Biological mysteries always drew me in, so it was natural to choose a career in research with the egg as its main subject. Remember the mythological sphinx with a human head and a lion’s body in Ancient Egypt? It guarded the temple secrets. Eggs may look plain and pure, but next time pause before you smash the shell of a biological sphinx on your breakfast table!
Eggs are the largest, the rarest, and the most paradoxical cells in the body. They possess contradictory characteristics: as ancestors of all other cells they are generalists, but also arch-specialists for no other cell engages in fertilization, except of course a sperm. You might think that these biological curiosities would keep young scientists employed in some quiet, arcane corner for their whole lives, but soon after wading into eggs they get into deep water.
I should have known better when I started because there were Egg and Sperm Wars as far back as the 18th Century. Scientists and philosophers were speculating whether it is the egg or sperm that makes the baby. For a while the Spermists were winning because no one had ever seen eggs in any mammal, let alone a human being – there was nothing like a hen’s egg. But when the tiny mammalian egg was found in 1827 the Ovists counterattacked and soon afterwards it was known that eggs must be fertilized with a sperm, so both cells are needed. This settled a conflict that had been dangling since Aristotle’s days,* and put storks out of business.
But eggs can sometimes go it alone without help from a sperm. Some animals reproduce by virgin birth (parthenogenesis), but no mammal. That we are among the exceptions was an enigma until an old colleague showed that a subset of genes (fewer than 1%) are “imprinted” to make them behave differently in the sexes. Imprinted genes in sperm carry responsibility for the placenta whereas in eggs others are needed for the embryo. So that neatly explained why we always need fathers and mothers. Perhaps sperm are from Mars and eggs from Venus.
During fertilization male genetic material is injected into an egg, and if we think of the combined genes as hardware of the future embryo, the bulky cytoplasmic goo in the egg contains the clever software. So eggs and sperm make equal genetic contributions, but eggs are more equal than sperm!
Dolly the sheep came from Venus. Looking like any other in the flock outside Edinburgh, she was the only one to nuzzle in your pocket for a treat and the only celebrity there. My colleagues named her for Dolly Parton who once said of her second most important asset, “I wanted to be the first woman to burn her bra, but it would have taken the fire department four days to put it out.” Dolly the sheep was cloned from an adult udder cell.
Her arrival in 1996 shook modern biology. I remember receiving a call from a London newspaper asking for comments about the breakthrough, but I knew nothing because the secret was so closely kept. Dolly was created by removing the genetic material from an egg which was replaced by that from the udder cell. After delivering an electric jolt to the “Frankenegg”, a new creature was conceived and time’s arrow was reversed. She was a clone of a deceased animal.
Afterwards there was a furore whether humans should ever be cloned … or had been cloned! There were a few attention-seekers raising their megaphones to claim that several cloned babies already existed around the world. We found their stories preposterous, and it was just as unbelievable that the profession did not oust those doctors.
Cloning was momentous for science because by cracking the sphinx-like egg we can peep past the door into the temple of regenerative medicine. We can hope to create to order cells of a certain type and matching a particular patient who needs organ or tissue replacement. There would be cardiac cells to patch up dead tissue after a heart attack, pancreatic islet cells to treat diabetes, retinal cells for macula degeneration, and so on throughout the body.
By an odd coincidence another hugely important breakthrough hit the stage just two years after Dolly. Human embryo stem cells were created. No other stem cell is as versatile as those from the embryo’s inner core, because they make every cell type in the body, except those specific to the placenta. These cells are harvested at the blastocyst stage from embryos donated by patients in in vitro labs. Although only a minority among 100 or so cells in a blastocyst, when released into a culture fluid and surrounded by feeder cells they grow rapidly – and almost indefinitely (movie courtesy of Nikica Zaninovic).
George Bush blocked federal dollars for this research, but progress that was hampered in the U.S. continued nonetheless elsewhere. In 2004 there was news from South Korea that after injecting human eggs with genetic material cloned “embryos” were generated. Since regenerative medicine was the aim, the clones were used to harvest stem cells. It almost seemed at the time as if the holy grail had been discovered, creating the chance to help patients who were suffering or might die without a transplant. But then we heard a whistle blowing.
The Korean research director was accused by some of his associates of making fraudulent claims. His fortunes changed precipitately, absolutely, and irreversibly when this particular f-word was voiced, and to say that the innocent helpers around him had egg on their faces is an understatement. They suffered anyway because science is the most unforgiving profession when lied to. Moreover, the tide of hope was ebbing because no other lab had been successful, and public confidence was being lost. We even wondered if cloning was a biologically impossible feat in humans.
But soon after that low point, Shinya Yamanaka announced an amazing breakthrough that offered another path, and one that avoided bitter arguments about the use of human embryos. Like the rest of us, he had been intrigued when Dolly proved the molecular goo in eggs can reprogram the genetic software of body cells. For my part, then working at McGill, we were building an inventory of all the proteins in the egg, hoping to identify those with reprogramming potential. It was like looking for needles in a haystack, but Yamanaka succeeded because he took a clever short-cut to find four molecules needed to turn back the clock of adult cells, making them think they were embryos and avoiding the controversial use of human eggs and embryos. He called the cells treated with these molecules, induced pluripotent stem cells or iPS cells, and no one was surprised when last year he received flight tickets to Stockholm for a Nobel Prize.
But were we only sitting on a see-saw, not making as much headway as we thought? Are iPS cells too close to cancer for comfort? Could stem cells develop abnormalities after a sojourn in culture? Are they as good as embryo stem cells, if those cells can be made? They can. This year we heard that scientists in Oregon have succeeded in making stem cells from human clones after a long, labyrinthine struggle. So now there are two players for the prize, with supporters on both sides.
I wonder how I will regard this post in a year or two? Progress is accelerating with hopeful news of stem cell applications announced every month. I sometimes wish I were back in the lab squeezing pipettes again, but science is becoming more of a young man’s sport than for graybeards. At least we have a long view, remembering how biology turned out to be so much more plastic than we ever thought, but knowing there are always ups as well as downs before we know whether iPS cells or embryo stem cells open the door to revolutionary medical care.
Eggs are mothers of all stem cells but it is better to avoid controversy with human embryos and hope that iPS cells will succeed. But wait a minute! iPS cells are very similar to embryo stem cells, and improvements in technology bring them ever closer. On the other side of the same coin, they could be put to the same use as embryo stem cells – which can be made into babies, with genetic modification if desired, using a technique known as tetraploid complementation. For every bright side of a coin there is often a spooky opposite in science. The egg that started us down this road is not perhaps so much like the benign Egyptian sphinx but more the treacherous Greek variety.
*Read the full story in my article in Biology of Reproduction by email request and which will be publicly accessible online from 2014. To be published in fall 2013: The Oocyte: Biology, Pathology and Technology, Edited by Alan Trounson, Roger Gosden, and Ursula Eichenlaub-Ritter. Cambridge University Press. I doubt any of my readers has an appetite for this 450 page tome.
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