embryology Archives - Roger muses about Nature

Dear Jean

I couldn’t leave my students to say farewell. Our friends told me it was one of those miserable days before the daffodils bloom along the Cambridge College Backs: Scots would call it a “dreich day”. Pronounced correctly, everyone knows exactly what they mean.

So much water passed under the bridge in thirty years. You’d be amazed to see my hair now—but better a silver noggin than a shiny nut.

As summer grows old, I’m feeling sentimental and looking back on salad days again. I never forgot the first time you showed me a human embryo. Alive! Gazing down the microscope I needed your help to see the tiny ball of cells floating in a pink ocean of culture fluid. You hovered behind me, probably worried that a green student might spill the precious mite you had just created by in vitro fertilization. It took five more years of struggling research until your breakthrough with the embryo that became Louise Brown. Now there are millions like her.

Jean and Bob arriving at Gare du Nord, Paris, for a conference

Did you ever mind standing in Bob Edwards’ shadow? He was generous with compliments, saluting you as the third pioneer of IVF beside Patrick Steptoe and himself, but as the assistant to a famous scientist and a gynecologist (and being female) you didn’t have much visibility with biographers and the press. The longer you are away the deeper the mystery of your part in the program, and now that both men are gone there is no one left to tell the full story.

Why did you quit nursing? Why did you switch to a lab job for which you were hardly qualified? Of course it wasn’t any ordinary job. Bob’s goal was no less than to forge a medical revolution, and Patrick was aiming to help infertile couples that his profession had virtually abandoned because it had nothing to offer them. Your work was accused of being unethical, “playing God,” and was excoriated in the press, by doctors, and from church pulpits. I wondered what your friends said, what your family thought, and how you coped with it all.

All those struggles were quickly forgotten when it all came right, but then you couldn’t foresee the triumph at the end of the tunnel of nearly ten disappointing years of trials, working long hours and often away from home until Louise was born. Besides the immense challenge of nurturing embryos in the dish and the thicket of critics, you had to glue two different personalities together, for if Bob and Patrick had parted nothing would have been achieved.

I guess you seasoned the setbacks and stresses with humor. I remember you used to laugh when we goofed in the lab, and when you struggled to spell the name of the Philadelphia biologist, Beatrice Mintz, you posted attempts on your bulletin board. It’s funny how trivial things get stuck in my memory. Visitors would remark about your “humor station” before stepping past to Bob’s office for some heavy scientific discussion. Once when I was sitting in his office soon after Louise was born and you were setting up Bourn Hall Clinic I asked him how he managed to publish his huge tome, said to be the bible of reproductive medicine. He nodded towards your desk, which you leant over, cracking a cheeky smile that was so endearing.

I always knew you had a sterner spirit under the sunny exterior. One day during the public hullaballoo about banning the South African national sports teams from international tournaments I saw you in a heated debate with an overseas visitor who was defending apartheid. Afterwards, I realized you felt the same passion for patients depending on you, and Bob had hired you over more qualified assistants because he saw what you were made of.

I wish I had asked if you ever wanted to be famous. Had you stayed you would have been queen of the realm—earning awards, dinners in your honor, and guest lectureships everywhere. I guess you were happy to be spared that kind of attention, preferring the undisturbed backroom where you could counsel patients and care for their embryos. You were content for Bob and Patrick to be the front men. Bob will go down in history as a scientific pioneer. Patrick passed away too soon to share the Nobel Prize and earn a knighthood, but won’t be forgotten. I’m told that quite a few patients from Bourn Hall still wander across the lawn to stand reverently at his graveside outside the chapel. He’s lying just 15 minutes away from you, but no one makes that journey.

Some of our nurses in America inquired about your story a few years ago. They only knew you were first in the field, but that was enough to create the Jean Purdy Visionary Award. I shared everything I knew for their introductory speech for award-winners, but my knowledge was threadbare and I never managed to find your family to fill the gaps. They have vanished. I found an unrelated woman called Jean Purdy in London; she works as a magician, but you were the real thing. The award was a wonderful naming legacy and I’m terribly sorry that it too has disappeared. You would just put your arm over my shoulder to console me, saying it doesn’t really matter.

If I could go back in time I would love to ask how you felt when you started working with human embryos. The first were experimental because you needed to check they were healthy before Patrick dared to give them a chance of making a pregnancy. I heard you had a devout faith, though I didn’t know your church denomination. Did you ever have qualms about making and destroying embryos? For myself, I believe they deserve respect, but could never understand people who wanted to endow full human rights from the moment of fertilization. Moral philosophers and theologians are still arguing the point, although every nation I can think of has either legitimized IVF or turned a blind eye to the practice. Since your time, embryos have been used to create stem cells for regenerative medicine, which Bob dreamt about half-a-century ago and George W. Bush tried to can a dozen years ago. Although it really started in your lab, I doubt you ever imagined that your work might one day help to cure the incurable. If you read nothing else in this post I would want you to know your endeavors weren’t wasted.

When I asked a friend at the Hall where I could find you she offered to drive me to Grantchester. I hadn’t visited the village since I was a student. Then I used to cycle over from college or punt on the Granta against the stream, feeling I deserved a drink at The Green Man when I arrived. It was mead in those days. Sometimes I joined students enjoying a cream tea under the apple trees in The Orchard, which is still associated with Rupert Brooke. His patriotic war poems fell out of popularity long ago, but his own tragedy still draws me to his romantic verse, even the schmaltz about his Grantchester home.

The church at Grantchester. Thanks to Kay Elder

And laughs the immortal river still

Under the mill, under the mill?

Say, is there Beauty yet to find?

And Certainty? and Quiet kind?

Deep meadows yet, for to forget

The lies, and truths, and pain? . . . oh! yet

Stands the Church clock at ten to three?

And is there honey still for tea?

The Old Vicarage, Grantchester by Rupert Brooke (1912)

I ask myself why it has taken so long to write to you, and why now? Perhaps Bob’s passing is prompting me (Blog date April 2013). Perhaps news of Louise’s 35^th birthday last month nudged me. But I think it is because the book I finished today jogged something in my unconscious. You might have enjoyed the life story of a remarkable but long forgotten New York surgeon.* Had I more data, I might have started your biography next. Stories of people who made a difference but now lounge in obscurity fascinate me so much more than those still celebrated. They resonate with the last lines George Eliot wrote in her tribute to Dorothea, … the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who have lived faithfully a hidden life, and rest in unvisited tombs.

When we reached Grantchester churchyard I could imagine the dreich day when you were laid under the grass beside your mother. It’s a rather unkempt, inauspicious corner with nothing to draw the eye of casual visitors who meander between the stones. Had I been asked to order your memorial I would have insisted on a granite carving, Here lies Jean Purdy, the World’s First IVF Nurse and Embryologist, died 1985 aged 39. But your name painted on a gray headstone is being eaten away by rain and wind, the plastic flowers the most cheerful feature of that bleak spot. Rupert Brooke would have walked over from his rooms at the Vicarage to compose an ode.

*A Surgeon’s Story by Roger Gosden and Pam Walker will be available on Amazon soon. See Jamestowne Bookworks for news.

Next Post: Gold in my Garden

Baby’s First Picture

The first picture of a baby is usually in the mother’s arms soon after delivery, and becomes pasted into an album for posterity. My mother missed out on that snapshot since I was born in austere post-war London when a box Brownie camera was a luxury my parents couldn’t afford. But nowadays the picture is taken earlier and with a much more expensive camera. My granddaughter, Pippa, was snapped by an ultrasound scanner when she was barely past the fishy stage in her mother’s womb. The next picture taken a few weeks later showed her looking like a real child, and the obstetrician could confirm everything was fine, including beating heart and nuchal transparency. Pictures reassure us all is well, even if we can’t put absolute trust in them.

The first picture can be taken even earlier nowadays – in fact, as early as can be. For most of her thirty years as an embryology lab director, Lucinda gave prospective parents of IVF children a picture of their embryos which she had taken immediately before medical staff transferred them to their Mom’s body. These were embryos that had been fertilized in a Petri dish and grown to a ball of about 8 cells in three days, or had formed a blastocyst with about a hundred cells after a slightly longer incubation. Giving these photos to patients is now a common courtesy in fertility clinics, and more and more couples are having this extraordinary preview. Last year there were over 60,000 babies born after IVF procedures in the USA alone, or 1% of all births.

For such couples (and single mothers undergoing the same treatment) pictures of their embryos probably find a temporary place of honor on a kitchen bulletin-board until the next picture at the six week ultrasound scan – or taken down if the pregnancy test proves negative. But for embryologists and physicians, pictures of embryos are records of the best-looking in the bunch which they hope stand the best chance of getting Mom pregnant. Generally one or two are chosen (sometimes three) for transfer from the half-a-dozen eggs (more or less) that were fertilized, but these pictures say so much less about the embryos’ prospects than my first picture or Pippa’s, and even ours hardly say anything about things that most matter to us – future health, vigor, brains, and beauty.

Upwards of 50% of all human embryos conceived in the IVF lab (and probably the same in the body) have abnormal sets of chromosomes, and therefore no chance of making a healthy child. It is possible to genetically screen embryos so that only the healthy ones are placed in the uterus, but although this can be helpful it is far from foolproof. Some embryos are mixtures of normal and abnormal cells, meaning that a test produces misleading results if only one cell is removed, which is all that most embryologists dare take. And then there is the unanswered question of whether certain kinds of abnormalities can correct themselves spontaneously, implying that embryos could be discarded unnecessarily.

The upshot of this uncertainty is that deciding which one to transfer is still mainly based on how they look at the time when the photo is taken. It’s a beauty contest which Machiavelli would have derided because “men in general judge more from appearances than from reality.” Unfortunately, “reality” is much too deep to plumb, and so, despite the best efforts, the embryos with the best chances of success are not always chosen.

A single snapshot at the end of a growth process that had been going on for days mostly unseen inside the lab incubator is not much to go on. We wondered if a picture is worth a thousand words, perhaps a thousand pictures would better convey the whole story.

Back in the 1990s Lucinda had already started making movies of embryos in Petri dishes, but had to build her own equipment and record them on magnetic tapes. When I joined the project some years later, digital time-lapse recorders, more advanced microscopes, and miniature incubators were available for the job. We could take a snapshot of individual embryos every few minutes, which over five days added up to over two thousand frames. Imagine how eager we were to compile them for a motion picture of the first days of human embryo development! But we didn’t anticipate surprises, accustomed as we were only to static images, but the embryos educated us.

On the first day nothing seemed to be happening, although appearances are deceptive because there was a lot of activity at the sub-microscopic level. But the next day the fertilized eggs made an almighty heave and in a strange contortion never to be repeated divided into two equal halves within their shells. They tolerate only so much fragmentation of cells at this stage, which you can see in the movie. The next division to make four cells started later in the day, and more divisions created a ball of tiny cells without any net increase in overall size. Clinics are now using customized equipment to monitor the rate of embryo development to help to choose which to transfer.

On the fifth day, healthy embryos became blastocysts, hollow balls of cells with a tiny knot at one side that make up the embryo proper. The movies revealed that blastocysts undergo cycles of swelling and collapse rather like a beating heart, although far more slowly and not from muscles contracting because no such cells exist yet. Just as a heart sound or pulse is a sign of life, the blastocyst’s beat is a sign, and probably a better token of vitality than a static picture ever gave.

We had another surprise after pressing the PAUSE button at a random frame if the embryo looked sick, its cells more opaque and less plump. Sometimes it really was unhealthy and had reached the end of the road to development, but in other cases when we pressed RESUME the embryo would shrug off its frumpy appearance to continue growing, often even turning out to be a beauty. So Plato was right for embryos too – beauty really is in the eye of the beholder. A sad-looking embryo might have been discarded or, at the very least, frozen in reserve if its fate had hung on only one picture. Besides, we already knew that, like judges scrutinizing models on a catwalk, embryologists don’t always agree on their scores for embryos. They can tell you stories about patients who produced only a very few scrawny-looking embryos which were transferred to wombs “just in case”, only to find that at least one was successful and made a bonnie baby.

What about the rest, the ones that never survived long enough to be photographed? We seldom mourn things that pass beyond the focus of our eye or camera lens, nor give a moment’s thought to the far, far greater slaughter going on day-in and day-out in the wombs of the world where most embryos never thrive. Embryos may have started out looking hopeful after fertilization and even grow some, only to perish in the dish unnamed and unknown in a Greek tragedy of their own.

Sometimes I am moved to wonder about wasteful nature. I wonder why I can watch in deep sympathy a bee writhing after it has strayed into an insecticide spray or an earthworm wriggling its last as it dries out on the pavement, while we never spare a thought for the anonymous multitudes ending their lives prematurely by being trampled physically or chemically.

I suppose it is the connection with individuals, especially at tender ages, that makes the difference. No matter how alien to the subject we feel there is a biological link and by witnessing the life and death struggle of another creature we are jolted into thinking about our own. Patrick Steptoe (1913-88), who was Bob Edwards’ clinical partner in pioneering IVF, pondered the same thoughts as I do in idle moments. I remember him playing at a conference his musical elegy, For a Dying Embryo. Steptoe_PCS Before striking a key he told us he was sad for the couple who would never have that proud picture of their offspring, but he also had some sort of feeling for the embryo in his care, wondering what it might have become and achieved. Thank goodness Pippa and have pictures so we can muse in the future how we got here.

Next Post: Stem Cell Stuff

Robert Edwards (1925-2013)

A memorial service for Bob Edwards was held last weekend at Bourn Hall, near Cambridge, England. That is the Jacobean mansion house where he founded the world’s first in vitro clinic for fertility treatment (IVF) with Patrick Steptoe in 1980. Lying in its beautiful grounds, Patrick’s grave is often visited by grateful patients. On Saturday the ancient wooden front door swung open for Bob’s wife, five daughters, twelve grandchildren, and a troop of colleagues, friends, and admirers who came to give thanks for his life. He leaves a legacy with few parallels in science and reproductive health, and most of all he gave joy to parents of five million babies who owe their existence to his pioneering struggles for a medical revolution with Patrick and Bob’s assistant, Jean Purdy.

We miss him terribly. It seems impossible that anyone endowed with that much vigor is gone. We imagine him turning up at any minute when the angels push him out after disturbing the peace upstairs. Well into his eighties, Bob was still full of boundless energy and infectious enthusiasm. After retiring from Cambridge University and Bourn Hall, he was busy lecturing and collecting honors and awards around the globe, and he founded several new biomedical journals which soon attracted the best research papers. But, finally, time caught up and frailty captured him.

Bob needed lots of energy and a gritty Yorkshireness seasoned with humor for the hard journey to a controversial goal. The uproar that his research agenda caused between the 1960s and the 1980s is becoming a fading memory, and may even puzzle a younger generation for whom IVF is conventional treatment and knowing people who depended on it for building their family. But for those who remember the old times it’s hard to understand how he endured so much professional antagonism, even personal animosity, that tried to stop him in his tracks.

Most people would have quit. He told us it was the appeals of childless couples and heart-rending stories that drove him on. A reactionary medical profession in those days had nothing much to offer for infertility and, too proud to admit defeat, often ignored the problem. No one could have guessed that the boy who grew up in a northern mill town would become their champion and one of Britain’s greatest scientists, any more than we expected a grocer’s daughter from Lincolnshire would become the first woman Prime Minister and the Iron Lady.

Bob obtained his PhD in genetics and embryology at Edinburgh University in 1951 where he collaborated with Ruth Fowler, whom he later married. After short spells in the USA – at Caltech, Johns Hopkins, and Chapel Hill – he returned to London to take up contraception research, but it wasn’t long before he was studying his first love again – eggs and embryos. Ever boiling with ideas, he started to air dreams of launching IVF in medicine, but babies had only been born after IVF in rabbits and in no other species. He imagined how IVF could help women with blocked tubes and avoid children being born with cystic fibrosis, hemophilia and other inherited diseases. In the end, it had many more applications, but then almost everyone thought he was barmy. To be sure that he didn’t cause any trouble, a new director in London banned his work on human ovaries.

He moved to Cambridge University to join Sir Alan Parkes, whom I remember as a crusty old school chap, but who had an eye on the future. Bob flourished there, staying the rest of his career and ascending the academic ladder to full professor. For human IVF he needed help from medical doctors as gatekeepers to patients, but they were keeping the “maverick” at arm’s length. In 1968, Bob met a gynecologist who not only welcomed collaboration but had developed a new technique, called laparoscopy, which he needed to collect eggs from patients’ ovaries. That man was Patrick Steptoe. He was based in the north of England, far from the seats of power, and he too was regarded as an outsider by the gynecology community.

They were the perfect pair as it would take a special chemistry to spark a medical revolution in a climate in which colleagues constantly poured water over them. One day their story will no doubt become one of those Hollywood movies that will make people who remember them and their times cringe to see the story crafted for the box office.

A year after starting together, Bob and Patrick reported a breakthrough – they had fertilized human eggs in the Petri dish (or test-tube, if you prefer). It would take almost a decade of flip-flopping between Cambridge and Patrick’s hospital, with many disappointing results and hostility along the way, until the next breakthrough. That was when they were rewarded with the birth of the world’s first test-tube baby, Louise Brown.

Back in the 1960s, few people took him seriously. He was regarded somewhat like a cranky Old Testament prophet, and the venom didn’t pour out until his research started to make traction. There were ghastly newspaper headlines demonizing the pair for creating human embryos in the lab. Being called Dr. Frankenstein was the least offensive. Perhaps hardest of all to bear was condemnation by so many in their own professions, as well as a good number of politicians, theologians, and even Nobel Prizewinners. After Louise’s birth, The Daily Mail ran the headline, “Baby of the Century”, and so the news echoed around the world. Had she been an unhealthy child, fertility treatment would be different today, but she was bonny and it seemed heartless to say an in vitro baby should never have been born.

I joined Bob’s lab to study for a PhD in 1970 when his work was starting to heat up. I thought it would be cool studying embryos, although it would mean I had to sacrifice a love of animal behavior which I could have studied in another lab. That post was taken up later by an American in my college, Dian Fossey, who, as you probably know, went off to Rwanda to study gorillas in the misty mountains. A decision made at a fork in the road when aged 21 often has a lifelong impact.

Bob was different to other Cambridge dons, perhaps because he hadn’t been born with privileges but had to earn them. He led his graduate students and fellows in a very egalitarian way, encouraging us to think and explore, teaching us to argue about data and theories, sometimes teasing us by playing the devil’s advocate. With the exception of Barry Bavister who had developed a culture medium for fertilizing eggs, we were hardly involved in the clinical program which was out of sight nearly 200 miles away. I have been asked why Bob didn’t draw on the growing expertise in his own group, but I think he was keeping us at arm’s length from a controversial program that might have been harmful at tender stages of our careers. Today, he might be criticized for supervising students so lightly because of frequent absences, but in those days Cambridge had an unofficial “sink or swim” policy. We could swim because he had built a strong team that provided mutual support,

Bob and I chairing a scientific session. Helsinki, 1983

and I never again knew a happier workplace. Besides, we often felt happy to see the back of him to a conference or loading his station wagon for another trip to see Patrick. You would have to know Bob to understand what I mean, how maddening our beloved professor could be. Ideas poured out of him like newsprint from a press. When he proposed to us an exciting experiment, you feared that by the next morning the idea would be scrapped and he’d have a better one. I never encountered a more fertile scientific mind, and although most of his ideas were raw and forgettable, some were so precious that they have already been absorbed into mainstream medical practice or their implications are still being worked out.

My first project was to test his brilliant theory about the cause of Down’s syndrome, which is so much more common in babies of older moms. I labored over it for several years but, never able to prove it, grew more skeptical. Long after I had left Cambridge, he continued to rib me, “Haven’t you proven my theory yet, Roger?” The supple balance between scientific seriousness and light-heartedness was so endearing.

My wife, Lucinda, has fond recollections of his visits to Virginia when she was the embryologist for Drs. Howard and Georgeanna Jones’s team, which was the first in America to have an in vitro baby. One day she gave him a tour of the lab of which they were so proud and had taken great pains to maintain a sterile work area. Not wishing to be impressed too easily, he stretched up to the top of a tall incubator to wipe a minute film of dust on his finger, before grinning like a Cheshire cat.

On another occasion when he was visiting my young family in Scotland, he took us out for dinner. After my boys turned up their noses at whole fish on the menu he ordered a plate piled high with whitebait, which he then started devouring, his eyes darting from one boy to the other to watch them wide-eyed with horror as he swallowed each little fish head-first. We cherish pictures of him sitting on the lawn at Bourn Hall in the middle of a crowd of children conceived by IVF.

If he had any disappointment at the end I think it would be that his gift of fertility treatment was too expensive for low income couples to afford, especially in the U.S.A. It had made some doctors, and now the companies behind them, rich, which seemed to run against his socialist principles. That’s how he styled himself, but he was impossible to label.

The last time I saw Bob and Ruth was over three years ago when I visited them at their mini-farm outside Cambridge with Kay, a doctor from Bourn Hall. His health had obviously deteriorated. Although Kay said he was having a good day, he seemed far-away, locked in an old memory or stewing over something. He showed us his honors and awards that completely covered the wall of a side room, then explained them in turn – Legion d’Honneur (France), C.B.E. (UK), Fellow of the Royal Society (London), honorary degrees (Cambridge, York, Wales, Belgium, Greece, Romania, etc.), King Faisal Prize (Saudi Arabia), Lasker Award (USA), and many more that I can’t remember. But despite so many tributes I knew him well enough to see he was holding back a disappointment.

We were sorry he was passed over for the 2007 Nobel Prize which was awarded for stem cell research, something that he was pioneering as long ago as the 1960s. It seemed that his chance had passed and, unless a call came from Stockholm soon, time would run out. Nobel Prizes are not awarded posthumously, so Patrick was already out of the running, having died the day he was due to receive a C.B.E. with Bob from the Queen at Buckingham Palace. We knew there was Vatican pressure on the Nobel Committee to stop an award for IVF, so it was with a mixture of surprise and delight when the following year Bob did indeed receive that call. He won the 2010 Nobel Prize for Physiology or Medicine, the highest scientific accolade he could be given, and one to savor as it finally vindicated his work.

Sadly, he was too unwell to travel to Stockholm so one of his former students, now himself an emeritus Cambridge professor, accepted the Prize on his behalf. Two weeks ago in an obituary notice, the New York Times printed that Bob was “unable to appreciate the tribute”. I am delighted to correct the writer – he knew and celebrated it.

A few weeks before he died, I attended a conference in his honor at his college, Churchill. Displayed in a glass cabinet next to his papers was Margaret Thatcher’s famous handbag. Wags have told a story that the bag was full of iron weights for swinging at her liberal opponents or at conservative “wets”.

Bob and Margaret were born and died within days of each other and, although from opposite political poles, they were both visionaries who drew immense loyalty and intense opposition in equal measure. The juxtaposition of their artifacts seemed odd until I recalled that she had never openly criticized IVF, as a good number of her party had, and, moreover, it was her government that had awarded his first public honor in 1988, albeit a ‘middling’ one. It would take another twenty years and the Nobel Prize before one of her successors as prime minister recommended him for a knighthood. But I guess he would still prefer to be remembered as just plain “Bob”, the family man who helped folks to have children.

************************************

Bob never belonged to a faith community and once told me he didn’t like “churchy music”. But there was an undefinable spiritual core in his heart, and he would have enjoyed the Gaelic Blessing on Saturday. Composed by John Rutter, this rendering is sung by the Cambridge Singers. Click here. (Sorry I can’t cut the ads.)

Deep peace of the running wave to you

Deep peace of the flowing air to you

Deep peace of the quiet earth to you

Deep peace of the shining stars to you

Deep peace of the gentle night to you ….

This personal tribute to Bob was posted because copyright law prevents me from posting the obituary I authored in Nature or another I wrote for Fertility & Sterility with Dr. Howard Jones. Pdf copies are available by email after publication.

Next Post: Marvel in the hive

Tag: embryology

Dear Jean

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Baby’s First Picture

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Robert Edwards (1925-2013)

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