The Era of the Genome and Dental Medicine

Abstract

Understanding the “code of life” and mapping the human genome have been monumental and era-defining scientific landmarks—analogous to setting foot on the moon. The last century has been characterized by exponential advances in our understanding of the biological and specifically molecular basis of health and disease. The early part of the 20th century was marked by fundamental theoretical and scientific advances in understanding heredity, the identification of the DNA molecule and genes, and the elucidation of the central dogma of biology. The second half was characterized by experimental and increasingly molecular investigations, including clinical and population applications. The completion of the Human Genome Project in 2003 and the continuous technological advances have democratized access to this information and the ability to generate health and disease association data; however, the realization of genomic and precision medicine, to practically improve people’s health, has lagged. The oral health domain has made great strides and substantially benefited from the last century of advances in genetics and genomics. Observations regarding a hereditary component of dental caries were reported as early as the 1920s. Subsequent breakthroughs were made in the discovery of genetic causes of rare diseases, such as ectodermal dysplasias, orofacial clefts, and other craniofacial and dental anomalies. More recently, genome-wide investigations have been conducted and reported for several diseases and traits, including periodontal disease, dental caries, tooth agenesis, cancers of the head and neck, orofacial pain, temporomandibular disorders, and craniofacial morphometrics. Gene therapies and gene editing with CRISPR/Cas represent the latest frontier surpassed in the era of genomic medicine. Amid rapid genomics progress, several challenges and opportunities lie ahead. Importantly, systematic efforts supported by implementation science are needed to realize the full potential of genomics, including the improvement of public and practitioner genomics literacy, the promotion of individual and population oral health, and the reduction of disparities.

A Brief History of the Human Genome Discovery and Exploration

Exploring the origins and boundaries of the observable universe, discovering the elementary particles that make up our world, deciphering the human genome—there have been few human achievements of such magnitude and ambition. Understanding the “code of life” and mapping the human genome have been 2 of these monumental and era-defining scientific landmarks, analogous to setting foot on the moon. While the origins of theories on heredity can be referenced to ancient philosophers, including Hippocrates and Aristotle, Mendel’s (1865) work on pea plants, conducted >2,000 years later, is considered the foundation of most contemporary work on biology and genetics. The last century has been characterized by unprecedented and exponential advances in our understanding of the biological, hereditary, and specifically molecular basis of health and disease. This article reviews the progress and landmark events in the study of the human genome during the last century and summarizes the achievements and key contributions in the domain of oral and craniofacial health genomics.

First Part of the 21st Century: Heritability, Chromosomes, and Genes

By the beginning of the 21st century, it was already understood that cells are the fundamental units of life, largely owing to Schwann’s “cell theory” in the mid-19th century. In the early 20th century, Wilhelm Johannsen (2014) defined and pioneered the use of the terms genotype, phenotype, and gene, and independent work by Walter Sutton and Theodor Boveri supported the notion that chromosomes carry the genetic material. Around the same time, research done by European scientists, including Hugo De Vries, Erich von Tschermak and Carl Erich Correns affirmed and repopularized Mendel’s work on genetics and inheritance, although most of its mechanistic aspects remained elusive.

Building on this momentum, Thomas Hunt Morgan’s (1919, 1926) experimental work, in collaboration with Alfred Henry Sturtevant, Calvin Blackman Bridges, and Herman Joseph Muller, provided the much-needed first scientific evidence for hereditary transmission mechanisms explaining Mendel’s theory, including the fact that chromosomes carry genes. Importantly, Sturtevant’s (1913) graduate work under the supervision of Morgan demonstrated that genes can be arranged onto a linear map on a chromosome. In sum, Morgan’s scientific and conceptual contributions set the stage for subsequent genetics research and initiated a new wave in experimental and evolutionary biology.

For the next 2 decades, the building blocks for the discovery of structure and function of the genome were incrementally set. In 1933, Jean Brachet suggested that DNA is found in the cell nucleus. Seven years later, setting the stage for the central dogma of biology, Beadle and Tatum (1941) proposed the “one gene–one enzyme” hypothesis, and in 1944, Oswald Avery (Avery et al. 1944) suggested that DNA is a “transforming principle.” In 1950, Erwin Chargaff reported that adenine: thymine and cytosine:guanine ratios are equal while the balance of A-T and C-G ratios varies among species, and he went on to suggest that DNA “could very well serve as one of the agents, or possibly the agent, concerned with the transmission of inherited properties.”

Second Part of the 21st Century: DNA and the “Code of Life”

In 1953, James Watson and Francis Crick, aided by observations made by Rosalind Franklin and Maurice Wilkins, publish their seminal work on the double-helix structure of the DNA molecule (Fig. 1). Less than a decade later, Nirenberg and Matthaei (1961) started to unravel the genetic code by reporting that a synthetic triplet of DNA polynucleotide letters (a UUU codon) could direct protein synthesis and encode a polyphenylalanine protein. Subsequently, Nirenberg went on to report the “code of life,” the nucleotide sequences encoding amino acids (Bernfield and Nirenberg 1965)—an achievement for which he was awarded the Nobel Prize in Physiology and Medicine in 1968. Further advances were catalyzed by the rapid development of techniques and technologies for DNA sequencing pioneered by Frederick Sanger in 1977 (Sanger et al. 1977) and subsequently the development of polymerase chain reaction by Kary Mullis (Saiki et al. 1988). In the 1960s, a pioneer in the field, Victor McKusick, developed a catalog of Mendelian traits and disorders, entitled Mendelian Inheritance in Man (McKusick 2016). Today, the online evolution of the catalogue (OMIM) is the reference, authoritative compendium of human genes and genetic phenotypes. Meanwhile, genetic discoveries with immediate clinical relevance began to emerge. Trisomy 21 was linked to Down syndrome (Lejeune et al. 1959), while Huntington’s disease was mapped to chromosome 4 (Gusella et al. 1983) and attributed to a specific trinucleotide repeat (Andrew et al. 1993).

Figure 1.

X-ray diffraction images of fibrous DNA used to theorize and support the double-helix structure by Watson and Crick in 1953 (reprinted with permission).

The New Era: Three Decades of Genomics

The term genomics made a bold debut in an editorial by Victor McKusick and Frank Ruddle (1987), published in the first issue of the eponymous journal Genomics. Shortly after, one of the most ambitious undertakings ever was launched: the Human Genome Project—a $2.7 billion, 15-y project carried out by an unprecedented collaboration of several US-based and international public and private institutions (Collins et al. 2003). The first draft of the human genome was announced in 2001, and a finished sequence was achieved in 2003 (International Human Genome Sequencing Consortium 2004). The completion of this milestone was quickly followed by intense discourse by multiple stakeholders regarding its relevance to health care and the ways that it was expected to change the practice of medicine (i.e., “genomic medicine”; Strasser 2003; Green et al. 2011).

The completion of the Human Genome Project has given birth to several other large projects that extend or build on it, including the HapMap (International HapMap Consortium 2003), ENCODE (ENCODE Project Consortium 2012), 1000 Genomes Project Consortium (2015), and the Haplotype Reference Consortium (McCarthy et al. 2016). Although most of the genome’s function remains unknown, epigenetics is now understood as a key mechanism of DNA regulation (Felsenfeld and Groudine 2003). In parallel, the Human Microbiome Project (Turnbaugh et al. 2007) has spearheaded the study of microbial genomics and its role in human health and disease.

At present, technological advances have made it possible to sequence an entire human genome (i.e., whole genome sequencing) in a matter of days and at a cost of ~$1,000. Consequently, several investigations have been undertaken during the last 10 y seeking to identify genomic markers (i.e., single markers, often referred to as single-nucleotide polymorphisms) associated with rare and common diseases or traits. Currently, an impressive number of associations between genomic regions and health traits have been reported (MacArthur et al. 2017)—as of September 1, 2016, there were >24,000 unique single-nucleotide polymorphism–trait associations reported from genome-wide association studies. In contrast, only 59 genetic polymorphisms are considered reportable (to research participants) according to the American College of Medical Genetics and Genomics (Kalia et al. 2017). It is uncommon for genome-wide association studies or whole genome sequencing results to be immediately actionable, especially in the context of common complex diseases with substantial environmental or behavioral components; however, these studies continue to generate valuable insights and novel discoveries in the etiology of several important human diseases (Manolio et al. 2009). At the same time, ethical, legal, social, and diversity issues have been long recognized in genomics research, and the US National Institutes of Health has embarked on a bold strategy and research program to tackle some of these challenges (Sankar and Parker 2017). Ultimately, the advent of precision medicine (Collins and Varmus 2015) is expected to improve health via a more precise accounting for individual variability via (but not limited to) genomics.

Advances in Genomics and Dental Medicine

Genetics Insights for Dental and Craniofacial Health Traits and Conditions

There have been great strides and early reports on the heritable nature of oral and craniofacial traits, parallel to other systemic conditions and traits (Fig. 2). Observations regarding a hereditary component of dental caries were reported as early as in the 1920s (Kappes 1928; Bunting 1934; Klein and Palmer 1940; Hunt et al. 1944). In a key paper while at the National Institute of Dental Research, Carl Witkop, who later edited the book Genetics and Dental Health, presented an overview of dental hereditary diseases, including dentinogenesis imperfecta, dentin dysplasia, enamel hypoplasia, tooth agenesis, Ehlers-Danlos, ankyloglossia, and dental caries (Witkop 1958).

Figure 2.

Timeline of genome research (left side) and oral health–specific landmark evolvements and illustrative reports (right side) since 1900.

Mansbridge (1959) reported on the joint contribution of environment and genetics to dental caries among a group of 224 Scottish twins. Similar to previous investigators, he found that discordance in dental caries experience (e.g., as measured in first permanent molars; Fig. 3) was less in monozygous than dizygous twins. On the basis of these observations, he went on to suggest that environmental and genetic factors are both important for caries development. A few years later, Garn et al. (1963) reported on the genetic basis of third molar agenesis and the associated size reduction of remaining teeth, while Goodman (1965) discussed the genetic contribution of dentofacial development in general. Gorlin et al. (1967) conducted a literature review and concluded that although a genetic contribution to periodontal disease is plausible and likely, it was not possible to be confirmed from the available data and the inherent complexity and multifactorial etiology of the disease. Some of these issues, relevant to and affecting the outcomes of genomic studies of caries and periodontal disease, remain today. In 1984, Marazita and colleagues reported on genetic findings for orofacial clefting from an analysis of a large sample of Danish kindreds.

Figure 3.

Proportion of discordant (in terms of dental caries) pairs of first permanent molar teeth among monozygotic and dizygotic twins, used by Mansbridge in 1959 to support the joint environmental and genetic contributions to dental caries (reprinted with permission).

In more recent contributions, Lagerström et al. (1991) identified a deletion in the amelogenin gene as causative for X-linked amelogenesis imperfecta. Wright et al. (1996) reported that the CFTR cystic fibrosis–causing mutation also caused enamel defects. In 1997, Kornman and colleagues reported on an association between an interleukin 1 beta genotype and periodontal disease.

The discovery of the role of PAX9 in tooth organ development (Stockton et al. 2000) and palatogenesis (Lan et al. 2004) in the early 21st century, aside from providing novel mechanistic insights into signaling pathways at play, set the stage for the subsequent development of effective, molecularly based therapies. This was accomplished in the context of X-linked hypohidrotic ectodermal dysplasia, which is known to result in oligodontia. Schneider et al. (2018) recently reported the successful in utero protein replacement therapy with recombinant ectodysplasin in 3 embryos: at ages 14 to 22 mo, the 3 infants had shown clinical improvements and demonstrated more-than-expected tooth buds. In parallel, Jia et al. (2017) demonstrated that anti-ectodysplasin receptor agonist antibody therapy was effective in resolving palate defects in PAX9-deficient mice. Enzyme-replacement therapy has also been recently used for the treatment of hypophosphatasia, showing improved clinical outcomes in human trials (Whyte et al. 2012) and reduction of associated dental, specifically enamel, defects in mice (Yadav et al. 2012).

Numerous other investigations undertaken during the last century have led to discoveries of the genetic causes of rare diseases, such as ectodermal dysplasias, orofacial clefts, and other craniofacial and dental anomalies. A detailed and insightful overview of genetics and genomics developments as they relate to oral and craniofacial health research was published by Slavkin (2012). Along the same lines, Vieira et al. (2014) offered an excellent review of human genomics research specifically in dental caries, and Schaefer (2018) and Morelli et al. (2019) recently reported comprehensive reviews on the genetics of periodontal disease and tooth morbidity (i.e., dental caries and tooth loss).

The Genomics Era

More recently, genome-wide association studies have enabled interrogation of large proportions of the variation in the human genome (as opposed to candidate-gene studies)—they have been conducted and reported for several oral and craniofacial diseases and traits, including periodontal disease (Schaefer et al. 2010; Divaris et al. 2013; Teumer et al. 2013), adult (Wang et al. 2012; Zeng et al. 2014; Morrison et al. 2016) and childhood (Ballantine et al. 2018; Haworth et al. 2018) dental caries, tooth agenesis (Jonsson et al. 2018), orofacial clefts (Marazita et al. 2009; Dixon et al. 2011), cancers of the head and neck (Lesseur et al. 2016), orofacial pain and temporomandibular disorders (Sanders et al. 2017; Smith et al. 2018), and facial shape (Claes et al. 2018). Above and beyond the discovery of novel genomic contributions to these conditions, information that has been generated from this line of research and its aggregation in the context of large-scale collaborative consortia has enabled the application of novel methodological approaches for the investigation of causal effects (e.g., Mendelian randomization; Shungin et al. 2015) and the study of oral systemic disease connections via derivation of genetic correlations between oral and systemic traits (Shungin 2018).

The Future: Translation of Genomics Knowledge to Genome Editing and Molecular Therapies

The available information on phenotype-genotype associations will continue to increase, likely at an accelerated pace. There is an opportunity for the oral health community and dentistry to accelerate their pace on both the discovery and education fronts. With saliva being an accessible, easy-to-collect medium enabling genomic studies and with routine dental visits occurring at regular intervals, oral health professionals are in an advantageous position. Importantly, the realization that the human microbiome is key player for health (Cho and Blaser 2012), essentially functioning as an organ that is influenced by factors both environmental and innate, further increases the value of potentially sampling or monitoring the oral microbiome via meta- (i.e., microbial) genomics. For these and more reasons, the dental and allied health education communities should be on the forefront of genomics education. Meanwhile, direct-to-consumer genetic and genomics testing services are a reality, exerting positive pressure to both the professional and educational aspects of dentistry.

Importantly, gene therapies and gene editing with clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated nucleases (CRISPR/Cas) systems represent the latest frontier surpassed in the era of genomic medicine (Cong et al. 2013; Allen et al. 2019). Personalized (or, rather, precision) cancer treatment, targeted pharmacotherapies, and prenatal testing and interventions are currently some of the most active areas for genomics applications. The opportunity for the oral and craniofacial domain is enormous and extends beyond the acceleration of mechanistic, biological research (Fig. 4). Potential applications include the development of precise molecular therapies, tissue engineering and craniofacial defect restoration, and microbiome- and pharmacotherapy-related interventions (Yu et al. 2018).

Figure 4.

Illustration of applications of the clustered, regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated nucleases (CRISPR/Cas) system in oral and craniofacial biology, as reported by Yu et al. 2019 (reprinted with permission). iPSCs, induced pluripotent stem cell; MSCs, mesenchymal stem cells.

Our Responsibility: Improving Individual and Population Oral Health via Advances in Genomics

In this era of rapid genomics developments and expanding applications, several challenges and opportunities lie ahead. First, and based on the experience of the Human Genome Project, maintaining a truly collaborative spirit is key for the acceleration and translation of scientific discovery. International cross-disciplinary collaborations and intentional team science approaches, as embodied by Trans-Omics for Precision Medicine (Brody et al. 2017) and Gene-Lifestyle Interactions in Dental Endpoints (Shungin et al. 2019), are ideal vehicles for advancing the field. At the same time, oral health endpoints and clinical data collection have yet to be included in the protocol of bold large-scale genomics efforts such as the All of Us research program (Sankar and Parker 2017). The oral health community and its stakeholders must remain at the discussion table and advocate for the inclusion of oral health as a fundamental element of precision health and care (versus strictly precision medicine).

The improvement of individual and population health via the emerging genomics discoveries and knowledge base is a major opportunity, but it is also faced with numerous challenges—arguably, an implementation science approach is needed to realize the full potential of genomics and precision health care (National Academies of Sciences, Engineering, and Medicine 2016; Roberts et al. 2017). Improving the genomics literacy of current and future oral health professionals should be a priority, and efforts in this direction can be made while discoveries are being made, in all levels of oral health education. Community engagement is another major direction of necessary action—in terms of increasing the diversity and representativeness of genomics results but also for illuminating gaps and opportunities in our translational program. There is a growing ethical responsibility for the dissemination of genomics knowledge and the increase in genomics research diversity. Genomics information can and will be used to keep people healthier and improve their lives—and with it, there remain the responsibilities to do no harm and reduce health inequalities.

Author Contributions

K. Divaris, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript. The author gave final approval and agrees to be accountable for all aspects of the work.