One of my early mentors in genetics had never learned to use word processing software. When editing our drafts, he literally cut and pasted text: cutting out pieces of my writing he thought worthy of use and pasting them on pieces of graph paper amid his better phrased or better thought through additions. After he finished, I would come into the lab in the morning to find a mismatched, ungainly sheaf of printer and graph paper. While receiving extensive edits is always somewhat demoralizing, there is nothing quite like the effect of seeing one’s beautiful (or so I thought) first draft physically hacked apart and stitched back together. Then there was the arduous task of turning that mass of papers into a revised draft. In its messy physicality, it was so much more difficult than simply clicking “Accept Changes” in Microsoft Word.
I mention these memories because this cumbersome process is the first image that pops into my mind when I hear genetics and “editing” combined in the same sentence. Contemporary proponents of “gene editing” using the CRISPR/Cas9 technology, by contrast, use the phrase to recall the ease of editing with word processing software. Jennifer Doudna, one of the technology’s developers, and Samuel Sternberg, for example, argue in their popular book on the topic that CRISPR will make the genome “as malleable as a piece of literary prose at the mercy of an editor’s red pen.”[1]
Bioethicist Hank Greeley even compares CRISPR to Microsoft Word’s cut and paste function.[2]
It is so easy that even do-it-yourselfers are trying it out.
CRISPR is indeed much easier and more precise than previous technologies for modifying genes, one well worth the Nobel prize Doudna and her collaborator Emmanuelle Charpentier received in 2020. With CRISPR, an adaptation of a bacterial system for responding to viral infection, scientists can design 20 base pair “guide RNAs” that correspond to any part of a genome. These guide RNAs lead Cas9, a protein that cuts DNA, “like a guided missile” to a specific target in the genome, where it snips the DNA strand “like molecular scissors.” However, cut DNA is dangerous for the stability of the genome. In the process of repairing the damage, cellular proteins frequently mutate the targeted gene in the process. The faulty repair process means that CRISPR is highly efficient at making genes inactive, which is the primary use of CRISPR. Researchers have also developed techniques that replace the targeted DNA by inserting another DNA sequence, changing the function of the gene. This latter process, however, is far more complicated and only succeeds a small percentage of the time, so is used less often than merely inactivating a gene.
As you may have noticed, it was difficult for me to describe CRISPR without using technological metaphors—and mixed ones at that—of “missiles” directing “scissors.” The preferred metaphor, though, is that of editing.[3]
This metaphor is relatively recent. The first references to “genome editing” do not appear in PubMed, the database of biomedical research articles, until 2004. “Gene editing” appears earlier, beginning in the 1980s, but largely in relation to natural processes in the cell. The phrase does not start generally referring to directed modification of the genome until the early 2000s, and its use is not widespread until later that decade. Prior to this, the most prominent metaphor for genetic change was “genetic engineering,” which was in use from the 1960s. “Editing” and “engineering” draw on fundamentally different images of the body. Where genetic engineering suggests overhauling a complex machine, gene editing implies the precise copy editing of a manuscript. This metaphorical shift is in part due to that fact that tools like CRISPR are more exact than older technologies. The key reason, though, is that the metaphor of editing is much more consistent with the vision of the body that now drives molecular biology.
The body is a living thing rather than a machine, flesh rather than text. If we do think of it as a text, let it be not as a computer program edited at will, but as a classic work containing wisdom that must be engaged hermeneutically.
Modern science has always envisioned the body as a kind of machine, but the specific type of machine has varied according to the technologies at hand. Descartes thought of the body as a kind of hydraulic machine similar to the mechanical infrastructure powering the fountains that filled the ornate gardens of seventeenth-century European nobility. For those inspired by this metaphor, fixing the body would be a type of mechanical engineering. Late nineteenth- and early twentieth-century physiologists viewed the body as a chemical machine subject to chemical engineering. Molecular biology, as historian Lily Kay has noted, has long thought of the body as a cybernetic machine controlled by information.[4] DNA, in this paradigm, is information and genes—a blueprint for the organism that controls the organism’s bodily development and adult behavior. The genome is like a computer program running the machine of the body. One sees this cybernetic, information-based metaphor everywhere in modern biology: DNA is a code; the genome is the Book of Life; the brain is an integrative control center. Doudna even encourages her readers to imagine the genome as “a large piece of software.”[5]
In contemporary biology, the body is a text, and that text is a computer program.
If the body is fundamentally a coded text, then it makes sense that researchers can transform the body by editing that text. They are merely reprogramming the code. Individuals can even “hack” their own bodies. This digital imaginary, as anthropologist Gaymon Bennett has called it, has become even more solidified as the worlds of software design and biotech have merged.[6]
The Human Genome Project of the 1990s and early 2000s drew a huge influx of computer programmers into biology to analyze the massive amounts of data generated by genome sequencing. The data analysts seldom had any experience of traditional biological lab work. The whole field shifted so that much published work in biology no longer even involves living organisms. Data analysis rules. Moreover, the corporate realms of tech and biotech draw from many of the same venture capitalists and entrepreneurs: Google, Apple, and other tech companies have divisions focused on health; Jeff Bezos and other entrepreneurs are seeking the keys to eternal youth; Elon Musk aims to implant chips in our brains. Their funding, based in the conceptual cybernetic metaphor of a coded text, has made many enhancement projects, such as uploading a mind to a computer, a conceivable, and seemingly realizable, goal. In Ray Kurzweil’s thought, it is all just patterns of information, and that information is modifiable and customizable.[7]
With CRISPR, we now have the perfect tools to edit the information.
Nonsense. Editing is a deeply misguided metaphor for altering the genome. First, CRISPR technology is not in fact a precision guided missile or a molecular scissors. CRISPR relies on organic molecules, proteins and nucleotides. By their very nature, these organic molecules act in a stochastic and often unpredictable manner, leading to possible unintended side effects. Sometimes, CRISPR causes what are called off-target effects: Cas9 cuts at sites other than the one intended. For example, if there is too much Cas9 in a cell, it acts even where it is not directed. If the guide RNA is not designed well, it can bind to similar sites elsewhere in the genome. CRISPR can also cut out a larger region than desired, leading to what is called a microdeletion. The repair mechanisms can go awry as well and reattach cut DNA to a totally different chromosome, causing dangerous rearrangements in the genome. Each of these changes can themselves lead to diseases like cancer, a problem that has long bedeviled genetic therapies. Researchers are working on technical fixes for many of these problems, and many will indeed be solved (and already are in particular cases), but most geneticists recognize the need for extensive error checking if CRISPR is to be used in human therapies. As these problems suggest, the editing functions of Microsoft Word bear little relationship to technology like CRISPR. It is much more like the empirical tinkering of an engineering project, or even the messy editing of my former mentor, than a simple edit in a text.
The second major conceptual problem is that the genome is not like a computer program. Before the genome project, it was thought that each single gene would code for a single trait or a single disease. Geneticists in the 1990s and earlier sought the “gay gene,” the gene for aggressiveness, or the gene for heart disease. This hope was fueled by studies in model organisms and some early successes in humans. There are indeed some monogenetic diseases caused by single mutations, like cystic fibrosis or Huntington’s disease. Other single mutations lead to significantly increased risk for a disease like breast cancer. Yet, the idea that each disease could be traced to one or a few mutations quickly faded after the genome was sequenced. It turns out that humans have many fewer genes than previously thought (~22,000 rather than 100,000), meaning that genes interact with each other to cause certain traits. Genome-wide studies that try to associate genes with traits find that hundreds of genes contribute to a common disease like heart disease or a trait like height. No one gene has a particularly large effect. They each change the probability of having a certain trait by a small amount. Therefore, if a geneticist wanted to raise IQs (if you believe the research on the genetics of intelligence, which has many problems), she would need to edit hundreds of genes, rather than just one—a very difficult task. The genome is a very complicated thing.
Not only does each trait depend on many genes, but most genes have multiple functions, many of which are unknown. Take the CCR5 gene that Chinese researcher He Jiankui altered in three embryos using CRISPR, leading to the birth of three transgenic children in 2018.[8]
CCR5 is the gene for a protein that we know is involved in HIV infection; people with a natural mutation in CCR5 are resistant to HIV infection. Researchers believe that editing CCR5
is a possible way to treat or prevent HIV, with at least two HIV patients seemingly cured by bone marrow transplants from donors with CCR5 mutations.[9] The problem is that CCR5 seems to have other uses in the immune system, with preliminary investigations suggesting that people with mutations might be vulnerable to other diseases. So, an enhancement to treat HIV would leave the person more at risk for other dangers. Similar unintended consequences might arise with any gene edits. It may be worth the risk for people with a serious illness, but for few others.
Finally, the genome is not isolated from its larger contexts. The genome resides in a complex cellular environment and the activation of genes is modified by cellular history. Gene editing must also contend with the complexities of the body as a whole. It seems, for example, that the immune system attacks CRISPR components, leading to difficulties for successful gene editing in the adult body. Whether a trait appears in a person is heavily dependent on the person’s environment. In the simplest case, someone who is chronically undernourished will have reduced height and academic performance no matter what their genetic inheritance. As many commentators have pointed out, talk of altering genes must take account of these social conditions, many of which would be much more worthwhile to address than engaging the complex and uncertain task of modifying the genome. Genomes, proteins, and bodies are complex, interdependent things rather than transparent, easily manipulated programs or documents of literary prose.
Yet, this critique of metaphor should not be taken too far. Even limited metaphors have their uses, as do complex technologies. Metaphor is inescapable, and an apt analogy can make concrete and graspable ideas otherwise difficult to express. Metaphors are widely used in science and medicine, as with the heart as a mechanical pump or Paul Ehrlich’s magic bullet. But we must know the limitations of the metaphors that we use and keep in mind that they are indeed metaphors. Otherwise, metaphors can easily cause us to stray, leading to projects like uploading minds to computers.
CRISPR has many wonderful uses, especially in research settings where its complexities can be controlled and geneticists have the space to safely tinker with them. Further, though most diseases are caused by multiple genes, there are some monogenetic disorders in which removing a gene can cure the condition. Already, CRISPR has shown promise in diseases like sickle-cell anemia or β-thalassemia in which hemoglobin is mutated.[10] It turns out that there is another form of hemoglobin that is only produced in fetuses and infants. By mutating a gene that suppresses fetal hemoglobin, geneticists are able to turn it back on in adults with these diseases. Given the pain and lethality of these genetic diseases, it is reasonable for patients to accept the risks and uncertainties of genetic therapy.
Even in these cases, though, geneticists try to target the therapies to particular tissues to limit possible consequences. Blood diseases are a good therapeutic target, since the stem cells that make blood can be removed from the bone marrow and manipulated outside the body in the lab. This allows geneticists to check for any mistakes CRISPR might have made, such as off-target cuts or chromosomal rearrangements. Other often-targeted tissues include the eyes, which are relatively accessible to manipulation but segregated from other parts of the body. Other therapies target the liver. Here we see a hearkening back to older images of the body as a set of independent parts and systems.
If these uses of CRISPR in adults should be celebrated and cautiously encouraged, most commentators are extremely skeptical of extending the use of CRISPR to the early embryo in a way that would affect the entire adult body and be heritable, even though a number of scientists and scientific bodies would like to explore this path.[11]
Reasons to avoid germline manipulation in the embryo include the risk and difficulty of the procedures; the small number of genetic conditions for which it would be appropriate; and the difficulty of ensuring that it would be safe. A deeper concern than those discussed by most bioethicists is that current procedures for altering embryos’ DNA would require IVF, separating the unitive and procreative dimensions of sexuality and subjecting nascent life to the power of technology. In evidence of this subjection of life to power, embryos in which “editing” went awry would be “discarded” as just a mistake, with no thought for their status as persons.
Gene editing is only one aspect of our desire to gain ever more control over our bodies and offspring. This desire for control, however, too often drives us to mistaken, overly simplistic understandings of the body, such as thinking it is a machine run by a computer program. While the metaphor of editing has led to some opportunities for healing illness, for which we should be grateful, and provides a helpful way to explain a complicated technology, its utility is limited. The body is a living thing rather than a machine, flesh rather than text. If we do think of it as a text, let it be not as a computer program edited at will, but as a classic work containing wisdom that must be engaged hermeneutically. Perhaps sections need commentary or correction, a translation might be mistaken, but it should be handled with reverence and care. Ultimately though, we may need to develop new, or perhaps recover old, understandings of the body. Most of all, we will need humility in the face of the complexity of living things.
[1] A Crack in Creation (New York: Houghton Mifflin Harcourt, 2017), 90.
[2] CRISPR People (Cambridge, MA: MIT Press, 2021), 41.
[3] This use of metaphors has been discussed in the literature. E.g. Meghan O’Keefe, et al. “‘Editing’ Genes: A Case Study about How Language Matters in Bioethics,” AJOB 15: 12 (2015): 3–10.
[4] Who Wrote the Book of Life? (Stanford: Stanford, 2000).
[5] A Crack in Creation, 5.
[6] “Digital Enchantment,” in Gene Editing, Law, and the Environment. Ed. Paterson, Webb, and Braverman (London: Routledge, 2017), 169–85. See also my “The Displacement of Human Judgment in Science,” Social Research
86: 4 (2019): 957–76.
[7] The Singularity Is Near (New York: Viking, 2005).
[8] For details, see Greely, op. cit.
[9] The transplants were to treat blood cancer rather than being purely an HIV treatment.
[10] Frangoul, et al. “CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia,” NEJM
384:3 (2021): 252–60.
[11] See discussion in Francoise Baylis, Altered Inheritance (Cambridge, MA: Harvard, 2019).
