Some would argue that Zhang and Church were merely confirming the obvious, extrapolating from Doudna and Charpentier’s work in bacteria to engineer human DNA. After all, several teams reported success within a couple of months of each other. But getting the system to work in human cells was a major step forward in developing a new type of genetic therapy. It also set the stage for a massive legal dispute about the invention of genome editing (see Chapter 13). Any doubts that Cas9 could work in human and other animal cells had been well and truly answered.
One might ask what if eLife, located in Cambridge, England, had expedited review and publication of Doudna’s follow-up paper and published it before the New Year. Shepherding reviewers over the festive break isn’t easy, especially when Brits typically log off from Christmas to New Year. By the time Doudna’s paper was published, few took notice. A few years later, Doudna was asked: Why did Zhang and Church demonstrate CRISPR gene editing in human cells before her? “They were absolutely set up to do that kind of experiment,” she acknowledged. “They had all the tools, the cells growing, everything was there. For us, they were hard experiments to do because it’s not the kind of science we do. What speaks to the ease of the system was that a lab like mine could even do it.”31
The media still didn’t fully grasp the implications of the genome editing papers from Zhang and Church.VI One of the first to comment was author and columnist Matt Ridley, who marveled in the Wall Street Journal at scientists’ ability to precisely edit a single base.32 Two months later, Forbes science correspondent Matthew Herper surmised, “The [Cas9] protein could change biotech forever.” Herper’s story focused on Church, who had a much bigger profile than his former fellow, and said CRISPR was “spreading like wildfire.” Not only was Zhang not quoted, but ironically, he also fell victim to an editing error: his name was misspelled “Zheng.”33
Steadily, interest in CRISPR from scientists and media alike picked up. Geneticist Konrad Karczewski recapped the buzziest terms of 2013 in a game of catchphrase bingo popular at conferences. “CRISPR” was included along with nanopores, big data, and Myriad (for the blockbuster supreme court ruling banning gene patents).34 A report from the Harvard labs of Chad Cowan and Kiran Musunuru compared CRISPR and TALENs side by side, with CRISPR winning convincingly.35 “It was a surprisingly important paper,” said T. J. Cradick,36 the former head of genome editing at CRISPR Therapeutics, not least because it gave venture capitalists the green light to explore CRISPR’s commercial potential.37 The Boston Globe covered CRISPR for the first time in a story about the launch of local biotech company, Editas Medicine, featuring Zhang, Doudna, and Church among the cofounders. Science recognized CRISPR in its annual “Breakthrough of the Year” awards—albeit as a runner-up to cancer immunotherapy.38 CRISPR achieved top billing two years later, having “matured into a molecular marvel.”39
I. In the single letter code, each of the twenty amino acids, encoded by a three-letter codon of DNA, is represented by a single letter. For example, M-A-R-K stands for methionine-alanine-arginine-lysine.
II. This idea was initially proposed by Francis Crick, who spent the final three decades of his life at the Salk Institute studying the brain and consciousness. Crick called for a new technique that could probe brain function at the single-cell level, and even suggested that this level of control could be achieved through light.
III. Every Christmas, McGovern toured every IDG office location, meeting with each employee in person to hand them a cash gift and thank them for their specific contributions to the company, which he knew cold.
IV. The Miami 2011 Winter Symposium, “Epigenetics in Development and Disease.” co-organized with Nature Publishing Group.
V. Angelman syndrome is an example of a class of genetic diseases called imprinting disorders, in which mutations effectively silence one copy of a gene, depending on whether it was inherited from the mother or father.
VI. Two industry publications ran reports based on press releases: Genetic Engineering & Biotechnology News (GEN) covered the Zhang paper, while Genomeweb highlighted the Church lab report.
CHAPTER 7 PRIZE FIGHT
In 1994, I attended a science conference in Philadelphia for my journal, Nature Genetics. During a coffee break, a geneticist named Dennis Drayna took me to one side and whispered that his team at Mercator Genetics had made a thrilling discovery: the gene mutated in patients with hemochromatosis, one of the most common genetic disorders in people of European descent. I said we’d be thrilled to review the paper and would handle it expeditiously. I sent copies by courier to four referees to ensure the results were thoroughly vetted. But a week later, as the faxed reviews landed on my desk, my worst fears were realized: a split decision, two reviewers loved the paper but the other two expressed concerns. In desperate need of a tiebreaker, I called the best man for the job: Eric Lander. He read the paper over a weekend, and transmitted his unequivocal endorsement, which we proudly published in 1995.I
Lander trained as a mathematician and taught economics at Harvard. He’s a Rhodes Scholar and a MacArthur Genius Award recipient. In the late 1980s, he decided to apply his skills to biology—his brother is a leading neuroscientist—taking a fellowship at the Whitehead Institute in Cambridge, a new flagship research center on the fringe of the MIT campus. His stature grew rapidly in the 1990s, as he helped build the theoretical framework for human gene mapping before helping to lead the international genome project consortium’s response to the Celera threat. Lander wrote the lion’s share of the landmark draft human genome paper published in Nature in 2001.
After you’ve helped to orchestrate the successful effort to sequence the human genome, and quietly cofounded several successful biotech companies, what do you do for an encore? Lander set his sights on building a new biomedical institute (literally overshadowing the Whitehead) affiliated with both Harvard and MIT, anchored by a world-class genome center but venturing into cancer biology, neuroscience, cell biology, chemistry, and eventually CRISPR and genome editing. The philanthropists Eli Broad and his wife Edythe have committed $700 million to Lander’s institute, which the billionaire art collector calls his greatest treasure. In 2008, President Obama named Lander to cochair the White House science council, praising Lander’s work on the Human Genome Project as “one of the greatest scientific achievements in history.”1
Over the years, like the general manager of a dynastic baseball team, Lander has assembled a team of all-star scientists including top Harvard chemists Stuart Schreiber and David Liu, former Harvard provost Steve Hyman, and Merck’s former head of research, Ed Scolnick. He identified Zhang’s potential before CRISPR became the biggest game in science and Lander could take some personal pride in having this rising phenom under his roof at the Broad.
As the competition for credit and awards heated up, one McGovern Institute executive, Charles Jennings, was concerned that Zhang was in danger of not receiving the recognition he deserved. The press was warming to the story of the Doudna-Charpentier alliance forged in Old San Juan. Jennings took it upon himself to nominate Zhang for his first prize. To be sure, the annual Popular Science magazine “Brilliant Ten” award for scientists and engineers may not rank as one of the world’s most prestigious scientific awards, but Zhang happily joined the class of 2013.2 Jennings’s nomination praised Zhang for his work developing gene-editing tools and his willingness to share them widely with his fellow scientists. “These technologies are so fundamental, it’s best to keep them as open as possible,” Zhang said. “If someone had protected the HTML language for making Web pages, then we wouldn’t have the World Wide Web.” Three years later, MIT awarded Zhang tenure. Desimone’s nomination letter to the tenure committee began by saying this was probably the easiest decision the committee would ever have to make.