How CRISPR lets us edit our DNA
Geneticist Jennifer Doudna co-invented a groundbreaking new technology for editing genes, called CRISPR-Cas9. The tool allows scientists to make precise edits to DNA strands, which could lead to treatments for genetic diseases ... but could also be used to create so-called "designer babies." Doudna reviews how CRISPR-Cas9 works -- and asks the scientific community to pause and discuss the ethics of this new tool.
Act now on CRISPR babies
A worldwide debate is under way on how to regulate gene editing in human sperm, eggs or embryos.Credit: Yorgos Nikas/SPL
A researcher steps forward and says he has plans to edit the genes of babies. He wants to alter a gene called CCR5 to protect children from HIV. He seems to have the skills, tools and position to do so — and he starts to tell other scientists about his plans.
When Chinese scientist He Jiankui did this, the story went famously wrong. Jiankui pushed ahead with his work quietly, and last November announced the birth of the world’s first gene-edited babies. He was quickly and universally condemned for acting recklessly and ignoring risks. Meanwhile, scientists whom He had told about the work beforehand were criticized for not raising the alarm.
Now this scenario is playing out again. Nature this week reports that molecular biologist Denis Rebrikov at the Pirogov Russian National Research Medical University in Moscow says that he plans to create babies with an edit of the same gene. The proposals are controversial, and already scientists are raising doubts about the credibility of Rebrikov’s claims and his understanding of the risks. But whether or not his plans go forwards, the proposal shows that He was not a lone rogue and that other scientists will move swiftly to pursue human germline gene editing in the clinic — making changes to DNA in sperm, eggs or embryos that will be inherited by future generations. That steps up pressure on the scientific community to intervene and regulate such work.
He’s announcement triggered a worldwide debate on how to discourage rogue gene editing in human reproduction. Some scientists and stakeholders have called for a global moratorium on human germline editing to make genetically modified children, until agreement can be reached on whether safe, acceptable uses exist. Others, including an advisory committee to the World Health Organization (WHO), and this journal, have called for proposals for experiments involving gene editing of embryos or gametes to be deposited in an open global registry. An international commission involving many national academies is examining the issues. The one thing that almost everyone agrees on is that, right now, it is irresponsible to pursue further human germline editing to make babies.
So where does this leave Rebrikov, who wants to start down that road? He has at least been willing to discuss his plans ahead of transferring any edited embryos into women.
He has worked at a fertility clinic using preimplantation genetic diagnosis to help couples avoid passing on genetic diseases to their children, and he knows that this and other techniques are better, safer choices than gene-editing. He acknowledges that there are only rare situations in which the benefits offered by gene editing of human embryos for reproduction clearly outweigh the risks. One of them, he argues, is the group of patients he wants to target: women who are infected with HIV but do not respond well to anti-HIV drugs and thus stand a considerable chance of passing the virus on to their children. But other scientists have been highly critical of Rebrikov’s plans and say the risks are too high to proceed. Having two disabled copies of the CCR5 gene comes with a range of health risks; a study published this month suggesting it is linked to a shortened lifespan (X. Wei and R. Nielsen Nature Med. 25, 909–910; 2019) has triggered much discussion.
The scientific community now has an opportunity to do what they couldn’t with He — work with Rebrikov to identify and discuss the risks. That’s better done by engaging with him than by branding him a maverick. And Rebrikov must listen to the concerns and the critics, and not move forward until the dangers are assessed.
Time is of the essence. The committee advising the WHO is not likely to issue its final recommendations on an international framework to govern the use of human-gene-editing technologies before 2020. Rebrikov says he might start his experiments this year; perhaps elsewhere, plans are already further ahead. Plenty has been said about the need for debate, consensus and regulation on human germline gene editing, but that process has to keep up with the speed at which researchers can actually do the work.
Nature 570, 137 (2019)
Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed. A recent one is known as CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.
CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to "remember" the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses' DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.
The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short"guide" sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell's own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.
Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.
Ethical concerns arise when genome editing, using technologies such as CRISPR-Cas9, is used to alter human genomes. Most of the changes introduced with genome editing are limited to somatic cells, which are cells other than egg and sperm cells. These changes affect only certain tissues and are not passed from one generation to the next. However, changes made to genes in egg or sperm cells (germline cells) or in the genes of an embryo could be passed to future generations. Germline cell and embryo genome editing bring up a number of ethical challenges, including whether it would be permissible to use this technology to enhance normal human traits (such as height or intelligence). Based on concerns about ethics and safety, germline cell and embryo genome editing are currently illegal in many countries.
Submitted by eClub Rotarian Russ K.
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