Get the full ebook with Bonus Features for a Better Reading Experience on ebookgate.

com

Textbook of assisted reproductive techniques

Volume 2 Clinical Perspectives 4th Edition Edited
By David K. Gardner

https://ebookgate.com/product/textbook-of-assisted-
reproductive-techniques-volume-2-clinical-perspectives-4th-
edition-edited-by-david-k-gardner/

OR CLICK HERE

DOWLOAD NOW

Download more ebook instantly today at https://ebookgate.com

Instant digital products (PDF, ePub, MOBI) available
Download now and explore formats that suit you...

Human Assisted Reproductive Technology Future Trends in

Laboratory and Clinical Practice 1st Edition David K.
Gardner
https://ebookgate.com/product/human-assisted-reproductive-technology-
future-trends-in-laboratory-and-clinical-practice-1st-edition-david-k-
gardner/
ebookgate.com

Surveying Volume 2 4th Edition S. K. Duggal

https://ebookgate.com/product/surveying-volume-2-4th-edition-s-k-
duggal/

ebookgate.com

Harper s Textbook of Pediatric Dermatology 2 Volume Set

4th Edition Peter H. Hoeger

https://ebookgate.com/product/harper-s-textbook-of-pediatric-
dermatology-2-volume-set-4th-edition-peter-h-hoeger/

ebookgate.com

Textbook of Human Reproductive Genetics Karen Sermon

https://ebookgate.com/product/textbook-of-human-reproductive-genetics-
karen-sermon/

ebookgate.com
Textbook of Veterinary Internal Medicine 6th Edition 2
Volume Set Volume 2 Stephen J. Ettinger

https://ebookgate.com/product/textbook-of-veterinary-internal-
medicine-6th-edition-2-volume-set-volume-2-stephen-j-ettinger/

ebookgate.com

LogoLounge 5 2 000 International Identities by Leading

Designers Bill Gardner

https://ebookgate.com/product/logolounge-5-2-000-international-
identities-by-leading-designers-bill-gardner/

ebookgate.com

Bedside Techniques Methods of Clinical Examination 4th

Edition Muhammad Inayatullah

https://ebookgate.com/product/bedside-techniques-methods-of-clinical-
examination-4th-edition-muhammad-inayatullah/

ebookgate.com

Methods and Applications in Reservoir Geophysics Edited

By: David H. Johnston

https://ebookgate.com/product/methods-and-applications-in-reservoir-
geophysics-edited-by-david-h-johnston/

ebookgate.com

SDG18 Communicaton for All Volume 2 Regional Perspectives

and Special Cases 4th Edition Jan Servaes

https://ebookgate.com/product/sdg18-communicaton-for-all-
volume-2-regional-perspectives-and-special-cases-4th-edition-jan-
servaes/
ebookgate.com
 Textbook of
Assisted Reproductive
Techniques
The editors (from left to right: Colin M. Howles, Ariel Weissman, David K. Gardner,
and Zeev Shoham) at the annual meeting of ESHRE, Stockholm, July 2011
 Textbook of
Assisted Reproductive
Techniques
Fourth Edition

Volume 2: Clinical Perspectives

Edited by

David K. Gardner DPhil

Chair of Zoology, University of Melbourne, Australia

Ariel Weissman MD
Senior Physician, IVF Unit, Department of Obstetrics and Gynecology,
Edith Wolfson Medical Center, Holon and Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel

Colin M. Howles PhD, FRSM

Vice President, Regional Medical Affairs Fertility, External Scientific Affairs,
Global Development and Medical, Merck Serono SA, Geneva, Switzerland

Zeev Shoham MD
Director, Reproductive Medicine and Infertility Unit, Department of Obstetrics and
Gynecology, Kaplan Medical Center, Rehovot, Israel
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2012 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Version Date: 20130604

International Standard Book Number-13: 978-1-84184-973-7 (eBook - PDF)

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have
been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibil-
ity or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions
expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect
the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical,
scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own
judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best
practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or
diagnoses should be independently verified. The reader is strongly urged to consult the drug companies’ printed instruc-
tions, and their websites, before administering any of the drugs recommended in this book. This book does not indicate
whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility
of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately.
The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication
and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material
has not been acknowledged please write and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or uti-
lized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopy-
ing, microfilming, and recording, or in any information storage or retrieval system, without written permission from the
publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.
copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-
750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organiza-
tions that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for iden-
tification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents

List of contributors viii

The beginnings of human in vitro fertilization xii

Robert G. Edwards

Robert Edwards: The path to IVF xxv

Martin H. Johnson

IX Quality Management Systems

32. Quality management in reproductive medicine 1

Christoph Keck, Cecilia Sjöblom, Robert Fischer, Vera Baukloh, and Michael Alper

X Patient Investigation and the Use of Drugs

33. Lifestyle, periconception, and fertility 10

Robert J. Norman, Lisa J. Moran, and Sarah A. Robertson
34. Indications for IVF treatment: From diagnosis to prognosis 18
Ido Ben-Ami, Arie Raziel, Shevach Friedler, Yariv Gidoni, Raphael Ron-El, and Bart C. J. M. Fauser
35. Initial investigation of the infertile couple 31
Isabelle Roux, Togas Tulandi, Peter Chan, and Hananel Holzer
36. Prognostic testing for ovarian reserve 41
Frank J. Broekmans, Simone L. Broer, Bart C. J. M. Fauser, and Nick S. Macklon
37. Drugs used for ovarian stimulation: Clomiphene citrate, aromatase inhibitors,
metformin, gonadotropins, gonadotropin-releasing hormone analogs,
and recombinant gonadotropins 51
Zeev Shoham and Colin M. Howles
38. The role of FSH and LH in ovulation induction: Current concepts 75
Juan Balasch

XI Stimulation Protocols

39. Endocrine characteristics of ART cycles 99

Jean-Noël Hugues and Isabelle Cédrin-Durnerin
40. The use of GnRH agonists 115
Roel Schats and Judith A. F. Huirne
41. GnRH-antagonists in ovarian stimulation for IVF 124
Efstratios M. Kolibianakis, Georg Griesinger, and Basil C. Tarlatzis
42. The use of AMH to tailor ovarian stimulation for IVF 131
Scott M. Nelson
43. Monitoring ovarian response in IVF cycles 140
Matts Wikland and Torbjörn Hillensjö
44. Oocyte collection 145
Gab Kovacs
45. Luteal support in ART 153
Dominique de Ziegler, Isabelle Streuli, Vanessa Gayet, Usama Bajouh, Juliane Berdah,
and Charles Chapron
vi CONTENTS

46. Treatment strategies in assisted reproduction for the poor responder patient 162
Ariel Weissman and Colin M. Howles
47. Repeated implantation failure 208
Mark A. Damario and Zev Rosenwaks

XII Technical Procedures and Outcomes

48. Ultrasonography in assisted reproduction 225

Ilan Tur-Kaspa and Laurel Stadtmauer
49. Sperm recovery techniques: Clinical aspects 242
Herman Tournaye and Patricio Donoso
50. Processing and cryopreservation of testicular sperm 258
Kathleen Hwang, Joseph P. Alukal, Dolores J. Lamb, and Larry I. Lipshultz
51. Embryo transfer technique 263
Ragaa Mansour
52. Cycle regimes for frozen–thawed embryo transfer 272
Ingrid Granne and Tim Child
53. Anesthesia and in vitro fertilization 278
Shmuel Evron and Tiberiu Ezri
54. Medical considerations of single embryo transfer 284
Outi Hovatta

XIII Special Medical Conditions

55. Endometriosis and ART 288

Marli Amin, Andy Huang, and Alan H. DeCherney
56. PCOS and assisted reproduction 298
Susie Nicholas, Christopher Brewer, Thomas H. Tang, and Adam H. Balen
57. Management of hydrosalpinx 308
Annika Strandell
58. Fertility preservation strategies 318
Stine Gry Kristensen, Tine Greve, and Claus Yding Andersen
59. Viral disease and Assisted Reproductive Techniques 333
Carole Gilling-Smith

XIV Complications of Treatment

60. Severe ovarian hyperstimulation syndrome 341

Zalman Levine, Inna Berin, and Daniel Navot
61. The environment and reproduction 360
Machelle M. Seibel
62. Bleeding, severe pelvic infection, and ectopic pregnancy 374
Raoul Orvieto and Zion Ben-Rafael
63. Iatrogenic multiple pregnancies: The risk of ART 382
Isaac Blickstein

XV Egg Donation and Surrogate Motherhood

64. Egg and embryo donation 394

Mark V. Sauer and Matthew A. Cohen
65. Gestational surrogacy 405
Peter R. Brinsden

XVI The Support Team

66. The evolving role of the ART nurse: A contemporary review 415
Joanne L. Libraro
 CONTENTS vii

67. Patient support in the ART program 424

Sharon N. Covington
68. The relationship between stress and in vitro fertilization outcome 434
Andrea Mechanick Braverman

XVII Ethics, Religion and Legislation

69. The impact of legislation and socioeconomic factors in the access to

and global practice of assisted reproduction 441
Fernando Zegers-Hochschild, Karl G. Nygren, and Osamu Ishihara
70. Religious perspectives in human reproduction 451
Raphael Ron-El and Botros Rizk

Index 457
List of contributors

Michael Alper Inna Berin

Boston IVF, Waltham, Massachusetts, USA Fertility Institute of New Jersey and New York
Westwood, New Jersey, USA
Joseph P. Alukal
Clinical Assistant Professor of Urology, Isaac Blickstein
Department of Urology, NYU School of Medicine Department of Obstetrics and Gynecology, Kaplan
New York, New York, USA Medical Center, Rehovot, Israel

Marli Amin Andrea Mechanick Braverman

Department of Obstetrics and Gynecology, David Geffen Director, The Braverman Center for Health Journeys
School of Medicine, Los Angeles, California, USA Bala Cynwyd, Pennsylvania, USA

Claus Yding Andersen Christopher Brewer

Laboratory of Reproductive Biology, Copenhagen Leeds Centre for Reproductive Medicine, Seacroft
University Hospital, Copenhagen, Denmark Hospital, Leeds, UK

Usama Bajouh Peter R. Brinsden

Faculté de médecine, Université Paris Descartes, Bourn Hall Clinic International, Bourn, Cambridge, UK
Paris Sorbonne-Cité, and Department of Obstetrics,
Gynecology, and Reproductive Medicine, Assistance Frank J. Broekmans
Publique Hôpitaux de Paris, CHU Cochin, Department of Reproductive Medicine and Gynecology,
Paris, France Division of Woman and Baby, University Medical
Center Utrecht, Utrecht, The Netherlands
Juan Balasch
Department of Obstetrics and Gynecology, Faculty of Simone L. Broer
Medicine, Hospital Clinic, University of Barcelona, Department of Reproductive Medicine and Gynecology,
Barcelona, Spain Division of Woman and Baby, University Medical
Center Utrecht, Utrecht, The Netherlands
Adam H. Balen
Leeds Centre for Reproductive Medicine, Seacroft Isabelle Cédrin-Durnerin
Hospital, Leeds, UK University of Paris XIII, Division of Reproductive
Medicine, Hôpital Jean Verdier, Bondy, France
Vera Baukloh
Fertility Center Hamburg, Hamburg, Germany Peter Chan
Division of Reproductive Endocrinology and Infertility,
Ido Ben-Ami Department of Obstetrics and Gynecology, McGill
Fertility and IVF Unit, Assaf Harofeh Medical Center, University, Montreal, Quebec, Canada
Tel Aviv University, Tel Aviv, Israel
Charles Chapron
Zion Ben-Rafael Faculté de médecine, Université Paris Descartes,
Sackler Faculty of Medicine, Tel Aviv University, Paris Sorbonne-Cité, and Department of Obstetrics,
Tel Aviv, Israel Gynecology, and Reproductive Medicine, Assistance
Publique Hôpitaux de Paris, CHU Cochin, Paris, France
Juliane Berdah
Faculté de médecine, Université Paris Descartes, Tim J. Child
Paris Sorbonne-Cité, and Department of Obstetrics, Oxford Fertility Unit, Institute of Reproductive
Gynecology, and Reproductive Medicine, Assistance Sciences, and Nuffield Department of Obstetrics and
Publique Hôpitaux de Paris, CHU Cochin, Gynaecology, John Radcliffe Hospital, University of
Paris, France Oxford, Oxford, UK
 LIST OF CONTRIBUTORS ix

Matthew A. Cohen Yarev Gidoni

Department of Obstetrics and Gynecology, College of Fertility and IVF Unit, Assaf Harofeh Medical Center,
Physicians & Surgeons, Columbia University, New York, Tel Aviv University, Tel Aviv, Israel
New York, USA
Carole Gilling-Smith
Sharon N. Covington The Agora Gynaecology and Fertility Centre, Hove, UK
Psychological Support Services, Shady Grove
Fertility Reproductive Science Center, Rockville, Ingrid Granne
Maryland, USA Oxford Fertility Unit, Institute of Reproductive
Sciences, and Nuffield Department of Obstetrics and
Mark A. Damario Gynaecology, John Radcliffe Hospital, University of
Department of Obstetrics, Gynecology and Women’s Oxford, Oxford, UK
Health, University of Minnesota, Minneapolis,
Minnesota, USA Tine Greve
Laboratory of Reproductive Biology, Copenhagen
Alan H. DeCherney University Hospital, Copenhagen, Denmark
Department of Obstetrics and Gynecology, David Geffen
School of Medicine, Los Angeles, California, USA Georg Griesinger
Department of Reproductive Medicine and
Patricio Donoso Gynecological Endocrinology, University Hospital of
Centre for Reproductive Medicine, Clinica Alemana de Schleswig-Holstein, Luebeck, Germany
Santiago, Santiago, Chile
Torbjörn Hillensjö
Robert G. Edwards Fertility Centre Scandinavia, Carlander’s Hospital,
Duck End Farm, Dry Drayton, Cambridge, UK Göteborg, Sweden

Shmuel Evron Hananel Holzer

Obstetric Anesthesia Unit, Wolfson Medical Center, and Division of Reproductive Endocrinology and Infertility,
Sackler Faculty of Medicine, Tel Aviv University, Department of Obstetrics and Gynecology, McGill
Tel Aviv, Israel University, Montreal, Quebec, Canada

Tiberiu Ezri Outi Hovatta

Department of Anesthesiology, Wolfson Medical Center, Karolinska Institute, Karolinska University Hospital
and Sackler Faculty of Medicine, Tel Aviv University, Huddinge, Stockholm, Sweden
Tel Aviv, Israel
Colin M. Howles
Bart C. J. M. Fauser External Scientific Affairs, Global Development and
Departments of Reproduction and Gynecology, Division Medical, Merck Serono SA, Geneva,
of Woman and Baby, University Medical Center Utrecht, Switzerland
Utrecht, The Netherlands
Andy Huang
Robert Fischer Department of Obstetrics and Gynecology, David Geffen
Fertility Center Hamburg, Hamburg, Germany School of Medicine, Los Angeles, California, USA

Shevach Friedler Jean-Noël Hugues

Fertility and IVF Unit, Assaf Harofeh Medical Center, University of Paris XIII, Division of Reproductive
Tel Aviv University, Tel Aviv, Israel Medicine, Hôpital Jean Verdier, Bondy, France

David K. Gardner Judith A. F. Huirne

Department of Zoology, University of Melbourne, Department of Obstetrics and Gynecology, Division of
Victoria, Australia Reproduction and Fertility Investigation, IVF Center,
Vrije Universiteit Medical Center, Amsterdam, The
Vanessa Gayet Netherlands
Faculté de médecine, Université Paris Descartes,
Paris Sorbonne-Cité, and Department of Obstetrics, Kathleen Hwang
Gynecology, and Reproductive Medicine, Assistance Assistant Professor of Surgery (Urology),
Publique Hôpitaux de Paris, CHU Cochin, Division of Urology, Alpert Medical School
Paris, France of Brown University Providence, Rhode Island, USA
x LIST OF CONTRIBUTORS

Osamu Ishihara Daniel Navot

Department of Obstetrics and Gynaecology, Saitama Fertility Institute of New Jersey and New York,
Medical University, and Saitama Medical Centre Westwood, New Jersey, USA
Hospital, Kawagoe, Japan
Scott M. Nelson
Martin H. Johnson Department of Obstetrics and Gynaecology,
The Anatomy School, Department of Physiology, School of Medicine, University of Glasgow,
Development and Neuroscience, and The Centre for Glasgow, UK
Trophoblast Research, University of Cambridge,
Cambridge, UK Susie Nicholas
Leeds Centre for Reproductive Medicine, Seacroft
Christoph Keck Hospital, Leeds, UK
IVF Group, Endokrinologikum, Hamburg, Germany
Robert J. Norman
Efstratios M. Kolibianakis Robinson Institute and School of Paediatrics and
Unit for Human Reproduction, First Department of Reproductive Health
Obstetrics and Gynaecology, Medical School, Aristotle University of Adelaide, Adelaide, South Australia,
University of Thessaloniki, and Papageorgiou General Australia
Hospital, Thessaloniki, Greece
Karl G. Nygren
Gab Kovacs Karolinska Institute, Institute of Medical Epidemiology
Monash IVF, Richmond, Victoria, Australia & Biostatistics, Stockholm, Sweden

Stine Gry Kristensen Raoul Orvieto

Laboratory of Reproductive Biology, Copenhagen Infertility and IVF Unit, Department of Obstetrics
University Hospital, Copenhagen, Denmark and Gynecology, Barzilai Medical Center, Ashkelon,
and Faculty of Health Sciences, Ben Gurion University
Dolores J. Lamb of the Negev, Beer Sheva, Israel
Division of Male Reproductive Medicine and Surgery,
Scott Department of Urology, Baylor College of Arie Raziel
Medicine, Houston, Texas, USA Fertility and IVF Unit, Assaf Harofeh Medical Center,
Tel Aviv University, Tel Aviv, Israel
Zalman Levine
Fertility Institute of New Jersey and New York, Botros Rizk
Westwood, New Jersey, USA Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology,
Joanne L. Libraro University of South Alabama, Mobile,
Center for Reproductive Medicine and Infertility, Weill Alabama, USA
Medical College, New York, New York, USA
Sarah A. Robertson
Larry I. Lipshultz Robinson Institute and School of Paediatrics and
Division of Male Reproductive Medicine and Surgery, Reproductive Health, University of Adelaide, Adelaide,
Scott Department of Urology, Baylor College of South Australia, Australia
Medicine, Houston, Texas, USA
Raphael Ron-El
Nick S. Macklon Fertility and IVF Unit, Assaf Harofeh Medical Center,
Department of Obstetrics and Gynaecology, Tel Aviv University, Tel Aviv, Israel
University of Southampton, and Complete Fertility
Centre Southampton, Princess Anne Hospital, Zev Rosenwaks
Southampton, UK Center for Reproductive Medicine and Infertility,
Weill Medical College of Cornell University, New York,
Ragaa Mansour New York, USA
The Egyptian IVF Center, Cairo, Egypt
Isabelle Roux
Lisa J. Moran Division of Reproductive Endocrinology
Robinson Institute and School of Paediatrics and and Infertility, Department of Obstetrics and
Reproductive Health, University of Adelaide, Adelaide, Gynecology, McGill University, Montreal,
South Australia, Australia Quebec, Canada
 LIST OF CONTRIBUTORS xi

Mark V. Sauer Basil C. Tarlatzis

Department of Obstetrics and Gynecology, College of Unit for Human Reproduction, First Department of
Physicians & Surgeons, Columbia University, New York, Obstetrics and Gynaecology, Medical School, Aristotle
New York, USA University of Thessaloniki, and Papageorgiou General
Hospital, Thessaloniki, Greece
Roel Schats
Department of Obstetrics and Gynecology, Division of Herman Tournaye
Reproduction and Fertility Investigation, IVF Center, Center for Reproductive Medicine, University Hospital
Vrije Universiteit University Medical Center, of the Brussels Free University, Brussels, Belgium
Amsterdam, The Netherlands
Togas Tulandi
Machelle M. Seibel Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology, University of Department of Obstetrics and Gynecology, McGill
Massachusetts School of Medicine, Worcester, University, Montreal, Quebec, Canada
Massachusetts, USA
Ilan Tur-Kaspa
Zeev Shoham Institute for Human Reproduction (IHR), and
Reproductive Medicine and Infertility Unit, Department the Department of Obstetrics and Gynecology,
of Obstetrics and Gynecology, Kaplan Medical Center, The University of Chicago, Chicago, Illinois, USA
Rehovot, Israel
Ariel Weissman
Cecilia Sjöblom IVF Unit, Department of Obstetrics and Gynecology,
Westmead Fertility Centre, University of Sydney, Edith Wolfson Medical Center, Holon, and Sackler
Western Clinical School, Westmead Hospital, Faculty of Medicine, Tel Aviv University, Tel Aviv,
Westmead, New South Wales, Australia Israel

Laurel Stadtmauer Matts Wikland

The Jones Institute for Reproductive Medicine, Eastern Fertility Centre Scandinavia, Carlander’s Hospital,
Virginia Medical School, Norfolk, Virginia, USA Göteborg, Sweden

Annika Strandell Fernando Zegers-Hochschild

Department of Obstetrics and Gynecology, Institute of Unit of Reproductive Medicine, Clínica las Condes,
Clinical Sciences, Sahlgrenska Academy, University of Santiago, Chile
Göteborg, Göteborg, Sweden
Dominique de Ziegler
Isabelle Streuli Faculté de médecine, Université Paris Descartes,
Faculté de médecine, Université Paris Descartes, Paris Sorbonne-Cité, and Department of Obstetrics,
Paris Sorbonne-Cité, and Department of Obstetrics, Gynecology, and Reproductive Medicine,
Gynecology, and Reproductive Medicine, Assistance Assistance Publique Hôpitaux de Paris, CHU Cochin,
Publique Hôpitaux de Paris, CHU Cochin, and Cochin Paris, France
Institute, Paris, France

Thomas H. Tang
Leeds Centre for Reproductive Medicine, Seacroft
Hospital, Leeds, UK
The beginnings of human
in vitro fertilization
Robert G. Edwards

In vitro fertilization (IVF) and its derivatives in preim- Pincus et al. also studied human oocytes (1). Extracting
plantation diagnosis, stem cells, and the ethics of assisted oocytes from excised ovaries, they identified chromo-
reproduction continue to attract immense attention sci- somes in a large number of oocytes and interpreted this as
entifically and socially. All these topics were introduced evidence of the completion of maturation in vitro. Many
by 1970. Hardly a day passes without some public recog- oocytes possessed chromosomes after 12 hours, the pro-
nition of events related to this study, and clinics spread portion remaining constant over the next 30 hours and
ever further worldwide. Now we must be approaching longer. Twelve hours was taken as the period of matura-
1.5 million IVF births, it is time to celebrate what has tion. Unfortunately, chromosomes were not classified for
been achieved by so many investigators, clinical, scien- their meiotic stage. Maturing oocytes would be expected
tific, and ethical. to display diakinesis or metaphase-I chromosome pairs.
While much of this chapter “Introduction” covers the Fully mature oocytes would display metaphase-II chro-
massive accumulation of events between 1960 and 2000, mosomes, signifying they were fully ripe and ready for
it also briefly discusses new perspectives emerging in the fertilization. Nevertheless, it is well known that oocytes
21st century. Fresh advances also increase curiosity can undergo atresia in the ovary involving the formation
about how these fields of study began and how their eth- of metaphase-II chromosomes in many of them. These
ical implications were addressed in earlier days. As for oocytes complicated Pincus’ estimates, even in controls,
me, I am still stirred by recollections of those early days. and were the source of his error which led later workers
Foundations were laid in Edinburgh, London, and to inseminate human oocytes 12 hours after collection
Glasgow in the 1950s and early 1960s. Discoveries made and culture in vitro (2,3). Work on human fertilization in
then led to later days in Cambridge, working there with vitro, and indeed comparable studies in animals,
many PhD students. It also resulted in my working with remained in abeyance from then and for many years.
Patrick Steptoe in Oldham. Our joint opening of Bourn Progress in animal IVF had also been slow. After many
Hall in 1980, which became the largest IVF clinic of its relatively unsuccessful attempts in several species in the
kind at the time, signified the end of the beginning of 1950s and 1960s, a virtual dogma arose that spermatozoa
assisted human conception and the onset of dedicated had to spend several hours in the female reproductive
applied studies. tract before acquiring the potential to bind to the zona
pellucida and achieve fertilization. In the late 1960s,
Austin and Chang independently identified the need for
INTRODUCTION
sperm capacitation, identified by a delay in fertilization
First of all, I must express in limited space my tributes to after spermatozoa had entered the female reproductive
my teachers, even if inadequately. These include investi- tract (4,5). This discovery was taken by many investiga-
gators from far-off days when the fundamental facts of tors as the reason for the failure to achieve fertilization in
reproductive cycles, surgical techniques, endocrinology, vitro, and why spermatozoa had to be exposed to secre-
and genetics were elicited by many investigators. These tions of the female reproductive tract. At the same time,
fields began to move in the 20th century, and if one pio- Chang reported that rabbit eggs that had fully matured in
neer of these times should be saluted, it must be Gregory vitro failed to produce normal blastocysts, none of them
Pincus. Famous for the contraceptive pill, he was a dis- implanting normally (6).
tinguished embryologist, and part of his work dealt with
the maturation of mammalian oocytes in vitro. He was
MODERN BEGINNINGS OF HUMAN IVF,
the first to show how oocytes aspirated from their folli-
PREIMPLANTATION GENETIC DIAGNOSIS, AND
cles would begin their maturation in vitro, and how a
EMBRYO STEM CELLS
number matured and expelled a first polar body. I believe
his major work was done in rabbits, where he found that My PhD began at the Institute of Animal Genetics,
the 10 to 11-hour timings of maturation in vitro accorded Edinburgh University in 1952, encouraged by Professor
exactly with those occurring in vivo after an ovulatory Conrad Waddington, the inventor of epigenesis, and
stimulus to the female rabbit. supervised by Dr Alan Beatty. At the time, capacitation
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xiii

was gaining in significance. My chosen topic was the reproductive cycles. In fact, they worked wonderfully
genetic control of early mammalian embryology, specifi- well. Doses of 1–3 IU of PMS induced the growth of
cally the growth of preimplantation mouse embryos with numerous follicles, and similar doses of hCG 42 hours
altered chromosome complements. later invoked estrus and ovulation a further 6 hours later
Achieving these aims included a need to expose mouse in almost all of them. Often, 70 or more ovulated oocytes
spermatozoa to x-rays, ultraviolet light, and various crowded the ampulla, most of them being fertilized and
chemicals in vitro. This would destroy their chromatin developing to blastocysts (9). Oocyte maturation, ovula-
and prevent them from making any genetic contribution tion, mating, and fertilization were each closely timed in
to the embryo, hopefully without impairing their capac- all adults, another highly unusual aspect of stimulation
ity to fertilize eggs in vivo. Resulting embryos would (10). Diakinesis was identified as the germinal vesicle
become gynogenetic haploids. Later, my work changed to regressed, with metaphase I a little later and metaphase II,
exposing ovulated mouse oocytes to colchicine in vivo, expulsion of the first polar body, and ovulation at
in order to destroy their second meiotic spindle in vivo. 11.5–12 hours after hCG. Multiple fertilization led to
This treatment freed all chromosomes from their attach- multiple implantation and fetal growth to full term, just
ment to the meiotic spindle, and they then became as similar treatments in anovulatory women resulted in
extruded from the egg into tiny artificial polar bodies. quintuplets and other high-order multiple pregnancies a
The fertilizing spermatozoon thus entered an empty egg, few years later. Years afterward, germinal vesicle break-
which resulted in the formation of androgenetic haploid down and diakinesis were to prove equally decisive in
embryos with no genetic contribution from the maternal identifying meiosis and ovulation in human oocytes in
side. For three years, my work was concentrated in the vivo and in vitro. Even as these results were gained, Ruth
mouse house, working at midnight to identify mouse and I departed in 1957 from Edinburgh to the California
females in estrus by vaginal smears, collecting epididy- Institute of Technology, where I switched over immu-
mal spermatozoa from males, and practicing artificial nology and reproduction, a topic that was to dominate
insemination with samples of treated spermatozoa. This my life for five or six years on my return to the United
research was successful, as mouse embryos were identi- Kingdom.
fied with haploid, triploid, tetraploid, and aneuploid The Institute at Edinburgh had given me an excellent
chromosomes. Moreover, the wide range of scientific tal- basis not only in genetics, but equally in reproduction.
ent in the Institute made it a perfect place for fresh col- I had gained considerable knowledge about the endocrine
laborative studies. For example, Julio Sirlin and I applied control of estrus cycles, ovulation, and spermatozoa; the
the use of radioactive DNA and RNA precursors to the male reproductive tract; artificial insemination; the stages
study of spermatogenesis, spermiogenesis, fertilization, of embryo growth in the oviduct and uterus; superovula-
and embryogenesis, and gained knowledge unavailable tion and its consequences; and the use of radiolabeled
elsewhere. compounds. Waddington had also been deeply interested
An even greater fortune beckoned. Allen Gates, who in ethics and the relationships between science and reli-
arrived newly from the United States, brought commer- gion, and instilled these topics in his students. I had been
cial samples of Organon’s pregnant mares’ serum (PMS) essentially trained in reproduction, genetics, and scien-
rich in follicle-stimulating hormone (FSH), and human tific ethics, and all of this knowledge was to prove to be of
chorionic gonadotropin (hCG) with its strong luteinizing immense value in my later career. A visit to the California
hormone (LH) activity to induce estrus and ovulation in Institute of Technology widened my horizons into the
immature female mice. Working with Mervyn Runner molecular biology of DNA and the gene, a field then in its
(7), he had used low doses of each hormone at an interval infancy.
of 48 hours to induce oocyte maturation, mating, and After a year in California, London beckoned me, to
ovulation in immature mouse females. He now wished to the National Institute for Medical Research to work
measure the viability of three-day embryos from imma- with Drs Alan Parkes and Colin (Bunny) Austin. I was
ture mice by transferring them to an adult host to grow to fortunate indeed to have two such excellent colleagues.
term (8). I was more interested in stimulating adult mice After two intense years in immunology, my curiosity
with these gonadotropins to induce estrus and ovulation returned to maturing oocytes and fertilization in vitro.
at predictable times of the day. This would help my Since they matured so regularly and easily in vivo, it
research, and I was by now weary of taking mouse vagi- should be easy to stimulate maturation in mouse oocytes
nal smears at midnight. My future wife, Ruth Fowler, and in vitro by using gonadotropins. In fact, to my immense
I teamed up to test this new approach to superovulating surprise, when liberated from their follicles into culture
adult mice. We chose PMS to induce multifolliculation medium, oocytes matured immediately in vast numbers
and hCG to trigger ovulation, varying doses and times in all groups, with exactly the same timing as those
from those utilized by Allen Gates. PMS became obsolete maturing in vivo following an injection of hCG. Adding
for human studies some time later, but its impact has hormones made no difference. Rabbit, hamster, and rat
stayed with me from that moment, even till today. oocytes also matured within 12 hours, each at their own
Opinion in those days was that exogenous hormones species’ specific rates. But to my surprise, oocytes from
such as PMS and hCG would stimulate follicle growth cows, sheep, and rhesus monkeys, and the occasional
and ovulation in immature female mammals, but not in baboon, did not mature in vitro within 12 hours. Their
adults because they would interact badly with an adult’s germinal vesicles persisted unmoved, arrested in the
xiv THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

stage known as diffuse diplotene. Why had they not While looking in the library for any newly published
responded like those of rats, mice, and rabbits? How papers relevant to my proposed Nature manuscript, I dis-
would human oocytes respond? A unique opportunity covered those earlier papers of Pincus and his colleagues
emerged to collect pieces of human ovary, and to aspirate described earlier. They had apparently succeeded 30 years
human oocytes from their occasional follicles. I grasped earlier in maturing human oocytes cultured for 12 hours,
it with alacrity. where I had failed. My Nature paper (11) became very
different from that originally intended, even though it
retained enough for publication. Those results of Pincus
MOVING TO HUMAN STUDIES
et al. had to be repeated. After trying hard, I failed com-
Molly Rose was a local gynecologist in the Edgware and pletely to repeat them, despite infusing intact ovaries in
District Hospital who delivered two of our daughters. She vitro with gonadotropin solutions, using different cul-
agreed to send me slithers or wedges of ovaries such as ture media to induce maturation, and using joint cultures
those removed from patients with polycystic disease, as of maturing mouse oocytes and newly released human
recommended by Stein and Leventhal, or with myomata oocytes. Adding hormones to culture media also failed.
or other disorders demanding surgery. Stein–Leventhal It began to seem that menstrual cycles had affected oocyte
wedges were the best source of oocytes, with their numer- physiology in a different manner than in nonmenstruat-
ous small Graafian follicles lined up in a continuous rim ing mammalian species. Finally, another line of inquiry
just below the ovarian surface. Though samples were emerged after two years of fruitless research on the pre-
rare, they provided enough oocytes to start with. These cious few human oocytes available. Perhaps the timing
oocytes responded just like the oocytes from cows, sheep, of maturation in mice and rabbits differed from that of
and pigs, their germinal vesicles persisting and diakine- those oocytes obtained from cows, baboons, and humans.
sis being absent after 12 hours in vitro. Even as my days in London were ending, Molly Rose
This was disappointing, and especially so for me, since sent a slither of human ovary. The few oocytes were
Tjio and Levan, and Ford had identified 46 diploid chro- placed in culture just as before. Their germinal vesicles
mosomes in humans, while studies by teams in Edin- remained static for 12 hours as I already knew, and then
burgh (Scotland) and France had made it clear that many after 20 hours in vitro. Three oocytes remained, and
human beings were heteroploid. This was my subject, I waited to examine them until they had been in vitro for
because chromosomal variations mostly arose during 24 hours. The first contained a germinal vesicle, so did
meiosis and this would be easily assessed in maturing the second. There was one left and one only. Its image
oocytes at diakinesis. Various groups also discovered under the microscope was electrifying. I gazed down at
monosomy or disomy in many men and women. Some chromosomes in diakinesis and at a regressing germinal
women were XO or XXX; some men were XYY and vesicle. The chromosomes were superb examples of
XYYY. Trisomy 21 proved to be the most common cause human diakinesis with their classical chiasmata. At last,
of Down’s syndrome, and other trisomies were detected. I was on the way to human IVF, to completion of the
All this new information reminded me of my chromo- maturation program and the onset of studies on fertiliza-
some studies in the Edinburgh mice. tion in vitro.
For human studies, I would have to obtain diakinesis This was the step I had waited for, a marker that Pincus
and metaphase I in human oocytes, and then continue had missed. He never checked for diakinesis, and appar-
this analysis to metaphase II when the oocytes would be ently confused atretic oocytes, which contained chromo-
fully mature, ready for fertilization. Despite being disap- somes, with maturing oocytes. Endless human studies
pointed at current failure with human oocytes, it was were opening. It was easy now, even on the basis of one
time to write my findings for Nature in 1962 (11). There oocyte in diakinesis, to calculate the timing of the final
was so much to write regarding the animal work, and stages of maturation because the postdiakinesis stages of
describing the new ideas then taking shape in my mind. maturation were not too different from normal mitotic
I had heard Institute lectures on infertility, and realized cycles in somatic cells. This calculation provided me
that fertilizing human oocytes in vitro and replacing with an estimate of about 36 hours for full maturation,
embryos into the mother could help to alleviate this con- which would be the moment for insemination. All these
dition. It could also be possible to type embryos for gaps in knowledge had to be filled. But now, my research
genetic diseases when a familial disposition was identi- program was stretching far into the future.
fied. Pieces of tissue, or one or two blastomeres, would At this wonderful moment, John Paul, an outstanding
have to be excised from blastocysts or cleaving embryos, cell biologist, invited me to join him and Robin Cole at
but this did not seem to be too difficult. There were few Glasgow University to study differentiation in early
genetic markers available for this purpose in the early mammalian embryos. This was exciting, to work in bio-
1960s, but it might be possible to sex embryos by their chemistry with a leading cell biologist. He had heard
XX or XY chromosome complement by assessing mitoses that I was experimenting with very early embryos, trying
in cells excised from morulae or blastocysts. Choosing to grow cell lines from them. He also wanted to grow
female embryos for transfer would avert the birth of boys stem cells from mammalian embryos and study them in
with various sex-linked disorders such as hemophilia. vitro. This began one of my most memorable 12 months
Clearly, I was becoming totally committed to human IVF of research. John’s laboratory had facilities unknown
and embryo transfer. outside, with CO2 incubators, numerous cell lines in
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xv

constant cultivation, cryopreservation facilities, and the I had already met Victor McKusick, who worked in Johns
use of media droplets held under liquid paraffin. We Hopkins, at many conferences. I asked for his support for
decided to start with rabbits. Cell lines did not grow eas- my request to work with the hospital gynecologists for
ily from cleaving rabbit embryos. In contrast, stem cells six weeks. He found a source of funds, made laboratory
migrated out in massive numbers from cultures of rabbit space available, and a wonderful invitation that intro-
blastocysts, forming muscle, nerves, phagocytes, blood duced me to Howard and Georgeanna Jones. This signifi-
islands, and other tissues in vitro (12). Stem cells were cant moment was equal to my meeting with Molly Rose.
differentiating in vitro into virtually all the tissues of the The Joneses proved to be superb and unstinting in their
body. In contrast, dissecting the inner cell mass from support. Sufficient wedges and other ovarian fragments
blastocysts and culturing it intact or as disaggregated were available to complete my maturation program in
cells produced lines of cells which divided and divided, human oocytes. Within three weeks, every stage of meio-
without ever differentiating. One line of these embry- sis was classified and timed (14). We also undertook pre-
onic stem cells expressed specific enzymes, diploid liminary studies on inseminating human oocytes that
chromosomes, and a fibroblastic structure as it grew over had matured in vitro, trying to achieve sperm capacita-
200 and more generations. Another was epithelioid and tion by using different media or adding fragments of
had different enzymes but was similar in other respects. ampulla to the cultures, and even attempting fertilization
The ability to make whole-embryo cultures producing in rhesus monkey oviducts. Two nuclei were found in
differentiating cells was now combined with everlasting some inseminated eggs, resembling pronuclei, but sperm
lines of undifferentiated stem cells which replicated tails were not identified so no claims could be made (15).
over many years without changing. Ideas of using stem During those six weeks, however, oocyte maturation was
cells for grafting to overcome organ damage in recipients fully timed at 37 hours, permitting me now to predict
began to emerge. My thoughts returned constantly to with certainty that women would ovulate at 37 hours
growing stem cells from human embryos to repair defects after an hCG injection.
in tissues of children and adults. A simple means of access to the human ovary was now
Almost at my last moment in Glasgow, with this new essential in order to identify human ovarian follicles in
set of ideas in my mind, a piece of excised ovary yielded vivo and to aspirate them 36 hours after hCG, just before
several oocytes. Being placed in vitro, two of them had the follicular rupture. Who could provide this? And how
reached metaphase II and expelled a polar body at about sperm capacitation? Only in hamsters that fertil-
37 hours. This showed that another target on the road to ization in vitro had been achieved, using in vivo matured
human IVF had been achieved as the whole pattern of oocytes and epididymal spermatozoa (16). I met Victor
oocyte maturation continued to emerge but with increas- Lewis, my third clinical colleague, and we noticed what
ing clarity. seemed to be anaphase II in some inseminated eggs.
Cambridge University, my next and final habitation, is Again, no sperm tails were seen within the eggs.
an astonishing place. Looking back on those days, it An attempt to achieve human capacitation in Chapel
seems that the Physiological Laboratory was not the Hill, North Carolina, United States, working with Robert
ideal place to settle in that august university. Neverthe- McGaughey and his colleagues, also failed (17). A small
less, a mixture of immunology and reproduction intrauterine chamber lined with porous membrane was
remained my dominant theme as I rejoined Alan Parkes filled with washed human spermatozoa, sealed, and
and Bunny Austin there. I had to do immunology to inserted overnight into the uterus of human volunteers at
obtain a grant to support my family, but thoughts of mid-cycle. Molecules entering it could react with the
human oocytes and embryos were never far away. One spermatozoa. No matured human eggs were fertilized.
possible model of the human situation was the cow and Later evidence indicated that the chamber contained
other agricultural species, and large numbers of cow, inflammatory proteins, perhaps explaining the failure.
pig, and sheep oocytes were available from ovaries given
to me by the local slaughterhouse. Each species had its
DECISIVE STEPS TO CLINICAL HUMAN IVF
own timing, all of them longer than 12 hours (13). Pig
oocytes were closest to humans, requiring 37 hours. In Back in the United Kingdom, my intention to conceive
each species, maturation timings in vitro were exactly human children in vitro had grown even stronger. So
the same as those arising in vivo in response to an hCG many medical advantages could flow from it. A small
injection. This made me suspect that a woman ovulated number of human embryos had been flushed from human
36–37 hours after an injection of hCG. Human oocytes oviducts or uteri after sexual intercourse, providing slen-
also trickled in, improving my provisional timings of der information on these earliest stages of human embry-
maturation, and one or two of them were inseminated, ology. It was time to attain human fertilization in vitro, in
but without signs of fertilization. order to move close to working with infertile patients.
More oocytes were urgently needed to conclude the Ethical issues and moral decisions would emerge, one
timings of oocyte meiosis. Surgeons in Johns Hopkins after the other, in full public view. Matters such as clon-
Hospital, Baltimore performed the Stein–Leventhal ing and sexing embryos, the risk of abnormalities in the
operation, which would allow me to collect ovarian tis- children, the clinical use of embryo stem cells, the ethics
sue, aspirate oocytes from their follicles, and retain the of oocyte donation and surrogate pregnancy, and the
remaining ovarian tissues for pathology if necessary. right to initiate human embryonic life in vitro would
xvi THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

never be very far away. These issues were all acceptable, of the Oldham and District General Hospital (18), it
since I was confident that studies of human conception described laparoscopy, with its narrow telescope and
were essential for future medicine, and correct ethically, instruments and the minute abdominal incisions. He
medically, and scientifically. The increasing knowledge could visualize the ampulla and place small amounts of
of genetics and embryology could assist many patients if medium there, in an operation lasting 30 minutes or less
I could achieve human fertilization and grow embryos and maybe even without using anesthesia. This is exactly
for replacement into their mothers. what I wanted, because access to the ampulla was equiv-
Few human oocytes were available in the United King- alent to gaining access to ovarian follicles. Despite advice
dom. Despite this scarcity, one or two of those matured to the contrary from several medical colleagues, I tele-
and fertilized in vitro possessed two nuclei after insemi- phoned him about collaboration and stressed the uncer-
nation. But there were no obvious sperm tails. I devised tainty in achieving fertilization in vitro. He responded
a cow model for human fertilization, using in vitro most positively, just as Molly, Howard and Georgeanna,
matured oocytes and insemination in vitro with selected and Victor had done. We decided to get together.
samples of highly active, washed bull spermatozoa Last but by no means least, Molly Rose sent a small
extracted from neat semen. It was a pleasure to see some piece of ovary to Cambridge. Its dozen or more oocytes
fertilized bovine eggs, with sperm tails and characteristic were matured in vitro for 37 hours, when Barry and
pronuclei, especially using spermatozoa from one par- I added washed spermatozoa suspended in his medium.
ticular bull. Here was a model for human IVF and a pre- We examined them a few hours later. To our delight,
lude to a series of events, which implied that matters in spermatozoa were pushing through the zona pellucida,
my research were suddenly changing. A colleague had into several of the eggs. Maternal and paternal pronuclei
stressed that formalin fixatives were needed to detect were forming beautifully. We saw polar bodies and sperm
sperm tails in eggs. Barry Bavister joined our team to tails within the eggs. That evening in 1969, we watched
study for his PhD and designed a medium of high pH, in delight virtually all the stages of human fertilization in
which gave excellent fertilization rates in hamsters. We vitro (Fig. I.1). One fertilized egg had fragments, as Chang
decided to collaborate by using it for trials on human fer- had forecast from his work on oocyte maturation and fer-
tilization in vitro. tilization in vitro of rabbit eggs. This evidence strength-
Finally, while browsing in the library of the Physiolog- ened the need to abandon oocyte maturation in vitro and
ical Laboratory, I read a paper in The Lancet which replace it by stimulating maturation by means of exoge-
instantly caught my attention. Written by Dr P C Steptoe nous hormones. Our 1969 paper in Nature surprised a

Figure I.1 A composite picture of the stages of fertilization of the human egg. (Upper left) An egg with a first polar body and spermatozoa
attached to the outer zona pellucida. (Upper central) Spermatozoa are migrating through the zona pellucida. (Upper right) A spermatozoon
with a tail beating outside the zona pellucida is attaching to the oocyte vitelline membrane. (Lower left) A spermatozoon in the ooplasm, with
enlarging head and distinct mid-piece and tail. (Lower central) Further development of the sperm head in the ooplasm. (Lower right) A pronu-
cleate egg with two pronuclei and polar bodies. Notice that the pronuclei are apparently aligned with the polar bodies, although more dimen-
sions must be scored to ensure that polarity has been established in all axes.
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xvii

world unaccustomed to the idea of human fertilization in pioneers, Palmer in Paris (23) and Fragenheim in Germany
vitro (19). (24). He improved the pneumoperitoneum to gain working
Incredibly fruitful days followed in our Cambridge space in the abdominal cavity and used carbon fibers to
laboratory. Richard Gardner, another PhD candidate, and pass cold light into the abdomen from an external source
I excised small pieces of trophectoderm from rabbit blas- (25). By now, Patrick was waiting in the wings, ready to
tocysts and sexed them by staining the sex chromatin begin clinical IVF in distant Oldham. We had a long talk
body. Those classified as female were transferred into about ethics and found our stances to be very similar.
adult females and were all correctly sexed at term. This Work started in the Oldham and District General Hospi-
work transferred my theoretical ideas of a few years ear- tal and moved later to Kershaw’s Hospital, set up by my
lier into the practice of preimplantation diagnosis of assistants, especially Jean Purdy. We knew the routine. It
inherited disease, in this case for sex-linked diseases was based on my Edinburgh experiences with mice. Piero
(20). Alan Henderson, a cytogeneticist, and I analyzed Donini from Serono Laboratories in Rome had purified
chiasmata during diakinesis in mouse and human eggs, urinary human menopausal gonadotropins (hMG) as a
and explained the high frequencies of Down’s syndrome source of FSH and the product was used clinically to
in offspring of older mothers as a consequence of meiotic stimulate follicle growth in anovulatory women by Bruno
errors arising in oocytes formed last in the fetal ovary, Lunenfeld (26). It removed the need for PMS, thus avoid-
which were then ovulated last at later maternal ages (21). ing the use of nonhuman hormones. We used low-dosage
Dave Sharpe, a lawyer from Washington, joined forces to levels in patients, that is, 2–3 vials (a total of 150–225 IU)
write an article in Nature (22) on the ethics of IVF, the given on days 3 and 5, and 5000–7000 IU of hCG on day
first ever paper in the field. I followed this up with a 10. Initially, the timing of oocyte maturation in vitro was
detailed analysis of ethics and law in IVF covering scien- confirmed, by performing laparoscopic collections of
tific possibilities, oocyte donation, surrogacy by embryo oocytes from ovarian follicles at 28 hours after hCG to
transfer, and other matters (22). So the first ethical papers check that they were in metaphase I (27). We then moved
were written by scientists and lawyers and not by phi- to 36 hours to aspirate mature metaphase II oocytes for
losophers, ethicists, or politicians. fertilization. Those beautiful oocytes were surrounded by
masses of viscous cumulus cells and were maturing
exactly as predicted. We witnessed follicular rupture at
THE OLDHAM YEARS
37 hours through the laparoscope. Follicles could be clas-
Patrick and I began our collaboration six months later in the sified from their appearance as ovulatory or nonovulatory,
Oldham and District General Hospital, almost 200 miles this diagnosis being confirmed later by assaying several
north of Cambridge. He had worked closely with two steroids in the aspirated follicular fluids (Fig. I.2).

18.798

16.832

14.866
110.9
Within-group variation

12.900

99.3 10.935
Within-group variation

87.6 8.969

7.003
29.6
5.038
18.0
3.072

6.3 1.106

Group 1 2 Follicle no. 12 101125 3 4 8 17 5 822212 3 24 7 20121416 9

Ovulatory Nonovulatory Group 1 2 3 4

Figure I.2 Eight steroids were assayed in fluids extracted from human follicles aspirated 36–37 hours after the human chorionic gonadotropin
(hCG) shot. The follicles had been classified as ovulating or nonovulating by laparoscopic examination in vivo. Data were analyzed by cluster
analysis, which groups follicles with similar features. The upper illustration shows data collected during the natural menstrual cycle. Note that
two sharply separated groups of follicles were identified, each with very low levels of within-group variance. Attempting to combine the two
groups resulted in a massive increase of within-group variation, indicating that two sharply different groups had been identified. These different
groups accorded exactly with the two groups identified by means of steroid assays. The lower figure shows the same analysis during stimulated
cycles on fluids collected 36–37 hours after injecting hCG. With this form of stimulation, follicle growth displays considerable variation within
groups. Attempts to combine all the groups result in a moderately large increase in variation. This evidence suggests that follicles vary consid-
erably in their state of development in simulated cycles using human menopausal gonadotropin (hMG) and hCG.
xviii THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

Figure I.3 Successive stages of human preimplantation development in vitro in a composite illustration made in Oldham in 1971. (Upper
left) 4-cell stage showing the crossed blastomeres typical of most mammals. (Upper middle) 8-cell stage showing the even outline of blasto-
meres and a small piece of cumulus adherent to the zona pellucida. (Upper right) A 16 to 32-cell stage, showing the onset of compaction of
the outer blastomeres. Often, blastocelic fluid can be seen accumulating between individual cells to give a “stripey” appearance to the
embryo. (Lower left and middle) Two living blastocysts showing a distinct inner cell mass, single-celled trophectoderm, blastocelic cavity, and
thinning zona pellucida. (Lower right) A fixed preparation of a human blastocyst at 5 days, showing more than 100 even-sized nuclei and
many mitoses.

Patrick’s laparoscopy was superb. Ovarian stimulation,

even though mild, produced five or six mature follicles per
patient, and ripe oocytes came in a steady stream into my
culture medium for insemination and overnight incuba-
tion. The next morning, the formation of two pronuclei
and sperm tails indicated fertilization had occurred, even
in simple media, now with a near-neutral pH. Complex
culture media, Ham’s F10 and others, each with added
serum or serum albumin, sustained early and later cleav-
ages (28), and, even more fascinating, was the gradual
appearance of morulae and then light, translucent blasto-
cysts (Fig. I.3) (29). Here was my reward—growing embryos
was now a routine, and examinations of many of them
convinced me that the time had come to replace them into
the mothers’ uterus. I had become highly familiar with the
Figure I.4 A hatched human blastocyst after 9 days in culture. teratologic principles of embryonic development, and
Notice the distinct embryonic disc and the possible bilaminar struc-
knew many teratologists. The only worry I had was the
ture of the membrane. The blastocyst has expanded considerably, as
chance of chromosomal monosomy or trisomy, on the
shown by comparing its diameter with that of the shed zona pellu-
cida. The zona contains dying and necrotic cells and its diameter
basis of our mouse studies, but these conditions could be
provides an estimate of the original oocyte end embryo diameters. detected later in gestation by amniocentesis. Our human
studies had surpassed work on all animals, a point rubbed
in even more when we grew blastocysts to day 9 after they
It was a pleasure and a new duty to meet the patients had hatched from their zona pellucida (Fig. I.4) (30). This
searching for help to alleviate their infertility. We did our beautifully expanded blastocyst had a large embryonic
best, driving from Cambridge to Oldham and arriving at disc which was shouting that it was a potential source of
noon to prepare the small laboratory there. Patrick had embryonic stem cells.
stimulated the patients with hMG and hCG, and he and his When human blastocysts became available, we tried to
team led by Muriel Harris arrived to prepare for surgery. sex them using the sex chromatin body as in rabbits.
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xix

Unfortunately, they failed to express either sex chroma- be given every five days to sustain pregnancies, since it
tin or the male Y body so we were unable to sex them as was supposed to save threatened abortions. So, we began
female or male embryos. Human preimplantation genetic embryo transfers to patients in stimulated cycles, giving
diagnosis would have to wait a little longer. this luteal phase support. Even though our work was
During these years there were very few plaudits for us, slowed down by having to wait to see whether pregnan-
as many people spoke against IVF. Criticism was mostly cies arose in one group of patients before stimulating the
aimed at me, as usual when scientists bring new chal- next, enough patients had accumulated after two to three
lenges to society. Criticism came not only from the Pope years. None of our patients was pregnant, and disaster
and archbishops, but also from scientists who should loomed. Our critics were even more vociferous as the
have known better, including James Watson (who testi- years passed, and the mutual support between Patrick
fied to a U.S. Senate Committee that many abnormal and me had to pull us through.
babies would be born), and Max Perutz, who supported Twenty or more different factors could have caused our
him. These scientist critics knew virtually nothing about failure, for example cervical embryo transfers, abnormal
my field, so who advised them to make such ridiculous embryos, toxic culture dishes or catheters, inadequate
charges? Cloning football teams or intelligentsia was luteal support, incompatibility between patients’ cycles
always raised by ethicists, which clearly dominated their and that imposed by hMG and hCG, inherent weakness in
thoughts rather than the intense hopes of our infertile human implantation, and many others. We had to glean
patients. Yet one theologian, Gordon Dunstan, who every scrap of information from our failures. I knew Ken
became a close friend, knew all about IVF from us, and Bagshawe in London, who was working with improved
wrote an excellent book on its ethics. He was far ahead of assay methods for gonadotropic hormones. He offered to
almost every scientist in my field of study. Our patients measure blood samples taken from our patients over the
also gave us their staunch support, and so did the Old- implantation period using his new hCG-® assay. He tele-
ham Ethical Committee, Bunny Austin back home in phoned: three or more of our patients previously undiag-
Cambridge, and Elliott Philip, a colleague of Patrick’s. nosed had actually produced short-lived rises of hCG-®
Growing embryos became a routine, so we decided to over this period. Everything changed with this informa-
transfer one each to several patients. Here again we tion. We had established pregnancies after all, but they
were in untested waters. Transferring embryos via the had aborted very early. We called them biochemical
cervical canal, the obvious route to the uterus, was vir- pregnancies, a term that still sticks today. It had taken us
tually a new and untested method. We would have to do almost three years to identify the cause of our failure, and
our best. From now on, we worked with patients who the finger of suspicion pointed straight at Primulot. I knew
had seriously distorted tubes or none whatsoever. This it was luteolytic, but it was apparently also an abortifa-
step was essential, since no one would have believed cient, and our ethical decision to use it had caused much
we had established a test-tube baby in a woman with heartache, immense loss of work and time, and despair for
near-normal tubes. This had to be a condition of our ini- some of our patients. The social pressures had been
tial work. Curiously, it led many people to make the big immense, with critics claiming our embryos were dud
mistake of believing that we started IVF to bypass and our whole program was a waste of time; but we had
occluded oviducts. Yet we already knew that embryos come through it and now knew exactly what to do next.
could be obtained for men with oligozoospermia or anti- We accordingly reduced the levels of Primulot depot,
bodies to their gametes, and for women in various stages and utilized hCG and progesterone as luteal aids. Suspi-
of endometriosis. cions were also emerging that human embryos were very
One endocrinological problem did worry me. Stimula- poor at implanting. We had replaced single embryos into
tion with hMG and hCG shortened the succeeding luteal most of our patients, rarely two. Increasingly we began to
phase, to a very short time for embryos to implant before wonder whether more should be replaced, as when we
the onset of menstruation. Levels of urinary pregnane- replaced two in a program involving transfer of oocytes
diol also declined soon after oocyte collection. This con- and spermatozoa into the ampulla so that fertilization
dition was not a result of the aspiration of granulosa and could occur in vivo.
cumulus cells, and luteal support would be needed, pref- This procedure was later called gamete intrafallopian
erably progesterone. Csapo et al. stressed how this hor- transfer (GIFT) by Ricardo Asch. We now suspected that
mone was produced by the ovaries for the first 8–10 single embryo transfers could produce a 15–20% chance
weeks before the placenta took over this function (31). of establishing pregnancy, just as our first clinical preg-
Injections of progesterone in oil given over that long nancy arose after the transfer of a single blastocyst in a
period of time seemed unacceptable since it would be patient stimulated with hMG and hCG (32). Then came
extremely uncomfortable for patients. While mulling the fantastic news—a human embryo fertilized and
over this problem, my attention turned to those earlier grown in vitro had produced a pregnancy. Everything
endocrinologists who believed that exogenous hormones seemed fine, even with ultrasound images. My culture
would distort the reproductive cycle, although I doubt protocols were satisfactory after all. Patrick rang: he
they even knew anything about a deficient luteal phase. feared the pregnancy was ectopic and he had to remove
This is how we unknowingly made our biggest mistake it sometime after 10 gestational weeks. Every new
in early IVF days. Our choice of Primolut (Sigma Chemical approach we tested seemed to be ending in a disaster, yet
co., St Louis, USA) depot, a progestogen, meant it should we would not stop, since the work itself seemed highly
xx THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

ethical, and conceiving a child for our patients was per- Mrs. MP
1 preovulatory oocyte +
ODGH 12/1/73
haps the most wonderful thing anyone could do for them. 1.6 × 106 sperm into ampulla
In any case, ectopic pregnancies are now known to be a

LMP ampules

Laparoscopy
8000 IU hCG
regular feature with assisted conception.
hMG
I sensed that we were entering the final phase of our

RTM
(amps)
hCG (IU)
Oldham work, seven years after it began. We had to speed 3 3 3 3 1500 15001500 1500
up, partly because Patrick was close to retiring from the
National Health Service. Four stimulation protocols were 150
tested in an attempt to avoid problems with the luteal

Urinary pregnanediol (mg/day)

phase: hMG and hCG; clomiphene, hMG, and hCG to

Urinary estrogens (µg/day)

gain a better luteal phase; bromocriptine, hMG, and hCG 100 10
because some patients had high prolactin concentra-
tions; and hCG alone at mid-cycle. We also tested what
came to be known as GIFT, calling it ORTI (oocyte recov-
ery with tubal insemination, by transferring one or two 50 5
eggs and spermatozoa to the ampulla) (Fig. I.5). Natural-
cycle IVF was introduced, based on collections of urine
samples at regular intervals eight times daily, to measure
0 0
exactly the onset of the LH surge, using a modified HiGo- 0 4 8 12 16 20 24 28 32 36
navis assay (Fig. I.6). Cryopreservation was also intro- Days of cycle
duced, by freezing oocytes and embryos that looked to be
in good condition when thawed. A recipient was given a Figure I.5 The first attempts at gamete intrafallopian transfer (GIFT)
were called oocyte recovery with tubal insemination (ORTI). In this
donor egg fertilized by her husband’s spermatozoa, but
treatment cycle, using human menopausal gonadotropin (hMG) and
pregnancy did not occur.
human chorionic gonadotropin (hCG), including additional injec-
Lesley and John Brown came as the second entrants tions of hCG for luteal support, a single preovulatory oocyte and 1.6
for natural-cycle IVF. Lesley had no oviducts. Her egg million sperm were transferred into the ampulla. Abbreviations: LMP,
was aspirated in a few moments and inseminated simply last menstrual period; ODGH, Oldham and District General Hospital
and efficiently. The embryo grew beautifully and was return to menstruation (RTM) indicates stages of the menstrual cycle.

LH lapy LH lapy LH lapy

surge surge surge

110

60
Total estrogens
(µg/24h)

40

20

0
Pregnanediol
(mg/24 h)

0
LH by HiGovanis

6
(IU/h)

4
2
1
<1

12 13 14 15 16 17 11 12 13 14 15 16 11 12 13 14 15 16
Days Days Days

Figure I.6 Recording the progress of the human natural menstrual cycle for in vitro fertilization (IVF). Three patients are illustrated. All three
displayed rising 24-hour urinary estrogen concentrations during the follicular phase and rising urinary pregnanediol concentrations in the luteal
phase. Luteinizing hormone (LH) levels were measured several times daily and the data clearly reveal the exact time of onset of the LH surge.
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xxi

transferred an hour or so after it became 8-cell. Their clomiphene and hCG and replacing two or three embryos
positive pregnancy test a few days after transfer was (34), so they had moved ahead of us during the delayed
another milestone—surely nothing could now prevent opening of Bourn Hall. Our own effort now expanded pro-
their embryo developing to full term in a normal repro- digiously. Thousands of patients queued for IVF. Simon
ductive cycle, but those nine months lasted a very long Fishel, Jacques Cohen, and Carol Fehilly joined the
time. Three more pregnancies were established using embryology team among younger trainees, and new clini-
natural-cycle IVF as we abandoned the other approaches. cians joined Patrick and John Webster. Patients and preg-
A triploid embryo died in utero—more bad luck. A third nancies increased rapidly, and the world was left standing
pregnancy was lost through premature labor on a moun- far behind. Howard and Georgeanna Jones began in
tain walking holiday, two weeks after the mother’s Norfolk using gonadotropins for ovarian stimulation. Jean
amniocentesis (32,33). It was a lovely, well-developed Cohen began in Paris, Wilfred Feichtinger and Peter
boy. Louise Brown’s birth, and then Alistair’s, proved to Kemeter in Vienna, Klaus Diedrich and Hans van der
a waiting world that science and medicine had entered Venn in Bonn, Lars Hamberger and Matts Wikland in
human conception. Our critics declared that the births Sweden, and Andre van Steirteghem and Paul Devroey in
were a fake, and advised against attending our presenta- Brussels. IVF was now truly international.
tion on the whole of the Oldham work at the Royal Col- The opening of Bourn Hall had not deterred our critics.
lege of Obstetricians and Gynaecologists. They put up a fierce rearguard action against IVF, along-
side LIFE, Society for the Unborn Child, individual gyne-
cologists, and others.
IVF WORLDWIDE
Objections raised against IVF included low rates of
The Oldham period was over. Good facilities were now pregnancy (no one mentioned the similar low rates
needed, with space for a large IVF clinic. Bourn Hall was of pregnancy with natural conception), the possibilities
an old Jacobean house in lovely grounds near Cambridge of oocyte and embryo donation, surrogate mothers,
(Fig. I.7). Facilities on offer for IVF in Cambridge were far unmarried parents, one-sex parents, embryo cryopreser-
too small, so we purchased it mostly with venture capital. vation, cloning, and endless other objections.
It was essential to conceive 100 or 1000 IVF babies to LIFE issued a legal action against me for the abortion
ensure that the method was safe and effective clinically. of an embryo grown for 14 days and longer in vitro.
The immense delays in establishing Bourn Hall delayed Their action was rejected by the U.K. Attorney General
our work by two years after Louise’s birth. Finally, on since the laws of pregnancy began after implantation.
minimal finance, Bourn Hall was opened in September We fully respected the intense ethical nature of our pro-
1980 on a shoestring, supported by our own cash and ceedings. We also recognized the need for research, and
loans. The delay gave the rest of the world a chance to join the necessity to protect or cryopreserve the best embryos
in IVF. Alex Lopata delivered an IVF baby in Australia, for later replacement into their mothers. Those not
and one or two others were born elsewhere. Natural-cycle replaced had to be used for research under strict con-
IVF was chosen initially at Bourn Hall since it had proved trols, combined with open publication and discussion
successful in Oldham, and we became experts in it. Preg- of our work.
nancies flowed, at 15% per cycle. An Australian team of Each year, 1000, rising to almost 2000, patients passed
Alan Trounson and Carl Wood announced the establish- through Bourn Hall. Different stimulation regimens or
ment of several IVF pregnancies after stimulation by new procedures could be tested in very little time.

Figure I.7 Bourn Hall. Source: Courtesy of Dr P Brinsden.

xxii THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

Clomiphene/hMG was reintroduced. Bourn babies and Mike Ashwood-Smith and Peter Holland’s in
increased: 20, 50, 100 to 1000 after five to six years. This embryology, as the old team faded away. Fascinating
was far more than half of the world’s entire IVF babies, days had returned. Working with barristers, we
including the first born in the United States, Germany, designed consent forms which were far in advance of
Italy, and many other countries. Detailed studies were those used elsewhere. Oocyte donation and surrogacy
performed on embryo culture, implantation, and abor- by embryo transfer were introduced. The world’s first
tion. We even tried aspirating epididymal spermatozoa paper on embryo stem cells appeared in Science in
for IVF, without achieving successful fertilization. 1984, sent from Bourn Hall, and the world’s first on
Among the immense numbers of patients, people with human preimplantation diagnosis in 1987 appeared in
astonishingly varied conditions of infertility emerged. Human Reproduction. However, embryo research fal-
Some were poor responders in whom immense amounts tered as all normal embryos were cryopreserved for
of endocrine priming were essential, women with a natu- their parents, so almost none were available for study.
ral menstrual cycle that was not as it should have been, Alan Handyside, one of our Cambridge PhDs, joined
previous misdiagnoses which had laid the cause of infer- Hammersmith Hospital in London to make major steps
tility on the wife when the husband had never even been in introducing preimplantation genetic diagnosis (36).
investigated, and men bringing semen samples that we As we reached 1000 pregnancies, our data showed the
discovered had been obtained from a friend. The collabo- babies to be as normal as those conceived in vivo.
ration between nurses, clinicians, and scientists was Test-tube babies (an awful term) were no longer unique
remarkable. Yet trouble—ethical trouble—was never far and were accepted worldwide, exactly as Patrick and I
away. I purchased a freezing machine to resume our Old- had hoped. Our work was being recognized (Fig. I.8).
ham work, but, unknown to me, Patrick talked to officers Clinics sprang up everywhere. Ultrasound was intro-
of the British Medical Association (BMA) and for some duced to detect follicles for aspiration by the Scandina-
reason agreed to delay embryo cryopreservation. Appar- vians (37), making laparoscopy for oocyte recovery
ently, the BMA felt it would be an unwelcome social largely redundant. Artificial cycles were introduced in
development. I did not approve of these reservations: Australia and intracytoplasmic sperm injection (ICSI)
David Whittingham had shown how low-temperature in Belgium (38), and gonadotropin-releasing hormone
cryostorage was successful with mouse embryos, without agonists were used to inhibit the LH surge. Ian Craft in
causing genetic damage. “Freezing and cloning” became London showed how postmenopausal women aged 52 or
a term of intense approbation at this time. I unwillingly more could establish pregnancies using oocyte donation
curtailed our cryopreservation program. and endocrine support. Women over 60 years of age con-
One weekend, a major trouble erupted as a result of ceived and delivered children. This breakthrough was
this difference between Patrick and me. My duties in especially welcome to me, since older women surely
Bourn Hall prevented me from attending a conference in have the right to have children at ages almost the same as
London. Trying to be helpful, I telephoned my lecture to those possible for men.
London. Reception at the other end was apparently so Ethics continued side by side with advancing science
poor as to lead to misinterpretations of what I had said. and medicine. The U.K. governmental Warnock report
Next morning, the press furore about my supposed prac- recommended permitting embryo research and proposed
tice of cryopreserving embryos after IVF was awful, so a Licensing Authority for IVF. A year or so later, the U.K.
bad, indeed, that legal action had to be taken. Luckily, House of Lords, in all its finery, responded with a 3:1
my lecture had been recorded, and listening to the tapes vote in favor, decisive support for all we had done in Mill
with a barrister revealed nothing contentious. I had said
nothing improper in my lecture or during the question-
answer session. That day, I issued seven libel actions
against the cream of British society: the BMA and its sec-
retary, the BBC, The Times, and other leading newspa-
pers. There were seven in one day and another one later!
If only one was lost, I could be ruined and disgraced.
However, they were all won, even though it took several
years with the BMA and its secretary. These legal actions
had inhibited our research, the cryopreservation program
being shut down for more than a year. Every single
embryological note of mine from those days in Oldham
and from Bourn Hall was examined in detail for my
opponents by someone who was clearly an embryologist.
Nothing was found to incriminate me.
That wretched period passed. The number of babies
kept on growing, embryo cryopreservation was
resumed, and Gerhard Dealmaker in The Netherlands
beat us and the world to the first “ice” baby (35). Colin Figure I.8 A happy picture of Patrick and me, standing in our robes
Howles and Mike McNamee joined us in endocrinology, after being granted our Hon. DSc by Hull University.
 THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION xxiii

Hill, Cambridge, and Oldham. What a wonderful day! aware of these findings when practicing human IVF, for
The British House of Commons passed a liberal IVF law example by assessing the role of sera in human culture
after intense debate, and so did the Spanish government, media.
although elsewhere things were not so liberal. Ten years
after the birth of Louise Brown, the British Parliament
IVF OUTLOOK
had therefore accepted IVF, research on human embryos
until day 14, and establishing research embryos. Cloning In one sense, opening up human conception in vitro was
and embryo stem cells still bothered the politicians in perhaps among the first examples of applied science in
1988, to re-emerge in 1998, gray shadows of my earlier modern “hi tech.” Human IVF has since spread through-
times in Glasgow. IVF had also become fundamental to out the world, with apparently more than 3.5 million
establish embryonic stem cells for organ repair, or clon- babies born worldwide by 2008— yet Louise Brown is
ing. During all this activity, tragedy struck all of us in only just 30 years of age. The need for IVF and its deriva-
Bourn Hall. Jean Purdy died in 1986 and Patrick Steptoe tives is greater than ever, since up to 10% of couples may
in 1988. They at least saw IVF come of age. suffer from some form of infertility. Major advances in
By the 1990s, burgeoning medical science was digging genetic technologies now identify hundreds of genes in a
deeper into endless aspects of human conception in single cell, and diagnosing genetic disease in embryos
vitro. The intracytoplasmic injection of a single sperma- promises to help avoid desperate genetic diseases in
tozoon into an oocyte to achieve fertilization, ICSI, was newborn children. Indeed, the ethics of this field have
one of the greatest advances since IVF was introduced. It now become even more serious, since the typing of
transformed the treatment of male infertility, enabling embryo genotypes provides detailed predictions of future
severely oligozoospermic men to father their own chil- life and health.
dren. It did not stop there, since epididymal spermatozoa IVF has now combined closely with genetics to elimi-
and even those aspirated from the testis could be used for nate disease or disability genes, or lengthen the life span.
ICSI. Spermatids have also been used. ICSI became so But most of all, practicing IVF teaches a wider under-
simple that many clinics reduced IVF to fewer and fewer standing of the desire and love for a child and a partner,
cases. New gonadotropin-releasing hormone antagonists the wonderful and ancient joys of parenthood, the pain
introduced novel ways to control the cycle, enabling of failure, the deep motivation needed in donating and
many oocytes to be stimulated by hMG and, subse- receiving an urgently needed oocyte or a surrogate uterus.
quently, using recombinant human FSH. Treatment in Parenthood is more responsible than ever before. Its com-
the natural cycle could be improved, since these antago- plex choices are gathered before couples everywhere by
nists control LH levels and prevent premature LH surges. the information revolution, placing family responsibili-
My own interests were returning to embryology, as the ties on patients themselves, where it really matters. And
molecular biology revolution influenced our thinking. IVF now reveals more and more about miracles preserved
I am convinced that the oocyte and egg must be highly in embryogenesis from flies and frogs to humankind,
programmed, timewise, in embryonic polarities and inte- over 600 million years of evolution.
grating genetic systems such that the tight systems place The human genome project is now complete and will
every new gene product in its right place in the one-cell inevitably assist IVF since we will soon understand the
egg and cleaving embryo. This must be right; there can genetic aspects of early embryo growth and how to detect
surely be no other explanations for the fabulous modifi- abnormal genes in embryos. This textbook contains chap-
cation in embryonic growth in the first week or two of ters which describe in detail the several advances and
embryonic life. I have been delighted to work with Chris developments which have expanded the possibilities of
Hansis on identifying a gene (for hCG-®) in one blasto- treating diverse causes of human infertility as well as
mere of four- and eight-cell human embryos, providing numerous genetic disorders.
evidence of blastomere differentiation at this early stage Already it is clear that a staggering array of genes oper-
of embryogenesis (39). ates in preimplantation stages in mammalian including
This topic returns me to my scientific origins studying human embryos, and new methods are being introduced
mouse embryos in the Institute of Animal Genetics in to deal with such highly multigenic embryonic systems.
Edinburgh, where Waddington reported the amazing We are indeed enmeshed in a field embracing some of the
story of the gene Aristapedia in Drosophila, which he most fundamental evolutionary stages of our existence as
had induced to grow legs in place of eyes. These unusual we pass from oocyte to blastocyst and to implantation.
flies then bred true, showing he had uncovered a gene
that had been silenced for millions of years and how this
could be an essential component of normal differentia- REFERENCES
tion. He called it epigenesis, and we fear today that some
1. Pincus G, Saunders B. The comparative behavior of
aspects of IVF may lead to deleterious epigenetic changes
mammalian eggs in vivo and in vitro. VI. The matura-
in children such as Angelman or Beckwith–Wiedemann tion of human ovarian ova. Anat Rec 1939; 75: 537–45.
syndrome. Risks of epigenetic changes in cattle embryos 2. Menkin MF, Rock J. Am J Obstet Gynecol 1949; 55: 440.
and those of other species may be heightened by adding 3. Hayashi M. Seventh International Conference of the
serum to media used to culture embryos to cause, for International Planned Parenthood Federation. Excerpta
example large-calf syndrome. It would be wise to be well Medica, 1963: 505.
xxiv THE BEGINNINGS OF HUMAN IN VITRO FERTILIZATION

4. Austin CR. Adv Biosci 1969; 4: 5. 22. Edwards RG, Sharpe DJ. Social values and research in
5. Chang M. Adv Biosci 1969; 4: 13. human embryology. Nature (London) 1971; 231: 81–91.
6. Chang MC. The maturation of rabbit oocytes in culture 23. Palmer R. Acad Chir 1946; 72: 363.
and their maturation, activation, fertilization and sub- 24. Fragenheim H. Geburts Frauenheilkd 1964; 24: 740.
sequent development in the fallopian tubes. J Exp Zool 25. Steptoe PC. Laparoscopy in Gynaecology. Edinburgh:
1955; 128: 379–405. Livingstone, 1967.
7. Runner M, Gates AH. Sterile, obese mothers. J Hered 26. Lunenfeld B. In: Inguilla W, Greenblatt RG, Thomas
1954; 45: 51–5. RB, eds. The Ovary. Springfield, IL: CC Thomas, 1969.
8. Gates AH. Viability and developmental capacity of eggs 27. Steptoe PC, Edwards RG. Laparoscopic recovery of pre-
from immature mice treated with gonadotrophins. ovulatory human oocytes after priming of ovaries with
Nature 1954; 177: 754–5. gonadotrophins. Lancet 1970; 1: 683–9.
9. Fowler RE, Edwards RG. Induction of superovulation 28. Edwards RG, Steptoe PC, Purdy JM. Fertilization and
and pregnancy in mature mice by gonadotrophins. cleavage in vitro of preovulatory human oocytes.
J Endocrinol 1957; 15: 374–84. Nature (London) 1970; 227: 1307–9.
10. Edwards RG, Gates AH. Timing of the stages of the mat- 29. Steptoe PC, Edwards RG, Purdy JM. Human blastocysts
uration divisions, ovulation, fertilization and the first grown in culture. Nature (London) 1971; 229: 132–3.
cleavage of eggs of adult mice treated with gonadotro- 30. Edwards RG, Surani MAH. The primate blastocyst and
phins. J Endocrinol 1959; 19: 292–304. its environment. Uppsala J Med Sci 1978; 22: 39–50.
11. Edwards RG. Meiosis in ovarian oocytes of adult mam- 31. Csapo AI, Pulkkinen MO, Kaihola HL. The relationship
mals. Nature (London) 1962; 196: 446–50. between the timing of luteectomy and the incidence of
12. Cole R, Edwards RG, Paul J. Cytodifferentiation and complete abortions. Am J Obstet Gycecol 1974; 118:
embryogenesis in cell colonies and tissue cultures 985–9.
derived from ova and blastocysts of the rabbit. Dev Biol 32. Steptoe PC, Edwards RG. Reimplantation of a human
1966; 13: 385–407. embryo with subsequent tubal pregnancy. Lancet 1976;
13. Edwards RG. Maturation in vitro of mouse, sheep, cow, 1: 880–2.
pig, rhesus monkey and human ovarian oocytes. Nature 33. Edwards RG, Steptoe PC, Purdy JM. Clinical aspects of
1965; 208: 349–51. pregnancies established with cleaving embryos grown
14. Edwards RG. Maturation in vitro of human ovarian in vivo. Br J Obstet Gynaecol 1980; 87: 757–68.
oocytes. Lancet 1965; 2: 926–9. 34. Trounson AO, Leeton JF, Wood C, et al. Pregnancies in
15. Edwards RG, Donahue R, Baramki T, Jones H Jr. Pre- humans by fertilization in vitro and embryo transfer in
liminary attempts to fertilize human oocytesmatured in the controlled ovulatory cycle. Science 1981; 212: 681–2.
vivo. AmJ Obstet Gynecol 1966; 96: 192–200. 35. Zeilmaker GH, Alberda T, Gent I, et al. Two pregnan-
16. Yanagimachi R, Chang MC. J Exp Zool 1964; 156: 361–76. cies following transfer of intact frozen–thawed
17. Edwards RG, Talbert L, Israestam D, et al. Diffusion embryos. Fertil Steril 1984; 42: 293–6.
chamber for exposing spermatozoa to human uterine 36. Handyside A, Kontogianni EH, Hardy K, Winston RML.
secretions. Am J Obstet Gynecol 1968; 102: 388–96. Pregnancies from biopsied human preimplantation
18. Steptoe PC. Laparoscopy and ovulation. Lancet 1968; embryos sexed by Y-specific DNA application. Nature
2: 913. (London) 1990; 344: 768–70.
19. Edwards RG, Bavister BD, Steptoe PC. Early stages of 37. Wikland M, Enk L, Hamberger L. Transvesical and trans-
fertilisation in vitro of human oocytes matured in vitro. vaginal approaches for the aspiration of follicles by use
Nature (London) 1969; 221: 632–5. of ultrasound. Ann NY Acad Sci 1985; 442: 182–94.
20. Gardner RL, Edwards RG. Control of the sex ratio at full 38. Palermo G, Joris H, Devroey P, et al. Pregnancies after
term in the rabbit by transferred sexed blastocysts. intracytoplasmic injection of single spermatozoon into
Nature (London) 1968; 218: 346–8. an oocyte. Lancet 1992; 340: 17–18.
21. Henderson SA, Edwards RG. Chiasma frequency and 39. Hansis C, Edwards RG. Cell differentiation in the pre-
maternal age in mammals. Nature (London) 1968; 218: implantation human embryo. Reprod BioMed Online
22–8. 2003; 6: 215–20.
Robert Edwards: The path to IVF*
Martin H. Johnson

*This article is based on the research undertaken in prep- working-class family, and Edwards, who was known by
aration for the introductory lecture to the Nobel Sympo- his middle name of Geoff until he was 18, was the second
sium held in the Karolinska Institute, Stockholm, in of three brothers, with an older brother, Sammy and a
December 2010 to celebrate the award of the Nobel Prize younger one, Harry. These brothers he describes as com-
in Physiology or Medicine to Robert Geoffrey Edwards. petitive, “all determined to win or, if not to win, to go
An abbreviated account of the contents of this paper was down fighting” (3). Sammy was named after his father,
published as “Robert Edwards: Nobel Laureate in Physi- Samuel, who was frequently away from home working
ology and Medicine” in “Les Prix Nobel 2010,” edited by on the railways, maintaining the track in the Blea Moor
Professor Karl Grandin, and published by the Nobel tunnel on the Carlisle-Settle line. It was an unhealthy
Foundation; this version is reproduced as published in place to work, some 2600 m long and filled with coal-
Reproductive BioMedicine Online (2011) 23, 245–262, fired smoke that exacerbated Samuel’s bronchitis, a con-
with the permission of the Editors and Publishers of sequence of being gassed in World War I. The one perk of
Reproductive BioMedicine Online. working on the railways was the free rail pass for the
family’s annual holiday, which was regularly taken in
far-away Southend-on-Sea, located near the mouth of the
INTRODUCTION
Thames and considered then to be a top-spot resort by
Robert G Edwards was awarded the 2010 Nobel Prize for working-class families.
Physiology or Medicine “for the development of in vitro Edwards’ mother, Margaret, was a machinist in a local
fertilization” (1). There is a variety of accounts of the mill. She came originally from Manchester, to where the
events leading up to this discovery and its acceptance, family relocated when Edwards was about five, having
most of them by participants (2), but historical scholar- been offered the relative security of a council house at 25
ship is rarer. This account uses verifiable sources to pro- Highgate Crescent in the suburb of Gorton. It was in
duce a historical narrative of the path to in vitro fertilization Manchester that Edwards was to receive his education. In
(IVF) that differs in a number of places from the conven- those days, bright working-class children could take a
tionally accepted version and adds further detail. scholarship exam at age 10 or 11 to compete for the few
coveted places at a grammar school: the potential path-
way out of poverty and even to University. All three
EDWARDS’ LIFE HISTORY: SOURCES
brothers passed the exam, but Sammy decided against
Primary sources used were the publications by Edwards grammar school, preferring to leave education as soon as
and Steptoe during the 1950s, 1960s, and 1970s; archives he could to earn. His mother was reportedly furious at this
of the Royal Society of Medicine, Cambridge University, wasted opportunity, and so when her two younger sons
the Physiology Library at Cambridge, and the personal passed, there was no question that they would continue in
papers of RG Edwards (courtesy of Ruth Edwards); education and it was with that that Geoff/Bob progressed
unpublished transcripts of interviews with RG Edwards, in 1937 to Manchester Central Boy’s High School (the
K Elder, and RL Gardner; personal recollections from the building that now houses Shena Simon College in
late 1970s by Edwards and Steptoe as recalled in inter- Whitworth Street), which also claims James Chadwick
views with Danny Abse for the autobiographical account FRS (1891–1974) as an alumnus. Chadwick, like Edwards,
“A Matter of Life” and on film with Peter Williams; mem- was a Cambridge professor and the 1935 Nobel Laureate
bers of RG Edwards’ family and his colleagues and for- in Physics for discovering the neutron (4). The Edwards’
mer students and staff members for clarificatory evidence summers were spent in the Yorkshire Dales, to where
about personal recollections by Edwards, for additional their mother took her sons to be closer to their father’s
verifiable information and with whom to test some new place of work. There, Edwards labored on the farms and
interpretations. developed an enduring affection for the Dales.
These early experiences were formative. Edwards first
became a life-long egalitarian, for five years a Labour
CHILDHOOD BACKGROUND
Party Councillor (5), willing to listen to and talk with all
Robert Geoffrey Edwards was born on September 27, and sundry, regardless of class, education, status, and
1925 in the small Yorkshire mill town of Batley, the year background. Second, he developed an enduring curiosity
of the Batley deluge and “great flood.” He arrived into a about agricultural and natural history and especially the
xxvi ROBERT EDWARDS

reproductive patterns among the Dales’ sheep, pigs, and the anticipatory attractions of agricultural science. So
cattle. Finally, he claimed great pride in being a “York- his disappointment in the course offered at Bangor was
shire man,” traditionally having attributes of affability acute. By that time, he was a relatively experienced
and generosity of spirit combined with no-nonsense 23-year-old, described by his impressionable 18-year-
blunt-speaking. Indeed, following his only meeting with old public-school educated and self-described
Gregory Pincus [1903–1967; (6)] at a conference in “unlikely” friend, John Slee (Fig. 2) (7), as being “both
Venice in May 1966, at which Edwards, the young pre- ambitious and flexible, and unusually confident in his
tender, clashed with the “father of the pill” over the tim- own judgement.” In Edwards’ confident judgment, the
ing of egg maturation in humans; he paid Pincus the course on offer was not “scientific,” and he was bored
biggest compliment he could imagine, saying “He would through two tedious years of agricultural descriptions,
have made a fine Yorkshireman!” (3). after which he reported that his teachers were “glad to
The intervention of World War II was to provide an see the back of him” in Zoology for a year, a course
unwelcome interruption to Edwards’ education: when he much more to his style and led by the more intellectu-
left school in 1943, he was conscripted for war service ally challenging Rogers Brambell FRS [1901–1970; (8)].
into the British Army for almost four years (Fig. 1). To his However, that year was not enough to salvage his hon-
surprise, as someone from a working-class family, he was ors degree, and in 1951, aged 26 he gained a simple
identified as potential officer material and sent on an pass. Unbeknown to him at the time, he was not alone
officer-training course, before being commissioned in in this undistinguished academic embarrassment, as
1946. However, his army experiences were broadly nega- neither “Tibby” Marshall FRS [1878–1949; (9)], the
tive, the alien lifestyle of the officers’ mess not being to founder of the Reproductive Sciences, nor Sir Alan
his taste and reinforcing his socialist ideals. The one pos- Parkes FRS [1900–1990; (10)], the first Professor of
itive feature of his war service was the chance to travel Reproductive Sciences at Cambridge, who was later to
overseas; particularly appreciated was his time in the recruit Edwards there, distinguished themselves as
Middle East. The years in the army were broken by nine undergraduates. In 1951, however, Edwards “was dis-
months’ compassionate leave back in the Yorkshire consolate. It was a disaster. My grants were spent and I
Dales, to which he was released to help and run a farm was in debt. Unlike some of the students I had no rich
when his farmer friend there fell ill. So engaged did he parents … I could not write home, ‘Dear Dad, please
become in farming life that, after discharge from the army send me £100 as I did badly in the exams’” (3).
in 1948, he returned home to Gorton, from where he However, his low spirits did not last long. He learnt that
applied to read agricultural sciences at the University John Slee had been accepted on a postgraduate diploma
College of North Wales at Bangor. course in Animal Genetics at Edinburgh University under
Having gained a place and a government grant to fund Conrad Waddington FRS [1905–1975; (11)], who had
it, the six or so months that intervened were occupied moved there in 1947 from Christ’s College in Cambridge,
in a government desk job in Salford, Greater Manches- home also to both Marshall and Parkes. Edwards applied,
ter, helping to organize the newly formed National and, despite his pass degree and to his amazement, he
Health Service. This office-work experience reinforced was accepted. That summer, he worked in Yorkshire and

Figure 1 Edwards on National War Service in the1940s. Source:

Courtesy of Ruth Edwards. Figure 2 John Slee in the 1960s. Source: Courtesy of Ruth Edwards.
 ROBERT EDWARDS xxvii

Wiltshire harvesting hay, as well as portering bananas although himself unwell, was to undertake grueling high
and heaving sacks of flour in Manchester docks and taking security war work at the Ordnance Board and later at the
a menial job with a newspaper, all to earn enough to pay Admiralty during World War II. His health deteriorated
his way in Edinburgh (3). and he died at the relatively young age of 55 when Ruth
was 13.
FAMILY LIFE
EDWARDS, THE RESEARCH SCIENTIST
In Edinburgh, Edwards not only started to map out his
scientific career, but importantly also met Ruth Fowler The intellectual spirit of scientific enquiry that Edwards
(Fig. 3), who was to become his life-long scientific col- experienced in Edinburgh fitted his aptitudes well, for
laborator and whom he was to marry in 1954, their five Waddington rewarded his Diploma year with a three-year
daughters arriving between 1959 and 1964: Caroline, PhD place (1952–55), followed by two years of postdoctoral
Sarah, Jenny, and twins Anna and Meg. When they met, research, and funded it to the princely sum of £240 per year
according to Edwards, in a statistics class, Ruth was (3). His chosen field of research was the developmental
studying for a genetics degree. Edwards claims that he biology of the mouse. Edwards saw that to understand
was initially somewhat overwhelmed, even “intimi- development involved engaging in an interdisciplinary
dated” by Ruth’s august family background. Her father, mix, not just of embryology and reproduction, the conven-
Sir Ralph Fowler FRS [1889–1944; (12)] and her maternal tional view at the time, but also of genetics. Given the scien-
grandfather, Lord Ernest Rutherford FRS [1871–1937; tific and social emphasis on genetics over the last 40 or so
(13)], were not only both “titled,” but both also had the years, it is important to understand how advanced this
most impressive academic credentials imaginable: a view was in the 1950s, when genetic knowledge was still
world away from a working-class Northern family. Ralph rudimentary and largely alien to the established develop-
Fowler was Plummer Professor of Mathematical Physics mental and reproductive biologists of the day, as Edwards
in Cambridge from 1932 to 1944. He was evidently an himself was later to recall (14). For example, it was in the
exceptionally talented mathematical physicist, a fine 1950s that DNA was established as the molecular carrier of
sportsman and “an inspirational teacher and leader of genetic information (15–18), that it was first demonstrated
men” (12). Back in Cambridge in 1919 after World War I, that each cell of the body carried a full set of DNA/genes
he was stimulated to work with Rutherford, who had (19–21) and that genes were selectively expressed as mRNA
recently arrived there to take the chair of Experimental to generate different cell phenotypes (22). Moreover, it was
Physics. Rutherford was the first Nobel laureate in Ruth’s only by the late 1950s that cytogenetic studies led to the
family, having been awarded the 1908 Nobel Prize for accepted human karyotype as 46 chromosomes (23,24),
Chemistry “for his investigations into the disintegration that agreement was reached on the Denver system of clas-
of the elements, and the chemistry of radioactive sub- sification of human chromosomes (25) and that the chromo-
stances” (13). somal aneuploidies underlying developmental anomalies
Ralph Fowler not only worked under Rutherford, but such as Down, Turner, and Klinefelter Syndromes were
in the course of doing so met his only daughter, Eileen, described (26–29).
whom he married in 1921. They had four children, of The dates of these discoveries make Edwards’ research
whom Ruth was the last, born in December 1930. Tragi- between 1952 and 1957 all the more remarkable. Work-
cally her mother died shortly afterwards and Ruth was ing under his supervisor Alan Beatty, he generated hap-
to know only Mrs Phyllida Cook as her “mother”; both loid, triploid, and aneuploid mouse embryos and studied
families moved into Cromwell House in Trumpington, their potential for development. In order to undertake
Cambridge and were brought up together (12). Her father, what were, in effect, early attempts at “genetic engineer-
ing” in mammals, he needed to be able to manipulate the
chromosomal composition of eggs, spermatozoa, and
embryos. In mice, spermatozoa were abundant, and were
studied in experiments mostly undertaken with a visit-
ing Argentinean postdoc, Julio Sirlin (Fig. 4), whom
Edwards describes as being “… the first man with whom
I collaborated who was prepared to work at my pace” (3).
Together they labeled spermatozoa radioactively in vivo
in order to study the kinetics of spermatogenesis and
then to follow the radioactive products post fertilization,
thereby to demonstrate the fate of the male contributions
to early development. They also exposed males and/or
their spermatozoa to various agents, such as chemical
mutagens and UV- or x-ray irradiation, and examined the
effects on sperm-fertilizing capacity, and where it was
shown to be present, how the treatment impacted on
Figure 3 Ruth Fowler in the laboratory, Edinburgh in the 1950s. development. In some cases, sperm activation of the egg
Source: Courtesy of Ruth Edwards. was evident, but in the absence of any functional sperm
xxviii ROBERT EDWARDS

chromatin, and so gynogenetic embryos were formed. His six years in Edinburgh, between 1951 and 1957,
These experiments resulted in 14 papers, including four give an early taste of his prodigious energy, resulting in
in Nature, between 1954 and 1959 (see ref. (30), for a full 38 papers (30). Indeed so productive was this period that
bibliographic record of Edwards). the last of the Edinburgh-based papers did not appear in
Eggs and embryos were not as abundant as spermato- print until 1963. These papers firmly placed the young
zoa, and overcoming this problem led Edwards to two Edwards at the forefront of studies on the genetic manip-
discoveries that proved to be of particular significance ulation of development and started to attract attention.
for his later IVF work. First, working with his wife Ruth, It was also in Edinburgh that Edwards’ interest in eth-
he devised ways of increasing the numbers of synchro- ics was first sparked by the interdisciplinary debates
nized eggs recoverable from adult female mice through a among scientists and theologians that Waddington orga-
series of papers, the first published in 1957 (31), on the nized, and, as a result, he went on what he describes as a
control of ovulation induced by use of exogenous hor- “church crawl,” trying the 10 or so variants of Christian-
mones. In doing so, they overturned the conventional ity on offer in 1950s Edinburgh. He did not emerge from
wisdom that superovulation of adults was not possible. his consumer testing “God-intoxicated” (3), but con-
Second, working with an American postdoc, Alan Gates vinced that man held his own future in his own hands.
(Fig. 5) (32), Edwards described the remarkable timed Edwards’ humanist ethical sympathies and antipathy to
sequence of egg chromosomal maturation events that led the “revealed truths” of religion were to be developed
up to ovulation after injection of the ovulatory hormone, further in all his later encounters (30).
human chorionic gonadotropin.
AN AMERICAN DIVERSION
These 1950s studies in science and ethics were to form
the platform on which Edwards’ later IVF work was to be
based, but before that his interests and life took a diver-
sion to the California Institute of Technology for the year
1957–1958. He describes his year at Caltech as being “a
bit of a holiday,” but it was a holiday which with hind-
sight had both distracting and significant consequences.
He went there to work with Albert Tyler [1906–1968;
(33)], an influential elder statesman of American repro-
ductive science, working on spermatozoon–egg interac-
tions. Caltech was then a hot bed of developmental
biology, and Tyler had clustered around him an exciting
group of young scientists, which included that year a visit
by the English doyen of fertilization, Lord Victor Roths-
child FRS [1910–1990; (34)]. Rothschild was later to clash
Figure 4 Julio Sirlin with Edwards in the 1950s. Source: Courtesy of scientifically with Edwards over his IVF work (35), a
Julio Sirlin. clash in which the younger man triumphed again (36),

Figure 5 Edwards as “a very recent PhD student” (centre) and Alan Gates (extreme left) at a meeting in Trinity College Cambridge in the late
1950s. Source: Courtesy of Ruth Edwards.
 ROBERT EDWARDS xxix

just as he had with Pincus. Tyler was exploring the at Mill Hill, between 1958 and 1962, seems to have been
molecular specificity of egg–spermatozoon interactions a period of increasing intellectual conflict for him. While
and had turned for a model to immunology. Immunology being enthusiastic about the science underlying immu-
was then at an exciting phase in its development, with nocontraception, his old interests in eggs, fertilization
the engaging Sir Peter Medawar FRS [1915–1987, Nobel and, in particular, the genetics of development were
Laureate in Physiology or Medicine, 1960; (37)], influen- gradually reasserting themselves. His day job was there-
tially for Bob, extending his ideas on immunological tol- fore increasingly supplemented by evening and weekend
erance to the paradox of the “fetus as an allograft”: a flirtations with egg maturation.
semi-paternal graft nonetheless somehow protected from
maternal immune attack inside the mother’s uterus (38).
THE CRUCIAL EGG-MATURATION STUDIES
This confluence of reproduction and immunology excited
Edwards’ restless curiosity and hence the choice of Tyler. The stimulus that re-awakened Edwards’ interest in eggs
Significantly, the subject also offered funding possibili- was provided by the then recent consensus about the
ties via the Ford and Rockefeller Foundations and the number of human chromosomes and, more particularly
Population Council, which were increasingly concerned the descriptions in 1959 of the pathologies in man that
about world population growth and the need for better resulted from chromosomal anomalies. Thus, his 1962
methods to control fertility (39–41). Immunocontracep- Nature paper begins: “Many of the chromosomal anoma-
tion then seemed to offer tantalizingly specific possibili- lies in man and animals arise through non-disjunction or
ties, alas not much closer to being realized today (42). lagging chromosomes during meiosis in the oocyte.
So when Edwards returned to the United Kingdom Investigation of the origin and primary incidence of such
from CalTech in 1958 at Alan Parkes’ invitation to join anomalies would be greatly facilitated if meiotic stages
him at the Medical Research Council (MRC) National etc., were easily available” (44).
Institute for Medical Research (NIMR) at Mill Hill in The idea that these aneuploidies in humans might
north London, it was to work on the science of immuno- result from errors in the complex chromosomal dance
contraception (5). This period in the United States initi- that he and Gates had observed in maturing mouse eggs
ated a series of 23 papers on the immunology of drove his thinking. The possible clinical relevance of his
reproduction between 1960 and 1976 (30). It also work on egg maturation and aneuploidy in the mouse
prompted Edwards’ first involvement in founding an was becoming significant.
international society in 1967 in Varna Bulgaria, (Fig. 6) So Edwards resumed his experimenting with mice,
when the International Coordinating Committee for the trying to mimic in vitro the in-vivo maturation of eggs,
Immunology of Reproduction was created (43). Immu- one rationale being that this route would open the pos-
noreproduction was, in retrospect, to prove a distracting sibility of similar studies in humans, in which not even
diversion from what was to become Edwards’ main work, induced ovulation had then been described (45). He
albeit one that continued to enthuse and stimulate his tried releasing the immature eggs from their ovarian fol-
imagination for many years. Indeed, it was his research licles into culture medium containing the ovulatory hor-
into immunoreproduction that led serendipitously to his mone human chorionic gonadotropin, to explore
first meeting with Patrick Steptoe (see later). The period whether he could simulate their in-vivo development.

Figure 6 Edwards at one of the Varna meetings on Immunoreproduction; Schulman is speaking and to Edwards’ left is Bratanov, and seated
two to his right is Shanta Rao. Source: Courtesy Barbara Rankin.
xxx ROBERT EDWARDS

Amazingly he found it worked first time; the eggs seemed FRS [1897–1972; (53)], who banned any work on human
to mature at the same rate as they had in vivo. However, IVF at NIMR (3). Alan Parkes was no longer able to defend
they did so whether or not the hormone had been added. Edwards, having left in 1961 to take up his chair in Cam-
The eggs evidently were maturing spontaneously when bridge and, although he had asked Edwards to join him
released from their follicles. The same happened in rats there, funding was not available until 1963. So by the
and hamsters. If this also were to happen in humans, time Edwards left Mill Hill in 1962 for a year in Glasgow,
then the study of the chromosomal dance during human he had encountered a taste of the opposition to come.
egg maturation was a realistic practical possibility, as
was IVF and thereby studies on the genetics of early
GLASGOW AND STEM CELLS
human development. Edwards’ excitement at seeing
eggs spontaneously maturing was temporarily blunted Edwards had accepted an invitation from John Paul to
by his library discovery that Pincus in the 1930s (46,47) spend a year in the biochemistry department at Glasgow
and M C Chang [1908–1991; (48,49)] earlier in the 1950s University. Paul was then the acknowledged master of
had been there before him, using both rabbit and, Pincus tissue culture in the United Kingdom and had got wind
claimed, human eggs. of some experiments that Edwards had been doing on the
In order to pursue his cytogenetic studies on matura- side at NIMR attempting to generate stem cells from rab-
tion, he needed a reliable supply of human ovarian tissue bit embryo cultures (14). The objective of this strategy
from which to retrieve and mature eggs. This require- was to use these stem cells to study early developmental
ment posed difficulties for a scientist with no medical mechanisms, either in vitro, or in vivo after their incor-
qualification, given the elitist attitudes and lack of scien- poration into embryos. Paul had proposed that they work
tific awareness then prevalent amongst most of the U.K. together, with fellow Glasgow biochemist Robin Cole, to
gynecological profession (2,50,51). His first breakthrough see what progress might be made. This must have been
came with Molly Rose, who was a gynecologist at the an attractive invitation, not simply because the challenge
Edgeware General Hospital, northwest London, near Mill was scientifically interesting, but also because Edwards
Hill. Edwards was introduced to her through John Hum- could learn more about culture media for his eggs and
phrey FRS [1915–1997; (52)], who was the medically hopefully later embryos, then an uncertain prospect, suc-
qualified Head of Immunology at Mill Hill. Humphrey, cessful mouse embryo culture only recently having been
notwithstanding his more privileged social background, described (54). However, by this time, the Edwards fam-
was a kindred spirit for Edwards, sharing his passion for ily was growing, so Ruth remained in north London with
science, its social application and utility, as well as his their young daughters, while her husband commuted to
left-wing politics; indeed he had been a Marxist until Glasgow for the working week.
1940 and was for many years denied entry to the United The collaboration was to result in two papers (55,56)
States as a result. Edwards asked Humphrey if he knew remarkable for their prescience. They described the pro-
anyone who might be helpful, and he not only suggested duction of embryonic stem cells from both rabbit blasto-
Rose, but also offered to arrange an introduction. Rose cysts and the inner cell masses dissected from them. The
was to provide biopsied ovarian samples intermittently cells were capable of proliferating through over 100 gen-
for the next 10 years. erations and of differentiating into various cell types.
Between 1960 and 1962, Edwards used human ovarian These experiments were initiated some 20 years before
biopsies provided by Rose to try to repeat and extend Evans and Kaufman (57) described the derivation of
Pincus’ observations from the 1930s. Given the sporadic embryonic stem cells from mice. That this work has
supply of human material, he also tried dog, monkey and largely been ignored by those in the stem cell field is
baboon ovarian eggs, but in all cases with limited success probably mainly attributable to its being too far ahead of
compared with smaller rodents. In the 1962 Nature paper its time (58). Thus, reliable molecular markers for differ-
(44), he cautiously interprets the few maturing human ent types of cells were not available then, nor were
(3/67), monkey (10/56) and baboon (13/90) eggs that he appropriate techniques with which to critically test the
had observed as most likely arising from in-vivo stimula- developmental potential of the cultured cells.
tion and thus partially matured at the time of their recov-
ery from the biopsy. He suggests that Pincus’ observations
THE MOVE TO CAMBRIDGE
on human eggs are also likely to be artifactual, the source
of his Venice spat with Pincus some 4 years later (vide Edwards arrived in Cambridge from Glasgow in 1963 as a
supra). This 1962 paper ends with the report of an inge- Ford Foundation Research Fellow. He had previously
nious experimental approach to try and persuade the visited Cambridge at least once, as “a recently graduated
reluctant human eggs to mature. Thus, the ovarian arter- PhD” in the late 1950s for a conference on Reproduction
ies of patients undergoing ovarian removal were cannu- held in Trinity College (Fig. 5), where he recalls meeting
lated and perfused with hormones post-removal, perhaps some of the big names in the subject, including John
unsurprisingly in retrospect, without success. Hammond, Alan Parkes, MC Chang, Thaddeus Mann,
However, by this time, his quest for human eggs, and Rene Moricard, Bunny Austin, and Charles Thibault (14).
his dreams of IVF and studying the genetics and develop- Although Edwards was to remain in Cambridge for the
ment of early human embryos, had reached the ears of rest of his career, in 1963 his reactions to the place were
the then Director of the Institute, Sir Charles Harington mixed. He describes how he immediately reacted against
 ROBERT EDWARDS xxxi

the then extant “misogynist public-school traditions; the (64)], who had been in Cambridge intermittently since
exclusivity,” “the privileges given to the already privi- 1962 (Figs. 8 and 9). Austin was elected the first Charles
leged.” But he set against that the “sheer beauty of the Darwin Professor of Animal Embryology (1967–1981)
place,” the concern with the truth and high seriousness,” and began attracting several upcoming reproductive
the ambience of scientific excellence… I was surrounded biologists to the Marshall Laboratory, including John
by so many talented young men and women” (3). He, Marston, David Whittingham, and Matthew Kaufmann.
Ruth, and his five daughters settled in a house in Gough In addition, a new group was formed in 1967, with the
Way, off the Barton Road. arrival from the Strangeways laboratory of Denis New
Edwards worked in a cluster of seven smallish rooms (1929–2010), as university lecturer in histology (65).
at the top of the Physiological Laboratory backing onto New built a group comprising initially research assistant
Downing Place (Fig. 7). These were collectively known Pat Coppola (to be followed later by Stephanie Ellington)
as the “Marshall laboratory” and were to be shared even- and PhD students Chris Steele and David Cockroft, later
tually with two other groups. One group was led initially joined by postdoc Frank Webb, and visiting scientists
by Sir Alan Parkes, the first Mary Marshall and Arthur such as Joe Daniels Jr, on leave from the University of
Walton Professor of Reproductive Physiology at the Uni- Colorado.
versity (10), who had arrived in 1961. His group included It was against this varied scientific background that
scientists with mainly zoological or comparative inter- Edwards, who was already 38 when he arrived in Cambridge,
ests, such as his wife Ruth Deansley, Bunny Austin, and began for the first time to assemble his own group. Initially,
Dick Laws FRS, who with Parkes was often away “in the
field” collecting material, especially in Uganda at the
Nuffield Unit of Tropical Animal Ecology (10). Much of
this material was examined histologically under the
skilled eye of Frank Lemon, the senior technician.
Research students included Martin Richards, CJ Dominic,
Margaret Mitchell, and Barbara Weir (59). Parkes was
also much involved at this time in writing and committee
work, especially with the World Health Organization
which was then becoming concerned about world popu-
lation growth and ways to curb it (10). Parkes was also
acting as an unpaid company secretary to the then fledg-
ling Journal of Reproduction and Fertility [called Repro-
duction since 2001; (59–61)].
In 1967, Parkes retired. Edwards applied for his chair
on January 6, 1966 (62), but was unsuccessful, the chair
passing to Thaddeus Mann FRS [1908–1993; (63)], who
worked on the biochemistry of semen. Mann decided not
to relocate to the Physiology Laboratory from his Cam-
bridge base at the Agricultural Research Council Unit of Figure 8 Edwards with “Bunny” Austin (1960s). Source: Courtesy
Reproductive Physiology and Biochemistry at Hunting- of Ruth Edwards.
don Road, where he was Director. Neither was the leader-
ship of the Marshall laboratory to pass to Edwards, as the
University appointed as its head his more senior col-
league and friend Colin “Bunny” Austin [1914–2004;

Figure 9 Barbara Rankin holding a cartoon of Edwards, Steptoe,

and Purdy holding Lousie Brown drawn by Alan Handyside who
also took the photograph. With Austin are (left) Edwards and Purdy
Figure 7 Edwards in his office backing onto Downing Place in the (right) after the return of the latter two from Oldham and the birth of
Marshall laboratory (1970s). Source: Courtesy of Barbara Rankin. Louise Brown in 1978. Source: Courtesy of Barbara Rankin.
xxxii ROBERT EDWARDS

his technical assistance was provided by Clare Jackson and workers also arrived, including Ginny Papaioannou
then Valerie Hunn, after whom he recruited Jean Purdy (1971–1974), Hester Pratt (1972–1974), and Frank Webb
(Fig. 10) in 1968, one of her attractions being her nursing (1976–1977). Ruth Fowler-Edwards also resumed work-
qualification, a sign of the increasing importance that his ing in the laboratory, developing hormonal assays and
forays into use of clinical material was assuming. Purdy studying the endocrine aspects of follicle development
was to stay with him until her early death at age 39 in 1985 and early pregnancy. Thus, slowly until 1969, and more
(66). Also joining him as a part-time secretary in 1969, Bar- rapidly thereafter, Edwards built a lively group, its mem-
bara Rankin (b. 1933; Fig. 9) was to remain with him until bers working in diverse areas of reproductive science
1987. He also began recruiting his first graduate students. that reflected his own broad interests and knowledge.
Initially, he helped co-supervise (with Alan Parkes) Anne Moreover, Edwards encouraged a spirit of open commu-
Vickers (67), who sexed fixed whole-mouse blastocysts by nication and egalitarianism, which extended across all
karyotyping. This work led directly to his collaboration on three groups, with sharing of resources, space, equip-
preimplantation genetic diagnosis (PGD) (see later) with ment, knowledge, and ideas, as well as social activities.
Richard Gardner, one half of his first pair of graduate stu- Through the 1960s, Edwards was funded by the Ford
dents, the other being this author. The two students started Foundation via grants first to Parkes and then to Austin to
PhD training with Edwards in 1966 (68,69). Gardner stud- continue work on basic reproductive mechanisms, with
ied early mouse embryology from 1966 to 1971 and until an eye to developing new methods of fertility control. So
1973 as a postdoctoral worker, before moving to Zoology in he continued to pursue both the immunology of repro-
Oxford. This author worked on immunoreproduction from duction and egg maturation, for the latter collecting pig,
1966 to 1969, returning as a postdoc between 1971 and cow, sheep, the odd monkey, and some human eggs. He
1974 after two years in the United States before moving to showed that eggs of all these species would indeed mature
the Anatomy Department in Cambridge. in vitro, but that the eggs of larger animals simply needed
From 1969 onwards, Edwards’ group increased in size a longer time than those of smaller ones, human eggs tak-
substantially as more accommodation was made avail- ing up to 36 hours rather than the 12 hours or less errone-
able to the Marshall laboratory. David Griffin (now retired ously reported by Pincus. These cytogenetic studies were
from the World Health Organization) was to join as Head reported in two seminal papers in 1965 (70,71), both of
Technician between 1970 and 1975, with junior techni- which are primarily concerned with understanding the
cians including Sheila Barton, Sally Fawcitt, Sylvia Jack- kinetics of the meiotic chromosomal events during egg
son, Vinitha Dharawardena, and Brenda Dickstein, in maturation. In its discussion, the Lancet paper displays a
addition to Jean Purdy. Early graduate students recruited breathtaking clarity of vision as Edwards sets out a pro-
included Roger Gosden (1970–1974), Carol Readhead gram of research that predicted the events of the next
(1972–1976), and Rob Gore-Langton (1973–1978), all 20 years and beyond (Table 1). Significantly, if not sur-
working on follicle growth, Craig Howe (1971–1974) prisingly given his research interests, the early study and
working on immunoreproduction, and Azim Surani detection of genetic disease is afforded a heavy focus com-
(1975–1979) on implantation. A “third generation” of pared with the slight emphasis on infertility alleviation.
graduate students also arrived; for example, Janet Ros-
sant (from 1972) studied with Gardner and Alan Handy-
side (from 1974) studied with Johnson. Postdoctoral
Table 1 Key Points in the Program of Research Laid Out in the
Discussion to Edwards’ 1965 Lancet Paper

1. Studies on non-disjunction of meiotic chromosomes as a cause

of aneuploidy in humansa
2. Studies on the effect of maternal age on non-disjunction in
relation to the origins of trisomy 21a
3. Use of human eggs in IVF to study fertilization
4. Study of culture methods for human eggs fertilized in vitro
5. Use of priming hormones to increase the number of eggs per
woman available for study/use
6. Study of early IVF embryos for evidence of (ab) normality –
especially aneuploidies arising prior to or at fertilizationa
7. Control of some of the genetic diseases in mana
8. Control of sex-linked disorders by sex detection at blastocyst
stage and transfer of only female embryosa
9. Intracervical transfer of IVF embryos into the uterus
10. Use of IVF embryos to circumvent blocked tubesb
11. Avoidance of a multiple pregnancy (as observed after hormonal
priming and in vivo insemination) by transfer of a single IVF
embryo
a
Five aims relating specifically to genetic disease.
Figure 10 Jean Purdy (1946–1985). Source: Courtesy of Barbara b
One aim relating specifically to infertility relief.
Rankin.
 ROBERT EDWARDS xxxiii

This genetic focus continues in his research papers Johns Hopkins, he made a second transatlantic summer
over the next four years. Thus, within three years, work- journey in 1966 to visit Luther Talbot and his colleagues
ing with a graduate student called Gardner, he provided at Chapel Hill. He tried a variety of ways (79) to over-
proof of principle for PGD, in a paper on rabbit embryo come the problem of “sperm capacitation,” one of the
sexing published in 1968 (72), a paper that was to antici- most ingenious of which was to construct a 2.5 cm-long
pate the development of PGD clinically by some 22 years chamber from a nylon tube, plugged at each end, and
(73). Likewise, working with the Cambridge geneticist with holes drilled in the walls which were encased in
Alan Henderson, Edwards was to develop his “produc- panels made of Millipore membrane (80). The chamber,
tion line theory” of egg production to explain the origins which had a short thread attached to it, fitted snugly
of maternal aneuploidy in older women. Thus, the earli- inside the inserter tube of an intrauterine device and so
est eggs to enter meiosis in the fetal ovary were shown to could be placed into the volunteer woman’s uterus intra-
have more chiasmata and to be ovulated earlier in adult cervically at mid-cycle, where it sat for up to 11 hours
life than those entering meiosis later in fetal life (Fig. 11) before being recovered by gently pulling on the thread,
(74,75). exactly as was being done routinely for insertion and
removal of intrauterine devices. By placing spermatozoa
within the chamber, the membrane of which permitted
THE PROBLEM OF FERTILIZATION OF
equilibration of its contents with uterine fluid, he hoped
THE HUMAN EGG
to expose them to a capacitating environment. However,
Notwithstanding his broad range of scientific interests, this ingenious approach, like the many others, failed in
Edwards’ ambitions to achieve IVF in humans remained this case most probably because the chamber itself
undiminished. In 1966, this was no trivial task, having induced an inflammatory response or a local bleed. For
been accomplished convincingly only in rabbit and ham- all the ingenuity of his various experimental approaches
ster (76,77). In trying to achieve this aim, he was engag- to achieve capacitation, and despite the occasional evi-
ing in two struggles: the first being simply but critically dence of early stages of fertilization using such spermato-
the continuing practical difficulty in obtaining a regular zoa, no reliable evidence for the completion of the
supply of human ovarian tissue. Local Cambridge sources process was forthcoming. Then in 1968 both struggles
proved unreliable and Rose was now two to three hours’ began to resolve.
drive away in London; so, during the summer of 1965,
Edwards turned to the United States for help and
THE MEETING WITH PATRICK STEPTOE
approached Victor McKusick, a leading American cyto-
geneticist at The Johns Hopkins University. There he ini- Patrick Steptoe (1913–1988; Fig. 12) had been a consul-
tiated his longstanding contact with Howard and tant obstetrician at Oldham General Hospital since 1951
Georgeanna Jones in Obstetrics and Gynecology (78). The (81), where for several years he had been pioneering the
supply of American eggs they generated during his six- development and use of the laparoscope in gynecologi-
week stay allowed him to confirm the maturation timings cal surgery (81,82). Much to his frustration, his progress
that were published in 1965. had fallen on the largely deaf ears of the conservative
However, it was the second scientific struggle that was gynecological hierarchy, and indeed incited considerable
then occupying most of his attention, namely that in
order to fertilize these in-vitro matured eggs, he had to
“capacitate” the spermatozoa, a final maturation process
which spermatozoa undergo physiologically in the
uterus and that is essential for the acquisition of fertiliz-
ing competence. Failing to achieve this convincingly at

Figure 11 Edwards talks about his “production line” hypothesis Figure 12 Patrick Steptoe (1913–1988). Source: Courtesy of Andrew
(late 1960s). Source: Courtesy of Ruth Edwards. Steptoe.
xxxiv ROBERT EDWARDS

Table 2 Edited Record from the RSM Endocrinology Section: General Minutes, 1946–1975 (ref: RSM/J/19/4/1) p.365 (with permission)

A joint meeting of the SECTION OF ENDOCRINOLOGY of the Royal Society of Medicine with the SOCIETY FOR THE STUDY OF FERTILITY was
held at 1 Wimpole Street, W.1., Wednesday, February 28, 1968, at 10.00 am.
The meeting was attended by approximately 127 Fellows, members, and guests and the program was as follows:

“FERTILITY AND INFERTILITY”

10.00: Chairman’s opening remarks
10.10: Sperm capacitation. C.R. Austin, Department of Embryology, Cambridge
10.35: Immunological aspects of infertility. R.G. Edwards, Department of Physiology, Cambridge
11.00: Coffee
11.30: The rating of semen quality by chemical methods. Dr T Mann, Department of Physiology of Reproduction, Cambridge
11.55: Endocrine studies in women with secondary amenorrhea. Prof. Ivor H Mills and RJ Wilson, Department of Investigative Medicine,
Cambridge
12.20: Some investigation in male hypogonadism. Prof. FTG Prunty, Department of Chemical Pathology, St Thomas’s Hospital Medical School,
London
12.45: Lunch
2.15: A gonadotropin stimulation test for ovarian responsiveness. GIM Sawyer, University College Hospital Medical School, London
2.40: Factors affecting the response to clomiphene therapy. D Ferriman, AW Purdie, and M Corns, North Middlesex Hospital, London
3.05: Comparison of clomiphene and FSH for treatment of anovulation. AD Tsapoulis and AC Crooke, Department of Clinical Endocrinology,
Birmingham
3.30: Tea
4.00: Time cause of urinary oestrogen excretion after various schemes of Pergonal therapy. JK Butler, GD Searle and Co., High Wycombe, Bucks
4.25: Recent developments in the control of fertility. Sir Alan S Parkes, Cambridge
4.50: General discussion
[signed] CL Cope 26/6/1968 [pasted in] 26th June 1968

opposition and some outright hostility (83). Edwards’ attention? Looking at Steptoe’s possible publications in
claim was that he was scanning the medical and scien- journals, there is none listed for 1967, but there are two
tific journals in the library and came across a paper by 1967 conference reports and Steptoe’s book on gyneco-
Steptoe describing his experiences with laparoscopy logical laparoscopy (82,89,90). Of the few journal papers,
(3,81,84). Edwards goes on to describe how he rang only two concern laparoscopy, one from January 1966 in
Steptoe to discuss a possible collaboration, but was the British Medical Journal (BMJ), and one from August
“warned off” Steptoe by London gynecological col- 1965 in the Journal of Obstetrics and Gynaecology of the
leagues (85). This warning and the daunting prospect of British Commonwealth (JOGBrC). Which of these five
collaboration in far-away Oldham, deterred him from publications (Table 3) did Edwards read? The 1966 BMJ
following through. Finally, Edwards reported actually publication (91) is a letter entitled “The fifth freedom.” It
meeting Steptoe later at a meeting at the Royal Society of responds to a paper by Sir Dugald Baird on the “problem
Medicine, at which, ironically, Edwards was talking of excessive fertility in women.” Steptoe concurs that
about his work on immunoreproduction, not his attempts there is a problem, but disagrees with the proposed con-
at IVF. traceptive solution, advising laparoscopic sterilization for
The Steptoe paper that Edwards found that day in the women as safer and more effective. He also discusses how
library was cited in his tributes to the then-deceased Step- laparoscopy can be used postoperatively to confirm that
toe (81,84) as being a Lancet paper entitled “Laparoscopy tubes were indeed blocked. The JOGBrC paper (92) is
and ovulation” (86). However, these later recollections do entitled “Gynaecological endoscopy – laparoscopy and
not withstand scrutiny. Thus, the Lancet paper cited was culdoscopy” and reviews the history of endoscopy and
published in October 1968, but their first meeting was in Steptoe’s experiences with it. It is in essence a very abbre-
fact earlier that year, on Wednesday February 28, 1968 at viated version of his book (82), which was to be published
a joint meeting of the Section of Endocrinology of the in the following year. The two reports of the conference
Royal Society of Medicine with the Society for the Study proceedings (89,90) are slightly more detailed accounts
of Fertility held at 1 Wimpole Street (Table 2) (87). More- than the BMJ letter and are much abbreviated versions of
over, according to Steptoe (88), they had already com- the JOGBrC paper.
menced collaborating prior to October 1968; indeed their Of these five publications, the Sydney conference pro-
first paper together was submitted for publication later ceedings (90) can probably be dismissed as they only
that year in December 1968 (see next section). Clearly, the arrived in the Cambridge library in May 1968. The pro-
paper read by Edwards must have been another, earlier ceedings from Stockholm (89) are now no longer avail-
than October 1968, one that proceeded February 1968 by able in Cambridge, but evidence of their presence in the
several months. Indeed, in an earlier account, Edwards Physiology library in 1967 has been uncovered in an old
describes the library “Eureka” moment as occurring in catalog record, and so they would have been newly avail-
“one autumn day in 1967” (3). So which was the paper by able to Edwards from November 1967 at the earliest. The
Steptoe that Edwards saw and what about it attracted his BMJ letter (91) seems unlikely.
 ROBERT EDWARDS xxxv

Table 3 Steptoe’s Papers from 1967 and Earlier

Publication Title Type of publication Location in Cambridge; date of arrival

Steptoe (82) Laparoscopy in gynaecology Book University library; March 1967

Steptoe (89) A new method of tubal sterilisation Conference proceedings (Stockholm) Physiology library; arrival date unknown,
published in November 1967
Steptoe (90) Laparoscopic studies of ovulation, its Conference proceedings (Sydney) University library; May 1968
suppression and induction, and of
ovarian dysfunction
Steptoe (91) The fifth freedom BMJ letter (22 January), 234 Physiology library; January 1966
Steptoe (92) Gynaecological endoscopy – Paper in J Obstet Gynaecol Br University library; August 1965 (moved to
laparoscopy and culdoscopy Commonw 72, 535–543 Clinical School library after 1973)

Although Edwards was involved in contraceptive THE FERTILIZATION OF THE HUMAN EGG
studies over this period through his work on immunore- RESOLVED
production and was a member of the Royal Society Popu-
Despite the initiation of the collaboration with Steptoe,
lation Study Group at the time (10), and so may well have
the actual solution to the capacitation problem existed
read this correspondence, it seems unlikely that the BMJ
nearer to home than Oldham, in the laboratories shared
letter would have caught his eye to such dramatic effect
with Austin. In the early 1950s, Austin, and indepen-
and so long after its publication in January 1966, being
dently MC Chang, had discovered the requirement for
readily available each week in the Physiology Library.
sperm capacitation (94,95). After his appointment to
The JOGBrC paper from 1965 was located in the Univer-
the Cambridge chair, Austin’s first graduate student
sity library, which was physically more remote from
(1967–1972) was Barry Bavister, who set to work to try
Physiology and not so immediately available to Edwards.
and resolve the factors influencing the capacitation of
However, it was in exactly the sort of clinical journal that
hamster spermatozoa in vitro. In 1968, Bavister discov-
he might then have been trawling retrospectively in his
ered a key role for pH, showing how higher rates of fer-
attempts to solve the problem of sperm capacitation.
tilization could be obtained by simply increasing the
Thus, although in the more recent accounts of these
alkalinity of the medium (96). Edwards seized on this
events, Edwards (84,81) records his motivation for con-
observation and co-opted Bavister to his project. That
tacting Steptoe as being the potential value of the laparo-
proved to do the trick, and in December 1968 Edwards,
scopic approach for egg collection, in 1967 eggs was not
together with Bavister and Steptoe, submitted the paper
the foremost subject on his mind. Indeed in two earlier
to Nature, in which IVF in humans was described con-
accounts, one written (3) and one spoken ((85); Supple-
vincingly for the first time (97).
mentary video), Edwards claims he saw laparoscopy as a
The 1969 Nature paper makes modest claims. Only
way of recovering capacitated spermatozoa from the ovi-
18 of 56 eggs assigned to the experimental group showed
duct by flushing with a small volume of medium: “a
evidence of “fertilization in progress”; of which only two
practical way … of letting spermatozoa be in contact with
were described as having the two pronuclei to be
the secretions of the female tract” (3). He says he actually
expected if fertilization was occurring normally (Table 4).
rang Steptoe to ask whether this really was possible and
However, like Edwards’ other papers, this one is a model
was reassured by him that this was the case.
of clarity, describing well-controlled experiments, cau-
However, the only publication by Steptoe that explic-
tiously interpreted. Despite the relatively small num-
itly lays out this possibility is his book (82). Thus, on
bers, this paper convinced where previous claims had
page 27 he reports “By means of laparoscopy, Sjovall
failed (98–103), precisely because the skilled hands and
(1964) has carried out extended post-coital tests and has
creative intellect that were behind it are so evident from
recovered spermatozoa from the fimbriated end of the
its text.
tubes …”; and on page 70, he writes “An extended post-
The provenance of the eggs described in the 1969
coital test can be done by aspirating fluid from the tubal
paper is not immediately clear from the paper itself. All
ostium …”. Moreover, Steptoe’s book arrived in the Uni-
were obtained by in-vitro maturation after ovarian
versity library in March 1967. However, against this con-
biopsy. In addition to Steptoe’s coauthorship, four other
clusion sits Steptoe’s recollection that Edwards had rung
gynecologists are thanked in the Acknowledgements
him just before his book was published, that is before
section of the paper: Molly Rose, Norman Morris [1920–
March 1967 (3). This memory conflicts with both his and
2008; Professor of Obstetrics and Gynecology at Charing
Edwards’ memories elsewhere of the phone conversa-
Cross Hospital, London from 1958 to 1985; (104)], Janet
tion being in the autumn of 1967, so the matter remains
Bottomley (1915–1995; Consultant Obstetrician and
one for conjecture, but the book seems the most likely
Gynecologist at Addenbrooke’s Hospital, Cambridge
source. It is possible that Edwards’ attention was drawn
from 1958 to 1976) and Sanford Markham (b. 1934; Chief
to the book by a review of it in the BMJ on November 11,
of the Section of Obstetrics and Gynaecology at the U.S.
1967 (93).
xxxvi ROBERT EDWARDS

“a spermatozoon was just passing into the first

Table 4 Summary of Data from Ref. 97
egg … An hour later we looked at the second egg.
Experimental Control
Yes, there it was, the earliest stages of fertiliza-
Egg characteristic group group tion. A spermatozoon had entered the egg with-
out any doubt – we had done it … We examined
Assigned 56 17 other eggs and found more and more evidence.
Surviving 54/56 17/17
Some ova were in the early stages of fertilization
Matured to metaphase II 34/54 7/17
with the sperm tails following the sperm heads
Some evidence of sperm 18/34
penetration into the depths of the egg; others were even more
Spermatozoon within the zona 6/18 advanced with two nuclei – one from the sperm
pellucida and one from the egg – as each gamete donated
Spermatozoon inside zona 5/18 its genetic component to the embryo.”
pellucida (c.7 hr post
insemination) This (unverified) account suggests that Rose provided
Evidence of pronuclei (c.11 hr 7/18 0/7 the first group of eggs to be fertilized in “Bavister’s
post insemination) medium.” Moreover, since only 18 of the eggs in the
No. with two pronuclei 2/18 paper showed evidence of fertilization (Table 4), nine of
those seem to have come from Rose, including presump-
tively the two described as having two pronuclei. Rose
was invited to be a co-author, but she declined for rea-
Air Force Hospital, South Ruislip, to the north west of sons unknown. The source of the remaining nine eggs is
London from 1967 to 1972). Markham, now Professor of unknown, but may have come from Oldham General
Obstetrics and Gynecology at Florida International Uni- Hospital. The Acknowledgements section thanks Drs C
versity, Miami, writes: Abberley, G Garrett, and L Davies “for their help,” all
“I believe that I met Bob by introduction from Dr. Roger from Oldham General. John Webster, a later gynecologi-
Short at a Royal College of Medicine conference in Lon- cal colleague of Steptoe, having consulted his colleague
don … probably in early 1968 [possibly the Royal Society John Battie, writes of these:
of Medicine’s 28 February meeting at which Steptoe and “Cyril Adderley, not Abberley, was the Group
Edwards first met?]. Bob mentioned that he was in need Pathologist in Oldham. Geoff Garrett … was also
of ovarian tissue from reproductive aged women … I a pathologist there … there was no L. Davies
offered to obtain tissue if we could work out a scheme to there but a John Davies, a haematologist, and a
transport the tissue … to Cambridge … He provided the Vincent John Davies, a histologist … and my
media and container and a driver that came to our hospi- money would go on V. J. as I think a histologist
tal … I remember three samples, however, there may rather than a haematologist would have been of
have been others. In each case the whole wedge … or … more help to him …?”
ovary was sent (after sampling for pathology). In all cases
the patients provided their consent for utilization of their The first two of these have elsewhere been described as
tissue for research. They were not told what the research helpful in setting up the embryology laboratory in Old-
work involved. These samples were most likely sent in ham, largely through the provision or loan of equipment
mid to late 1968 and possibly in early 1969. … These … required locally for egg maturation and fertilization, so
were planned surgeries which were accomplished at spe- their involvement in direct provision of eggs seems
cific times in their menstrual cycle. Unfortunately, I do unlikely.
not know if the tissues supplied were indeed the tissues The Nature paper also supports Oldham as the source
used in data for his 1969 paper published in Nature.” of the remaining eggs: “Some eggs were transported from
It is possible that they were used, but unsuccessfully, Oldham to Cambridge” (97), and in his retrospective
not contributing to the 18 eggs showing fertilization. 1980 account of the events, Edwards says that at Oldham
Thus, according to Edwards (3), Jean Purdy drove to they began to repeat the experiment:
Edgeware General Hospital to collect: “Twelve women whose ovaries had to be removed
[presumably laparoscopically] for serious medical condi-
“the last piece of ovarian tissue that I was to
tions provided us with the necessary eggs over the next
obtain from the Edgware General Hospital. It
few months. We fertilized many more eggs and were able
yielded me 12 human eggs. Those eggs were
to make detailed examinations of the successive stages of
soon ripening in mixtures of culture medium I
fertilization (3).”
had used over many years to which some of
So it seems reasonable to conclude that those eggs
Barry [Bavister]’s fluid had been added. Thirty-
described in the paper as “undergoing fertilization” were
six hours later we judged that they were ready
provided in roughly equal numbers by Rose and Steptoe.
for fertilization.”
However, with Steptoe on board, Rose no longer fea-
Nine of these were inseminated, leaving three as con- tured as a supplier of eggs (3). While the initial attraction
trols. Ten hours later, when Edwards and Bavister of laparoscopy for Edwards had been the recovery of
returned to the laboratory late at night: capacitated spermatozoa from the oviduct, once working
 ROBERT EDWARDS xxxvii

with Steptoe he rapidly saw the wider possibilities for in the MRC rejecting the grant application (2). The practi-
recovery of in-vivo matured eggs from the ovary (86). cal consequences of this rejection were profound – both
Indeed, the 1969 paper includes the following statement: psychologically and physically – not least that for the
“Problems of embryonic development are likely to next seven years, Edwards and Purdy shuttled on the
accompany the use of human oocytes matured and fertil- 12-hour round trip between Cambridge and Oldham,
ized in vitro. When oocytes of the rabbit and other Greater Manchester, paradoxically just north of his
species were matured in vitro and fertilized in vivo, the schoolboy haunts of Gorton, where Steptoe and he set up
pronuclear stages appeared normal but many of the a small laboratory and clinic in Dr Kershaw’s cottage hos-
resulting embryos had subnuclei in their blastomeres, pital, all the while leaving Ruth and his five daughters in
and almost all of them died during the early cleavage Cambridge.
stages … When maturation of rabbit oocytes was started The professional attacks on Edwards and his work took
in vivo by injecting gonadotropins into the mother, and a number of forms (2), and one must try to make a mental
completed in the oviduct or in vitro, full term rabbit time trip back to the 1960s and 1970s to understand their
fetuses were obtained (97).” basis. Despite the nature of the political and religious
The paper goes onto discuss how the use of hormonal battles to come, his scientific and medical colleagues did
priming to stimulate intrafollicular egg maturation might not focus on the special status of the human embryo as an
be achieved and reports: “Preliminary work using lapa- ethical issue. Ethical issues were raised professionally,
roscopy has shown that oocytes can be recovered from but took quite a different form. It is perhaps difficult now
ovaries by puncturing ripening follicles in vivo. …” to comprehend the complete absence of infertility from
Through these preliminary collaborative studies, the consciousness of most gynecologists in the United
Edwards and Steptoe were already building a research Kingdom at the time, of whom Steptoe was a remarkable
partnership. Although both were very different personali- exception (81). Indeed, even Edwards’ strong commit-
ties, and brought very different skills to the project, they ment to treating infertility came to the fore only after he
shared energy, commitment, and vision. Each was also had teamed up with Steptoe, his previous priority being
marginalized by his professional peers, a marginalization the study and prevention of genetic and chromosomal
that also perhaps helped to cement their partnership (2). disorders.
With the paper’s publication, announced to the media In the several reports from the Royal College of Obste-
on St Valentine’s day (105), all hell was let loose. The tricians and Gynaecologists and the MRC during the
impossible tangle of TV cables and pushy reporters try- 1960s examining the areas of gynecological ignorance
ing to force their way up the stairs to the fourth floor that needed academic attention, infertility simply did
laboratories proved a major disruption to the Physiologi- not feature (50,51). Overpopulation and family planning
cal laboratory in general and to the members of the Mar- were seen as dominant concerns and the infertile were
shall laboratory in particular. It was something that was ignored as, at best, a tiny and irrelevant minority and at
to recur episodically over the next 10 years. worst as a positive contribution to population control.
This was a values system that Edwards did not accept
(111), and the many encouraging letters he received
THE BATTLES BEGIN
from infertile couples spurred him on and provided a
However, 1969 seemed to be a good year for Edwards. Not major stimulus to his continued work later, despite so
only did IVF succeed at long last, and his partnership with much professional and press antagonism. For his profes-
Steptoe seemed set to flourish, but also so impressed were sional colleagues, however, the fact that infertility was
the Ford Foundation with his work that in late 1968 they not seen as a significant clinical issue meant that any
had established, at Austin’s prompting (106), an endow- research designed to alleviate it was viewed not as
ment fund with the University of Cambridge to cover the experimental treatment, but as using humans in experi-
salary cost of a Ford Foundation Readership [a half-way ments. Given the sensitivity to the relatively recent Nazi
step to a professorship; (107)]. Elated by his promotion “medical experiments,” the formal acceptance of the
and their achievement, Edwards and Steptoe pressed on, Helsinki Declaration (112,113) and the public reaction
the latter’s laparoscopic skills coming to the fore, first in and disquiet surrounding the recent publication of
1970 with the collection of in-vivo matured eggs from fol- “Human guinea-pigs” (114), this distinction was critical.
licles after mild hormonal stimulation (108), and then The MRC, in rejecting the grant application, took the
achieving regular fertilization of these eggs and their early position that what was being proposed was human
development through cleavage to the blastocyst stage experimentation, and so were very cautious, emphasiz-
(109,110). So well was the work going that in late 1970 ing risks rather than benefits, of which they saw few if
and early 1971 they confidently applied to the U.K. Medi- any (2).
cal Research Council for funding. Edwards and Steptoe were also attacked for their will-
However, any illusions that Edwards may have had ingness to talk with the media. It is difficult nowadays,
that their achievements would prove a turning point in when the public communication of science is embedded
his fortunes were soon shattered. The hostility of much institutionally, to understand how damaging to them
of the media coverage to his work in 1969 heralded the this was. The massive press interest of the late 1960s was
dominant pattern of scientific and medical responses for unabated in the ensuing years, and so Edwards was faced
the next 10–15 years and resulted just two months later with a choice: either he could keep his head down and
xxxviii ROBERT EDWARDS

allow press fantasies and speculations to go unanswered

and unchallenged, or he could engage, educate, and
debate. For him this was no choice, regardless of the con-
sequences professionally (30). His egalitarian spirit
demanded that he trust common people’s common
sense. His radical political views demanded that he
fought the corner of the infertile: the underdog with no
voice. The Yorkshireman in him relished engagement in
the debate and argument. In Edwards and Sharpe (111),
he sets out his reasons for public engagement and
acknowledges the risk to his own interests:
“Scientists may have to make disclosures of their
work and its consequences that run against their
immediate interests; they may have to stir up
public opinion, even lobby for laws before legis-
latures.”
And risk it was. One of the scientific referees on their
MRC grant application started his referee’s report declar- Figure 13 Louise Brown holding the 1000th Bourn Hall baby,
ing the media exposure distasteful: 1987. Source: Courtesy of Bourn Hall Clinic.
“Dr. Edwards feels the need to publicise his
work on radio and television, and in the press, so
that he can change public attitudes. I do not feel DISCUSSION
that an ill-informed general public is capable of
This paper describes some of the early years of Edwards’
evaluating the work and seeing it in its proper
life and work, in order to provide a context for the events
perspective. This publicity has antagonised a
leading up to the 1969 Nature paper describing IVF and
large number of Dr. Edwards’ scientific col-
the final validation of the claims made in that paper
leagues, of whom I am one (2).”
with the birth of Louise Brown in 1978. It is evident even
Edwards’ pioneering role in the public communication from the earliest stages of his late entry into research that
of science proved to be disadvantageous to his work. Edwards is a man of extraordinary energy and drive,
The Edwards and Sharpe (111) paper is a tour de force qualities sustained throughout his long career, witness-
in its survey of the scientific benefits and risks of the sci- ing his prodigious output of papers between 1954 and
ence of IVF, in the legal and ethical issues raised by IVF, 2008 (30). Indeed, several of the referees on the unsuc-
and in the pros and cons of the various regulatory cessful MRC grant application specifically criticized his
responses to them. It sets out the issues succinctly and “overenthusiasm,” doubting that he could achieve the
anticipates social responses that were some 13–19 years program he sets out therein as “too ambitious” (2). Tenac-
into the future. Edwards built on his strong commitment ity of purpose comes through clearly in Edwards’ work, a
to social justice based on a social ethic in subsequent trait he is inclined to attribute to his Yorkshire origins,
years, as he engaged at every opportunity with ethicists, but which may also be fuelled by his working-class deter-
lawyers and theologians, arguing, playing “devil’s advo- mination to show himself as good as the next (wo)man.
cate” (literally, in the eyes of some), and engaging in The influence of Waddington’s Edinburgh Institute, of
what would now be called practical ethics as he ham- Waddington himself, and of his supervisor, Alan Beatty,
mered out his position and felt able to fully justify his on Edwards’ interests and values is also clear from the
instincts intellectually. dominant role that developmental genetics played in his
However, the establishment was, with few exceptions, thinking, especially until the time he met Steptoe.
unwilling to engage seriously in ethical debates (115,116) Indeed, from examination of Edwards’ papers and inter-
in advance of the final validation of IVF that was to come ests, his passionate conversion to the cause of the infer-
in 1978 with the birth of Louise Brown (Fig. 13) (117). tile seems directly attributable to Steptoe’s influence.
Only then did the UK social, scientific, and medical hier- Admittedly, Edwards’ forays into immunoreproduction
archies, such as the MRC, the British Medical Associa- did involve consideration of immunological causes of
tion, the Royal Society, and Government move gradually infertility, but these were more usually of interest to him
from their almost visceral reactions against IVF and its as models for developing new contraceptive agents.
possibilities to serious engagement with the issues (118). Indeed, Edwards was as captured as most reproductive
Then, to their credit, both the MRC and the Thatcher biologists of the time by the 1960s’ consensus on the
Government of the time came on board, but it was not need for better methods of world population control.
until 1989, 24 years after Bob’s 1965 visionary paper in This position was understandable given the reality of
the Lancet, that the UK Parliament finally gave its stamp those concerns, as is demonstrated now in the problem of
of approval to his vision, and then only after a fierce bat- global warming that is attributable at least in part to a
tle lasting some 11 years (118,119). failure to control population growth. It is a measure of
 ROBERT EDWARDS xxxix

his imagination and empathy that he could grasp so rap-

idly Steptoe’s understanding of the plight of the infertile
and so flexibly incorporate this understanding into his
plans. That empathy clearly reflects his underprivileged
origins, his espousal of the cause of the junior, the disad-
vantaged, the ill-informed, and the underdog being a
thread running through his career. Edwards can be very
critical, but I have found no one who can remember him
ever being nasty or vindictive. Even when he disagrees
with someone passionately, he never loses his respect for
them as people. That Steptoe tapped into this sentiment
is clear.
The way in which Edwards met Steptoe has been
absorbed into folklore, but an examination of the evi-
dence seems to warrant some revision to commonly held
later reminiscences. It remains uncertain exactly which
publication(s) by Steptoe it was that Edwards read in
Figure 14 Edwards, Purdy, and Steptoe at Bourn Hall, 1981. Source:
1967, but seems likely that he did read Steptoe’s book. Courtesy of Bourn Hall Clinic.
Thus, it was spermatozoa, not eggs, that were exercising
Edwards in 1967, and it was the problem of sperm capac-
itation, not egg retrieval, to which Steptoe and his lapa-
for her help with locating books and periodicals, and
roscope seemed to offer a solution. The book is the only
Kay Elder, Ralph Robinson, and Sarah Franklin for their
place that this issue is specifically addressed. Their
unfailing wisdom and help. I also thank Barry Bavister,
actual meeting at the Royal Society of Medicine is also
Richard Gardner, Roger Gosden, David Griffin, Ginny
re-evaluated: Edwards was an invited speaker lecturing
Papaioannou, Barbara Rankin, Carol Readhead, Martin
about his work on immunoreproduction; so paradoxi-
Richards, Janet Rossant, Pat Tate, and Frank Webb for
cally, what has been seen as a side track to his main work
contributing their own memories from their own papers
was, albeit serendipitously, the reason for their actual
and for correcting mine. I thank Ruth Edwards for per-
meeting.
mission to reproduce Figures 1–3, 5, 8, and 11, Barbara
The early collaboration between them involved the
Rankin for permission to reproduce Figures 6, 7, 9, and
recovery of ovarian biopsies, just like those Rose and oth-
10, Andrew Steptoe for permission to reproduce Figure
ers had been providing. However, the attractions of pre-
12, Bourn Hall Clinic for permission to reproduce
ovulatory follicular egg recovery were already clear to
Figures 13 and 14, and Peter Williams for permission to
them both by the end of 1968, and became, with embryo
include the movie clip in the Supplementary material.
replacement, the central planks of their partnership.
The research was supported by a grant from the Well-
Steptoe and Edwards were in many ways an unlikely
come Trust (088708), which otherwise had no involve-
partnership. Their personal styles were very different,
ment in the research or its publication.
and there are clear hints in his writings that Edwards
found their early days together difficult. But like most
successful partnerships, their differences were sunk in a REFERENCES
mutual respect for the other’s pioneering skills and will-
ingness to take on the established conventions. In Jean 1. Nobel, 2010. [Available from: http://nobelprize.org/
nobel_prizes/medicine/laureates/2010/announce-
Purdy, they also had a partner who smoothed the bumps
ment.html].
on the path of their work together (Fig. 14).
2. Johnson MH, Franklin SB, Cottingham M, Hopwood N.
However, it remains Edwards’ extraordinary foresight Why the medical research council refused Robert
that marks him out so distinctively. His combination of Edwards and Patrick Steptoe support for research on
vision and intellectual rigor is evident not just in his work human conception in 1971. Hum Reprod 2010; 25:
on stem cells, PGD and, with Steptoe, infertility, but also 2157–74.
in his pioneering work in the public communication of 3. Edwards RG, Steptoe PC. A Matter of Life: The Story
science, in how ethical discourse about reproduction is of a Medical Breakthrough. London, UK: Hutchinson,
conducted, and in consideration of regulatory issues. The 1980.
epithet “the father of Assisted Reproductive Technique” is 4. Massey H, Feather N. James Chadwick. 20 October
surely deservedly appropriate. 1891–24 July. Biogr Mems Fell R Soc 1974; 22: 10–70.
5. Ashwood-Smith M. Robert Edwards at 55. Reprod
BioMed Online 2002; 4(Suppl 1): 2–3.
ACKNOWLEDGMENTS 6. Ingle DJ. Gregory Goodwin Pincus. April 9, 1903-
August 22, 1967. Biogr Mems Natl Acad Sci USA 1971:
I thank the Edwards’ family for their help in writing this 229–270. [Available from: http://www.nap.edu/read-
account, for which, however, I take full responsibility. I ingroom.php?book=biomemsandpage=ggpincus.html].
also thank Sandy Markham and John Webster for allow- 7. Slee J. RGE at 25 – personal reminiscences. Reprod
ing me to quote our correspondence, Margaret Wilson BioMed Online 2002; 4(Suppl 1): 1.
xl ROBERT EDWARDS

8. Oakley CL. Francis William Rogers Brambell. 1901– first cleavage of eggs of adult mice treated with gonad-
1970. Biogr Mems Fell R Soc 1973; 19: 129–171. otrophins. J Endocr 1959; 18: 292–304.
9. Parkes AS. Francis Hugh Adam Marshall. 1878–1949. 33. Horowitz NH, Metz CB, Piatigorsky J, Piko L, Spikes
Biogr Mems Fell R Soc 1950; 7: 238–251. JD, Ycas M. Albert Tyler. Science 1969; 163: 424.
10. Polge C. Sir Alan Sterling Parkes. 10 September 1900–17 34. Reeve S. Nathaniel Mayer Victor Rothschild, G.B.E.,
July. Biogr Mems Fell R Soc 2006; 52, 263–283. G.M. Third Baron Rothschild. 31 October 1910–20
11. Robertson A. Conrad Hal Waddington. 8 November March. Biogr Mems Fell R Soc 1994; 39: 364–80.
1905–26 September. Biogr Mems Fell R Soc 1977; 23: 35. Rothschild. Did fertilization occur? Nature 1969;
575–622. 221: 981.
12. Milne EA. Ralph Howard Fowler. 1889–1944. Biogr 36. Edwards RG, Bavister BD, Steptoe PC. Early stages of
Mems Fell R Soc 1945; 5: 60–78. fertilization in vitro of human oocytes matured in
13. Eve AS, Chadwick J. Lord Rutherford. 1871–1937. vitro. Nature 1969b; 221: 632–5.
Biogr Mems Fell R Soc 1938; 2: 394–423. 37. Mitchison NA. Peter Brian Medawar. February 1915–2
14. Edwards RG. An astonishing journey into reproduc- October. Biogr Mems Fell R Soc 1990; 35: 282–301.
tive genetics since the 1950’s. Reprod Nutr Dev 2005; 38. Medawar PB. Some immunological and endocrino-
45: 299–306. logical problems raised by the evolution of viviparity
15. Watson JD, Crick FH. Genetical implications of the in.vertebrates. Symp Soc Exp Biol 1953; 7: 320–38.
structure of deoxyribonucleic acid. Nature 1953a; 39. Clarke AE. Disciplining Reproduction: Modernity,
171: 964–7. American Life Sciences, and the Problems of Sex.
16. Watson JD, Crick FH. Molecular structure of nucleic Berkeley, California, USA: University of California
acids: a structure for deoxyribose nucleic acid. Nature Press, 1998.
1953b; 171: 737–8. 40. Connelly M. Fatal Misconception: The Struggle to
17. Franklin R, Gosling R. Molecular configuration in Control World Population. Cambridge, USA: Harvard
sodium thymonucleate. Nature 1953; 171: 740–1. University Press, 2008.
18. Wilkins MHF, Stokes AR, Wilson HR. Molecular 41. Marks LV. Sexual Chemistry: A History of the Contra-
structure of deoxypentose nucleic acids. Nature 1953; ceptive Pill. New Haven, USA: Yale University Press,
171: 738–40. 2001.
19. Gurdon JB. The developmental capacity of nuclei 42. Naz RK, Gupta SK, Gupta JC, Vyas HK, Talwar GP.
taken from intestinal epithelium cells of feeding tad- Recent advances in contraceptive vaccine develop-
poles. Development 1962a; 10: 622–40. ment: a mini-review. Hum Reprod 2005; 20: 3271–83.
20. Gurdon JB. Adult frogs derived from the nuclei of 43. Rukavina D. The history of reproductive immunol-
single somatic cells. Dev Biol 1962b; 4: 256–73. ogy: my personal view. Am J Reprod Immunol 2008;
21. Gurdon JB, Elsdale TR, Fischberg M. Sexually mature 59: 446–50.
individuals of Xenopus laevis from the transplanta- 44. Edwards RG. Meiosis in ovarian oocytes of adult
tion of single somatic nuclei. Nature 1958; 182; 64–5. mammals. Nature 1962; 196: 446–50.
22. Weinberg AM. Messenger RNA: origins of a discov- 45. Gemzell CA. The induction of ovulation with human
ery. Nature 2001; 414: 485. pituitary gonadotrophins. Fertil Steril 1962; 13:
23. Ford CE, Hamerton JL. The chromosomes of man. 153–68.
Nature 1956; 178: 1020–23. 46. Pincus G, Enzmann EV. The comparative behavior of
24. Tjio JH, Levan A. The chromosome number of man. mammalian eggs in vivo and in vitro I. the activation
Hereditas 1956; 42: 1–6. of ovarian eggs. J Exp Med 1935; 62: 665–75.
25. Conference, Denver. A proposed standard system of 47. Pincus G, Saunders B. The comparative behavior of
nomenclature of human mitotic chromosomes. Lancet mammalian eggs in vivo and in vitro VI. The matu-
1960; 275: 1063–65. ration of human ovarian ova. Anat Rec 1939; 75:
26. Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH. 537–45.
A sex-chromosome anomaly in a case of gonadal dys- 48. Greep RO. Min Chueh Chang. October 10, 1908–
genesis (Turner’s syndrome). Lancet 1959a; 273: 711–13. June 5, 1991. Biogr Mems Natl Acad Sci USA. 2010.
27. Ford CE, Polani PE, Briggs JH, Bishop PM. A pre- [Available from: http://www.nap.edu/readingroom.
sumptive human XXY/XX mosaic. Nature 1959b; 183: php?book=biomemsandpage=mchang.html].
1030–32. 49. Chang MC. The maturation of rabbit oocytes in cul-
28. Jacobs PA, Strong JA. A case of human intersexuality ture and their maturation, activation, fertilization and
having a possible XXY sex-determining mechanism. subsequent development in the Fallopian tubes. J Exp
Nature 1959; 183: 302–3. Zool 1955; 128: 379–405.
29. Lejeune J, Gautier M, Turpin R. Etude des chromo- 50. MRC. 1969. Research in Obstetrics and Gynaecology:
somes somatiques de neuf enfants mongoliens. Report to the Secretary of the Council by Section A1,
Comptes Rendus Hebd Seances Acad Sci 1959; 248: General Clinical Medicine. National Archives, FD
1721–22. 7/912.
30. Gardner RL, Johnson MH. Bob Edwards and the first 51. RCOG. Macafee Report. The Training of Obstetricians
decade of reproductive biomedicine. Online Reprod and Gynaecologists in Britain, and Matters Related
BioMed Online 2011; 22: 106–24. Thereto: The Report of a Select Committee to the
31. Fowler RE, Edwards RG. Induction of superovulation Council of the Royal College of Obstetricians and
and pregnancy in mature mice by gonadotrophins. Gynaecologists. London, UK: RCOG, 1967.
J Endocr 1957; 15: 374–84. 52. Askonas BA. John Herbert Humphrey. 16 December
32. Edwards RG, Gates AH. Timing of the stages of the 1915–25 December. Biogr Mems Fell R Soc 1990; 36:
maturation divisions, ovulation, fertilization and the 274–300.
 ROBERT EDWARDS xli

53. Himsworth H, Pitt-Rivers R. Charles Robert Harington. 75. Henderson SA, Edwards RG. Chiasma frequency and
1897–1972. Biogr Mems Fell R Soc 1972; 18, 266–308. maternal age in mammals. Nature 1968; 218: 22–8.
54. McLaren A, Biggers JD. Successful development and 76. Chang MC. Fertilization of rabbit ova in vitro. Nature
birth of mice cultivated in vitro as early embryos. 1959; 184: 466–7.
Nature 1958; 182: 877–8. 77. Yanagimachi R, Chang M.C. Fertilization of hamster
55. Cole RJ, Edwards RG, Paul J. Cytodifferentiation in eggs in vitro. Nature 1963; 200: 281–2.
cell colonies and cell strains derived from cleaving 78. Jones Jr HW. From reproductive immunology to Louise
ova and blastocysts of the rabbit. Exp Cell Res 1965; Brown. Reprod BioMed Online 2002; 4(Suppl 1): 6–7.
37: 501–4. 79. Edwards RG, Donahue RP, Baramki TA, Jones Jr HW.
56. Cole RJ, Edwards RG, Paul J. Cytodifferentiation and Preliminary attempts to fertlilize human oocytes
embryogenesis in cell colonies and tissue cultures matured in vitro. Am J Obstet Gynecol 1966; 96:
derived from ova and blastocysts of the rabbit. Dev 192–200.
Biol 1966; 13: 385–407. 80. Edwards RG, Talbert L, Israelstam D, Nino HN, John-
57. Evans MJ, Kaufman MH. Establishment in culture of son MH. Diffusion chamber for exposing spermatozoa
pluripotential cells from mouse embryos. Nature to human uterine secretions. Am J Obstet Gynecol
1981; 292: 154–6. 1968: 102: 388–396.
58. Edwards RG. IVF and the history of stem cells. Nature 81. Edwards RG. Patrick Christopher Steptoe, C. B. E. 9
2001; 413: 349–51. June 1913–22 March 1988. Biogr Mems Fell R Soc
59. Parkes AS. Off-beat Biologist. Cambridge, UK: The 1996; 42: 435–52.
Galton Foundation, 1985. 82. Steptoe PC. Laparoscopy in Gynaecology. Edinburgh,
60. Cook B. JRF – the first 100 volumes. Reproduction UK: E and S. Livingstone, 1967a.
1994; 100: 2–4. 83. Philipp E. Obituary: P C Steptoe CBE, FRCSED,
61. Clarke J. The history of three scientific societies: the FRCOG, FRS. Br Med J 1988; 296: 1135.
Society for the Study of Fertility (now the Society 84. Edwards RG. Tribute to Patrick Steptoe: beginnings of
for Reproduction and Fertility) (Britain), the Societe laparoscopy. Hum Reprod 1989; 4(Suppl): 1–9.
´Francaise pour l’Etude de la Fertilite´, and the Soci- 85. Edwards RG. Interviewed in: To Mrs. Brown a daugh-
ety for the Study of Reproduction (USA). Stud Hist ter. Peter Williams TV: The Studio, Boughton. Faver-
Phil Biol Biomed Sci 2007; 38: 340–57. sham, UK (see Supplementary Material), 1978.
62. Edwards RG. Letter to Cambridge University Regis- 86. Steptoe PC. Laparoscopy and ovulation. Lancet 1968;
trary, plus supporting documents, applying for the 292: 913.
Mary Marshall and Arthur Walton Professorship of 87. Hunting P. The history of the royal society of medi-
the Physiology of Reproduction. Edwards’ papers, cine. London, UK: The Royal Society of Medicine
6 Jan 1966. Uncatalogued, Churchill College Archive. Press Ltd, 2002.
1966. 88. Steptoe PC. Laparoscopy: diagnostic and therapeutic
63. Polge C. 1993. Obituary: Professor Thaddeus Mann. uses. Proc Roy Soc Med 1969; 62: 439–441.
The Independent, 9 December. 89. Steptoe PC. A new method of tubal sterilisation. In:
64. Short R. Colin Austin. Aust Acad Sci Newslett 2004; Westin B, Wiqvist N, eds. Amsterdam: Fertility and
60: 11. Sterility: Proc 5th World Congress June 16–22, 1966.
65. Arechaga J. Technique as the basis of experiment in Stockholm: International Congress Series no. 133,
developmental biology: An interview with Denis A.T. Excerpta Medica Foundation, 1967b: 1183–1184.
New Int J Dev Biol 1997; 41: 139–52. 90. Steptoe PC. Laparoscopic studies of ovulation, its
66. Edwards RG, Steptoe PC. Preface. In: Edwards RG, suppression and induction, and of ovarian dysfunc-
Purdy JM, Steptoe PC, eds. Implantation of the Human tion. In: Wood C, Walters WAW, eds. Fifth World
Embryo. London, UK: Academic Press, 1985: vii–viii. Congress of Gynaecology and Obstetrics, held in Syd-
67. Vickers AD. A direct measurement of the sex-ratio in ney, Australia, September, 1967. Butterworths, Syd-
mouse blastocysts. Reproduction 1967; 13: 375–6. ney, Australia, 1967c: 364.
68. Gardner RL. Bob Edwards – 2010 nobel laureate in 91. Steptoe PC. The fifth freedom. Br Med J 1966; 1: 234.
physiology or medicine. Physiology News 2011; 82: 92. Steptoe PC. Gynaecological endoscopy–laparoscopy
18–22. and culdoscopy. J Obstet Gynaecol Br Commonwealth
69. Gardner RL, Johnson MH. Robert Edwards. Hum 1965; 72: 535–43.
Reprod 1991; 6: iii–iv. 93. Morrison DL. Laparoscopy. BMJ 1967; 4: 34.
70. Edwards RG. Maturation in vitro of human ovarian 94. Austin CR. Observations of the penetration of sperm
oocytes. Lancet 1965a; 286: 926–929. into the mammalian egg. Aust J Sci Res B 1951; 4:
71. Edwards RG. Maturation in vitro of mouse, sheep, 581–96.
cow, pig, rhesus monkey and human ovarian oocytes. 95. Chang MC. Fertilizing capacity of spermatozoa depos-
Nature 1965b; 208: 349–51. ited into the fallopian tubes. Nature 1951; 168: 697–8.
72. Gardner RL, Edwards RG. Control of the sex ratio at 96. Bavister BD. Environmental factors important for in
full term in the rabbit by transferring sexed blasto- vitro fertilization in the hamster. Reprod 1969; 18:
cysts. Nature 1968; 218: 346–9. 544–545.
73. Theodosiou AA, Johnson MH. The politics of human 97. Edwards RG, Bavister BD, Steptoe PC. Did fertiliza-
embryo research and the motivation to achieve PGD. tion occur? Nature 1969a; 221: 981–2.
Reprod BioMed Online 2011; 22: 457–71. 98. Hayashi M. Fertilization in vitro using human ova. In:
74. Edwards RG. Are oocytes formed and used sequen- Proceedings of the 7th International Planned Parenthood
tially in the mammalian ovary? Phil Trans R Soc B Federation, Singapore. Excerpta Medica International
1970; 259: 103–5. Congress Series No. 72. Amsterdam, Netherlands, 1963.
xlii ROBERT EDWARDS

99. Petrov GN. Fertilization and first stages of cleavage of 109. Edwards RG, Steptoe PC, Purdy JM. Fertilization and
human egg in vitro. Arkhiv Anatomii Gistologii i cleavage in vitro of preovulatory human oocytes.
Embriologii 1958; 35: 88–91. Nature 1970; 227: 1307–9.
100. Petrucci D. Producing transplantable human tissue in 110. Steptoe PC, Edwards RG, Purdy JM. Human blasto-
the laboratory. Discovery 1961; 22: 278–83. cysts grown in culture. Nature 1971; 229: 132–3.
101. Rock J, Menkin M. In vitro fertilization and cleavage 111. Edwards RG, Sharpe DJ. Social values and research in
of human ovarian eggs. Science 1944; 100: 105–7. human embryology. Nature 1971; 231: 87–91.
102. Shettles LB. A morula stage of human ovum devel- 112. Helsinki Declaration, Human Experimentation: Code
oped in vitro. Fertil Steril 1955; 9: 287–9. of Ethics of World Medical Association. Br Med J
103. Yang WH. The nature of human follicular ova and fer- 1964; 2: 177.
tilization in vitro. J Jpn Obstet Gynecol Soc 1963; 15: 113. Hazelgrove J. The old faith and the new science.
121–130. the Nuremberg Code and human experimentation
104. Anon, 2008. Morris, Prof. Norman Frederick. In: Who ethics in Britain 1946–73. Soc Hist Med 2002; 15:
Was Who 1920–1980. A & C Black and Oxford Univer- 109–135.
sity Press. [Available from: http://www.ukwhoswho. 114. Pappworth MH. Human Guinea-Pigs. London, UK:
com/view/article/oupww/whowaswho/U28190]. Routledge and Keegan Paul, 1967.
105. Anon, 1969. New step towards test-tube babies. Nature- 115. Edwards RG. Fertilization of human eggs in vitro:
Times News Service; The Times 14 February, 1. morals, ethics and the law. Q Rev Biol 1974; 49: 3–26.
106. Holmes RF. Letter to D Kellaway, (Sec Fac Board Biol. B), 116. Jones A, Bodmer WF. Our Future Inheritance: Choice
dated 21 May. University of Cambridge Archives, 1968; or Chance? London, UK: Oxford University Press,
731.020. 1974.
107. Hankinson GS. Letter (G.B.6812.534) from the 117. Edwards RG, Steptoe PC. Birth after the reimplanta-
General Board of the Faculties, the Old Schools, tion of a human embryo. Lancet 1978; 312: 366.
Cambridge to RG Edwards detailing some aspects of 118. Johnson MH, Theodosiou AA. PGD and the making of
the Ford Foundation endowment fund, 20 December the genetic embryo as a political tool. In: McLean S,
1968. Edwards papers uncatalogued, Churchill Col- ed. Regulating PGD: A Comparative and Theoretical
lege Archive.1968. Analysis. London, UK: Routledge, 2011.
108. Steptoe PC, Edwards RG. Laparoscopic recovery of 119. Mulkay M. The embryo research debate: science and
preovulatory human oocytes after priming of ovaries the politics of reproduction. Cambridge, UK: Cam-
with gonadotrophins. Lancet 1970; 295: 683–9. bridge University Press, 1997.
32
Quality management in reproductive medicine
Christoph Keck, Cecilia Sjöblom, Robert Fischer, Vera Baukloh, and Michael Alper

INTRODUCTION including the referring physicians, the company’s suppli-

ers, and the company’s own employees are customers as
Although quality management (QM) in the healthcare
well. The individual elements of a quality management
industry is not a household term, quality management
system are developed to different degrees, always accord-
systems (QM systems) have become an integral manage-
ing to the tasks and the orientation of the particular insti-
ment tool in many IVF centers around the world. The
tution. They exist in varied, yet always definable
European Union Tissue Directive, issued in 2004, clearly
relationships, to one another. All of these elements and
demands a quality management system for any institu-
their interconnection as a whole enable a clinic or private
tion handling human gametes/embryos. The primary
practice to reach the expected and agreed results with the
concern of any healthcare system is, and will continue to
customer on a timely basis, and with an appropriate use
be, medical performance. However, if we regard health-
of resources. The sum of directive elements and elements
care systems as “corporations” dealing with patients,
that transcend or relate to the process is called the “qual-
referring doctors, and employees, in addition to medical
ity management system” of a clinic or a private practice.
performance, then other qualities will have to be taken
Of all the medical fields, reproductive medicine has led
into consideration. More and more hospitals as well as
the way (in Europe) with the introduction of QM systems
independent medical practices will have to document
over the past several years. In this chapter, different QM
the quality of their services to their patients and cost-
systems are described, the instruments of these systems
bearers. This will mean that strict procedures for docu-
are discussed, and the question of how QM systems con-
mentation of results will be needed and, furthermore,
tribute to success in reproductive medicine is addressed.
medical institutions will have to answer the question of
whether or not they provide their services in
a cost-effective way. Many rules (such as the measures for DIFFERENT QUALITY MANAGEMENT SYSTEMS
limiting the spread of infections and the statute on pro-
tection against radiation) are set by law. However, beyond In the past, a series of specific QM systems for various
these rules, many medical institutions currently develop industries have come into existence worldwide. In 1964,
their own internal standards. These standards are often the Good Production Practice [World Health Organiza-
only informally documented and, most of the time, are tion (WHO) directive] was developed for the pharmaceu-
fragmentary. Although it is not always obvious, these tical and food industries. The Good Laboratory Practice
standards can affect and direct the internal workings of [Organization for Economic Cooperation and Develop-
the organization and the interaction of various areas ment (OECD) directive] followed in 1978 and the Hazard
within the company. They may also affect the interaction Analysis of Critical Control Points (National Advisory
of the company with external partners. With internal sys- Committee on Microbiological Criteria for Foods direc-
tems such as these, enormous differences can exist from tive) in 1992. The EU with its “Global Concept” (1985)
one system to another with respect to the importance and strongly promoted the development of QM systems and
validity of various sections and procedures. The Joint expanded them to production and services, which there-
Commission on Accreditation of Health Care Organiza- fore covered the documentation of ecologically justifi-
tions calls these elements of quality management “func- able dealings in energy, material, and waste.
tions.” One can show that these “functions” differ from
one institution to another, no matter whether or not they
ISO 9001 Standards
are applied in clinics or private practices, group or single
provider practices, or government medical institutions. The systems that followed – the manuals of the Interna-
Essential elements are identifiable and applicable to tional Standardization Organization (ISO 9000 series) –
every institution that aims at fulfilling the wishes and became the most widespread, worldwide standard. In
demands of its customers. It is not only patients who are the 1980s, the ISO created regulations for QM systems
considered “customers,” but all communication partners, with the standard series 9001 through 9004 developed
2 TEXTBOOK OF ASSISTED REPRODUCTIVE TECHNIQUES: CLINICAL PERSPECTIVES

for the production of goods and services. These manuals nurses. Treatment can only be successful when
described the basic elements of the QM system in a rela- a structured interaction exists between the clinical and
tively abstract manner. Medical institutions were laboratory departments. ISO 9001:2000 (3) is very much
required to adapt these standards to suit them and this concentrated on a process approach and directed to the
required some interpretation and modification. The outcome of the process; i.e., the products or services
introduction of ISO 9000 states: “The demands of the meet the previously determined requirements. Since
organizations differ from each other; during the creation this does not necessarily assure that a laboratory will be
of quality management systems and putting them into successful, or that it will achieve the highest level of
practice, the special goals of the organization, its prod- care for the patients that it serves, assisted reproduction
ucts and procedures and specific methods of acting technique (ART) laboratories may also want to consider
must be taken into consideration unconditionally.” additional requirements, including standards concern-
This means that, for medical applications, the standards ing qualification and competence. Relevant standards
state which elements should be considered in the QM are provided by the ISO/IEC 17025:1999 (4) (IEC being
system, but the manner in which these elements should the International Electrotechnical Commission). This
be realized in the specific medical organization have to standard, entitled “General requirements for the compe-
be defined individually. The ISO standards have now tence of testing and calibration laboratories,” replaces
been adapted to medicine, which is fortunate since both the ISO/IEC Guide 25 (5) and the European stan-
there is no QM system specifically designed for hospi- dard EN 45001 (6). Compliance with the ISO 17025
tals or medical practices. ISO 9001 through 9003 stan- standard can lead to accreditation (defined as “a proce-
dards contain the elements important for a quality dure by which an authoritative body gives formal recog-
system (Table 32.1). The criteria according to which nition that a body or person is competent to carry out
QM systems are applied vary with the type of enter- specific tasks”), which exceeds certification (defined as
prise. For example, the 9001 standard is applicable to “a procedure by which a third party gives written assur-
the manufacturing and complicated service companies ance that a product, process or service conforms to spe-
including hospitals. On the other hand, the 9002 stan- cific requirements”). ART laboratories should consider
dard is more suitable for rehabilitation and foster-care ISO 17025 accreditation (see chap. 3). However, one
institutions (1). The application of a certified QM sys- should realize that both ISO/IEC Guide 25 and EN 45001
tem for hospitals can be performed on the basis of ISO are focused more on the technical aspects of compe-
9001 or ISO 9004 (2). As mentioned earlier, in vitro fer- tence, and do not cover all areas within clinical labora-
tilization (IVF) units occupy a special place within clin- tories. It has already been stated that although the ISO
ical medicine. It is a highly specialized area involving standards are the most widely accepted standards in the
the interaction of staff in various areas, including the world, there is no appropriate international standard for
laboratory, ultrasound, administration, physicians, and laboratories in the healthcare sector. To fill this “vac-
uum,” several professional associations and laboratory
organizations have also framed and published stan-
dards and guidelines, most of which are confined to
a specific clinical laboratory discipline. Some specific
Table 32.1 Elements/Criteria of the ISO Standard and relevant examples of guidelines for ART laborato-
ries commonly available are: (7–10).
Number Quality element according to ISO 9000 ff.
1. Guidelines for human embryology and andrology
1 Responsibility
2 Quality management system
laboratories, the American Fertility Society, 1992.
3 Contract control 2. Guidelines for good practice in IVF laboratories,
4 Design management the European Society of Human Reproduction and
5 Document and data management Embryology (ESHRE), 2000.
6 Measures 3. Reproductive laboratory accreditation standards,
7 Management of products provided by customers College of American Pathology, 2002.
8 Designating and retrospective observation 4. Accreditation standards and guidelines for IVF labo-
9 Process management
ratories, the Association of Clinical Embryologists,
10 Revision
2000.
11 Control of the revision resources
12 Evidence of revisions
13 Defective product management The above-mentioned guidelines and standards describe
14 Corrections and preventive measures the specific requirements for reproductive laboratories,
15 Handling, storage, packaging, conservation, and include various aspects of the implementation of a
distribution QM system. These well-defined standards describe the
16 Quality report management minimum conditions that should be met by laboratories/
17 Internal quality audits clinics. Recently, the EU Tissue Directive (11) has been
18 Training released, which demands a quality QM system for every
19 Maintenance
medical institution dealing with human gametes or
20 Statistical methods
embryos.
 QUALITY MANAGEMENT IN REPRODUCTIVE MEDICINE 3

TQM and EFQM QUALITY POLICY

There is a wide range of quality management models and One of the first steps for the implementation of a QM
strategies based on continuous improvement. Two of the system in medical institutions is to define the quality
best-documented models/strategies are Total Quality policy. Quality policies are a group of principles that
Management (TQM) and the Excellence Model of the establish the workings of the institution. Although suc-
European Foundation for Quality Management (EFQM). cessful treatment of an existing disease or reduction of
Total Quality Management is an all-encompassing con- discomfort is certainly the highest priority for most med-
cept that integrates quality control, assurance, and ical institutions, it might be an important goal to achieve
improvement. It is more a philosophy than a model. The this in the most efficient manner possible. This means
basics of this concept were developed after World War II that structure is needed to assure that diagnostic and
by Deming. Both the TQM and the EFQM models incor- therapeutic procedures are performed using as little
porate the objective of continuously striving to improve financial, organizational, personnel, or time resources as
every aspect of a service, and require continuous scrutiny possible, while still striving for a high quality of treat-
of all components of the quality management system of an ment. After all, optimum quality is achieved by the
organization. Measurement and feedback are crucial ele- “right” balance of cost with quality achievement. The
ments in quality management. This can be illustrated by quality policy of a medical institution cannot be defined
the so-called Deming cycle (“Plan–Do–Check–Act” cycle) by a single person (e.g., the owner or medical director),
(Fig. 32.1). Important elements of a TQM program are: but should be developed as a consensus between man-
agement and employees. Only in this way will person-
1. Appropriately educated and trained personnel with nel identify with the quality policy of the institution. A
training records. quality policy should be formulated in an active manner
2. Complete listing of all technical procedures per- and the formulation should also be short and simple so
formed. that every employee can repeat the quality policy at any
3. Housekeeping procedures: cleaning and decontam- time. The most important aspects of the quality policy
ination procedures. should be posted in suitable and accessible areas of the
4. Correct operation, calibration, and maintenance of institution for employees, patients, and visitors, to
all instruments with manuals and logbook records. strengthen the employees’ knowledge of common goals,
5. Proper procedure policy and safety manuals. improve their identification with their own fields of
6. Consistent and proper execution of appropriate competence, and communicate these principles to oth-
techniques and methods. ers. It is important to state that quality policies should
7. Proper documentation, record keeping, and report- be reviewed periodically to make sure that the princi-
ing of results. ples are still valid and that management and employees
8. Thorough description of specimen collection and still agree with them. As an organization’s perspectives
handling, including verification procedures for and goals change, the quality policy needs to be modified
patient identification and chain of custody. accordingly.
9. Safety procedures, including appropriate storage of
materials.
10. Infection control measures. MANAGEMENT’S RESPONSIBILITY
11. Documentation of suppliers and sources of chemi-
In spite of the fact that the responsibility of management
cals and supplies, with dates of receipt/expiry.
(or the governing structure) can be defined differently in
12. System for appraisal of test performance correction
various medical institutions, according to ISO standards,
of deficiencies and implementation of advances
certain generally valid aspects can be defined. The hierar-
and improvements.
chy of the institution has to be defined and outlined
13. Quality materials, tested with bioassays when
clearly. While, in most cases, hospitals are administered
appropriate.
by an appointed director, the structure might be more dif-
14. Quality assurance programs.
ficult in private centers with multiple partners in equal
positions. In such cases, an agreement that describes the
division of responsibilities for particular fields among the
Plan for improvement
4 partners must be in place and in these cases several pos-
1
sibilities are available. For example, it is possible to place
Plan specific responsibilities permanently under the authority
of one of the partners (e.g., personnel development/
Continuation or Act Do Performance of plan
adjustment accounting/billing, etc.). However, for many privately
Check held practices, a model of dividing these tasks on a rota-
tional basis has been successful; i.e., dividing the respon-
3 sibility for various fields equally among all of the partners
Assessment of realization 2
(in leadership positions) so that all partners are familiar
AUDITS with the different responsibilities. The picture becomes
Figure 32.1 Total quality management (TQM): the Deming cycle. far more complex if there are many administrative layers
4 TEXTBOOK OF ASSISTED REPRODUCTIVE TECHNIQUES: CLINICAL PERSPECTIVES

Nursing care Department head Administration

Patient Staff Research Administration

Reception Laboratory
care physicians group and billing

Gynecologic
Blood-drawing, IVF laboratory, Secretaries,
office visits,
intraoperational, andrologic billing,
andrologic
and hospital care laboratory medical records Figure 32.2 Organizational diagram. Abbre-
office visits
viation: IVF, in vitro fertilization.

to the organization and it is here that clear descriptions of because of an organizational problem such as a substan-
authority for all positions within the organization are dard secretarial or administrative problem rather than a
required and must be available to everyone within the medical deficiency. Even with properly working medical
organization. The more complex the hierarchic structures treatment, poor communication with colleagues can
within a medical institution are, the more precisely these endanger or directly destroy the positive result of the
structures have to be defined for the system to work effec- treatment. When establishing a QM system, it is neces-
tively and robustly at all times and under all (extraordi- sary to precisely define and describe all relevant pro-
nary) conditions. The “decision” of the head of the cesses and to structure them according to QM guidelines.
organization must be available at any time, even if he or These descriptions are often best realized by flow dia-
she is absent. Therefore, this must be absolutely clear to grams that can overlap in various places. These areas of
everyone within the organization who has the compe- contact between two flow diagrams are called “boundar-
tence and authority to make decisions. It is also impor- ies, interferences, joints, or areas of juncture.”
tant for all partners outside of the company to be aware of
who the decision makers are for various tasks. There are
Documentation in a QM System
various ways of making these structures as transparent as
possible. One easy way is the development of an organi- In addition to defining the processes relevant for the sys-
zational diagram (Fig. 32.2). This organizational diagram tem, it is important for everything to be documented. The
can be placed in a suitable and accessible location, help- different levels of documentation are shown in Figure
ing employees to understand everyone’s roles and respon- 32.3. One of the most important documents in a QM sys-
sibilities. Furthermore, making the organizational tem is the quality manual. The main purpose of the quality
diagram available to everyone strengthens trust, coopera- manual is to outline the structure of the documentation
tion, and professionalism within the company. It is also used in the quality system (12). It should also include or
important in communication with patients, interested refer to the standard operating procedures (SOPs). There
parties, or cooperating departments. The organizational should be clear definitions of the management’s areas of
diagram should be updated frequently. Management responsibility, including its responsibility for ensuring
should strongly support the quality policies for the com- compliance with the international standards on which the
pany, and should take an active part in its development system is built. A simple overview of the quality system
and implementation. It is important to lead by example. requirements and the position of the quality manual are
shown in Figure 32.3. A good-quality manual should be
precise and brief; it should be an easily navigable hand-
MANAGEMENT OF PROCESSES
book for the whole quality system. The most important
Processes are all the procedures that are necessary for the procedures are preferably included in the manual itself,
completion of tasks. For medical facilities, the most but deeper descriptions should be referred to in the under-
important processes are those of diagnostic and thera- lying documentation. An easy way to start building a sys-
peutic procedures. In addition, many other processes are tem is to make up a table of contents for the quality manual
involved in the care of patients, such as the scheduling of and to decide which processes should be described in the
patients for tests, communication, and anything else that manual and which should rather be described in the
may greatly affect the patient’s (= customer’s) perspec- underlying documentation (e.g., SOPs). Whereas the qual-
tive. Sometimes poor communication can ruin a patient’s ity manual contains more general information, the indi-
experience, despite the best diagnostic procedures within vidual processes and procedures are described in a more
the organization. In fact, it is our observation that it is detailed way in handbooks/job instructions or SOPs.
more likely that a patient will leave a medical facility These SOPs go through the processes step-by-step and
 QUALITY MANAGEMENT IN REPRODUCTIVE MEDICINE 5

Level 1

Quality Defines approach and responsibility

manual
Level 2
Procedures
Defines Who? What? When?

Level 3
Job instruction
SOPs Answers How?

Results and other Level 4

documentation Figure 32.3 Levels of documentation. Abbreviation:
Shows the system is operating
SOP, standard operating procedure.

describe the materials and methods used and the way the 5. Where can I find the document: physical location,
process is performed precisely. Standard operating proce- level in the system, and on computer file?
dure manuals should be available to all personnel and 6. Who assures that only the latest issue of the docu-
every single procedure in these manuals must be fully ment is present in the system, removes outdated
documented with signature, date, and regular review. issues, and files them?
7. Are amendments to documents clearly marked, ini-
tialled, and dated?
Document Control 8. How are changes in a document implemented with
According to ISO 9001:2000 4.2.3, the clinic should estab- the personnel?
lish and maintain procedures to control all documents that
form part of its quality documentation. This includes both
Documentation of Results
internally generated documentation such as SOPs and pro-
tocol sheets, and externally generated documentation such A very important level of documentation is that of the
as law texts, standards, and instruction manuals for equip- “results.” This includes not only the results of treatment
ments. Document handling and control are an important such as pregnancy rate per treatment cycle, but also all
part of the quality system and, if not designed properly, can documents referring to:
become a heavy load for a smooth running system. Since it
is something that touches every part of the system, it is 1. Control of quality records,
important to sit down and think through how this system of 2. Internal audits,
paperwork shall be handled in your clinic and to ensure 3. Control of nonconformity,
that the system you choose covers the demands of the stan- 4. Corrective and preventive action.
dards. The identification of the documents should be logi-
cal, and it is a good suggestion to use numbers as unique Incubators are one of the most important pieces of
identifiers. The same identification number could then be equipment in the IVF laboratory and need to be con-
used for the file name within the computerized version. The trolled properly. Two markers of incubator performance
issue number in parentheses or after a dash could follow are the temperature and the CO2 level. These two param-
this number. Pagination is important. If you choose not to eters are documented on the control cards, and upper
use pagination, you must clearly mark where the document and lower limits of tolerance are defined to determine
starts and ends. The dates of issue together with informa- when corrective actions are needed (Fig. 32.4). It is use-
tion on who wrote the document and who approved it (sig- ful to plot results of system checks on a graph, so that
nature) are usually included in the document header. there is a clear visual image that can monitor:
Questions that should have an answer in your document
control system: 1. Dispersion: Increased frequency of both high and
low numbers.
1. Is all documentation in the laboratory or clinic cov- 2. Trend: Progressive drift of reported values from
ered by your document control system? a prior mean.
2. Who writes or changes the document? 3. Shift: An abrupt change from the established mean.
3. Who approves and has the authority to issue docu-
ments? If nonconformity to the standard is diagnosed, it is
4. Does the document have important to collect data on:
a. A unique identification?
b. Issue number and current revision status? 1. When the problem was realized.
c. Date of latest issue? 2. How often the problem could be identified.
d. Pagination? 3. How conformity to the standards could be reassured.
6 TEXTBOOK OF ASSISTED REPRODUCTIVE TECHNIQUES: CLINICAL PERSPECTIVES

37.4°C
OG
5.2% CO2 37.2°C = upper
action
limit
5.0% CO2 37.0°C

UG
4.8% CO2 36.8°C
= lower
action
5.2% CO2 36.4°C limit

Figure 32.4 Monitoring temperature and CO2

1
2
3
4
5
6
7
8
9
10

25
26
27
28
29
30
31
37.4°C
levels in an incubator.

Audits and Management Reviews of the clinic with executive responsibility shall periodi-
cally conduct a review of the quality system and testing
Audits are essential to ensure that a quality system is
activities. The quality manual shall include a written
working. Audits can be internal, initiated by the organiza-
agenda for these reviews, which should fulfill the
tion itself, or external, initiated by a governing body, certi-
demands in the standard.
fication, or accreditation body. ISO 9001:2000 8.8.2 lays
out the rules for internal audits and demands that the
clinic undertakes internal audits at planned intervals to INCIDENTS AND COMPLAINTS
determine how well the system is functioning and if it is
All clinics should have a policy and procedure for the
effectively implemented and maintained. Audits are tools
resolution of incidents and complaints received from
for improving and keeping your system up to date with the
patients, clients, and/or other parties. The routines of
standards and it is the quality manual that should include
how these are filed and how corrective actions are taken
specific instructions covering both how and how often
should be documented in a clinic’s quality manual.
they shall be performed. The management usually chooses
When applying a quality system it is important not to
internal auditors, and they should be familiar with both
hide these incidents and complaints, but to use them as
the standards and the activities performed in the clinic.
resources to improve the system. The management
The manual should include a document describing the
reviews should ensure that the incidents and complaints
approach and the areas of responsibility for the internal
lead to long-term corrections and improvements in the
auditors and have well-documented procedures for how
quality of work.
internal auditors are trained. To achieve a certification
according to ISO 9001:2000, the clinic needs to be audited
externally by a certification body. Many organizations STAFF MANAGEMENT
believe that having an audit and not finding any noncon-
formities is a proof of an outstanding performance. How- High-quality treatment can only be realized with quali-
ever, the other possibility is that it could be due to an fied staff. Therefore, recruitment, training, and motiva-
inadequate audit procedure. If an audit is properly con- tion of highly qualified people are the most important
ducted, even in organizations with outstanding perfor- tasks for the management team of an organization. To
mance, areas for improvement will be found; therefore, make sure that a sufficient number of qualified people are
people should put in a lot of effort to find the right certifi- working within the respective areas of the institution,
cation body to undertake the audits. Some questions that a staff requirement plan should be developed. This can
might help to identify a good certification body are: be organized in different ways:

● Are they accredited to certify medical institutions? 1. Allocating people according to their abilities.
● Have they previously certified IVF clinics and how 2. Allocating people according to different responsibil-
many? ity levels.
● Do they have IVF experts on their audit team? 3. Allocating people according to the type of work that
● How much time do they allocate to the audit? has to be done.

While to some it may seem obvious, it is important to In most medical institutions it is recommended to define
mention, especially with respect to the factors above, that the levels for which the number of staff should be planned.
the cheapest certifying body is not necessarily the best. Thus, the leading level (management) and other levels
Together with the audits, the management review is (which can be further divided according to qualification)
important for improvement of the system and for the are defined. The number of employees should be deter-
long-term correction of errors and incidents that might mined, for particular fields, according to their tasks and
occur. According to ISO 9007:2000 5.6, the management the range of treatments. This is why a regulation for the
 QUALITY MANAGEMENT IN REPRODUCTIVE MEDICINE 7

equalization of staff must be created. This system makes or with regard to the abilities of the entire institution,
planning easier, and emphasizes the qualifications and, educational activities should be evaluated and analyzed
for instance, the procedure of substitution. The develop- at regular intervals. For example, at the beginning of each
ment of work descriptions is crucial for this system. They year, the employee should decide which educational
must be created for particular posts, and must state, among events he or she would like to visit or take part in. This
other things, at which post a given employee works, what helps the management to introduce new fields of activity,
his or her qualification is, and which qualification attri- and also allows them to perform advance planning of the
butes are required. In addition to this formal information, specialization. It is striking to see that, in most ART cen-
the work description should also contain information ters, detailed and prospective plans have been developed
about the employee’s personal attributes. For various for the training of medical doctors, but far less attention
posts, different qualities are important: has been paid to the training of nurses, technicians, etc.
However, a well-trained nurse can significantly reduce
1. Social competence the workload for the doctor and tremendously increase
2. Organizing abilities the patient’s trust in the institution while also improving
3. Communication abilities, etc. the referring doctor’s satisfaction.
Therefore, besides training activities for the doctors,
The staff requirement plan must be set up so that it is adequate educational events for nurses and technicians,
possible to react sufficiently to unexpected situations. etc., should be considered.
Furthermore, it must consider staff absenteeism caused
by holidays, illness, and further education. A minimal
Interaction between Management and Employees
presence of employees must be determined for certain
fields, which does not depend on the actual workload. Success in reproductive medicine clearly depends on an
For the development of a staff requirement plan for an optimal interaction between different professional
IVF center, the medical as well as the nonmedical areas groups: i.e., success can be achieved only if doctors
have to be defined and considered. The question of how communicate and work together with staff in the labora-
many people are needed to do the job properly can be tory, nurses, receptionists, etc. The same is true for the
answered on the basis of calculating the “influence mag- interaction between management and employees. Com-
nitudes.” The type of services offered strongly influences munication and collaboration between different profes-
the number of people required. Thus, the staff require- sional groups of the same hierarchic rank is called
ments are different in a center in which predominantly “horizontal” communication, whereas communication
conservative treatments and intrauterine inseminations and collaboration between professional groups of differ-
are performed, compared with a center in which predom- ent hierarchic ranks is called “vertical” communication.
inantly IVF/intracytoplasmic sperm injection (ICSI) and One of the most important instruments to optimize verti-
cryopreservation cycles are performed. cal communication is the “staff interview.” The staff
interviews should occur periodically. At these inter-
views the empolyees and their direct superiors discuss
Training of Employees
their collaboration and identify areas for improvement.
One of the most important principles for the manage- The interview should take place in a structured way and
ment of a medical institution is: “Give your employees a protocol should be written and signed by both sides,
the chance to be the best.” This means that if you expect so that the content of the interview is assigned some
your employees to do their work at the highest quality kind of formal character. However, details of the inter-
level possible, you should give them proper training. In view can never be communicated with others without
principle, there are two different types of educational mutual consent. For the employee, the goals/opportuni-
events: ties of the interview are:

1. Internal events of further education 1. To become familiar with the goals of the department,
2. External events of further education (i.e., conven- 2. To realize weaknesses and strengths,
tions, conferences, workshops, etc.). 3. To be able to discuss own experiences/opinions on
the management style,
The advantage of internal events of further education 4. To discuss further strategies for professional devel-
is that they can be offered on a regular basis and are usu- opment,
ally “low-budget projects,” whereas external events need 5. To participate in planning goals/strategies for the
more organizational and financial input. However, when future.
carefully planned, external educational events some-
times have a higher motivational aspect. So the manage- For the superior, the goals/opportunities of the
ment team should take care to offer a balanced program interview are:
of internal and external educational events. To make it
possible to use the clinics’ resources adequately and to 1. To discuss the coworker’s performance,
estimate and plan the potential of development with 2. To focus the activities of the employee on future
regard to the individual abilities of particular employees goals of the institution,
8 TEXTBOOK OF ASSISTED REPRODUCTIVE TECHNIQUES: CLINICAL PERSPECTIVES

3. To increase mutual understanding in the event of QM system. ART practitioners in particular have the
problems, unique opportunity to set the standard in medicine for
4. To increase the employee’s responsibility, quality management principles.
5. To get feedback on his/her management skills.
SUGGESTED READING
For the above-mentioned reasons, the staff interview is
one of the most important and powerful tools in staff Alper MM, Brinsden PR, Fischer R, Wikland M. Is your
development, and should be widely used in the process IVF programme good? Hum Reprod 2002; 17: 8–10.
of continuous improvement. American Society for Reproductive Medicine. Revised
minimum standards for in vitro fertilization, gamete
intrafallopian transfer and related procedures. http://
The EU Tissues and Cells Directive
www.asrm.com/media/practice/revised.html (1998)
The increase in use, donation, and storage of human tis- Bloor G. Organisational culture, organisational learning
sue has led to the creation of directives from the Euro- and total quality management: a literature review
pean Council. In March 2004, the European parliament and synthesis. Aust Health Rev 1999; 22: 162–79.
issued a new version of the directive on setting standards Bron MS, Salmon JW. Infertility services and managed
of quality and safety for the donation, procurement, test- care. Am J Manag Care 1998; 4: 715–20.
ing, processing, preservation, storage, and distribution of Brown RW. Errors in medicine. J Qual Clin Pract 1997;
human tissues and cells. When these directives were 17: 21–5.
issued, there was a need to adapt the requirements to the Carson BE, Alper MM, Keck C. Quality management sys-
actual setting of an IVF laboratory. However, in the mean- tems for assisted reproductive technology. London:
time, these directives have been implemented by many Taylor and Francis, 2004.
IVF centers around the world and a position paper has Clancy C. AHRQ: coordinating a quantity of quality.
been issued by the ESHRE outlining how these directives Healthplan 2003; 44: 42–6.
should be applied. Independent of this position, paper Collings J. An international survey of the health economics
authorities in each country interpret the directive differ- of IVF and ICSI. Hum Reprod Update 2002; 8: 265–77.
ently, which makes it difficult to share experiences Colton D. The design of evaluations for continuous
between centers in different countries. Furthermore quality improvement. Eval Health Prof 1997; 20:
auditing processes need to be adapted from country to 265–85.
country. Darr K. Risk management and quality improvement:
The main differences between the countries concern together at last – Part. Hosp Top 1999; 77: 29–35.
requirements for (1) air quality (2) frequency of screening Garceau L, Henderson J, Davis LJ, et al. Economic impli-
of patients, and (3) staff training. cations of assisted reproductive techniques: a sys-
However, the central part of the EU directive is very tematic review. Hum Reprod 2002; 17: 3090–109.
clear, concerning the demand for a quality system. There- Geraedts HP, Montenarie R, Van Rijk PP. The benefits of
fore the directive states that “Tissue establishments shall total quality management. Comput Med Imaging
take all necessary measures to ensure that the quality sys- Graph 2001; 25: 217–20.
tem includes at least the following documentation: stan- Glattacker M, Jackel WH. [Evaluation of quality assur-
dard operating procedures, guidelines, training and ance – current data and consequences for research].
reference manuals.” Certainly by achieving accreditation Gesundheitswesen 2007; 69(5): 277–83.
to either ISO17025 or ISO15189 this demand will be Gondringer NS. Benchmarking: friend or foe. AANAJ
fulfilled together with several other demands of the 1997; 65: 335–6.
directive. Greenberg L. Accreditation strengthens the disease man-
agement bridge over the quality chasm. Dis Manag
2003; 6: 3–8.
CONCLUSIONS
ISO/DIS 15189:2:2002. Medical Laboratories – Particu-
No internationally accepted standards exist for quality in lar requirements for quality and competence.
the IVF laboratory and the IVF center as a whole. To Geneva: International Standardization Organiza-
assure high quality and continual improvement, it is rec- tion, 2002.
ommended that all IVF centers striving for excellence Matson PL. Internal quality control and external quality
should consider a QM system. Furthermore, legal guide- assurance in the IVF laboratory. Hum Reprod 1998;
lines and the recently released EU Tissue Directive 13(Suppl 4): 156–65.
clearly demand a QM system for medical institutions. A Minkman M, Ahaus K, Huijsman R. Performance
QM system allows the organization to gain control of its improvement based on integrated quality manage-
documents and procedures and to monitor the clinical ment models: what evidence do we have? A system-
and nonclinical outcomes. Furthermore, the issues of atic literature review. Int J Qual Health Care 2007;
staff recruitment and staff development can be addressed 19(2): 90–104.
systematically and thereby, again, the overall outcome Sackett DL, Rosenberg WMC, Gray JAM, et al. Evidence
will be improved. The ISO standards offer the medical based medicine: what it is and what it isn’t. Br Med J
facility access to an internationally endorsed and proven 1996; 312: 71–6.
Exploring the Variety of Random
Documents with Different Content
The Project Gutenberg eBook of The Craft of
Athenian Pottery
 This ebook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this ebook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.

Title: The Craft of Athenian Pottery

Author: Gisela M. A. Richter

Release date: August 31, 2020 [eBook #63091]

Most recently updated: October 18, 2024

Language: English

Credits: E-text prepared by ellinora and the Online Distributed

Proofreading Team (http://www.pgdp.net) from page
images generously made available by Internet Archive
(https://archive.org)

*** START OF THE PROJECT GUTENBERG EBOOK THE CRAFT OF

ATHENIAN POTTERY ***
 The Project Gutenberg eBook, The Craft of Athenian Pottery, by
Gisela M. A. (Gisela Marie Augusta) Richter

Note: Images of the original pages are available

through Internet Archive. See
https://archive.org/details/gri_33125000024550

Some characters might not display in this html

version (e.g., empty squares). If so, the reader
should consult the original page images noted
above.

THE METROPOLITAN MUSEUM

OF ART
PUBLICATION OF
THE COMMITTEE ON EDUCATION
THE CRAFT OF ATHENIAN POTTERY
BY GISELA M. A. RICHTER
 OF THIS BOOK
500 COPIES WERE PRINTED
IN MAY 1923
500 ADDITIONAL COPIES
WERE PRINTED
IN MARCH 1924

THE METROPOLITAN MUSEUM

OF ART

THE CRAFT OF
ATHENIAN POTTERY
AN INVESTIGATION OF THE
TECHNIQUE OF BLACK-FIGURED AND
RED-FIGURED ATHENIAN VASES

BY
GISELA M. A. RICHTER, Litt.D.
ASSOCIATE CURATOR, DEPARTMENT OF CLASSICAL ART
 NEW HAVEN
YALE UNIVERSITY PRESS
LONDON · HUMPHREY MILFORD · OXFORD UNIVERSITY PRESS
MDCCCCXXIV

COPYRIGHT 1923 BY THE

METROPOLITAN MUSEUM OF ART

PRINTED IN THE UNITED STATES OF AMERICA

 CONTENTS

Page

List of Illustrations vii

Preface xi

Chapter I. Technical Processes in the Making of Modern

Pottery and their Application to the Technique of
Ancient Vases 1
Preparation of the Clay 1
Ingredients and Properties 1
Washing 2
Wedging 2
Fashioning the Vases 4
(1) Wheelwork 4
Types of Wheel 4
Throwing 7
Turning 10
Work in Sections 15
Polishing 19
Attachment of handles 20
(2) Building 26
(3) Moulding 27
Firing the Vases 29
Production of Temperature 29
Types of Kilns 32
Packing the Kiln 34
Firing 35
Number of Firings 37
Injuries in the Firing 44
Glazing 47
Red Ochre Wash 53
 Were Athenian Vases Made for Every-Day
Use? 59

Chapter II. Representations of Ancient Potters 64

Fashioning the Vases 64
Decorating the Vases 70
Firing the Vases 75
Miscellaneous Scenes 78
Representations Wrongly Interpreted as
Pottery Scenes 83
Potter’s Implements 84

Chapter III. References to the Pottery Craft in Ancient

Literature 87
Preparation of the Clay 87
Fashioning the Vases 89
(1) Wheelwork 89
(2) Building 93
Firing the Vases 94
Red Ochre Wash 96
Porosity of Greek Pottery 98
The Status of Potters 98

Conclusion 106

Selected Bibliography 109

Index 111
 ILLUSTRATIONS
Figure Page
1. Wedging (a) 3
2. Wedging (b) 4
3. Kick-wheel with treadle 5
4. Kick-wheel with disk 6
5. Wheel put in motion by assistant turning
handle 6

Processes of throwing:
6. Centering ball 7
7. Pressing clay down 7
8. Squeezing clay into cone 7
9. Inserting thumb 7
10. Making cylinder 8
11. Making bowl 8
12. Making jar 8
13. Making bottle 8

14. Turning a vase 10

15. Turned foot 11
16. Foot left as thrown 12
17. Turning marks on outside of vase 13
18. Turning marks on inside of vase 13
19. Finishing marks left in handwork 14
20. Unturned inside of amphora 15
21. Vase thrown in sections 16
22. Sections in place 17
23. Vase after turning 17
24. Wet cellar 18
 25. Detail of kylix showing joint 19
26. Detail of amphora showing difference between
polished and unpolished surfaces 20
27. Attachment of handles 21
28-33. Athenian vases showing treatment of handles 22, 23, 24
34. Detail of krater showing under part of handle
left rough 25
35. Making coils 26
36. Vase poured in a mould 28
37. Inside of moulded vase 29
38. Vase showing joint of two parts of mould 30
39. Open kiln 31
40. Muffle kiln with biscuit ware 32
41. Open kiln showing saggers 33
42. Muffle kiln with glazed ware 34
43. Detail of amphora showing preliminary sketch 37
44. Design on red-figured krater.
(a) Preliminary sketch 38
(b) Completed painting 38
45. Detail of hydria showing dent with mark over
black glaze 41
46. Detail of amphora showing dent with clay from
other body still adhering 42
47. Unfinished kylix 43
48. Foot of unfinished kylix 43
49. Black-glazed amphora with large red spot on
one side 46

Methods of Glazing:
50. Dipping 48
51. Pouring 49
52. Use of the brush 50
53. Spraying 51
 54. Hydria showing brush marks 52
55. Detail of psykter showing relief line 53
56. Detail of amphora showing diluted black glaze
line (on arm) going over red ochre left in
preliminary sketch line 57
57. Inside of krater showing extensive wear 63

Representations of ancient potters fashioning vases:

58. Athenian pottery establishment 64
59. Potter throwing 66
60. Potter throwing 66
61. Potter attaching handles 67
62. Potter incising lines (?) 68
63. Potter joining sections (?) 68
64. Boy finishing a vase 69
65. Potter building a vase 70

Representations of ancient potters decorating vases:

66. Athena and Victories crowning potters at work 71
67. Youth decorating kylix 72
68. Potter glazing kylix 73
69. Potter painting bands on a krater 73
70. Three youths, one painting a krater 74
71. Pottery establishment 75

Representations of ancient potters firing:

72. Potter stoking fire 76
73. Potter stoking fire 76
74-79. Potters regulating draught 77
80. Vases stacked in potter’s kiln 78

Representations of ancient potters: miscellaneous scenes:

81. Youth removing vase from oven with two
sticks 79
 82. Youth working on vases (?) 79
83. Master potter(?) 80
84. Woman potter(?) 81
85. Client in potter’s shop 82
86. Ship with cargo of pottery 82

Potter’s Implements:
87. Wheel-head 84
88. Tools found at Arezzo 85
89. Stilt 85
 PREFACE

F
or our knowledge of the technique of Athenian vases we have
various sources of information. There are a number of references
to the craft in ancient literature; we have several actual
representations of potters at work among extant vase paintings; and
there is the important testimony of the vases themselves. The
information gleaned from these three sources has been duly worked
over by archaeologists, and the many accounts we have of the
technique of Greek vases are all based more or less on this
evidence. There is, however, another very important source of
information ready to our hand which has not been fully utilized,
namely, the study of the technical processes employed in the making
of modern pottery. For, the nature and properties of clay being the
same now that they were in Greek times, the manner of working it
must have been essentially the same then as now. Many
archaeologists have, of course, seen potters at work in different
places, or perhaps consulted potters on specific points; but that is a
different thing from getting a thorough knowledge of the craft
oneself and learning once for all what is possible and what is not
possible in clay-working.
The neglect of this highly valuable source of information has led to
some surprising theories regarding the technique of Greek vases;
and these theories have been repeated over and over again in our
books on vases, for the simple reason that, not having any first-hand
knowledge, we have copied these statements from one another. A
modern potter reading these accounts finds them remarkable
literature. The present writer, realizing her own ignorance on the
many questions of clay-working, went to a modern pottery school.
The result of this first-hand study was not only the acquisition of
new knowledge, but a totally new insight into the whole subject. The
present essay is an attempt to revise the current theories of the
technique of Athenian pottery in the light of this practical
experience.
Not only does such practical experience supply us with the
knowledge essential for the consideration of technical problems, but
it gives us a new appreciation of the beauty of Athenian vases. If we
try to make such shapes ourselves we shall begin to observe many
details which perhaps passed unnoticed before—the finely designed
handles, the well-proportioned feet, the practical mouths; and the
curves, the mouldings, and the subtle variations will become a
constant delight to the eye. Moreover, we shall be impressed more
than ever with the wonderful sense of proportion in Athenian vases.
For the relation of the height to the width, the proportions of the
neck, the body, the foot, and the handles to one another appear to
be all nicely thought out. There is no hit-or-miss about it; the whole
is an interrelated theme evidently planned carefully before making,
either by the potter himself or by a professional designer.
In short, any one who has tried his hand in the production of
Greek forms will understand very well that the makers of such vases
were proud of their work and that the signature of a well-known
potter was at least as valuable as that of a popular decorator.[1]
The pottery school to which I went was the New York State School
of Ceramics at Alfred, New York. Throughout my work at the school
and later in my investigation of Greek vases at the Metropolitan
Museum, I had the great benefit of the advice of Professor Charles F.
Binns, director of the school. In fact, any value which this paper may
possess is largely due to this opportunity of appeal to someone who
possesses the rare combination of expert knowledge in the field of
practical pottery with a scholar’s attitude toward the problems
presented by the ancient ware. It is also a pleasure to acknowledge
the many helpful suggestions made from time to time by Miss Maude
Robinson, director of the pottery work at Greenwich House, New
York, as well as by Miss Elsie Binns and Harold Nash, modern potters
whom I have had the advantage of consulting on various questions.
I am indebted to Miss Helen McClees for valuable assistance in the
section dealing with the references to pottery craft in ancient
literature. In my examination of Greek vases, which necessitated
handling of the specimens, I was greatly helped by the courteous
assistance of many museum directors.
The plan of this book is as follows: The first chapter gives a
concise account of the processes in use in the making of vases at
modern pottery schools[2] and their application to the technique of
ancient vases. The second chapter contains a description of the
various representations we have of ancient potters at work. In the
third chapter are collected the chief Greek and Latin texts referring
to the ancient pottery craft. After this presentation of all the
evidence on the technique of Athenian vases comes a short
summary of the new conclusions arrived at, and a selected
bibliography.
The illustrations of modern pottery scenes were taken under the
direction of Charles F. Binns at the New York State School of
Ceramics, Alfred,[3] and of Maude Robinson at pottery studios in
New York City.[4]
 I. TECHNICAL PROCESSES
IN THE MAKING OF MODERN POTTERY AND
THEIR APPLICATION TO THE TECHNIQUE OF
ANCIENT VASES

PREPARATION OF THE CLAY

Ingredients and properties.

T
he making of a pot begins in the clay bed. The clay has to be
found, it has to be transported, and above all it has to be tested
to see whether it is adapted to the potter’s needs. For there are
many different kinds of clay and they are as individual as human
beings; so that a thorough understanding of them is essential to the
successful potter.
The chief ingredients of clay are silica, alumina, and water. Other
possible ingredients are iron oxide, lime (calcium oxide), magnesia,
and potash. To the iron compounds are due the different colors of
the clay. When potters speak of the color of a clay—red, yellow,
white—they refer to the color after burning, not in the raw state.
The tones of the color are controlled by heat; for instance, a red clay
becomes first pink, then in a higher fire a deeper red, and in a still
higher fire a brownish red.
The potter demands three properties of his clay: (1) plasticity, the
property which enables the clay to acquire form; (2) porosity, the
property which enables the water to escape; and (3) vitrification, the
property which enables the clay to be fired. These three properties
are due to the three chief component parts of the clay; namely, clay
base, quartz, and feldspar. It will be found that some clays are not
plastic enough, others not sufficiently porous, and others again not
properly vitrifiable; in such cases the addition of certain substances
is necessary to make the clay usable. The actual composition of the
clay, therefore, is of great importance, as no amount of skilful labor
will avail if the clay itself has not the right consistency.

Washing.

When the right composition of the clay has been assured, the next
step is to wash it and separate it from the many natural impurities,
such as stones, sticks, etc., with which it is mixed. A clay not
properly washed is a source of great vexation in the later stages of
pottery making. The best method is that of “blunging,” that is, the
dry clay is put into water and stirred constantly until it reaches the
consistency of cream, technically called “slip,” whereupon it is
poured through sieves, coarse or fine according to the desired
consistency. The liquid clay or slip must then be dried sufficiently to
become plastic and workable. This can be done either in filter
presses in which the water is squeezed out in a comparatively short
time, or in shallow receptacles in the open air where the water is
allowed slowly to evaporate.

Wedging.

But even at this stage the clay is not yet ready for use; it has first
to go through the important process of kneading or “wedging.” This
consists of cutting a ball of clay in two against a wire (fig. 1),
slapping the two parts on a plaster or wooden board, one on top of
the other (fig. 2), then lifting up the whole lump, cutting it in two
again, and slapping it down as before. The purpose is to remove all
air bubbles and to correct irregularities in hardness. The operation
has sometimes to be repeated fifteen or twenty times before a good
texture is secured.[5]
 Fig. 1. Wedging (a)

We learn from the above survey that the fine consistency of the
clay in Athenian and in some other Greek wares is not necessarily
due to its natural state, but to the careful washing and kneading
undergone in its preparation for use. When different particles are
found in the fired clay they are due to indifferent washing. And the
varying shades of pink and red of Greek vases likewise do not
presuppose different kinds of clay, but are due largely to the various
temperatures to which the vases were fired. We have too often
made our analyses of clays of Greek vases without due cognizance
of these facts.

FASHIONING THE VASES

 (1) WHEELWORK

There are three principal ways of making vases—fashioning them

on the wheel, building them, and making them from moulds. Let us
examine first the work on the wheel, the potter’s tool par excellence.

Fig. 2. Wedging (b)

Types of wheel.

There are various types of wheel in general use today. The wheel
run by electric power does not concern us here since it cannot have
been used by the Greeks. In studio potteries, a kick-wheel is often
used. In this the operator stands and kicks with his left foot against
a treadle, the weight of his body being supported by the right (fig.
3). Another fairly popular type has a large, heavy disk at the bottom
revolving in a horizontal plane, and kept in motion by one foot of the
operator (fig. 4). A very simple type of wheel in use some time ago
is illustrated in fig. 5. Here the motion is imparted by an assistant
turning the handle.

Fig. 3. Kick-wheel with treadle

Any one of these three types may have been used by the Greeks.
In the representations of ancient potters at work (cf. pp. 64 ff.) the
wheel appears to have been propelled either with the foot or by an
assistant.

Fig. 4. Kick-Wheel with disk

 Fig. 5. Wheel put in motion by assistant turning handle

Barber, The Pottery and Porcelain of the United States, p. 4, fig. 2

Throwing.

Figs. 6-9. Processes of throwing

 Fig. 6. Centering ball

Fig. 7. Pressing clay down

Fig. 8. Squeezing clay into cone

Fig. 9. Inserting thumb

Figs. 10-13. Processes of throwing

Fig. 10. Making cylinder

Fig. 11. Making bowl

Fig. 12. Making jar

 Fig. 13. Making bottle
The first task in fashioning a vase on the wheel—or “throwing” it,
as it is technically called—is to center the ball of clay on the wheel-
head. It is accomplished by pressing the left hand against the ball of
clay as it revolves rapidly, care being taken to keep the left forearm
absolutely rigid (fig. 6). The right hand is used for keeping the clay
wet by sprinkling it with water, and for pulling the clay inward, thus
squeezing it up to a cone. The cone is pressed up and down in this
manner several times (figs. 7 and 8). When the ball runs perfectly
true, it is time to open it by inserting the thumb in the center (fig.
9); then by placing the fingers of one hand inside the hollow, and
the fingers of the other on the outside,[6] and by raising both hands
gradually several times and squeezing the clay lightly while so doing,
a cylinder is formed (fig. 10). The cylinder is the foundation of all
other shapes. For to produce a bowl, one need only pull out the
cylinder a little at the top (fig. 11); to make a globular jar, pull it out
at the bottom and in at the top (fig. 12); to fashion a long-necked
vase, pull it out at the bottom and in at the top, leaving enough clay
to spin the top into a tall, narrow cylinder which will serve as a neck
(fig. 13); and by various other manipulations one can produce
almost every variety of shape. To throw a vase to specific
measurements, a careful drawing of the shape should first be made
and calipers and measuring sticks kept close at hand for checking
the work as it proceeds.
The earliest Greek vases are made by hand; but from the Early
Minoan III and Middle Helladic I periods (i.e., about 2200 B.C.) in
certain places at least, vases were regularly thrown on the wheel.
They could not have the regular and symmetrical outlines they have
if they were built by hand, and many would show traces of vertical
joints if they were made in moulds.
That the processes of throwing were identical with those
described as in use today, there is of course no means of
determining; but they certainly must have been similar, as clay has
not changed its nature from Greek times to ours. The evidence
which we glean from representations on Greek vases of potters at
work, scanty though it is, bears out this self-evident fact. From the
above description it will be noted that in this work of throwing the
simultaneous use of both hands is necessary—an important fact to
remember when interpreting scenes to be related to the fashioning
of vases.

Turning.

Fig. 14. Turning a vase

After a piece has been thrown on the wheel, it has assumed its
general shape, but that is all. The thinning of the walls, the
refinements of foot and lip, all such finishing touches must be
reserved for the next process. This is known among modern potters
as “turning.” In this the clay is no longer in a wet state, but in a
“leather-hard” condition, and it is not worked with the hands but
with steel cutting tools. A newly shaped vase becomes leather hard
after it has been kept in the air and the water allowed to evaporate
for about twenty-four hours. Pieces in this state are hard enough to
be handled with care and to be cut easily with a knife. They are not
so fragile as either in the wet or in the “bone-dry” state, but they are
still delicate and exposed to many dangers. Not until a vase has
been fired is it safe to handle it freely. The cutting with the steel
tools is done on the wheel (or “jigger”[7]), the right hand which
grasps the tool being kept steady by letting it rest on a stick held in
the left hand; the stick should have a sharpened nail on one end,
the point of which is pressed into a wooden board at the height
required (fig. 14). By continued cutting off of thin shavings of clay
and by adding more clay in slip form when more is needed, the final
outline of the shape and the various grooves and mouldings for lip
and foot can be obtained. But it is a slow process, requiring time,
care, and great patience. For the smoothing of the surface, scrapers,
sandpaper, and sponge are useful.

Fig. 15. Turned foot Fig. 16. Foot left as thrown

Met. Mus. Acc. No. 12.234.2 Met. Mus. Acc. No. 07.232.30
Fig. 17. Turning marks on outside of vase

Met. Mus. Acc. No. 06.1021.64

Fig. 18. Turning marks on inside of vase

Met. Mus. Acc. No. G.R.1228

 This turning or refining of the shape after throwing, was, as we
might expect, not in universal use in ancient times. Prior to the sixth
century B.C. it was used occasionally here and there, and often only
to a limited extent. But there cannot be the slightest doubt that in
the Athenian black-figured and red-figured vases extensive use was
made of the turning tools. The grooves and mouldings for lip and
foot were produced by this turning process, not, as modern
archaeologists tell us, by the use of moulds.[8] For this there is
abundant proof. The feet of Athenian vases are almost all turned at
the bottom, some with remarkable care and finish (fig. 15), not left
flat, as they would be after throwing (fig. 16). The lids of pyxides
and similar vases could not have been made to fit so neatly on their
ledges without the use of turning. Above all, the wonderful finish
and precision of Athenian vases could never have been attained by
mere throwing. But there is even more convincing proof. Unless the
marks of the turning tools are very carefully obliterated (with
scrapers, sandpaper, and sponge), traces of them are always visible.
And this is the case also in Athenian vases. The outside surfaces are
generally carefully smoothed, but even there the ridges formed by
the tools are often discernible (fig. 17); and on the inside of the
necks or feet or lids such ridges and concentric or spiral scratches
are quite frequent (fig. 18). They are very different, however, from
the finishing marks left in handwork (fig. 19). To appreciate the fine,
smooth surface which work with the turning tools produces, we need
only examine the insides of most Athenian amphorai and hydriai; for
these, being more or less concealed, are generally left as thrown,
often showing the spiral ridges which rapidly revolving clay will
cause (fig. 20). They thus form a striking contrast to the finely
smoothed outside surfaces.
 Fig. 19. Finishing marks left in handwork

Met. Mus. Acc. No. G.R.834

The fact that the Athenian potter made use of the turning process
shows incidentally that he was able to make his vases to very exact
measurements. This is important in connection with Jay Hambidge’s
theory that Athenian pottery was carefully designed on certain
geometrical principles;[9] for if the Athenian potter had confined
himself merely to throwing on the wheel that would not have been
possible. It is during the second process of turning that an expert
potter can effect many changes in width and height or in details, and
thus make his product correspond exactly with his carefully planned
design. Modern potters of standing work in the same way today.
They first make a drawing of a vase, full size or to scale, and then
proceed to follow this drawing in every detail, using rules and
calipers for their guidance. Of course it needs a great deal of skill
and patience to be able to work so exactly; but Greek potters, we
can be quite sure, had a good supply of both of these qualities.
 Fig. 20. Unturned inside of amphora

Met. Mus. Acc. No. G.R.545

Work in sections.

So far we have spoken only of comparatively small vases, which

can be thrown all in one piece. Larger vases are best thrown in
sections. To throw large jars in one piece requires great physical
strength, and it is very difficult to finish such jars properly on the
inside and to prevent them from being unduly heavy. The section
work is by no means easy. At first a drawing of the vase has to be
made, either full size or to scale, and the heights of the different
parts marked off. While throwing the respective pieces use must be
made of measuring sticks and calipers, to obtain the right heights
and diameters. The measurements should be those of the soft clay,
which will of course be slightly larger than those of the final shape.
About one-eighth is the average allowance for the shrinkage of the
clay in drying and firing. This shrinkage will naturally be
proportional; so that the relation of every part to the whole will be
the same in the fired vase as in the thrown product. The joining is
obtained by applying a thick slip of the same clay as was used for
the vase, to act as a binder. When all the sections are in place the
outside of the vase can be “turned.” If this and the foregoing
processes are done skilfully the final joints will hardly be visible,
even before the glaze is applied. Figs. 21, 22, 23 show the three
chief stages in the making of a vase in sections.

Fig. 21. Vase thrown in sections

To obtain good results in this work it is important that it should

not be hurried. It is best, for instance, before joining the sections, to
let them stand on top of one another for a day or longer, in order
that they may mature together. To retain the pieces during this time
in leather-hard condition, they must be kept in a “wet cellar,” that is,
in a moist place where the water in the clay will not evaporate (fig.
24). With this simple precaution pieces can be kept leather hard
practically indefinitely.
 Fig. 22. Sections in place Fig. 23. Vase after turning

Section work was used by the Greeks, as it is now. There would,

in fact, be nothing gained in throwing the very large vases, such as
some of the kraters and amphorai, all in one piece; and though the
joints are, as a rule, skilfully concealed, they are plainly visible on
certain examples, especially on the inside. Where possible the joints
seem to have been made at the natural angles or “articulations” of
the vase (that is, at the neck, the foot, etc.); and further to simplify
the work, a thin ridge of clay was often added to conceal the joint.
[10]
Welcome to Our Bookstore - The Ultimate Destination for Book Lovers
Are you passionate about books and eager to explore new worlds of
knowledge? At our website, we offer a vast collection of books that
cater to every interest and age group. From classic literature to
specialized publications, self-help books, and children’s stories, we
have it all! Each book is a gateway to new adventures, helping you
expand your knowledge and nourish your soul
Experience Convenient and Enjoyable Book Shopping Our website is more
than just an online bookstore—it’s a bridge connecting readers to the
timeless values of culture and wisdom. With a sleek and user-friendly
interface and a smart search system, you can find your favorite books
quickly and easily. Enjoy special promotions, fast home delivery, and
a seamless shopping experience that saves you time and enhances your
love for reading.
Let us accompany you on the journey of exploring knowledge and
personal growth!

ebookgate.com