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Newsletter No. 10

Genetics and medicine

historical network



December 2006

Editor: Peter S Harper (Email:



Paul Polani, 1914 – 2006

ICHG Historical Session, Brisbane, August 2006

The Human Genetics Historical Library, update

Note from Dr Arno Motulsky

Plans for future historical workshops


First, greetings to all Newsletter readers and every good wish for 2007.

Please note two important points: First, our website address is now, (not as before).  Apologies to those who have been trying to access it on the latter address.

Second, from 2007 we shall try to include images to make the newsletter look more attractive.  When we tried this before, it proved a problem to some whose email had limited capacity, but I think that this should no longer be the case.  If you would still prefer to receive a text only version, please email Joanne Bolton (

Paul Polani, 1914 – 2006

Many readers will have seen that Professor Paul Polani, founder and former director of the Guy’s Hospital, London, Paediatric Research Unit, and one of the pioneers of medical genetics, has died at the age of 92.

A number of obituaries have appeared and are cited here:

Adinolfi M, Alberman E (2006) Paul Polani. The Guardian, 18th March 2006.

Harper PS (2006) Paul Polani. Brit Med J 332:670

A longer piece on his life and work is in Human Genetics (electronic version Harper PS, Paul Polani and the development of medical genetics, Hum Genet (2006) DOI 10.1007/s00439-0 06-0271-5; printed version not yet out).

The Paediatric Research Unit’s Polani Research Library will house many of Paul Polani’s books, but a substantial donation (around 350) of the older ones has come to the Human Genetics Historical Library.

The Polani Research Library also holds a file on Paul Polani’s records and correspondence, but this is at present very scanty, so anyone in possession of such items may wish to give them (or copies) to augment the file.  Please contact Lesley Exton, Librarian of the Polani Research Library (; tel. 020 7188 3702.


Update, November 2006

The library continues to grow steadily, with several large donations of books, notably from Professor Malcolm Ferguson-Smith and from the estate of the late Professor Paul Polani.  The current total of books stands at 1012, excluding a number of duplicates.

Detailed cataloguing by specialists, made possible by the Wellcome Trust funding at Cardiff University, is in progress and will allow searching by a wide range of criteria.  It is hoped that this should increasingly permit research on the collection as a whole, in addition to those interested in searching for individual books.

As the collection grows, some basic questions arise; in particular how many books actually exist on human and medical genetics?  Even interpreting this broadly, the number is clearly finite, and perhaps limited to a few thousand.  Relatively few are pre-world war II, and it is possible that the number published each year may decline as electronic communication grows at the expense of print.  On the other hand, in contrast to journals, it does not seem likely that electronic format will directly involve books in the near future, especially not old books.

Readers may like to know what the Library now contains; the ‘simple’ catalogue is available electronically and is given on the website.  Everyone will have their favourites among historic human genetics books, but a few notable ones in the library include:

Julia Bell. Treasury of Human Inheritance (a complete bound set)

McKusick’s Mendelian Inheritance in Man (a virtually complete set of editions from 1 – 10)

Human Gene Mapping Workshop reports. (a complete set)

Birth Defects ‘blue volumes’ (an almost complete set)

Francis Galton’s Natural Inheritance (an early edition)

Oxford University Press Medical Genetics monographs (an almost complete set from 1963 to the present)

Tage Kemp Institute monographs, Copenhagen.

(Published theses on a wide range of genetic disorders).

The library is extremely grateful for these and other donations and encourages all readers to consider donating further books, since there are no funds currently for book purchase.  (Please check the catalogue to see if a book is already present in the library).

The Beginnings of Human Cytogenetics

A historical symposium was held on this topic on 10th August 2006, forming part of the 11th international Human Genetics Congress, Brisbane, Australia.

The year 2006 marks the 50th anniversary of the publication of the correct normal human chromosome number, as well as of the first International Human Genetics Congress, so it was fitting that the International Congress Programme Committee accepted the proposal for a session on this theme.  Around 250 people attended, and the whole session was recorded by the Congress organisers.

The programme was as follows:

The Beginnings of Human Cytogenetics


Mac Gardner, Royal Children’s Hospital, Australia

Peter S Harper, Cardiff University, United Kingdom

The discovery of the human chromosome number

Maj A Hulten, Department of Biological Sciences, University of Warwick, United Kingdom

The first human chromosome abnormalities

Patricia A Jacobs, Wessex Regional Genetics Laboratory, United Kingdom

The development of the Q-banding technique for identification of the 46 human chromosomes

Lore Zech, University of Uppsala, Sweden

Fragile sites on human chromosomes

Grant R Sutherland, Women’s and Children’s Hospital, Adelaide, Australia

The full text of the lectures by Patricia Jacob and Grant Sutherland are on the genmedhist website.

Originally, a talk by Dr Janet Rowley on chromosomes and leukaemia was included, but she had to withdraw due to ill health, so Professor Pat Jacobs extended her talk to cover this theme.

Maj Hulten’s opening talk gave a vivid picture of the background to the discovery of the correct human diploid chromosome number as 46 in Lund, Sweden, from the perspective of someone who was there at the time.  She also traced the previous work and the reasons for the number being persistently misidentified as 48.

Patricia Jacobs’ account of the discovery of the first human chromosome abnormalities concentrated on the key year 1959, describing not only her own contributions based in Edinburgh, but also the discoveries of other groups in Paris, Harwell and Philadelphia, on sex chromosomes and autosomal abnormalities, providing the foundations of human clinical cytogenetics.

Lore Zech was unable to travel to present her paper on the discovery of chromosome banding personally, so her slides were combined with excerpts from an earlier recorded interview on the topic to form a presentation.

Finally Grant Sutherland gave the history of fragile sites on human chromosomes, concentrating on the cytogenetic and later molecular understanding of fragile X mental retardation, as seen from his own lifetime work on the subject.

The combination of topics, and particularly the fact that all the contributors had been personally involved with the key early work and could give eye witness accounts of it, gave this session a special character that was greatly appreciated by all who were present.  It is hoped that placing some of the material on this website will allow others to share in these key historical events.


The Discovery of the Human Chromosome Number

Maj A Hulten, Department of Biological Sciences, University of Warwick, United Kingdom

The discovery, in 1956, by Joe-Hin Tjio and Albert Levan in Lund, Sweden that the correct human chromosome number is 46 was facilitated by technical advances, in vitro cell culture, colchicine and hypotonic pre-treatment followed by squashing.  Yet again, all these techniques had been used before; perhaps advantageous was the rapid divisions of foetal lung fibroblast, grown in bovine amniotic fluid, provided by Rune Grubb, these cells grown for a completely different purpose, namely to harbour viruses.

Previous attempts to count human chromosomes had mainly relied on spontaneous cell divisions, observed in testicular histological sections or in preparations of cancer cell populations.  Publications on attempts to count human chromosomes were first published as early as 1892, by Hansemann and Bardeleben, only a year after the discovery of chromosomes per se.  Both these and some early work to follow arrived at very low counts, in the order of 23 – 24.  On the other hand, in 1912, Hans de Winiwarter, analysing Spermatogonial Metaphases, counted 47 chromosomes in 29, 46 chromosomes in two and 49 chromosomes in one.  He proposed the correct male number to be 47, while at the same time dismissing the clear observation of 23 chromosomes in Metaphase II plates (!).  Theophilus Shickel Painter, also using testicular biopsy material, concluded in his first paper, in 1921, that in his best Spermatogonial Metaphases the chromosome number was clearly 46, but in a paper to follow two years later, remarkably, he converted to 48.  One problem here is that Spermatogonial Metaphases are not the ideal type of material for counting purposes.  The heterochromatic blocks of chromosomes 1, 9, 16 and 20 may vary substantially between cells, often being extended and thin, leading to the false impression of the pa and q arms as separate chromosomes.

The dogma of 48 human chromosomes was upheld during the following decades up until 1956, apparently leading many researchers in this interim period to jump to the wrong conclusion, even when it is in retrospect obvious they were on the right track.  In this presentation I will provide some illustrative examples of what I think is a fascinating part of early human cytogenetics.

The First Human Chromosome Abnormalities

Patricia A Jacobs, Wessex Regional Genetics Laboratory, United Kingdom

We are here to celebrate Tjio & Levan’s epic discovery in 1956 of the correct number of human chromosomes.  This was followed three years later by one of the most momentous years in human genetics. In 1959 the first chromosome abnormalities were described in our species: the additional X chromosome in Klinefelter syndrome which showed, contrary to established dogma, that the mammalian Y chromosome was male determining, and the first autosome abnormality, namely the additional chromosome 21 in mongolism, as Down syndrome was then called.  In the same year the 45.X constitution associated with Turner syndrome, the first case of mosaicism, an XXY/XX male with Klinefelter syndrome, and sex chromosome reversal in a female with Testicular Feminisation were all described.  In addition the first structural abnormality, a D/D Robertsonian translocation, and the first condition actually defined by a chromosome abnormality, the Trisomy X female, were published.  But 1959 was only a beginning.  1960 saw the description of the other two major autosomal trisomies found in the newborn, trisomies 13 and 18, the first syndrome, “cri-du-chat”, caused by a demonstrable deletion of chromosome material and the first specific chromosome abnormality, the Philadelphia chromosome, associated with a malignant disease.  In the same year the blood culture technique was described which enabled high quality preparations to be made from an easily obtained tissue thereby revolutionising human cytogenetics.  Thus by the end of 1960 all was in place for the burgeoning of cytogenetics as both a research and a diagnostic discipline.

It was a great privilege to be a young scientist at that time and to have the opportunity of contributing to some of these momentous discoveries.  I hope to share some of the excitement with you.

Full article

The Development of the Q-banding Technique for Identification of the 46 Human Chromosomes

Lore Zech, University of Uppsala, Sweden

The Q-banding technique was the first method developed for identification of all 46 human chromosomes.  This work was performed at the end of 1960 as collaboration between the late Torbjörn Caspersson, head of the department of Cell Research and Genetics, Karolinska Institute, in Stockholm and myself, a scientific assistant at the same department.

We wanted to study the structure of DNA with highly sensitive fluorescence dyes.  The material chosen for our first experiments were plants, many of which have fewer and larger chromosomes than mammals.

More than 30 DNA binding fluorochromes were tested but faded after a few seconds of irradiation with UV light and the morphology of the biological structures became blurred.  The best results were obtained with quinacrine mustard which was more stable and produced characteristic banding patterns.

The next step was the application of quinacrine mustard staining to human chromosomes which, however, gave so poor results that we could not distinguish individual structures.  However, after contrast enhancement of photographs we detected in male nuclei the Y chromosome as a weakly fluorescent dot.  From there to the first karyotype it was a long and painful struggle.  Especially the centromeres of the acrocentric chromosomes and the polymorphic regions on chromosomes 1, 3 and 9 were confusing.

From our work with plant material we remembered, that in Vicia faba often 2 chromosomes had shown identical banding patterns.  Controlling this phenomenon in human chromosomes we understood that homologous chromosomes were identical with respect to distribution and fluorescent intensity of bands.  This observation made possible to find the chromosome pairs and finally to arrange the first human karyotype.

Fragile Sites on Human Chromosomes

Grant R Sutherland, Women’s and Children’s Hospital, Adelaide, Australia

Fragile sites were seen intermittently in the early days of cytogenetics.  They were regarded as normal variants and were seen in some laboratories only.  The first rare autosomal fragile site was reported in 19651 and a fragile site on chromosome 2 was shown to be inherited in 19682 .  The fragile X was first recorded in 19693 .  It was not until 19774 that it was recognised that cytogenetic expression of most of the rare fragile sites was tissue culture medium dependent.  They were seen only if the old culture medium TC199 was used and not if the more modern (at that time) RPMI 1640 or Ham’s F10 were used.  The critical ingredients absent from TC199 that allowed for fragile site expression were folic acid and thymidine.  In 1984 common fragile sites were described and a method for their induction published5 .  While a number of new types of fragile site were described, and fragile X syndrome became recognised as the most common form of familial intellectual disability, fragile sites remained an enigmatic phenomenon until 1991 when the fragile X was cloned6 . The discovery that expansion of a naturally occurring polymorphic trinucleotide repeat (CCG) could produce premutations and full mutations that transcriptionally silenced the FMRI gene provided a new mechanism of mutation in human genetics.  The cloning of a few of the autosomal fragile sites allows the inference that all the rare folate sensitive fragile sites will be CCG expansions and the others more complex expansions of minisatellite repeats.  The common fragile sites occur over megabase regions DNA and while this DNA has some common properties no satisfying molecular explanation of these fragile sites has emerged.

1 Dekaban 1965 J Nucl Med 6:740

2 Lejeune 1968 C R Acad Sci Paris 266:24

3 Lubs 1969 Am J hum Genet 21:231

4 Sutherland 1977 Science 197:265

5 Glover et al 1984 Hum Genet 67:136

6 Yu et al 1991 Science 252:1179; Oberlé et al 1991 Science 252:1097; Verkerk et al 1991 Cell 65:905

Full article

Note from Dr Arno Motulsky

Dear Peter,

I very much appreciated reading the last issue (#9) of your medical genetics history newsletter on the web.

You should know some developments regarding my books and archival material.

1)  A collection of almost 1000 items has been donated by Professor Arno G. Motulsky from the Departments of Medicine (Medical Genetics) and Genome Sciences at the University of Washington (UW) in Seattle, Washington to the Library of the UW Department of Medical History & Ethics for study and research.  The collection is shelved separately as the Motulsky Collection.

Items are largely books and monographs (not reprints) dealing with human and medical genetics, human biology, physical anthropology, evolution, race, sociobiology, radiation genetics, eugenics, human biology, biomedical ethics and policy matters that were published between the 1950's to 1990 and reflect Dr. Motulsky's broad interest in human and medical genetics and related fields and include foreign language books.  Serial monographs of the Galton Laboratory (London), Technical reports by the Genetics branch of the World Health Organization (WHO) and Proceedings of various Human Genetics meetings and Congresses as well as some older books relevant to the history of human and medical genetics in the early part of the 20^th century are also in the collection.

The collection is available for study in the library of the Department of Medical History and Ethics of the University of Washington in Seattle.  Inquiries should be directed to the chair of that department (Wylie Burke, M.D., 206.221.5482,

All items are available in the library for reading and viewing and may not be borrowed through interlibrary loan.

Note that this information was published in the last issue of the Mendel Newsletter (March 2006).

2)  Extensive material of my work and related professional activities has been deposited in the Library of the American Philosophical Society in February 2006.  This will be part of their archives of geneticists papers.

You might want to know about these developments and publish about them in the newsletter.

Kind personal regards,


Arno G. Motulsky, M.D., Sc.D.

Professor Emeritus (Active)

Departments of Medicine (Division of Medical Genetics)

and Genome Sciences

School of Medicine

University of Washington

Box 357730

1959 N.E. Pacific Street

, HSC K-343A

Seattle, WA  98195-7730

Phone: (206) 543-3593

Fax: (206) 685-7301


Plans for future historical workshops

The third International Workshop on Genetics, Medicine and History is planned to coincide with the 2008 European Society of Human Genetics meeting, which will be in Barcelona between May 31 – June 3rd, 2008.

Professor Toine Peters (Amsterdam) and colleagues in Barcelona will be planning the workshop and the exact date with further details will be circulated in the next newsletter.  Meanwhile please put a note in your diary.


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