I’m surprised when I find others who haven’t yet heard of CRISPR gene-editing. Application of this groundbreaking technology has exploded over the past six years. One such effort, the alteration of the human genomes in twin girls born by in vitro fertilization (IVF) in China last year just before the Second International Summit on Human Gene Editing, made international headlines and raised widespread concern and outcries from the scientific community.1 I’ll discuss why and offer guidelines for responsible progress.
Although we’ve learned much about manipulating the genomes of all kinds of organisms using this cheap and comparatively simple technology, gene-editing human embryos is, in most people’s minds, premature, too risky, extremely irresponsible, and even unethical. People familiar with the technical and ethical challenges for potential application in human germline editing (in which alterations are passed on to the next generation) have publicly discouraged use of CRISPR technology for use in IVF and intended pregnancies.2 But that hasn’t kept some scientists from trying to and (possibly) succeeding in altering the human genome.
Gene Editing Attempts HIV Resistance
A Chinese biophysicist, He Jiankui, has purportedly, and in my estimation almost certainly, altered the genomes of three babies born (one set of twins and another girl) to two sets of parents.3 The alterations were made following IVF and prior to transfer and implantation of the embryo. In order to make the girls resistant to HIV infection, He attempted specific alterations by targeting a gene that varies in the general population and whose protein is necessary for many forms of HIV to enter susceptible cells.
He’s efforts and “success” in altering these genomes, by all assessments in the international scientific community, were not only irresponsible and unwarranted but may even have put the children’s health at risk. People have responded by denouncing this activity and calling for various responses including a moratorium, a ban, and strict regulation on CRISPR human germline editing. Even those who had previously only publicly discouraged such applications have now strengthened their language, condemning He’s cavalier approach and questioning any necessity for such germline modifications.4
Incomplete Knowledge Calls for Caution
In light of my previous blog on the incomplete nature of the human genome sequence, any attempt to alter the germline through CRISPR technology is unwarranted and highly irresponsible. One major concern is that the CRISPR gene-editing process involves the real possibility of off-target hits. This means that editing errors can cause unintended mutations possibly creating unwanted outcomes, e.g. defective genes or even genetic disorders. Identification of off-target hits depends on the capability of sequencing an entire genome and checking for changes in that sequence by comparing it to a completed reference genome.5 In the absence of a completed reference template and the lack of tools to look for mutations in unsequenced and uncharacterized portions of the human genome, He’s claim of no off-target effects is unfounded, potentially inaccurate, and irresponsible.
Despite our growing knowledge of the human genome, we still don’t know what the majority of our genes do. And what we do know suggests that most genes/proteins are multifunctional. The most recent phases of the ENCODE project are seeking to identify specific environmental conditions that are linked to particular gene-expression profiles. And sequencing into previously intractable areas of the genome continues to uncover additional genes and regulatory RNAs. These areas of research highlight how incomplete our understanding of our genome still is. A recent NIH news release even claims the current human reference genome is becoming obsolete!
Furthermore, the gene altered to protect these girls from potential HIV infection has likely rendered them more susceptible to other viral infections (e.g. West Nile and influenza viruses) and possibly other physiological effects/defects even if only the targeted gene is altered and there are no other off-target hits.
Additional Procedural and Ethical Issues
Other problems highlighting the premature nature of this life-altering experiment result from poor experimental design, inadequate knowledge, and a failure to disclose intentions to the medical or scientific community. A status report on the two girls reveals that the desired changes were not obtained. The target gene was altered but the mutations achieved are not the well-characterized mutation carried in a subset of the human population, and the mutations are not present in both pairs of chromosomes in one girl. Furthermore, modification occurred in only some cells (not in all cells) in the developing embryos—an effect known as mosaicism since the outcome is a mosaic of changed and unchanged cells.
Although the CRISPR gene-editing machinery was introduced into the single-cell zygotes, post-fertilization, the activity of the gene-editing machinery did not affect all subsequent cell divisions. The cause of mosaicism, not uncommon in human embryo studies implementing CRISPR technology, is not well understood. It may be due to delayed gene activation following fertilization. In the zygote, gene transcription is driven by maternal proteins and RNAs. Although zygotic DNA undergoes replication for cell division, genes encoded in the embryonic DNA are not expressed until later. With improvements in analyses, embryonic (or zygotic) gene activation (ZGA), once thought to initiate between the 4- and 8-cell stage, is now known to begin at low levels at the 2-cell stage of human embryogenesis.6 Perhaps targets for CRISPR gene-editing are not readily accessible nor edited until post-ZGA stages as well, thus contributing to mosaicism.
Responsible Use Guided by an Ethical Foundation
Suffice it to say, He’s experiments were not well thought through, they did not achieve the intended results, and they were not necessary. There are many other ways to prevent HIV infections than recklessly altering the human germline. (In a future blog post, we’ll look at ways CRISPR gene-editing could be applied in more responsible ways.)
It is truly amazing that we are gaining the knowledge to use machinery from bacterial immune systems to responsibly alter the genomes of multiple organisms. Our shared biology allows fertile soil for our use of such technologies in creation care and human health, and it reflects one way God has provided for our stewardship and co-regency in creation. But a healthy and humble acknowledgement of our limited understanding should also forge the ethical foundation for not charging ahead rashly with hubris to alter genomes in potentially undesirable ways. A Christian moral and ethical framework encourages us to proceed with caution and deep value for human life and creation. That ethical base will help secure our future well-being while providing grounds for patience as fuller understanding accumulates and technical hurdles are overcome.
- Eric S. Lander et al., “Adopt a Moratorium on Heritable Genome Editing,” Nature 567, no. 7747 (March 2019): 165–68, doi:10.1038/d41586-019-00726-5; Robin Lovell-Badge, “CRISPR Babies: A View from the Centre of the Storm,” Development 146, no. 3 (February 6, 2019), doi:10.1242/dev.175778; Haoyi Wang and Hui Yang, “Gene-Edited Babies: What Went Wrong and What Could Go Wrong,” PLoS Biology 17, no. 4 (April 30, 2019): e3000224, doi:10.1371/journal.pbio.3000224; Niall Firth, “CRISPR Experts Are Calling for a Global Moratorium on Heritable Gene Editing,” MIT Technology Review (March 13, 2019), https://www.technologyreview.com/s/613120/crispr-experts-are-calling-for-a-global-moratorium-on-heritable-gene-editing/.
- David Baltimore et al., “A Prudent Path Forward for Genomic Engineering and Germline Gene Modification,” Science 348, no. 6230 (April 3, 2015): 36–38, doi:10.1126/science.aab1028; Jennifer A. Doudna and Samuel H. Sternberg, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, (Boston: Houghton Mifflin Harcourt, 2017), 205–12; Edward Lanphier et al., “Don’t Edit the Human Germ Line,” Nature 519, no. 7544 (March 12, 2015): 410–11, doi:10.1038/519410a; Kelly E. Ormond et al., “Human Germline Genome Editing,” American Journal of Human Genetics 101, no. 2 (August 3, 2017): 167–76, doi:10.1016/j.ajhg.2017.06.012; Rita Vassena et al., “Genome Engineering through CRISPR/Cas9 Technology in the Human Germline and Pluripotent Stem Cells,” Human Reproduction Update 22, no. 4 (June 21, 2016): 411–19, doi:10.1093/humupd/dmw005.
- Antonio Regalado, “Chinese Scientists Are Creating CRISPR Babies” MIT Technology Review (November 25, 2018), https://www.technologyreview.com/s/612458/exclusive-chinese-scientists-are-creating-crispr-babies/; Wang and Yang, “Gene-Edited Babies.”
- Lander et al., “Adopt a Moratorium”; Lovell-Badge, “CRISPR Babies.”
- Kayla Carey et al., “Frequency of Off-Targeting in Genome Edited Pigs Produced Via Direct Injection of the CRISPR/Cas9 System into Developing Embryos.” BMC Biotechnology 19, no. 1 (May 6, 2019): 25, doi:10.1186/s12896-019-0517-7.
- Rita Vassena et al., “Waves of Early Transcriptional Activation and Pluripotency Program Initiation during Human Preimplantation Development,” Development 138, no. 17 (September 2011): 3699–709, doi:10.1242/dev.064741; Peter Braude, Virginia Bolton, and Stephen Moore, “Human Gene Expression First Occurs between the Four- and Eight-Cell Stages of Preimplantation Development,” Nature 332, no. 6163 (March 31, 1988): 459–61, doi:10.1038/332459a0.