Portal de Periódicos da CAPES

In Memoriam: “Holstein cows in Holstein.” Victor A. McKusick : 40 years of remembrance from Europe

2021; Wiley; Volume: 185; Issue: 11 Linguagem: Inglês

10.1002/ajmg.a.62390

1552-4833

Eberhard Passarge,

BRCA gene mutations in cancer

This personal account is based on numerous professional contacts with Dr. Victor Almon McKusick between 1968 and 2008. These reflect McKusick's international role in establishing medical genetics as an independent field of medical science. He nearly single-handedly introduced a systematic order into medical genetics. In addition, he paved the way to understanding the multiple genetic and genomic causes of genetic disorders. “Stop, stop, Holstein cows in Holstein!” Victor Almon McKusick demanded repeatedly. I had to ask for patience, explaining that it was not a good idea to stop on the autobahn. We were on our way from Hamburg to Lübeck in Schleswig-Holstein on May 6, 1972. Victor added: “I have seen Holstein cows many times before, but never in Holstein”. Eventually I found a safe place to stop. We got out of my Volkswagen, climbed a fence, jumped over a ditch, and walked into the wet field. Victor began to take photographs (Figure 1). When I commented, “I guess they will never know who took their pictures”, he answered “Yes, I'm afraid they are rather blasé about it.” Holstein Friesian cows, in the United States shortened to Holsteins, are dairy cows originating from Schleswig-Holstein, the most northern state of Germany bordering on Denmark, and from the Dutch provinces Friesland and Northholland (Meyer, 2021). Their coat is characterized by distinctive black and white patches. Piebald spots of unpigmented areas may occur (Fonatenesi et al., 2011). Being raised on a dairy farm in Parkman, Maine, Victor McKusick was quite familiar with Holstein cows and their genetics. Victor was on his way to the Medical University of Lübeck to visit Alfred Gropp (1924–1983), who was at that time one of the leading scientists in the field of evolutionary cytogenetics. Together with Helga Rehder, Gropp established the field of human fetal pathology (H. Rehder, personal communication, May 6, 2021). They recognized the relationship between the spectrum of fetal malformations and their chromosomal aberrations in comparison to the wide range of phenotypes in mouse fetal trisomies and monosomies (Gropp, 1982). Gropp and Rehder had established a recognizable relationship between the spectrum of human fetal malformations and their underlying chromosomal aberrations (Gullotta et al., 1981). This had caught Victor McKusick's attention and, characteristic of him, the by then leading medical geneticist wished to obtain firsthand information on a new related field. On that visit to Germany, Victor McKusick arrived at Hamburg airport on May 4, 1972 after an overnight flight. Meeting him there I asked whether he would like to rest a little. He responded “Oh, no. Let's get straight to work.” For the next day I had arranged for a presentation of patients with different heritable disorders of connective tissue (Figure 2). He commented extensively on each patient and followed with a full lecture on the subject with the same title as his 1956 book (McKusick, 1956). Victor A. McKusick is recognized as one of the founders of medical genetics, if not THE founder. Prior to 1949, genetics did not involve human and medical aspects. Whereas the origins of human genetics can best be dated to 1949 (Passarge, 2021), medical genetics arose about from 1959 on, when newly discovered chromosome abnormalities, hereditary metabolic defects, and molecular technology helped in defining new human diseases due to different genetic causes. Victor McKusick was one of the first to recognize how important the integration of genetic considerations into patient care would be. Human genetics includes medical genetics, which is devoted to research on the causes and inheritance of genetic conditions, and clinical genetics, which deals with the diagnosis and management of genetic disorders. When genetics included medical aspects, this was promoted and reviewed on several occasions by McKusick (1975, 1992, 1993). In two of these articles (McKusick, 1975, 1992), he stated that clinical genetics originated in 1959 when human cytogenetics and biochemical genetics and their medical applications developed into mainstream subjects of research. In 1992, summarizing the development of human genetics between 1956, when the First International Congress of Human Genetics was held in Copenhagen, and 1991, McKusick (1992) noted that human genetics had become “medicalized, subspecialized, professionalized, molecularized, consumerized, commercialized.” Eventually, organized genetic services including disease diagnosis, management and genetic counseling also became part of patient care. The later stages in the development of medical genetics were reviewed in detail by McKusick and Harper (2013). In addition, together with Frank H. Ruddle, McKusick introduced the concept of genomics and started the publication of a new journal under the name Genomics (McKusick & Ruddle, 1987), which still plays a leading role today. Nowhere is the enormous progress in medical genetics, in particular for monogenic disorders, more visible than in Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders initiated by Victor A. McKusick in 1966. Each disorder and each gene is assigned a unique six-digit number for individual identification. It went through 12 printed editions (1966–1998, Figure 3). Since then, it has been maintained online as Online Mendelian Inheritance in Man (OMIM, online freely available at: omim.org). OMIM (2021) today reflects the systematics of medical genetics. The impact of OMIM on medical genetics is comparable to first periodic table of chemical elements by Dimitri Mendeleyev in 1869 on chemistry or the first chronological systematic list of the musical works by Wolfgang Amadeus Mozart by Ludwig Alois von Köchel in 1862 in the history of music. Victor very much liked this comparison (personal communication). Another of V.A. McKusick's major contributions are the five Baltimore Conferences with the overall title Clinical Delineation of Birth Defects, which he conducted single-handedly between 1968 and 1972 by reviewing research on various genetic disorders affecting different organ systems. These further introduced a systematic order into medical genetics, aside from that of OMIM, by reviewing the genetics of all human organ systems. Victor McKusick together with Barton Childs (1916–2010), also at Johns Hopkins (Valle and Mcintery, 2010), distinguished two principal views of the concept of disease, the Oslerian and the Garrodian, reviewed in detail by Childs (1999, 2013). One view is based on William Osler (1849–1919), the first Professor of Medicine at Johns Hopkins in 1888. It is highly important in the practice of medicine. Osler established his view amply in 1892 in the first edition of his Principles and Practice of Medicine. He directs all attention to the diagnosis and therapy of diseases. This system of classification of diseases is based on the phenotype, that is, the clinical manifestations. McKusick's work at Johns Hopkins University falls within the cultural framework of its medical school, the first in the world to develop a curriculum for the training of medical students centered on genetics and genomics. In contrast, Archibald Garrod (1857–1936) early on raised the question of predisposition to a disease. Garrod (1931; Bearn, 1993) asked why one particular individual is affected by a disease and another one is not (Childs, 1999, 2013). Garrod's views are aimed at the genotype (Bearn, 1993; Childs, 1999, 2013; Garrod, 1931; Scriver, 1989). Recognizing etiological (genetic) heterogeneity, Victor McKusick clearly favored a classification of genetic disorders based on their genotypes, that is, the types of mutation, structural rearrangements of the genome, genomic disorders, receptor defects, etc. (McKusick, 1969, 1973). Elsewhere I have outlined in more detail the bases for a genetic classification according to pathogenesis and etiology (Passarge, 2021). Victor McKusick was the first to study human population genetics within a medical context (McKusick, Egeland, et al., 1964; McKusick, Hostettler, & Egeland, 1964). His systematic investigations of the population structure and the prevalence of genetic diseases, some new, of the Amish populations in Pennsylvania, Ohio, and Indiana are a landmark even today. McKusick's anticipation of future developments was impressive. He pointed out that he expected new advances once the molecular bases of these disorders were known, and we would be able to understand how the disease-causing mutations of these disorders affect the DNA. This was in 1972 shortly after the first recombinant DNA techniques had been described, but before the Asilomar Conference on Recombinant DNA was held in 1975 and the first sequencing of DNA was developed in 1977. Another example of McKusick's prescient anticipation relates to Marfan syndrome, one of his favorite subjects (OMIM 154700). He suspected that an absent function of a fibrillary protein could be involved. He argued that the absent or rearranged suspensory ligaments of the lens, leading to lens dislocation, might be a clue to the pathogenesis (personal communication in the early 1980s). This was several years prior to the discovery of fibrillin-1 in 1986 (FBN1; OMIM 134797). In conclusion, Victor A. McKusick played a decisive role in establishing a systematic structure for human medical genetics. Today human genetics is both a medical and a non-medical basic science. This dual structure makes human genetics unique among all medical subspecialities. The current status of medical human genetics is described comprehensively in two multi-volume books (Pyeritz et al., 2019; Valle et al., 2019). Helga Rehder, Vienna, and Mary F. Passarge, Essen, contributed helpful comments. The author would like to thank two anonymous reviewers for constructive criticism with good suggestions for clarity. The author declares no conflict of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.