The yin and yang of genome editing

Director of the FRAME Alternatives Laboratory, Dr Andrew Bennett, speaks out about the genome editing of animals to investigate human conditions, and explains why genome editing in human cell and organ models must be the priority for human relevant science.

New technologies often present scientists with exciting new opportunities to acquire data and knowledge that was impossible using previously available methods. However, as Alfred Nobel’s invention of dynamite illustrates, technological advances come with both risk and reward. Used ethically and prudently, dynamite was of great benefit and enhanced safety in the construction and mining industries, but its application in armed conflict led to thousands of deaths and Nobel himself wrote about his regret that dynamite could be used as ‘an accelerator of war.’

CRISPR-CAS9 technology

Genome editing, a technique used to modify DNA within a cell or organism, has advanced dramatically in the last 5 years. Development of a bacterial genome editing system called CRISPR-Cas9 has enabled scientists to change the DNA of almost any cell or organism quickly and relatively cheaply.

The research potential of CRISPR-Cas9 technology was demonstrated by recent work by the University of Toronto in which CRISPR-Cas9 was used to modify patient-derived, glioblastoma stem cells (GSCs) gene by gene, in order to identify genes essential for tumour growth. Glioblastoma is the most common form of brain tumour in adults and shows considerable variability in response to treatment. Prognosis for patients with glioblastoma is generally very poor. The combination of the use of cells derived from human patients and CRISPR-Cas9 technology holds real promise in terms of identifying new drug targets to treat one of the deadliest neurological cancers.

The advent of CRISPR-Cas9 also has potential for use in studies that FRAME believes will not enhance our knowledge of human biology and disease and will lead to increased use of a variety of animal species, simply because new technology allows their genomes to be modified. Prior to the advent of this technology, genome editing was expensive, time consuming and limited by technical difficulties primarily to mice.

Questioning monkey gene editing

In a study published in the National Science Review Journal in January 2019, scientists edited macaque monkey genomes using CRISPR-Cas9 to model human sleep disorders by knocking out BMAL1, an important gene for circadian regulation. Circadian rhythm is the internal biological clock that regulates body functions based on the wake/sleep cycle. Sleeping in the day and being awake during the night is an example of a disrupted circadian rhythm and may be caused by disruption of the genes involved in circadian regulation. The scientists from the Institute of Neuroscience in Shanghai edited monkey embryos, aiming to induce loss of sleep and changes in blood hormones.

These BMAL1-deficient monkeys were found to exhibit increases in anxiety, depression, and ‘schizophrenia-like’ behaviours according to the study authors.

By creating identical animals with sleep disorders, the authors claimed they could identify causes and potential cures more quickly. Causing pain and suffering in highly sentient non-human primates presents a serious ethical issue – there should be a clear and obvious outcome from such research that is of major benefit to human health and wellbeing if such research is to be considered at all. In scientific terms, the contention that monkeys are biologically closer to humans and therefore represent a reliable model of human disease and biology has been shown to be context dependent and often plain wrong.

The differences between humans and monkeys are significant when we get to the level of disease models and response to drugs. In this instance, the production of identical, cloned transgenic animals also removes natural variability which nearly all scientists agree plays a major role in susceptibility to disease and response to treatment.

Carefully managed use of genome editing technology

The development of exciting and ground-breaking new technologies allows science to advance with ever increasing speed, and improvements in human health and treatment will follow. What must be guarded against is the use of technology just because it exists and is relatively easy and cheap to use. Genome editing in primates is now achievable, but whilst the technique itself is a breakthrough, its use to produce animal models of disease is a retrograde step. Use of genome editing in human cell and organ models must be the priority for human relevant scientific outcomes.