Overview - A Crack in Creation by Jennifer Doudna and Samuel Sternberg

A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution is a very engaging from-the-trenches account of what is arguably the biggest breakthrough in biology in the last few decades. Jennifer Doudna, a professor of Chemistry and Molecular Biology at the University of California, Berkeley1, is one of the two people (the other being the Max Planck Insitute for Infection Biology’s Emmanuelle Charpentier) who are the two main brains behind the discovery of the CRISPR-Cas9 gene editing system. Standing for Clustered Regularly Interspaced Short Palindromic Repeats, this system primarily exists in bacteria, as a system to fight against invading viruses. However, in studying this bacterial system as RNA biochemists, Doudna and Charpentier uncovered the power of CRISPR-Cas9 to act as an incredibly precise gene-editing system, potentially changing many aspects of biology and biotechnology forever. A Crack in Creation, co-written by Doudna with her former graduate student Samuel Sternberg2, who is currently a faculty at the Department of Biochemistry and Molecular Biophysics at Columbia University, is her first hand account of this revolution, from the perspective of her role in it.

Divided into two parts, the book, in its first half, titled “The Tool”, deals with the technical aspects of the CRISPR system: the path which lead to its discovery, and the biological mechanism underlying its function, while the second part, titled “The Task” deals with the potential ethical conundrums surrounding the use of gene-editing in plants, animals, and humans. Doudna begins the first part outlining the various potential diseases that have known genetic causes, like sickle cell anemia, and outlines the observations made by biologists and doctors, like inheritance of certain diseases, as well as surprising spontaneous cures in certain (very rare) cases of people sufferring from what were previously thought as incurable diseases. This led to the discovery that genetic mutations causes these diseases, and likewise, processes which can fix those mutations can be used to cure those diseases. Early approaches like using chemical mutagens, viral recombinant therapy, or special endonucleases were the first tools which were brought to bear on this problem.

Throughout the narrative, Doudna intersperses science and policy with personal anecdotes about her part in this epic journey of discovery. She tells the story of how her work with studying RNA brought before her the problem of a bacterial defense system called CRISPR, a powerful weapon in the bacterial arsenal in their war against their sworn viral enemies, called bacteriophages. The history of relevant scientific discoveries, the science of bacteria and viruses, as well as the molecular biology involved intertwine very interestingly through this first half of the book. Doudna explains in detail, with some amazing illustrations by Jeffery Mathison, the various basic concepts of molecular and cell biology. Although having some technical knowledge of biology makes this book a very easy read, I think even the layman should be able to gain a basic grasp of the concepts to the level required to understand the basic mechanism and the implications of the biological systems involved. Working through the basic biology of the CRISPR-Cas9 system as it works in its natural environment, Doudna then moves to explaining how in the past five years it has been harnessed as a tool for actually performing the gene editing at desired sites in the genome.

In the second part of the book, Doudna describes the various applications to which CRISPR has been applied so far, and what potential other applications seem very close on the horizon. Current genetically modified crops have mainly been created by methods like selective breeding, mutagenesis, or gene splicing. Each of these introduces many more changes in the plant genome than the precise one or few that are actually needed to bring about the desired changes. CRISPR based editing changes that to give us the power to perform precise edits to the desired locations, which is likely to result in much fewer unintended consequences3. Many mutations in animals have also been performed to endow them with multiple desired properties, and offer many promising potential avenues for biomedical research, like being able to grow human-compatible organs for transplantation in pigs, a discovery which would work wonders for the many patients who suffer because they are unable to receive transplant organs.

Inevitably, the book then turns to the big question of editing the human genome, and here Doudna makes the important distinction between editing somatic cells and germline cells, which is one of the key points in this debate. Editing somatic cells is essentially modifying existing cells in a human body, cells which perform their specific functions, but are not involved in the reproductive process. Any modifications to these cells will be restricted to that specific individual. This, on the one hand, makes it a much easier ethical problem, reducing everything to almost a medical treatment procedure for certain diseases. On the other hand, it makes it a much harder technical problem, because large numbers of cells need to be edited for this kind of modification to have an effect. Editing germline cells, however, is modifying the cells which are going to give rise to a new individual, namely, the sperm and egg cells. This makes it a technically easier problem, because large numbers of cells do not need to be edited to achieve results. However, it makes it a much, much harder ethical problem, because any changes made to these cells will not only apply to the individual who will be born from these cells, but also be carried forward to that individual’s progeny. This essentially is making a change in the entire line of individuals who will be the descendents of that first edited human. Doudna suggests much more caution before attempting any germline changes in humans.

Towards the end Doudna suggests the practical steps that can be taken to make sure that we, as a species, make the best decisions possible regarding the monumental question we are facing here, with this immensely powerful technology in our hands. And, unusually for a scientist, she has taken a lead in spearheading the discussions understanding the ethical implications of this problem. Following the blueprint of the first Asilomar Conference on Recombinant DNA, where a similar ethical question regarding the first type of genetic modifications, i.e. the technology of recombinant DNA, was tackled, Doudna discusses her active part in the effort of the science, technology, ethics, and policy communities, who are trying to come together to address this problem head on. Not only the scientific or biological issues, but issues of social justice and equality also dominate the gene editing discussion, and Doudna outlines all of them towards the end of the book.

In an otherwise engaging personal account, which scrupulously awards credit to other scientists where it is due, sometimes Doudna comes across as projecting back in time, when on a few occasions, she mentions how she was electrified by the possibilities of CRISPR, or how she felt that the discoveries they were making would have such a major impact on the world. I’m not sure whether she actually thought that way when those discoveries were happenning, or whether those memories are being retrofit due to the current massive impact that CRISPR has had on the fields of biology and biotechnology. Also, an interesting omission from an otherwise detailed book is the complete lack of any mention of the ongoing Berkeley-Broad CRISPR patent dispute. How that is going to play out in the long run, will be interesting to watch.

All in all, this book is a must read for anyone interested in the biggest revolution happenning in biological sciences in decades, if not centuries, not the least because it is written by a scientist at the forefront of this revolution, but also because it is a very well written account that would help even a lay audience grasp the basic concepts, as well as the grand issues as stake in this discussion. Throughout the ethics discussions at the end of the book, Doudna repeatedly emphasizes the need to bring the general public up to speed with the technology, and to bring them to the table for the discussion. I think this book is an admirable step by her towards achieving that goal.

  1. As an interesting (but ultimately trivial) personal note relating to the CRISPR revolution, I did my PhD in the UC Berkeley-UCSF Graduate Program in Bioengineering from 2011-2017, working in the Teresa Head-Gordon lab, located on the second floor of Stanley Hall, which houses many labs from the departments of Chemistry, Molecular and Cell Biology, and Bioengineering. The Doudna lab is located on the seventh floor of the same building. Pretty much the entire period of over which the CRISPR-Cas9 gene-editing system was discovered, I was working in the same building, 5 floors below where this revolution was taking place. Right from the beginning, I was hearing of some amazing work that the Doudna lab was doing, in the same building, but it wasn’t really until the public awareness of the power of CRISPR increased that I realized just how revolutionary a discovery it was. ↩︎

  2. While this book is written by the two co-authors, its narrative is entirely in Prof. Doudna’s voice. Hence in my overview, I will continute to refer to that single voice as representative of both of them. ↩︎

  3. It is therefore sad, in this context, that the European Union has, last week, chosen to categorize gene edited crops along with other kinds of GMOs, effectively judging these plants based on their method of creation, rather than their actual safety and efficacy. This is likely to result in valuable nutrients not being able to reach areas where they are needed the most, in poverty ravaged parts of the globe. ↩︎