The advent of gene editing technology has given humans the ability to go beyond treating symptoms of disease, to now being able to ‘fix’ the actual root cause of many serious disorders – our genes. Although stopping Huntington’s Disease or Turner’s Syndrome in its tracks is an incredible offer that is hard to refuse, there are several safety and ethical concerns that come with such powerful technology. This month, a report from the US National Academies of Sciences, Engineering, and Medicine sets international regulatory standards for the use of gene editing in human research.
Gene editing, the novel strategy of inserting, replacing, or removing specific genetic material using custom designed nucleases, emerged in the 1990s with Zinc Finger Nucleases (ZFNs) and later, Transcription Activator-Like Effector Nucleases (TALENs). These gene editing tools allowed scientists to generate germline knockout or knockin mice with unprecedented efficiency.
Previously, it would have taken at least one to two years and thousands of dollars to generate a genetically modified mouse using homologous recombination. With novel gene editing technologies, a genetically modified mouse can be created in a few months.
The latest discovery and characterization of a component of the bacterial adaptive immune system known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (Cas) have led to an even more efficient and economical method for gene editing.
In 2012, researchers began applying the CRISPR/Cas9 system, which uses the Cas9 enzyme along with guide RNA molecules to disrupt DNA or insert new DNA at specific sites. The CRISPR/Cas9 system is easy to use, and can generate multiplexed mutations with high efficiency.
In addition, while ZFNs can cost at least $5,000, the total cost for a CRISPR/Cas9 system can be as low as $30. Thus, this powerful gene editing technology is now widely accessible, further raising safety and ethical concerns.
In April 2015, a group of scientists in China used the CRISPR/Cas9 system to modify the hemoglobin-B gene (HBB) in 86 non-viable human embryos that had been donated to research by an in vitro fertilization clinic. The aim of the work was to use gene editing as a method to prevent the development of beta thalassemia in embryos carrying the mutation.
At the end of the experiment, the researchers found that only four of the 54 surviving embryos contained the genetic changes. Apart from having random mosaics of cells with the desired genetic changes, numerous off-target effects were also reported. That is, gene editing appeared to have taken place in other genes besides the targeted HBB gene, potentially causing unanticipated harmful mutations.
Following this report, The Center for Genetics and Society in Berkeley, California “call[ed] for a halt to experiments aimed at the creation of genetically modified human beings… and a moratorium on human germline modification.”
The resulting upheaval in the scientific community led to the 2015 International Summit on Human Gene Editing at the National Academy of Sciences, where scientists and leaders concluded that “it would be irresponsible to proceed with any clinical use of germline editing” without further investigation into safety standards and a public discussion on the ethics of the matter.
This month, the National Academies of Sciences, Engineering, and Medicine released the latest report outlining the criteria that must be met in order to perform gene editing research, and in particular germline editing clinical trials. The expert committee, which comprised world renowned scientists and ethicists from eight countries, including Canada’s own Dr. Janet Rossant, recommended that the scientific community tread with caution, rather than completely ban human gene editing.
Furthermore, the report lays out a set of principles to which scientists around the globe must adhere when using the CRISPR/Cas9 gene editing technology. The four main areas that the report covers include: 1) basic human research, where current existing regulations over genome editing in laboratory settings should continue to be followed; 2) somatic gene editing (non-heritable changes), where existing regulations for gene therapy in human clinical trials should continue to be followed; 3) germline gene editing (heritable gene changes), which is now reserved for the treatment and prevention of serious illnesses; and 4) gene editing for human enhancement, into which research is halted and prohibited at this time.
“The report is strong, balanced and sets out clear criteria under which germ line gene editing might be considered in the future,” said Rossant, former chief of research at The Hospital for Sick Children.
The report outlines the possibility of germline editing in situations where a heritable change to an individual’s genome might be justified by “absence of reasonable alternatives, restriction to editing genes that have convincing evidence to predispose to a serious disease or condition,” “credible pre-clinical and/or clinical data on risks and potential health benefits, ongoing rigorous oversight during clinical trials,” “comprehensive plans for multi-generational follow-up, continued reassessment of health and societal benefits and risks with wide-ranging, ongoing input from the public,” and “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease.”
However, “in Canada, any editing of the DNA that would be inherited in the next generation is criminally banned,” said Dr. Rossant. Indeed, under Canada’s Assisted Human Reproduction Act, such treatments are prohibited. Dr. Rossant added that “over the next years, as the technology develops, we will need to have a full public debate in Canada on how to move forward.”
While the notion of genome editing still elicits fears of designer babies, disrupted ecosystems, and deleterious off-target effects in human clinical trials, this latest report is a step forward in that it establishes an international set of rules that allows us to exploit such powerful technology with high safety and ethical standards.
Dr. Ronald Cohn, Chair of Pediatrics at U of T and Pediatrician-in-Chief at The Hospital for Sick Children is excited about the set of principles that have been outlined by the latest report, although he expresses caution and concern about using CRISPR/Cas9 for germline editing.
“The recent announcement is further support and endorsement of utilizing CRISPR/Cas9 for the development of new genome editing therapies, which I think has the potential to revolutionize medicine [in] the way we have been practicing it,” said Dr. Cohn.
He added that germline editing “is the only aspect… I feel a bit more cautious and hesitant about. I think it is critical to perform the research around germline editing in order to assess any potential side effects this may have. It is important to assess those risks as germline editing will have consequences for generations to come, which is inherently different than somatic cell treatments that affect the individual only.”