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Abstract

With the advent of gene-editing tools, changes to sequences encoding genes or regulatory elements can be made with relative ease compared to prior technologies. The development and anticipated commercialization of new applications using gene-editing technologies may span the gamut from therapeutic interventions to agricultural applications to cosmetic or enhancement procedures. Although objections have been raised about the purpose and on whom gene editing should be performed, limiting its uses in the absence of demonstrated harm may be difficult and unwise at this time, even at this early stage of development. The fledgling field may benefit from a review of the history of plastic and cosmetic surgery that underwent a similarly rocky start and continues to evolve to this day. From this brief comparative historical analysis, we may gain some insight about the path forward regarding the use of gene-editing tools for cosmetic purposes.

Keywords

plastic surgery gene editing enhancement profession

Introduction

We are entering the dawn of a new era of genome sciences, one that enables not only changes or “edits” to genes but potentially an entire genome. Numerous commentaries, national reports, and sci-fi scenarios have amply covered the subject matter. Many have focused on the purpose of the edits (therapeutic vs enhancement), the intended recipient (embryo, newborn, and adult), and the heritability of the edits (germline vs somatic modifications). Although these are early days, technology can move quite rapidly after the first few success cases (or proof of principle). If the safety and technology of gene editing can be initially demonstrated for conditions in which interventions are currently unavailable or inadequate (a presumably acceptable use of the technology), the scope of applications can explode, entering the domain of “slippery slope” debates.¹ In other words, the same technology may be used for other potential and more controversial uses such as physical or cognitive enhancement. In some cases, an argument could be made that these other (nontherapeutic) uses or applications of the technology could be acceptable in certain situations if deemed safe and improve the quality of life or psychological well-being of an individual, or societal acceptance of a currently questionable application may increase based on evolving cultural norms, demonstrated safety, and greater public understanding and familiarity with the technology. Eventually, the issues of concern today may dissipate, as new applications become reality and utilization increases. These scenarios may paint a potentially unsettling vision of gene-editing technology for some individuals, but it provides a rationale to begin to explore other technologies that have tread a similar path to understand how non-health-related gene editing may develop and how these new applications may be delivered to patients or consumers. Specifically, we may learn from the history of plastic and cosmetic surgery and apply lessons learned moving forward to maximize patient/consumer safety.

Materials and Methods

A review of the published literature (PubMed, Google Scholar), gray literature through online searches (historical documents) and professional organization websites, was conducted. The history of the development of the practice and practitioners of plastic and cosmetic surgery was compared to gene editing to assess similarities and differences. Given the futuristic vision for gene-editing applications, the discussion was primarily based on speculation about potential services.

Results and Discussion

A Precedent: Plastic and Cosmetic Surgery

The development in the field of cosmetic surgery may serve as a model for the new field of gene editing due to its dual-use applications—one health-related and the other nonhealth-related. Although nonsurgical practices date back to Egyptian times with oils and other substances to improve the appearance of skin, interest in cosmetic surgery arose in the United States in the late 19th century, with reports of experimental rhinoplasty.² At the time, the surgical goal was dubbed “self-preservation” of physical beauty, not health related in any way, and viewed skeptically by the medical community. However, as cultural norms changed with respect to physical beauty and the role of women in society grew, public views evolved and cosmetic surgery practices expanded. World War I, however, demonstrated the medical value of these same surgical techniques to repair deformities, particularly facial traumas, incurred by servicemen to enable their successful return to civilian life. Reconstructive surgery could also be performed on patients impacted by birth defects or physical abnormalities related to disease. Thus evolved 2 types of practices utilizing overlapping surgical techniques for distinct purposes—reconstructive (or plastic) surgery and cosmetic surgery.

Assuming that most medical professionals and the general public do not object to the practice of plastic surgery for reconstructive purposes due to its alignment with the overarching goal of medical practice of promoting health, the remainder of the commentary will focus on plastic surgery for aesthetic purposes and its similarities to potential uses of gene editing for enhancement.

Today, cosmetic surgery is a well-established and thriving practice. According to the American Society for Aesthetic Plastic Surgery,³ in 2016, 13.6 million cosmetic procedures (surgical and nonsurgical) were performed (85% were nonsurgical). More than US$15 billion was spent in 2016, up 3.5% from 2015, with surgical procedures accounting for just more than half of total expenditures (56%). The top surgical procedures performed were liposuction (414 335 procedures), breast augmentation (310 444), tummy tuck (181 540), eyelid surgery (173 883), and breast lift (161 412). The most popular nonsurgical services were botulinum toxin (4 597 886 procedures), hyaluronic acid (2 494 814), laser hair removal (1 035 783), photorejuvenation (657 172), and chemical peel (616 225). Almost 40% of procedures were performed on individuals aged 35 to 50 years, 91% overall on women and 76% on white patients. The top procedure for this age-group (and for both men and women) was liposuction. While trends in popular procedures have changed over the past few decades, cosmetic procedures have enjoyed a steady growth and are part of the medical tourism industry.

Cosmetic surgery and noninvasive procedures are generally accepted in society today.^4
-6 The debate about the value and morality of physicians performing cosmetic procedures continues to this day.^7,8 In particular, cosmetic surgeons face ongoing criticism of the ethics of their practices and choice to offer services driven by economic motives and capitalization on society’s obsession with body image. Although studies report positive outcomes of patients undergoing surgical procedures including quality of life,^9
-11 the risks and discomfort associated with cosmetic surgery may be disproportional to the benefits gained. Developments in biotechnology have also capitalized on society’s obsession with body image with a variety of products and noninvasive procedures to rejuvenate, refresh, and erase unwanted physical features. The provision of cosmetic procedures has expanded outside medically trained professionals and settings to settings such as med spas and beauty salons.

A New Form of Cosmetic Enhancement?

Gene editing represents the latest development in efforts to enhance a person’s physical or other traits through the alteration in genetic impact on the phenotype. In the 1990s, gene therapy or gene transfer was used to replace mutated genes with a corrected version for rare genetic disorders. A variety of methods were developed and evaluated, most successfully using viruses that carried the corrected version of the gene to the affected tissue. The field encountered a range of technical difficulties and adverse responses reported in research participants, including death, which dampened initial excitement of the field.¹² However, recent advances^13,14 and the first approvals by the US Food and Drug Administration of gene therapy interventions^15,16 appear to have rejuvenated interest and excitement in the field.

Starting in 2000, a series of tools were developed that enabled gene editing, first with the creation of a complex of zinc finger-binding proteins with an enzyme that can cleave DNA (endonuclease),¹⁷ followed by the discovery of transcription activator-like effector proteins,^18,19 and subsequent fusion with an endonuclease.²⁰ In 2012, the discovery of naturally occurring RNA–protein complex of clustered, regularly interspaced, short palindromic repeats (CRISPR; the RNA component) and the Cas9 endonuclease was reported.²¹ The CRISPR–Cas9 complex behaves like a pair of scissors in the cell, cutting DNA at specific locations. Gene edits can essentially target any location in any genome using one of these tools. The function and/or structure of a protein can be altered through edits to the sequence of the gene encoding that protein. Alternatively, if the intended effect is to alter gene expression (turning the gene on or off or regulating expression levels), gene edits can be targeted to the sequence of the promoter region that controls gene expression or epigenetic modifications can be made. It is possible to control gene expression with the addition of a gene sequence that is responsive to another substance (known as an “inducible” promoter).

These tools may be applied to study gene function and identify targets for drugs. The first potential use of gene editing as a therapeutic intervention for a genetic condition was first demonstrated in 2005 for correction of the mutated IL2R γ gene in X-linked severe combined immune deficiency.²² The benefits are not limited to humans, as these tools have been used for plant pathogens,²³ agriculture,^24
-26 and livestock breeding.²⁷ A pair of papers on butterfly-wing patterns demonstrates the relative ease of changing color patterns with the deletion of a gene using CRISPR–Cas9 technology.^28,29

Opposition to the potential use of gene-editing technologies has carried over from earlier debates surrounding genetic testing and selection and gene therapy. Limited interventions currently exist to prevent or correct genetic diseases identified through testing, with the primary application being in vitro fertilization/preimplantation diagnosis. Medical or behavioral interventions could be undertaken to reduce overall genetic risk, such as prophylactic surgery or adapting a healthier diet. The relative ease of use of new gene-editing tools compared to older technologies such as gene therapy provides increased accuracy and specificity. However, this has amplified the debate regarding germline gene modification (permanent changes that could be passed on to the next generation).

Compounding the debate is the potential use of these technologies for nondisease-related genes such as those that impact intelligence, specific talents, or athletic ability.^30
-32 This use of gene editing, referred to as genetic enhancement in humans, may exacerbate disparities in access to these procedures, since cosmetic procedures are not covered by health insurers or public programs. Disregard or disrespect for the benefits of natural diversity and potentially the creation of non-naturally occurring gene sequences or functions are also to be considered.

Others feel that use of genetic technologies for enhancement is permissible,³³ inevitable,³⁴ and defensible.³⁵ Indeed, some have repurposed arguments in favor of cosmetic surgery to support the use of genetic enhancement.³⁵ One of the major issues about altering genes, that of germline gene modification, is not likely to be relevant if we focus on the use of genetic enhancement for targeted interventions, whereby the changes would be limited to specific (somatic) cells. For example, imagine if the genes and pathways behind the skin aging process are better understood and genetic adjustments could be made to targeted areas of the skin. Increasing gene expression of collagen, elastin, and glycosaminoglycans, which normally decrease with age and contribute to the appearance of the aging epidermis and dermis, may result in smoother, younger-looking skin. In another example, an overweight individual may be interested in having a gene-editing procedure to convert white fat to brown instead of undergoing liposuction surgery. A 2017 paper reported development of a microneedle skin patch that transferred 2 drugs into fat cells, converting the common version of fat cells in adults (white fat) to that predominantly present in infants (brown fat).³⁶ Brown fat does not store fat long term as does white fat, and therefore conversion to brown fat can potentially result in weight loss in that defined area. Gene editing could possibly be designed to reactivate the genes that are needed for a brown cell fate through gene editing. Yet, a third possible application may be to enable individuals interested in changing the pair of sex chromosomes from XX (genetically female) to XY (genetically male) or vice versa, in some undifferentiated stem cells (cells that have not committed to a certain fate or type) for a genetic gender reassignment. The impact on the individual’s phenotype from such a change is unknown at this time.

Would any of these genetic enhancement procedures be perceived as another type of cosmetic procedure and therefore subject to the same issues raised with dermabrasion, chemical peels, or liposuction, or are they distinctly different? Such objections include moral objections, safety concerns, oversight of the procedures and the practitioners who perform them, cost, and access to services based on ability to pay. For example, like many current cosmetic procedures, a gene-editing “procedure” may require multiple rounds of editing to achieve the desired outcome until either the desired changes are visible (eg, laser hair removal) the number of procedures needed may depend on the number of genes to be edited, cell type, and the efficiency of the procedure. Thus, potential health risks of repeated procedures, the training and experience of the practitioner, and costs need to be considered. While many current cosmetic procedures are aimed at correcting changes in adults, such as those associated with aging (though this is not the only motivating factor to seek cosmetic surgery⁶), some genetic enhancement procedures may be targeted to children. For example, genetic enhancement to optimize academic or athletic achievement or other talents may be performed at younger ages. Some adolescents are interested in cosmetic surgery for psychological reasons,³⁷ and parents have reported improved child well-being and reduced anxiety as benefits of cosmetic surgery.³⁸ But evidence of safety and postoperative outcomes is limited for cosmetic procedures performed on children,^39,40 and the same may be true of genetic enhancement.

Similar to presurgical testing and examination required of many surgical procedures, this new form of “molecular surgery” will likely require patients to have genetic testing performed first to confirm the patient’s gene sequence or the preediting level of gene expression. Different options for testing are available: whole genome or exome sequencing, gene panels, or a single gene test. This type of “companion diagnostic” is similar to current testing performed to determine whether a patient carries a genetic variant for a particular drug target. Providers should be aware that comprehensive genome-wide analysis may identify additional variants in patients unrelated to the reason for testing.

Dawn of a New Profession?

Making a leap of faith that the techniques of gene editing can become both simpler and more effective, with improved accuracy and minimized side effects, another issue to consider is who can (or should) provide these services. In the first half of the 19th century during the initial rise and expansion of cosmetic surgery procedures and expanding marketplace, questions regarding the skill/training of individuals offering these services were of concern. In the 1920s, practitioners of cosmetic enhancements ranged from quacks to beauticians and surgeons, mixing professionally trained medical professionals with those of little to no education or licensure and less than honorable intentions to capitalize on society’s interest in physical beauty. Following the end of World War I, in 1921, the American Association of Oral and Plastic Surgeons was founded, followed by the establishment of the American Society of Plastic and Reconstructive Surgeons 10 years later.⁴¹ In 1937, the American Board of Plastic Surgery was established, recognized as a specialty of the American Board of Surgery in 1938, and soon thereafter recognized as its own specialty by the American Board of Medical Specialties in 1941. Thus, training requirements were defined and board certification available for physicians who wished to practice in this field, legitimizing the profession. However, in addition to board-certified plastic surgeons, several cosmetic procedures today are performed by other physicians including primary care, obstetricians/gynecologists, and dermatologists with varying levels of training.⁴² The latter group was identified as the preferred provider of cosmetic procedures of the skin,⁴³ but the extent of their training on these procedures has not been standardized and may vary.⁴⁴

With this history in mind, let’s first consider who may provide therapeutic gene-editing services. All medical specialties may one day have the option of gene editing as an intervention for their patients. Thus, gene editing may be administered, perhaps as an injection, by the physician providing care for patients afflicted with that condition. Or, similar to other medical procedures, patients may be referred to a specialist trained in administering or performing a therapeutic intervention, such as a medical oncologist would refer a patient to a radiation oncologist for treatment. Or, referral to a clinical or laboratory geneticist may be most appropriate.

With respect to genetic enhancement procedures, delivery or access to these services may follow the path of other noninvasive cosmetic procedures, which are increasingly offered by physician extenders as well as nonmedically trained individuals (cosmetologists, aestheticians, and electrologists) in health and nonhealth-care settings (eg, med spas and beauty salons). Although cosmetic surgical procedures were and are still exclusively practiced by licensed medical professionals, there is some confusion among the public about other types of procedures.⁴⁵ With the wide range of providers and services, the quality of service can differ substantially due to provider type, state regulations, and licensure requirements as well as setting. In contrast to the rise in cosmetic surgery performed by the early “beauty doctors,” it does not seem likely that cosmetic gene editing will be predominantly performed by 1 group of practitioners (the “gene editors”). If cosmetic gene enhancement procedures can be simplified and not require expertise in genetics or genomics or in-depth knowledge about the focus of treatment (skin), it is within the realm of possibility that such procedures can be offered alongside other currently available cosmetic procedures in a variety of settings by a range of providers. In the not-so-distant future, a provider may not even be required if gene-editing procedures can be self-administered through the development and commercialization of gene-editing “kits” for popular genes. Such kits may be sold over the counter (like other cosmeceuticals) or require a health provider’s authorization (“prescription”) to edit a certain gene sequence.

In addition to the need for providers to undergo the appropriate training to perform gene-editing procedures however that will be defined, patient education and consent are important responsibilities of the provider. Parental consent is required for most medical procedures and assent from adolescents recommended. With the growing number of plastic surgeries performed on children, some have recommended that adolescents should be able to demonstrate knowledge of the procedure, recuperation, and short- and long-term implications.^46,47 As with some cosmetic procedures, achieving a desired appearance or change may not be completely possible. Likewise, changes to a single gene or even multiple genes may not have much effect on a given behavior or physical trait until the impact of other genetic and environment factors is better understood. Patients should be made aware of these limitations. In addition, providers should discuss patients’ motivations and evaluate psychological well-being.⁴⁸ Parental motivations for genetic testing of nonhealth conditions in children and how such tenuous results may be used by parents to steer their child’s participation toward certain activities (eg, sports vs music lessons) have been debated.^49,50 With the prospect of gene editing, requested changes in certain genes in a young child can be motivated by parental desires for specific skills or talents for their child. In addition, long-term implications should be raised with prospective customers; for example, those seeking gene enhancement to improve athletic performance may adversely impact eligibility for collegiate programs or professional sports. Thus, training programs should incorporate the necessary knowledge and patient communication skills to promote informed decision-making and the appropriateness of the procedure.

Conclusion

It may seem premature to engage in conversations about the delivery of gene enhancement procedures, as the science is still in its infancy and the focus has been on scientific discovery, therapeutic, or other societal-benefitting applications. However, given the complexity of gene-editing technologies and potential scope of application, moral and other objections to some types of applications, and involvement of multiple stakeholders (regulatory officials, health professionals, states, professional organizations, advocacy groups, and the public), the earlier these issues are raised, the better prepared society will be to address them as research continues at a rapid pace. The practice of cosmetic surgery endured a shaky start, and the development of numerous noninvasive cosmetic procedures expanded not only on the practice but also on the range of practitioners offering these services. If gene editing can be simplified to a level where expert knowledge or skill is not required to perform the procedure, the delivery of the services will likely reflect the current approach for noninvasive cosmetic procedures.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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A Brief Comparative History Analysis

Abstract

Keywords

Introduction

Materials and Methods

Results and Discussion

A Precedent: Plastic and Cosmetic Surgery

A New Form of Cosmetic Enhancement?

Dawn of a New Profession?

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References