Tag: genetics

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

About Redheads

Sandy was not only his name but his nature too. He was a Saunders, a name that came down from Scotland via Ireland, as it had for one of my grandparents.  He was also a blazing redhead, his hair as hot as the Red Sand Beach on Maui.  When Sandy wasn’t being called by his nickname he was a “ginger nut”.  Remembering our friendship in school, I wonder if we ever offended him, and hope that he knew that naming him after a favorite cookie (called ginger snaps in America) was a token of chumminess. I envied his handsome thatch, which stood out in a class of browneys.

According to ScotlandsDNA, a company that mines genetics for Scottish ancestry, redheads are more common in Scotland and Ireland than anywhere else, although greater numbers call America home.  The northern climate is kinder to people with light skins because they are less exposed to the damaging ultraviolet rays of sunlight. But the fewer rays that penetrate the “dreich” weather make vitamin D more efficiently in them than in darker-skinned folk who have a higher risk of vitamin deficiency and rickets, making them less fertile too. That seems a likely explanation for why redheads originated in north-western Europe, and perhaps for their occurrence among Neanderthal people.

I won’t venture to write much about other skins except that the bottom of a red Irishman looks the same color as a blonde Swede’s (that’s what I am told). But the similarity is deceptive because after they are both exposed to strong sunlight the Celtic posterior is much more likely to burn, matching his hair. The difference is in the genetics. For eons while they stayed at home, photosensitivity barely mattered for Celts, but after moving to sunnier climes or when skinny-dipping in Ireland’s new nudist beaches they’ve had to lather on SPF.

Skin is shielded from damage to its DNA by two types of melanin pigment: either brown-black or red-yellow, which is the more abundant type in redheads.  The dark stuff has a SPF of around 13 in African Americans, four times more effective as a sunscreen than in the average White. But a dark skin does not afford anyone absolute protection, and the sun’s rays are not the sole cause of melanoma, the most dangerous form of skin cancer. Bob Marley, the Jamaican reggae star, died with the disease, and so did my Indian friend in Edinburgh.

Skin pigmentation is controlled by the hormone melanocortin, or MSH for short. The hormone works by engaging a protein called MC1R on the surface of pigment cells which in turn sends a signal to fire up the internal machinery, rather like turning a key to start your car engine. These cells are called “incontinent” because they extrude pigment they manufacture for pick-up by neighboring cells, including those that grow hair.

The MC1R gene has over 10,000 DNA units (nucleotides).  If this genetic code is changed by only one unit there is usually no effect, but changing one of three specific units dramatically reduces the amount of dark melanin made, causing hair to be colored from red to gold.

Two reds, one brown and one blonde born to parents with red and brown hair
Two reds, one brown and one blonde born to parents with red and brown hair

These DNA variants are called SNPs (pronounced “snips”) which, genetically speaking, are mutations. I prefer to avoid the word “mutant” in sociological contexts because it can sound pejorative. Besides, SNPs are abundant in environments in which they are well-fitted, so we should regard those for hair color as “good genes”.  Red is the rarest natural color because the genes are recessive, meaning you need to inherit one from both parents to be a redhead.  Forty percent of Scots carry at least one of the SNPs, but only 13% have red hair. When cells have two copies of the gene the “key” doesn’t fully turn in the MC1R lock.  In most of us brown pigments hide the red; it is like green leaves whose reds and yellows are out of sight until the chlorophyll disappears in fall to give a wonderful display.

So much for biology, what about sociology?  Redheads have often gotten a raw deal, but there is absolutely no shortage of brains and beauty or star-power among them – Galileo, Thomas Jefferson, Winston Churchill, Lucille Ball, and Nicole Kidman to mention a few off the top of my head.  Artists love their hair, splashing canvases with red pigments to signal a subject’s beauty, passion, and heat.  Dazzling red hair is the first thing you notice in the painting by Dante Gabriel Rossetti of the mythical Lilith. It is a study of timeless

Lady Lilith by Dante Gabriel Rossetti of the Pre-Raphaelite Brotherhood
Lady Lilith by Dante Gabriel Rossetti of the Pre-Raphaelite Brotherhood @ http://www.metmuseum.org

concupiscence, modeled by his mistress, Fanny Cornforth, and the artist was so enamored that he composed a sonnet to celebrate Lilith:

…And her enchanted hair was the first gold.

And still she sits, young while the earth is old …

The opposite side of the coin for red hair reads like an ABC of prejudice – abuse, bullying, and condemnation.  Gingerism still stalks England’s streets, more often as a sour joke but sometimes violently. Some say that hard attitudes and feelings are the smoldering ends of ancient feuds.

Late Sixteenth Century England was becoming more cosmopolitan, and Londoners were growing more suspicious of foreigners.  Shakespeare shrewdly cast Othello as a noble and distinguished man of color who became bewildered by the malice of enemies he didn’t deserve in his adoptive country: …Then must you speak of one that loved not wisely but too well; of one not easily jealous, but being wrought, perplexed in the extreme…  The Bard never singled out redheads for persecution or mockery. Had he done so his own head might have been laid on the block because his queen was one of them and had made red hair fashionable in her life time.

Human color prejudice contrasts with colorblindness in animals. In our teens, Sandy and I would watch badgers when they emerged in the twilight from underground dens in the woods.  Occasionally, there was an adorable cub with a red coat (called erythristic) born in a litter of black and white cubs. The badger family was oblivious to the difference because its main sense organ lies at the end of a long snout. But I guess that a badger fed on garlic or sprayed with Chanel might, ahem, be badgered.

Emily is a seventeen-year-old family member who lives in Sewickley, PA. She told me that it is easier to be red in America than in England, and easier still as a girl.  She gets plenty of compliments about her flowing red tresses, and any other remarks she wisely shrugs off.  Red makes her feel special, and the color “pops”.  On the other hand, her Dad had to put up with school bullies because of his red hair, although old ladies fawned over the cherubic boy.

I sometimes wonder how Sandy feels about his hair now. If he was bullied at school, did he have the satisfaction later on of seeing redheads born into the families of those who formerly brow-beat him, because some of them were doubtless carriers of the red gene? Did a girl fall in love with his “ginger nut”, or did he marry a strawberry blonde and make more gingers together? I imagine he feels differently about his nut after passing a sixtieth birthday because it grows paler by the year. Perhaps he would even be happy if we called it an angel cake.

Next post: Serendipity or Chance

A Dog’s Dinner

Banana Joe stole the show!

No, not the LA radio presenter, I mean the affenpinscher from Attleboro who won Best in Show last week at the Westminster Dog Show in NYC.

I’m not a pooch person, prefer big mushy dogs, but Joe the affenpischer who looks like a cross between a toy and a monkey is easy to love. And a monkey dog he is (ein Affe, a monkey). Like monkeys, Joe and our Golden enjoy a banana, which is not so surprising if you consider it is a perfectly natural food for their cousins – wolf packs in Minnesota and Alaska.  Erhh!

We changed their dietary preferences after the first wolf cub was adopted by a human family.  I ought to pause to correct myself because dogs can’t express preferences any more than I could as a London schoolboy. It is only a slight exaggeration to say that we were served Dickensian gruel for school lunch. I remember peering through the kitchen window at the cooks watching over steaming vats of bubble and squeak made from yesterday’s left-overs and stirring custard thick as tar but not so smooth. It was ‘Hobson’s choice’, or, in other words, no choice at all, just as it has always been for our dogs.

Until the food industry realized there was a canine market, most dogs had to make-do with human left-overs, living hopefully for a bone flung their way with a morsel of meat on it.  As members of the Order Carnivora, their ancestors enjoyed a high protein diet before they were domesticated around 10,000 years ago (some put it earlier). Neolithic people were then switching from hunting and gathering to agriculture, growing various cereal crops in the Old World, sweet potato, corn and beans in the New, and – yes – bananas in New Guinea.  Growing-their-own enabled them to form settlements with greater food security, and afterwards their diet became much richer in starch. So did the dogs’.

A new study of whole genome resequencing shows what an impact this change had on canine genetics. There are not as many genetic differences between dogs and wolves as you might think from their manner and appearance, but significant differences were found between genes involved in brain function and the digestion of starchy and fatty foods.  It seems that a genetic bottleneck occurred in the early prehistory of domestication. Animals with gene variants that favored compliant behavior and efficient starch digestion squeezed through, and those survivors became the founders of modern dogs. The wild-type wolf genes disappeared because dogs lacking genes that were better adapted to the new life were either kicked out for bad behavior or didn’t thrive on the new diet. Lying at your fireside is an example of how we sculpt the evolution of species.

Lilah
Lilah’s turn

Now to sweeter talk. Sweet is one of our five senses of tastes, but long before we celebrated it by inventing confectionary it was probably beneficial for distinguishing between good and bad food. Since wolves will occasionally eat vegetable matter it’s not surprising that they share the same sweet taste receptor gene, Tas1r2, as ourselves, and dogs inherited it from them.  Other mammals can taste sweetness too – raccoons and of course bears – but not all. Cats can’t taste it because their Tas1r2 is pseudogenized (meaning it doesn’t function), and likewise in sea lions, otters, dolphins, and hyenas.  Since they are flesh-eaters that swallow their food whole there’s no time for tasting and therefore no point in having a sweet taste receptor. But biologists who love to tell a commonsense story are often embarrassed by an ugly fact that threatens a beautiful theory. We might expect a species that sips its food to have a well-developed sense of taste, but apparently vampire bats don’t have a sweet tooth in their heads.

Now back to bananas and Banana. Our dog, Lilah, has a more discerning palate than her owner because she turns her nose up at green bananas which are just full of starch but she will happily chomp on yellow ones in which much of the starch has been converted to sugar.  We throw away overripe bananas but, given the chance, she will gorge on them knowing they have the most sugar.  The French clearly know their bananas too because their grocery stores have premium prices on fruit with brown skins.  Belle banane.

Banana Joe deserved a better reward. He was taken to a swanky Manhattan restaurant where he was served filet mignon to celebrate victory. I expect he was glad to leave starch behind for a day if only to prove he is still a card-carrying carnivore.

Next Post: Cardinal robes

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