Leon (NHBS Catalogue Editor)
10 Sep 2018
Written for Paperback
If you follow science news, chances are you will have heard of CRISPR as a promising new way to modify DNA. It has been hailed as a breakthrough discovery. I knew little about it, and seeing that this book is written by one of the co-inventors, it seemed like a good place to start reading about it.
A Crack in Creation
is a book in two parts, describing the technique and how it was discovered, and looking at the wider implications. The first part of the book is a well-written history of recent DNA modification methods and the discovery and workings of CRISPR. Though accessibly written and featuring helpful illustrations, having a basic understanding of genetics will help you, as this part is technical.
So, what is CRISPR? I’ll try to give you the gist of it. CRISPR is a region of bacterial DNA that has repeating patterns in it and is widespread in bacterial genomes, found in many unrelated species. Research by Doudna and many others has shown it functions in the bacterial immune response to infection by viruses. It is a sort of molecular vaccination card. After overcoming a virus infection, the bacterium will incorporate bits of viral DNA in the CRISPR region of its DNA, acquiring future immunity. During subsequent immune responses, the bacterium uses these stretches of acquired DNA, coupled to a protein complex, to find the corresponding DNA sequence in the virus and earmarks it for destruction. Further work showed that this complex can be recreated in the lab, and that it is the CRISPR DNA sequence that determines where in the target DNA it will bind. It does so with incredible precision and works in the DNA of many organisms, meaning that, suddenly, here is a tool that allows you to find and target any stretch of DNA in any organism and cut it.
At this point, you may think: “Why the excitement?”. Consider that for millennia our attempts at genetic modification consisted of little more than breeding livestock and plants, selecting favourable traits and hoping they were heritable. Once we understood the structure of DNA in the ’60s, mutagenesis using irradiation or chemicals became an option, but we still had little control over the mutations induced. You just had to create many samples and work with those that through chance had acquired favourable new traits. Sometime later came retroviruses, where we removed the genetic material from a virus and loaded it with bits of DNA that we had created. This gave us control over what to implant in a genome, but, as it turned out, zero control over where the virus particles would insert it in the target DNA. It was the equivalent of throwing a monkey wrench in the machine, often causing malfunction, cell death, or unexpected proliferation (i.e. cancer). Again, through selection experiments, you can keep the samples where your procedure worked, and discard the others. But if, say, your goal is to fix a genetic illness in a human being your sample size is one, so that’s not much help. Later still came more targeted methods that were laborious and expensive, as they required the design of a custom protein for each DNA sequence you wanted to target. With the CRISPR complex, however, it’s the stretch of DNA (normally originated from a virus) that determines where the binding happens. The protein complex that does all the other hard work – finding that DNA, opening up the double strand and subsequently cutting it – is the same. Generating a different sequence of CRISPR DNA to bind to a different stretch of target DNA is peanuts.
The scientific community was very quick to take up this concept and run with it, as Doudna explains in the rest of this section, and it has rapidly enabled us to do things that before were very difficult, expensive, time-consuming, or simply not yet possible. For example:
– Damaged DNA will quickly elicit a response from the cell to repair it. If you provide a short stretch of synthesized DNA as well, the cell is likely to incorporate that DNA, allowing you to repair genetic diseases caused by single-letter mutations such as sickle cell disease, cystic fibrosis, or muscular dystrophy.
– you can easily knock out specific genes, which is useful in research.
– using several versions of the CRISPR assembly you can cut DNA in different places, targeting larger regions in the genome.
– You can break the tool so that it no longer cuts but still binds to DNA. This allows you to attach a protein payload influencing how genes are expressed. Being able to down- or upregulate gene activity is as important as being able to edit the genes themselves.
– You can edit the genes of one-cell embryos to create transgenic organisms used in for example cancer research, which normally requires extensive backcrossing and interbreeding and years of work.
The book is a very balanced account, and Doudna is at pains to point out that there are limitations and reminds us that the promise of gene therapy has failed us before. Many diseases are not caused by something as simple as a single-letter mutation, so are well out of reach of a quick fix with CRISPR.
The second half of the book is what really makes it stand out and makes me have a lot of respect for the authors. Now that we have discovered an incredibly versatile, cheap and powerful tool to literally edit genes in plants and animals as if they were a string of computer code, how will we use this new power? Curing diseases is great, but we need not stop there. The ability to easily make changes in egg and sperm cells means we can introduce new traits and genetic enhancements. Suddenly we’re entering a realm that was previously only trod by writers of dystopian fiction. Will this usher in a new era of eugenics?
So, Doudna and colleagues have left the comfort of their ivory towers and organised meetings to discuss these implications and how the scientific community should respond. Previous developments in genetic modification have met with resistance and caused unfounded GMO-scares amongst the general public. Therefore, what she and others have called for, is for the scientific community to take a step back and allow time for proper and thorough discussions to take place on the societal, ethical and philosophical implications of this tool. Part of her actions in bringing wider attention to these emerging issues has of course also been the writing of this book.
Doudna has shown herself to be an incredibly conscientious and talented scientist, eager to explain her findings, but also to explore the wider ramifications of it. CRISPR has the potential to radically change the future of life on earth, and it is imperative that these developments are widely understood. So I don’t care who you are, or what your background is: you need to read this book. The future is already here.