This is what reproduction looks like when capitalism’s invisible hand has a free rein. Where there is demand, a supply will be found.
In order to give birth, a woman first needs eggs, and then needs sperm. That’s how reproduction works today. If she doesn’t have good quality eggs of her own, and has no access to safe sperm, there are currently few channels through which she can acquire either, outside of the donor market. But doctors are developing ways to bypass the market – including a treatment that is already being used successfully.
Eggs develop in ovaries, of course, but what is contained in the ovaries are not strictly eggs but immature ‘follicles’, clumps of cells that contain a single oocyte that grows and develops into a mature, ready-to-be-fertilized egg. This is why the key hormone in timing of conception and in IVF treatments is called follicle-stimulating hormone (FSH): the hormone stimulates the follicles to grow and eventually erupt, releasing the egg during ovulation. This means, however, that acquiring a healthy ovary, or even strips of tissue from a healthy ovary, and transplanting it into a woman is another way of getting around the problem of scarce good eggs. If the tissue has follicles that are still receptive to FSH, a woman would once again be able to generate eggs, no matter what her age. Take the case of Susanne Butscher, a woman who became infertile at the age of fifteen when her ovaries failed, causing her to experience a very early menopause. In November 2008, at age thirty-eight, she became the first woman to give birth after receiving a transplanted ovary.
Ovary transplants were developed for women, like Butscher, who suffer early menopause, or for those undergoing chemotherapy or radiotherapy to treat cancer. While strips of ovary can be removed from a woman without ill effects, removing the ovaries themselves can trigger premature menopause, with all of the associated ill health effects. However, Dr Sherman Silber, who performed Butscher’s transplant surgery, sees the potential for using the procedure as allowing women who have delayed motherhood for any reason to improve their chances of having a baby later in life. Rather than freezing eggs and undergoing IVF with them, a whole ovary could be frozen; the tissue would be viable for up to a decade. While the extraction and transplant surgeries are invasive, they could circumvent some of the problems associated with other fertility treatments. Children conceived through ICSI or IVF, even those conceived simply through the use of drugs to induce a woman’s eggs to be released for harvest, appear more likely to have problems with genetic imprinting, growth, and defects. And, unlike with IVF, a preserved or new ovary gives women the option of conceiving a child via sexual intercourse with a fertile partner. After her transplant, Butscher started having periods again, for the first time in twenty-three years, and she and her forty-year-old husband used no other fertility treatments. Indeed, the oestrogen, progesterone, and testosterone produced in the ovaries affect the female body in many ways, including protecting the bones from osteoporosis, and Butcher’s bone health improved as well.
Not everyone found good news in Susanne Butscher’s case. Just as happened when Louise Joy Brown entered the world as the first test-tube baby in 1978, the delivery raised moral and social concerns in many quarters. Chief among them: were surgeons using science as a tool to alter the child-bearing age for women? The UK’s Royal College of Midwives, for instance, stated that it would be preferable for surgeons to limit ovarian transplants and other reproductive technologies to women who are ‘truly’ infertile – meaning that they have become infertile in their twenties or earlier – and who are desperate to conceive. This would include Susanne Butscher, of course, but also survivors of childhood cancers who show evidence of normal ovarian function, but who will require a therapy that would otherwise destroy their ovaries. Right now, women battling cancer at a young age must either become a mother before treating the cancer, or treat the cancer – hardly a happy choice to make. But is it fair to say that some women, because of a medical condition, ‘deserve’ to benefit from these technologies, while others, because of societal and economic conditions, do not?
Those working on the frontline with people who are infertile argue that modern lifestyles are altering the child-bearing age for women – making it difficult for women to have children earlier in life. And then there is the question of how to define a ‘truly’ infertile couple. Yes, a man or a woman may be biologically ill-equipped to have a child together because of the health of their sperm and eggs, but a lesbian couple could make the case that they fall into this category, too: they don’t have the healthy sperm they need to have a child. In a statement on why IVF treatments for infertile couples should be a priority for the National Health Service, the British Fertility Society wrote that those ‘involved in infertility services are all aware that we are not just dealing with a physical pathology. Infertility is a disease, but it also has fall-out beyond that… causing mental health problems, depression, stress-related illnesses, and so on.’ These are serious health conditions, and if we have the tools to treat the underlying problem – the inability to have a child, at a time in life when a child is desired – shouldn’t we do so?
Susanne Butscher, for one, would probably agree with that idea. She and her husband named their baby Maja, for the Roman goddess of rebirth and fertility, and Butscher said Maja gave her ‘a sense of completeness [she] would never have had otherwise’.
Ovary transplants require a supply of compatible ovaries, so the problems that come with the trade in eggs and sperm – replete with misstatements, privacy violations, skirting regulations across borders, and criminal scandal – may well apply here too. And there are documented reports of a black market in body parts for transplant surgeries, so the infrastructure is already in place for ovary trafficking if the surgery is allowed to go forward on a larger scale. So scientists are considering how to take the idea behind ovary transplants and apply it to reproduction, without the demon of a limited supply of organs to meet demand.
Eggs and sperm are collectively called germ cells for their potential, somewhat like seeds, for growth to emerge after a period of dormancy. Early in evolution, a process of segregation must have happened so that germ cells were kept apart from all our other cells, possibly as a way to protect the integrity of their essential genetic material, in case nutrients became scarce and reproduction had to be delayed. Germ cells, of course, have a special place in our life cycle because they are essentially immortal – they provide the fundamental link from one generation to another. They must also be able to re-create the entire organism. At the same time, as we have seen, they have a pernicious shelf life, made all the more frustrating to many people by the fact that each of us has a limited supply. The first question to tackle, then, is whether a woman’s body might somehow be triggered to make eggs on its own, without resorting to getting follicles from an outside source – in essence, creating a new supply of eggs. In fact, there is a debate around whether a woman is really born with all the eggs that she will ever have in her life, a debate that has been raging for nearly a hundred years, since the German anatomist Heinrich von Waldeyer-Hartz first proposed, in 1870, that all female mammals stop producing eggs around the time they are born.
‘Less evolved’ species, such as flies, birds, and fish, can and do generate new eggs throughout their adult life, which means that the ability to produce new eggs was lost somewhere during evolution, before the emergence of mammals. Yet the ability of males to produce sperm throughout adulthood was conserved in species from flies through to man. Why would the process of evolutionary selection deem it an advantage to endow women with only a fixed number of eggs that sit stagnant and are subjected to years, if not decades, of ageing before they erupt from a follicle during ovulation? The more logical, more robust approach would be to keep generating fresh eggs and fresh sperm. At least in theory. But theory aside, new evidence points to signs that mammals also have the potential to generate new eggs.
Stem cells have received a great deal of attention in the press for their ability to renew on their own, unlike all of ou
r other cells, which only age and die off. Every type of cell, tissue, and organ in our bodies must be created from the genetic material contained in the egg and sperm, the precursors of the embryo. This power to generate the totality of components required to build a human is called totipotency. Stem cells derived from embryos are better suited to fulfil this role than those taken from an adult body, because in early embryos every cell has the potential to generate into any number of different cell types. As development proceeds, and cells become more fixed and decided as to their ultimate fate – that is to say, after a certain point in development, one cell will only be able to become a brain cell, another will only become a muscle cell, and so on – the stem cells lose their totipotent potential and become pluripotent, able to generate several different cell types but not all. But because extracting embryonic stem cells currently requires destroying an embryo, the technique is besieged with controversy, particularly in the US. Whether it will become possible to coerce adult stem cells into acting in a similar manner has still not been proven, though researchers are trying to revert skin stem cells to an embryonic state.
Regardless, egg-making stem cells have been found in the ovaries of adult mice, monkeys, and humans that retain stem cells with the capacity to renew the egg pool. At the moment, there’s still no evidence that these cells form new eggs naturally inside a woman’s body, but experiments are being conducted to see if they could be coaxed in a dish to make eggs. And if they could be coaxed to do the same inside a woman’s body, these stem cells could provide an unlimited supply of eggs, and also be used to postpone age-related ovarian failure and perhaps the menopause. Instead of receiving donor eggs or undergoing a tricky ovary transplant, a woman could receive a transplant of stem cells and let nature take its course.
For now, research into the precursors of eggs has yielded more auspicious results, including the closest anyone has come to creating a virgin birth in mammals. In the 1980s, scientists had made the first attempts to create mice with two fathers or two mothers and, as we have seen, these experiments failed because of the way in which genes are imprinted – turned on or off by chemicals within the DNA. Trying to create a baby from two sets of DNA regardless of their origin went nowhere; instead of getting one ‘dose’ of a gene, the offspring usually ended up with double the amount from one parent and none from the other. Then, in 2004, came the breakthrough: Kaguya. Created by a group of Japanese scientists, Kaguya the mouse was named after a mythical princess whose true parentage was unknown – she was found inside a bamboo reed. In contrast, Kaguya the mouse’s heritage could not have been better recorded. She was the first mammal to be born without a father and, what is more, the first animal in history to be born to two mothers.
The team, led by Tomohiro Kono at the Tokyo University of Agriculture, suspected that certain portions of the genome were posing the critical stumbling blocks when it came to imprinting. To circumvent these two problem regions, they realized they could turn to the biology of egg development. Remember that the genes silenced by imprinting are only silenced as the egg grows to maturity. By using DNA from an egg at an early stage of development, the scientists could gain access to these genes before they were locked. Kaguya was created from constructing an egg out of material from one mature egg and one immature egg, the equivalent of synthetic fertilization. Admittedly, Kaguya, like Dolly the Sheep before it, won a bit of a reproductive lottery. Out of the 371 reconstructed eggs that were implanted, only ten live embryos reached maturity, and only two survived outside the womb; Kaguya’s sister was killed so that the genes involved could be studied in more detail. But within just three years, the scientists had honed the technology to produce fatherless mice that develop at a high success rate – equivalent, in fact, to the rate obtained with in vitro fertilization of normal embryos. Like Kaguya, these new generations of mice – all female, of course, since they only have sex chromosomes from eggs – have proved able to reproduce with males and produce fertile offspring.
To achieve this, Kono’s team deleted two bits of DNA, called H19 and Dlk1-Dio3, which are imprinted in the mother but also serve as key controllers of imprinting across the genome. The first imprinted gene to be identified, IGF2, is imprinted in the mother, and so is expressed in the child from the father’s copy. What was particularly striking is that a substantial number of genes that have subsequently been discovered to be imprinted act as part of a pathway in which insulin-like growth factor-2 is crucial – the very thing that IGF2 codes for. And one of these genes is H19.
The other critical imprinted region, Dlk1-Dio3, contains genes that encode proteins expressed only when they come from the father. The genes in the Dlk1-Dio3 area are found throughout the embryo, but after birth, they are predominantly located in the brain, where their instructions for constructing the tiny pieces of machinery that regulate the workings of other genes do their work. These instructions are expressed only from the chromosome inherited from the mother. Some switch had to be turned, in order for the father’s gene to stop influencing the offspring.
It was H19 and Dlk1-Dio3 that Kono and his team deleted to make Kaguya the mouse. Tampering with these sections effectively allowed them to use the egg’s chromosomes as though they had come from a sperm.
Making human babies using Kaguya-style genetic tinkering should be possible in the future. But doing so will yield only female offspring, unless we can get hold of a Y chromosome, even one manufactured in a lab. In 2007, a first step in this direction was taken: in a painstaking process, a synthetic chromosome was assembled using lab-made chemicals – that is, copies of the chemicals that make up DNA. The artificial chromosome contained 381 genes containing 582,970 base pairs – paired letters of the DNA alphabet. The pioneering biologist behind this construction was Dr Craig Venter, whose company, Celera Genomics, helped to unravel the sequence of the human genome, in parallel with the government-backed Human Genome Project, in 2003.
The initial design of Venter’s artificial chromosome was based on a parasitic bacterium called Mycoplasma genitalium, which is considered the smallest naturally occurring genome in cell form. Venter’s team extracted the bacterium’s own DNA and inserted the synthetic reconstruction in its place. When they finally succeeded, they branded the creation as the first truly new artificial life form on earth. In Venter’s words, the artificial chromosome was ‘a very important philosophical step in the history of our species. We are going from reading our genetic code to the ability to write it.’ Learning to write genetic code will be more complicated when it comes to creating artificial eggs and sperm, especially on the scale of Homo sapiens’ twenty-three thousand genes, even after taking account of the ‘non-coding’ portions of the genome.
Still, the ability to create artificial eggs and sperm from stem cells is hailed as the technology that will finally bring an end to infertility. And rightly so, as it will also help us to uncover many of the remaining secrets surrounding how reproduction works. Experiments to make artificial eggs and sperm are likely to yield an increased understanding of genetic imprinting and the diseases that arise when imprinting goes awry. Since the cells that become the placenta can also be derived from these stem cells, this research could allow scientists to investigate how the early placenta develops and how disorders arise in it. And of course, artificial germ cells would allow individuals to bypass donors, avoiding the ethical issues of the egg and sperm trade. In fact, because the children produced from these cells will not be ‘artificial’ babies, scientists prefer to call them in vitro-derived cells.
In vitro-derived cells should be able to withstand freezing and be stored for future use, just as their ‘natural’ donated counterparts already are. The freezing procedures used today are much the same as they were in the early 1950s, when the modern technique was established. Scientists had been able to freeze and store sperm by the 1930s, but had not found a way to ensure that the sperm were not damaged, rendering them useless for reproduction. In 1949, two British scientists, C. Folge and
A. D. Smith, were part of a team who finally succeeded in ‘reviving’ sperm after preservation, by using glycerol to maintain the sperm’s structural integrity as it is plunged into temperatures around minus 196 degrees Celsius (minus 320 degrees F), and the process was improved substantially a few years later by the ‘father of cryobiology’, American zoologist Jerome K. Sherman. UK law currently only allows sperm frozen in this way to be kept for ten years, but as there is no evidence of any changes in quality over time, in theory, sperm suspended like this can last forever – no matter the source of the sperm.
Things are not as straightforward, however, when it comes to freezing eggs. Unlike sperm, which are quite small, the egg is big – the biggest cell in the body. When an egg is frozen, the large cell’s greater fluid content often sustains ice-crystal damage. Even with an improved technique, known as vitrification, which flash-freezes the egg to avoid crystallization, there is only a ten percent success rate. If a young woman has her own eggs removed, chances are that when she is older and decides to use them, the process may very well have failed. And seeing that for women, removing eggs is quite invasive and uncomfortable, being able to make eggs in a lab from a woman’s DNA is very attractive: it would mean that most of the process takes place outside of her body with far less risk.
So, how close are we? Bone marrow stem cells have proved extremely promising in the early experiments to create in vitro-derived germ cells: given the right signals, bone marrow stem cells are capable of becoming sperm. Further, three types of stem cells exist in bone marrow and it contains the cell-level blueprints for much of the body, including the heart, lungs, liver, kidney, bone, cartilage, fat, muscle, tendon, skin, and even the brain.
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