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. Roger and MumBut 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.Pippa 3 month fetus

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.

Human 8-cell embryo
Human 8-cell embryo

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

Seventeen Year Itch

Back in 1996, Bill Clinton was still in his first term of office, Charles and Diana agreed to divorce, the Unabomber was apprehended, and Ella Fitzgerald died. That year I hadn’t even dreamed of moving permanently to North America: I was living in Yorkshire where mad cow disease was seizing the headlines in England. While so much history has flowed through newspaper presses since then, Brood II cicadas were all the while secretly sucking at tree roots waiting for the calendar to flip over to 2013.

I encountered the brood a couple of weeks ago at a rest area on the I-64 west of Richmond.  The first thing travelers noticed after stepping out of their cars was a chirping racket coming from every direction. I had heard the sound only once before when a 13-year brood of cicadas was emerging near home in 2011. This year it is the turn of the 17-year ensemble to sing.cicada on grass

For a few weeks every 17 years local residents have sleepless nights. The noise can be as loud as a passing truck, and at 90 decibels reaches a level at which the Occupational and Safety Administration warns we should not be exposed to for more than 8 hours a day to avoid hearing damage. Not being respecters of regulations, male cicadas chirp round the clock.

They are among the great wonders of the insect world, but not only because they have one of the longest life cycles. The question that intrigues me more is how they manage to coordinate mass emergence.  When ground temperatures rise above 64 °F (18 °C) in the Year of the Brood, the fossorial cicada nymphs start to burrow upwards, breaking the surface first at the southern edge of their range (North Carolina) and progressively towards northern limits (Connecticut).  Soon there are incalculable billions above ground, more than a million per acre, but during intervening years you are unlikely to see any at all.  So precise is their timing that local residents can plan when to be on vacation in 2030 during the next big pulse.

They look scary and are the biggest of their kind. They are an inch-and-a-half long with bulging red eyes, orange wing veins and leg stripes, and through their transparent wings you can see a black cigar-shaped body.  They look like bugs in zoot suits and were given the marvelous scientific name, Magicicada septendecim.

I was a member of a naturalist group heading for a wildlife center in the Blue Ridge, but the cicadas in the car park – not you would think the most auspicious place to watch wildlife – were the most memorable sights of the day. They were thought to be a bad omen by superstitious early colonists, who assumed (wrongly) that they were the same as locusts in the Bible which warned in the Book of Revelation: “Then from the smoke came locusts on the earth …” I guess that every seventeen (or thirteen years) there were particularly fiery sermons from the pulpit about the seven last plagues of Armageddon.

For all their fearsome appearance, they are harmless insects. They don’t bite or sting, nor do they eat vegetation as true locusts do. They can cause minor tree damage from “flagging” (browning) during nest-building, but are generally rather beneficial. Soon after mating and egg-laying the adults die, providing food for critters and fertilizing the soil. The only remaining cicadas are immature “instar larvae” hatched from eggs. These nymphs fall from the tree canopy to the ground where those that avoid predation burrow underground to find juicy roots to suck on … and on … and on until the calendar turns.

For the most part, the distribution of 17-year broods and 13-year broods don’t overlap, although they evolved from a common stock a few million years ago.  Today there are 15 broods in North America, twelve with 17-year cycles and three with 13-year, and you will not find them anywhere else.  Of the 3,000 species of cicada worldwide, only seven have periodical behavior.

Burrows and shells from which cicadas emerged in the car park
Burrows and shells from which cicadas emerged in the car park

We watched hordes of them lumbering up tree trunks and walls; we saw many flying unsteadily like old flying boats, often crashing into branches or to the ground where robins were waiting to pounce. For a small bird, a cicada is hamburger-sized (and probably just as nutritious), so the eaters were soon sated. Everywhere across the hard-trodden ground there were holes, about ten to the square yard and a little larger than earthworms make. These were the burrows from which cicadas had recently emerged, and scattered close by were the transparent brown shells (exuvia) which they had worn for so many years underground. They gave us a spectacle I may never see or hear again.

The greatest enigmas are how they know the time, and why coordinate their emergence instead of being independent like most insects. We know of genes that regulate daily cycles in animals, but I can’t understand how molecules make a 17-year timer. And if cicada nymphs were synchronizing eruption by communicating with each other underground, it stumps my imagination.  Perhaps it serves to overwhelm the appetites of predators so that at least some survive to breed, although that theory is controversial. A similar explanation has been offered for mast seeding of long-lived plants. Last year was a mast year for oaks, with acorns lying so thick in our yard that every step sounded like walking on cornflakes.  But mast years are unpredictable – they can be consecutive or after long gaps – whereas cicada years can be written into almanacs for years, even centuries, ahead.cicada on blue

There are few pat answers in nature and the life sciences. That was frustrating when I was a student preparing for exams, but now I think the mysteries are far more wonderful than the facts.

Next Post: Baby’s first picture

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
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.

Mrs. T's handbag
Mrs. T’s handbag

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.

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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