Caveat Editor: Competing Takes on CRISPR
By John DupréMay 20, 2021
The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race by Walter Isaacson
Editing Mankind: Humanity in the Age of CRISPR and Gene Editing by Kevin Davies
CRISPR People: The Science and Ethics of Editing Humans by Henry T. Greely
The Mutant Project: Inside the Global Race to Genetically Modify Humans by Eben Kirksey
In 1986, a Japanese PhD student, Yoshizumi Ishino, discovered an unusual feature in the genome of an E. coli bacterium. This consisted of a series of identical palindromic sequences, interspersed with apparently normal sequences of DNA, that came to be known as spacers. He offered no theory of what these might be for. A few years later, similar sequences were noted by a Spanish microbiology graduate student, Francisco Mojica. It is to Mojica that we owe the acronym CRISPR, for Clustered Regularly Interspersed Short Palindromic Repeats. In 2003, Mojica came up with the hypothesis, now universally accepted, that these CRISPR sequences were a bacterial immune system, devices for counteracting the viruses, or phages, that attack them. The spacers carried records of genetic sequences from previous encounters with phages and could be used to identify and destroy phages encountered in the future by the bacterium or its descendants.
The story of CRISPR then gathers momentum. Yogurt is made by bacteria that process milk, and it is very bad for yogurt manufacturers if their bacteria are attacked by phages. Two scientists working for the Danish company Danisco that makes starter cultures for yogurt manufacturing, Rodolphe Barrangou and Philippe Horvath, discovered that they could write their own spacers, and create CRISPR-based immunity against particular phages for their bacteria. They also established the importance of the Cas (CRISPR associated) enzymes in the functioning of this immune system. This work led to a successful patent application in 2005 and an article in Science in 2007. At this point, the main focus of the story moves to the United States, with an important subplot for peripatetic European biologist Emmanuelle Charpentier. The structure and mechanism of action of the Cas molecules is increasingly well understood. Interest grew rapidly in the potential for adapting the bacterial defense system into a method for making targeted alterations in the DNA of any organism. In 2020, Charpentier and the American structural biochemist Jennifer Doudna received the Nobel Prize in Chemistry “for the development of a method for gene editing,” CRISPR.
CRISPR, or CRISPR-Cas9 as the most widely used version is known, is not the first technology for making targeted changes in the genomes of living organisms, but it is generally considered to be the best, and is certainly the simplest and least expensive to implement. Over the last 10 years or so, it has become a staple of just about any laboratory anywhere doing research in genetics, molecular biology, and a cluster of related branches of biology; and applications to medicine, most obviously the treatment of genetic disease, are beginning to emerge. Although it is a small part of the current scientific work involving CRISPR, the most widely discussed and controversial potential application is to so-called human germline editing, changes to the human genome that have the potential to be transmitted indefinitely to future generations. A notorious attempt to apply a potentially heritable CRISPR-mediated genome modification to humans culminated in October 2018, when twin girls named Lulu and Nana were born in China.
Lulu and Nana were, as far as we know, the first humans to be born with their genomes deliberately modified or “edited,” specifically by alterations to a gene thought to increase resistance to HIV. The scientist mainly responsible, He Jiankui, appears to have thought that this was an epoch-making scientific achievement, bringing glory to Chinese science and perhaps a Nobel Prize for himself. He was mistaken. His work was almost uniformly condemned both by the international scientific community and by the Chinese authorities. He is currently serving a three-year jail sentence in China for his efforts. For all the books here discussed, He’s adventure is a pivotal event. As they illustrate, the story of CRISPR has now become inextricably entangled in public discussion with his exploits. It is worth repeating, however, that human germline editing, or human gene editing, is likely to remain a fairly small part of the impact of CRISPR on science and even, in view of the likelihood of increasing genetic alterations to the plants and animals we cultivate, its impact on human life.
Two books that tell the story of CRISPR, Walter Isaacson’s The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race and Kevin Davies’s Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing, have a fair amount in common. Both recount the main events that led to the development of the technology for which Doudna and Charpentier received the Nobel Prize, and do so in easily flowing and accessible prose. Davies is better at the precise scientific detail, but pays a price in accessibility with a moderate density of technical acronyms. Both books would serve, at a pinch, as doorstops. But the ways the CRISPR story is framed are rather different. Davies’s approach is fairly straightforward: it is, as it says on the cover, about editing the human genome. Isaacson takes a rather different approach.
The first thing to say about The Code Breaker is that it would be hard to exaggerate the inappropriateness of its title. First, there is no code in the story. The only relation that can sensibly be called a code in biology, in the sense of an ultimately arbitrary connection between a sign and a thing signified, is that relating particular trios of DNA nucleotides (“codons”) to amino acids, and this was “broken” in the 1960s. Second, the definite article implies that one person “broke the code,” presumably Doudna. But as the actual narrative makes clear, this was a process of discovery or invention to which numerous people made essential contributions. Without wishing to demean Doudna, who is undoubtedly an exceptionally talented scientist, even if there had been a code, there would have been no one code breaker. As Isaacson explains in considerable detail, the allocation of credit for the CRISPR gene-editing technology has been and still is bitterly debated. The book is, at least, about gene editing, but it has little or nothing to tell us about the future of the human race. I suppose that if the human race were somehow to be an entity reducible to its genetics, its future might be thought to lie in CRISPR or, more likely a successor technology for gene editing. But it isn’t, so it doesn’t.
Isaacson tells his story engagingly enough, and his book provides a good account of who the most prominent players in the story were, what their contributions were, and often there is a thumbnail sketch of the characters themselves. (Many of the characters are described as nerds or nerdy; George Church “looks like, and actually is, both a gentle giant and a mad scientist”; Charpentier is “charmante,” displaying “an alluring mix of mystery and Parisian insouciance”; both Charpentier and Doudna have “warm smiles that made their protective shells almost, but not totally, invisible.”) And though there is enough here to see that Doudna would be a fine subject for a biography, this isn’t it. Inevitably, given the multiple and contested contributions to the science, the narrative seems partial.
Isaacson is known for biographies of Leonardo Da Vinci, Albert Einstein, Steve Jobs, and Henry Kissinger, so perhaps he is strongly disposed to think that a story needs a hero, or at least an antihero. But as his own telling of it makes clear, there is no clear hero to this story. It is true that Doudna, together with Charpentier, did eventually receive the Nobel Prize (Isaacson’s is the only book here discussed written after this was known); but it is equally clear that this result was in dispute and a matter of serious negotiation at the pivotal moments in the story. Apart from the scientists involved in the early stages of the history already mentioned, possible candidates for the award included Lithuanian scientist Virginijus Šikšnys, George Church at Harvard, and Feng Zhang at MIT, among others. As Kevin Davies predicts in Editing Humanity, published on October 6, 2020, the day before the Nobel Prize for Doudna and Charpentier was announced, if it had been the prize for physiology or medicine rather than for chemistry, it would probably have gone to Church and Zhang.
What ended up as decisive in the race for the Nobel Prize was the publication in the prestigious journal Science of a paper on which Doudna and Charpentier were the senior authors. Despite its rather unexciting title — “A Programmable Dual-RNA–guided DNA Endonuclease in Adaptive Bacterial Immunity” — the final sentence of the abstract gave away its potential significance: “Our study […] highlights the potential to exploit the system for RNA-programmable genome editing.” The prize was awarded “for the development of a method for genome editing.” Many people made essential contributions to this development, but the Science paper, arguably and much argued, provided the last pieces needed to make the technology work.
It is perhaps unsurprising that the heroic genre permeates Isaacson’s account and, to a slightly lesser extent, Davies’s. Much of the story is indeed a battle for fame, glory, and cash, even when it is a slightly incongruous battle among heroic nerds. This warfare is by no means entirely made up. There really are enormous prizes. The Nobel is the most desired if not the richest of the big prizes, and the determination of who among a number of possible candidates will receive it is a major theme of Breaking the Code. Doudna and Charpentier appear on occasion quite exhausted by the circuit of prize collection. Furious races to publish results first in Nature or Science are often seen as essential for staking claims to prizes and intellectual property. And almost every scientist mentioned in the story has a few companies set up, often funded by billionaire investors, to use the intellectual property created by their research. It is no surprise that a bitter battle and many lawsuits were involved in the decision as to who had the rights to the intellectual property in the CRISPR process.
Though this titanic struggle makes a good story, it does tend to occlude the massive cooperation involved in scientific advances. Neither Isaacson’s nor Davies’s book is about the sociology of science, and it is fair enough to tell their story in terms of the actions of those in control. But for the army of postdocs and PhD students who do most of the hard and very unglamorous labor of scientific research, the main struggle is with an exploitative system in which big prizes are remote and improbable. It is occasionally jarring when little glimpses of this soft underbelly appear. In Breaking the Code, one might reflect on the gulf between the “young geniuses” on their way up in the Harvard Department of Molecular Biology, and the researchers in Charpentier’s lab in Vienna who declined to assist in a project she needed help with and who were “lost to history.”
The competitive aspect of science is not in dispute, and it is no doubt sometimes true, as Isaacson begins a chapter entitled “The Race,” that “competition drives discovery.” Whether, as he says on the same page, “[c]ompetition gets a bad rap,” I am less sure. One thing we should certainly ask when assessing a competitive activity is what the rules are and who makes them. The game that Isaacson describes is clearly delineated in the CRISPR story. While much of the basic scientific research is funded publicly, or at least by universities, a primary objective is to acquire valuable intellectual property, which accrues to universities with a cut for the researchers. The latter, in turn, are expected to set up companies, funded by private capital. As Kevin Davies reports in Editing Humanity, the first successful therapeutic application of CRISPR approved in the US, to treat a genetic disorder that causes degeneration of the retina, attracted a price tag of $425,000 per eye. Unsurprisingly, this payoff caught the eye of Big Pharma, and the company that developed the treatment was bought by Roche for $4.3 billion. This is the ultimate goal of the start-up companies that are part of the portfolio of a successful biologist.
Isaacson is enthusiastic about the arrangement. In describing Doudna’s first start-up, Caribou Biosciences (currently estimated to be worth somewhere in the low hundreds of millions of dollars), he suggests that as well as being a poster child for free-market capitalism it owes its success to a distinctively American arrangement of factors, traceable to the famous postwar inspiration of Vannevar Bush. This may all be true, but whether this should be seen as entirely successful in a wider frame is open to debate. Isaacson is very likely right in thinking that the scientists are motivated more by intellectual curiosity than money, but it is still unlikely that these rules of the game produce an optimal allocation of scientific effort. The prizes are awarded by the billionaires who fund the start-up companies (and often the prizes) and by the Big Pharma corporations who buy the successful companies. The priorities of the former are at least unpredictable; those of the latter not so much.
Having taken the story through the crucial publications on genome editing and the vicious — and still ongoing — battles over the related patents, The Code Breaker ranges over developing therapies, ethical debates, He Jiankui’s notorious experiments, and possible applications of CRISPR to the COVID-19 pandemic. Unsurprisingly, given the range of topics, Doudna’s role in the story becomes ever smaller, though she generally makes an appearance at the end of each section, in chapters with titles such as “Doudna Steps In” and “Doudna Pays a Visit.” Although, as I should perhaps repeat, I mean no disrespect to Jennifer Doudna, the incoherence of the book’s overall conception makes these sections of the book increasingly unsatisfying. There is plenty of information here, but most of these later topics are treated in more depth elsewhere.
Davies’s Editing Humanity has a more coherent topic — more or less what it says on the cover — though the story is not told in a strictly linear fashion. The first 100 pages tell pretty much the same CRISPR story as Isaacson with a little more scientific detail and a little less glorification of the competitive individualism. The story is about as clearly presented as the level of scientific detail allows and it is certainly better for avoiding the Procrustean transformation into a biography.
Whereas Isaacson does provide a little historical background through his biographical lens, there is not much specifically about the history of gene-editing. Davies, on the other hand, does provide a useful account of the history of this topic. While CRISPR has made gene-editing famous, as with anything interesting in science it could not have happened without a lot before it. Davies gives a nice account of early attempts at gene therapy, culminating in the disastrous and fatal treatment of Jesse Gelsinger for a rare genetic disorder with a recombinant adenovirus, an event that halted attempts at gene therapy for many years. He also describes the earlier editing technologies, known as zinc fingers (a feature of a protein that can be designed to bond to a particular DNA sequence), and TALENs (transcription activator-like effector nucleases). Both techniques are still used for some purposes today, though increasingly they are being displaced by CRISPR.
Davies then provides a quite detailed discussion of the He Jiankui affair. He was born in 1984 in a small village in Hunan Province in the South of China, the son of farmers. (Isaacson, in a briefer account, notes that this background “instilled in him a hunger for success and fame.”) His exceptional academic aptitude earned him a place at the highly competitive University of Science and Technology of China (USTC) in Hefei. USTC, Davies tells us, is also interpreted to mean “United States Training Center,” and He duly won a PhD position in bioengineering at Rice University. He then moved to Stanford to take up a postdoc with the biophysicist Stephen Quake, also “the entrepreneurial co-founder of a string of biotech companies.” Finally moving back to the Southern University of Science and Technology (SUSTech) in Shenzhen, a rapidly growing city already famous for the world’s premier genome sequencing institute, the Beijing Genomics Institute. (Eben Kirksey tells us that despite being a university on the cutting edge of biotechnology, He’s campus lacked drinkable running water.) With a hotly debated degree of collaboration with his American colleagues, he eventually launched the fateful project of editing the genomes of human babies.
He’s human genome editing work has been widely condemned. One major problem was the gene that He chose to edit, a gene known as CCR5, an allele of which appears to give some resistance to HIV infection. The volunteers in He’s project were couples in which the father was HIV positive. The trouble with this choice is that there already exists a technique, “sperm washing,” which in conjunction with in vitro fertilisation can prevent the transmission of HIV. Moreover, since the babies were not born with HIV, the editing was not the treatment of a disease but the addition of resistance to a disease, which is arguably enhancement rather than therapy. Questions were raised as to whether fully informed consent had been obtained by the parents. And it seems that the science was not well executed in various ways. Most notably, the editing did not appear to have come out quite as intended and, given this, the pregnancies should surely not have been allowed to go ahead.
For these reasons, He’s work was immediately criticized and his meteoric professional ascent moved into an equally rapid descent. There is little doubt that the criticisms just mentioned are legitimate, but I don’t think they really get to the heart of what was going on in this affair. A badly conceived and executed scientific experiment is not usually an international cause célèbre. Much of the explanation of the furor is usually provided in terms of the exceptional status of human germline editing. But before considering that, it is worth mentioning another factor.
I noted that there were a number of US scientists connected with He’s work, but only one, his supervisor at Rice, Michael Deem, seems to have been brought down with He. Yet it is clear in Davies’s account that even if they may have advised against the final disastrous execution of He’s work, several, perhaps dozens, were generally supportive colleagues and business partners. It is hard to escape the conclusion, explicitly advanced by some of the scientists involved, that the driving fear was that the premature attempt to apply germline editing to humans might put a stop to the whole project, as the Jesse Gelsinger case had done for an earlier generation of gene therapists. Hence the systematic distancing from He both in the United States and in China.
But is there really anything so special about human germline editing? Henry Greely’s book CRISPR People: The Science and Ethics of Editing Humans is explicitly focused on the He affair. Greely offers a good account of what CRISPR is and does, and a detailed account of the circumstances surrounding He’s experiments, though admitting at the outset that we still don’t know exactly what He did. Whatever He did, Greely doesn’t like it. Greely thinks He’s experiments were “criminally reckless,” and “grossly premature, and deeply unethical.” He was “a rogue scientist.” And he quotes many scientists saying the same thing. Greely thinks that He was endangering the lives and well-being of Nana and Lulu, which is certainly bad, but perhaps not so bad that it deserves a book. After all, as far as we know the girls are still perfectly well and given the robustness of the human genome they may very well stay that way. This is hardly egregious in the annals of human life endangerment.
So why does Greely have such a visceral reaction to He’s work? The puzzle gets deeper. Early in CRISPR People, Greely distinguishes germline editing from somatic editing, noting that public concerns are overwhelmingly directed to the former and that while the latter is likely to be the main actual application of CRISPR technology, his concern will for this reason be with the germline. One oddity in this position is that it is sometimes argued that germline editing is much safer. Germline editing typically involves manipulation of one cell, the sperm or egg, and allows in principle a complete check on whether the edit has been successful and whether there have been other unwanted changes. Somatic editing, on the other hand, affects billions or trillions of cells with no such check possible. Mosaicism, or different effects on different sets of genes, is likely, and damaging (e.g., carcinogenic) changes somewhere in the system are impossible to rule out.
But apart from the more or less serious dangers to the resulting persons, what is so bad about editing the germline? If I cure a horrible disease, say Huntington’s, in a person, is it not an additional benefit that I also prevent the disease in that person’s descendants? The problem, I suspect, is that we are easily led into thinking of genetic matters in a grossly exaggerated way. Unless I am a latter-day Genghis Khan, my descendants will be modest in number and I should be delighted if they lack a disease from which I suffer. And this is where hyperbole, such as Isaacson’s “future of the human race,” is unfortunate. And while in a mood to criticize titles, I must say also that Davies’s Editing Humanity would have been much better titled Editing Humans.
The irony is that unlike, apparently, Isaacson and Davies, Greely is well aware of the problematic status of the concept of the human germline. Much public concern about the human germline is tied in with naïve and simplistic views of the function of genes. Isaacson attributes to Watson and Crick the discovery that “instructions for building every cell in every form of life were encoded by the four-letter sequences of DNA,” and Davies believes that we will reach “into the genetic fabric in a human embryo to rewrite the book of life.” This is, not to put too fine a point on it, nonsense. There is no book of life to be read or rewritten, and there are no instructions of the kind Isaacson imagines. Greely explains clearly enough why this is so in the final part of his book. Contrary to the widespread notion that “The Human Germline Genome” is the common property of humanity, the essence of our species, and thus must be kept inviolate, Greely correctly observes that there is no such thing.
In reality, every human has a somewhat different genome, and every one of these is changing slightly over time. Human actions, from interaction with radioactive materials to choices of mating partners, are constantly changing human genomes. The reason that neither the imaginary universal human genome, nor the actual genomes of real people have inscribed within them the precise physiology or destiny of the individual is that the genome is only one of a dynamic set of factors that interact in the development of the human individual. The environment, including everything from the chemical background of the cytoplasm to the social status of the parents, has an equally crucial role. The causal upshot of a particular gene, far from being a fact in the book of life, is generally a function of these other factors, as well as of what other variants are present in that particular genome. And, finally, the genome is constantly being modified in the course of human life by “epigenetic” changes that affect what genes are expressed and when. These complex and dynamic interactions also explain why most modifications to the genome don’t do anything at all. The system is extremely robust.
Greely usefully distinguishes three kinds of cases that might be targets for genome modification. The first is by far the least problematic: the editing out of genes that cause disease. These are Mendelian genetic diseases (that is, the gene is a necessary and sufficient cause of the disease) and generally involve mutations that disable the function of an important gene. There are two concerns here. One is the question of what is disease rather than merely a variation and the concomitant worry that defining something as a curable disease can be bad for living people with that genetic condition. Paradigms are trisomy 21, or Down syndrome, and achondroplasia, or dwarfism. What are the consequences for people with these conditions of defining them as preventable diseases rather than natural variations? But no one, as far as I know, would object to removing Huntington’s disease, which causes fatal neurodegeneration, generally in middle age, from the gene pool. Another concern is that in most cases a medical solution already exists: in vitro fertilization combined with preimplantation genetic diagnosis allow the parents to select an embryo not affected with the defective gene. This is far from an ideal treatment, however, and Greely predicts that in the medium term it will be superseded by genome editing. This seems plausible provided that, in a world with many unwanted children, genetic parenthood continues to be seen as something deserving expensive technologies.
The second category, exemplified by the CCR5 gene targeted by He, is the editing in of variations that prevent, or reduce the probability, of disease. An immediate problem here, as instantiated by He’s patients, is that since no actual disease is being treated this is naturally interpreted as enhancement rather than therapy, and this is generally seen as far more problematic. The distinction between therapy and enhancement, however, is widely recognized as being difficult to draw. A more straightforward problem is that generally the genes in question are not Mendelian. Most inheritance is polygenic and pleiotropic. That means that the trait depends on numerous genes (polygeny) as well as environmental factors, and these genes affect many traits (pleiotropy). Polygeny implies that a single edit will not reliably prevent the disease, and pleiotropy, more worryingly, implies that there are always likely to be other effects. Since these consequences are often dependent on a wide variety of genetic and environmental conditions, a great deal of work is needed to establish the safety and efficacy of such a treatment, adding to the cost of what is never likely to be an inexpensive procedure.
The final category is that of pure enhancement. Here, finally, we meet the elephant in the room, the imagined “designer baby” that underlies a great deal of the horror invoked by genetic modification or, for some transhumanists, a utopian future. Two dystopian scenarios can be discerned. First is the homogeneous and dreary world in which everyone has the same “best” genes and all the variety of human life is lost. Slightly more realistic is the brave new world in which the wealthy elite optimize their offspring to the point that they barely belong to the same species as the less fortunate underclass.
Two points are crucial to evaluating these fears. First, the technical problems mentioned for the second category become greater the further we move from Mendelian disease toward normal development. Hence, as Greely notes, there are no, or almost no, clearly enhancing genes, and the pervasiveness of polygeny and pleiotropy make it likely that this will remain the case. Relatively trivial physiological features may be alterable through genetic editing, but the kinds of changes imagined in both utopian and dystopian visions of designer babies are impossible. A trait such as intelligence (in so far as it is even a well-defined trait) is affected by many hundreds of genes. Each of these is likely to affect, in turn, many other traits. The human organism is a massively integrated system, not a bundle of discrete traits.
But the even more important point that is inadequately stressed in so much of this discussion is that we already know very well how to enhance the development of children. Diet, exercise, and above all education are almost uniformly effective in producing healthier, happier, and more fulfilled humans. The disgrace that so many of our governments fail to provide many or most of their children with these fundamental conditions for optimal development is only obscured by fantasies of technological interventions in a mythical all-powerful genome.
But this is not, I suspect, why Greely thinks He Jiankui’s career “needs to be ruined […] for a long, long time.” The point on which his book ends is with the absolute imperative for public consent before human germline editing is permitted. Why is this so crucial if concerns about designer babies are fantasies, at least for the next century or two? Like many of the scientists quoted in all these books, the reasonable speculation is again that Greely’s main objection to He is that acting ahead of this democratic consent is likely to impede progress in the development of the technology. My basis for this speculation is that while many people would claim that public consent was essential because the issue — human germline editing — is so fundamental, Greely seems to understand that it is not only not fundamental, but not even coherent. And no great question of public consent is required to allow the cleaning up of badly executed and badly conceived science.
All the books so far discussed are well informed and informative about the CRISPR technology, its history, some of its potential applications, and some of their problems. But for more insight into the bigger picture, I recommend anthropologist Eben Kirksey’s The Mutant Project: Inside the Global Race to Genetically Modify Humans. This book is also focused primarily on He Jiankui but is also far from a linear narrative. Interwoven with the story of He are a diverse set of perspectives on the wider phenomenon of gene editing.
Kirksey attended the First International Summit on Human Genome Editing in Washington in 2015 (the Hong Kong conference at which He presented his results was the second). There he reports on a talk by a corporate lobbyist concerned to make sure that “there is no legislative or regulatory action that is going to hinder or delay or set back part of the field.” Meanwhile four start-ups — including Doudna’s Caribou Biosciences, Church’s and Zhang’s Editas Medicine, and two others closely connected with the scientific protagonists of the CRISPR story — have just raised $158 million in venture capital. Weeks before, Vertex Pharmaceuticals had announced a $2.6 billion dollar bet on CRISPR Therapeutics, the founders of which also include Charpentier and Doudna. Whatever the excellent motives of the scientists involved in the CRISPR story, Kirksey is interested in exploring who is ultimately pulling the strings.
Kirksey introduces us to a wide range of interested parties in the genetic modification world including individual “garage” biohackers, biotech entrepreneurs, and the usual cast of scientists. While at the Washington conference, he stays with a biohacker interested in mutant organisms, possibly including humans, as art. In a chapter on the racialized aspects of genome editing ambitions, he reports on the interest in aesthetic modifications aimed at eye or skin color, or eye shape. Unlike intelligence or height, these are sufficiently trivial physiological features that they may be affected by near-Mendelian genes and thus realistically open to a degree of genetic modification. While discussing these ambitions, Kirksey frequently reminds us that the enterprises involved in pursuing these goals are often set in countries where much of the population has little access to even basic health care.
One of the more striking differentiating features of Kirksey’s book is that he actually shows a serious interest in who He Jiankui is, and how his notorious behavior is to be understood. Kirksey visits the village in China where He grew up, finding it largely abandoned as the population, including He’s parents, have moved to the cities. He’s first exposure to modern medicine is a mass vaccination in elementary school where all the children were injected with the same needle, a practice responsible for some major HIV clusters — and perhaps relevant to better understanding He’s interest in resistance to this highly stigmatized illness. Kirksey identifies Stanford, where He’s advisor Stephen Quake had 10 start-ups, worth at their peak more than $1.5 billion, as the place where He brought science and capitalism together.
Kirksey follows He to Shenzhen, identifying it as the place where the American entrepreneurial style of science has been most firmly established in China, and SUSTech, whose founding president, Qingshi Zhu, had been recruited from Stanford. But while Zhu, Kirksey tells us, was a “thoughtful Buddhist” who doubted whether technology would make people happy, in 2015 the university appointed a new president Shiyi Chen, with a rather different style. Chen encouraged his faculty to imitate an “opportunistic race car driver […] using whatever maneuvers were necessary” or “like an insane card player who follows no logic or rules” so the competition doesn’t know what to expect. This background makes it easy to understand how He might have come to believe that he should take short cuts, and perhaps provides a more plausible explanation of his actions than the “hunger for success and fame” consequent on his upbringing in rural China.
Perhaps the psychopathological explanation of He Jiankui is ultimately of little importance. But what Kirksey does make clear and that none of the other books here reviewed really does, despite frequent allusions, is the extent to which biomedical science, especially but not exclusively in the United States, cannot be understood as merely a scientific pursuit of better health, but as a system inextricably intertwined with Big Pharma and Big Capital. Isaacson does perhaps understand this, but applauds it. Davies and Greely, in different ways, tend to steer carefully round it. The CRISPR story is a story of great scientific discovery and innovation, but the exact path it has taken has been driven as much by pursuit of profit as by either where the science leads or where the greatest human benefit lies. There are no doubt some people whose lives have been positively transformed by the availability of Zolgensma, a gene therapy for treating infants with spinal muscular atrophy, and priced at $2.1 million a dose. But when 400,000 people per year are dying of malaria, a disease that can be prevented, diagnosed, or treated for a few dollars per case, the development of million dollar therapies does seem concerning. Of course, the hope is that gene therapies will become cheap and available, and that the astronomically expensive treatment of the present will lead to cheap and routine procedures in the future. And this may be so. There are relatively common genetic diseases, notably sickle cell disease, and it may be that inexpensive treatments for rare genetic diseases will also, eventually become cheap (though it is unlikely that reproductive genetic medicine ever will). My point is not that CRISPR technology is an intrinsically bad thing, even the part of it that is concerned with the human germline, but that it is taking place in an intrinsically problematic system. He is not just a rogue scientist, but a symptom of this system pathology.
Let me offer one more illustration of the imbalance just suggested. Both Isaacson and Davies make much of the “war” between viruses (or phages) and bacteria. Isaacson describes this, rather extravagantly, as “the most massive and vicious war on this planet.” For Davies, it is “the most important arms race on the planet […] between two implacable enemies, the nuclear superpowers of the microbial world.” There is a more important point than these fanciful metaphors. At a time when one of the greatest threats to human health is the emergence of antibiotic resistant bacteria, why is nature’s way of killing bacteria of so much less medical interest than nature’s way of killing viruses, the latter repurposed as a clever way of fiddling about with our genomes? (On Google Scholar “gene therapy” generates about three million hits, “phage therapy” about 200,000.)
Using phages to treat bacterial infections is a well-established practice, but mainly only in Georgia and Russia. Occasional stories of successful treatment of antibiotic resistant bacterial infections with phages filter into the press, but there seems to be little interest in the West in developing this therapy. Of course, there are potential obstacles. But the decisive one may very well be that the development of phage therapy is of little interest to Big Pharma. Phages are highly specific to particular strains and a successful program of phage therapy will require a substantial library of phages. There is no equivalent of the blockbuster drug. It may well be that the way to pursue phage therapy is rather through training of people, as for surgery, rather than development of products. Moreover, both because there are obstacles to patenting a natural object and more crucially because phage therapy has existed for a long time, it would be difficult to patent a phage therapy. Indeed, even antibiotics are notoriously of limited interest to these multinational corporations, as the patient recovers and does not require further product. This would also be true of phages. The ideal drug is a lifetime habit. In short, for the people who pay for much of biomedical science, phage therapy is a threat rather than an opportunity.
Let me conclude by repeating that CRISPR is a wonderful technology and is transforming large parts of the life sciences. However, understanding its significance faces major obstacles. First, even among scientists and capable science journalists, gene fetishism is alive and well. Talk of books of life or the human blueprint are not just harmless ornamentation of the scientific facts. Ironically, indeed, it is just the scientists’ insistence on talking this way that has created the public horror at editing “the human germline.” There is a risk of harming individual developing humans that should be taken as seriously as anywhere else in medicine. But images of a future race of radically reinvented organisms are fanciful whether promoted by transhumanists blissfully innocent of genetic knowledge or biologists who should know better. And science is a wonderful thing, but it is not all wonderful. Its entanglement with global capitalism is a sometimes murky business, and raises ethical issues more far reaching even than the details of patient consent or the individual weighing of cost and benefit. All of these books have important information and insights to offer on the history and significance of CRISPR and none is completely successful in finding the right path through this very difficult terrain. But given my view that the least understood and most important aspect of the topic, at least as regards applications to human health and reproduction, is who is driving, if you read only one, I recommend Kirksey’s The Mutant Project.
John Dupré is professor of the Philosophy of Science, University of Exeter and director of Egenis, The Centre for the Study of Life Sciences, which he founded in 2002.
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