Pre-Mendelian Era (19th Century)

Nearly 2400 years after Aristotle and Hippocrates, Charles Darwin (1809-1882) proposed that the inherited particles passed from parents to offspring (“gemmules”) are “blended” together in the zygote through the process of pangenesis to produce a combination of discrete physical traits inherited separately from each progenitor. August Weismann (1834-1914), who is often called the father of genetics, added that the traits programmed by the units of heredity are predetermined and immutable; ie, they cannot be altered in development and form by environmental or other factors.

Classical Era (1900-1930)

The field of genetics began to emerge at the turn of the 20th century with the rediscovery of experiments on plant hybridization performed over 40 years earlier by Gregor Mendel. With Mendel’s laws of inheritance as a foundation, quantitative methods were developed to study traits across generations of animals and plants, giving rise to the study of transmission genetics and quantitative population genetics. Research in structural genetics led to the discovery that genes located on chromosomes are the principal units of heredity. Finally, developmental genetics arose with recognition that genes produce phenotypic traits through their expression during the process of development. Thus began transformation of the study of heredity into the field of genetics as the study of the transmission, structure, and function of the genes.

DNA Era (1930-1970)

The DNA era of genetics was remarkable for groundbreaking discoveries that had wide-ranging impacts in all the biologic sciences. At the outset, the integration of Mendel’s laws of inheritance with paleontology in the 1930s provided the basis for the synthetic theory of evolution. Also at that time, quantitative population geneticists developed approaches for analysis of the heritability of phenotypic traits.

Discoveries in the 1940s and 1950s about the function and structure of the gene initiated a whole new paradigm in genetics. Initially, discovery that genes code for proteins provided the basis for the “central dogma of genetics.” Subsequently, DNA was confirmed as the basic chemical ingredient of genes. Finally, one of the most important discoveries in the history of science occurred when James Watson and Francis Crick determined the structure of DNA as a double helix and thus provided a biochemical and structural basis for replication and transmission of genetic material to progeny.

Genomics Era (1970-2010)

Another paradigm shift in genetics occurred in the 1970s, primarily as a result of advancements in molecular biology leading to the development of methods to create recombinant DNA and sequence genes. In addition, new molecular methods for genetic engineering of experimental animals, such as transgenic and knockout mouse models, allowed for analysis of the function of individual genes and groups of genes in complex living animals. Advancement of molecular technology culminated with the sequencing of the human genome in 2003; this made it possible to identify genes and gene variants associated with a whole spectrum of genetic diseases and disorders.

Postgenomic/Epigenomic Era (2010- )

Equipped with new and ever more powerful molecular methods such as next-generation sequencing and genetic engineering as well as knowledge of the human and mouse genomes, the postgenomic/epigenomic era is characterized by emphasis on application of the principles of genomics in many interrelated areas. Those areas include studies of the function of specific genes and gene products (functional genomics); normal gene variants such as single nucleotide polymorphisms as the basis of normal phenotypic variability; intrinsic and extrinsic environmental factors regulating gene expression (epigenomics); and patterns of human genetic variation and disease based on genetic polymorphisms (haplotype mapping and genome-wide association studies). In addition, mathematicians, biostatisticians, and computer scientists together developed sophisticated computer-based technologies for comparative analysis of gene sequences and even whole genomes (bioinformatics).

Precision medicine period

The vast amount of information emerging from research on the human genome during the postgenomic/epigenomic era has now advanced sufficiently to begin to realize a major goal of biomedical research: understanding individual susceptibility to certain diseases and response to treatment. It is well known in medicine that the development, progression, and treatment outcomes associated with certain diseases and disorders vary considerably among patients. It is now understood that this susceptibility and variability may be due primarily to minor, typically normal, genetic variations, or polymorphisms, including single nucleotide polymorphisms (it is estimated that the human genome contains over 2 million single nucleotide polymorphisms). Awareness that there may be an underlying genomic basis for heterogeneity of response to treatment of many diseases and disorders led naturally to a still-evolving new paradigm in medicine referred to initially as personalized medicine and now called precision medicine. Precision medicine represents the current culmination of research in genetics based on application of information about individual genomes to improve diagnosis, prevention, and treatment of diseases and disorders with an underlying genomic basis on a patient-by-patient basis.

Orthodontia Era (1900-1930)

The orthodontia era (1900-1930) began with the inception of orthodontics in the United States, generally considered to have taken place in the latter part of the 19th century with the work of Kingsley (1825-1896) and Farrar (1839-1913). Although ideas about inheritance of dentofacial growth and form often were mentioned at the outset of discussions by these and other early leaders in orthodontics, emphasis typically shifted quickly to types and classifications of malocclusions as well as different mechanical approaches to orthodontic tooth movement.

The well-known controversy in orthodontics, the Great Extraction Debate of 1911, between followers of Edward Angle and Calvin Case, epitomizes opinions about the role of heredity and malocclusion during the orthodontia era. Edward Angle (1855-1930) and his followers believed in what he referred to as “nature’s plan” for the normal function and form of the occlusal plane. Angle was influenced by the work of Julius Wolff (1836-1902), a German orthopedic surgeon best known for development of Wolff’s law, which simply stated maintains that the form of a bone follows its function. Wolff, in turn, was greatly influenced by Naturphilosophie , which asserted that nature is essentially a mystical power that provides a blueprint for skeletal form, and that normal “function” is the process by which nature ensured the genesis of normal form. Angle and his many followers thus believed that abnormal growth of the jaws leading to malocclusion and dentofacial deformities is not inherited directly, but results from abnormal function caused by “perverted” behavioral habits and other external, environmental conditions. Furthermore, Angle asserted that orthodontic appliances can “unpervert” forces on the developing jaws and thereby stimulate normal growth of the occlusal arches.

Calvin Case (1847-1923) believed strongly that science must provide the foundation of the new field of orthodontics. Accordingly, he relied on accepted scientific beliefs of the time about heredity to assert that the skeletal structures of the face and occlusal arches are inherited in their final size and form through what he referred to as biologic laws, by which he primarily meant Darwin’s concept of pangenesis coupled with Weismann’s belief in predetermined inheritance of discrete traits. Case thus used then-accepted scientific concepts such as pangenesis and predetermination of inherited traits to support his views about atavism and the inability to influence growth of the jaws. According to Case, “the fantastic claims [by Angle and his followers] that ‘all malocclusions arise from local causes,’ and ‘God does not make such mistakes in forming human anatomies,’ and so on must be regarded as crass ignorance of the well established principles of heredity.” (Ironically, those concepts about heredity turned out to be erroneous.) Therefore, tooth extraction is required to accommodate an inherited mismatch between tooth size and the size of the jaws and occlusal arches.

Pangenesis was rejected by geneticists by the 1920s. Nevertheless, Case, Kadner, and even later orthodontic researchers continued to maintain that the sizes of the maxilla and the mandible are predetermined and inherited separately from the mother and father. Thus, a prominent belief in the orthodontic community through at least the first 3 decades of the 20th century was that malocclusion occurs primarily as a result of “atavistic heredity from distant inharmonious progenitors” caused by admixtures and blended inheritances with persons of “lower races.” Acceptance of the ideas of atavism and miscegenation was also undoubtedly fueled by contemporary ideas of a hierarchy of racial “types” and social prejudices regarding the mixing of certain ethnic and racial groups.

Hereditary vs Environment Era (1930-1970)

At the start of the hereditary vs environment era, emphasis in the orthodontic literature centered on the determining role of local environmental and behavioral factors such as airway (tonsils and adenoids); endocrine and metabolic disorders; disorders of the “blood glands”; pressure from the lips, tongue, and cheeks caused by “perverted” oral habits; and other “constitutional factors.” According to Wylie, many dentists and orthodontists at the time had an actual bias against the idea that heredity might play a role in the development and growth of the dentofacial region, and certainly that heredity might be important to their profession.

Nevertheless, in the aftermath of the Angle-Case debate, there was growing recognition in the orthodontic community at large of the need to become more cognizant of the principles of heredity to improve understanding of dentofacial growth and malocclusion. That trend is readily apparent by publication in the AJO-DO , beginning in the late 1920s, of invited articles by scientific experts from zoology, anthropology, and medicine as primers of the new sciences of heredity and evolution for orthodontists. For example, M. F. Guyer, professor of zoology at the University of Wisconsin, provided the first discussion of Mendelian inheritance and use of the term “genetics” in the AJO-DO in 1924. The practical but still theoretic basis for increased interest in the principles of heredity and their potential relevance for understanding malocclusion was well summarized by Salzmann: “Since rational treatment of any [malocclusion and dentofacial] abnormality necessitates a correct diagnosis and the determination and removal of underlying causes, the ability to distinguish developmental influences of an inherent nature, if they actually do exist, is imperative and such knowledge should be applied to diagnosis and treatment.” As evidence of this growing interest, by the mid-1930s and continuing through the 1940s, there was a burst of scholarly publications in the AJO-DO dealing with the proportionate degree that heredity controls dentofacial growth and form.

In the 1930s, a German orthodontist and a Belgian physician introduced the orthodontic community to the idea developed in quantitative population genetics that the study of twins provides a unique approach to separate the relative contributions of heredity and environment to physical constitution. From that point on, during the late 1930s and throughout the 1950s, much of orthodontic research focused on family pedigrees and especially on the study of twins from the perspectives of Mendelian genetics. Virtually all of those studies tended to support the newly popular opinion that heredity determines the size and shape of the jaws in both normal and abnormal development and growth. Thus, by the 1940s, opinions among most orthodontic educators and researchers had switched from abrogation of heredity as the primary factor determining normal and abnormal dentofacial growth and form to the position that “today, the hereditary factors are considered first in importance and [local environmental] factors second in the process of growth and development.”

During its first 25 years, the AJO-DO published over 20 articles that substantively addressed, positively and negatively, the role of heredity in the etiology of malocclusion ( Fig 1 ). The number of articles increased considerably through the end of the 1940s because of enthusiasm for intrafamilial and twin studies. During the next 10 years, however, studies on heredity and genetics in orthodontics dropped dramatically, until between 1960 and 1968 no substantive articles dealing with heredity and genetics were published in the AJO-DO . Although the hiatus in publications could have been an anomaly of the AJO-DO alone, that does not appear to be true. There also were no articles dealing substantively with genetics published in the Angle Orthodontist from 1960 through 1968 and only 18 articles in all major journals between 1960 and 1965.

A, Number of articles published in the AJO-DO per decade at 5-year intervals from 1930 through 2014 that dealt substantively with heredity, genetics, and orthodontics; B, results of Web-based searches for articles from all major scientific and clinical journals, 1960 through 2000, using the search terms heredity or genetics and orthodontics or malocclusion .

Sources: PubMed and Science Direct.

The hiatus of publications in the 1960s suggests strongly that by the middle of the 20th century the pendulum of opinion in the orthodontic community had swung back toward the view that contemporary concepts from genetics had questionable value for the practice of orthodontics. Representing that point of view, Harold Noyes, professor of orthodontics at the University of Oregon, noted that from a practical standpoint, knowledge that a patient’s malocclusion is due to genetics would not alter his treatment. Noyes most likely spoke for most orthodontists when he stated that “while I am intrigued with the science of genetics and impressed with its tremendous growth in the past few years, I feel that as yet it is essentially academic with respect to the clinical practice of orthodontics and of only occasional value as a tool in the diagnosis and treatment of malocclusion ” [italics added]. According to Kraus et al from the University of Washington, “The very nature of genic action, as far as geneticists understand it at present time, precludes the notion that [the dentofacial] complex has a simple genetic determinant or that, indeed, its heritability can be accurately assessed ” [italics added]. Frans van der Linden, professor of orthodontics at the University of Nijmegen in The Netherlands, similarly stated that “the effects of genetic and environmental factors on the structure of the facial complex have been oversimplified by many authors—partly because of the limited information available on hereditary influences and partly because of the typical approach” of classical Mendelian analysis of family pedigrees.

Heritability Era (1970-2000)

After the hiatus of the 1960s, in the 1971 John V. Mershon Memorial Lecture, J. A. Salzmann essentially issued a “call to arms” to the orthodontic community when he noted that “We do not at present have the knowledge and the instruments to enable us to obtain prediction on genetic growth and development in the antenatal stage or in the continuing dynamic phases after birth. . . . [However, orthodontists must] perforce keep up with newer developments in [genetics], as well as orthodontic therapy, if they expect to obtain better results in the prevention and treatment of malocclusion in the future.” About the same time, the National Institute of Dental Research organized 2 “state-of-the-art” workshops to review the contemporary status of orthodontic research on the role of genetics in malocclusion and occlusal variation. Both workshops concluded that univariate analysis of twins and family pedigrees in general using classical Mendelian models of monogenic inheritance had failed to show genetic mechanisms of dentofacial growth and malocclusion. They also jointly called for the development of more sophisticated multivariate statistical methods that theoretically could be used to analyze polygenic inheritance of dentofacial traits in human pedigrees to determine the multifactorial basis of dentofacial form.

Beginning in the mid-1970s, a number of orthodontic researchers adopted multivariate statistical methods to study the variability of specific metric features of the dentofacial complex to quantify proportionate degrees of genetic and environmental contributions to dentofacial form: ie, the heritability of specific dentofacial measurements. Researchers also continued to emphasize pedigree analysis with the idea that if it was done properly with multivariate statistical methods, information on heritability of dentofacial features would allow orthodontists to predict dentofacial growth and adult form with and without orthodontic treatment.

Advances in computer technology permitted orthodontic researchers to digitize radiographic cephalograms and use multivariate statistical methods to explore patterns of craniometric variation in families, again with the goal of providing more accurate predictions of dentofacial growth. It was apparent to some researchers, however, that even those more sophisticated methods for cephalometry and multivariate statistical approaches largely depended on the variables selected and could only provide a measure of statistical associations without consideration of their underlying genetic causes. Thus, according to Stuart Hunter and colleagues in the Department of Orthodontics at the University of Michigan, they are “of questionable value when used to predict adult dimensions in the offspring.”

During the first 15 years of the heritability era, from 1970 through the mid-1980s, the AJO-DO published approximately 20 articles that dealt substantively with heredity and the genetics of dentofacial growth and malocclusion. Then there was a second hiatus (1985-1990) during which no substantive articles about heredity and genetics appeared in the AJO-DO .

The reasons behind this second hiatus in research and publication undoubtedly were similar in general to those for the hiatus during the 1960s: ie, frustration with contemporary approaches to research on the genetics of dentofacial growth and malocclusion and a lack of confidence in the orthodontic community regarding the ability of the principles of genetics to predict dentofacial growth with and without treatment. That sense of frustration is readily apparent in an editorial entitled “Hereditary environment” by Wayne Watson, then editor of the American Journal of Orthodontics , who noted that although the field of genetics has undergone an “explosion” of research that “can be seen and heard around the world…research on the genetics of dental occlusion has had little effect on the daily practice of clinical orthodontics.”

By the mid-1980s, significant methodologic problems in contemporary studies of heritability overall had become apparent to several researchers. For example, Corruccini and Potter and Harris and Johnson, experts in quantitative genetics of dental and craniometric data, identified significant problems regarding the selection of sample populations, cephalometric variables, and overly simple assumptions about the meaning of estimates of heritability for understanding the underlying genetic mechanisms of craniometric and occlusal variables. They also admonished orthodontic researchers that estimates of heritability should be just the first step in understanding the role of genetics in malocclusion; they are not ends in themselves. Studies of heritability with cephalometrics and measurements of occlusion even in twins provide little direct information about the underlying genetic mechanisms and do not address the possibility of altered genetic expression caused by functional and other environmental factors.

An additional issue prominent in orthodontics leading up to the 1985 to 1990 hiatus resulted in an even more general sense of uncertainty about the value of research on the role of genetics in dentofacial growth. Beginning in the 1960s and extending through the 1980s, Melvin Moss, a preeminent craniofacial biologist from Columbia University, developed the functional matrix hypothesis as an evolving conceptual framework that provided an alternative explanation to genetics for the factors influencing development and growth of the craniofacial complex. Moss’s position about the growth of the cephalic cartilages and gene functions during craniofacial development and growth, as well as the significance of the functional matrix hypothesis for treatment, was extreme and therefore highly contentious. Nevertheless, the essentially all-consuming debate in the entire orthodontic community during the 1970s and 1980s related to the functional matrix hypothesis had a significant impact because it was a catalyst for a major shift of the prevailing concept in craniofacial biology to what has been called the functional paradigm as a theoretic basis for a broader consideration of epigenetic-environmental factors as part of orthodontic and dentofacial orthopedic treatment. It was also then that the name of the journal was changed to the American Journal of Orthodontics and Dentofacial Orthopedics , indicating that the pendulum had again swung from focus on heredity and genetics in dentofacial growth and malocclusion to emphasis on function, biomechanical forces, and other nongenetic factors that might affect dentofacial growth as well as the etiology and treatment of malocclusion.

Orthodontic Genomics Era (2000- )

The onset of the orthodontic genomics era at the start of the 21st century marked the start of a paradigm shift in orthodontic research, characterized most readily by the rise of new prevailing questions and concerns about the genetic basis of the specific molecular pathways underlying dentofacial development and deformities. It was at that point in time that orthodontic researchers adopted more fully the concepts and methods developed 20 years earlier in genetics that were now sufficiently understood so that they could be applied in meaningful ways to problems of dentofacial development and deformities.

Beginning in the 1990s, several orthodontic researchers, dentist-scientists, and craniofacial biologists achieved considerable prominence in the broader field of genetics as a result of their significant contributions published in the scientific literature outside of orthodontics to understanding the developmental biology and genetic basis of the spectrum of craniofacial anomalies. As a result of that research, tooth development, cleft lip and palate, and craniofacial dysmorphology became model systems that have proven to be especially relevant for understanding the basic processes of the genomics and epigenomics of development overall.

The number of articles published in the orthodontic literature underscores once again the new emphasis by orthodontic researchers on the genomics of craniofacial and dentofacial development. During the 30 years from 1970 to the end of the 20th century, over 400 articles on the combined topics of genetics or heredity and orthodontics were published in major scientific and clinical journals worldwide; over 30 of those articles, an average of about 1 per year, appeared in the AJO-DO . The beginning of the 21st century saw a significant increase in research on craniofacial genomics as indicated by more than double the number of articles published on genetics and craniofacial development in all scientific and clinical journals. This trend is mirrored closely by an increase in the number of articles dealing substantively with genetics published in the AJO-DO from the end of the 1990s, to an average of 5 per year in the 4 years from 2010 to 2014.

Despite the new focus on the molecular basis of development, analysis of heritability through quantitative genetics remained an important part of the overall research approach in orthodontics. However, researchers in dental genetics and craniofacial growth now emphasized that it is a mistake to assume that heritability can be used in a meaningful way to assist in the treatment of each patient because genomic research has demonstrated that the environment coupled with genetic variants plays a far greater role in the determination of intrafamilial variations of even common traits. For example, as noted by James Hartsfield and colleagues in the Department of Orthodontics at the University of Kentucky, “There is a common perception that knowing a trait’s heritability should affect how a patient is to be treated. This is a misconception. The ability of the patient to respond to changes in the environment (including treatment), which has nothing to do with estimates of heritability for the trait, will define this.”

An incredible amount of information was generated on the basic genetics of craniofacial and dental development with the shift in emphasis in orthodontic and craniofacial research during the late 1990s and early 2000s. The greatest progress in areas of primary importance to orthodontics, as evidenced in the AJO-DO during this period, took place in the identification of the genes for craniofacial dysmorphologies, including growth factors and transcription factors controlling morphogenesis and growth of craniofacial tissues, candidate genes for midfacial deformities, and genes affecting growth of the condylar cartilage of the mandible both normally and during treatment. With advances in molecular analysis of genes from both animals and humans, orthodontic researchers also began to address the specific effects of gene variants for growth factors and cytokines as they might affect dental development, tooth movement, root resorption, temporomandibular joint pain, and assessment of skeletal maturation.

Postgenomic/epigenomic period

In the postgenomic/epigenomic period, during the late 1990s and early 2000s, orthodontic and other craniofacial researchers began to make significant advances in genetic research by adopting the approaches and molecular methods of developmental biology generally common in genetics. The most obvious area for emphasis in research at that time was craniofacial dysmorphogenesis, both because it is a major clinical problem that demands attention and because dysmorphology is often associated with single-gene mutations and thus provides an excellent model system for the study of developmental processes in general and for the complex craniofacial region in particular. However, during the first decade or more of the 21st century, major interest in both genetic and orthodontic research had grown to include greater consideration of the role of gene variants, such as single nucleotide polymorphisms, and regulatory molecules, such as microRNAs, as well as more complex groups of genes, or haplotypes, in dentofacial development and growth.

The current postgenomic/epigenomic period of orthodontic research is a continuation of the orthodontic genomics era, but with 2 notable advancements. First and foremost, researchers have begun to consider genomic information to improve diagnosis and treatment of dental disorders and dentofacial deformities in orthodontic patients. Second, recent orthodontic research has moved toward greater emphasis on the genetic factors underlying clinical problems that are seen more regularly in orthodontic practices, such as malocclusion, tooth movement, and dental crowding, rather than on less common, genomically less complex craniofacial anomalies.

Precision orthodontics period

As noted previously, precision medicine is based on the idea that each patient’s genome as well as the way epigenomic factors affect gene expression can vary from person to person. The key principle of precision medicine is that even minor gene variants such as single nucleotide polymorphisms, which exist normally in the genome of everyone, are largely responsible for variations in development, growth, and response to environmental perturbations. As a result, individual genomes may vary with respect to susceptibility and progression of diseases and disorders as well as to response to clinical treatment.

Shortly after the Human Genome Project was completed, articles began to appear in the dental literature addressing the need to improve education in genetics so that new generations of dentists can take advantage of the significant advances that would inevitably emerge from detailed knowledge of the human genome. Several articles also extolled “personalized” dentistry. As with precision medicine, virtually all of those articles tended to focus on prevention and treatment of acquired diseases that may have an underlying genomic component: eg, caries, periodontal disease, and oral cancer. Although dentofacial disorders associated with monogenic defects, such as dental agenesis and certain craniofacial syndromes, are sometimes mentioned, there has been little substantive consideration regarding complex, polygenic developmental disorders. This is unfortunate, since the principles of precision medicine are ideally suited to basic and applied clinical research on the etiology, differential diagnosis, and treatment of developmental disorders such as malocclusion and dentofacial deformities.

An example of how the central concepts and principles that make up precision medicine can be used to account for variations in dentofacial growth and orthodontic treatment response can be found in an article published in the AJO-DO at the start of the orthodontic genomics era. In a theoretical discussion of the role of genetics in the treatment of a developing dentofacial deformity, a heuristic model was proposed based on the idea that the orthodontic patient population could be considered a continuum that can be stratified loosely into 3 broad and overlapping groups, each with a number of substrata, based on individual genomes ( Fig 2 ). At one end of the continuum is a group characterized by definitive defects related to mutations of key genes that affect the development of core craniofacial tissues and organs. These subjects’ craniofacial deformities are principally a direct consequence of significant abnormalities in their genomes. In addition, it should be expected that standard clinical approaches to change the growth of affected tissues and regions based on assumptions of normal growth processes are likely to be compromised because of the same underlying genetic abnormalities. The population at the other end of the broader continuum includes persons with a range of “standard” or “normal” genomes. Those in the “standard” group would be expected to express a range of normal phenotypic variation because of their spectrum of standard polymorphisms. Consequently, the process of dentofacial growth would be “normal”—the way it is supposed to occur according to textbooks on craniofacial growth. Similarly, response to orthodontic treatment to correct a malocclusion or a developing maxillomandibular discrepancy in this group should for the most part conform to expectations for “normal” growth processes.

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