The Case Against CRISPR Gene Editing, Part I
One year ago, the world’s first genetically edited babies were born, twin girls given the pseudonyms Lulu and Nana; Chinese scientist He Jiankui had used CRIPSR technology to edit the CCR5 gene in human embryos with the aim of conferring resistance to HIV. In response to the international furor, China began redrafting its civil code to include regulations that would hold scientists accountable for any adverse outcomes that occur as the result of genetic manipulation in human populations. Now, reproductive biologists at Weill Cornell Medicine in New York City are riding on the heels of controversy with their own experiment designed to target BRCA2 in sperm cells. But before we start reinventing ourselves and mapping out our genetic futures, maybe we should take a moment to reevaluate the risks and repercussions of gene editing and rethink our goals and motives.
A brief introduction to CRISPR-Cas9
How does CRISPR work? CRISPR-Cas9 takes advantage of the bacterial equivalent of adaptive immunity. CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is an RNA mediated bacterial defense against viral or plasmid DNA. When a bacterium is exposed to a pathogen such as a bacteriophage, it stores some viral DNA in its own genome in “spacers,” which serve as excerpts from sequences of past enemies that have attacked the bacterium or its ancestors. The spacers essentially function as genetic mug shots, allowing the bacterium to remember pathogens in case of future invasions. When required, the CRISPR defense system will slice up any DNA matching these genetic fingerprints.
In 2012, Jennifer Doudna and Emmanuelle Charpentier demonstrated how CRISPR could be used to slice any DNA sequence of choice. The CRISPR-Cas9 system allows researchers to not only recognize and remove DNA sequences but also modify them. The completion of the Human Genome Project in 2003 provided a copy of the genetic book of life; CRISPR offers a way to erase and “correct” certain words in that book. Treating blood disorders, such as sickle cell anemia, which is caused by a single point mutation, could be possible.
Of course, this newfound power raises several ethical concerns. The major worry among scientists revolves around the long-term consequences of germline modification, meaning genetic changes made in a human egg, sperm, or embryo. Edits made in the germline will affect every cell in an organism and will also be passed on to any offspring. If a mistake is made in the process and a new disease inadvertently introduced, these changes will persist for generations to come. Germline edits are essentially forever.
Human germline modification can also open the door to designer babies, allowing not only for the cure of genetic diseases but also the installation of genes to offer protection against infection, Alzheimer’s, and even aging. For many, the thought of controlling our own genetic destinies seems to be a very slippery slope, conjuring up dystopian images of Frankenstein or Brave New World. For these reasons and more, in 2015, Doudna and other scientists proposed a moratorium on the use of CRISPR-Cas9 for human genome editing until safety and efficacy issues could be more thoroughly addressed.
CRISPR-Cas9 gene editing technology may have unintended consequences.
CRISPR is currently being used in clinical trials for cancers and blood disorders; since these interventions won’t lead to heritable DNA changes, these trials don’t face the same ethical dilemmas as Dr. He’s experiment but may nevertheless carry risks. Doubts persist about the safety and efficacy of the CRISPR gene editing system, as many other initially promising technologies have failed. Conventional gene therapies, which attempt to insert healthy copies of genes into cells using viruses, faced many early setbacks, including the tragic death of 18-year-old Jesse Gelsinger in 1999 during a gene therapy trial for ornithine transcarbamylase deficiency.
While more precise than traditional gene therapy, CRISPR nonetheless sometimes results in unintended edits, which may be especially problematic for certain gene targets. Some pairs of genes are “linked” due to physical proximity on the same chromosome and are thereby almost always passed on together. Any imprecise edits to a gene belonging to a linked pair may hypothetically cause an off-target edit in its neighboring partner.
Even intended cuts can have unexpected consequences. Two separate 2018 studies published in Nature Medicine, one conducted by the Karolinska Institute in Sweden and the other by Novartis Institutes for Biomedical Research, concluded that CRISPR edits might increase the risk of cancer via inhibition of a tumor suppressor gene called P53, which has been described as “the guardian of the genome” due to its crucial role in maintaining genomic stability. Double-stranded DNA breaks made by CRISPR activate repair mechanisms encoded by P53 that instruct the cell to either mend the damage or self-destruct. Making these types of edits successfully would therefore require inhibition of P53; however, cells could become more vulnerable to tumorigenic mutations and the development of cancer as a result.
“We don’t always fully understand the changes we’re making,” says Alan Regenberg, a bioethicist at Johns Hopkins Berman Institute of Bioethics.
“Even if we do make the changes we want to make, there’s still question about whether it will do what we want and not do things we don’t want.”
Additionally, this new wave of studies will not be subject to the usual additional scrutiny check by the National Institutes of Health, as the NIH and FDA revised their rules in August 2018, giving rise to more concerns regarding safety.
But even if genetic editing technology like CRISPR-Cas9 could be made sufficiently accurate and precise, the idea that certain genes can be categorized as either advantageous or deleterious is fundamentally flawed.
Genetic strength or weakness is relative, as perceived imperfections may actually confer resilience in a changing environment.
“It is an error to imagine that evolution signifies a constant tendency to increased perfection. That process undoubtedly involves a constant remodeling of the organism in adaptation to new conditions; but it depends on the nature of those conditions whether the direction of the modifications effected shall be upward or downward. Retrogressive is as practicable as progressive metamorphosis.”
— English Biologist Thomas Henry Huxley, 1888
In biology, those organisms that are most suited to their environment exhibit the highest fitness, a measure that accounts for both survival and reproduction. The accumulation of mutations over time is thought to contribute to many disease processes, but genetic diversity can also be beneficial for an organism when faced with a changing environment or unanticipated stress, such as drought or illness. Discussions on rigid natural selection should give way to more nuanced conversations on “balancing selection, the evolutionary process that favors genetic diversification rather than the fixation of a single ‘best’ variant,” as described by Professor Maynard V. Olson at the University of Washington.
Evolution has allowed many potentially deleterious genes to remain in the gene pool due to their ability to impart a selective advantage to individuals with carrier status, a phenomenon referred to as heterozygote advantage. Sickle cell anemia is a disease inherited in an autosomal recessive pattern — two copies of the problematic gene variant are necessary for disease expression. However, having just one copy of that variant confers resistance to malaria, which may explain the increased prevalence of sickle cell anemia in areas where malaria is more common, namely India and many countries in Africa. In this manner, malaria acts as a selective evolutionary pressure maintaining the occurrence of the sickle cell variant in the gene pool.
To further examine the utility of genetic diversity, consider the fact that over half of all hepatocytes (liver cells) in humans exhibit polyploidy, meaning that instead of having two copies of each chromosome, they have four, eight, or even 16. Cells that contain an abnormal copy number of chromosomes are often seen as aberrant, but considering the liver’s role as a waste-processing plant, this type of built-in redundancy likely comes in handy upon exposure to DNA-denaturing substances. If a toxic substance damages a gene on one chromosome in a liver cell, the backup copies of that chromosome can ensure the gene will still function properly.
Harvard geneticist George Church offers some anecdotal evidence supporting the maintenance of neurodiversity in the gene pool, explaining how “autistics have historically been described as intellectually disabled. But very often, if they can become high-functioning, they’re the opposite. They actually contribute things to society that nobody else sees.” Church himself has narcolepsy and struggled with dyslexia as a child, differences that he feels have contributed to his creative abilities.
The Yale Center for Dyslexia & Creativity says dyslexia affects 20 percent of the U.S. population and accounts for 80–90 percent of all individuals with learning disabilities. A study conducted by London’s Cass Business School found that dyslexia is much more common in entrepreneurs than in the general population, as 35 percent of U.S. entrepreneurs that were studied exhibited dyslexic traits. The 2009 study also determined that compensatory strategies, such as ability to delegate and enhanced oral communication skills, likely contributed to success in the business arena.
Shark Tank investors Barbara Corcoran, Kevin O’Leary, and Daymond John all struggled with dyslexia but did not allow this difficulty to define them. Corcoran credits dyslexia for helping her develop empathy and making her “more creative, more social and more competitive.” Similarly, Richard Branson, Charles Schwab, and Ikea founder Ingvar Kamprad have spoken about how dyslexia fostered innovation and helped shape their unique worldviews. Considering the countless advantages of a perceived disability, any ill-conceived efforts to normalize the genetic bell curve could mean missing out on the incredible potential of genetic neurodiversity.