Is the human germline off limits?
By: Thomas Calder, Ph.D.
A new genetic engineering technology, known as CRISPR-Cas9, is allowing scientists to edit the human genome faster and easier than ever thought possible. This technology has the potential to treat and even cure several major diseases such as sickle-cell anemia, HIV, and many forms of cancer. As a result, many labs around the world are rushing to better understand the CRISPR-Cas9 system so they can eventually advance the technology into the clinic. However, such unparalleled potential comes with a risk. CRISPR-Cas9 could be used to alter the genetic code of germline cells, which are reproductive cells that could then pass these alterations onto further generations. This has scientists and the public asking the controversial question: is editing the human germline ethical?
This controversy is not new, as genetic engineering technologies have been around since the 1980’s. Zinc-finger nucleases (ZFNs) were discovered in the 1980’s and were determined to have genome-editing capabilities during 1996-2003. ZFNs are DNA cutting enzymes that can be engineered to target specific segments of DNA, and can thus alter sections of the human genome. Designing ZFNs proved to be difficult, so many scientists were excited when different genome-editing enzymes, TAL effector nucleases (TALENs), were found in 2009-2010 to be easier to engineer than ZFNs. Both ZFNs and TALENs have the same shortcoming though. They require scientists to design proteins specifically for a targeted segment of DNA, which then requires validation of each newly designed protein. Thus, these technologies are highly impractical for editing the genome on a large-scale.
The CRISPR-Cas9 system was first discovered in 1987 by a Japanese lab, but it was not well understood until recent years. Scientists determined in 2005-2007 that bacteria harbor this DNA editing system to digest foreign viral DNA. In 2011-2012, scientists began to understand the basic essentials of this system so they could utilize it for genetic engineering. They discovered that Cas9 is a DNA cutting enzyme that can be targeted to specific DNA fragments with the help of a specially designed guide-RNA molecule. This system proved to be much easier to use that ZFNs and TALENs, because scientists did not have to design different enzymes for each targeted DNA fragment. Instead, they only had to engineer RNA molecules to match with targeted DNA fragments. With this approach, CRISPR-Cas9 can be used to target and alter any gene based on its genetic code, and it can even be used for genome-wide studies.
With the recent characterization of CRISPR-Cas9, a new frontier in science has begun. Scientists have designed guide-RNA molecules for every gene in the genome to determine which genes are essential for various diseases, such as many forms of cancer. This approach is exciting because it may lead to the discovery of new targets for drug-based therapy. Scientists are also creating animal models of various genetic diseases by causing disease-specific alterations in the genome of animals such as mice and monkeys. For humans, this research has focused on non-reproductive cells, but the efficacy of this technology is making the human germline a tempting target. Theoretically, scientists could use CRISPR-Cas9 in an embryo to remove a disease-causing gene and replace it with a healthy version of the gene. This approach has the potential to ward off deadly diseases—but is it ethical? Most importantly, is it safe?
Both questions are controversial. In terms of safety, many scientists currently agree that it is not safe to create a permanent genetic alteration that can be passed onto future children. One concern is that Cas9 could have off-target effects that could damage the human genome in unpredictable ways. Another concern is that scientists do not understand the genome well enough to start making changes to the code. According to a Perspective article in the journal Science, by scientists that attended an ethics discussion in January on the topic of editing the human germline, “there are limits to our knowledge of human genetics, gene-environment interactions, and the pathways of diseases (including the interplay between one disease and other conditions or diseases in the same patient).” Also, side-effects from altering the genetic code of an embryo might not be noticeable until that embryo turns into a grown child, many years into the future. Therefore, more information on the human genome is necessary before genetic engineering of the human germline can be considered safe.
These safety concerns factor into the ethics debate, but other concerns are also drawing attention. While CRISPR-Cas9 is currently being proposed to prevent debilitating diseases, the use of this technology might start a slippery slope that could lead to the creation of “designer-babies.” For example, the genome of an embryo could be altered to impart a different eye color, hair color, or higher level of intelligence. These changes are certainly not worth the risk of side-effects, but some parents might pursue these options to provide their child with a “leg up”. Other ethical questions include:
- Would the use of this technology be regulated?
- Would a child be monitored if he/she was genetically modified as an embryo? Would the child’s future offspring be monitored?
- Which parts of society would have access to this technology? Would use of this technology lead to a greater divide between the poor and wealthy?
The CRISPR-Cas9 technology is advancing quickly, so scientists need to act now to reach a consensus on these ethical issues. Many scientists have already called for a moratorium on editing the human germline in the short-term. This would provide time for scientists to engage with the bioethics community and the public to discuss the ethical, social, and legal implications of altering the human genome.
The genetic engineering capabilities of CRISPR-Cas9 is exciting. Millions of lives could benefit from this new technology. It could cure certain cancers, prevent diabetes, ward of many age-related diseases, and even stop HIV from causing AIDS. But scientists must use extra caution when editing the human germline, because any negative effects that arise could last for many generations into the future.
- Germline editing: time for discussion, Nature Medicine
- Don’t edit the human germ line, Nature Comment
- A prudent path forward for genomic engineering and germline gene modification, Science Comment
- The new frontier of genome engineering with CRISPR-Cas9, Science Review
- Ethics of embryo editing divides scientists, Nature News
- Scientists Seek Ban on Method of Editing the Human Genome, New York Times