“EXCLUSIVE: Chinese scientists are creating CRISPR babies”

In the above-titled article in the November 25, 2018 MIT Technology Review, Antonio Regalado presents a striking and fear-inducing image—that genetic modification has progressed past making corn resistant to pesticides and into meddling with humanity itself. The hot, new, “it” technology in biology has finally resulted in living, genetically modified children in violation of biological best practices. In one headline, Regalado not only describes the birth of the first genetically modified humans through the research of Chinese biophysicist He Jiankui but also uses its urgent language to draw the reader’s mind to extreme, even fictitious outcomes. Powerpuff Girls¹ and other superhumans made by chemicals and radiation come to mind. As much as we may adore our favorite media mutants, we see them as just that–something not entirely human. In the real world, biotechnology evolves at a rapid, often alarming pace. Humans discover new biological processes in nature all the time, and sometimes we re-engineer them or use them as a springboard for new techniques that are applicable to humans. Though many require a long, arduous process for development and approval, once new biotechnologies get off the ground, possibilities for their use can seem unlimited.

One such technology is the CRISPR-Cas9 system, reengineered from bacterial immune systems for use in gene editing. The namesake segments of DNA (Clustered Regularly Interspaced Palindromic Repeats, or CRISPR sequences) and the Cas9 enzyme, both native to the bacterium utilizing CRISPR-Cas9, are some of the most notable scientific developments. Without this feat of nature, the entire tale of CRISPR-Cas9’s adaptation for use by humanity and the ethical dilemmas and mishaps that have occurred since would not be possible.

 

The Natural Basis of Genome Editing

Humans get sick, whether we like it or not. Germs invade, and our immune system fights them off. If the unwelcome visitors are bacteria, antibiotic drugs can help the healing process. On the other hand, viruses are a whole other beast: our bodies are left to their own devices to fight them off. Containing some genetic material yet unable to replicate on their own, virologist and professor of microbiology Luis Villarreal (2008) describes viruses as existing in “a gray-area between living and nonliving.” To continue the viral cycle, viruses must hijack another cell’s machinery to replicate their genetic material, which is then assembled and exported to other cells so that the cycle may repeat (Villarreal, 2008).

In humans, part of the immune system involves programmed cell death in cells too damaged to repair, a process known as apoptosis. If a cell’s DNA, for example, has been scrambled and intercepted by viral genetic material, it will not be able to divide into healthy cells, and allowing it to do so would spread the viral genome. Instead, the cell is degraded and its constituent molecules recycled. Considering the trillions of cells in a human’s body, one undergoing apoptosis is not too great a cost.

Bacteria can also be infected by viruses, and the process of infection and proliferation by the virus is largely the same as in humans. Unlike us, though, bacteria are single-celled organisms. If the cell is damaged, it is one out of one–the end of the evolutionary line for that organism. Natural selection states that single-celled organisms must have evolved a way to stave off their nasty little bugs, otherwise dying out due to a lack of defenses. So how do they do it?

For tiny organisms being picked off by even tinier enemies, a single invader represents a life-or-death situation. Who would have guessed that a bacterial immune system could be utilized as a new frontier in bioengineering and medicine? It seems unlikely, and this is exactly what makes the mechanism of CRISPR-Cas9 so fascinating. As UCLA molecular biologist Munshi Azad Hossain (2021) writes, bacteria and archaea (another type of single-celled organism) use a mechanism called CRISPR-Cas9 to cut the genetic material of viruses into small pieces.

CRISPR refers to specific DNA sequences in the bacterial genome (Hossain, 2021), while Cas9 is an enzyme that can recognize and cut specific sequences of DNA. Similarly to how the immune system in a human creates antibodies after the first time it sees a pathogen that will recognize that intruder a second time around, bacteria use CRISPR-Cas9 to recognize and more efficiently destroy invading viruses. When first exposed to a virus, a bacterium will cleave pieces of the viral genome, incorporating them into its own DNA at the CRISPR sequences. Upon further exposures, the viral sequences taken up by the bacteria are recognized and cut by the Cas9 enzyme, preventing the virus from hijacking the cell for its own replication (Hossain, 2021). It would take 30 years of work on this system from the initial discovery of bacterial CRISPR sequences in the 1980s (Hossain, 2021) to harness it for human applications—an enormous capacity for good, but also the frightening prospect (and sometimes reality, in the case of He Jiankui) alluded to by Antonio Regalado and countless other journalists in the 2010s.

Several innovations have seemed like they may crack the code to allow humans to edit their own DNA. From discoveries of the structure of enzymes like Cas9 to the exact process of how bacteria use CRISPR-Cas9, every piece of knowledge has unraveled a piece of this tangled web. Finally, though, an international duo of biologists, Emanuelle Charpentier and Jennifer Doudna, became the first to successfully turn suspicions of CRISPR-Cas9’s usefulness in editing DNA into reality. In 2012, they transformed CRISPR-Cas9 from a bacterial defense system to a highly customizable gene-editing tool. The press release from their 2020 Nobel Prize in Chemistry puts it aptly: they “…reprogrammed the molecular scissors. In their natural form, the scissors recognize DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.” (Nobel Press Release, 2020).

This “molecular scissors” metaphor foreshadows exactly what CRISPR-Cas9 technologies have been used to achieve since Charpentier and Doudna’s revolutionary research. The human genome is no longer set in stone. Instead, it has been turned into a malleable baseline that we can cut and paste into at will. Exactly how far down that road are we, though? As Emanuelle Charpentier puts it in a telephone interview, “CRISPR-Cas has facilitated a lot, and genetics in research and development. But as to have it as a technology that can be used safely for the editing of the human germline, it’s something else…indeed unfortunately we may see unfortunate and really unwanted experiments” (Nobel Interview, 2020).

 

The Ethics of CRISPR-Cas Systems

Myriad ethical dilemmas and debates about the usage of CRISPR-Cas9 have come along with its 2012 reengineering—discussions of the technology’s current and future limits, why and how it should be used, and how it certainly should not. Based on headlines alone, it becomes easy to imagine that at its most science fiction-esque, CRISPR-Cas9 could be used to reengineer ourselves down to our very core: to make heritable, permanent decisions about the traits of a human being. From the prevention of disease to an entirely new subset of tall, beautiful, intelligent people, perhaps there are simple edits or even entire sequences we could add that would bring humanity into a “better-designed” future.

In her 2017 article “The Designer Baby Distraction,” Lea Witkowsky, a microbiologist, describes a striking magazine cover seen in her doctor’s office–a 2015 issue of The Economist that showed “A healthy baby surrounded with arrows and phrases like ‘High IQ,’ ‘Sprinter,’ and ‘20/20 vision.’ The title read, ‘Editing Humanity.’” She also recalls an issue of the MIT Technology Review, also from 2015, with a similar headline. Familiar with these types of articles as well the science behind CRISPR-Cas9, she expresses concern that publicity around advances in genome editing has led to misguided beliefs by the public.

As it turns out, policymakers and scientists, in addition to journalists and the general public, have concerns regarding the ethics of CRISPR-Cas9 technology—and some of these fears may be well-founded. One question is of primary concern: When and how CRISPR research on human embryos should be allowed?  Researchers Carolyn Brokowski and Mazhar Adli (2019), in bioethics and CRISPR for medical uses, respectively, write that opinions on using CRISPR-Cas9 in the germline are diverse, from support of federal funding to “outright banning of the research.” Most however, do support some type of regulation, and some legislation is already in place. The UK and China, for example, disallow “initiating a pregnancy with genetically modified human embryos” despite being “the first two countries to use CRISPR in human embryos for research purposes” (Witkowski, 2017). In the United States, there are fewer specific regulations on the legality of using CRISPR in human embryos, but this kind of research cannot be federally funded (Detwiler-George, 2019).

There are several biological reasons for both thorough support and regulation of CRISPR-Cas9. When choosing a gene to edit with CRISPR, for example, researchers must consider the potential butterfly effects (where one small change can have very large consequences) of their edit. Though the human genome has been completely sequenced, the mechanisms behind many traits and the functions of many genes are still poorly understood. Sometimes, many genes are involved in regulating a single process or trait, while in others, one sequence of DNA can variably contribute to vastly different functions. Hair color, for example, is influenced by many genes. Removing or changing one of them with CRISPR-Cas9 may have little effect when the rest are intact. On the flipside, that edited gene may sit on multiple pathways in the intricate network of our body. Disrupting it could cut a signal in an entirely different system that scientists are yet to properly analyze.

There are also some concerns with the editing mechanism of CRISPR-Cas9 itself. Though CRISPR-Cas9 is one of the most refined and customizable gene-editing tools available, there remains a chance of several unintended effects, including “limited on-target editing efficiency, incomplete editing (mosaicism), and inaccurate on- or off-target editing” (Brokowski and Adli, 2019).  Mosaicism, one of the more interesting of these issues, is a condition in which an organism contains some cells of one genetic makeup and other cells with a different composition. In terms of CRISPR-Cas9 editing, mosaicism could occur in a zygote if some cells are not properly edited, or in an adult organism where editing all cells is impossible. In the latter case, mosaicism is not particularly worrisome because cells treated with CRISPR-Cas9 will not typically reach other systems. In a zygote of only 8 or 16 cells, though, mosaicism will affect every body system as the handful of edited cells multiply to over a trillion.

CRISPR systems may have revolutionized how we approach gene editing and gene therapies, but their risks and potential for abuse remain. Regardless of regulation and widely-accepted practice, ethical boundaries have been crossed, as in the case of He Jiankui, and mistakes made in embryonic gene editing—such as incomplete or incorrectly targeted edits–can permanently alter or end a life.

 

The CRISPR Twins

In 2018, a Chinese researcher named He Jiankui contributed to creating “the first babies born with edited genomes.” The twins, born of an HIV-positive father, were intended to be resistant to HIV, writes David Cyranoski for Nature News (2018). He’s experiments resulted in a third child as well, though the twins were the primary subject of news around the subject. He Jiankui indicated that the twins, Nana and Lulu, were living a “normal, peaceful” life in 2023, (Ruwitch), but this fails to ethically justify the circumstances surrounding their conception. Widespread reports and condemnation of He’s experiment demonstrate exactly how wrong CRISPR research can go. One commentary written by bioethics PhD student Erika Kleiderman and researcher Ubaka Ogbogu (2019) who focus on research into ethical and societal considerations of biotechnology, notes nineteen violations over seven different components of ethical research. Beyond explicitly breaking Chinese law regarding the use of CRISPR in human embryos, particularly of note are some violations within the “social and scientific value” and “favorable risk-benefit ratio” categories. In general, medical research should represent a significant innovation  or improve upon a procedure that already exists. Moreover, there should be sufficient evidence that any risks associated with the research are overshadowed by its benefits. He Jiankui largely disregarded these tenets, choosing edits and methods, which target a disease with established prevention methods and neglect the potential inaccuracies of CRISPR intervention.

He Jiankui has been heavily criticized regarding his choice of HIV resistance as the target for his experiments, as well as his use of the edited embryos. Specifically, He targeted the CCR5 gene, which codes for an entry point for the HIV virus (Cyranowski, 2018). Though CRISPR-Cas9 is an effective method to perform “knockouts” of entire genes, CCR5 may not be an ideal target, both in the purposes we know it serves and those we have yet to discover. Even assuming that editing CCR5 out of a human genome would perfectly induce HIV resistance, there are multiple criticisms leveled against He for the decision to target this phenotype. Primarily, He’s experiment “does not relate to treating a clear life-threatening disease or condition” and targets a disease “for which approved methods of prevention already exist” (Kleiderman and Ogbogu, 2019). According to George Daley, Dean of Harvard Medical School, there are other diseases that do not yet have treatments aside from potential gene therapies that may be better candidates to be edited out of the genome (Cyranowski, 2018). Huntington’s disease, for example, is a terminal condition arising from a single, known mutation in DNA, reducing the risk that gene editing could cause unwanted effects or off-target edits. It displays an autosomal dominant inheritance pattern where inheriting a single mutated gene from either parent invariably results in a long period of debilitating neurological illness and a premature, painful death. Though risks and benefits must still be considered, CRISPR experiments with Huntington’s disease could be far more precise and innovative than He’s. Other diseases are caused by single mutations as well, including sickle cell anemia, cystic fibrosis, Duchenne muscular dystrophy, and a form of congenital deafness (Genetic Alliance, 2010).

Past all the ethical problems with He’s experiments, a tangible error remains permanently etched into one of the twins’ genomes. In one sister, a single copy of CCR5 remains intact. At the very least, she remains susceptible to HIV infection, and at worst, those “necessary but still unknown functions” that genes can have may be permanently affected by this oversight (Cyranowski, 2018). Worst of all, He knew of the failed knockout prior to implanting the embryos and continued anyway. Despite acting as a modern Victor Frankenstein² and wreaking potential havoc on the lives of two young girls, He spent only three years in prison and is now back in a biology lab. This time at least, restrictions on his research will prevent a repeat of the “CRISPR twins” (Ruwitch, 2023).

 

Looking Forward

Given CRISPR-Cas9’s potential for misuse, exemplified by the case of He Jiankui, it is easy to deny the technology’s promise and conclude that it represents exactly what some late 2010s headlines suggested: not only the death of some diseases, but also the birth of eugenic superhumans and eradication of individuality. However, now years separated from the designer baby craze, though, CRISPR-Cas9 has new applications and potentialities.

Take the COVID-19 pandemic–in a matter of weeks, a desperate need arose for biologists to develop a rapid, accurate test for the virus. Established methods existed for adapting technologies to fit a new disease, which is how the first PCR tests for COVID-19 were developed. However, PCR tests had a long turnaround time, reducing the effectiveness of contact tracing and other efforts to mitigate the spread of the SARS-CoV2 virus (Broughton et al, 2020). Later on, at-home tests, which provide relatively accurate detection in a matter of minutes, became available. This rapid development was possible thanks to CRISPR-Cas12, a variation on the Nobel Prize-winning CRISPR-Cas9 where the Cas9 enzyme is replaced with Cas12, another enzyme that has a similar function.

This technology also has great potential to treat diseases in adults without introducing heritable mutations. For conditions in which the detrimental phenotype (physical manifestation of genetic code) is localized or genetic defects arise after conception, CRISPR may be valuable. For example, sickle cell disease affects approximately 100,000 Americans (Sudhakar, 2023), causing misshapen red blood cells that get caught in small blood vessels and cause excruciating pain, among other complications. In the first FDA-approved treatment involving a CRISPR-Cas system (Sudhakar, 2023), the symptoms of sickle cell disease can be greatly diminished. Red blood cells only form the “sickle” shape after the body stops producing a fetal version of hemoglobin, a compound that allows red blood cells to transport oxygen. By eliminating the gene that triggers a stop in production of fetal hemoglobin, the number of sickled blood cells is greatly reduced. (Sudhakar, 2023).

Since biochemists originally hacked a bacterial immune system, it has been proven that the human genome is neither immutable nor protected from unethical experiments and exploitation. Still, perhaps there are pieces of our genetic code that do not need to be permanent. Especially when working with cells that will not contribute genetic material to future generations, experimental CRISPR-based therapies are often the most promising options doctors and their patients have to work with, risky or not. To put it succinctly, “if this risk is considered morally (and legally) permissible, then it would seem unjustified and unreasonable to not allow risk posed by CRISPR investigation” (Brokowski and Adli, 2019). The “molecular scissors” of CRISPR systems can and have drastically improved the quality of life of many people. With a healthy dose of respect for the unknown and ethical medicine, hereditary hijacking might not be as scary as we think.

 

Footnotes

1. From a 1998 cartoon of the same name, the Powerpuff girls are a trio of young girls with superpowers, created when Professor Utonium accidentally spills “Chemical X” into his perfect formula of “sugar, spice, and everything nice” for the perfect little girl.
2. Victor Frankenstein is the namesake scientist from Mary Shelley’s 1818 novel, who creates an amalgamation of various dead body parts and reanimates them, effectively creating life.

 

References

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