast,” Back to the Future was almost released as “Spaceman from Pluto,” and the working title of Pretty Woman was “3,000.” Jane Austen’s “First Impressions” became Pride and Prejudice. Margaret Mitchell’s Scarlett O’Hara was originally named Pansy. “Editing, of text literary or genetic, (almost) always makes things better,” writes Fyodor Urnov.6
While I was watching the rapid progress in high-throughput DNA sequencing in the 2000s, scientists were devising a molecular word processor to edit the book of life—to search, cut, and paste words and letters, identifying typos, deleting misspellings, and pasting in corrections. Within a decade of crowning ourselves the first species to decode our genetic script, we were already testing our ability to engineer changes in any organism on a whim. Taken to its logical conclusion, we can now redirect and accelerate our own evolution, and that of almost every organism on earth.
“This is the nature of discovery,” says geneticist Shirley Tilghman, former president of Princeton University. Every major scientific discovery has the capacity to be deployed for good and ill. “It’s going to take wise societies to direct those discoveries down the right path.”7 The rapid development of genome editing is a daunting, unprecedented, and in some ways frightening responsibility. One that has already been violated.
Before we go any further, let’s consider what is so special about this revolutionary technology with the funny name that sounds like a cross between a candy bar and a refrigerator drawer. In striving to paint a picture of CRISPR, writers have reached for one metaphor after another: the hand of God, a bomb disposal squad, a pencil eraser, a surgeon’s scalpel, a retinal scanner, and frequently, a “molecular scissors.”8 STAT produced a top ten list of CRISPR analogies, culminating in the Offiziersmesser, better known as the Swiss Army knife of molecular biology. Likewise, CRISPR is more than just a single sharp blade for cutting DNA, but an ever-expanding array of molecular gadgets for editing and manipulating DNA with ever greater finesse and flexibility.
CRISPR is one of those once-in-a-generation breakthroughs that changes the way science is conducted almost overnight. Ironically, the technology harnessed from a bacterial antiviral immune system went viral. But it was not the first technique for genome editing. Earlier methods for gene editing were conceived in the early 2000s, refined, and even entered the clinic before the advent of CRISPR. Urnov and his colleagues at Sangamo coined the term “genome editing” in 2005 while refining a technology called zinc finger nucleases (ZFNs), which is still in clinical use. In 2011, the year before CRISPR burst into the scientific mainstream, the journal Nature Methods anointed genome editing its “Method of the Year.” ZFNs and another gene-editing platform called TALENs have their admirers, but were too fussy and expensive to break out the way CRISPR has.
CRISPR takes the premise of other forms of genome editing and (in the parlance of Spinal Tap) turns it up to 11. From Australia to Zaire, researchers worldwide are using CRISPR to edit genes in almost any organism on planet earth. The ease of uptake stems from the fact that CRISPR is, in essence, a technology honed by evolution over hundreds of millions of years. CRISPR doesn’t require expensive lab instruments such as $1-million state-of-the-art DNA sequencing machines—most of the reagents can be ordered over the Internet and handled in the lab without any special safety precautions, just as Zhang demonstrated for 60 Minutes. High-school students can learn the fundamentals of CRISPR in a biology classroom.9 A nonprofit in Boston called Addgene serves as a clearing house for CRISPR reagents. By early 2020, Addgene had distributed more than 180,000 CRISPR constructs to more than 4,000 laboratories around the world, according to director Joanne Kamens.10
In the summer of 2012, the groups of Charpentier and Doudna demonstrated that they could take the bacterial CRISPR system and, with some nifty molecular tweaking, transform it into an exquisitely tunable genetic cursor that could be used to cut more or less any specific stretch of DNA. Rodolphe Barrangou, the chief editor of The CRISPR Journal, calls that study a tipping point that showed that “you could repurpose this cool, idiosyncratic, revolutionary immune system in bacteria and turn that into a tool that people can use readily in the lab to cut DNA.”11 Six months later, Zhang’s group, in collaboration with the Rockefeller University’s Luciano Marraffini, and independently George Church’s group, demonstrated that the CRISPR-Cas9 tool could effectively edit mammalian DNA. “That changed the world,” says Barrangou.