Book Review: A Crack in Creation by Jennifer Doudna and Samuel Sternberg

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Shortly after I finished reading Jennifer Doudna and Samuel Sternberg’s book on the development of the CRISPR gene editing technology, CRISPR was leading the news headlines. Shoukhrat Mitalipov and his international team announced their successful and efficient correction of a mutant MYBPC3 gene which causes the condition hypertropic cardiomyopathy, the cause of many of the sudden heart attacks in young people, in non-viable human embryos.  Though it took some time for the news stories to use the word “CRISPR”, as it is not yet a household name, the news sparked many opinion pieces warning of  a slippery slop, down which we will be lead to “designer babies”. But these are the same arguments we have been having since the dawn of the recombinant DNA era in the 1970s, with little reconsideration in light of the actual facts of how the technology and the  human genome works. What I found lacking in these analyses was a thorough understanding of the actual scope and limits of CRISPR gene editing technology. Gladly, A Crack in Creation offers such a nuanced background straight from those deeply embedded in the science; Jennifer Doudna is one of the scientists leading the development of CRISPR gene editing and Samuel Sternberg started his career as Doudna’s doctoral student.

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Media coverage of the latest CRISPR story, from Eric Topol’s twitter.

The acronym CRISPR stands for the cumbersome phrase  “Clustered Regularly Interspaced Short Palindromic Repeats”. This refers to clustered stretches of base pairs in the genome of bacteria which are the same backwards as they are forwards, with non-repetitive “spacers” between them. Bacteria don’t tend to have superfluous parts to their genome, so researchers before Doudna were prompted to investigate their function. The spacer sequences were found to be derived from viral DNA, and the CRISPR sequences were found to be associated with the Cas proteins, which can cut DNA. With this information, the mechanism was pieced together. When the bacterium is infected with a virus, the cell copies this DNA and inserts it between the palindromic repeats. This acts as a cellular “memory”, so that when the same strain of virus infects the cell, it can transcribe into RNA the “memorised” sequence and use the RNA fragments to guide the Cas9 protein to the viral DNA. Cas9 then cuts the DNA with the characteristic double-strand cut. This allows bacteria to have something like the mammalian innate immune system, but unlike the immune system, CRISPR “immunity” involves infection leading to changes in DNA. This opens up the potential for this system of DNA editing, honed by evolution, to be adapted for human ends.

Doudna and Sternberg place CRISPR in the context of previous gene editing technologies, such as TALENs and zinc finger nucleases, which acted in a similar way to the CRISPR system, and the long history of largely unsuccessful gene therapies. This gives the reader the proper context of gene editing as not a quantum leap but a progression from cruder technologies. CRISPR seems startling only because we are now drawing on nature’s more efficient solutions rather than the fumbling designs of the human hand.

Jennifer Doudna was at the forefront of CRISPR emergence from obscure microbial trick to a potentially powerful tool. She and her colleagues modified Cas9 and produced a simpler guide RNA, allowing CRISPR to be used to alter the DNA of all organisms in which it has been attempted. Alongside their work, Doudna and Sternberg also stepped out from the shadows of academia and onto the public stage. These years of public engagement and consultation with policy makers have allowed Doudna and Sternberg to hone their explanations of the science and to explore the implication with skill, the great strength of the book.

Their main ethical concerns with CRISPR are in regards to its use in germ cells and embryos, as this would alter the genetic constitution of the person and their descendants permanently. Doudna and Sternberg don’t call for rigid ban on this editing in all cases, but would rather scientists refrain from implementing this until the safety and efficacy concerns are addressed and there has been a public conversation on whether we should alter the future of humanity in this manner. Instead, Doudna and Sternberg champion the therapeutic use of CRISPR by editing the DNA of somatic cells. This only alters the DNA of the organ or area treated in the patient, and cannot affect their offspring, and could potential eradicate HIV, hemophilia and similar diseases.

Doudna and Sternbrg do stress throughout the book that the technology is currently imprecise and produces a mosaic of altered and unaffected cells in treated tissues. However, the work done by Mitalipov et al and others show that these challenges are being rapidly overcome. The authors’ reliance on the current inefficiencies of CRISPR technologies to suggesting that it will not be the path to designer babies does lack persuasive power. For the non-specialists seeing seemingly miraculous developments emerge every month now, technical barriers seem only temporary, until the next bit of lab-based magic happens. They give little consideration to the main concerns of those predicting a eugenic future, not just that the genes of embryos may be edited but that they will be altered so as to produce a monoculture of blue-eyed Übermensch. This is unlikely to happen not necessarily due to technological limits, but most importantly due to the extreme ambiguity of human development and gene expression. There is no gene for musical virtuosity, and even a relatively simple trait like eye colour is determined and influence by a myriad of different genetic pathways, perturbations in any of which may or may not alter the outcome. And then there are the environmental influences which can make the difference between the virtuoso and the tone-deaf.

For all of these reasons, gene editing will have a limited impact on the complex traits that cause middle-class parents so much anxiety, but it could have a significant impact on the incidence of traits and diseases with simple or Mendelian genetic causes. CRISPR could never bring about the Übermensch, but if germ cell and embryonic editing occurs, if only in China, for example as there is already the desire to do so, then diseases like Huntington’s, but also deafness and some learning disabilities, could begin to disappear from the population.  CRISPR gene editing of embryos poses questions regarding the diversity of the human gene pool,  whether we can propose to alter it, and if so, what of the limited amount of diversity we can affect do we want to alter?

Stylistically, the book is written in Doudna’s voice, but I gather it was Sternberg’s idea to write it. This gives the work some anchoring in the life of human beings, conveying the collaborative nature of the field as well as the human frailties that lie behind the top-tier publications. The book opens with Doudna’s anxiety dream of being subsumed by a wave, which she suggests symbolises her being overwhelmed by the enormous ethical implications of her work. Later, they recount a far more unsubtle dream in which a pig-faced Hitler asks Doudna to explain the CRISPR technology to him, which needs no explanation. This gives the book an accessible moral sensibility, the ethics are not discussed entirely dispassionately and academically, but from the viewpoint of someone who do not want their work to be used for evil. But the personal slant is limited and Doudna’s emotional responses feel mediated as the book is co-authored, and so lose some of their power. I would have liked to have seen more of the mind of the scientist at work, to understand a real-life Victor Frankenstein, though given how soon after the introduction of CRISPR gene editing the book was written, the first Doudna et al. CRISPR paper was only published in 2012, it is too early to expect a tell-all memoir like Watson’s The Double Helix.

On the whole, A Crack in Creation is a very clear explanation of the science and considered and non-diadactic exploration of associated ethical concerns, inviting the reader to stop and consider the implications in an informed manner rather than being swept up in an ill-informed media furor. And at the very least, it will provide a wealth of material fro Doudna to draw upon when she makes her no-doubt forthcoming Nobel Prize acceptance speech.

 

 

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Book Review: How To Survive a Plague by David France

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My generation are some of the first to grow up with HIV infection as a treatable condition. We only know a world where combination HAART can give those newly infected an undetectable viral load and a nearly normal lifespan, so we largely lack the fear and stigma which surrounded AIDS from its beginning. It is easy for us to think, yes, HIV/AIDS was and is tragic, but the modern treatments are as good as a cure, so it’s no real problem now. But such complacency is wrong.

David France opens How to Survive a Plague with the funeral of Spencer Cox, a member of the AIDS Coalition to Unleash Power (ACT UP) who suggested that HIV researchers test  the drug Crixivan in large simple trials to produce data fast and get the drug on the market. This scene is not at the height of the plague but in 2013. The drug combinations he and many others were saved by in 1996 became ineffective, as his HIV strain mutated to snake past all available HIV drugs. What it is vital for those born after the plague years to know is that treatability does not entail dismissal. And France’s book details the struggle and stubbornness, as well as plenty of setbacks and self-aggrandizement, it took to get to where AIDS is today.

France runs a history of the science of HIV/AIDS alongside and intertwining with the history of activism. His writing is less pacy when writing on the research compared to when writing about the high drama of drug trials, but forgivable given his background. France is an AIDS activism insider. He is among the crowds of plague survivors at Cox’s funeral and is connected to the story’s main players. Though the scope and tone of the book somewhat resembles Siddhartha Mukherjee’s “Big Book of Cancer”, it does not attempt to magisterial objectivity. This means the book is How to Survive a Plague (as a gay male activist and journalist in New York, 1981-96). At the books heart is a small world of New York activists. San Francisco is a distant oasis separated by the dry sands of prejudice, to say nothing of the rest of the world. But narrowness is key to the intimacy France creates by following key figures like characters in a novel through what would otherwise be a fog of names, dates and acronymns.

Some of his stars include the musician Michael Callen, Richard Berkowitz and their physician Joseph Sonnabend, who together authored a 1982 book advising on safe sex. There is Larry Kramer, the mercurial playwright crucial in ACT UP’s founding and Peter Staley, the ex-Wall Street trader who protested against the high price of the drug AZT at the New York Stock Exchange. The book is rich in the tales of these and others fighting have AIDS taken seriously by scientists and law-makers.

What was new about the AIDS epidemic was how activists engaged with research. Theatre major and high school dropouts were reading the scientific literature on HIV/AIDS and presenting their own illnesses at conferences so they could challenge drug companies and government officials on funding and clinical trials. ACT UP’s famous mantra was “drugs into bodies”, they intended to get as many people on the best drugs quickly. This was strikingly at odds with a government and medical establishment characterized by it’s neglect, greed and indifference.

Successes finally emerged when researchers and activists worked together. AIDS activists suggested the parallel track method of clinical trials, which generated good data from a carefully controlled clinical trial, but those who aren’t the ‘perfect patient’ trials need can get the drugs. The drug Crixivan appeared promising in the early 1990s, so was rapid rushed from test tube to human trials via the substitution of animal trials for a ‘big chimp trial’, a scientist heroically took the drug themselves. But the manufacturer Merck faced was slow in producing enough of the drug for the Phase II trials, so driven by love and despair activist Tom Blout on Merck’s community advisory board was getting the drug bootlegged for lover Jim Straley, who died after his supply ran out.

Such a personal history of an emotive topic runs the risk of whiggish hagiography, but France’s acknowledgement of the failures and successes of activist groups keeps it balanced. The pitfalls of activist-driven medicine as shown in the case of AZT. Pressure from activists to value hast came at the cost of efficacy, when the good outcomes early in the Phase II clinical trial of the drug meant the trial was stopped prematurely and the drug approved in record time. But AZT was ultimately found to have no effect on lifespan, not captured in the short trial. But the scientists have plenty of flaws as well. There was a narrow focus by the NIH on trials of drugs which targeted the HIV virus, at the expense of developing treatment for the opportunistic infections which actually kill AIDS patients. But by the end of the plague, activists and scientists largely collaborated to temper each others’ faults. There is comedy in some of ACT UP’s stunts, such as the unfurling of a giant condom over the house of anti-AIDS research Senator Jesse Helms. But throughout the book runs a sense of the great, howling injustice of the willful ignorance of the AIDS crisis by those in power.

The book ends in 1996, the end of the plague years, the survivors dissipated. But the plague still shuffles on, wreaking havoc for those lacking access to treatment and bruised by previous treatments. AIDS casts a long shadow over the LGBTQ community, but the grief and anger spurred activists into becoming more vocal in demanding their own humanity be respected. The consequences of their actions reverberate in every pride march and every newly-out teenager today.