A Crack In Creation, Jennifer Doudna

A Crack in Creation is a great accessible introduction to CRISPR gene editing, easily one of the most significant scientific breakthroughs of the 21st century. Written by Jennifer Doudna who is one of the discoverers of CRISPR, this book both offers insight the basic science of how CRISPR works and gives a unique first hand insight into the forces that drive scientific discovery.

The first part of the book is mainly concerned with the basic science of CRISPR and describing the journey that led to Doudna and her collaborators making the key discovery. We learn that CRISPR wasn't actually invented but discovered as an immune system in bacteria. Researchers before Doudna had observed odd palindromic repeated segments in some bacterial DNA and also observed that these bacteria also had higher immunity to attacks from viruses. These curious palindromic segments gave rise to the name CRISPR - Clustered Regularly Interspaced Short Palindromic Repeats. Doudna and her collaborators' key contribution was realising that this mechanism, which works by cutting invading viral DNA in very specific spots, could also be used to cut any general segment of DNA with some modification. Due to this, it could be used as a general purpose Swiss army knife to cut and edit DNA with precision.

Once this connection is made, Doudna goes on to describe some of the potential applications, such as engineering staple crops to be more resistant to fungi and pests. The example she gives is of wheat being made resitant to a fungus called powdery mildew through a simple CRISPR edit to the wheat genome.

One incredible yet terrifying application of CRISPR she describes is a gene drive. Animals usually have two copies of most of their genes — one from each parent. During reproduction, only one copy of the gene is passed on. This means that any gene has a 50% chance of being inherited. If we edit one of the genes, our CRISPR mutation only has a 50% chance of being passed on. With these odds, the mutation might disappear altogether from the population unless we can edit a large number of individuals at the same time. This could work for livestock in a herd, but for something like malaria carrying mosquitoes this is impossible.

But what if we use CRISPR to insert not only the mutation we want, but also implant CRISPR DNA itself into the target genome? This is the key idea of a gene drive. More precisely, suppose that this CRISPR sequence targets the normal copy of the gene that wasn’t edited before. When the mutated gene drive is read by the cell, the CRISPR DNA will direct Cas9 to cut the other normal copy of the gene and disable it. When the cell attempts to repair this, the CRISPR mutated gene is available as a template, so the cell repairs the damage by replicating it. Voilà! Now we have two copies of the mutated gene, and inheritance is guaranteed.

The awesome power of gene drives lies in the fact that as long as one member if a population has the gene drive mutation, all members will inevitably get it. The CRISPR mutation will (almost) always replicate itself and guarantee inheritance. There is something terrifying about having such total control over evolution. While gene drives could clearly cause great benefit, there is huge potential for misuse. Gene drives are just one example of the incredible power that Doudna's discovery gives humans.

Of course, the most enticing prospect is to use CRISPR on humans themselves to modify our own genomes. This naturally comes with huge ethical dilemmas and this makes up most of the second part of the book.

The most obvious application of CRISPR is to try cure genetic diseases. For people suffering from diseases such as sickle cell anaemia or cystic fibrosis, a targeted CRISPR edit on the dysfunctional cells could fix the problem and cure what had previously been thought of as incurable. Such applications are known as somatic applications.

The second class of CRISPR applications in humans are germline applications which make edits in the germ cells, i.e. the egg and sperm. Because of this, CRISPR changes made here can be passed down to future generations. Somatic applications by contrast edit just normal body cells so any positive or negative effects stay localised to the individual, but germline changes could spread throughout the population. Removing this final guardrail on our power to edit the genome is what gives us the ability to really control evolution.

To her credit, Doudna does not shy away from the huge ethical conflicts this raises and the toll thinking about them had on her. She recounts how she was incredibly excited at the prospect of CRISPR being used to end disease but such happiness slowly gave way to a deep worry as she realised her discovery could also be used to advance eugenicist agendas by bad actors. One powerful example of the toll this took on her was the dream she had where she saw Adolf Hitler visiting her lab at Berkeley to learn more about CRISPR.

The book wraps up with her thoughts on the ethical dilemmas of germline editing, and she effectively conveys the personal conflict she went through. Initially, she was very scared of the negative possibilities of germline editing. Her fear was so intense that it led her to call for a global moratorium on CRISPR research. However after this she details how over time her position has evolved, and she has come around more to accepting germline editing. For Doudna, on the balance the positive possibilities to alleviate suffering outweigh the negative ones. Personally, I feel as if I went on a similar journey in my own thinking as I read her book. I'm not sure I left it as in favour of germline editing as her, but I certainly did evolve from rejecting it outright as dangerous and unnatural to cautious approval in certain cases. I have no doubt that other readers will go on similar evolutions on their thinking regarding germline editing. It is so important that Doudna presents positive and negative arguments for germline editing in a balanced way since it allows readers to come to their own conclusions about this revolutionary new technology.

Overall, I learned a tremendous amount from A Crack in Creation. It is a wonderfully accessible read that not only describes the basic science of CRISPR and why it's so powerful, but also does not shy away from the deep ethical questions such power raises. It is clear that CRISPR will have huge impact on the world, from crops to genetic diseases. It might even be the end of disease. Because of its huge potential impacts, it is vital that the public knows about CRISPR and is able to form informed opinions on it. Through her clear writing, Doudna does a fantastic job at this. Scientists writing for the public would do well to use A Crack in Creation as an exemplar for how to write an engaging book for a broad audience.