In the past decade Professor Jennifer Doudna and Dr Sam Sternberg, at the Universities of California and Columbia respectively, have discovered a cellular function that enables us to re-write our genetic code. This gives us, for the first time, the power to cure disease and alleviate suffering, but also to ‘redesign’ any species, including humans, for our own ends. It has the awesome power to change our biological future.
Altering the genetic code
This book describes a tsunami. It traces the authors’ fascinating search to uncover the mechanisms of gene function and immune protection, and how to alter our genetic code – for good or for … other purposes. The authors developed biotechnology tools that could cut specific DNA sequences in human cells and then insert, delete, or edit genes to restore their functional activity for therapeutic purposes. But in addition to use in somatic cells, these tools can also be used to modify human germ cells (eggs or sperm) which will alter the genetic composition of the next generation, thus changing the physical health, or mental and psychological characteristics of our descendants.
CRISPR
The book is an absorbing, urgent, and riveting read. Initially the authors found a new form of adaptive immunity against viruses (bacteriophages) that can attack and kill bacteria. Working with Professor Jill Banyard, they found that bacteria contained sequences in their genes which had clusters of regularly interspaced short palindromic repeats of the DNA letters (called CRISPRs). These repeats were all identical, but in the spaces between the repeats were other unique DNA sequences. The CRISPRs were present in a number of other prokaryote species, so represented an important basic function.
Protective design
It was then found that these unique DNA sequences were a perfect match with sequences in the DNA of known bacterial viruses. Furthermore, they found that CRISPR-associated genes (cas genes) coded for a protein (Cas9) that could cut viral DNA or RNA. Finally they discovered that bacterial CRISPR- RNA molecules could guide the Cas9 protein to a specific viral DNA site and unzip and destroy the attacking viral DNA (or RNA) according to the sequence in the CRISPR-RNA, thus conferring immunity to the bacteria. What an amazing protective design!
How amazing that bacteria have a system designed to recognise, cut and destroy viral DNA, but also to store a memory of the attack for specific immunity.
Invading viral attack
Doudna and Sternberg collaborated with work from many laboratories in this fascinating story and the pace of research increased. This mechanism of adaptive bacterial immunity was like a pair of molecular scissors that cut viral DNA and stored the ‘DNA memory’ of a past viral infection in their unique CRISPR-DNA sequences (a sort of bacterial vaccination card). In this way, it mimicked further invading viral attack. Of course this had major implications for understanding viral attack on human cells.
Therapeutic use
How amazing that bacteria have a system designed to recognise, cut and destroy viral DNA, but also to store a memory of the attack for specific immunity. Because this tiny molecular machine could be engineered to cut any DNA sequence of choice, it was the basis of gene-editing that could be used for therapy. An early target was sickle-cell disease, where a single DNA mutation prevents red blood cells from carrying oxygen. CRISPR-RNA/Cas-9 was used to cut the b’globulin gene, replace the faulty DNA letter A with the correct letter T, and insert a healthy piece of normal b’globulin gene DNA to repair the faulty gene and restore the lives of millions of people around the world. CRISPR has been used to edit thousands of genes in human cancer cells in the search for novel gene therapies and has been widely used in plants, insects and other species.
While the primary target was to heal the sick, gene-editing in some of the 50 trillion somatic cells in humans with genetic disease is very complex, whereas ex vivo gene-editing of stem cells (e.g. bone marrow) is simpler and safer, and has produced miracles (eg, the healing of a very small child with acute leukaemia, using her own gene-edited T cells – a wonderful transformation).
But gene-editing of human germ cells carries major concerns, has been the sole concern of conferences, and divides the scientific and philosophical community.
Ethical concerns
Gene-editing of germ cells, however, raises serious ethical problems, and the authors address these issues in the last two chapters – ‘The Reckoning’, and ‘What Lies Ahead’. The first ‘test-tube’ baby (1978) was a watershed moment in reproductive biology, and experiments with cloned or chimeric animals (‘Dolly’ the sheep in 1996), or gene-editing in a human egg or fertilised embryo ex-vivo for implanting in the womb (‘CRISPR-babies’ produced by in vitro fertilisation), have already been performed. But gene-editing of human germ cells carries major concerns, has been the sole concern of conferences, and divides the scientific and philosophical community.
Many questions
Selective breeding is one thing, in animals (Gen 30) or in humans (e.g. to generate children of high intelligence using sperm from a chosen ‘father’, as has been done), but deliberately altering genomes in germ cells that gives offspring certain physical or mental characteristics - while it has been done in animals (excess muscle in cattle) - is another. Do we have the right to make heritable changes in the human germline? Can we guarantee the effect of these edits? Where are the moral guideposts? The authors meet these questions head-on.
Meeting people with devastating genetic diseases makes one wish for almost any way to alleviate the pain and heal the cause. Professor Doudna suggests that the stakes are simply too high and too beneficial to exclude the possibility of eventually using germline editing. But there are huge problems in the control of its use: legal issues, social equitability, economics, eugenics, genetic enhancement, population control, etc.
Heads in the sand
As of 2017, the US Congress has been unwilling or unable to even look at petitions to use CRISPR clinically in human embryos, a legislative approach that is tantamount to burying heads in the sand. Refusing to review, or to ban novel research is not the best way to regulate practice - and it has already happened anyway (Liang et al. [2015] in Huang’s laboratory at Sun Yat-sen University in China).
Research in this rapidly growing area will continue, especially in countries with few ethical controls.
Considering how to proceed
Scientific breakthroughs come from unexpected places. For CRISPR, the thoughts raised by this important book focus upon:
1) Acknowledging its existing and potential value for healing: how do we apply our use of this amazing protective and restorative mechanism?
2) Do we have the foresight to consider its use – for good and for evil?
3) Can we (will we?) put sufficient ethical, legal and moral restrictions in the use of gene-editing to alleviate human suffering but also to regulate (prohibit?) its use for self-gratification and reputation, or as a cause for division in society?
Research in this rapidly growing area will continue, especially in countries with few ethical controls. In these times, as in the days of Noah (Gen 6:5, Matt 24:37) we need, particularly in the area of genetic research, to consider how to proceed, and learn to stand for truth and righteousness in the face of corruption and wickedness. Prof. Doudna and Dr Sternberg address these current issues honestly in this important and fascinating book.
A Crack in Creation’ (304 pp) is published by Vintage Books and is available from Amazon