Like a Virgin

by Prasad, Aarathi

  Regardless of the provenance of human embryonic stem cells, the proteins that act as signposts for developing male (sperm) and female (egg) cells can be detected in them. In fact, eggs have been made in the lab from both female and male embryonic stem cell lines. This is because the male embryonic stem cells have not yet expressed the SRY gene, which triggers the development of the testes and eventually the generation of sperm. Female embryonic stem cells, on the other hand, can only give rise to eggs. So without an artificial Y chromosome, women could only ever make artificial eggs, while men could make either artificial eggs or sperm. However, by keeping eggs fashioned from embryonic stem cells in a culture (that is, in a nutrient/chemical soup incubated with a prescribed mixture of gases at an appropriate temperature), scientists have been able to create parthenogenic embryos – embryos that begin to develop despite never having been fertilized by sperm. (Of course, this isn’t all that peculiar when you consider that parthenogenesis is a relatively normal phenomenon; whenever eggs are kept in culture, they tend to start dividing on their own.)

  In early 2006, two laboratories, one based in Germany and the other in the UK, reported some remarkable results using embryonic stem cell lines. Earlier, scientists had successfully developed immature sperm, or spermatogonial stem cells (SSCs), from embryonic stem cells that, when they were injected into mouse eggs, developed into early embryos. The new research went one better. The teams transplanted SSC artificial sperm into the testes of mice that had no sperm of their own. After four months, the scientists observed sperm in some of these mice, generated from the transplanted cells. Unfortunately, the sperm did not move, or move very far, unaided; they weren’t ever going make it to an egg. So to help the process along, the sperm were removed from the mice testes and injected into unfertilized eggs. Out of 210 eggs, 65 embryos were produced and transferred into surrogate mice mothers. Seven of these became baby mice, fathered by artificial sperm. But the baby mice sired this way were not very healthy, and they died at ages well below the average life expectancy of mice conceived naturally. Much remains to be worked out before artificial sperm are ready for humans.

  Then in 2010, the first artificial human ovary was made, signalling a significant step towards the creation of eggs outside of a woman’s body. The artificial ovary, built by researchers based at Brown University and the Women & Infants Hospital of Rhode Island, could move oocytes along the path to becoming mature eggs.

  An ovary is a complex organ, composed of three major cell types, all of which need to be developed in a tissue structure for an artificial organ to function fully. According to Sandra Carson, the obstetrician and gynaecologist at Brown who led the team, the ovary provides not only a living laboratory for investigating how healthy ovaries work but a way to test for exposure to toxins and other chemicals that can disrupt egg maturation and health. In the future, Carson believes an artificial ovary might play a role in preserving the fertility of women facing cancer treatment – immature eggs could be salvaged and frozen before the onset of chemotherapy or radiation, and then matured outside the patient in an artificial ovary.

  Carson’s group has already used a lab-grown ovary to mature human eggs. To do so, they used a ‘3D Petri dish’ made of mouldable gel, on to which two types of ovarian support cell could attach, forming a honeycomb structure. Seventy-two hours later, the third cell type was introduced, enveloping the immature egg cells in exactly the manner that would happen inside a real ovary. They managed to keep the structure healthy for up to a week. It is unclear whether the eggs developed in the artificial ovary contained all of the important genetic imprinting information, but Carson and her colleagues are performing further studies that they expect will make this possible. And even though it has not yet been dealt with in their investigations, the artificial ovary might equally well be used to mature artificial eggs too. In a university press release, Carson emphasized that the techniques are ‘really very, very new’ and that, setting aside her hopes for the future, it would be sensible to be cautious about where the experiments may lead.

  The obstacles to creating artificial sperm indistinguishable from healthy sperm created in a man are not so different, in some respects, to those faced in manufacturing mature eggs. Some of the labs that claim to have made sperm from bone marrow stem cells have made cells that can act as sperm but are not, strictly speaking, sperm. This makes a difference: the sperm ‘actors’ are basically little packages of DNA, and those sorts of packages can be extracted easily and directly from an infertile man’s testes. There’s little point in going through all the trouble of making sperm if they can’t do more than that.

  Sheffield University is home to one of the few labs around the world where artificial sperm is being manufactured properly. As part of this quest, Dr Allan Pacey, a male fertility specialist at the university, looks at semen on a day-to-day basis. In a very small room with a folding bed – installed for research purposes – Pacey explained the rigorous quality tests that are being used to understand what makes great sperm. In addition to the bed, Pacey’s lab keeps a supply of porn magazines in its efforts to collect semen samples. Two thousand men from the Sheffield area have donated sperm to the study, which has verified that a count of twenty million sperm per one millilitre of semen is the norm for a fertile man – and that some men’s semen contains no sperm whatsoever.

  In the lab next door to the bedroom, a student scientist was busy with a microscope. Images of three or four sperm were projected from the microscope on to a computer screen. Seen this way, the sperm appeared huge and robust – around ten thousand times their true size. Normal sperm contain just one set of DNA, and all of these checked out as normal; none of them displayed the characteristic signs of carrying two sets: a grossly enlarged head or a head split in two. The day I visited, the lab was focused on something quite basic to reproductive function, and central to making artificial sperm that do more than serve as a container for DNA: they were measuring the length of normal sperms’ tails.

  The definition of a ‘normal’ tail length is not yet understood. Though the length of a sperm’s tail affects how efficiently the sperm swims to the egg, one millilitre of a man’s ejaculate will contain sperm displaying a huge variety of different tail lengths. So what length should an artificial sperm’s tail be in order to have all the functionality of a real sperm? Making sperm, after all, is not just a case of making a cell with half as much DNA as the rest of our cells. ‘What you are trying to replicate in the lab is not just a case of taking a cell and letting it divide. A skin cell could easily be made like that,’ Pacey explains. To be a ‘true’ sperm, the cell has to move, and that requires a certain size and shape. In contrast, eggs, which start off round and remain that way, may be easier to construct. Pacey admits that, in theory, any cell might be altered to carry one set of DNA and be used to fertilize an egg in vitro, but that, he says, does not make a sperm or allow for natural conception using an artificial cell.

  Another issue involves replicating how sperm develop in the body. Sperm do not develop in one spot but evolve progressively more mature forms as they move through the tubes of the testicles. It is in the final stages of sperm development that the head and tail are ‘finished’ and which pose such a challenge to researchers in the lab. The Sertoli cells, also known as nurse cells, guide the proper development and maturing of sperm in the testes, no matter where they are. In fact, scientists have managed to insert immature human and rat sperm into mice testes and observe it mature there, alongside the mouse’s own sperm. Because human, mouse, and rat sperm look quite distinct, the researchers were able to confirm that nurse cells from one species can be used to mature sperm from another. In Pacey’s view, Sertoli cells are an exciting avenue for investigation – they offer a way to use something like an ‘artificial’ testis to produce real human sperm.

  These challenges are not impossible to overcome, and chances are that one or more of the three labs based in the UK and Japan that are competing to solve the problem w
ill do it within a generation. Scientists expect that in vitro-derived germ cells will be ready to test in clinical studies within thirty years, and possibly sooner.

  Using in vitro-manufactured eggs and sperm could remove a significant issue that arises when a child is conceived from donor material: every bit of information that we can now glean from our genetics will be available to the parents to judge and assess and decide what to pass along to their children, including such things as whether or not they will be more susceptible to a disease than the general population. The egg and sperm banks that now offer their services often provide some information, particularly around superficial characteristics such as a donor’s appearance and perceived intelligence: hair colour, eye colour, skin colour, and educational attainment. One solo parent specifically said that she had chosen a sperm bank because it released information about the donors’ looks, character, and health. But often, people do not know their own family medical history – a mother or grandmother may have died long before the BRCA1 gene could set her body on a path towards full-blown breast cancer. An artificial egg or sperm, in comparison, would come with a full genetic profile.

  Using lab-made germ cells might also make us think more biologically about the family. When a person or a couple turns to a donor’s egg or sperm, there’s a niggling sense that biology has some lurking trump card to play. Will the child’s genes harbour some undesirable disease or temperament? Will the child feel the tug of belonging, biologically, to another family, rather than the one into which he or she has been born? Are the children of a donor’s eggs, or sperm, siblings in any sense? One British fertility doctor based in Oxford told me, for instance, that he thought the probability of two half-siblings meeting and marrying in the future was so slim that it was never something that worried him in his work. But this is the sort of taboo that still carries weight in society, just as the chances of it happening goes up with the number of IVF pregnancies. Dr Pacey of Sheffield University told me that he had been inundated with phone calls from infertile couples following a December 2010 press report in which it was claimed that the team at the North East England Stem Cell Institute had succeeded in creating a functioning artificial sperm. There is no doubt that the ability to make sperm and eggs in the lab has an allure for infertile individuals, for the very fact that it would sweep away the ambiguity inherent in the donor system – every bit of genetic identity will be their own.

  If the option were to exist one day, the ultimate solo parent will probably be a woman who needs nothing but her own stem cells and an artificial Y chromosome to produce eggs and sperm. She might use two of her own eggs to create a child, converting one egg into a pseudo-sperm to fertilize herself, as scientists have already done in mice. And then, should an artificial womb become a reality, she might even forego pregnancy, allowing a doctor to set the ideal conditions for the foetus’s development. She could even keep working, as men do, until the moment the baby is born.

  This would be the great biological and social equalizer, a truly new way of thinking about sex. The question is not if it will happen, but when.

  EPILOGUE

  NEXT GENERATION

  Over the past century, every innovation in reproductive technology, from the use of anaesthesia during childbirth to the first successful ovary transplant, has been met with criticism and resistance. Most have been seen as a threat to the traditional family – a change in the roles of men and women. But science is always conceiving the inconceivable – looking for the next frontier to cross.

  In the 1950s, for instance, some scientists investigated the possibility of an all-female farm – a farm populated by only cows, sows, and ewes, with no bulls, boars, or rams. Animal breeding, as it has been conducted for millennia, requires raising and feeding big males for the sake of a little sperm. So why not create a line of virgin-born livestock that would improve farmers’ profits and, as a bonus, yield new insights into genetics and sex itself? The assumption, and indeed the aim, of the work was that males are mostly expendable.

  But this is not nearly the full story of reproduction. Going solo is not an option available to women alone. In fact, in a strange Aristotelian twist, the newest reproductive technologies – artificial wombs and artificial eggs – seem poised to give men more potential than women to make a baby without the opposite sex. And as shown in the studies of solo parents, the logistical route to parenthood – the how of having a child – is far less influential in a child’s life than is the choice of parenthood – the why. Perhaps the necessity of our lifestyle and the ingenuity of medical science will force us to accept families that have been marginalized previously. They may even spur the emergence of families such as have never before existed, as genetics and biology are ripped out of the egg and sperm and allowed to be combined freely. One such case: two baby girls, called ‘twiblings’ by their mother, who were born in New York City in 2010. After she had gone through four failed rounds of IVF, the mother ended up using a donor’s eggs, her husband’s sperm, and two surrogate mothers (pregnant at the same time) to have her daughters, who are ‘twins’ only in the sense that they were born around the same time. Both surrogate mothers continued to be involved after the babies’ births.

  What were once invisible, indivisible seeds of life will act as portals rather than as ingredients to be brought together to create a child. The constituent, beautiful machinery of which eggs are built will very soon broker successful pregnancies and healthier babies – with three genetic parents. This fast advancing area of research involves transferring the male and female parents’ DNA into a donor egg, which already contains a package of DNA from the donor, in a tiny organ in the egg called a mitochondrion. The child born from this process would inherit a fraction of his or her genetic code from the egg donor, breaking the rules of reproduction as we know them today.

  There already are children born from permutations of biological, gestational, and genetic input from more than two adults, and this will increasingly be humanity’s future. Whether or not medical intervention soon gives women and men the choice of having biological children with a person of their same sex or completely on their own – unrestricted by the physical limits of the human body as well as the socio-economic limits on the human soul – the reproduction of the future is set to rewrite much of the fabric of human society. Male plus female equals baby will no longer be our only path forward. As we conceive the once inconceivable and take full control of how and when we bring the next generation into the world, we are sure to dislodge many notions of sex and gender along the way.

  SELECTED BIBLIOGRAPHY

  Prologue

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  1. Planting the Seed

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  2. The Story of Safe Sex

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