Treatment of glabellar lines with Botox (onabotulinumtoxinA): Development, insights, and impact

Abstract

OnabotulinumtoxinA is an injectable medication that produces muscle relaxation through local chemical denervation at the neuromuscular junction. Discovery of onabotulinumtoxinA’s aesthetic benefits occurred serendipitously in the 1980s at the intersection of several medical disciplines, including ophthalmology, neurology, otolaryngology, and dermatology. Patients receiving onabotulinumtoxinA for blepharospasm, hemifacial spasm, and dystonia noticed their periorbital wrinkles disappearing, particularly frown lines between the eyebrows called glabellar lines (GL).

Aesthetic use of onabotulinumtoxinA necessitated rigorous training programs and vigilant monitoring by Allergan. Approval for the GL indication was based on 2 similarly designed, double-blind, randomized, multicenter clinical studies. Subjects with moderate to severe GL receiving onabotulinumtoxinA achieved significantly greater improvement in GL severity than those receiving placebo. In subsequent studies, more than 80% of subjects were satisfied with onabotulinumtoxinA treatment through day 60, and many reported looking approximately 4 years younger at weeks 4 and 12 than at baseline. OnabotulinumtoxinA has a rapid onset of action, and peak effect occurs between 30 and 60 days. The median duration of response for dynamic GL in the initial studies was 120 days and response progressively improved with subsequent treatments. OnabotulinumtoxinA was well tolerated, and the 2 most common adverse events, headache and blepharoptosis, tended to decrease in frequency with repeat treatment.

The novel use of onabotulinumtoxinA for treating GL was an important step in addressing the clinical need for a noninvasive, straightforward, office-based procedure for facial lines that also left patients extremely satisfied with its treatment effects and represented the beginning of its widespread use for numerous aesthetic indications.

1. Glabellar lines

The frown lines between the eyebrows, known as glabellar lines (GL), initially appear with negative facial expressions, such as frowning, but as individuals age, these lines persist and create an impression of a permanent negative emotional state.^[1,2] The continual action of the procerus and corrugator supercilii muscles results in GL, which often resemble the number 11 in the space between the eyebrows.^[3,4] When the lines remain visible at rest (static), they may erroneously project a state of constant anger or annoyance and may have an adverse impact on self-esteem, perception of attractiveness, social cues, and body image.^[5,6] For instance, they may miscommunicate anger, annoyance, anxiety, disapproval, or sadness,^[7] causing distress and affecting social interactions.^[8] In the 19th century, Darwin described the wrinkles between the eyebrows in chronically depressed individuals as resembling a horseshoe and attributed them to contractions of the corrugator muscle region.^[9] Greden and colleagues identified an association between electromyography activity from the corrugator region of the forehead and clinical ratings of agitation in patients with major depressive disorder.^[10]

Dr. J. Carruthers: “The power of the face is in the brow… the brows are framing the eyes, but the frame is probably what people notice first.”

The following historical narrative was compiled based on review of the literature and interviews with the authors, and the quoted portions reflect the personal observations and reflections of the individuals who were interviewed. In some instances, this article describes uses for which Allergan has not sought and/or received regulatory approval in individual countries and are mentioned for historical context or background only.

2. Evolution of the Indication

2.1. Unmet need and rationale for aesthetic treatments

Dr. J. Carruthers: “Fine lines are not a disease but a social commentary; the ultimate expression of ageism. In the world out there today, it makes a huge difference to look physically younger than they truly are….there is much more conflict in the work force between the younger people and the older people who do not want to be pushed aside, [especially] now that so many Baby Boomers are continuing to work”.

Earlier treatments for GL included extensive surgical procedures to lift the forehead and “threading,” in which sutures were placed in the lines to plump them up. Collagen fillers and autologous fat implants were other options, but each had a short duration of effect and could be associated with pain, allergic reactions, and embolic damage to the retina or optic nerve.^[2,11]

Dr. J. Carruthers: “What people want is a natural look. The problem with surgery is that the lift was too high, and often, the corrugator muscles reappeared in such a way that the glabellar frown was like a writhing motion. The fillers that were available at that time were somewhat limited in their effectiveness, and certainly in their safety.”

Dr. A. Carruthers: “The early injections [of fillers] were fraught with trouble, and there are references to vascular occlusion and problems with the circle of Willis and other important structures as a result of them….New treatments were needed because the old ones either didn’t work adequately, or had complications. They didn’t do what Botox does.”

Most of the earlier nonsurgical treatments did not address the underlying musculature causing the facial lines. Lift or threading procedures weakened the muscles that cause GL but did not denervate them, and were also associated with mixed results.^[12,13] In contrast, onabotulinumtoxinA acts by producing partial chemical denervation of the muscle, resulting in a localized decrease in muscle contractions.

Dr. J. Carruthers: “After [patients] had that endoscopic brow lift procedure, [they] lost that nice curvature of the brow [and developed a] hollow look…and so they had unusual movements in the forehead….When the eyebrows are over-elevated, such as with surgery, the magic triangle of the face (between the eyes and mouth) is distorted and people can’t connect emotionally. OnabotulinumtoxinA gave people a natural look and a mood elevation.”

2.2. Discovery of the aesthetic benefits of onabotulinumtoxinA

The neurotoxin produced by Clostridium botulinum has been used for medical applications since the early 1970s.^[3] This use expanded in 1987 as, during routine injection for blepharospasm, Vancouver-based clinical physicians, Drs. Jean and Alastair Carruthers serendipitously discovered the cosmetic benefits of onabotulinumtoxinA on the disappearance of upper facial rhytids, particularly GL.^[4,11] At the same time, New York‐based neurologist Dr. Mitchell Brin and otolaryngologist Dr. Andrew Blitzer discovered similar aesthetic benefits for facial rhytids, particularly in the periorbital area, in patients being treated for dystonias and hemifacial spasms.^[14]

Dr. Blitzer: “At our research center at Columbia University, onabotulinumtoxinA was being used at the time as a therapeutic for strabismus and dystonia. Patients treated into facial muscles were noticing that their wrinkles were getting smoothed out in the treated area. Patients and their relatives started requesting cosmetic treatments with onabotulinumtoxinA.”

Cosmetic treatments are not just for patients; Dr. Jean Carruthers even used onabotulinumtoxinA on herself for GL and was able to show her patients its effectiveness, as well as a lack of adverse effects.

Dr. J. Carruthers: “When we had our first cohort of patients, [the patients] would say...‘Well, isn’t that a terrible poison?’…I realized early on in this treatment that nobody was going to do this treatment unless they could see that somebody was still alive that did it to themselves.”

2.3. Clinical development of onabotulinumtoxinA for glabellar lines

As physicians began using onabotulinumtoxinA for GL, training courses were offered at medical congresses. Some investigators began conducting studies on the safety, efficacy, and dosing of onabotulinumtoxinA for cosmetic purposes.^[14–17] As part of a 1994 double-blind controlled evaluation of the effect of botulinum toxin on hyperkinetic facial lines, the 4-point Facial Wrinkle Grading System (FWGS) was developed, providing an early patient-reported method for assessing facial wrinkle severity before and after treatment (Table 1).^[16] The US Food and Drug Administration (FDA) began to recognize a need for clinical trial development to provide physicians with approved product labeling and instructions for use in cosmetic indications.

Table 1.

Facial Wrinkle Grading System (FWGS).^[16]

No wrinkles	0
Mild wrinkles	1
Moderate wrinkles	2
Severe wrinkles	3

Adapted with permission from Keen M, et al. Plast Reconstr Surg. 1994;94(1):94-99.

Ms. Eadie: “There was recognition of many opportunities, and much of it was physician driven because onabotulinumtoxinA was such a novel product. Allergan received incredible input regarding dosing and injection patterns for GL from physicians who were using it for their patients.”

A 1997 multicenter study of 210 hyperfunctional facial areas in 162 patients showed that upper facial lines treated with onabotulinumtoxinA injection, including GL, had statistically significant (P <.001) reductions in wrinkle severity on the 4-point scale compared with GL severity preinjection, with the improvements being even more apparent during dynamic facial expression (Figure 1).^[18]

Figure 1.

Wrinkle severity ratings on 4-point scale (0 = no wrinkles; 3 = severe wrinkles) before and after treatment with onabotulinumtoxinA. P <.001 for severity reductions in all facial areas shown (N = 201 regions). CFL, crow’s feet lines; FHL, forehead lines; GL, glabellar lines. Modified with permission from Blitzer, et al. Otolaryngol Head Neck Surg. 1997;123:389-392.

Dr. Brin: “When I presented the results of our early work to Allergan, it was met with a lot of enthusiasm.”

OnabotulinumtoxinA was first approved in Canada in 2001 as Botox Cosmetic for use in treating GL. In 2002, the US FDA approved onabotulinumtoxinA as Botox Cosmetic for use in the treatment of GL.^[3] It was the first product of its kind to be approved for moderate to severe GL. The injection pattern for GL includes 5 injection sites: 1 in the procerus muscle and 2 in each corrugator supercilia muscle, for a total onabotulinumtoxinA dose of 20 U.^[19] It is important to note that the FDA also required a statement in the product label indicating that units of onabotulinumtoxinA are not interchangeable with those of any other botulinum toxin preparation and cannot be compared to or converted into units of any other product.^[20] Each botulinum toxin product has its own dosing guidelines and clinical profile.

3. Efficacy and Safety Highlights

The efficacy and safety of onabotulinumtoxinA compared with placebo for treatment of GL were evaluated in 2 prospective, double-blind, randomized, multicenter clinical studies of identical design.^[2,19,21] The FDA did not require dose-ranging studies for onabotulinumtoxinA treatment of GL. Eligible subjects were adults who had moderate to severe GL at maximum frown based on investigator and subject assessment using the Facial Wrinkle Scale with photonumeric guide (FWS; score of 0=none, 1=mild, 2=moderate, and 3=severe). Subjects were randomized 3:1 to receive a single treatment of onabotulinumtoxinA 20 U or placebo evenly distributed among the 5 injection sites described above. In each of these studies, only subjects who had GL of at least moderate severity during maximum frown were eligible for treatment,^[2,21] thus introducing the concept of clinicians “treating to target”—ie, observing a threshold for treatment according to the severity of subjects’ facial lines.

Subjects in each of these studies who received onabotulinumtoxinA achieved significantly greater improvement in GL severity compared with subjects who received placebo, based on ratings from the 4-point FWS.^[2,21] In the first study, which was conducted at 14 US clinical centers, improvement was observed early; by day 7, the mean GL severity score had improved to 0.94 in the onabotulinumtoxinA group compared with minimal change from baseline in the placebo group (P <.001). Subjects receiving onabotulinumtoxinA achieved significantly higher responder rates, defined as the percentage of subjects with severity scores of none or mild based on physician assessment, compared with placebo at each time point (P <.001; Fig. 2). Among subjects with moderate to severe GL at rest, responder rates and improvements in mean severity score were significantly greater at every visit for onabotulinumtoxinA compared with placebo (P <.001). In addition, subjects’ assessment of the severity of their GL and global assessment of change in appearance also significantly favored onabotulinumtoxinA over placebo (P <.001).

Figure 2.

Physician’s assessment of GL severity at maximum frown. Responder rates for subjects achieving a rating of none or mild. *P <.001 vs placebo. Adapted with permission from Carruthers, et al. J Am Acad Dermatol. 2002;46:840-849.

In the second study, which was conducted at 1 Canadian and 15 US clinical centers, responder rates were significantly greater with onabotulinumtoxinA versus placebo at all visits, with a peak of 76.7% at day 30 (P <.001). Nearly one-fourth of subjects receiving onabotulinumtoxinA (24.4%) were rated as responders at day 120 compared with 2.9% of subjects receiving placebo. Among subjects with moderate to severe GL at rest, onabotulinumtoxinA resulted in significantly greater improvements in severity scores and responder rates compared with placebo at all visits (P ≤.023). Subjects receiving onabotulinumtoxinA also assessed the severity of their GL at every visit significantly better than those receiving placebo (P <.001).

Ms. Eadie: “We knew that onabotulinumtoxinA was effective, and we were able to demonstrate it in the clinical trials using the subjective none/mild/moderate/severe FWS and photographs. Prior to performing the study, we didn’t know how dramatic the efficacy would be….I never had results from a clinical study that approximated 100% in terms of patients showing improvement.”

OnabotulinumtoxinA treatment for GL was well tolerated. No subject in either study discontinued treatment because of adverse events.^[2,21] In the first study, adverse events that were reported in at least 5% of subjects in the onabotulinumtoxinA group were headache (15% of subjects in each treatment group) and blepharoptosis (onabotulinumtoxinA, 5.4%; placebo, 0.0%). In the 12 eyes affected by blepharoptosis, 8 cases were considered mild, with an average duration of 20 days, and 4 cases were considered moderate, with an average duration of 40 days. In the second study, headache occurred more frequently in the placebo group (20.0%) versus the onabotulinumtoxinA group (11.4%). Blepharoptosis was reported in 1% of subjects (2/202) receiving onabotulinumtoxinA; both cases were mild and unilateral. Treatment with onabotulinumtoxinA was well tolerated by subjects in both short-term and longer-term studies.^[2,21,22] In the longer-term (1-year) study, the frequencies of the 2 most common adverse events were shown to decrease with repeated treatment: headache from 8.2% to 0.8% and blepharoptosis from 3.0% to 0.8%. These findings suggest that physician experience with the administration of onabotulinumtoxinA, as well as with each individual subject over time, may have played a role in the declining incidences of these adverse events. Region-specific information regarding safety and efficacy can be found in local labeling.

Dr. Brin: “Rates of blepharoptosis declined over time as physicians gained experience with the procedure. I believe that Allergan’s steadfast commitment to comprehensive physician training may have helped reduce ptosis rates.”

In 2009, a large-scale meta-analysis, covering 9 trials (6 randomized, double-blind, placebo-controlled and 3 open-label), including data on 1678 subjects worldwide, was conducted to detect differences in adverse event incidence between treatment groups (onabotulinumtoxinA versus placebo) that may not have been apparent in the individual trials; all but 2 of these trials were for the treatment of GL.^[23] The meta-analysis demonstrated that serious adverse event incidence did not differ significantly by treatment group, no serious treatment-related adverse events occurred, and symptoms of weakness distant to the injection site or related to the central nervous system did not arise.^[23] Pooled adverse event data from the 4 randomized, double-blind, placebo-controlled studies for GL in this meta-analysis are shown in Table 2.^[23]

Table 2.

Adverse Events Reported by ≥1% of Subjects in Any Group. Pooled Data From 4 Randomized, Double-blind, Placebo-Controlled Studies of Botox Cosmetic 10 or 20 U for Glabellar Lines.^[23]

Adverse Event (%)	Botox Cosmetic 10 or 20 U (N=665)	Botox Cosmetic 20 U (N=619)	Placebo (N=236)
Headache	79 (11.9)	76 (12.3)	27 (11.4)
Nasopharyngitis	41 (6.2)	32 (5.2)	14 (5.9)
Eyelid sensory disorder*	22 (3.3)†	16 (2.6)†	1 (0.4)
Eyelid ptosis*	16 (2.4)†	15 (2.4)†	0 (0.0)
Injection site pain	14 (2.1)	10 (1.6)	3 (1.3)
Nausea	12 (1.8)	12 (1.9)	5 (2.1)
Influenza	10 (1.5)	10 (1.6)	1 (0.4)
Pharyngolaryngeal pain	8 (1.2)	6 (1.0)	2 (0.8)
Eyelid edema	10 (1.5)	9 (1.5)†	1 (0.4)
Sinusitis	10 (1.5)	8 (1.3)	3 (1.3)
Diarrhea	7 (1.1)	7 (1.1)	4 (1.7)
Bronchitis	6 (0.9)	6 (1.0)	3 (1.3)
Facial pain	7 (1.1)	7 (1.1)	0 (0.0)
Dental caries	6 (0.9)	6 (1.0)	0 (0.0)
Injection site erythema	6 (0.9)	6 (1.0)	2 (0.8)
Muscular weakness	6 (0.9)	6 (1.0)	0 (0.0)
Acne	3 (0.5)	3 (0.5)	3 (1.3)
Injection site pruritis	2 (0.3)	2 (0.3)	4 (1.7)†
Rash	0 (0.0)	0 (0.0)	3 (1.3)†

^*Included verbatim phrases tight, pressured, heavy, drooping feeling, and feeling of droopiness.

^† P < 0.05 vs placebo.

Adapted with permission from Brin MF, et al. J Am Acad Dermatol. 2009;61(6):961-970.

Dr. Blitzer: “The record of onabotulinumtoxinA speaks for itself — it is very safe over many, many years.”

In another meta-analysis, examining phase 3 clinical trials, the median duration of response to onabotulinumtoxinA, defined as a severity rating of none or mild on a 4-point scale, was 120 days for dynamic GL.^[1] For static or resting GL, the median duration of response was 139 days. Reduction in GL severity at rest was sustained for longer than the reduction at maximum frown, suggesting that the “smoothing” benefits of onabotulinumtoxinA last longer than its immediate muscle-modulating effects.^[5] In addition, response to onabotulinumtoxinA progressively improves with subsequent treatments.^[22,24] Thus, a remodeling of the face occurs, in essence, eradicating the scowl.^[5,21,22,24]

OnabotulinumtoxinA was also compared with 3 over-the-counter topical products that made advertising claims of similar or better outcomes than those associated with this neurotoxin’s use.^[25] Women with moderate to severe GL were randomized to onabotulinumtoxinA, placebo, StriVectin-SD cream, Wrinkle Relax, or HydroDerm cream. OnabotulinumtoxinA significantly reduced GL at maximum frown at all follow-up visits and resulted in significantly greater changes from baseline in FWS compared with any other treatment (P <.001). Subjects’ ratings of 4 self-perception items using Allergan’s Facial Lines Outcome Questionnaire were significantly lower with onabotulinumtoxinA compared with placebo (P <.05); ratings for the other treatment groups did not differ from placebo or baseline mean scores at any time point.

Subsequent studies examined the effects of repeated treatment with onabotulinumtoxinA on GL.^[22,24] Progressive improvements in physician-assessed treatment response rates at maximum frown and at rest were observed for subjects who received 3 onabotulinumtoxinA treatments 4 months apart. Subjects’ global assessment was significantly higher after the third treatment than after the first or second treatments at days 90 and 120. Over multiple treatments with onabotulinumtoxinA, the incidence of treatment-related adverse events declined,^[22] and after 3 successive treatments, no subject tested positive for neutralizing antibodies to onabotulinumtoxinA, which are considered to be associated with a loss of clinical efficacy.^[26]

When another study examined the effect of onabotulinumtoxinA on mild lines at rest based on data from 2 randomized, double-blind, placebo-controlled studies, it showed that a significant number of patients experienced elimination of their lines at rest, ie, the “smoothing” effect.^[5] For mild GL assessed at rest, treatment with onabotulinumtoxinA provides a smoother, more youthful facial appearance.^[5,24] Research has suggested that these effects are related to the local relaxation of transverse muscle cells and to tissue remodeling in response to reduced muscle activity^[5,24] that reduces average skin roughness.^[27]

An approach to optimization of aesthetic effect has evolved since these first studies of onabotulinumtoxinA were conducted on GL.^[1] Currently, not only are objective wrinkle measurements important, but subjective measurements, including subject satisfaction and improvements in self-esteem, global appearance, confidence, psychological impact, and quality of life, are also assessed. In one study, responses to Allergan’s Facial Line Satisfaction Questionnaire, a validated patient-reported outcome (PRO) measure, indicated that more than 80% of subjects were satisfied at day 60 with onabotulinumtoxinA treatment of GL compared with none of the subjects who received placebo, and satisfaction remained at 75% or greater up to 120 days after treatment.^[6] In another study, subject-reported responses to Allergan’s Self-Perception of Age questionnaire, a single-scale PRO measure in which subjects report how old they think they looked over the last 7 days, demonstrated that subject perception of their own appearance was significantly improved after treatment with onabotulinumtoxinA (P ≤.01).^[28] At study week 4, the onabotulinumtoxinA group reported that they looked approximately 4 years younger than they did at baseline whereas the placebo group reported essentially no change; these findings were maintained through week 12. Moreover, Allergan generated evidence supporting the psychological impact benefit of onabotulinumtoxinA treatment in order to address European regulatory health requirements; the summary of product characteristics specifically states that onabotulinumtoxinA is used for the “temporary improvement in the appearance of moderate to severe vertical lines between the eyebrows seen at maximum frown (GL)…when the severity of the facial lines has an important psychological impact in adult patients.”^[29]

Dr. A. Carruthers: “One of the things that Allergan has done a wonderful job with is with the PROs, the patient-reported outcomes. The [improvements in] self-perception of age held up every time.”

4. Lessons learned

Dr. Blitzer: “Because of the widespread use of onabotulinumtoxinA, it was not only being done by doctors but also by less-experienced professionals. The biomedical community, and even the patient community, realized the outstanding safety profile of onabotulinumtoxinA.”

In the treatment of GL, reduction of blepharoptosis is possible by avoiding the injection of onabotulinumtoxinA near the levator muscle of the upper eyelid, particularly in patients with larger brow depressor complexes.^[2,19,21] In addition, it is generally important to place lateral corrugator injections at least 1 cm above the bony supraorbital margin and to avoid injecting onabotulinumtoxinA closer than 1 cm above the central eyebrow.^[2]

Advantages of onabotulinumtoxinA treatment for GL include a rapid injection procedure that can be performed on an outpatient basis, a short recovery period, and the ability to tailor the treatment to the individual by administering injections serially and by titrating the dose based on muscle structure and size.^[2]

Dr. Blitzer: “After we [Drs. Blitzer and Brin] and Drs. Carruthers and Carruthers brought onabotulinumtoxinA into the medical community, it became a very popular tool for physicians to provide patients an aesthetic result...onabotulinumtoxinA provided a straightforward, in-office treatment to manage facial lines.”

5. Impact of the indication/summary

OnabotulinumtoxinA has effectively and safely reduced focal facial muscular activity responsible for dynamic and static GL.^[1] Both physicians and subjects report significantly greater improvement in GL severity with onabotulinumtoxinA treatment compared with placebo.^[2,21] OnabotulinumtoxinA had a rapid onset of action, and the peak effect occurs between 30 and 60 days.

Dr. J. Carruthers: “[During the early phases of clinical development,] we [the physicians] actually asked if we could purchase it from Allergan! We really believed in it….onabotulinumtoxinA gave such a natural look. It didn’t last forever, but it looked natural. That is the thing that people absolutely adored about it.”

Ms. Eadie: “Everyone recognizes onabotulinumtoxinA; it got into the media and into mainstream conversation.”

Dr. Blitzer: “It was part of television shows and has become a household name.”

OnabotulinumtoxinA has had a notable impact on society. Nearly 7.7 million botulinum toxin type A injections were performed in 2019 and represented the top minimally invasive cosmetic procedure of the year, demonstrating 878% growth since 2000.^[30] Botox has appeared on the cover of national magazines, including The New Yorker (December 10, 2021; Fig. 3), Time (January 18, 2017), and Newsweek (October 15, 2012). In the era of social media applications where facial photographs (“selfies”) can be easily edited to create the “ideal” image, the aesthetic use of onabotulinumtoxinA has become enticing and accessible to the general public. In an interview in The New York Times, dermatologist Dr. Patricia Wexler commented, “Botox is like grooming now. It’s socially acceptable, even expected.”

Figure 3.

Botox featured on the December 10, 2001 cover of The New Yorker. “New Yorkistan” by Maira Kalman and Rick Meyerowitz. Reprinted with permission.

Dr. Brin: “The use of onabotulinumtoxinA to treat glabellar lines was discovered fortuitously and had a substantial impact on clinical practice, evolving into treatment of other cosmetic indications, including forehead lines and crow’s feet lines.^[31] Patients also reported improvement in headaches after onabotulinumtoxinA treatment, which led to subsequent clinical trials and the approval of onabotulinumtoxinA for the treatment of migraine headaches.”

A continuous investment in research and development for over 30 years has established a robust safety and efficacy profile for onabotulinumtoxinA in 14 indications, including 3 for facial aesthetics in the United States alone. Efforts to further expand the evidence surrounding the safety and efficacy of onabotulinumtoxinA includes ongoing investigations to support first-of-kind indications, such as masseter hypertrophy in aesthetics and atrial fibrillation in therapeutics. OnabotulinumtoxinA is supported by 5561 clinical and non-clinical publications, 2.3 times more than that of all the other US-approved botulinum toxin type A products combined, which have also examined the real-world evidence and expanded both our clinical and scientific understanding of onabotulinumtoxinA.

Acknowledgments

Writing and editorial assistance was provided to the authors by Michelle McDermott, PharmD of Peloton Advantage, an OPEN Health company, and was funded by AbbVie.

Author contributions

Conceptualization: All authors.

Project administration: Mitchell F. Brin.

Supervision: Mitchell F. Brin.

Writing – original draft: Mitchell F. Brin.

Writing – review & editing: All authors.