[This is an entry to the 2019 Adversarial Collaboration Contest by Nita J and Patrick N.]

Introduction

In October 2018, the world’s first genetically edited babies were born, twin girls given the pseudonyms Lulu and Nana; Chinese scientist He Jiankui used CRISPR 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 conducting their own experiment designed to target BRCA2, a gene associated with breast cancer, in sperm cells. While sometimes considered controversial, gene editing has been used as a last resort to cure some diseases. For example, a precursor of CRISPR was successfully used to cure leukemia in two young girls when all other treatment options had failed. Due to its convenience and efficiency, CRISPR offers the potential to fight cancer on an unprecedented level and tackle previously incurable genetic diseases. However, 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.

How does CRISPR work?

CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is an adaptive bacterial immune response that protects against repeat offenders. When exposed to a pathogenic bacteriophage, a bacterium can store some viral phage DNA in its own genome in “spacers,” which function as genetic mug shots, allowing the bacterium to quickly mount a defense in case of future invasions. When necessary, 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 purportedly erase and “correct” certain words in that book.

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. Human germline modification could also theoretically allow for the installation of genes to confer protection against infections, 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.

How safe and efficient is gene editing?

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. However, the causes surrounding Gelsinger’s death may have included a systemic immune response triggered by the use of a viral vector.

While the death of Jesse Gelsinger marked a somber moment for the field, gene therapy also experienced successes when researchers from Paris treated two young infants who suffered from a fatal form of severe combined immunodeficiency disease (SCID), an inherited disorder characterized by low levels of T cells and natural killer cells, which leaves affected patients incredibly susceptible to infection. Fortunately, viral gene therapy was able to reverse the disease symptoms in this particular case. On the other hand, gene therapy trials using viral vectors were recently halted when 25-50 percent of gene therapy patients developed leukemia resulting from the insertion of a gene-carrying virus near an oncogene; a gene with the potential to cause cancer. Modern CRISPR technology is not affected by such hurdles, however, as it does not rely on the use of viral vectors. 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 therefore almost always passed on together. Any edits to a gene belonging to a linked pair may therefore inadvertently cause an 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.”

Nevertheless, a slight increase in cancer risk might be a worthwhile trade-off for many patients with genetic diseases, such as the aforementioned SCIDs, which affect 1 in 50,000 people globally. Usually, the only cure for SCIDs is a bone marrow transplantation, which requires a matched donor in order to avoid rejection by host immune cells or, alternatively, the depletion of T cells to avoid rejection in the case of an unmatched donor. CRISPR offers a safer, more efficient way to treat genetic diseases such as SCIDs. Bone marrow cells of a patient may be extracted and genetically modified using CRISPR, thereby avoiding rejection by the host immune system. Pre-clinical trials in mice are already underway to test the safety and efficacy of this approach. Stanford scientist Dr. Matthew Porteus demonstrated the efficiency of this technique and said in an interview, “We don’t see any abnormalities in the mice that received the treatment. More specifically, we also performed genetic analysis to see if the CRISPR-Cas9 system made DNA breaks at places that it’s not supposed to, and we see no evidence of that.”

CRISPR also offers the additional possibility of removing parts of a gene, providing extra value over standard viral gene therapy, which only allows for insertion of genes. This feature can be especially important for autosomal dominant genetic disorders, which are made manifest with only one copy of a deleterious mutation. In her book, A Crack in Creation, Jennifer Doudna speculates that as CRISPR becomes increasingly safe, the tool may be used to help people who aren’t fortunate enough to win the genetic lottery. Doudna intones, “Someday we may consider it unethical not to use germline editing to alleviate human suffering.” What was unthinkable just a few years ago will soon enter clinical praxis.

Are some genetic variants superior to others?

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.

Nevertheless, sickle cell disease has become prevalent in countries currently unaffected by malaria. In the United States, approximately 100,000 people suffer from sickle cell disease, but therapeutic options remain limited. Researchers have been investigating the possible insertion of wild-type, “anti-sickling” genes using viral vectors in affected patients as therapy. However, since the pathological mutation for sickle cell disease has already been clearly identified, correction of the mutated gene using CRISPR may offer a more straightforward approach. The biotech company CRISPR Therapeutics recently announced the results of a phase I clinical trial in which CRISPR technology was used to treat a patient with sickle cell disease, although the efficacy and safety of the intervention have not yet been evaluated.

Can gene editing eliminate disease?

To answer these questions, we need to first evaluate our understanding of genetics and weigh the importance of genetics against environmental factors such as diet and lifestyle.

How reliable is our understanding of gene-disease links?

A mutation is usually defined as a genetic sequence that differs from the agreed-upon consensus or “wild-type” sequence. After the completion of the Human Genome Project in 2003, the arduous process of genome annotation began. Genome-wide association studies, or GWAS, began examining population data over time to look for possible associations between genetic variants, or genotypes, and physical traits and diseases, or phenotypes. Unfortunately, these studies often fail to employ random sampling, and 96 percent of subjects included in GWAS have been people of European descent. In fact, scientific disciplines frequently disproportionately sample from WEIRD (western, education, industrialized, rich, democratic) populations, whether studying genetic diseases or human gut microbiota.

Given the sources of genetic information used to determine “wild-type” sequences, we may be using information that is relevant to one demographic but not another. According to Maynard Olson, one of the founders of the Human Genome Project, the wild-type human simply doesn’t exist, and “genetics is unlikely to revolutionize medicine until we develop a better understanding of normal phenotypic variation.” These words seem to have fallen on deaf ears, however, as evidenced by the burgeoning numbers of genome-wide association studies conducted over the last 12 years. Most of the associations discovered thus far are only correlative, and few studies have been conducted to determine whether observed associations are indeed causal.

Closer examination of the relationship between gene variants and certain diseases reveals weak associations in many cases. For example, the APOE gene, which encodes for the production of a protein known as apolipoprotein E, comes in three genetic forms- APOE2, APOE3, and APOE4 with the last being associated with an increased risk of developing Alzheimer’s disease (AD). However, the correlation is not determinative, as the Nigerian population exhibits high frequencies of the APOE4 allele but low frequencies of AD. Environment and nutrition also play significant roles in the disease pathophysiology, as illustrated by Dr. Dale Bredesen’s research demonstrating reversal of cognitive decline through a targeted dietary and lifestyle approach. In fact, the majority of afflictions commonly affecting the general population, such as type 2 diabetes, cardiovascular disease, cancer, Alzheimer’s, and Parkinson’s are not caused solely by mutations.

How often does disease arise as the result of genetic mutation alone?

Chronic diseases are the result of a complex interplay between host genetics and the environment. A study conducted by the Wellcome Trust Sanger Institute in Cambridge, England analyzed DNA sequencing data from 179 people of African, European, or East Asian origin as part of the 1000 Genomes Pilot Project and discovered that healthy individuals carried an average of 400 mutations in their genes, including around 100 loss-of-function variants that result in the complete inactivation of about 20 genes that encode for proteins. These findings indicate that deleterious mutations, even those that lead to protein damage, do not invariably give rise to disease. As Professor James Evans from the University of North Carolina, who was not involved in the study, summarized in an NPR health blog, “We’re all mutants. The good news is that most of those mutations do not overtly cause disease, and we appear to have all kinds of redundancy and backup mechanisms to take care of that.” The authors hypothesize that healthy individuals can carry disadvantageous mutations without showing ill effects for a number of possible reasons: an individual may carry just one copy of a gene mutation for a recessive disorder that requires two mutations in order to manifest the disease, the disease may exhibit delayed onset or require additional environmental factors for expression, or the reference catalogs used to identify gene-disease links may be inaccurate. One analysis found that 27 percent of database entries cited in the literature were incorrectly identified.

To account for the discrepancy between genetic predisposition and disease manifestation, in 2005, cancer epidemiologist Dr. Christopher Wild proposed the concept of the exposome, which encompasses “life-course environmental exposures (including lifestyle factors) from the prenatal period onwards” and accounts for factors such as socioeconomic status, chemical contaminants, and gut microflora. The risk of developing a chronic disease during one’s lifetime may be modeled by G×E: the interaction between a person’s genetics (G) and lifetime exposures (the exposome, E). Identical twin studies reveal that genotype alone cannot determine whether a given phenotype will be expressed, and the interaction between genes and the environment must be taken into account.

In fact, the “genes load the gun, environment pulls the trigger” paradigm may be overly simplistic, as Dr. Alessio Fasano at Harvard Medical School has shown that loss of intestinal barrier function is likely also necessary for the development of chronic inflammation, autoimmunity, and cancer. Two particular gene markers, HLA-DQ2 and HLA-DQ8, are observed in the vast majority of celiac disease cases. While over 30 percent of the U.S. population carries one or both of the necessary genes, only around one percent of Americans are affected by celiac disease. This data suggests that exposure to gluten through ingestion of wheat, barley, or rye is not sufficient to trigger the development of celiac disease even in individuals with a genetic predisposition. Without the additional loss of intestinal tight junction function, celiac disease is not made manifest. Thus, factors besides genetics are necessary for the development of chronic disease.

How does gene expression contribute to disease risk?

The concept of genetic determinism purports that our genes are our destiny, but genes are not nearly as important as gene expression. When most people think of evolution, the first name that comes to mind is Charles Darwin, but a contemporary of Darwin’s named Jean Baptiste Lamarck had proposed a theory of “acquired characteristics” by which individuals evolved certain traits within their lifetimes. The most oft-cited example discrediting this theory is that of giraffes elongating their necks by stretching to reach the treetops and then passing on this trait of long necks to their progeny. In contrast, Darwin proposed that those giraffes that had the longest necks went on to find food, survive, and reproduce. Eventually, Darwin’s theory of natural selection prevailed, but his 18th century French naturalist contender may have simply foreseen the field of epigenetics, the study of those drivers of gene expression that occur without a change in DNA sequence. The prefix “epi-” means above in Greek, and epigenetic changes determine whether genes are switched on or off and also influence the production of proteins. If you imagine your genetic code as the hardware of a computer, epigenetics is the software that runs on top and controls the operation of the hardware. Epigenetic changes control the expression of genes through various mechanisms and are influenced by diet, exercise, lifestyle, sunlight exposure, circadian rhythms, stress, trauma, exposure to pollutants, and other environmental factors.

The epigenetic mechanism of DNA methylation involves tagging DNA bases with methyl groups, a process that tends to silence genes. DNA methylation is responsible for X-chromosome inactivation in females, a process necessary to ensure that females don’t produce twice the number of X-chromosome gene products as males. Methylation is also responsible for the normal suppression of many genes in somatic cells, allowing for cell differentiation. Every somatic cell in the human body contains nearly identical genetic material, but skin cells, muscle cells, bone cells, and nerve cells exhibit different properties due to different sets of genes being turned on or off. Dietary nutrients such as vitamin B12, folic acid, choline, and betaine double as methyl donors, so even small changes in nutritional status during gestation can result in markedly different effects on gene expression and varied physical characteristics in the offspring. If differential gene expression can produce such drastic changes, is genome rewriting really necessary? Perhaps the centrality of the gene in driving human health has been overstated. Indeed, why worry about a potentially pathogenic gene if it is never expressed?

Inappropriate DNA methylation has been referred to as a “hallmark of cancer,” along with uncontrolled cell growth and proliferation. Almost all types of human tumors are characterized by two distinct phenomena: global hypomethylation, which may result in the expression of normally suppressed oncogenes, genes that promote tumor formation, as well as regional hypermethylation near tumor suppressor genes. In other words, genes that promote tumor formation are turned on while genes that suppress tumor formation are turned off. Cigarette smoke has been shown to promote both demethylation of metastatic genes in lung cancer cells as well as regional methylation of other specific genes via modulation of enzymatic activities. To succinctly summarize, genes themselves are not driving tumor formation; rather inappropriate gene expression is increasing the risk of tumor development.

Can gene editing treat cancer?

Cancers are front and center among the conditions gene editing therapies are targeted to treat. To answer the question of whether CRISPR can be used to treat cancer, we need to first examine how cancer arises. Medical textbooks frequently attribute the development of cancer to the accumulation of mutations over time. However, the accumulation of genetic mutations is not sufficient to cause cancer; the tumor microenvironment must be taken into account. In other words, the same oncogenic mutation that is adaptive for cancer in altered tissue is not advantageous to cancer in healthy, homeostatic cells.

James DeGregori at the University of Colorado School of Medicine offers the following analogy. When tackling drug dealing in the inner city, arresting all the drug dealers is unlikely to work; the ones left behind will be smarter and more conniving. Instead, one might focus on creating better jobs, schools, and infrastructure, so citizens won’t have to resort to crime as a means of survival. Addressing the environment that lead to the problem in the first place will provide a more stable long-term solution. Similarly, instead of simply targeting the cancer, altering the microenvironment to disfavor its proliferation may provide a more viable long-term strategy, as the former immediately selects for resistance, accounting for the difficulty in keeping a patient in remission. Highlighting the importance of the microenvironment in regulating development, homeostasis, and cancer, biologist Mina Bissell writes, “The sequence of our genes are like the keys on the piano; it is the context that makes the music.” Cancer depends on context, as should our approach to treatment.

Nevertheless, despite recent medical advances, cancer treatment has not seen significant improvement in decades. Standard therapies rely on toxic chemotherapy, which destroys both cancerous and healthy tissue. Furthermore, cancerous cells often evade detection and destruction by host immune defenses by expressing cell surface molecules that prevent killing by host T cells. A new and effective form of immunotherapy known as chimeric antigen receptor (CAR) T cell therapy attempts to harness the power of the human immune system to recognize and kill cancer cells. However, this method has several disadvantages. A patient must have a sufficient number of immune cells prior to beginning therapy, which may not be the case for patients who have already received chemotherapy. Additionally, the process is time-consuming, and the use of viral vectors may increase the risk of developing other cancers.

To address the issues of T cell collection and manufacturing delays, researchers are now developing “off-the-shelf” CAR T cells, which utilize gene editing to prevent rejection by the host immune system and the development of graft-versus-host disease (GvHD), a condition in which foreign immune cells attack the recipient’s body. In 2017, two infants with relapsing leukemia were successfully treated with these “off-the-shelf” CAR T cells, which were modified using the genome editing tool TALEN. Short for transcription activator-like effector nucleases, TALEN can be considered the predecessor to CRISPR and uses enzymes that are specifically guided to a genomic sequence to induce a cut. However, designing these enzymes requires extensive work, making the process costly and time-consuming. Additionally, in vitro studies have demonstrated that CRISPR techniques exhibit better correction efficiencies and fewer off-target effects than TALEN. Moreover, the use of CRISPR can speed up the manufacturing of CAR T cells and drive down costs of such therapies from hundreds of thousands of dollars to a few hundred dollars.

Can gene editing prevent HIV?

Another prospective application for CRISPR technology is the treatment of HIV. Today, approximately 37 million people around the world live with HIV. The use of antiretroviral drugs has greatly reduced the death rate from 1.9 million in 2004 to less than one million in 2017. Challenges still exist, as human immunodeficiency virus (HIV) inserts itself into the host genome and mutates rapidly, making complete eradication of the disease very difficult. About one percent of the population is naturally immune to HIV due to a CCR5 gene mutation, which prevents the expression of a cell surface receptor that HIV binds to in order to gain entry into host cells. As previously mentioned, the first genetically edited babies were born in October 2018 after Chinese scientist Dr. He Jiankui used CRISPR technology to edit the CCR5 gene in human embryos.

According to Dr. He, a married couple with the pseudonyms Mark and Grace consented to in vitro fertilization with additional CRISPR treatment to provide immunity to HIV for their offspring. First, a process called sperm washing was used to separate sperm from semen, the fluid that carries HIV. Next, eggs were fertilized by sperm to create embryos, on which Dr. He performed CRISPR gene editing. After several implant attempts, successful pregnancy was achieved. Nine months later, twins with the pseudonyms Lulu and Nana were born healthy and purportedly suffered no off-target effects from the CRISPR therapy.



Testing indicated that gene editing did not successfully alter both copies of the CCR5 gene in one of the twins, however. Chinese researchers were apparently knowledgeable of the gene editing failure prior to the pregnancy attempt; the decision to proceed with implantation regardless has numerous ethical implications. “In that child, there really was almost nothing to be gained in terms of protection against HIV and yet you’re exposing that child to all the unknown safety risks,” said Dr. Kiran Musunuru, a professor of stem cell and regenerative biology at Harvard University. The choice to use the unedited embryo suggests that the researchers may have been more focused on testing the accuracy of the gene editing technology than providing immunity to disease.

According to the Chinese government and his employers, Dr. He acted without the knowledge or consent of his superiors. Chinese authorities suspended all of He’s research activities, saying his work was “extremely abominable in nature” and a violation of Chinese law. In fact, the procedure was not medically necessary. When only the father is HIV-positive, as in this case, sperm washing alone is usually sufficient to reduce transmission of the virus. A meta-analysis that investigated the efficacy of sperm washing did not find a single case where HIV was transmitted to offspring.



Dr. He claims that the CCR5 gene is already very well characterized, but a recently published study found that decreased function of the CCR5 gene enhances cognitive function in mice. At first glance, this new knowledge may appear to be a boon, but the potential benefit also invites a discussion on the possibility of designer babies. Another point to consider is the fact that the CCR5 mutation that confers HIV immunity more commonly appears in Caucasians and may make individuals more susceptible to infections that are common in Asia.

Can gene editing be used to create designer babies?

A discussion on human genome editing would not be complete without evaluating the potential to create “designer babies,” a term commonly used in the vernacular to refer to babies with genetic enhancements. Both the utility of gene editing for basic research and the use of somatic gene editing to heal individuals who are sick are generally widely accepted among the public. The waters become murkier when we consider germline editing and the possibility of preventing disease or altering traits unrelated to health needs. In the 1970s, scientists first began to establish distinctions between somatic and germline genome modifications; somatic edits only affect a single individual while germline edits can be passed down over generations. By the mid-1980s, bioethicists began to argue that the morally relevant line was between disease and enhancement rather than somatic and germline. Discussions of heritable enhancements in particular raise fears of a possible return to eugenics.

John Fletcher, former head of bioethics at the National Institutes of Health (NIH), once wrote, “The most relevant moral distinction is between uses that may relieve real suffering and those that alter characteristics that have little or nothing to do with disease.” Many scientists today share the sentiment that treatment and prevention of “disease” constitute acceptable uses of CRISPR technologies while “enhancement” applications should be discouraged, but the boundary between the two is riddled with semantic discord. Moreover, the line delineating disability and disease is often blurred, and many perceived shortcomings may in fact represent normal variation on the phenotypic spectrum.

The discussion of whether we can or should modify human characteristics may be a moot point since our knowledge of which genes affect complex traits such as height, intelligence, and eye color is still limited. Additionally, most traits are influenced not only by genetics but also environmental factors, and monozygotic twin studies demonstrate that genes alone cannot predict whether physical traits will be expressed. Furthermore, genes that encode for physical traits may also impart increased vulnerability to certain diseases. For example, variations in the MC1R gene responsible for red hair color may also increase the risk of developing skin cancer. As indicated earlier, Dr. He’s efforts to confer resistance to HIV may have also resulted in increased susceptibility to infection by West Nile virus or influenza. As always, trade-offs exist, and the idea of the “perfect specimen” is a fallacy. Any efforts to gain genetic advantages will always be subject to the limitations of biology.

How should society move forward with gene editing technology?

CRISPR technology holds invaluable potential as a research tool and possible treatment for diseases caused by single-point genetic mutations. As previously described, some genetic diseases can be treated by stem cell gene editing without the need for germline modification, thereby minimizing the risk for potential mistakes that could be passed on to subsequent generations. On the other hand, trying to correct an error after a certain point during development is sometimes problematic, as the error has already been incorporated into billions of cells. Jennifer Doudna offers the following visual: “Imagine trying to correct an error in a news article after the newspapers have been printed and delivered, as opposed to when the article is still just a text file on the editor’s computer.” Germline editing may therefore provide a more expedient option for the prevention of some genetic diseases such as sickle cell disease or cystic fibrosis.

One of the most compelling arguments against CRISPR gene editing, namely the potential for misuse, can also be considered the most compelling argument for CRISPR gene editing. Banning progress on gene editing technology may create a black market, but the continuation of research on gene editing will allow the scientific community to control its use and ensure patient safety. Research into CRISPR is continually finding ways to make the technology safer and more effective; a paper published in September 2019 reported on the potential for a novel CRISPR system to affect gene expression in human cells. The process is reversible in theory and doesn’t involve the cutting of DNA, thereby reducing the risk of human harm and leveraging the power of epigenetics.

Moreover, while gene expression and the tumor microenvironment are viable targets for cancer treatment, gene editing can be considered a last resort therapy for certain cases in which other interventions have failed. Common chronic diseases, such as Alzheimer’s, type 2 diabetes, and cardiovascular disease, likely require a more nuanced approach, as gene expression, governed by factors such as diet and lifestyle, plays a significant role in disease pathogenesis. The use of gene editing to mold favorable traits, such as eye or hair color, likely exposes individuals to unnecessary risks and does not constitute medical necessity. Nevertheless, many consider mainstream germline gene editing an inevitability. Joseph Fletcher, one of the founders of bioethics, wrote in 1971, “Man is a maker and a selector and a designer, and the more rationally contrived and deliberate anything is, the more human it is.” The establishment of gene editing guidelines should include input from scientists, policy makers, and the public and incorporate the most current knowledge available in order to prevent misuse and realize potential. As the custodians of such powerful technology, we must take care to use it in an ethical and responsible manner. Whether our efforts will alleviate human suffering or ensure the survival of our species, only time will tell.