Obituary: Dame Dr Anne McLaren

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Regenerative MedicineVol. 2, No. 5 ObituaryFree AccessObituary: Dame Dr Anne McLarenSarah FranklinSarah FranklinAssociate Director, the BIOS Centre, London School of Economics and Political Science.Search for more papers by this authorPublished Online:1 Oct 2007https://doi.org/10.2217/17460751.2.5.853AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Anne McLaren, one of the most eminent and highly respected reproductive biologists of the twentieth century, died with her companion of 55 years and former husband, the computer scientist Donald Michie, in a road accident while traveling from Cambridge to London on the afternoon of Saturday July 7th, 2007. She had recently celebrated her 80th birthday in April at a symposium in her honor sponsored by the Gurdon Institute in Cambridge. ‚Germ cells and early mammalian development’ addressed one of Anne’s most enduring areas of interest and was attended by many of her closest friends and colleagues. Anne was the recipient of innumerable awards and honors, and held positions of highest office across a wide range of fields across her career of more than half a century. As Founding Director of the Medical Research Council (MRC) Mammalian Development Unit in London (UCL 1974–1992), Fellow of the Royal Society (FRS 1975), Fellow of the Royal College of Obstetricians and Gynecologists (1986), Fullerian Professor of Physiology at the Royal Institution (1990–1995), President of the British Association for the Advancement of Science (1993–1994), Fellow of the Academy of Medical Sciences (1998), and recipient of the prestigious March of Dimes and Japan Prizes (2002 and 2007), Anne’s contribution to medicine and the life sciences was simply huge. In 1993 she was created a Dame Commander of the British Empire (DBE). Famously she was the first woman to hold office in the 330 year history of the Royal Society, becoming its Foreign Secretary in 1991 (to 1996), and a year later its Vice President (1992–1996). In 1992 she became Principal Research Fellow at the Gurdon Institute (Cambridge, UK), where she continued to run a laboratory investigating the events involved in sex determination and emergence of primordial germ cells until her death.Anne’s influence extended far beyond science. Her polymathic intellect and steady, if often understated, leadership made her an excellent manager, teacher and communicator. As a me-mber of the Warnock Committee tasked with making recommendations to government concerning the regulation of human fertilization and embryology in the wake of the ‚legal vacuum’ created by the birth of Louise Brown in 1978, Anne proved as adroit an architect of successful public policy as she was of good research design. Mary Warnock described Anne’s influence as crucial to the passage of the landmark legislation: “My learning, and I believe that of all of the committee, even the medical members, was taken in hand by one indispensable member, Dr Anne McLaren. At our second meeting, in December 1982, she gave us a lecture, at my request; on the process of fertilization … I remember thinking that I would like above all things to learn more, and especially to be Anne’s pupil. She was a brilliant teacher.”A mother of three children herself, Anne was active throughout her professional life in support of the advancement of women in science. She was a founder of the Association of Women in Science and Engineering (AWiSE), and it’s President for many years. She played prominent roles in the national and international Pugwash groups, championing the cause of greater scientific cooperation, and the promotion of science in developing countries including Cuba, China, and India to which she traveled to establish stronger links with UK science. After the collapse of the Soviet Union during her tenure as Foreign Secretary of the Royal Society, Anne traveled frequently to Russia, strengthening ties with its science academies, sometimes carrying cash hidden in her clothing to support the work of her beleaguered colleagues. Anne was politically active in a wide range of causes – from the Women’s Association of Radiation Information in the 1950s to campaigns against nuclear testing and in support of improved reproductive services for women. She was a Marxist and a trade union member throughout her life, having been secretary of the Oxford branch of the Communist Party of Great Britain (CPGB) – of which she remained a member until its dissolution in the 1980s. A life-long reader of The Morning Star (“the only daily paper she ever read”, according to her daughter Susan), she was active in the Campaign for Nuclear Disarmament (CND), as well as medical charities and health promotion movements, particularly involving HIV/AIDS in Africa. Anne was renowned for her generous and supportive attitude toward her colleagues, and for her positive influence as a mentor to co-untless junior women.All of these influences were evident in Anne’s prominent role as a spokesperson for science, and one of its most eloquent and democratic interlocutors. Although frequently working in some of the most ethically sensitive areas of scientific research, Anne never struggled to reconcile her belief in the value of experimental science with an equally robust confidence in the ability of the general public to comprehend basic science, to understand its benefits and risks, and to make sound decisions about its future directions.Early backgroundAnne Laura Dorinthea McLaren was the daughter of Sir Henry Duncan McLaren, 2nd Baron Aberconway, and Christabel Mary Melville MacNaghten, a leading London socialite. She was born and spent her childhood in London’s West End near Hyde Park and at Bodnant, her family’s 80 acre estate in North Wales, of which the garden now belongs to the National Trust. Anne was the fourth of five children, with one older sister, two older brothers and a younger brother spanning 23 years. Her father, Lord Aberconway, was a Liberal MP and wealthy businessman with interests in coal, china clay, shipping and steel, whose grandfather, Duncan McLaren, had risen from a poor crofting background to become Lord Provost of Edinburgh in 1851. Anne’s paternal grandfather, Sir Charles Benjamin Bright McLaren, was a barrister, QC, Liberal MP, Privy Counselor and was made the first Baron of Aberconway in 1911. He was Chairman of several Companies and Trade Associations including John Brown & Co, the Metropolitan Railway Company, the British Iron Trade Association, the Institute of Naval Architects, the Sheepbridge Coal and Iron Company, and the Tredegar Iron and Coal Company. His book Basic Industries of Britain was published the year Anne was born (1927). Anne’s mother Christabel, from London, was the daughter of Sir Melville MacNaghten, the head of Central Intelligence (CID). She was one of London’s most celebrated hostesses at the center of a glittering social circle of literary and artistic figures, including the Sitwells and HG Wells. At the age of seven Anne successfully auditioned for a child-role in the London film production of HG Wells novel Things to Come, starring Raymond Massey and Ralph Richardson. During her brief scene with actor Charles Carson, Anne is taught a history lesson on a large video screen on which mice are shown being flown to the moon to escape disease – a feat Anne later very nearly completed through a project with NASA intended to send mouse embryos into space that was thwarted by the Challenger disaster. Anne learned to read at an early age, even before she began kindergarten in Regents Park. She subsequently attended the private school in Gloucester Place, and later at Queens Gate, but her brief exposure to formal schooling was interrupted by the Second World War, which was declared in 1939. The family left London to live at Bodnant that summer. The London house in which Anne had spent her early childhood, at 38 South Street, was closed up, and she was never to return. In an interview in 1998 Anne described her early life dividing into two eras – before and after Wales.In the early period of the war the Bodnant estate served as a retreat of sorts for other displaced families and children, but within a year only Anne’s parents, her older sister Elizabeth and her younger brother Christopher remained. Anne was initially put under the tutelage of the local Priest at Bodnant, but she learned little, and organized her own education. For 5 years she plied a solitary tutelage by correspondence, unable to leave the estate in part due to her having become an indispensable carer to her older sister’s three young children, born during her husband’s military service. Again anticipating her later life as an experimentalist, Anne secretly built a chicken coop (from plans she found in a newspaper) where she could raise hens as a contribution to the war effort. For added measure she named them Alpha, Beta, Gamma and Delta, and fed them Carswood Poultry Spice to increase their egg-laying yield. In addition to essays for her correspondence courses, which she took pleasure in writing, Anne was keen on mathematical puzzles and arithmetic, favoring the books and pamphlets designed for students by Lewis Carroll.In 1944 Anne returned to private school in Cambridge, at Longstow Hall, where, although she was taught biology, she anticipated pursuing english literature at university. No female member of her family had ever attended university, however, and it took her mother’s considerable determination to enable Anne to sit the scholarship and entrance exams at Oxford, where her elder two brothers and her father had studied. Upon receiving the sample exam papers for English Literature, Anne faced the bitter realization that her rather patchy secondary education was wholly inadequate to the command of Milton, Chaucer and ‚the Greats’ she needed. Biology instead appeared to be the subject in which she had, somewhat inadvertently, trained herself to a sufficiently comprehensive academic level. Thus despite her thoroughly excellent School Certificate results, it turned out to have been the long walks in the Conway Valley with HG Wells, her experiments with accelerated poultry ovulation and her family’s dedication to horticulture that ensured Anne’s entry into university.At the age of 17 Anne moved to the only place in the country that offered coaching for university entrance in science, Oxford, where, by chance, her Quaker cousins, descendants of John Bright (the British radical of Anti-Corn Law fame), resided. Arthur and Margaret Gillet lived in North Oxford at 102 Banbury Road, which became Anne’s new home in 1944. Oxford was to remain her home for the next 8 years, which she described as ‚mind blowing’, opening up new doors and filling her with enthusiasm for ideas.Higher educationAnne was interviewed at Lady Margaret Hall in 1945 by Principal Lynda Grier, who awarded Anne the Senior Scholarship for the coming academic year. She did Honor Mods in Zoology, Maths and Physics, being the only woman in the latter class. The post-war influx of thousands of ex-servicemen being demobbed did much to alter the strict and somewhat old-fashioned mores of higher education at places like Oxford, and in her recollections of this era Anne described everyone having been ‚a bit shaken up in their ideas’ with the consequent emergence of a vibrant, open atmosphere of social and intellectual exchange. She remembered many of her Oxford tutors vividly, from Alistair Hardy, with his continuous plankton recorder that towed behind ships, to Harold Pusey, whose research on fossil frogs had been influenced by his wartime experience of interpreting aerial photographs. Above all it was EB Ford’s lectures on genetics that captured her imagination. She became his first female tutee.Anne graduated with a first and a clear ambition to pursue a career in research, beginning with a doctorate, for which she would need a studentship. Through a chance laboratory contact with the nephew of JBS Haldane, she was able to pursue a mini-research project on mite infestation of Drosophilia in his lab at University College London (UCL), as part of her application for a doctoral position. In 1949, having successfully secured her place, she began her postgraduate research as the first woman Christopher Welsh scholar, based at UCL, and with Peter Medawar as her supervisor (in absentia as he had moved to a Chair at Birmingham).Initially working with Medawar on acquired trait inheritance in rabbits (a cul de sac due to an inexplicable shortage of rabbits), and later under Kingsley Sanders on neurotropic viruses in the mouse, she obtained her doctorate in1952 – the same year she married her fellow UCL graduate student Donald Michie (one of the leading code-breakers working at Bletchley Park during the war). It was during the next 7 years of post-doctoral research at UCL and later the Royal Veterinary College in Camden, while she was working closely with Michie and John Biggers, that Anne extended her interest on the interaction between genes and development through a series of pragmatic, but often conceptually radical, and technically daunting, experiments. With the support of Emmanuel Amaroso, then head of the Physiology Department, and access to the constant temperature rooms of the Animal Husbandry Department (Haldane’s fly rooms), Anne and Donald became mouse impresarios in the 1950s. As she recalled of her and Donald’s ‚cottage industry’ of mouse breeding: ‚We got a small grant from the Royal Society … in the last part of our DPhils, when we were writing up or something. I think it was for £100 … and we bought a whole lot of baking tins and that sort of thing from Woolworths and made mouse cages out of them’. In what was to become a longstanding interest in the effects of environment on cells and embryos, one of Anne’s earliest experiments with John Biggers demonstrated that mammalian embryos cultured outside of the womb for over 24 h would result in a normal birth – a key discovery leading to the first successful clinical application of IVF some 20 years later.A grant application to the Agricultural Research Council followed from the McLaren–Michie mouse house made of Woolworths baking tins. They set up a large experiment using embryo transfer to attempt to distinguish genetic (embryonic) from uterine (environmental) influences on the expression of a rare maternal effect on lumbar vertebrae in two inbred strains of mice. Straightforward in its experimental design, the actual techniques of embryo transfer required considerable skill and dedication, and contributed an important aspect in the eventual publication. The lumbar study of maternal influence was also highly statistical, drawing on Michie’s wartime expertise: large numbers of mice were needed to reliably confirm inheritance patterns. In the end, in spite of initially neglecting to factor in the effect of sex differences on the aggregate data, the effect was confirmed as uterine.Anne and Donald’s first daughter, Susan, was born in 1955. Like her brother Jonathan and sister Caroline, born in 1957 and 1959, Susan was brought to work as a small baby, and throughout her childhood came with her siblings to the laboratory to play with mice at weekends. In the same way that Anne felt it was important to break down the family/work barrier by creating a more child friendly environment in the workplace, so too she was known to chastise colleagues who stayed too late in the lab, urging them to return home to be with their families. Interviewed on the BBC about the challenge of being a successful mother and a successful scientist, she replied: “I am sure I would have been a better mother if I had not been a scientist, and I am sure I would have been a better scientist if I had not been a mother”. In fact she was a model of how to combine both to their mutual advantage, and is remembered by her family as a devoted parent and grandparent. As her daughter Susan recalls: ‚She always appeared to put family first. I never heard her say she was too busy to do anything for us or her grandchildren, insisting on fetching, carrying and doing anything else we wanted’. Anne instructed all her grandchildren that jam donuts were full of nutrition.Edinburgh, Waddington & the Institute of Animal GeneticsWhile the study of genetics, reproduction, physiology and sex determination were crucial to Anne’s scientific work on ‚everything involved in getting from one generation to the next’, these interests were cross-cut by an overarching theme that might best be described as an irritation at the neglect of the role of environmental influences, and in particular the role of the maternal environment. Moving to Edinburgh in 1959, following the end of her marriage to Donald (with whom she remained close friends for the rest of her life), Anne joined Conrad Hal Waddington’s well-funded and well-managed Institute of Animal Genetics. ‚It was the most wonderful scientific atmosphere I have come across anywhere’, she recalled. One of the things ‚Wad’ did was to subsidize the Institute canteen, so that ‚people used to come from all over, zoology, molecular biology, and there were these wonderful lunchtime conversations’. At Waddington’s Institute an unusual level of infra-structure could be funded on an economy of scale (somewhat unconventionally, as it later turned out) – from a graphics department with specialist draughtsmen, to a photography and even a time-lapse film unit. Support for statistical calculation, histology preparation and an excellent library were accompanied by top-notch animal facilities – in addition to the ever popular canteen. Working initially on immunocontraception and later with Alan Beatty, with funding from the Ford Foundation, Anne extended her interest in the role of maternal influence by researching the process of implantation. This critical point in the establishment of a pregnancy was also a key target for potential contraceptive control, as well as being an important aspect of inf-ertility, and a CIBA symposium on these aspects of development remained one of the highlights of Anne’s career.In 1967, Anne received her first major scientific award. In a ceremony on 9th May at the Zoological Society of London she was awarded the Society’s Scientific Medal in recognition of her ‚far ranging investigation into the physiology of reproduction in mammal’. This included not only the factors underlying changes in performance with increasing maternal age, but also the influence of the environment on the growth and development of embryos. The award, for distinguished work by a scientist under 40 years of age in the zoological sciences, also recognized Anne’s leading role in the development of techniques to permit the transfer of blastocysts into the uterine horns of recipient mice, citing specifically “her meticulous analysis of the factors which must be controlled if transfers are to be successful [that] was a major factor in stimulating the use of the method in laboratories in many parts of the world”. Her experiments were praised as ‚elegantly designed to provide unambiguous answers’ to the problems they set out to solve.The important role of experimental embryology in the elucidation of developmental genetics was already well-established in the post-war era through the work of Briggs and King (1952), followed by John Gurdon’s (1962) studies using somatic cell nuclear transfer and cloning in amphibians to demonstrate cellular equivalence in terms of totipotency. Mammalian studies had begun to explore similar avenues, particularly in mice. Beatrice Mintz had begun to experiment with mosaic mouse embryos in the early 1960s, as had Andrzej Tarkowski. Anne began experimental work with chimaeras in the early 1970s to investigate cell lineage. Chimaeric compounds provided ‚ideal material’ in her view to study the interaction between inherited and environmental effects, enabling insights into the direction of development and the determination of cell fate. In time, Anne was to become one of the world’s leading experts in this field, eventually publishing her now classic text on Mammalian Chimaeras in 1976.London & the Mammalian Development UnitAnne remained at Edinburgh for 15 years before returning to UCL, to the vacated laboratories left behind by Gruneberg’s unit, and the new MRC-funded Mammalian Development Unit, of which she was appointed the founding Director in 1974. She was joined by David Whittingham, Mike Snow and Marilyn Monk as her senior scientists in the Unit. For nearly two decades, until it closed in 1992, Anne’s Unit functioned as a unique experimental research site for the examination of the precise mechanisms of gene-development interactions, and the invention and refinement of methods to study them. This was also the era that was to see the emergence of radically new therapeutic means of intervening into the processes of human reproduction, including both in vitro fer-tilization (IVF) and preimplantation genetic dia-gnosis (PGD).At the beginning of what was to become one of the most prolific periods of twentieth century developmental biology and genetics, Anne’s unit continued to expand the uses of the mouse model into questions spanning developmental biology, reproductive biology, and genetics – including molecular genetics. In part this was a direct result of Anne’s ‚irritation’ not only with ‚expected’ genetic events, but with what she called ‚the Weismannist view’ of a strict separation of germline and soma . She ended her 1981 publication Germ Cells and Soma, subtitled ‚a new look at an old problem’ and based on a series of three lectures she gave in 1980 at Yale, with three conjectures summarizing the importance of epigenetics. The first and second of these, following Gurdon, that ‚the potential for totipotency resides in all cells’, and that ‚to realize this potential for totipotency, the cell must be exposed to the appropriate environment’ have gained increasing importance in the post-Dolly era. The third proposition, that ‚the selection of certain cells to form the germ line and others to form the somatic tissues depends on their position within the epiblast’ similarly derives from work that began to show, in the late 1970s and early 1980s, that unlike the ‚preformed’ germline of worms and flies, the entire mammalian embryo (germ and soma) shared the same origin.That the therapeutic implications of the pluripotency of the mammalian embryo could be almost limitless has been the premise of much early twenty-first century bioscience, perhaps epitomized by the field of regenerative medicine. Anne both anticipated and encouraged these new directions, as she had early ‚radical’ clinical applications, and not only in scientific terms. Throughout her career she had been drawn to lines of experimentation that might yield practical clinical outcomes, such as IVF, to which her work with John Biggers in the 1950s had made a significant scientific contribution. In the 1980s, in collaboration with her colleagues Marilyn Monk and Bernadette Modell, she became a proponent of the possibility of genetic diagnosis of the preimplantation embryo, or what was then referred to as preimplantation diagnosis (PID). Ever pragmatic on a range of difficult fronts simultaneously, Anne could also confirm to the then Prime Minister Margaret Thatcher and Secretary of Health Kenneth Clarke that IVF and embryo research could be used not only to relieve the distress of infertility, but to reduce the incidence of serious genetic disease as well. The possibility of human embryo research leading to vital improvements in the effort to reduce the high cost of serious genetic disease, and the first clinical success of PGD on the eve of the Parliamentary vote in 1990, proved crucial to the Bill’s successful enactment by a -parliamentary vote of almost 3–1 in its favor.Anne similarly anticipated the social and ethical controversy that would later surround cloning and (human embryonic) stem cell research, and she became a prominent voice in bioethical discussion of them both. Much as she had done in an earlier era in relation to IVF and PGD, she played a leading role in addressing the social, ethical and political dimensions of cloning and stem cell research, as well as continuing to make important contributions to its scientific development. With Massimo De Felici, Anne had published as early as 1982 on the isolation and culture of primordial germ cells (PGC) – although the ability to derive long-term germ cell cultures, or to confirm pluripotency, would not occur for another decade. In her analysis of the events involved in germ cell segregation, including the guidance mechanism for migration and the onset and inhibition of meiosis, she leaned toward ‚the possibility that some underlying epigenetic timing mechanism underlies this whole developmental process’ (2003). Influenced by the scientific ideas of Lysenko, whom she interviewed in Russia and whose work she and Donald translated into English, as well as Waddington’s ‚epigenetic landscape’, Anne contributed to the understanding of the gene–environment interactions shaping early mammalian development with an eye to both their practical and theoretical implications.The Gurdon InstituteAfter the closure of the MMU in 1992, Anne moved to Cambridge to the Wellcome Cancer Research Centre, later to become the Wellcome Trust/Cancer Research UK Gurdon Institute. Continuing her studies into the development of primordial germ cells as head of one of the Gurdon laboratories, she simultaneously maintained an active calendar of speaking engagements, taking her on regular international trips for conferences, committee work, and as part of her continuing effort to establish stronger links between UK science and developing countries. As Jim Smith, Chairman of the Gurdon Institute, recalls: ‚Her energy was the stuff of legend, whether at the bench, at institute retreats or on the dance floor.’ She continued to publish regularly and to report scientific findings in highly ranked publications, as well as to report on developments in her field with the same inimitable accuracy and precision that won her admiration throughout her career. Anne was a Fellow of King’s College and Fellow Co-mmoner of Christ’s College.Maternal influenceAnne played a central role in the transformation of developmental biology as it gained increasing molecular precision in the post-war period, paving the way forward for new definitions of epigenesis. Like Waddington before her, she took on the difficult experimental work, and team approach, to tackling the precise mechanisms of gene-environment interaction. She was a scientist strongly committed to the practical outcomes of experimental research, while also fascinated by the basic mechanisms of human reproduction. At the same time, she was never dismissive of the ethical sensitivity of intervention into the reproductive process, and she committed both her time and her keen intellect, as well as her wisdom and humanity to the effort to find an acceptable and appropriate path through the complex social and political challenges of research into the very basis of life itself. Her ab-ility to think socially, politically and ethically, as well as scientifically, in a truly global fashion distinguished her contribution as a professional scientist as well as a progressive thinker. At the same time she set a personal standard of compassion, dedication and generosity toward her family, friends and colleagues that is as legendary as her scientific achievements. As a social scientist who benefited greatly from Anne’s willingness to assist in the often clumsy effort to comprehend the uncertain futures of ‚the biosociety’, I am among many who will deeply regret the loss of a scientist who brought great wisdom, discipline and intelligence to some of the most challenging questions of our time.AcknowledgementsAnne McLaren was interviewed by Martin Johnson and Sarah Franklin at the Gurdon Institute in February 2007 as part of a project on the history of mammalian developmental biology and reproductive biomedicine in the UK. This obituary draws on that interview, as well as those conducted by Max Blythe in 1998 for the Royal College of Physicians and Oxford Brookes. Thanks is given to the University Medical Sciences Video Archive. Additional material and assistance was provided by Susan and Jonathan Michie, Christopher McLaren, Brigid Hogan, Janet Rossant, Marilyn Monk, Azim Surani, Jim Smith, The Royal Society, the Zoological Society, the Gurdon Institute and Lady Ma-rgaret Hall.FiguresReferencesRelatedDetailsCited ByAnne Laura Dorinthea McLaren DBE. 26 April 1927—7 July 20071 March 2023 | Biographical Memoirs of Fellows of the Royal Society, Vol. 74IntroductionThe National EnvironmentThe Hormonal EnvironmentThe Dietary EnvironmentThe Maternal EnvironmentThe Laboratory EnvironmentCodaEpilogueNotesReferences Vol. 2, No. 5 Follow us on social media for the latest updates Metrics History Published online 1 October 2007 Published in print September 2007 Information© Future Medicine LtdAcknowledgementsAnne McLaren was interviewed by Martin Johnson and Sarah Franklin at the Gurdon Institute in February 2007 as part of a project on the history of mammalian developmental biology and reproductive biomedicine in the UK. This obituary draws on that interview, as well as those conducted by Max Blythe in 1998 for the Royal College of Physicians and Oxford Brookes. Thanks is given to the University Medical Sciences Video Archive. Additional material and assistance was provided by Susan and Jonathan Michie, Christopher McLaren, Brigid Hogan, Janet Rossant, Marilyn Monk, Azim Surani, Jim Smith, The Royal Society, the Zoological Society, the Gurdon Institute and Lady Ma-rgaret Hall.PDF download