Abstract
There are 2 types of crisper. One is the useless thing at the bottom of my refrigerator that freezes lettuce with annoying unpredictability. The other is the CRISPR of CRISPR/cas systems, a central component of acquired immunity in archaea and bacteria. The exploitation of
Likely impacts of CRISPR on veterinary medicine are exemplified by recent papers on CD163-null pigs, which were developed for resistance to PRRSV. Other genetically modified species are in the pipeline, some with the goal of establishing patented animals resistant to infectious disease. The ease, precision, cost-effectiveness, and programmable nature of CRISPR has largely supplanted older, expensive, and technically more demanding gene-editing approaches such as ZFN and TALEN.
The book under review is the first one on CRISPR to be aimed at a general audience. It was written to explain the technology and its medical and ethical ramifications. One of its 2 authors, Dr. Jenifer Doudna, heads a UC Berkley laboratory that reported several seminal breakthroughs on CRISPR. The second author is one of her former PhD students, although the book is in Doudna’s voice. A paper she co-authored in 2012 is generally accepted as the first to propose one CRISPR system (CRISPR/Cas9) as a versatile RNA-directed laboratory approach to create double-stranded DNA breaks for subsequent editing. In addition to her day job, Doudna is visible in the media, academic-government fora, and venues such as TED talks. It is useful this early in the game to have a personal account of CRISPR’s research and commercial applications.
I winced at the title and the book’s occasionally breathless tone. As a veterinarian who deals with spontaneous disease in animals, it was difficult to control my eyebrows at statements such as ‘I sometimes can’t help but view the work being done with plants and animals as a sort of dry run for the ultimate goal of gene editing…the dream that, someday, our work would help rewrite the DNA in human patients to cure disease’. While fond of my species—it depends on the day—I question whether humans and their mortal ills should be at the core of genetic biotechnology. But CRISPR will take its place as a useful medical tool, alongside cloned genes, whole genome sequencing, recombinant proteins, and PCR. As a colleague remarked recently, CRISPR does not come with the understanding of biology required to use it sensibly and without unintended consequences.
The book focuses on human medicine, ethical issues that attend editing DNA in germline cells, and using CRISPR with gene drives to target “unwanted species” for extinction. The CRISPR literature has become vast in the wake of key papers published in 2012 and 2013. As the book makes clear, much current research addresses editing natural genetic mutations in germline and somatic human cells. Multiple startup companies, including Doudna’s, have raised >$1B in venture capital. Investors and financial magazines now pay close attention. In 2013, Forbes Magazine published an article about CRISPR-cas, titled This Protein Could Change Biotech Forever. Hype, yet probably accurate.
Although gene editing, human disease, and ethical worries are at the book’s core, impacts on animals and agriculture are addressed. A series of studies demonstrated the ease with which CRISPR-Cas9 can be used to create novel strains of mice and other laboratory species to serve as models for inherited and infectious disease.
The book is short and well-written, with a personable tone. Key papers in the CRISPR-cas field are cited and explained, there is a useful index, and the personalities of several key researchers are sketched. If, like me, you are intimidated by the CRISPR literature, the book offers an accessible portal to its applications and proximate concerns about their use. Cartoon-like line drawings illustrate basic principles. The first part of the book explains how CRISPR was explored and exploited (The Tool). The second half (The Task) focuses on ethical pitfalls, and technical issues such as DNA non-target breaks.
A common sin of reviewers is to complain a book failed to anticipate their specific interests. I will commit that sin here. Doudna highlights perils and promises attending this “new age…of biological mastery.” As explained in the introduction, she does not intend it to be a rigorous history of CRISPR. Yet there are surprising elisions and omissions. There has been a bitter legal fight over patent rights between UC Berkeley (Doudna’s institution) and the Howard Hughes Medical Institute on one hand, and the Broad Institute, a Harvard-MIT consortium, on the other. Currently, the Broad is “winning.” The issue hovers in the book’s background, barely touched, I assume on the advice of patent lawyers. The institutions cannot agree on intellectual stepping stones leading to landmark advances in 2012 and 2013. The head of the Broad recently wrote one account, eliciting a withering response from one of Doudna’s colleagues about how credit should be assigned. In the United States, the use of federal funds to generate patents for personal and institutional enrichment is largely a consequence of the Bayh-Dole Act (P.L. 96-517, Patent and Trademark Act Amendments of 1980), and 2 subsequent amendments. Bayh-Dole ensures that technical advances made in part on the public’s dime are more likely to make it to market. It would have been interesting to hear Doudna’s take on Bayh-Dole and CRISPR. Its fairness in directing benefits to some researchers who lay the final bricks on the wall, rather than pioneers who did the initial trowel work, merits at least a paragraph. Other accounts, often in commentary or news sections of Nature, Cell, or Science, give a sense of how advances like CRISPR are created in part through public funds and then privatized.
When I read statements that new gene-editing tools demonstrate “supreme mastery” over genetic material in living cells, I shudder. Nonchalant quotes from others are less than reassuring about potential impacts of using CRISPR to eliminate inconvenient species: “If we eradicated [mosquitos] tomorrow, the ecosystem where they are active will hiccup and get on with life.” Yet this is an accessible, timely, well-written, thought-provoking book. Sooner rather than later, veterinary diagnosticians will be presented with samples from animals and medical products in which CRISPR-mediated gene editing was used. We may help answer the question: did we get it right?