Festschrift for Victor A. McKusick on the Centenary of his Birth: Introduction

Victor A. McKusick was a man of few spoken words and many written ones, with an extraordinary commitment to education and a work ethic developed during his dairy farming childhood in Maine. He was a keen observer and documented his observations in thousands of little brown notebooks and through his photography. These observations led to a bibliography of over 700 publications, including papers on heart sounds, novel syndromes, his work with the Amish, and many books including Heritable Disorders of Connective Tissue and Mendelian Inheritance in Man and its online version, OMIM^®. Over the course of a more than 60-year career at Johns Hopkins University, he founded the field of medical genetics, established courses on two continents to share knowledge of its principles, and documented the progress in understanding Mendelian phenotypes and their associated genes. He was the founding President of the Human Genome Organization and was a chief advocate for the Human Genome Project, the results of which have fundamentally altered biological research and clinical medicine. It is only fitting that we honor the accomplishments of this remarkable man with this festschrift on the centenary of his birth.

The goal of this special issue is to provide readers with a historical perspective of Victor McKusick’s many contributions to the field of medical genetics and the impact those contributions have on the field today. The first article in the issue is a biography titled “Victor Almon McKusick: In the Footsteps of Mendel and Osler” written by Clair Francomano (2021). In this biography, Francomano documents a personal side of McKusick, including a review of his childhood, his 59-year marriage to Dr. Anne Bishop McKusick, their family life, and many of his key academic accomplishments. She notes several parallels between the lives of McKusick and Gregor Mendel and discusses McKusick’s similarities to William Osler, one of the founders of Johns Hopkins Hospital, including their shared dedication to the training of medical students and house officers in the Osler tradition. The next paper by Judith Hall (2021) is titled “The Contributions of Careful Clinical Observations – A Legacy”. Hall discusses the importance of careful clinical observations in the understanding of genetic disorders, and how McKusick trained fellows to develop these critical skills. She notes that clinical observations are essential not only to making a diagnosis, but also to answering many questions families have about natural history of genetic disorders and to the development of treatment and preventive strategies. Hall also discusses the role that rare disease networks, parent support groups, information technologies, and international collaborations play in clinical genetics today and in the future. In the next paper, Eberhard Passarge (2021) provides a European perspective of McKusick in his paper titled “‘Holstein Cows in Holstein’: Victor A. McKusick: Forty Years of Remembrance from Europe”. This paper provides a personal account of McKusick’s visits to Europe and the fundamental role that McKusick played in the field of medical genetics not only in the United States, but in Europe. In a paper written by Sonja Rasmussen et al. (2021), titled “Viewing Victor McKusick’s Legacy through the Lens of his Bibliography”, McKusick’s contributions to the peer-reviewed literature are summarized. The progression of his academic interests from his formal training as an internist and cardiologist to an interest in single-gene disorders, especially those related to disorders of connective tissue, to a passion for gene mapping and eventually the Human Genome Project, is reviewed. Parallels between the evolution of McKusick’s bibliography and the emerging field of medical genetics are made.

McKusick spent his entire career at Johns Hopkins Hospital, from his matriculation to medical school until his death; thus, it is fitting to provide a historical perspective of genetics at Johns Hopkins as part of this special issue. The first paper in this series is by Barbara Migeon and Haig Kazazian (2021), long-time members of the Johns Hopkins faculty, titled “Reflections on the History of Genetic Medicine at Johns Hopkins University”. They provide personal views of how the genetics units in Pediatrics (led by Barton Childs) and Medicine (led by Victor McKusick) became the McKusick-Nathans Department of Genetic Medicine in 2019. Continuing in this historical theme, Virginia Corson and Barbara Bernhardt (2021), who served as genetic counselors at Johns Hopkins for many years, provide a history of genetic counseling as a field, including its development at Johns Hopkins. The paper discusses how the genetic counseling profession has changed through the more than 50 years since its birth with the initiation of a program to train genetic counselors at Sarah Lawrence College in 1969. The article also notes McKusick’s early appreciation for the important place that genetic counselors hold as part of the genetics team because of their understanding of family dynamics and their superior communication skills. In the final paper in this section, Malcolm Ferguson-Smith (2021) writes an account of the introduction of human cytogenetics to medical genetics at Johns Hopkins Hospital. In this paper, he notes McKusick’s foresight to include investigation of human chromosomes in the Division of Medical Genetics at Johns Hopkins and his commitment to the development of the cytogenetics laboratory, including initially providing Ferguson-Smith with a microscope to study chromosome preparations to his later provision of resources in the form of research assistants to help with the volume of cytogenetics work. Ferguson-Smith, who received fellowship training at Hopkins from 1959-1962, also discusses the discoveries of Turner and Klinefelter syndromes during the early years of cytogenetics. The paper ends with a discussion of the many fellows inspired to develop international centers for excellence in the field because of their introduction to medical genetics by McKusick.

The next two papers focus on the Short Course in Human and Mammalian Genetics and Genomics (the Short Course) held at the Jackson Laboratory in Bar Harbor, Maine, and its counterpart in Europe. In a paper by Charles Wray et al. (2021) entitled “Victor McKusick and his Short Course”, the history of the Short Course is reviewed, beginning with the initial meeting between McKusick and John Fuller, director of education at the Jackson Laboratory, in 1959. Following this meeting, McKusick proposed development of a course on mammalian genetics, with the first course being held in August of 1960. The paper discusses the central role that the Short Course played in the development of the field of medical genetics, with the training of more than 7,000 students and over 600 participating faculty (including 17 Nobel prize winners) from around the world. The course was held annually in Bar Harbor, Maine, from 1960 through 2019, and provided virtually in 2020 and 2021 (its 61^st and 62^nd years) during the COVID-19 pandemic. The paper ends by recognizing how the Short Course continues to guide the future of genetics, even more than 10 years after McKusick’s death. The next paper authored by Giovanni Romeo et al. (2021) is titled “Victor McKusick and his Role in the Founding of the European School of Genetic Medicine”. Modeled after the Short Course that Romeo had attended 20 years earlier during his postdoctoral training at Johns Hopkins, the first medical genetics course was held in Sestri Levante, Italy, in 1988. McKusick assisted with course planning and attended the annual week-long course for nearly 20 years. The format of the Sestri Levante course in medical genetics was later duplicated to provide other subspecialty courses as part of the European School of Genetic Medicine, an entity with substantial impact on the field of medical genetics in Europe.

One of McKusick’s greatest contributions to medicine and medical genetics is Online Mendelian Inheritance in Man (OMIM®), his catalog of Mendelian phenotypes and genes. In a paper by Ada Hamosh et al. (2021) titled “Online Mendelian Inheritance in Man (OMIM®): Victor McKusick’s Magnum Opus”, a history of the development of the catalog, first in book form (with 12 editions of the book Mendelian Inheritance in Man published), and subsequent transition to the online version (OMIM) are summarized. Many decisions made by McKusick early in the development of Mendelian Inheritance in Man (MIM) (e.g., to maintain the data in a computer-readable format and to use a unique identifier [MIM number] for each phenotype and gene) have been essential to ensure OMIM’s flexibility, longevity, and utility to more than 2.7 million unique users throughout the world in 2020. Hamosh et al. summarize the most common uses of OMIM in 2021, demonstrating how the catalog serves geneticists to the present day and continues to adapt to serve their needs in the future. The next paper, titled “History of the Methodology of Disease Gene Identification” by Stylianos Antonarakis (2021), reviews the landmarks of disease gene identification and the consequences of technological advances to the pace and type of gene discovery, ranging from the biochemical age to linkage, to chromosome walking and jumping, to the recent explosion of disease gene identification that has resulted from the advent of exome and genome sequencing. More directly focused on the “The Genes of OMIM”, Scott and Amberger (2021) share the history of the days of gene mapping and Dr. McKusick’s push to map all genes, which eventually became the Human Genome Project, as well as the international collaborative efforts to organize and clean the duplicative “discovery” of identical genes with different names through the database (NomeMIM, then LocusXRef, now Entrez Gene) that allowed backend, real-time communication between OMIM, NCBI, and the Human Gene Nomenclature Committee, responsible for giving official gene symbols. This paper also addresses how information about genes is organized in OMIM. In a paper titled “Using OMIM in Low- and Middle-income Countries”, Sobreira et al. (2021) write about the critical importance of free access to OMIM in resource-limited countries. OMIM’s literature-based descriptions are used for differential diagnosis, teaching, and variant interpretation throughout the world but are essential where journal subscriptions and fee-based tools are unavailable. The next paper titled “Magnitude of Mendelian versus Complex Inheritance of Rare Disorders” by Aravinda Chakravarti (2021) takes us through a carefully reasoned analysis of the role of genes in Mendelian disorders and complex traits and the continuum that this represents, as well as the limitations of the information that can be included in a knowledgebase such as OMIM. Finally, in the last paper in this section titled “Clan Genomics: From OMIM Phenotypic Traits to Genes and Biology”, James Lupski (2021) presents an update and overview of the concept of clan genomics that he originated in 2011, which posits that recent mutation has a more powerful phenotypic effect than that which we inherit but occurred in distant evolutionary times. He also describes our growing knowledge of genome organization and structure, the many ways that it can go awry, and the impact of that knowledge on fundamentals of biology and precision medicine.

In a paper titled “Three Decades of the Human Genome Organization (HUGO)”, Lee et al. (2021), discuss McKusick’s role as the founding president of the Human Genome Organization (affectionately known as “Victor’s HUGO”). As one of the chief and earliest proponents of the Human Genome Project, McKusick and several prominent international geneticists were committed to ensure that the benefits of this projects accrued to all the people in the world. HUGO established the Human Gene Nomenclature Committee, and spun off both the Human Gene Variation Society and the Human Variome Project, pioneered by the late Richard Cotton, and supported by McKusick. Recently those three separate organizations have come back together as HUGO, with Dr. Charles Lee as the inaugural President of the newly combined organization and leaders of the other groups serving on the Executive Board.

The next several papers provide a view to the future of medical genetics including options for treatment of Mendelian disorders and how this future was informed by McKusick’s groundbreaking work. The first paper in this section is a paper by Erik Puffenberger titled “Mendelian Disease Research in the Plain Populations of Lancaster County, Pennsylvania”. This paper begins with a discussion of McKusick’s initial work with the Amish population, first focusing on a cluster of cases of what was thought to be achondroplasia, but was later recognized to be two autosomal recessive forms of skeletal dysplasias. McKusick’s work with the Amish population continued, with the identification of 16 new genetic syndromes that were first described in this population. Puffenberger’s paper goes on to describe the work of other geneticists who have worked with the Plain population of Lancaster County, with work that has moved from a focus on clinical identification of new syndromes to development of a next-generation sequencing panel aimed at identifying known pathogenic variants seen in the Amish population. Other work in recent years has included development and testing of treatments for conditions affecting the Amish population (e.g., glutaric aciduria type 1 and spinal muscular atrophy). As with the times of McKusick, lessons from study of the Amish populations are continuing to provide benefit to the Amish population, but also insights into the understanding of general principles in medical genetics. The next paper titled “Heritable Disorders of Oxygen Sensing” was authored by Gregg Semenza (2021), a former postdoctoral trainee with McKusick and winner of the 2019 Nobel Prize in Physiology or Medicine for his work on how cells respond to hypoxia. In this paper, he provides a summary of the discovery of hypoxia-inducible factors and Mendelian disorders (von Hippel-Lindau syndrome and five types of familial erythrocytosis) that occur when these factors are dysregulated. Future opportunities for treatment of these disorders are also discussed. The next paper authored by Ziegler et al. (2021), titled “Toward Precision Medicine in Vascular Connective Tissue Disorders”, provides a historical perspective from identification of Marfan syndrome and other vascular connective tissue disorders to understanding of the genes responsible for these disorders to life-saving treatments for these diseases. The paper reviews the role that better understanding of basic science, clinical heterogeneity, biomarkers, imaging, and surgical interventions, combined with multi-institutional consortia and patient advocacy, will play in development of precision medicine approaches that allow for provision of the optimal treatment of an individual patient at the right time in the future care of persons with these disorders.

The next two papers continue on the theme of treatment of patients with Mendelian disorders. The first by Hilary Vernon and Irini Manoli (2021) is titled “Milestones in Treatments for Inborn Errors of Metabolism: Reflections on Where Chemistry and Medicine Meet”; the title refers to a book by Sir Archibald Garrod published in 1911 with the title Where Chemistry and Medicine Meet. The paper by Vernon and Manoli provides a review of therapeutic approaches for inborn errors of metabolism. The authors present case patients with a wide range of inborn errors of metabolism and discuss therapies including dietary therapy, ammonia scavengers, enzyme replacement therapy, enzyme cofactor therapy, hematopoietic stem cell transplantation, and genomic therapies. Also discussed in the article is the importance of newborn screening in the early diagnosis of these metabolic disorders. The next paper titled “Current State of the Art in Treatment of Mendelian Disease - Skeletal Dysplasias” by Julie Hoover-Fong et al. (2021) provides a summary of the therapies for skeletal dysplasias that are approved for clinical use and those that are investigational for which clinical trials are ongoing or proposed. The authors give a historical perspective regarding how Victor McKusick’s work through the years set the stage for current therapeutic approaches for persons with skeletal dysplasias through his early delineation and focus on standardized nomenclature, which allowed for identification of the genetic etiology and disease-specific treatment for many of these disorders.

Another important contribution of Victor McKusick to the field of medical genetics is related to how ethical, legal, and social implications of advances in human genetics have been and continue to be addressed. In a paper by Eric Juengst (2021) titled “Anticipating the Ethical, Legal, and Social Implications of Human Genome Research: An Ongoing Experiment”, he reviews the history of the “Joint Working Group on Ethical, Legal and Social Issues (ELSI) related to mapping and sequencing the human genome”, an ad hoc committee of which McKusick was a founding member. Given the history of the eugenics movement in the United States, it was critical to the success of the Human Genome Project to address these issues directly. From the start, the National Institutes of Health dedicated 3-5% of the funding for the Human Genome Project for research on these issues. The paper summarizes how the design of the ELSI effort, with a focus on anticipating questions before they became major issues, has allowed the genomics community to respond rapidly to new developments in the field.

The special festschrift issue ends with a paper titled “Memories of Victor A. McKusick” compiled by Sonja Rasmussen and Ada Hamosh, which includes memories of McKusick written by family, friends, and colleagues. These reminiscences provide a view of the human side of McKusick, the person behind the “father of medical genetics” icon. For those who never met McKusick, this paper provides an appreciation of his kindness, generosity, humility, quiet and thoughtful nature, and sense of humor.

This festschrift, published in honor of his 100^th birthday and inspired by the Scientific Advisory Board of OMIM, provides an overview of the many contributions made to the field of medical genetics by Victor McKusick. The series of papers also provide a personal view of McKusick, his childhood, family life, and his relationship with many trainees and colleagues through the years. We hope this review of the many contributions of Victor A. McKusick serves to remind contemporaries and trainees of fond memories, to educate a new generation of medical geneticists of our humble beginnings and the golden age through which we are now living, and to inspire us all to do more by “working very hard, sharing what we know, and keeping a positive attitude”, the lasting legacy of Victor McKusick.

Figure:

Victor A. McKusick, Welch Medical Library, Johns Hopkins University, Baltimore, Maryland, 1965. Credit: Johns Hopkins University Archives.

Data Availability Statement:

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study