CRISPR, Patents, and Nobel Prizes
By Henry T. GreelyAugust 23, 2017
A Crack in Creation by Jennifer A. Doudna and Samuel H. Sternberg
A Crack in Creation is also not a history — that is, a detailed and precise explanation of who did what and when to produce CRISPR/Cas9, this century’s biggest biological discovery to date. That history awaits its Horace Freeland Judson, whose magisterial The Eighth Day of Creation provided a gripping blow-by-blow account of the birth and adolescence of molecular biology, or its Robert Cook-Deegan, whose The Gene Wars illuminated the beginnings of the Human Genome Project.
Nor is this a “how to” book for aspiring do-it-yourself CRISPR users; or a deep analysis of the ethical, legal, and social issues CRISPR and its progeny will raise; or a legal analysis of the already (in)famous CRISPR patent fight; or a look at the unresolved Nobel Prize race. And it is not a gossipy inside look at the people intimately involved in CRISPR’s invention.
So what is A Crack in Creation? It is an essential start to educating the public.
Humans’ use of the bacterial defense mechanism called “clustered regularly interspaced short palindromic repeats” (CRISPR), with or without “CRISPR associated protein 9” (Cas 9) — along with the technologies that eventually will modify or displace it — is of vast importance. That’s not because it is the first way we have found to edit DNA. It misses that distinction by over 40 years. But it is the first truly fast, cheap, easy, and accurate way to do so. It is biotechnology’s Model T. The Model T was not, by several decades, the first automobile, but it transformed cars from expensive, unreliable, inconvenient, and rare objects to something everyone could, and soon did, own. It is the change in degree, not in kind, that has transformed the world we live in (nowhere more than California). Similarly, humans have been manipulating living organisms, including ourselves, at least since the dawn of modern man, but CRISPR is the change in degree that turns gene editing from expensive, unreliable, inconvenient, and rare to ubiquitous. It vastly increases our powers to edit all life, including our own.
A Crack in Creation tells the story of CRISPR through the eyes and in the voice of Jennifer Doudna, the UC Berkeley biochemist who was a central figure in harnessing it. (The co-author, Samuel Sternberg, is Doudna’s former graduate student.) It divides elegantly into two four-chapter parts, plus prologue and epilogue. The first part describes what CRISPR is and how it was discovered; and the second sets out CRISPR’s possible uses in the environment and medicine, and in editing humankind.
It is not, however, the first publication to recount the origins of CRISPR. Indeed, as with the double helix, the identity of the originators is contested. In January 2016, Eric Lander, director of the Cambridge, Massachusetts–based Broad Institute (jointly owned by Harvard and MIT), published a 7,200-word essay titled “The Heroes of CRISPR” in Cell, one of three leading journals for bioscience publications. It was widely criticized for minimizing the contributions of Doudna and one of her key collaborators, Emmanuelle Charpentier, and highlighting instead the work of Feng Zhang, a researcher at the Broad (and hence Lander’s employee). As well as triggering, fairly or not, debate over the issue of sexism in science, Lander’s piece was particularly controversial in that the publication never mentioned its author’s conflicts of interest, not just in promoting Zhang as CRISPR’s hero, but because of the very expensive patent fight over CRISPR between the Broad Institute and Doudna’s employer, the University of California (“UC”).
This said, what both Lander and Doudna do well is reveal the complex, interlocking, and thoroughly international nature of today’s bioscience. They acknowledge the work of a dizzying number of contributors to CRISPR. The first publication to show that CRISPR could be used to edit bacterial DNA was Doudna and Charpentier’s Science article in June 2012 — but, by that time, scores of researchers had already been exploring what was regarded as a tantalizing bacterial curiosity.
In his Cell article, Lander writes that “[t]he story starts in the Mediterranean port of Santa Pola, on Spain’s Costa Brava,” with Francisco Mojica who published a report in 2005 on the existence of, and possible immune system function of, certain odd, largely palindromic, DNA repeats in several bacterial species. Researchers at a yogurt company, Danisco, also played important roles, as did Sylvain Moineau in Quebec and John van der Oost from the Netherlands. Even before her first meeting with Doudna in March 2011, Charpentier and her lab at the University of Umeå in Sweden had also contributed to the development of the CRISPR system.
Virginijus Šikšnys, a Lithuanian researcher, greatly improved researchers’ understanding of the proteins bacteria used with CRISPR. He saw some of the possibilities of CRISPR as a tool and submitted a paper to Cell on the topic on April 6, 2012. Cell rejected his paper, which was eventually published on September 4, 2012, in the Proceedings of the National Academy of Sciences. In the meantime, Doudna and Charpentier’s paper was submitted to Science on June 8 and published 20 days later.
But if this is more or less the beginning of the CRISPR discovery story, it is certainly not the end.
Feng Zhang, a brilliant young researcher at the Broad, had spent much of 2011 and 2012 working on a way to use CRISPR in mammalian cells. Zhang submitted his first CRISPR publication on October 5, 2012. Later that month, George Church, an exceptionally wide-ranging and creative Harvard researcher, submitted a paper on using CRISPR in human cells, which Science published in the same issue as Zhang’s on January 3, 2013.
This summary does not come close to mentioning all the laboratories involved in discovering and developing CRISPR and does not even begin to talk about the vital contributions of the post-docs and graduate students in those labs, all of them highlighted in A Crack in Creation.
Whose version is closest to the “true” history of CRISPR? Lander’s history was widely attacked and A Crack in Creation has already been criticized in a review in Nature for downplaying Zhang’s role (though it mentions him more than Lander mentioned Doudna). I suspect neither Lander nor Doudna and Sternberg could tell the full story for at least one sad reason — lawyers probably wouldn’t let them. Their employers are locked in a patent struggle. The details of who did, said, or knew what when could be crucial to its outcome. How many changes in the manuscripts came as a result of lawyers’ comments? Probably more than a few.
In fairness, A Crack in Creation never promises to be the definitive history of CRISPR — much less a story of all its “heroes.” It tells Doudna’s CRISPR story, as well as the authors’ thoughts on its potential uses and implications. These uses and implications make up the book’s second part, “The Task.” It begins with the use of CRISPR in the non-human world for agricultural purposes and beyond, including the ongoing development of “gene drives,” an important adaptation of CRISPR that can speed the spread of desired genetic changes in sexually reproducing species, as well as plausible speculation about future unicorns (in this case, the mythical animal). It then addresses the medical applications of CRISPR to living people in the form of so-called “somatic” gene editing, intended to heal their bodies without changing their eggs or sperm and so not affecting future generations. The authors rightly view this as the least controversial use of CRISPR. The last chapters address what has become the stickiest question for most people: the use of CRISPR to make changes in the genome of the human “germline” (eggs and sperm) that can be inherited from generation to generation.
Doudna’s interest in these last issues is neither new nor shallow. In October 2014, I was invited to a small meeting she was organizing in Napa Valley the following January to discuss the ethical issues of CRISPR. (Coincidentally, this was almost exactly 40 years after the famous 1975 Asilomar meeting to assess safety issues of the first “gene editing,” recombinant DNA.) The Napa meeting involved about a dozen prominent scientists — including Paul Berg and David Baltimore, the two Nobel Prize winners who helped organize the Asilomar meeting — and two law professors who work in the field, Alta Charo from the University of Wisconsin and myself. Doudna’s genuine concern was evident, not just in calling the meeting but in her active and thoughtful participation in it. And human germline genome editing was clearly the focus of that concern.
The Napa meeting reached consensus surprisingly quickly: the somatic cell uses of CRISPR should be pursued actively, but human germline modifications needed more thought. Doudna took the lead in drafting a commentary, signed by the meeting’s participants and several others, which Science published in March 2015.
The commentary made four recommendations about human germline editing:
- “Strongly discourage” germline genome modifications in humans while the implications are discussed.
- “Create forums” of experts to discuss the issues raised by genome editing,
- “Encourage and support transparent research” into the safety and efficacy of CRISPR for germline gene therapy, and
- “Convene a globally representative group” to further consider these issues.
The Science article was not alone. Nature had published a commentary on human gene editing the week before, endorsing somatic cell uses of genome editing, but rejecting germline changes. And two weeks later, an obscure journal published an article in which Chinese scientists reported their (slightly) successful efforts using CRISPR to edit human embryos.
The Chinese group had carefully used human embryos that were not viable and thus could never become babies, but the article still set off a firestorm. One of its results was a US National Academies of Sciences, Engineering, and Medicine initiative to study genome editing. A major part of that initiative was an “International Summit on Human Gene Editing” held in Washington, DC in December 2015, with additional sponsorship from the Chinese Academy of Sciences and the UK Royal Society. At its end, the summit’s planning committee (not the sponsoring academies) issued its conclusions, roughly echoing the March Science commentary.
As A Crack in Creation usefully points out, the debate over germline modification is not new. The issue was discussed in print at least 30 years before CRISPR was imagined. But a sense of urgency — and some specificity about both the likely intervention and the societies into which it will be launched — helps focus discussions. Since the International Summit (and submission of the last manuscript of the book), the National Academies alone have published at least three relevant reports — two concerning non-human uses of CRISPR in October 2016 and March 2017, and the third, issued in February 2017 on Valentine’s Day, on CRISPR and humans, endorsing somatic cell uses of CRISPR and opening the door for possible germline editing for medical reasons.
A Crack in Creation hints that the discussions thus far have modified Doudna’s views. Like the February 2017 report, the book shows some openness to human germline modification, at least for addressing clearly genetic diseases.
Personally, I think we focus too much on human germline genome modification. There is no “human germline genome” — there are over seven billion of them, each changing slightly by mutation in every generation. Editing out rare, disease-causing DNA variations or replacing them with the more common “safe” variants hardly seems radical. The real concerns — for germline or somatic human gene editing — should be about “enhancements” (as opposed to disease), but that is just one part of a much wider conversation about all kinds of biological, electronic, and mechanical enhancements. The combination of our great concern about the safety of babies and our ignorance regarding “enhancing” genetic variants, however, means we have time to get this right. But we’re way behind in regulating the use of CRISPR in non-humans. The medical, practical, and political constraints around human babies do not exist for mosquito babies, let alone genetically modified microbes or plants. For the moment, we need to concentrate on this much less constrained use of CRISPR, which is already beginning.
Doudna called for discussions about the uses of CRISPR in Napa in January 2015 and A Crack in Creation amplifies that plea, providing the interested public with the background critical to such discussions. But CRISPR has raised two other interesting questions, which, though not discussed in the book, are worth mentioning: the Nobel Prize and the patent fight.
A Crack in Creation says nothing about the likely Nobel Prize for CRISPR, but CRISPR junkies regularly discuss it. A Nobel Prize in either Chemistry or in Medicine and Physiology seems almost certain, and will likely be granted soon. But who will receive it?
Scores of people in many countries contributed to its discovery, but Nobel Prizes in the sciences are limited to not more than three people. Doudna and Charpentier should be shoo-ins, for their own insights, for the work of their labs, and for their first publication. Plausible other candidates include at least Mojica, Šikšnys, Zhang, and Church — but four into one won’t go.
Many have read Lander’s Cell article as an effort to tilt the third spot toward his faculty member, Zhang, but the fight over the patent rights for CRISPR could also influence who wins the prize. A Crack in Creation mentions the patent fight only once, as “a disheartening twist to what had begun as collegial interactions and genuine shared excitement about the implications of the research.” But the patent cases over CRISPR have been unusual, and unusually fascinating, from the beginning. (For more details see various pieces by Jacob Sherkow, the law professor who has followed this most closely.)
In December 2012, Zhang and others (meaning the Broad Institute on behalf of Zhang and others) filed a patent application on the use of CRISPR in any cells from complex organisms, called eukaryotic cells, which include everything from algae to us, as opposed to prokaryotic cells (bacteria and archaebacteria) and viruses. Doudna and Charpentier’s patent application had been filed seven months earlier, claiming the use of CRISPR in all cells. But the Broad paid for and got a special expedited patent procedure so that its patent application, though filed after the UC’s, was granted in April 2014, before the UC’s was decided.
A year later, in April 2015, the UC invoked an interference proceeding, asking the Patent and Trademark Office (PTO) to resolve an apparent inconsistency in patent applications and determine who was the first inventor. In February 2017, the PTO ruled in favor of Zhang and the Broad. But the UC has appealed this decision, and even if it stands, it is possible that the Doudna and Charpentier patent and the Zhang patent will be held valid, in which case someone who wanted to use CRISPR in eukaryotic cells, including human cells, would need licenses from both UC and the Broad.
Furthermore, all patents are limited to the jurisdiction that granted them. US patents have no force outside the United States. This past March, the European Patent Organization granted CRISPR patents to UC, as have the patent authorities in China and the United Kingdom. So we could have a world where the Broad seems to control important US uses and the UC the European, British, and Chinese uses. The rest of the world is, at this point, up for grabs.
What does all this mean? In terms of the ultimate ownership of the most basic CRISPR patent rights, stay tuned. It is too soon to tell. But, in a larger sense, I don’t think it matters.
This is mainly a fight about money: about which American universities will make money, and how much of it, off some uses of CRISPR. If the money goes to the UC system, as a Californian I would be pleased. But the question of who profits shouldn’t change the adoption of CRISPR. That is, as long as either entity uses a good licensing strategy. Of course, even that may not matter. The CRISPR patents will give the players ownership of some approaches, but they will be of little value if novel approaches are developed. Already various inventors have come up with alternatives to Cas9 as part of the CRISPR complex. Bacteria invented CRISPR billions of years ago and have had time, and selective pressure, to invent variations on it. The harder the Broad or UC try to enforce rigorous patent terms, the more they encourage researchers to invent around their patents. The more they tighten their grip, the sooner the money will slip through their hands.
This raises the more fundamental question of why the CRISPR patent fight is happening at all. Like many people, I initially thought the UC and the Broad would settle their patent dispute quickly. Each would take a certain percent of the royalties for their combined patents and be happy — not least because they would avoid tens of millions of dollars of expense, months of distraction for their researchers, and years of uncertainty. If one of the institutions involved were a novice in technology licensing, then it might get greedy and seek a complete victory, but neither the UC system nor the Broad (and certainly not the Broad’s owners, Harvard and MIT) are novices. They have some of the most experienced and sophisticated technology licensing offices in the world.
So why are they spending so much money on this fight? It might, in part, relate to the Nobel Prize. If Lander really wants to bolster Feng Zhang’s case for winning a CRISPR Nobel Prize, then he may think that having Feng win some or all of the patents will be helpful. That seems a bit far-fetched, and yet it could be one factor in the Broad’s litigation strategy. If so, it is not clear whether it will succeed, even if the Broad patents eventually sweep the field. The Nobel Prize decision-makers need not follow the patent office of any country.
In the end, the history, the prizes, and the patents don’t really matter. The structure of DNA would have been discovered without Watson and Crick, and CRISPR did not require Doudna and Charpentier (or Zhang). The discoveries, not those who make them, are important — and those discoveries are only important as they affect people. CRISPR heralds a new era of massively increased human control over life, one that will affect every person on Earth, directly or indirectly, and much of the rest of our planet’s biosphere. If humans are to have any chance of harnessing its benefits, avoiding its risks, and using it in ways consistent with our values and cultures, then we all — not just the scientists, ethicists, and patent lawyers — need to understand something about CRISPR and its implications. A Crack in Creation is a great place to start.
In the interest of full disclosure, the author has met, been on panels with, and likes Doudna, Charpentier, Zhang, Church, and many of the other scientists discussed in the review. He also has lectured the last three summers in a CRISPR program held by the Innovative Genomics Institute at UC Berkeley for modest honoraria.
Henry T. Greely is a professor of Law, and professor by courtesy of Genetics, at Stanford University, where he directs its Center for Law and the Biosciences and Program in Neuroscience and Society. He is an expert on the ethical, legal, and social implications of advances in the biosciences.
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