OF HUMAN

rctrodaetyly, cleft hands aud fret, defects of radius arid ulna, and congenital amputations.

T has been obvious from very early times that parents and their offspring are alike in some ways, unlike in others; that relatives present similarities and differences, partly because of their inherited nature and partly owing to environmental influences.
From antiquity it has been well known that many defects and diseases run in families, frequently being destructive to the tainted lineage.
During the last centurieb when the science of medicine and 11osography have developed very fast, numerous hereditary lesions have been investigated and pedigrees have been described. Some few of the earliest instances of the innumerable publications will be mentioned in the sequel.
A classic hereditary disease is hemophiliu. The familial occurrence was described by SIR FORDYCE in 1784, and in 1820 NASSE formulated the laws for its inheritance. In 1877 GRANDIDIER gave an account 01 some large European hemophilic families and the same year LOSSEN'S rule, which later turned out to he erroneous, was set forth. In 1922 BAUER showed definitely that the inheritance is sex-linked recessive, in 1930 SCHLOESSMANN discovered the protracted coagulation time in the blood from female conductors, and in 1943 ANDREASSEN published a method of diagnosing heterozygous women by measuring the coagulation time of their blood. In 1935 HALDANE estimated the mutation rate of hemophilia, and later ANDREASSEN carried out a calculation of thc frequency of mutation for this disease in the Danish population. Hemophilia exemplifies how the knowledge of the heredity of a disease has increased steadily during the last 150 years.
Other diseases known as hereditary ones for many years will be instanced. As early as 1769 MORGACNI advanced the opinion that cerehrnl cxpoplexy may occur on a hereditary basis; he founded his view on the frequent occurrence of cerebral hemorrhages in certain families.
The heredity of cancer has also been discussed for centuries; the problem seems to have been first put forward by HOFFMANN about the year 1700, and in 1773 the Academy of Lyons offered a prize for the best paper answering the question: Qu'est-ce que le Cancer? The problem was discussed during the following years, but about the year 1800 the general opinion was that it was impossible to deny the existence of n certain hereditary disposition to cancer, because the evil so often transmits itself from parents to children.
The heredity of several congenital malformations is so clear that it has been known for many years. The familial occurrence of hare-lip and clt.ft palute and of hermuphroditism was described nearly two hundred years ago; and the same holds good for osteogenesis iniperfectu.
The inheritance of some eye diseases was observed a great inany years ago. In 1671 THOMAS BARTHOLIN published a case of hereditary congenital defect of the iris, colobomu. And during the nineteenth century the inheritance oS colour-blindness, ulbinism, optic-nerve atrophy, congenital hydrophthulmus, glaucoma and caturuct were pointed out.
The oldest pedigree of familial deaf-mutism is presumably that oi' the Spanish noble family VELASCO, covering the period 1420-1 664, later published by WERNER. In 1853 WILDE stated that congenital deaf-mutism is due, i. u., to heredity and consanguinity, and 40 years later FAY published his famous statistics of deaf-mutes.
The heredity of epilepsy was suggested several hundred years ago, and during the nineteenth century THOMSEN described the familial occurrence of m yotonia, and HUNTINGTON that of chorea, while MOREL and MAGNAN wrote on the "hhgditaires dbgCnCrCs", and LOMBROSO on "l'uomo delinquente". During the same period quite a number of treatises were published on "l'h6r6dit6 de la folk", "l'h6r6ditC l'alcoolisme", "Relations of Mental Diseases to Inheritance", "Erblichkeit von Seelenstorungen", "Die erbliche Anlnge als Krankheitsursache", etc.
Medical Genetics is a very essential part of Human Genetics, the two disciplines are not, however, identical.
GALTON, the lirilliant student of Human Genetics, illustrated this in his book on "Hereditary Genius, an inquiry into its laws and consequences" (1869) and in his later publications. GALTON proposed that a man's natural abilities are derived by inheritance, under exactly the same limitations as are the form and physical features of the whole organic world; and he tried to classify men according to their natural gifts.
In consequence of his ideas, GALTON started the stCldy of The Inheritance of Qualities in Families and took up twin research. The Galton Laboratory at the University of London began editing the Treasury of Human Inheritance in 1912. In the preface of the first volume PEARSON emphasizes that even if the whole of human heredity is not based upon the inheritance of abnormality and of pathological conditions, their inheritance must always play a large part in eugenic inquiry; the inheritancc of abnormality and special diatheses is, however, (1 subject which requires trained medical knowledge.
The rediscovery of MENDEL'S laws, the observation and study of mutation, the distinction between phenotype and genotype, between nature and nurture and the investigation of linkage and crossing-over, which all took place at the beginning of this century, of course also meant a mile-stone in human geneticr. Human beings are subject to the same fundamental laws of heredity as other living organisms. This is the reason that the suppositions and possibilities of human, including medical, genetics were coinpletely altered and essentially improved after the year 1900. During the last fifty years, in the wake of the development of genetics as a whole, an enormous rise in the study of the heredity of human characters, abilities, defects and diseases has been in progress.
Within human medical genetics we meet, however, with numerous difficulties, which do not occur in experimental genetics, as for instance the small number of children in the human race, the long time of generation, and the fact that experiments of cross-breeding are out of the question. Here we must rest content with the combinations of parents that occur spontaneously. Moreover, many diseases only manifest themselves at a certain age, the diagnosis may be difficult to make and, what is more, is often impossible to verify in the case of already deceased persons, unless there exists an elaborate case record. Unknown illegitimacies and adoptions occur with some frequency, but can rarely be accurately determined. Furthermore it must be remembered that to a large extent human beings are capable of controlling their own environments.
The study and analysis of hereditary characters in human beings require special techniques and methods, which have developed step by step during the last four decades.
In 1905 FARABEE, by investigating some large families, proved that brachydactyly is inherited according to MENDEL'S laws as a monomeric, dominant character, and some years later LUNDBORG showed, in a very large family, that mgoclonus epilepsy is a recessive character. Since then, an increasing number of pedigrees and family histories concerning hereditary lesions have been published. Before the first world war GODDARD investigated feeble-niindedness, its causes and consequences, and social problem families, and RUDIN studied the inheritance of schizophrenia. Contemporaneously the study of crosses between human races that differ very distinctly from each other and that live in isolated areas was started with "Die Rehobother Bastards", later continued with investigations of "Race-crossing in Jamaica" and "Die Mestizen auf Kisar".
When a large inaterial of pedigrees was collected it appeared that some characters and lesions are simple dominant, recessive, sex-linked or conditioned dominant, for many others, however, it is obvious that genetic factors are playing a part in the development of the character or in the etiology of disease, but it is not possible to explain the inheritance according to MENDEL'S laws in a plain and uncomplicated way.
For that reason the statistico-genealogical methods were worked out and used extensively, at first by the Munich school for the study of the inheritance of several mental diseases. In applying the probandor propositus-method (WEINBERG) the empirical figures of genetic prognosis have been calculated for a considerable number of diseases.
In biology and medicine, especially in genetics and demography, an extensive application of calculations and statistics is necessary. This appears from the pioneer work of MENDEL, MORGAN, JOHANNSEN and numerous later investigators. But it has to lie remembered that in the natural sciences statistics are never inore than an auxiliary science of secondary importance; in these fields the most important demand is that the primary observations are carefully made and exactly described, in medical genetics that the diagnoses for the propositus and his relatives are correct and the material collected and selected in the right way. It is a conditio sine qua non.
In human genetics, too, statistics have heen abused to a certain extent. The methods of WEINBERG have been criticized and improved by several investigators, e. C J . SCHULTZ, RERNSTEIN and STROMGREN. Comprehensive demographic investigations have been carried out in several countries and in various ways to find out the morbidity, especially the psychiatric niorbidity of the average population ( LUXENBURGER and collaborators, RLEGLER, LEWIS, SLATER, ESSEN-MOLLER, STROM-GREN, FREMMING and others); the morbid risk and gene frequency of a great many hereditary lesions are well-known to-day.
Methods are given for estimating the mode of inheritance in the various diseases on the basis of the frequency figures in the different groups of relatives to propositi suffering from a certain disease, in the first place by HULTKRANTZ and DAHLBERG.
Statistical methods have also been applied to investigate the evolution of dominance and recessivity (FISHER, HALDANE, WRIGHT a. 0.). Several of these investigations are very ingenious, but some of thern also of a rather theoretical and speculative description. Furthermore, statistical calculations have been carried out to ascertain whether linkage and crossing-over are demonstrable in human beings; plenty of publications on x-and y-linked genes have appeared, not all of them very convincing.
An essential part of human genetics is formed by twin examinations. The twin method has been used widely and has given valuable results, but it has certain limitations and consequently the results obtained by this method ought to be appraised with some caution. The environmental circumstances of the members of dizygotic twins of one sex will generally differ somewhat more than those of monozygotic twins, because the uniformity of the latter as to emotional nature and faculties brings about a greater inclination in them to seek the same livelihood and the same associates than is the case with dizygotic twins. This source of error has not been considered sufficiently in all investigations, it has especially been of consequence in psychology when studying the inheritance of normal mental characters. In investigating pathological traits it is difficult to avoid a certain selection of the twin material and to collect representative, unselected series. In small countries, it is impossible to procure a number of twins sufficiently large to investigate the heredity of rare diseases.
Nevertheless, by means of twin investigations very important information has been obtained concerning the influence of hereditary factors and the manifestation of the gene by a number of lesions and other characters, for instance feeble-mindedness, schizophrenia, manio depressive psychosis, criminality, epilepsy, tuberculosis, diabetes, congenital malformations ( SMITH, GEYER, KALLMANN, ESSEN-MOLLER, LUXENBURGER, ROSANOFF, LANGE, STUMPFL, KRANZ, CONRAD, VER-SCHUER, BERG, IDELBERGER, DAHLBERG, and others).
The vast science of anthropology is intimately connected with human genetics. Constitutional pathology, defined rather vaguely, has developed through KRETSCHMER'S intuitive and artistic typology and characterology to SHELDON'S more analytico-constitutional studies of this kind. In anthropological physiology the most amazing development has taken place in the domain of blood types or groups, starting from THE RISE OF HUMAN GENETICS 303 LANDSTEINER'S discovery in 1901 of the ABO system, continuing with the MN system, the A,, ill, A, subgroups, the P, H and L types and the marvellous Rhesus system with its numerous subgroups. Together with the taster-non-taster and the secreter-non-secreter allelomorphs, these monomeric, normal characters create new and surprising possibilities for genetic analysis, identification and paternity tests.
Medical genetics is supported by experimental animal genetics in, for instance, cancer research and the study of the heredity of malformations, endocrine disturbances and other diseases, and in investigating the manner of action and the mechanism of the pathogenic genes during ontogenetic development. The study of human chromosomes in connection with medical genetics is merely in its nascent stage.
During the decades before the second world war research in human genetics was progressing rapidly. In several places, for instance the Eugenic Records O f f i c e in Cold Spring Harbor, N. Y., a medico-genetic or eugenic registration ("erbpathologische Bestandsaufnahme") was tried, without quite satisfactory results, however. At the same time an increasing number of pedigrees and propositi-investigations concerning hereditary diseases were published.
As a prototype of these works SJOGREN'S brilliant and thorough studies on the heredity of amaurotic idiocy and other mental lesions may be mentioned.
No country and no scientist, however, had succeeded before the second world war in following, controlling and studying the whole body of the hereditary lesions in a population, and therefore research in medical genetics was to a certain degree scattered and accidental. This is the reason it was decided to organize the work of The University Institute of Human Genetics in Copenhagen, established in 1938, on new lines and principles.
In the Department for Medical Genetics of this institute the foundation of the work is formed by the Medico-Genetic Registry including a systematic registration, a card index, so far as possible complete, covering all the more serious hereditary affections observed in Denmark during recent years. In collaboration with the Board of Social Affairs all patients in Special Relief Institutions are registered; this registration comprises patients suffering from feeble-mindedness, epilepsy, deafmutisni and excessive hardness of hearing, defects of speech, blindness and excessive weakness of sight and certain categories of malformations. Further, in collaboration with the hospitals for mental diseases all hospitalized mentally ill persons in Denmark are registered; and from several other hospitals various physical diseases are reported. In collaboration with police psychiatrists and prison medical officers registration is made of a number of criminals. In connection with the councils of education psychopathic and backward children are registered.
At present more than 100,000 patients and their families are registered in the department of registration, and every year several thousands are added.
In the Department for Medical Genetics investigations are furthermore being made into the inheritance of various diseases with the aid of statistico-genealogical methods and, to a smaller extent, twin examinations.
In the Medico-Genetic Registry we have the starting-point for more thorough studies into particular fieldsin many instances of the inheritance of a special lesion or disease. The procedure then is as follows: The physician, who is trained as a specialist in the field concerned, makes a thorough investigation of the individual patients having the disease or the lesion in question and of their families, partly on the basis of hospital records, other docunientary material and genealogic investigations, partly by travelling about, visiting and examining the individual patients in their homes or by calling the patients in to the institute or to some hospital for observation and more thorough investigation.
In this way several diseases or malformations have been studied hy various specialists attached to the institute. The medical staff of the institute, partly working voluntarily, is divided into several groups, the members of each group working together forming a team having the task of investigating diseases of a certain type or speciality, for instance eye diseases, malformations, cancer, etc.
The following diseases investigated by the institute may be mentioncd: Through the studies of these diseases and Iesions, their mode of' inheritance, their frequency and geographical or social distribution in the population, their etiology and pathogenesis, their clinical picture, the possibilities of their treatment and prevention, and the effective fertility of the affected persons have been investigated.
Furthermore, on the basis of the material collected in the abovementioned way it has been practicable to show that the laws of heredity known from experimental genetics also correspondingly apply to hereditary lesions in man. Several hereditary diseases have been examined, about which it is reasonable to assume that relatively often they arise through mutation; the mutation rate in the various diseases has been calculated and the causes of mutation have been considered. The manifestation, penetrance and expressivity of the pathological dominant and recessive genes have been estimated. Conditioned dominance and polymerism in morbid inheritance have been observed and discussed, and it was found that most normal traits should be regarded as polymeric, the majority of pathologic traits as monomeric. Sex-linked genes in females, the effects of intermarriages, isolates and lethal genes in human populations were studied. The theories of progressive inherited degeneration, anticipation and fraternal degeneration were tested but not confirmed.
Beside these investigations of the inheritance of the individual diseases the institute is also occupied with other tasks such as, for instance, investigations of twins and of certain definite groups of the population, e. g. gipsies, prostitutes, some asocial elements, and adopted children. In this way the registration of the hereditary diseases in Denmark is supplemented.
On the basis of the experiences gained during these investigations, the institute exercises its hereditary-hygienic or eugenic activity as adviser on questions of sterilization, induced abortion, marriage, adoption, and of special relief. The material of the registration department

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has proved to be of much use to this activity. The recent Danish experiences in negative eugenics have been registered, and an attempt is made to follow and control the development and the fluctuation of' the hereditary diseases in the Danish population.
The way we have organized the study of human genetics in Copenhagen answers, I feel, its purpose fairly well. It would be desirable that a similar permanent medico-genetic registration be carried out in other countries, too, for only international collaboration will be able to elucidate in time the many problems of human genetics.
In the future it will be necessary, from the point of view of preventive and prophylactic medicine, to follow and control the serious hereditary diseases in the population in the same way as, for instance, epidemic diseases are followed and controlled; for that purpose a medico-genetic registration will be an indispensable remedy.
The conditions for the realization of such a registration will be particularly good in small countries with a relatively uniform, welleducated and medically well-examined population. In the larger countries it will probably be preferable to limit the registration to smaller districts of the whole country.
International collaboration in medical genetics is especially desirable as regards very rare diseases and twin investigations of infrequent lesions. For that purpose The International Bureau of Human Heredity was established in London, chiefly through the work of C. B. S. HODSON, before the last war, and the Bureau was transferred to Copenhagen in 1947.
In the hook "Genetics, Medicine and Man", published in 1947, C. C. LITTLE predicts about genetics: "In no field of the natural sciences is the opportunity greater for fruitful and fascinating experimentation bearing directly upon the health and happiness of man." The rise of medical genetics during recent years creates new possibilities for improving the health and happiness of man.