Development and Evolution1

ASHG AWARDS AND ADDRESSES 2011 William Allan Award: Development and Evolution1 John M. Opitz2,* tens of thousands of patients and their families, fellow students and fellow humanists, staff, and faculty in Iowa, Wisconsin, Montana, Utah, and Italy, happily so many here today. When pondering my modus operandi over the past half- century (MD, 1959), I must confess to a feeling of unease if not downright false pretense, reinforced by a recent letter (an e-mail) from a colleague in China wanting to ‘‘work in my lab’’ (I never had one) but hesitant because of the ‘‘strangeness’’ of my work and ‘‘what does a Julia Creek Dunnart have to do with anything’’? Trivially one might say, Julia Creek Dunnart, (Figure 1) a marsupial, hence no nursing bras or diaper services; but seriously, what can we learn about the evolution of the eutherian placenta, the bane of every woman who has had eclampsia, toxemia, or lost a baby (and almost her life) to HELLP ‘‘syndrome,’’ or suffered the consequences of maternal-fetal cell traf- ficking (so beautifully delineated by Diana Bianchi2)? Also, the protherians (duckbilled platypus and echidna), metatherians (marsupials of Australia and the Americas), eutherians, other animals, plants, fungi, bacteria, and archaea are all descendants of a last universal common ancestor (LUCA), which then becomes an organism of exceptional interest and evolvability (Figure 2). But to make this confiteor honest, I must also confess to Dear Judy, Max, Lynn, Colleagues, and Friends, the inclination or plain fact that for decades I have been In so far as this award is not a complete delusion on my practicing medicine, pediatrics, medical (clinical) genetics, part, an act of collective madness on your part, or a case of and developmental genetics and developmental pathology mistaken identity, I should still like to quote a letter from from the perspective of a zoologist (BA Zoology, 1956), a great, far better man than I: having been trained in comparative vertebrate embryology ‘‘I am extremely sorry not to be with you all. As you will (1954), evolution, basic genetics, and the biological basis of probably appreciate, things like being honored are not my sex determination and sex differentiation at the University cup of tea. John’’1 of Iowa by Emil Witschi (Figure 3), a student of Richard Thus, allow me to paraphrase John L. Emery, a giant of Hertwig who, together with his brother Oscar, had studied British pediatric and developmental pathology;1 honors with Ernst Haeckel in Jena (who, in turn, had studied are not my cup of tea either, but I am truly grateful to be with Rudolf Virchow in Wu¨rzburg and then briefly with here today with you all, with profound gratitude for the Johannes Mu¨ller in Berlin before Mu¨ller’s untimely death honor you have bestowed on me, happily ante- rather in 1858). Among other matters, Mu¨ller was renowned for than postmortem. In repeating the Domine non sum his studies on human physiology, echinoderms, female dignus., I am overwhelmed by the totally unmerited genitalia (the Mu¨llerian duct), the smooth shark of Aristotle and undeserved ‘‘amazing’’ grace that has accompanied (a placental animal) and the radiolarians, one-celled marine me over the last 60 years since coming to America due to protozoa he named and which engaged Haeckel, Richard family, teachers, and many friends throughout the world, Hertwig, and Valentin Haecker for decades (Figure 4). 1This article is based on the address given by the author at the meeting of the International Congress of Human Genetics on October 13, 2011, in Montreal, Quebec, Canada. The audio of the original address can be found at the web site of the American Society of Human Genetics 2Departments of Pediatrics (Medical Genetics), Human Genetics, Pathology, and Obstetrics and Gynecology, School of Medicine, University of Utah, Salt Lake City, UT 84108, USA *Correspondence: [email protected] DOI 10.1016/j.ajhg.2011.12.025. Ó2012 by The American Society of Human Genetics. All rights reserved. 392 The American Journal of Human Genetics 90, 392–404, March 9, 2012 with Emil Witschi,5 membership in the American Society of Human Genetics, exposure to the many advances in medical genetics being made at that time, and the chance to attend (with Dr. Witschi) my first meeting of the American Society of Human Genetics, then assembling together with the American Society of Zoology in College Park, PA—Dr. Witschi just having been elected its President. It was in Dr. Witschi’s office that I had met Charles E. Ford and Josef Warkany; thus was confronted by a choice between genetics or teratology, Madison (Smith and Patau) or Cincinnati (Warkany), a choice made easier after attending the ASHG meeting in College Park and applying to the Cincinnati and Madison programs (to make sure of either), accepting the latter a few minutes before being invited to the former at close to midnight late in June, 1961. Madison (1961–1979): Developmental Field Theory At the University of Wisconsin, I completed a residency in pediatrics (the last six months as chief resident), translated much of Overzier, wrote a grant application for fellowship support to the NIH (successful), served two years as fellow during the time David Smith was metamorphosing from an endocrinologist (a student of Lawson Wilkins at Johns Hopkins) into a pediatric morphologist (after a one-year sabbatical, 1964–1965, study embryology with Gian To¨n- dury in Zu¨rich) before his move to Seattle (1966) where Smith continued, until his death, a successful program in ‘‘dysmorphology.’’ And it was in the pediatric genetics clinic that I had the ‘‘eureka’’ experience of seeing in quick succession auto- Figure 1. Representative Metatherian or ‘‘Look Ma, No Placenta’’ somal-dominant and autosomal-recessive radius a/dysgen- Top: koala; bottom Julia Creek dunnart, an Australian marsupial, esis, later supplemented on the basis of actual dissections 71 with two young. From Opitz. Copyright retained by Trudy Nich- of trisomy 18 infants.6 Eureka: different causes resulting olson; used with permission. in identical malformations identifying dysmorphogenetic units of the human embryo, which must also be morpho- The Developmental Field First Noted genetic units under normal circumstances, the ‘‘fields’’ Fortunately, or unfortunately, Witschi’s Development of mentioned by Huettner4 and identified and discussed in Vertebrates3 was not published when I took his course in detail by Spemann,7 and Huxley and DeBeer8 (q.v. espe- 1954; instead, Dr. Witschi assigned us Alfred F. Huettner’s cially their Figure 112, amphibian neurula to show the Fundamentals of Comparative Embryology of the Vertebrates4 main regional fields), Needham,9 (see also Oppenheimer10). with its beautiful illustrations and excellent historical To my knowledge, no complete inventory of all fields introduction where I learned: in the vertebrate body has ever been made, and continued ‘‘This organizer is now better known as the chorda-meso- inability to identify biochemical substances causing dermal field which is the first or primary field to exist in the induction in the 1930s led to disillusionment with and amphibian germ. Secondarily it gives rise to secondary virtual abandonment of work on the developmental organizers or subordinated fields, such as nose, eye, ear, field concept. And when this appeared to be a viable gill and others.. notion in medical genetics in the 1960s and early 1970s, . a piece of information filed away in the back of my Dr. Wiedemann and I made a major effort to determine if mind in 1954 until ready ‘‘to put two and two it had ever been introduced into medicine or human together.’’4 embryology to begin with, all to no avail. One of the last mentions of the developmental field concept in Western 1959 biology seems to have been in 1954 by Curt Stern, a former My final year of medical school afforded the opportu- President of the American Society of Human Genetics.11 nity of training with Hans Zellweger and Jacqueline A. In discussions with Oswaldo Frota-Pessoâ, from Saõ Paulo Noonan (after whom I named the eponymic syndromes), and then visiting professor at the University of Wisconsin completing the chapter on the biologic basis of sex determi- in the mid-1960s, heavy emphasis was placed on the nation and sex differentiation for the Overzier textbook statistical correlations within developmental field defects. The American Journal of Human Genetics 90, 392–404, March 9, 2012 393 Figure 2. Not Born Yesterday or ‘‘Age Is Relative’’ Attempt at an animal phylogeny with rough dates at bottom showing origin of most animal groups to a pre-Cambrian (pre-542 million years ago) era with the most recent origin for vertebrates and urochordates (our closest chordate relatives) and a somewhat older origin for cephalochordates (amphioxus, previously considered our closest chordate relative). Based on various sources, sequencing data, and personal communications (C. Nielsen). And it was as such a statistical entity that the develop- monkeys. Meckel14 cites the unilateral lack of a lung ‘‘als mental field concept was first put into print again,12 to be Fehler der Urbildung,’’ that is as a primary malformation, redefined later in its original morphogenetic sense. In this but points out that in most snakes the left lung is rudimen- connection it is of interest that nowhere in his Silliman tary or absent; complete cleft of bladder, each receiving one lectures7 or his Nobel lecture13 does Spemann use the ureter, is normal in snakes. He repeats and abstracts from concept of the gene when in fact it was genetic and evolu- the literature several human cases with a tail; fusion of tionary studies that shaped the modern field concept on ribs as in birds and turtles; persistence of the pupillary the basis of heterogeneity, homology, and phylogeneity.

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