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

crack in creation

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.

crispr front page
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.

 

 

Innovation through Synthesis: the Methodology of Gregor Mendel

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I wrote this essay for entry earlier this year for entry to the Galton Institute’s Mendel Essay Prize 2016, an essay competition open to British and Irish A-Level Students to write on Gregor Mendel and his legacy. I chose to write on what I identified to be Mendel’s principle contribution to biological thinking, a novel fusion of mathematical methods with biological subject matters, which in addition to furthering out understanding of inheritance and opening up the new field of genetics also provided a more rigourous mathematical framework which Biology has followed for much of the 20th century.

Abstract: Gregor Mendel is well known as the Moravian monk who in 1866 presented what became known as his Laws of Inheritance, later incorporated with Darwinian Natural Selection in the Modern Synthesis to form the basis of modern genetics. He is popularly seen as a model Baconian inductive scientist, however I will argue that Mendel’s true innovation was his synthesis of the two disciplines of combination theory and the study of inheritance. This allowed Mendel to describe a biological phenomenon using a mathematical model, a methodology adopted by that vast majority of 20th and 21st century scientists.

Scientific creativity is commonly seen as being either one of two apparently incompatible extremes. The first is that of logical creativity, whereby scientific discoveries are made and problems are solved through the use of logic and deductive and inductive reasoning. By this view, it is very likely that any particular theory would be postulated eventually, as all scientists use the same methods of reason and logic to reveal the same truths about the world. The other extreme is that of the creative genius, whereby the idiosyncratic cognitive patterns of a particular gifted individual allows, as William James writes, “the most abrupt cross-cuts and transitions from one idea to another”.1 Therefore, it is very unlikely that two geniuses will ever construct exactly the same theory, as each will have different ways of connecting ideas, whereas the laws of logic are always the same.

Gregor Mendel is popularly seen as the former; as a logical, deductive toiler. This concept of Mendel has it that, by carrying out many experimental crosses between plant strains, Mendel gained a large data set from which he logically coaxed out his Laws of Inheritance; making him a model Baconian inductive scientist.2 However, a closer reading of Mendel’s biography reveals that Mendel’s work was, as it is for all scientists, as much a product of his “standing on the shoulders of the giants” allowing him to “see further”, drawing on past scholarship in order to be creative. But crucially, Mendel’s creative innovation came through his ability to place one foot on the ‘shoulder’ of two different ‘giants’ and straddle the disciplines of mathematics and biology, and hence synthesis the two in an entirely novel and creative way.

Before Mendel, the study of inheritance was predominated by the idea of blending inheritance, whereby offspring inherited a combination all their parents’ traits, so would have an appearance midway between those of the parents. However, by the mid-19th century, other scientific disciplines had fallen in the path of an all-consuming “‘avalanche of numbers’”3. Therefore, it was arguably inevitable in this mathematically-fashionable context that another scientist would have applied some sort of mathematics principles to the problems of inheritance; indeed, both Hugo de Vries and Carl Correns did so independently, but not in so precise a manner as Mendel over thirty years earlier. The precision of Mendel’s Laws derived from his novel use of combination theory, which was taught to Mendel by its originator Andreas von Ettingshausen. Combination theory is a way of describing mathematically the arrangement of objects in a group in term of underlying laws, which Mendel readily understood and adopted.3 Therefore, Mendel’s innovation came in his ability to use his teacher’s tool to construct a mathematical model in the novel context of biological inheritance.

Though the destruction of Mendel’s experimental notes after his death means that the motivations for his experiments can only be guessed at, it is likely that Mendel approached the issue of inheritance with the hypothesis that the inheritance of particular traits was governed by underlying mathematical laws, derived from combination theory. In order to elucidate any laws present, Mendel had to use a deductive Newtonian, not Baconian, method: he first formulated a hypothesis and designed experiments to prove or disprove this hypothesis.4 The success of Mendel’s Newtonian methodology is shown by his ability to predict the ratio of pea pod colour in offspring produced by a monohybrid cross. Using modern terminology, Mendel’s experimental data shows that crossing together two heterozygous (Gg) green podded F1 plants produces F2 offspring with the phenotypic ratio of 3 green: 1 yellow, but with the genotypic ratio of 1 GG (green): 2Gg (green): 1gg (yellow), as the G (green) allele is dominant to the recessive g (yellow) allele. This F2 genotypic ratio can be determined using combination theory by simply multiplying out the F1 genotypes of Gg and Gg. Therefore, experimental observations confirm this mathematical model of the biological phenomenon of inheritance, permitting the adoption of this deductive, Newtonian methodology by much of 20th and 21st century natural science, to great success.

The Philosopher of Science Thomas Kuhn argued that scientific understanding consists of paradigms, or broad frameworks of theories. As experiments throw up anomalies in the current paradigm, the paradigm enters a period of crisis, leading a revolution after which a new paradigm is established.5 By synthesising the concepts of two different fields together, Mendel was able to creatively provide a revolutionary solution to the anomalies of blending theories of inheritance. Though Mendel lived in a period of interest in the application of mathematics, his ability to, as Robin Marantz Henig writes, “maintain […] two different mental constructs of the world simultaneously and apply […] the principles of one model to problems in the domain of the second”3 allowed Mendel to mathematically describe biological phenomena, a truly creative innovation not merely derived from inductive toil.

Mendel’s creativity does not fit neatly into either of the common conceptual extremes of scientific creativity. Mendel both carried out the “abrupt cross-cuts” of the genius in using combination theory to solve biological problems and underwent inductive toil to gather empirical evidence. Therefore, Mendel’s example suggests that scientific creativity cannot be achieved by one of these two extremes; rather only by combining logical problem solving with the “seething cauldron of ideas”1 of the mind of a genius can truly innovative and revolution science occur.

1William James in: Simonton, D.K. 2004. Creativity in Science: Chance, Logic, Genius and Zeitgeist. Cambridge, UK. Cambridge University Press.
2O’Hear, A. 1989. An Introduction to the Philosophy of Science. UK. Clarendon Press.
3Henig, R.M. 2001. A Monk and Two Peas: The Story of Gregor Mendel and the Discovery of Genetics. London, UK. Phoenix.
4 Schwarzbach E., Smýkal P., Dostál O., Jarkovská M., Valová S. 2014. Gregor J. Mendel – genetics founding father. Czech J. Genet. Plant Breed. 50 pp. 43–51.
5Kuhn, T.S. 1996. The Structure of Scientific Revolutions. 3rd Edition. London, UK, University of Chicago Press