Reproductive Technology and Germ-Line Engineering: Utopia or Nemesis?

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Germ-line Engineering a Brave New Universe
Cloning and Synthetic Human Genomes
Surviving by Caesarian, Womb Transplant and IVF
Benefits and Risks of IVF and ICSI
Pre-implantation Genetic Diagnosis and Non-Invasive Pre-natal Genetic Screening
IVF and Heritable Defects
Contraception, Abortion and the Divorce of Social Sexuality from Reproduction
Sex Determination and Sexual Imbalance
Declining Fertility, Feminization of Nature and Ephemeral Males
The Three Parent Child and The Sexual Chimaera
Demise of the Egg and Sperm
Sex on Ice: Transplanted Generations
Human Evolution: Accelerated, Inverted or Extinguished?

Research Updates

The future of human evolution and how it will be effected, both by the relationship between the sexes and new emerging technologies is a key question overshadowing all our reproductive futures. Major changes have happened to our entire reproductive profile as a result of effective contraception, choices in sex roles and careers, and increasing use of highly technological medical science, in fertility treatments, genetic testing, in-vitro fertilization and emerging new techniques such as germ-line engineering. These are issues that effect everyone, their hopes for a reproductive future for their progeny and the whole nature of what it is to be human. Changes in genetic technology are overtaking us so rapidly that there is a large risk of watersheds being crossed before we have even begun to consider their potential future implications. This chapter asseses these and their impact on our reproductive futures.

Fig 1: Click to enlarge. (a) The gene-editing technique CRISPR uses an enzyme (white) and RNA guides [green] to cut DNA at a point specified by a DNA fragment [magenta] (Cyranoski D 2015 Scientists sound alarm over DNA editing of human embryos Nature doi:10.1038/nature.2015.17110). (b) The CRISP system originates from an ancient viral immunity system shared by bacteria and archaea, similar to the RNAi-DICER viral immunity system in eucaryotes, in which Cas protein units form an alternating modular 'string of beads' with captured snippets of invading viral sequences to generate an immune 'memory' of previous invasions. Processed modules are used as templates to destroy subsequent invasions (Gottesman S 2011 Dicing defence in bacteria Nature 471 588-9). (c) The cas9 system in Strep. pyogenes utilizing a crRNA-tracrRNA duplex can be amended by using a single chimeric RNA to produce specific gene targets for the CRISP editing process to specific gene sites (Jinek M et al. 2012 A Programmable Dual-RNA−Guided DNA Endonuclease in Adaptive Bacterial Immunity Science 337 816 doi: 10.1126/science.1225829). In April 2015 a Cas9 from Staph. aureus was reported which is small enough to be able to be inserted in vivo in tissues using an adeno-associated (AAV) virus vector and was successfully applied to disrupt the Pcsk9 gene involved in hypercholesterolemia (F.A. Ran et al. 2015 In vivo genome editing using Staphylococcus aureus Cas9, Nature, doi:10.1038/nature14299).

Germ-line Engineering a Brave New Universe

The greatest threat to our own evolutionary paradigm comes from precisely the area containing the greatest visionary utopian potential. At stake here is not just a question of human ethics and freedom of choice but the very principles upon which the survival of living species depends. Each species which survives is part of an unbroken genetic web which runs from the beginning of life on earth. It survives because its reproductive process is an evolutionarily stable strategy which is also robust to change and fluctuation over evolutionary time scales. Our social structures are already becoming unstable to slighter and slighter disturbances, with food production depending on modified species which cannot survive in the wild and sophisticated networks of information and transport, the failure of which could cause most of the world's population to die out overnight .

In a Comment published on 12 March 2015 in Nature (Lanphier, E. et al. Nature 519, 410-11 See: doi:10.1038/nature.2015.17110), Edward Lanphier, chairman of the Alliance for Regenerative Medicine in Washington DC, and four co-authors call on scientists to agree not to modify human embryos - even for research. Known as germline modification, edits to embryos, eggs or sperm are of particular concern because a person created using such cells would have had their genetic make-up changed without consent, and would permanently pass down that change to future generations. "Don't edit the human germ line" expresses grave concerns regarding the ethical and safety implications of this research, partly because of a fear of the negative impact it could have on important work involving the use of genome-editing techniques in somatic (non-reproductive) cells. Lanphier is CEO of Sangamo Biosciences, a California biotechnology company that is using another gene editing technique, zinc finger nucleases, to try to treat HIV in adults by altering their blood cells. But other scientists disagree with that stance. Although there needs to be a wide discussion of the safety and ethics of editing embryos and reproductive cells, they say, the potential to eliminate inherited diseases means that scientists should pursue research.

Every application to use gene-editing technology for a therapy would have to be validated independently as safe and effective, says Jennifer Doudna of the University of California, Berkeley, who invented the CRISPR-Cas9 along with Emmanuelle Charpentier of Umea University in Sweden. "It would be necessary to decide, for each potential application, whether the risks outweigh the possible benefit to a patient. I think this assessment must be made on a case-by-case basis". A meeting of leading scientists to discuss a forward strategy at Napa has led to a call to discourage the use of germ-line CRISPR technology until society has had time to develop an ethical framework and the safety of the procedure is fully guaranteed (Baltimore D et al. 2015 A prudent path forward for genomic engineering and germline gene modification Science doi: 10.1126/science.aab1028).

Germline gene editing is already banned by law in many countries - a 2014 review by Tetsuya Ishii, a bioethicist at Hokkaido University in Sapporo, Japan, found that of 39 countries, 29 have laws or guidelines that ban the practice. In western Europe 15 of 22 nations prohibit the modification of the germ line, but 7 do not. Ishii remains concerned about countries such as the United States, where germline editing is not banned, but requires only government approval - albeit curently not envisaged. The US National Institutes of Health's Recombinant DNA Advisory Committee states that it "will not at present entertain proposals for germ line alterations" (see go.nature.com/mgscb2). However, such restrictions have a history of being circumvented, as in the case of unproven stem-cell treatments. Ishii is also concerned about China, where gene-editing techniques in primates have developed fastest, which prohibits gene-editing of embryos but does not strictly enforce similar rules, illustrated by failed attempts to curb the use of ultrasound for sex selection and to stamp out unauthorized stem-cell clinics.

There are two broad schools of thought on modifying the human germline, said R. Alta Charo, a bioethicist at the University of Wisconsin and a member of the Doudna group. One is pragmatic and seeks to balance benefit and risk. The other "sets up inherent limits on how much humankind should alter nature," she said. Some Christian doctrines oppose the idea of playing God, whereas in Judaism and Islam there is the notion "that humankind is supposed to improve the world." She described herself as more of a pragmatist, saying, "I would try to regulate such things rather than shut a new technology down at its beginning" (Wade N 2015 Scientists seek ban on method of editing the human genome New York Times, 19 Mar).

Fig 2: Left: Primate pioneers: Twin infant macaques whose genomes were modified within three different genes. The Chinese researchers injected single-cell macaque embryos with RNAs to guide the genome-editing process. The team modified three genes in the monkeys: one that regulates metabolism, another that regulates immune cell development and a third that regulates stem cells and sex determination. Right: Survey of US adults Auguast 2014 by the Pew Research Center showing attitudes to changing a baby's genetic characteristics.

However in "Engineering the Perfect Baby", Antonio Regalado (2015) notes that several research teams are actively engaged in precisely this development, including Luhan Yang, a Harvard recruit from Beijing who had been a key player in developing CRISPR-Cas9 and is working with George Church of the Harvard Medical School. Yang notes that by editing the DNA of egg or sperm cells, or the embryo itself, it could be possible to correct disease genes and to pass those genetic fixes on to future generations. Such a technology could be used to rid families of scourges like cystic fibrosis. It might also be possible to install genes that offer lifelong protection against infection, Alzheimer's, and, Yang told me, maybe the effects of aging. Several people interviewed by MIT Technology Review said that such experiments had already been carried out in China and that results describing edited embryos were pending publication.

The gene-editing technique CRISPR (fig 1) uses an enzyme and RNA guides to cut DNA at a point specified by a DNA fragment thus providing a specific code-guided change rather than the more random site changes caused by inserting genes using viral integrases. Church notes that what is driving everything is the "incredible specificity" of CRISPR. Although not all the details have been worked out, he thinks the technology could replace DNA letters essentially without side effects. "Any scientist with molecular biology skills and knowledge of how to work with [embryos] is going to be able to do this," says Jennifer Doudna who in 2012 invented how to use CRISPR to edit genes (see Jinek et al fig 1).

  1. Who Owns CRISPR? The Scientist 2015
  2. Alternative CRISPR system could improve genome editing Nature 2015
  3. Where Could the First CRISPR Baby Be Born? Nature 2015
  4. CRISPR The Disruptor Nature 2015
  5. Enzyme tweak boosts precision of CRISPR genome edits Nature 2016
  6. How the US CRISPR patent probe will play out 2016
  7. Gene-editing hack yields pinpoint precision Nature 2016
  8. CRISPR gene-editing system unleashed on RNA 2016

However, at present, the efficiency with which CRISPR can delete or disable a gene in a zygote is about 40%, whereas making specific edits should work less frequently - say 20% of the time. Since all embryos have two copies of most genes, one from each parent, sometimes both copies get edited, but sometimes just one does, or neither. Only about half the embryos will lead to live birth, and of those that do, many could contain a mixture of cells with edited DNA and cells without. This presents obvious problems for using the process on humans. Though highly efficient, the technique occasionally cuts the genome at unintended sites. The issue of how much mistargeting could be tolerated in a clinical setting is one that Dr. Doudna's group wants to see thoroughly explored before any human genome is edited. In articles 2 and 5 linked above, significant improvements have been made, reducing collateral mutations to much less significant 'undetectable' levels.

Fig 2b: Gene editing using zinc finger proteins has been used to cure intractable acute lymphoblastic leukemia in a one year-old who had had unsuccessful chemotherapy and bone marrow transplant. T-cells from a healthy donor were modified so they could potentially be given to hundreds of patients. Normally if T-cells from another person are injected into a recipient who is not a perfect match, they will recognise the recipient's cells as foreign and attack them. To prevent this, Waseem Qasim's team used gene editing to disable a gene in the donor cells that makes a receptor that recognises other cells as foreign. But the recipient's immune system also recognises non-matched T-cells as foreign and will attack them. In leukaemia patients, this is not a problem because they are given drugs that destroy their immune system, but one of these drugs - an antibody - also destroys donor T-cells. So Qasim's team also disabled a second gene in the donor T-cells, which made them invisible to the antibody. At the time that Qasim was contacted by Layla's doctors, his engineered T-cells, called UCART19 cells and developed in collaboration with New York biotech company Cellectis, had only ever been tested in mice (Gene editing saves girl dying from leukaemia in world first New Scientist 5 Nov 2015).

The development of precise gene-editing techniques in recent years has brought fresh urgency to the issue. These techniques use enzymes called nucleases to snip DNA at specific points and then delete or rewrite the genetic information at those locations. The methods are simple enough to be used in a fertility clinic, raising fears that they might be applied in humans before safety concerns have been addressed. One concern, for example, is that the nucleases could cause mutations at locations other than those targeted. Guanghui Liu, a stem-cell researcher at the Chinese Academy of Sciences Institute of Biophysics in Beijing, collaborated on a study that showed that modifying one gene in stem cells resulted in minimal mutations elsewhere (Suzuki, K. et al. Cell Stem Cell 15, 31-36), but he warns that this is only one case.

In February 2014, Geneticist Xingxu Huang of Shanghai Tech University in China reported using a gene-editing technique to modify embryos that developed into live monkeys (Niu, Y. et al. Cell 156, 836-43). As of March 2015 he was seeking ethics committee permission to try genetically modifying discarded human embryos. Human embryos would not be allowed to develop to full term in his experiments, but the technique "gives lots of potential for its application in humans".

This experiment has already been performed, opeing the era of human germ-line engineering. In April 2015 Chinese scientists led by Junjiu Huang, a gene-function researcher at Sun Yat-sen University in Guangzhou reported editing the genomes of human embryos (Liang, P. et al. Protein Cell doi:10.1007/s13238-015-0153-5). The team attempted to modify the gene responsible for β-thalassaemia, a potentially fatal blood disorder, using CRISPR/Cas9. Their results reveal serious obstacles to using the method in medical applications. The embryos, obtained from the fertility clinics, had been created for use in in vitro fertilization but had an extra set of chromosomes, following fertilization by two sperm. This prevents the embryos from resulting in a live birth, though they do undergo the first stages of development. The team injected 86 embryos and then waited 48 hours for the CRISPR/Cas9 system and the molecules that replace the missing DNA to act - and for the embryos to grow to about eight cells each. Of the 71 embryos that survived, 54 were genetically tested. This revealed that just 28 were successfully spliced, and that only a fraction of those contained the replacement genetic material. "If you want to do it in normal embryos, you need to be close to 100%," Huang says. "That's why we stopped. We still think it's too immature."

Off-target cleavage sites detected in a sequencing assay after applying CRISPR/Cas9.

The process also resulted in off-target effects of CRISPR/Cas9 affecting other sites in the genome. In the paper the researchers note: "Because the edited embryos are genetically mosaic, it would be impossible to predict gene editing outcomes through pre-implantation genetic diagnosis (PGD). Our study underscores the challenges facing clinical applications of CRISPR/Cas9".

The same day another group of scientists reported a form of gene editing in mitochondria which could cure mitochondrial diseases which affect about 1 in 5000 people. They injected RNA producing an endonuclease targeting mutated mitochondria in mouse ova containing both normal and mutated mitochondria, selectively reducing the mutated mitochondria to levels low enough so disease would not occur in the resulting embryo. This could avoid the prospect of three parent embryos where a mother's egg nucleus is transplanted into the cytoplasm of anothers woman's dotated egg containing healthy mitochondira (Reddy, P. et al. Cell doi: 10.1016/j.cell.2015.03.051 ).

Researchers have already been tweaking the components of CRISPR-Cas9 through genetic engineering to drive down its error rate. They have tweaked the RNAs that guide the Cas9 enzyme to a specific site in the genome, engineered the system so that researchers can easily switch it off, so that the enzyme does not have as much opportunity to make unwanted changes and also altered the enzyme itself so that it is less likely to act at sites with mismatches between the RNA that guides the enzyme and the DNA that it targets, reducing the error rate by 90% (doi:10.1038/nature.2015.18932).

Scientists at several centers, think they will soon be able to use stem cells, which unlike embryos can be grown and multiplied clonally, to produce eggs and sperm in the laboratory. By editing the genes of the stem cells and then turning them into an egg or a sperm, large numbers of edited embryos could be produced. OvaScience, a company that was founded four years ago to commercialize the scientific work of Harvard's anti-aging expert David Sinclair and Jonathan Tilly, an expert on egg stem cells raised $132 million in new capital. Sinclair in a speech said it would it would let parents determine "when and how they have children and how healthy those children are actually going to be". Sinclair told the investors that he was trying to alter the DNA of these egg stem cells using gene editing, work he later told me he was doing with Church's lab. Once the technology works, he said, infertile women will be able to produce hundreds of eggs, and maybe hundreds of embryos. In December 2013, OvaScience announced it was putting $1.5 million into a joint venture with a synthetic-biology company called Intrexon, whose R&D objectives include gene-editing egg stem cells to "prevent the propagation" of human disease "in future generations."

Editing sperm stem cells could become a driving force for human germ-line editing because current techniques for overcoing male infertility, such as ICSI, risk dooming the male children to the same reproductive fate in cases where the source of the infertility is genetic, creating a chain of genetic infertility in the human population. Subfertility affects around 15% of all couples, and a severe male factor is identified in 17% of these couples. While the etiology of a severe male factor remains largely unknown, prior gonadotoxic treatment and genomic aberrations have been associated with this type of subfertility. In the latter case CRISPR could provide the most ethically acceptable route to restoring fertitility in a naturally viable manner actually curing the condition, rather than merely perpetuating it (doi:10.1093/humupd/dmw017).

Fig 3: How to make babies from pluripotent stem cells. Katsuhiko Hayashi and his senior professor, Mitinori Saitou have spent more than a decade piecing together the details of mammalian gamete production. In the mouse, germ cells emerge just after the first week of embryonic development, as a group of around 40 primordial germ cells (PGCs), which go on to form the tens of thousands of eggs that female mice have at birth, and the millions of sperm cells that males produce every day. Saitou has identified several genes - including Stella, Blimp1 and Prdm14 - that play a crucial part in PGC development. In 2009, he found that when culture conditions are right, adding a single ingredient - bone morphogenetic protein 4 (Bmp4) - with precise timing converts embryonic cells to PGCs. This careful tracing of the natural process contrasts with other researchers, who try to create specific cell types in vitro by bombarding stem cells with signalling molecules and then picking through the resulting mixture of mature cells for the ones they want. It it is never clear by what process these cells are formed or how similar they are to the natural versions. Hayashi then used activin A and basic fibroblast growth factor to convert cultured early embryonic stem cells into epiblasts and then to apply Saitou's previous formula to push these cells to become PGCs. The approach was successful. They repeated the experiment with induced pluripotent stem (iPS) cells - mature cells that have been reprogrammed to an embryo-like state. Again, the sperm were used to produce pups (see fig 12). They expected eggs to be more complex, but Hayashi made PGCs in vitro with cells from a mouse with normal colouring and then transferred them into the ovaries of an albino mouse. The resulting eggs were fertilized in vitro and implanted into a surrogate producing coloured pups. However there are many problems translating this into a medical fertility procedure for humans. Although the offspring generated by their technique usually seem to be healthy and fertile, the second-generation PGCs often produce eggs that are fragile, misshapen and sometimes dislodged from the complex of cells that supports them. When fertilized, the eggs often divide into cells with three sets of chromosomes rather than the normal two, and the rate at which the artificial PGCs successfully produce offspring is only one-third of the rate for normal in vitro fertilization (IVF). The group has already started tweaking human iPS cells using the same genes, but human signalling networks are different from those in mice and the ethical dilemmas of dealing with human embryos make human research more difficult. Work will first proceed with monkeys (Cyranoski D 2013 How to make babies Nature doi:10.1038/500392a).

On the agricultural and farming front, CRISPR's ability to precisely edit existing DNA sequences makes for more-accurate genetic modifications, but it also makes it more difficult for regulators and farmers to identify a modified organism once it has been released than is the case with current GM organisms generated by conventional genetic engineering techniques.

The process is even more loaded with potential pitfalls, when the elimination of some existing diseases such as malaria and lyme disease is envisaged using CRISPR with gene drive. Anthony James and colleagues have in November 2015 announced that they have used the CRISPR gene editing technique to create a gene drive, which they claim could eliminate malaria from Anopheles stephensi by spreading a malaria-inactivating antibody through a population. (doi:10.1073/pnas.1521077112). Researchers have since engineered Anopheles gambiae mosquitoes - which spreads malaria across sub-Saharan Africa - to pass on genes that cause infertility in female offspring, making it possible to effectively wipe the species out (doi:10.1038/nbt.3439). Would it be wrong to eliminate mosquitos?

Usually, a genetic change in one organism takes a long time to spread through a population, because a mutation carried on one of a pair of chromosomes is inherited by only half the offspring. But a gene drive allows a mutation made by CRISPR on one chromosome to copy itself to its partner in every generation, so that nearly all offspring will inherit the change, leading to the complete loss of the other characteristic. If that mutation reduced the number of offspring a mosquito produced for example, the population could be wiped out, along with any malaria parasites it is carrying.

But many researchers are deeply worried that altering an entire population, or eliminating it altogether, could have drastic and unknown consequences for an ecosystem: it might mean that other pests emerge, or it could affect predators higher up the food chain. And researchers are also mindful that a guide RNA could mutate over time such that it targets a different part of the genome. This mutation could then race through the population, with unpredictable effects and potentially irreversible consequences.

Some reassurance can be gained from the fact that resistance to gene drive modifications tends to emerge naturally to to accidental excisions of the target gene (doi: 10.1101/057281). According to a model developed by George Church’s team at Harvard University, this means that while existing CRISPR gene drives can spread rapidly at first, resistance will appear and the gene drive will disappear after a hundred generations or so. But they have a plan to make the target DNA part of a crucial gene and to cut this gene in several places, so that the crucial gene is destroyed. The gene drive includes the sequences needed to repair the gene. This means that if the copy and paste process works perfectly, the crucial gene is repaired along with the gene drive. If the process goes awry, the target DNA will be wrecked. Because it is crucial to the organism’s survival, the chromosome carrying it will not spread despite becoming resistant to the gene drive. So we are back full circle to serious concerns.

A further somewhat ingenious method is to create a chain of drive elements which will reproducre rapidly but eventually die out. To create gene drives that don’t spread indefinitely, a team have split them up into three or more parts – which Esvelt calls elements – to create a "daisy chain". Each element contains one or more genes that contribute towards the whole gene drive. In Esvelt’s design, element A can only copy and paste itself if element B is present. Element B can only copy and paste itself if element C is present. And element C, crucially, cannot copy and paste itself at all – it can only spread by normal breeding, to half of offspring. The idea is to release thousands of mosquitoes, say, carrying all three elements. When they mate with wild mosquitoes, all the offspring will inherit element A and B, but only half will inherit element C. In the following generations, element B will spread rapidly and A will spread even more rapidly, but C will gradually die out. Once it does, B will start to disappear, and finally A will too (BioRxiv, doi: 10.1101/057307).

A decade ago, Monsanto tried to exploit 'terminator technology' - genetically engineering proprietary seeds, so that the plants they grew would be infertile because the second generation seeds will inherit a lethal change which had been suppressed in the first round by the company. This led to concerns that viable food species could become supplanted by commercially captive products which could not survive naturally, leading to a potential collapse of natural varieties if the terminator products flooded the world agricultural market. Gene drive raises very similar concerns about the irreversible loss of genes, essential varieties, or even whole species from the ecosystem. Notably early experiments on gene drive failed to test reversibility accentuating ethical fears about this 'final fix' technology.

There are immense pressures from those who harbour deleterious genes and who wish to have children to invoke techniques of gene manipulation which will free their offspring from such defects. Leading on from this there are those who believe we have left the age of natural evolutionary stability and now wish for a variety of medical elitist and cosmetic reasons to enter the brave new world of endless human genetic design. Finding a course through this futuristic mire is the greatest challenge facing humanity outside mass extinction of the biosphere. Many bioethicists are sympathetic about using germ-line therapy to shield a child from a family disposition to cancer or atherosclerosis or other illnesses with a strong genetic component. As James Watson co-discoverer of the double-helical structure of DNA said: 'We might as well do what we finally can to take the threat of Alzheimers or cancer away from a family.' No law prohibits germ-line engineering. None of us want to pass on to our children lethal genes if we can prevent it. - that's what is going to drive this. At a UCLA symposium on germ-line engineering, two thirds of the audience supported it. Few would argue against using the technique to eradicate a disease that has plagued a family for generations. As one commentator put it: 'We know where to start. The harder question is do we know where to stop?'

Critics cite a host of fears. Children would be the subject of experiments. Parents would be influenced by genetic advertising from IVF clinics. Germ-line engineering would lead to "positive eugenics," encouraging the spread of allegedly superior genes. And it would affect people not yet born, without their being able to agree to it.

Already we have mice genetically engineered to have three rather than two copies of the tumor suppressing to resist cancer. At present these are experimental animals for human drug research, but the development of highlights how pressure could grow for germ line engineering to achieve a cancer-free or cancer-reduced human race:

Scientists have bred a family of 'supermice' highly resistant to cancer. They have 3 instead of 2 copies of genes that keep cell division in check. Cell growth and division is normally kept under control by a group of gatekeeper genes called tumour suppressors. Dr Manuel Serrano used DNA technology to breed mice that had an extra copy of part of the tumour suppressor genes called Ink4a/ARF locus. This locus controls the production of two proteins that together appear to stop most human cancer cells developing. When the animals were exposed to various carcinogens they developed tumours at a much lower rate than normal. What's more, the presence of the extra copy of the locus and increased cancer resistance had no apparent effect on the lifespan or fertility of the 'supermice' (The supermice that resist cancer BBC 2 Nov 2004).

Some researchers question why these considerations need to lead to germ-line engineering at all. Parents known to be at risk of certain serious genetic abnormalities are already offered genetic testing and the option of an abortion if their fetuses have the disorders. Using this approach, the number of Tay-Sachs births has been reduced by more than 95 per cent among American Jews. For women willing to have IVF, an embryo can even be tested before pregnancy starts and as a combination of IVF and genetic testing becomes more available most of its techniques appear to have the same protective effect without active gene splicing.

Clearly, pre-implantation genetic diagnosis (PGD) creates an ethical problem for anyone who believes that life begins at conception. But even people who don't share this view may be troubled by, say, PGD for conditions that take many years to show up. Take for example, the cancer of the bowel that is caused by the familial polyposis coli gene (FAP) or the breast and ovarian cancers that are linked to mutations in the BRCA1 and 2 genes. Is it right to test-and discard-an embryo for a disease that would not develop until after several decades of a presumably fulfilling life? Surely, in those intervening years, better methods of prevention, detection and treatment could be developed. So, is PGD really eugenics? We usually think of eugenics as a societal or governmental effort to advance humanity by 'improving' heredity. But can it seem more benign - merely the sum of individual choices that prevent children with certain genetic defects from being born? Are such genetically based interventions aimed at improving the lot of our children akin to piano lessons, or are they more sinister? ('Great expectations' New Scientist 1 May 99).

Then there's the possibility of cosmetic changes and enhancements that have nothing to do with saving lives and preventing disease. Many behaviourat traits, from cheerfulness to sexual orientation, have already been linked, if tenuously, to variations in single genes. Many more such links will be reported in the near future. For example, if we become able to dramatically affect intelligence, it will be pretty irresistible.

One reason for cold feet is that systematic genetic engineering could actually rob society of desirable traits. Many traits, from sexual orientation to religiosity and intelligence are multi-gene effects linked only weakly to a given protein-producing gene, and also involve concerted gene regulation involving non-coding regions of DNA and/or micro-RNAs. Conditions such as autism are beleived to result from many de-novo alterations of such non-coding regions. Many diseases from sicle-cell aneamia through hemochromatosis to high cholesterol are actually a result of adaptive changes which promoted survival. Sickle-cell in monozygous form confers resistance to malaria, heamochromatosis to plague and high-cholesterol to vitamin-D deficiency in the Northern winter. 'Disease' genes in combination with other genes, or in people who are merely carriers, may also help produce such intangibles as artistic creativity, a razor-sharp wit, or the ability to wiggle ones ears. Wipe out the gene, and you risk losing those traits too. And while no one would wish manic depression on anyone, society might be the poorer without the inventiveness that many psychologists believe is part and parcel of the disorder, or the visionary nature that accompanies schizophrenia.

If esoteric worries about what might happen in a genetically engineered society are unlikely to change people's views, safety issues could. With germ-line engineering there's scope for unpredictable, even monstrous, alterations. The so-called 'Beltsville pig', was engineered by scientists at the US Department of Agriculture to produce human growth hormone that would make it grow faster and leaner. They added a genetic switch that should have turned on the growth hormone gene only when the pig ate food laced with zinc. But the switch failed. The extra growth hormone made the pig grow faster, but it also suffered severe bone and joint problems and was bug-eyed to boot. Unlike human experiments, slaughtering 'failures' is no problem for animal genetic engineers.

Cloning and Synthetic Human Genomes

Cloning is one of the aspects of germ-line modification which strikes the rawest nerves and excites the basest instincts. Cloning is both feared as a potentially totalitarian form of extreme eugenics and focal power. Abhorred as defying our God-given sexual nature. Many geno-technophiles consider it the utopia of created immortality. Cloning is really just one very rigid form of germ-line engineering designed to produce a parthenogenetic copy of the original organism. Reproductive cloning does however raise major issues of genetic uniformity and extreme lack of genetic diversity.

Coupled to this prospect is the recent announcement by a team composed of researchers, including George Church, and a private start-up software company called Autodesk. Andrew Hessel of Autodesk, who first proposed the human genome synthesis project in 2012, is at think-tank Singularity University, which embraces a future in which technology outpaces biology. Hessel has often spoken of his plans to make genetic engineering into an accessible "programming language", using Autodesk software. The team says it expects the final bill to be less than the $3-billion cost of the first Human Genome Project. The primary goal of the Human Genome Project-Write, as it is known, is to engineer large genomes of up to 100 billion base pairs, including "whole genome engineering of human cell lines and other organisms of agricultural and public health significance", the team writes. This will require technological development early on in the project "to propel large-scale genome design and engineering" (Science, doi.org/bjmv).

However the approach clearly has very disquieting utopian implications. In an interview with US radio station NPR, Marcy Darnovsky of the California-based Center for Genetics and Society said: "The worry is that we're going to be synthesising entire optimised human genomes - manufacturing chromosomes that could be used ultimately to produce synthetic human beings that they see as improved models."

  1. Scientists discuss creating an entirely synthetic human genome from scratch
  2. New Scientist commentary 2016
  3. The Genome Project - Write 2016

Besides reproductive cloning there is a burgeoning market in therapeutic cloning. Techniques that would for example save a few stem cells from an early embryo to use as cells for organs for tissue transplant or replacement of essential cell types in cases of cancer treatments which kill reproductive or immune cells. There is also the idea of using therapeutic cloning to generate stem cell lines from aborted fetuses to provide embryonic stem cells which although not genetically the same could still be of use in regenerating damaged systems in the body. This in turn involves unresolved ethical issues about the status of the unborn human embryo, when does consciousness begin, abortion and to what extent the embryo should become a market or medical research commodity.

Therapeutic cloning itself uses human eggs and raises the barrier to reproductive cloning, since the same technology would apply.

South Korean scientists say they have made stem cells tailored to match the individual for the first time. Each of the 11 new stem cell lines that they made were created by taking genetic material from the patient and putting it into a donated egg. The resultant cells were a perfect match for the individual and could mean treatments for diseases like diabetes without problems of rejection. But the researchers told Science that there were still hurdles to overcome. ('Patient-specific stem cell first' BBC 19 May, 2005)

However problems with regenerating the telomeres essential for continued replication may remain, the stem cells need to be reprogrammed to specific tissue types, genetically-modified to remove disease bearing traits and concerns have been raised that such stem cells could give rise to cancers.

Every time a cell divides, it sheds tiny snippets of telomeres, which serve as protective caps on the ends of chromosomes. After perhaps a hundred divisions, a cell's telomeres become so truncated that its chromosome to fray, rather like shoelaces that have lost their plastic tips. Eventually, such aged cells die - unless, like 'immortal' cancer cells, they produce telomerase, an enzyme that protects and even rebuilds telomeres. Scientists have long dreamed of drugs that would inhibit the immortalizing enzyme because, maybe cancer cells would run out of telomeres and just poop out. Papers published a week apart in Science and Cell, have announced a breakthrough. Both teams have managed to clone a gene that controls the activity of the telomerase enzyme in human cells. (The telomerase gene is Isolated Time, Sep 1, 1997)

Fig 4: Telomeres fluoresce at the tips of chromosomes (Jones R348).

Huntington Willard and colleagues reported that they had created artificial chromosomes in cultured human cells that replicated every time the cells divided. 'We cultured them for six months, and they looked like perfectly normal chromosomes,' says Willard. These human artificial chromosomes (HACS) promise one ultimate form of genetic engineering. Once perfected, HACs will make it possible for genetic engineers to ship complex custom-made genetic programmes into human embryo cells. Each gene could come with control switches geared to trip only in particular tissues, or when the patient takes a particular drug. Suppose, for instance, that men in your family tend to get prostate cancer at a young age. Insert into your fertilised egg an HAC containing a gene for a toxin that kills any cell that makes it, and two switches for that gene one that is turned on only by prostate cells and another by ecdysone, an insect hormone that humans cannot make. Nine months later, you're delivered of a bouncing baby boy. Fifty years later, he gets prostate cancer. He takes ecdysone, which activates the prostate poison, killing every prostate cell in his body Even cancer cells that have spread to other parts of the body should be wiped out. However inserting extra chromosomes or other DNA even into sex cells is liable to produce a 'mosaic' organism because the DNA is not integrated into the chromosomal genome, so will not be perpetuated in the germ-line as a fully heritable trait. A first step to full germ-line engineering of sperm has been made in zebra fish by growing sperm precursor cells and using retroviruses to insert a new gene into their genome and then letting them mature to make fully GM sperm (Proc. Nat. Acad. Sci. 101 1263).

But something else is suddenly making it okay to discuss the once forbidden possibility of germ-line engineering. Molecular biologists now think they have clever ways to circumvent the ethical concerns. There may be ways for instance to design a baby's genes without violating the principle of informed consent. This is the belief that no one's genes, not even an embryos - should be altered without his or her permission. Presumably a few people would object to being spared a fatal disease. But what about genes for personality traits, such as risk-taking or being neurotic? The child of tomorrow might have the final word about the genes says UCLA geneticist John Campbell. The designer gene for say patience could be paired with an of-off switch, he says. The child would have to take a drug to activate the patience gene. Free to accept or reject the drug, he retains informed consent over his endowment ('Tomorrow's Child' Sharon Begley NZ Herald Nov 98).

Researchers are experimenting with tricks to make the introduced gene self-destruct in cells that become eggs or sperm. That would confine the tinkering to one generation. Then if it became clear that eliminating the genes for say mental illness also erased genes for creativity that loss would not also become part of the man's genetic blueprint. In experiments with animals Mario Capecchi if the University of Utah has designed a string of genes flanked by the molecular version of scissors. The scissors are activated by an enzyme that would be made only in cells that become eggs or sperm. Once activated the genetic scissors snip out the introduced gene and presto it is not passed along to future generations. 'What I worry about' says Capecchi 'is that if we start mucking around with eggs and sperm at some point - since this is a human enterprise - we are going to make a mistake'. You want a way to undo that mistake. And since what may seem terrific now may seem naive in 20 years you want a way to make genetic change reversible (ibid).

There is no easy technological fix for another ethical worry however. With germ-line engineering only society's haves will control their genetic traits. 'If you are going to disadvantage even further those who are already disadvantaged' says bioethicist Ruth Macklin 'then that does raise serious concerns' (ibid). Lee Silver (1999) predicts in 'Remaking Eden' that cloning and other genetic technologies could create a genetic elite, or what he dubs the 'GenRich' class, who would refuse to mate with 'natural' human beings and ultimately become a separate species. 'The notion that the upper and the lower classes will become further and further apart until they separate into different species I think would be the most horrible thing that ever happened to humanity. It would give those who were genetically enhanced a rationale for severe discrimination against those who were not. The enhanced would treat the unenhanced the same way we treat other species right now. We treat human beings as equals, but we put other highly intelligent primates, such as chimpanzees and gorillas, into zoos and cages' ('Us and Them' New Scientist 9 May 98 36). But Steve Jones doubts the reproductive isolation will hold. 'The GenRich would be hard pressed to keep their new genes to themselves', he says. History shows that even in a highly stratified society, the classes still mingle due to our basic, animal instincts. 'I believe in the healing power of lust' (NS 13 Jan 2001).

'The potential power of genetic engineering is far greater than that of splitting the atom, and it could be every bit as dangerous to society,' says Liebe Cavalieri, a molecular biologist at the State University of New York in Purchase. Cavalieri, who has worked in the field for more than 30 years, thinks it unlikely that the ugly side of genetic engineering will stop development of the technology in its tracks. 'It is virtually inevitable it will get used and for the most banal reasons possible-to make some money, or to satisfy the virtuoso scientists who created the technology' (New Scientist 3 Oct 98 25)

Some people go so far as to say germ-line engineering is the key to our race to the stars. Our destiny, says Robert Zubrin, is to leave the planet, just as our ancestors left Africa and colonised the rest of the world. He believes that a fully functional Martian city will be built in this century. And as surely as our descendants shape that world, it will shape them. There would be incredible selection for people whose genes help them survive in the harsh environment, and even on a terraformed Mars this would long persist. While providing Earthly children with genetic enhancements may seem like a frivolity, it would just be good sense to endow Martian kids with the ability to endure a thinner atmosphere and stronger solar radiation. And since the gravity on Mars is only about one-third the strength of Earth's, Zubrin suggests it might also be wise to give its inhabitants long, springy legs to cover terrain more easily ('The Future of Human Evolution' New Scientist 13 Jan 2001).

To survive over time we need natural evolutionary stability, so that even if humanity does split into two races, we also need to make sure the naturally selected genome of humanity survives, particularly as it does with almost no resources in places like the Kalahari Desert. Unfortunately the very people upon whom our best human traditions of long-term survival depend are being driven from their habitat by the government of Botswana, to turn the Kalahari into a wildlife park, leaving the world vulnerable to the complete loss of the most evolutionarily stable mode of long-term existence on planet Earth.

We thus urgently need to understand how to evoke the principles of sexual complementation in an era of nascent technological change in ways which preserve the intrinsic robustness of the genetic endowment which makes us human and which ensures our emergence and survival over evolutionary time scales - massively parallel natural genetic algorithms with their deep variety and emergent novelty - so that we can provide for the evolutionary possibilities the uncertain future may demand. We need urgently to develop a future ethic to deal with reproductive technology in terms of our evolutionary fitness as a species, as well as individual choice and utopian ambitions. If we don't we could suddenly find ourselves becoming extinct overnight because of an ever-so-slight disruption of the technological civilization on which we depend, having become unable to feed ourselves or reproduce without the intervention of sensitive high technology.

Surviving by Caesarian, Womb Transplant and IVF

Entering into such questions come a host of questions in reproductive technology and medical science which are transforming the very nature of the reproductive process and even our viability as a species. The first of these is the ancient art of the Caesarian section which goes back at least to Roman times. Although many of these ancient operations may have been lethal to the mother, Caesarians are now becoming so routinely common that they threaten to undermine the natural viability of human birth. The rates of Caesarian births are rising to epidemic levels partly for social or cosmetic 'designer deliveries'.

Fig 5: Caesarian deliveries are beginning to overtake natural births

Gynecologists have predicted rates of over half live births within ten years, although health authorities seek to reduce current levels of around 25% of all births to the WHO guideline of 10-15%. This raises a huge issue of balancing individual needs against the future viability of the human race, if a majority of the population come to be delivered by unnatural means. Human delivery is already at the threshold of difficulty. Human evolution has progressively delayed brain development to keep natural delivery viable as head size has increased. Caesarian delivery also leads to increased risks of complications in future pregnancies rather than the realtively greater ease with natural childbirth, as well as an increase of the still birth rate from 1.4 to 2.4 per 10,000.

As of 2015 rates of Caesarian section have soared in developed countries across the world far beyond safe limits for infant health and safe limits to ensure future human reproductive viability. In Brazil for example over 50% of live births are now by C-section with 45.9% in public hospitals. In Europe a 2015 study of C-section rates (MacFarlane et al. doi: 10.1111/1471-0528.13284) found them varying widely from a low of 16.8% in Finland and a high of 52.2% in Cyprus. Such variations have no basis in medical health and reflect social changes of fashion in which women are turning away from natural vaginal delivery in favour of a surgical operation under anesthetic for cosmetic and life-style reasons that divorces birth from natural viability.

In the early 2000's a leading British doctor predicted that more than half UK women having babies would opt for Caesarian deliveries by 2010 stating that patient choice is all important to maternity care and given this 'I believe efforts to reduce Caesarian deliveries are doomed'. Professor Nicholas Fisk said the risks were finely balanced between Caesarian and vaginal birth. It was wrong to deny women the choice when research indicated attempting a vaginal birth could be riskier for the mother or the baby. As of the above 2015 study rates in the UK remained at 27.1% with 11.9% elective and 15.2% emergency.

But New Zealand health leaders sounded warnings over the risks of a Caesarian delivery. There are still serious risks including a woman have a subsequent caesarian haemorrhaging so badly her uterus would have to be removed. Caesarians still carry a risk nine times higher than births. New Zealand's Caesarian rate has soared - in 1989 it was 12% but in 2000 it was 27% at National Women's Hospital, Australasia's largest, and in 1999 it was 45.8% at St. George's Hospital, Christchurch (Untimely from the Womb NZ Listener 25 Jan 2003). In the UK it is 25% (BBC Huge rise in Caesarian births Friday, 26 Oct 2001) and in some countries it is now up to 35%. The World Heath Organization recommends a rate no higher than 15% (Caesarians Normal by 2010 NZ Herald 16 Mar 2000).

In mid 2015 new rules have come into force in Brazil aimed at reducing the country's high number of caesarean births. 85% of all births in Brazilian private hospitals are caesareans and in public hospitals the figure is 45.9% adding to an over 50% caesarian rate:

The new rules oblige doctors to inform women about the risks and ask them to sign a consent form before performing a caesarean. Doctors will also have to justify why a caesarean was necessary. They will have to fill in a complete record of how the labour and birth developed and explain their actions. However, experts say that a scarcity of maternity beds and wards equipped to deal with natural births means that for many women in Brazil, caesarean birth is seen as the best option. There have been numerous reports of women going into labour without a caesarean scheduled and being forced to travel from hospital to hospital in search of a bed. Researchers say many women also see caesareans as more civilised and modern, and natural birth as primitive, ugly and inconvenient. In Brazil's body-conscious culture, where there is little information given about childbirth, there is also huge concern that natural birth can make women sexually unattractive. Gynaecologist Renato Sa told BBC Brasil: "Doctors are responsible for what happens and in a situation of risk they chose a caesarean, because if there is a death or complication they will be asked why they didn't do this. Doctors are afraid of natural childbirth." (2015 BBC Brazil introduces new caesarean birth rules).

Fig 6: WHO 2010 survey of C-section rates: Caesarian section rates are increasing worldwide in developed countries far beyond safe limits for infant health and safe limits to ensure future human reproductive viability. In Brazil for example ove 50% of live births are now by C-section. Comparison of C-section rates (horizontal) with infant mortality rates (vertical) shows two distinct phenomena, with newly developing countries having C-section rates below 10% and increasing C-section rates correlating strongly with reductions in infant mortality (-0.65) while developed countries have widely varying C-section rates which overall have a low correlation (0.14) with increasing infant mortality due to the greater risks of the procedure over natural birth. Within Europe C-section rates vary between a low of 16.8% in Finland and a high of 52.2% in Cyprus with an overall correlation of 0.52 with increasing infant mortality under C-section. When the available data is split between elective and emergency C-section, rates again vary between 6.6% in Finland and 38.8% in Cyprus, with emergency C-section varying between 8.6% in Sweeden and 33.1% in Romania. Elective C-section has a positive correlation with increasing infant mortality of 0.16 and emergency C-section of 0.68. There is no biological advantage whatever in elective C-section and the high correlation of emergency C-section with increasing infant mortality needs to be investigated further.

Overall fertility is reduced in those who deliver by Caesarian section. A study of 25,371 women from 1980 to 1997 found that just 66.9% of mothers undergoing Caesarean section went on to have another pregnancy, compared with 73.9% of women who had spontaneous deliveries. They then took an average of 36.3 months to conceive a second child, compared with the 30.4 months taken by women who gave birth naturally. And they were more likely to suffer an ectopic pregnancy next time around, with 9.5 per 1000 pregnancies, than women with spontaneous delivery, who suffered 5.7 per 1000 pregnancies (Bhattacharya R62).

Women opting for a Caesarean also face a possibility that it will jeopardise later natural births. They face a higher risk of serious medical problems, including tearing of the womb, Ohio State University researchers conclude based on a study of 46,000 women. Of the 46,000 women included in the study, about 16,000 chose to undergo a repeat Caesarean delivery, 12,000 had to have a Caesarean for medical reasons and 18,000 attempted a vaginal birth - 73% successfully. In the UK about a third of Caesarians are elective rather than because of a medical emergency (Caesarean 'low birth risk link' BBC 15 Dec 2004).

Rates of in-Vitro Fertilization, or IVF birth are rising precipitously. This introduces into the human gene-pool genetic defects which will multiply and continue to plague future generations, resulting in perpetuated infertility. This raises again a very serious question of balancing future human viability against individual rights and needs. Multiple births as a result are coming to dominate the population, with a huge increase of medical costs and genetic defects. Estimates of triplet births as high as 350,000 a year are conceived of in the US as a result, costing billions of dollars.

The developed world is facing a disastrous 'epidemic' of twin and triplet births. Changes to fertility treatments are being called for to prevent a huge increase in problem pregnancies and birth defects. Increased use of IVF is one reason for the rise in multiple births. 'The incidence of multiple pregnancy after IVF in Britain is about 25 per cent. That is a real concern' says Robert Winston. Multiple births often occur after IVF because doctors transplant more than one embryo to make a successful pregnancy more likely. Another problem is that the drugs used to induce ovulation often make ovaries release several eggs at once. Multiple pregnancies are plagued by complications. Babies are often premature, underweight and need expensive intensive treatment, and their mothers need more prenatal and antenatal care. Multiple births can also lead to neurological disorders, with triplets being 20 times more likely than singletons to have cerebral palsy. The epidemic of multiple births arising from fertility treatments escalated swiftly, experts warn. Between 1980 and 1997, the twin birth rate in the US increased by 42 per cent. Triplet and higher multiple births increased by 370 per cent. If current trends for triplet births continue, almost 1/3 of all people born will be a triplet in some countries within a decade or so. In the US, triplet births could rise to around 350,000 each year. The figure for the health care costs is into billions of dollars a year, not even counting the psychosocial costs for the families and for the triplets themselves (Two's a crowd New Scientist 14 Jul 2001).

However vaginal birth also presents some problems:

Vaginal birth increases the risk of brain haemorrhage in newborns, a new study suggests. But it is unclear if this causes problems with subsequent child development, so natural births should not be eschewed in favour of caesarean sections, experts warn. The study by MRI which can detect very small haemorrages found that 26% of the babies born vaginally had bleeding in or on the brain, while none of those born through caesarean were affected. The haemorrages found were mostly subdural - meaning the blood pooled outside the brain, rather than within the tissue (Vaginal birth boosts risk of baby brain haemorrhage New Scientist 30 Jan 07).

The first woman to have given birth to triplets with two wombs, (one on either side) was announced in Dec 2006. Womb transplants are also at the threshold:

A team of doctors in New York say they are planning to perform the first womb transplant in the US. The procedure would potentially allow women who have had their wombs damaged or removed to develop a pregnancy and give birth. The plan is use a womb from a woman who has died. A womb transplant has been tried once before, in Saudi Arabia in 2000, but then the womb came from a live donor, and was rejected after three months (US doctors plan womb transplant BBC 17 Jan 07)

Two Swedish women could be able to give birth using the wombs in which they were carried, doctors say, hailing the world's first mother-to-daughter uterus transplants. Doctors caution they will not consider the operations successful unless the women achieve pregnancy. Both women started in-vitro fertilisation before the surgery. Their frozen embryos will be thawed and transferred if the women are considered in good enough health after a year-long observation period (Mother-to-daughter womb transplant 'success' in Sweden BBC Sept 2012)

Benefits and Risks of IVF and ICSI

Current techniques of IVF are causing concern because of the higher fetal abnormality rates between 2 and 3 times ('IVF babies at risk of defects' NZ Herald 2002) as high as natural conceptions. Some of the reason for this is the frequency of multiple births which themselves lead to complications.

One of the most comprehensive studies to date suggests that babies conceived by IVF are more than twice as likely to suffer major birth defects as babies conceived naturally. The controversial findings, which are the first to suggest such a high rate of malformations, come amid concern about the aggressive marketing and growing use of IVF in countries such as the US. No one knows whether the defects are linked to the factors that make couples infertile in the first place, or to aspects of IVF, or to both. But even with the increased risk, a couple who conceive after IVF or intracytoplasmic sperm injection (ICSI) still have over a 90% chance of having a healthy baby. Of the 837 IVF babies, 9% had major defects, such as a hole in the heart or a cleft palate. For the 301 babies conceived by ICSI, the figure was 8.6 %. By contrast, only 4.2% of the 4000 naturally conceived babies had major defects (Test tube trauma New Scientist 16 mar 02).

As of 2012 this figure had risen to 10% of all pregnancies. About 10 per cent of couples using ICSI were found to have a baby with abnormalities - such as bowel and urinary tract problems, heart and lung conditions and cerebral palsy - making it the riskiest treatment. This compared with IVF, which has a risk of 7.2 per cent.

On the other hand a 2016 suggests that older women actually appear to have babies with fewer birth defects after IVF.:

An analysis of 300,000 births has suggested that older women who fall pregnant with help from assisted reproduction techniques are less likely to have children with birth defects than those who conceive on their own. Higher maternal age and assisted reproduction are both linked to congenital anomalies, including Down's syndrome, heart defects and cleft palates, meaning that IVF babies conceived by older mothers are thought to be especially at risk. But a study led by Michael Davies at the University of Adelaide, Australia, challenges this assumption. Analysing births registered in the state of South Australia between 1986 and 2002, his team found that older women who conceived via IVF or intra-cytoplasmic sperm injection (ICSI) were less likely to have children with abnormalities. In addition, older women who had assisted pregnancies were less likely to have babies with birth defects than younger women who conceived using the same technologies. Women aged 29 or under who conceived naturally had children with major birth defects at a rate of 6 per cent, compared to 8 per cent in women aged 40 or over. But in women who had IVF, birth defects dropped from 9 per cent in the younger group to 4 per cent in the older group, while for those who had ICSI, the rate fell from 11 per cent to 6 per cent (British Journal of Obstetrics and Gynaecology, DOI: 10.1111/1471-0528.14365).

In a development which is rewriting text books, young healthy women donating eggs have been found to have chromosomal abnormalities including incorrect numbers of chromosomes (aneuploidy) in 42% of their eggs, leading to a recommendation that people undergoing IVF should have preimplantation genetic screening (PGS). Experts believe it might be that the drugs used for IVF that stimulate a woman's ovaries to produce eggs add to the risk of genetic damage. It could also be that defective eggs are common among the general population but are rejected early on by the body if they are fertilised as up to a third of conceptions are believed to misscarry early term (IVF defects higher than expected BBC 19 Oct 2005).

However ICSI babies appear to fare as well as the naturally born in development:

The first study of ICSI children at age 8 suggests children conceived this way are slightly more intelligent than normal, allaying fears that the technique is not as safe as standard IVF. Lize Leunens' team at the Free University of Brussels (VUB) in Belgium has compared the intelligence and motor skills of 151 ICSI children at age eight with those of 153 naturally conceived children. There was no difference in motor skills, and the ICSI children scored slightly higher on intelligence tests than those conceived naturally. There was no difference in the education levels of the mothers, which is known to influence children's intelligence, so Leunens thinks the most likely explanation for the finding is that mothers of ICSI children provide more stimulation (Le Page M 2005 ICSI kids become smarter than average New Scientist 21 Jun).

Sons born with fertility treatment 'inherit problems' BBC 2016

Boys born to fathers who needed help conceiving have poorer sperm quality as adults than peers conceived without help, a study suggests. This study, carried out by a team from the Universiteit Brussels - where ICSI was developed - looked at 54 men aged 18 to 22. They were compared with 57 men of the same age. Men born from ICSI had almost half the sperm concentration and a two-fold lower total sperm count and motile sperm - that can swim well - than men of a similar age whose parents conceived naturally. They were also nearly three times more likely to have sperm concentrations below the World Health Organization's definition of a "normal" level - 15 million per millilitre of semen - and four times more likely to have total sperm counts below 39 million.Prof Andre Van Steirteghem, who led the study, said it was a more complex picture than might have been expected: "Semen characteristics of ICSI fathers do not predict semen values in their sons. Allan Pacey, professor of andrology at the University of Sheffield, said "Twenty years ago we were telling parents that their sons might have the same problems as they did and that they would also need ICSI to reproduce. But this suggests that might not always be the case."

Further technical advances may take ICSI further towards chromosomal manipulation:

Removing the tiny cap of potent enzymes from human sperm prior to the common assisted-fertility treatment, ICSI, could boost the efficiency of this reproductive technology, new research suggests (Stripped sperm may boost ICSI success rate New Scientist 19 Sept 2005).

Babies born after IVF are 3 times more likely to develop neurological disorders including cerebral palsy than children conceived naturally, a study has found. Scientists believe the findings could be explained by the complications that often arise when two or more IVF embryos share the same womb, rather than because of the IVF techniques themselves. Dr Bo Stromberg, said the findings supported the view that only one IVF embryo should be implanted into a woman rather than the two or more routinely used in many countries. The study compared 5680 IVF children aged between 18 months and 14 years with 11,360 youngsters of the same age who were conceived naturally. Stromberg also compared twin births with single births. IVF in Sweden produces a relatively high number of twins because two embryos are routinely implanted into patients to raise the chances of a successful pregnancy. Worldwide, there are about 50,000 IVF children born a year, yet next to nothing is known of any possible long-term effects on their health (IVF babies at risk of defects NZ Herald 2002).

A major survey in 2004 has focussed more on premature death and prematurity:

Children conceived by IVF are at greater risk of certain health problems, the first comprehensive analysis of medical data has found. Around 1% of babies in the US are conceived in vitro. Babies born after IVF are at least twice as likely to die at or soon after birth, or to be born prematurely or with a clinically low birth weight. Premature and low-birth-weight babies are thought to suffer more health and developmental problems later in life. The evidence also suggested that IVF children are at greater risk of some rare genetic abnormalities. Twins born after IVF were at no greater health risk than twins born conventionally. However, doctors know that bearing twins or triplets is itself linked to a range of long-term health problems, and that IVF boosts the risk of multiple births tenfold. The evidence does not show any increase in major birth malformations, cancer or psychological development. However, the cause remains unknown. One possibility is that the technique of fertilizing and growing young embryos in the lab somehow disrupts their normal development, resulting in problems later on. But it is also possible that infertile couples themselves are the source of the problem, perhaps because they pass on detrimental genetic sequences to their babies (Pearson H 2004 IVF health risks pinpointed Nature 20 Oct doi:10.1038/news041018-9).

Multiple implantation has been found to be unnecessary as well as potentially harmful:

Pia Saldeen and her colleagues at IVF Klinken CURA in Malmö, Sweden, examined the pregnancy rate in Swedish fertility clinics. In January 2003, health authorities in the country banned the transfer or more than one embryo at a time except in exceptional circumstances. Saldeen found that the rate of pregnancies after the legislation was just as high as it was before (around one-third were successful). [The pregnancy rate among those given single embryos and saving a second frozen embryo was 39.7%, compared to 43.5% in the double embryo group IVF 'should use one embryo' BBC 29 June, 2004,]. However, the frequency of twin pregnancies fell from 23% to less than 6%. Transferring a single embryo can still result in twins if one embryo splits naturally into two. Two studies from US fertility clinics mirrored the Swedish results. When otherwise healthy women were offered the choice of having one embryo implanted instead of two, pregnancy rates remained just as high (over 70%). (Pearson H 2004 Big success for single embryos in IVF Nature 22 Oct doi:10.1038/news041018-15).

IVF has been linked to an increased risk of ovarian tumours in later life, according to a preliminary study. Women given fertility drugs to produce eggs had more than triple the risk of an ovarian tumour that may turn cancerous. But the absolute risks are very low. The study tracked more than 25,000 women attending IVF clinics in The Netherlands in the 80s and 90s.

PGD or pre-implantation genetic diagnosis has itself been found to present no problems:

Carrying out tests on embryos to screen for genetic disorders, does not harm their health, a large scale review of the procedure has found. The Reproductive Institute of Chicago study looked at 754 babies born after IVF pregnancies where preimplantation genetic diagnosis was used. It found they were no more likely to suffer birth defects than babies born after natural pregnancies (Embryo screening 'no health risk' BBC 18 Aug, 2004).

A method of detecting maternal genetic defects in embryos wthout taking cells from the embryo has been developed:

Couples at risk of having a child with genetic abnormalities can reduce this risk by undergoing IVF and having their embryo genetically sequenced before it is implanted. This usually involves removing a cell from the dividing embryo, which can jeopardise the chances of it implanting. But in 2013 a team developed a way to sequence the maternally inherited genome of the embryo without taking a biopsy, using a technique called MALBAC (Multiple Annealing and Looping Based amplification Cycles) to sequence the polar bodies - the two cells expelled from the developing egg as it divides. The new approach doesn't capture any genetic defects passed down by the father but more than 70 per cent of chromosome abnormalities, the most common cause of miscarriage in older woman undergoing IVF, occur in the egg (Botelho A 2013 Genetic test screens embryo without disturbing it New Scientist 20 Dec).

Advertisements for egg donors have been published on the internet and in several American college newspapers. The specifications include: height, 5 foot 10 inches, athletic build, high score on the test given to all college applicants, and no major family medical problems. The reward for the lucky winner, $50 000! 'Egg donation' has been banned in the UK because of the strain on a mother's health.

IVF watchdogs have ruled out a scheme that would allow women to have cheap treatment if they are prepared to do it twice and donate half their eggs. The Human Fertilisation and Embryology Authority (HFEA) says that 'egg giving' means a woman risks her health by having extra treatment for financial reasons (Ban imposed on IVF egg 'giving' 29 Nov 2003).

Screening techniques are also improving:

A new way of screening out bad eggs could boost IVF pregnancy rates and level the playing field for older women seeking their own child. Around 75% of all miscarriages are thought to be caused by an embryo having the wrong number of chromosomes, and the risk increases as a woman gets older. Until now, one of the only ways of screening eggs or embryos for aneuploidies was to use fluorescence in-situ hybridization, where a cell is removed and stained with small pieces of fluorescent DNA, revealing the structure of specific chromosomes. But the technique cannot spot abnormalities in at least 13 of the 23 pairs of chromosomes. The new technique is known as 'comparative genomic hybridization' (CGH). It involves taking a sample of DNA from the polar body, a set of cells that are expelled from the egg before it fuses with a sperm. This can then be used to predict which eggs will produce embryos with the correct number of chromosomes (New IVF test may double success rates New Scientist 30 Jan 07).

Time-lapse imaging can spot small differences in embryo growth that could have a big impact on the success rate of IVF:

Around half of all human embryos have a chromosomal abnormality. After fertilisation, these embryos normally fail to attach to the wall of the uterus or end in miscarriage. For couples having IVF, chromosomal abnormalities are the largest single reason treatment fails. Until now, the only way to identify chromosomal abnormalities was by an invasive biopsy to remove one or two cells from the outside of the developing embryo, which can risk damaging remaining cells. The team used the time-lapse footage to study 88 embryos from 69 couples. They found that embryos with chromosomal abnormalities generally take about six hours longer to form a blastocyst. The team then devised an algorithm that can identify embryos that grow more slowly than usual. Those that take more than 100 hours to begin forming a blastocyst are considered at high risk of chromosomal abnormality. The algorithm also monitors when a blastocyst becomes fully formed, a secondary indicator of good health. (Time-lapse spots faulty embryos before IVF New Scientist 17 May 2013, Reproductive BioMedicine, DOI: 10.1016/j.rbmo.2013.04.013).

For people undergoing IVF, the nutrient-rich liquid their embryos grow in could tip the balance in the sex of the offspring:

For people that had sperm injected into eggs, the sex of their healthiest embryo - and therefore their baby - was associated with the type of culture media that had been used to first grow the developing embryos before selection of the best for implantation. The proportion of males at birth was 56 per cent for one type of medium, but just 45 per cent for another. (Hamzelou J 2015 IVF nutrients may dictate if the baby's a boy or girl New Sco 19 Mar, Human Reproduction, doi.org/2t4). The effect wasn't seen in embryos not fertilised by sperm injection.

A new more natural stimulation of ovaries for IVF is in the pipeline:

During IVF, a woman's ovaries are stimulated to boost ovulation and harvest eggs. This is usually done by an injection of human chorionic gonadotropin (hCG), a hormone involved in progesterone secretion. But sometimes this leads to ovarian hyperstimulation syndrome. OHSS is mild in a third of women having IVF, causing abdominal bloating, but for one woman in 20 it also causes vomiting and diarrhoea. In extreme cases it can be fatal. Women with polycystic ovary syndrome - a leading cause of infertility - are at greater risk of OHSS. Waljit Dhillo hypothesised that another hormone, kisspeptin, may be gentler. Its effects are short-lived and during pregnancy it naturally increases to 7000 times the usual level, so should have minimal side effects. Dhillo tested the hormone in 30 women having IVF. Suzannah Kidd became the first to give birth as a result – Heath, a healthy boy, was born on 26 April. (World's first baby born from 'natural' IVF Jun 13).

A private UK fertility clinic is offering couples a new form of IVF treatment that lets conception occur in the womb rather than in the lab. The Complete Fertility clinic in Southampton is first in the UK to use the AneVivo device method - a tiny tubular capsule that is loaded with the sperm and egg before being placed into the uterus. The technique, which costs around £700 per go, has been approved by the UK's fertility watchdog, the HFEA. International trials in around 250 women suggest that it achieves a similar pregnancy rate to conventional IVF, says Prof Macklon. But it reduces how long the growing embryo is kept artificially outside of the womb in a dish of culture fluid. Although it allows fertilisation to occur within the body, the resulting embryo still needs to be removed and given a health check in the lab before being reimplanted (Roberts M 2016 'Natural' fertilisation device for IVF BBC 19 Jan).

Women having IVF can now incubate embryos in their own bodies before they are implanted in the womb:

Results from a clinical trial suggest the incubation device could work as well as conventional IVF [using lab incubators] and be far cheaper. Cylindrical in shape, INVOcell is held in the vagina by a flexible diaphragm. The embryos are kept in an inner chamber at body temperature and gases such as carbon dioxide and oxygen diffuse in and out at levels matching natural fertilisation. After five days the embryos will have grown into balls of about 100 cells. The device is then removed and doctors choose the embryo that looks healthiest to implant. In a US trial of 40 women, the device performed almost as well as conventional incubation, with 65 per cent of the women becoming pregnant regardless of the method used. Fifty-five per cent who used in-body incubation went on to give birth compared with 60 per cent who had the standard method (Women can ‘grow’ their own IVF embryos with in-body incubator New Scientist 6 Jan 2016).

The nutrient medium also seems to affect the sexual selection of the successful embryos, with higher glucose media favouring boys:

For people that had sperm injected into eggs, the sex of their healthiest embryo - and therefore their baby - was associated with the type of culture media that had been used. For example, the proportion of males at birth was 56 per cent for one type of medium, but just 45 per cent for another. The equivalent figure for natural births in the UK and US is 51 per cent. The association remained even after Zhu's team had accounted for possible confounding factors such as the parents' age, body mass index and the type of infertility they were experiencing (Human Reproduction, doi.org/2t4). The effect wasn't seen in embryos not fertilised by sperm injection. "It's a highly significant finding," says Roger Sturmey at Hull York Medical School, UK.

Pre-implantation Genetic Diagnosis and Non-Invasive Pre-natal Genetic Screening

While finding an egg or sperm donor with certain characteristics might give prospective parents an edge in designing their children, a more predictable way to 'intervene' comes with genetic diagnosis before implanting an embryo produced through IVF.

[Robert] Winston, developed the technique of 'pre-implantation genetic diagnosis' (PGD) in the mid-1980s using sex selection as a proxy for genetic testing for diseases, such as haemophilia, most of which are carried by women and affect only their sons. The technique has since been developed to detect a range of genetic defects. One or two cells are removed from an embryo at the eight-cell stage, amplified and then biopsied. Only embryos that are found to be healthy are then implanted in the uterus (Klotzko A 1999 Great expectations New Scientist 1 May). A recent study has found the technique does not increase the risk of fetal abnormalities (Embryo screening 'no health risk' BBC18 August, 2004).

All IVF embryos should be checked for genetic abnormalities before the pregnancy is allowed to go ahead, say international genetic experts:

A London conference on preimplantation genetic diagnosis (PGD) heard how this technique greatly increases the chance that a healthy child will be born. IVF pioneer 'By selecting to transfer only a normal embryo, we fulfil our dreams to have a healthy child' Dr Verlinsky. Robert Edwards and PGD leader Yury Verlinsky also said couples should be allowed to choose a child's sex for 'family balance'. Critics strongly opposed these ideas. Both Life and Comment on Reproductive Ethics (CORE) said these approaches were unethical and discriminatory. At the Sixth International Symposium on PGD, Dr Verlinksy, famed for selecting a test-tube baby whose tissue matched that of a sick sibling, presented new results showing PGD increased the take home baby rate seven-fold. His team at the Reproductive Genetics Institute in Chicago looked at the pregnancy outcomes of 709 women undergoing IVF.Overall, PGD increased the chance that a woman would take home a baby from 11% to about 80%, due to fewer miscarriages and better foetal implantation rates. Dr Verlinsky said: 'It should be implemented to all IVF cases. ('Make IVF genetic screen routine' BBC 19 May, 2005.)

IVF is blossoming into a central technique of choice rendering natural conception obsolete. A new technique of routine IVF by 'chip' combined with genetic testing for a battery of genetic defects could become so inviting for parents that its attraction could lead to it becoming standard for all births. Another reason potentially driving such a process is the extraction of a few cells to be kept as a clone for stem cell transplants or organ replacement clones with perfect genetic matching. Couples are flocking to use the technique simply to chooose the sex of their child, despite the risks to the woman of ovarian hyperstimulation, because it has higher reliability than sperm sorting (Westphal R739). Routine IVF and genetic selection could have a major irreversible effect on the gene pool, whose implications we have not begun to research. It will also render all conceptions potentially inviable naturally, through loss of the genes supporting natural conception over time as a result of lack of natural selection.

Fig 7: New Scientist

Children in future may be conceived and spend their first few days on a computer-controlled chip:

In a move recalling Aldous Huxley's famous production lines in Brave New World, researchers are building a 'chip' that can automatically carry out all the steps involved in IVF, from fertilising eggs to preparing embryos for implantation. Ultimately, such devices which amount to artificial reproductive tracts - may even be able to sort and test embryos for genetic flaws. Far more mouse embryos develop successfully on these devices than by traditional IVF methods. The work could be the first step towards a future in which IVF becomes the norm, says George Seidel 'Fifty or 100 years from now, our in vitro procedures for parts or even all of pregnancy may end up being safer than dealing with the various things that occur in the body-in terms of viruses that the mother comes across, toxins, and so on.' In conventional IVF, sperm and eggs are dumped into a Petri dish where the fertilised eggs grow until they're ready to be implanted. As embryos need different culture media at different stages, embryologists transfer them from one dish to another via a pipette. 'In 48 hours, in the traditional Petri dish, none of them made it to the blastocyst stage. In our channels, about 75 per cent made it' says Beebe. 'The embryos were transplanted into hosts and live pups were born. So there doesn't appear to be any detrimental effect' (Brave New Babies: An automated IVF chip could lead to production-line embryos New Scientist 26 May 2001).

Complementing this the procedures for whole genome genetic testing for signs of abnormality are advancing rapidly:

Within a few years it could be possible to boost the success of IVF by checking for major chromosomal abnormalities before embryos are transferred to the womb. 'Potentially, this is a major advance,' says Mark Johnson of Imperial College, London. At present, it is only possible to check a handful of chromosomes. But by adapting existing techniques, Joy Delhanty and Dagan Wells of University College London were able to check all the chromosomes in 12 three-day-old embryos. Abnormalities were surprisingly common, Delhanty says. Only three of the 12 embryos had the right number of chromosomes in all their cells. The researchers used a technique called comparative genomic hybridisation (CGH). They compared the chromosomes from the embryos with ones from normal cells by staining them with different dyes. Any departures from the normal number of chromosomes, or any large deletions or insertions, show up as differences in the amount of fluorescence. Large amounts of DNA are needed for CGH, so Delhanty and Wells had to make many copies of a cell's DNA by improving on a second method known as whole genome amplification. At present the test takes three or four days-far too long for pre-implantation screening, says Delhanty. The time will have to be reduced to around 24 hours to make it practical, she says. 'It'll be a year or two before it might be applied.' (Only the best New Scientist 29 Oct 2000 13).

PGD is to become a tool of choice for avoiding genetically-inherited forms of cancer:

The Human Fertilisation and Embryology Authority UK approved the screening following a request from couples for IVF treatment. The watchdog said there was a strong chance of bowel cancer being passed from parent to child. One of the couples to win the right to have their IVF embryos screened said they were delighted with the decision. 'We are overjoyed to have been given this chance, not only to do as much as possible to make sure our children don't have the gene, but to stop them passing it on.' The technique is already used in screening for other disorders such as cystic fibrosis. But this is thought to be the first time it has been used for a disease that does not affect the sufferer until early adulthood.Dr Mohammed Tarannisi, director of the Assisted Reproduction and Gynaecology Centre in London, said the latest decision should have been 'put to a wider audience'. 'We are still talking here about medical conditions that have serious implications, but we are talking about conditions that are not going to be there at the time of birth. These are conditions that may or may not develop 20, 30, 40 years down the line. Is this the right thing to do?' Dr Tarannisi has an application for a licence to test for breast cancer genes being considered by the HFEA. Josephine Quintavalle of Comment on Reproductive Ethics said: 'It's a very big ethical step forward. 'The HFEA has yet again taken a big ethical decision without consulting the public.' She said it was moving down a slippery slope from what had started as intervention for only disease that threatened the viability of the embryo to diseases that might appear in adulthood. 'We should be looking for medicines that cure not medicines that kill'.

The combination of IVF and genetic testing makes it possible for couples who know they have a defect or who have a child with a potentially lethal defect which could be repaired using gene therapy from a healthy sibling's genes, to raise 'designer babies' either to escape a genetic flaw or as therapy for an existing child:

Six more couples plan to apply for permission to have a designer baby to save a sibling's life. The Human Fertilisation and Embryology Authority Britain's fertility watchdog insisted it had not opened the floodgates after Raj and Shahana Hashmi got the go ahead for embryo selection last weekend. The couple at the centre of the medical row say they are not 'playing God' by creating a child to save the life of their terminally ill son. Dr Simon Fishel, who is treating the Hashmis, said he had six other patients who were eager to -go ahead. (Couples queue for Designer Babies NZ Herald 2002).

A woman has chosen to have a genetically selected baby to ensure it does not develop early onset Alzheimer's disease which runs in the family. The child is now 18 months old and genetically 'safe'. The woman, who is 30 and has not been identified, may be unable to recognise or care for her daughter within 10 years. She and her family carry a mutation which causes the onset of Alzheimer's disease before the age of 40. However, the child, who is now about 18 months old, did not inherit the tendency to develop the disease. Researchers said the baby's birth marked the first time pre-implantation genetic diagnosis, as the technique is called, has been used to weed out embryos carrying the defect that causes early onset Alzheimer's (Screening creates 'disease free' baby BBC 27 Feb, 2002).

It also makes possible some very unusual forms of 'incestuous' parenting between brother and sister without genetic inbreeding:

A 62-year woman who this month became France's oldest mother has revealed that her brother was the biological father of the baby. The woman said she got pregnant using her brother's sperm and a donor egg, and that a second baby fathered by her brother a girl was born to a surrogate mother. The 62-year-old woman, identified in the media only as Jeanine, said she underwent treatment at a Los Angeles clinic and gave birth on May 14 in southern France. The woman told Le Parisian newspaper that her child was conceived from her brother's sperm and an egg donated by an American woman. The woman also said her 52-year old brother's sperm was used to conceive a second baby born in May with the same egg donor, who acted as a surrogate. Both babies live in Frejus with the woman and her brother, who share their house with their 80-year-old mother. Jeanine, a retired teacher, said she told the clinic that her brother was her husband. 'We are both healthy in mind and body,' she told the paper. 'I couldn't pass on my genes because of my age, so I wanted to pass on his and give life so our line could continue.' The woman and her brother are both single and had been childless. According to a 1994 French law., only couples can have 'medically -assisted procreation,' and the techniques are forbidden for menopausal women (Mum at 62, pregnant by brother NZ Herald June 2001).

Fetal genetic screening has now become publicly accessable to prospective parents without invasive techniques such as amniocentesis or CVS (chorionic villus sampling):

Fetal gene screening comes to market (2011 Nature 478 440 doi:10.1038/478440a) Until last week, scrutinizing a fetus's DNA for indications of genetic abnormalities meant tapping into the mother's womb with a needle. Now there's a test that can do it using a small sample of the mother's blood. MaterniT21, a Down's syndrome test that Sequenom of San Diego, California, launched in major centres across the United States on 17 October, is the first of several such tests expected on the market in the next year. It signals the arrival of a long-anticipated era of non-invasive prenatal genetic screening, with its attendant benefits and ethical complications (see Nature 469, 289-291).

Techniques are emerging to non-invasively test the genes of individual egg cells amid research into sperm recombination diversity:

The first genetic comparison of individual sperm cells has revealed just how diverse they can be. The technology used to study these tiny cells might also be used to study cancer and allow doctors to screen eggs for in vitro fertilisation (Sperm sequencing could help fight infertility New Sci. 2012). Quake and Wang's team were able to scan each of 91 sperm cells' genomes to see if recombination had taken place at any of 1.2 million positions in the DNA. There are certain "recombination hotspots" where recombination often occurs, they say. The team's analysis revealed that chromosomes in some of the sperm cells had recombined in unexpected regions. The findings suggest that the process of genetic reshuffling is unique to each sperm cell. This further adds to the genetic diversity between siblings. Wang hopes that the technique could also help in selecting eggs for in vitro fertilisation (IVF). Each egg cell is produced alongside three other non-functional cells that contain the same genetic code but do not develop into eggs.

IVF and Heritable Defects

In a state of the science study of fetal abnormalities associated with IVF 2012 study, among 4795 babies born after IVF and 46,025 infants who were conceived naturally, 3,463 babies had congenital birth defects. Even after controlling for factors that can affect such birth defects, such as mother's age, and race, which can influence rates of genetic and environmentally driven developmental disorders, 9% of infants born after IVF had birth defects compared to 6.6% of babies who were conceived naturally. It's possible that the higher rate of abnormalities with IVF is due in part to whatever was contributing to infertility in the first place, say the researchers. In a bivariate analysis comparing 1,749 babies born after non-ART fertility-related services with 17,748 naturally conceived infants propensity matched on maternal age, parity, plurality, race, gender, and year of birth, there were no differences in rates of various major birth defects. The fact that an increase was not seen among babies conceived using artificial insemination or ovulation induction suggests that process of IVF itself, in which eggs are removed from a woman, fertilized in a dish with sperm and then allowed to develop into embryos, which are transplanted back into the womb, is the primary culprit (Sifferlin A 2012 IVF Linked to More Birth Defects Time Oct 22).

An earlier study in the New England Journal of Medicine also reported a link between fertility treatments and a higher risk of birth defects, but risk varied greatly by procedure. In that study, IVF was not associated with birth defects, but other procedures such as intracytoplasmic sperm injection (ICSI) and ovulation stimulation medications were. They also reported that frozen embryos created through IVF were less likely to result in babies with birth defects than fresh embryos. Assisted reproductive technology or ART was associated with an 81% increase in the relative risk for defects of the eye, a 41% increase in relative risk for congenital heart defects, and a 40% increase in relative risk for defects of the genitourinary system. There was, however, almost a 70% reduction in the rate of chromosomal abnormalities. The latter finding requires further study, but it may be explained by a lower threshold for termination among couples using assistance to get pregnant (Neale T 2012 IVF Increases Risk for Heart Defects Medpage).

A rare defect Beckwith-Wiederman syndrome is increased 9-fold to 1 in 4000 (Holding R324 2004). Some techniques of IVF such as intra-cytoplasmic sperm injection ICSI appear to cause higher rates of malformations (New Scientist 12 July 2003 18) including Angelmans syndrome . ICSI is specifically prone to generating infertility which is passed down the generations, resulting in the dissemination of defective genes and unstable chromosomes, which undermine natural human viability. In some cases these are already known to create deleterious effects in future generations, but are still used because parents assume their offspring can also rely on the technology.

Since its introduction in the early 1990s, controversy has dogged the IVF technique called intra-cytoplasmic sperm injection. ICSI involves injecting a single sperm into an egg and is used mainly when men cannot fertilise an egg because their sperm count is too low or their sperm abnormal. A series of recent studies has associated ICSI with infertility in children, chromosomal abnormalities, birth defects and delays in mental development. The latest research suggests that children created by ICSI have a raised risk of being born with Turner's syndrome or ambiguous genitalia. For roughly 5 per cent of men seeking fertility treatment because they have few or no sperm, the cause is a tiny mutation in the Y chromosome called a microdeletion. As long as the man still produces a few sperm, however, it is sometimes possible to inject one directly into the egg. One of the reasons ICSI is controversial is that if there's a genetic reason for the man's infertility, it will be passed on to his sons. Many couples are prepared to use ICSI anyway, arguing that it will also be available to their children. But evidence suggests that microdeletions on the Y chromosome are a precursor to more serious genetic faults. Ken McElreavey found that in eight men with microdeletions, Y chromosomes were missing in about 10 per cent of the cells in their bodies. In the three who had enough sperm to test, up to 18 per cent of the sperm lacked a Y chromosome. These findings suggest that the microdeletion is a sign of a chromosomal instability that causes some cells to lose the entire Y chromosome, The loss of the Y chromosome in some of a baby's cells-called genetic mosaicism can cause either ambiguous genitalia or Turner's syndrome, or both. Women with Turner's have normal female genitals, but they are unusually short and do not go through puberty. Men with Y chromosome microdeletions make up just a small fraction of those using ICSI, but they might be largely responsible for offspring with Y chromosome losses. If so, then the technique may be too risky to use on them. David Page from MIT reports (NS 22 jun 02) the results of treating 26 men who were infertile because of a deletion in their Y chromosome. Of these, 11 were able to have children thanks to ICSI, but all 10 sons inherited their father's deletion-which probably means they will be infertile when they grow up, Page says (Genetic roulette: A small problem for a man can become a disaster for his children New Scientist 15 dec 2001).

Offspring of women who had fertility problems were found to have higher rates of cancer than the offspring of fertile women, but the study isn't specific as to whether these changes relate to IVF or other infertility treatments such as diethylstilboestrol, which caused a specific, rare form of cancer in female offspring. There was a 17% overall increase in the relative risk of cancer. In children: a 33% increased risk of leukaemias. In adult offspring: 82% increased risk of skin cancers, 187% increased risk of urinary-tract cancers, 229% increased risk of endocrine gland cancers (Johnson M. 2012 Cancer linked to fertility problems NZ Herald Oct 31).

There appears to be no link with increased autism risk:

A Karolinska Institute team looked at the health of 2.5 million children born in Sweden between 1982 and 2007, following them for an average of 10 years. Of these children, about 31,000 were born following an IVF procedure. Some 19,500 of these IVF births followed simple mixing of sperm and egg in a dish, but in 10,500 cases, the sperm were unable to penetrate and fertilise the egg under their own steam, and were instead artificially injected into the egg. For the remaining cases - fewer than 1000 in total - there were no sperm in the prospective fathers' ejaculate, so the sperm were extracted from their testicles through a surgical procedure before being injected into the egg. Once they had taken into account the fact that IVF is more likely than natural conception to lead to a risky multiple birth, Nygren and his colleagues found that the 31,000 IVF-born children were at no greater risk of developing autism than the 2.47 million children in the study who were conceived naturally. However, they found that the IVF procedures which involved injecting sperm into eggs do increase by 50 per cent the risk of intellectual disability - defined as an IQ lower than 70 together with limitations in adaptive behaviour. The absolute risk of intellectual disability is still tiny though (IVF procedures do not boost autism risk New Scientist 2 Jul 13)

A warning has also been issued over heritable failures of correct imprinting in men with a low sperm count who use IVF (Lancet 363 1700): In a study led by Mario Souza, one in four of 96 men with low sperm count had imprinting faults in H19 a gene which switches on the growth factor IGF2 important for placental growth. Imprinting conditions include Beckwith-Wiedemann syndrome, which causes too much growth and is linked with an increased chance of tumours, and Angelman's syndrome, which affects the development of the brain. No such errors were found in 27 men with normal sperm.

There are some notable exceptions to the heritability of ICSI. Men with an extra X-chromosome can father normal children from selected sperm:

Several men with a serious genetic fault have been able to father normal children thanks to the controversial IVF technique known as ICSI. Men with Klinefelter's syndrome have an extra X chromosome. While many don't know about the condition until they discover they're infertile, others have symptoms such as mental retardation. Since the men cannot produce viable sperm, for the past few years Zev Rosenwaks's team has been retrieving immature sperm directly from their testicles. The best-looking ones are used to fertilise eggs from their partners using ICSI, or intracytoplasmic sperm injection, in which a sperm is injected into the egg. Rosenwaks told a conference in Montreal last month that 9 of the 15 patients with Klinefelter's treated this way have managed to have children. All 14 babies have a normal number of chromosomes, even though some parents refused pre-implantation genetic diagnosis to ensure that this was the case. The result is surprising because there's concern that ICSI allows genetic abnormalities to be passed on to the next generation. His team is also using the method of retrieving sperm directly from the testicles to help men unable to father children after chemotherapy (Men with extra X chromosome father normal children New Scientist 22 jun 2002).

Time-lapse imaging can spot small differences in embryo growth that could have a big impact on the success rate of IVF:

Around half of all human embryos have a chromosomal abnormality. After fertilisation, these embryos normally fail to attach to the wall of the uterus or end in miscarriage. For couples having IVF, chromosomal abnormalities are the largest single reason treatment fails. Until now, the only way to identify chromosomal abnormalities was by an invasive biopsy to remove one or two cells from the outside of the developing embryo, which can risk damaging remaining cells. The team used the time-lapse footage to study 88 embryos from 69 couples. They found that embryos with chromosomal abnormalities generally take about six hours longer to form a blastocyst. The team then devised an algorithm that can identify embryos that grow more slowly than usual. Those that take more than 100 hours to begin forming a blastocyst are considered at high risk of chromosomal abnormality. The algorithm also monitors when a blastocyst becomes fully formed, a secondary indicator of good health. (Heaven D 2013 New Scientist May 18, Reproductive BioMedicine, DOI: 10.1016/j.rbmo.2013.04.013).

In-vitro maturation (IVM) is a safer treatment than IVF for women with poly-cystic ovary disease because they are at increased risk of ovarian hyper-stimulation syndrome, a usually mild but potentially life-threatening complication of IVF hormone treatment. IVM is also offered to women who wish to avoid or do not have time to use hormone stimulation before starting cancer chemotherapy which may impair their fertility. Immature eggs are collected from the woman's ovaries. Eggs are matured in laboratory for 24 to 48 hours. Eggs are fertilised, as in IVF, to create embryos. Embryos are implanted into the woman or frozen.

Contraception, Abortion and the Divorce of Social Sexuality from Reproduction

Human fertility has throughout our evolutionary emergence been naturally regulated by the inhibition caused by lactation and regular demand feeding, which as we have noted in the !Kung (p 107) markedly reduces the number of children a woman will bear in her lifetime. The release of prolactin in turn suppresses progesterone production provided in is very regular. Societies have often also practiced forms of infanticide to avoid a new offspring becoming too burdensome on existing children to protect the overall parental investment in children who can survive and fend for themselves.

The Greeks, for all their patriarchal fetishism, were intimately familiar with female hormonal feedback mechanisms: Hippocratic aphorism V50 says 'to restrain a woman's menstruation, apply the largest possible cupping glass to the nipples'. V39 also: 'If a woman who is neither pregnant nor has given birth produces milk, her menstruation has stopped. Caustic or blocking vaginal pessaries were known and used in the ancient world. The Egyptian Kahun gyneacological papyrus (1900 BC) prescribes hydrated sodium carbonate mixed with crocodile droppings. The Ebers papyrus mentions acacia gum. Many herbal abortifacients were also used in earlier times, such as penny royal or Queen Anne's lace, mentioned by Hippocrates and later by Aristophanes, as well as species of fennel, myrrh, Artemisia and rue. Eight out of ten plants mentioned by Soranus in the 2nd century AD for either contraception or abortion are now known to have distinct effects. Dioscorides also mentions a male contraceptive herb. Ayurvedic medicine mentions 28 plants useful in this respect ( Taylor R683 86). Knowledge of medicinal plants appears to go back 40,000 to 100,000 years, where plum stones and borage seeds have been found (R683 108).

Now with the advent of modern 'scientific' forms of contraception, from the pill, through condoms, intra-uterine devices, to male or female tubal ligations, for the first time social sex between reproductively fertile partners has become functionally divorced from the reproductive quest (p 100) and more recently the period as well:

Specialists in reproductive medicine claim menstrual periods are an unnecessary nuisance that could be eliminated from women's lives with little harm. A study of over 2100 women showed that a continuous contraceptive pill appeared just as safe as others over the short term and that women suffered from fewer menstrual problems (from cramps to mood swings) each month. The researchers found that the pill is as effective a contraceptive as others, and side-effects ranging from headaches to changes in cholesterol levels were no worse. One downside of the new continuous-use pill is that around 40% of women still experienced unpredictable bleeding. Nearly 60% of women in the study chose to stop taking the pills before the year was up (Archer D.A., et al. Contraception, 74. 439-445 (2006) doi:10.1016/ j.contraception.2006.07.005).

Contraception is continuing to have far-reaching consequences and leads to deep evolutionary contradictions. At the same time the various techniques of abortion from the morning-after pill to late term partial birth terminations have created a near continuum, from contraception to infanticide which raises a host of new ethical questions that wrack society. While no one wants to see dehumanization of the value of life, the debate pits the rights of a mother against those of the child and patriarchal religious attitudes against the rights of a woman to make choices over her own reproductive life. Although there are obvious exceptions, particularly in an alienated society, mothers don't generally abort for fun or evil intent. Every woman in history who has aborted has risked her life and limb for a child a male has causally impregnated her with, at no risk to himself.

Not only has Christianity adamantly opposed abortion throughout its history, but contraception as well. Up to the Lambeth Conference of 1936, Christian churches, following the fecund pronunciation of Genesis 1 'be fruitful and multiply' have opposed all forms of contraception (O'Grady R513). Catholics, citing also the 'natural law' theory of Aristotle, Augustine and Aquinas vehemently oppose contraception to the present day, despite a world in population crisis which can't or won't look after all the children well that we are bringing forth. Although birth rates in traditional Muslim societies remain some of the highest in the world (p 421), most Muslim traditions permit the use of birth control, although the emphasis remains on procreation within the family.

In several developed countries, the reproduction rate, especially of successful career women, who by any sociobiological measure would normally be at a reproductive advantage, has fallen to catastrophic lows, so that many of the more socially successful genetic traits which would support the creative viability of future generations are likely to be lost. At the same time members of cultural sectors who have religious or social attitudes against contraception advocate unrestricted reproduction. Those who are too dysfunctional or incompetent to contraceive, now also tend to reproduce disproportionately. Against this trend, several societies from China, through India to Peru have embarked on mass campaigns to restrict human population, often discriminating against certain classes of people, including ethnic minorities.

Men have also responded by taking up vasectomies. 'At 18 per cent of all men, 25 per cent of all married men, and a leg-crossing 55 per cent of 40-49 year-olds, New Zealand's vasectomy rate towers above places such as the United States, where just 7 per cent of men have gone under the knife' (NZPA16 Jan 07). At an opposite extreme we find certain men have begun to use sperm donation as a means of spreading wild oats, with no parental commitment in a manner similar to lekking displays in birds. Thus a young doctor Matthew Niedner, a 34-year-old pediatrician living in Ann Arbor, Michigan with a codename 48QAH doesn't know how many children he's fathered, although he thinks it's around a couple of dozen. 'QAH,' it turns out, stood for 'quite a hunk' at the clinic where he had donated sperm for seven years. Of course this is well below the excesses of the great potentates or even Bob Marley's bass player, who fathered 52, but given the superficial criteria, there is little stopping a popular sex figure becoming a paternity pop star, based only on an internet profile. Given the fact that many of the recipients are single women, or lesbians, the implications for the children of a father who has divested any parental responsibility, in donating only his genes have yet to be realized (http://www.cbsnews.com/stories/2006/03/17/60minutes/main1414965.shtml).

Coupled to this phenomenon are around 60,000 children of same-sex couples in California alone, many of who have been sired through sperm donation, or genetic technology, raising a whole new set of issues, in terms of social expectations, as same sex-couples begin to share some of the concerns of heterosexual parents, in the face of purely social sexuality and its more exploitatative manifestations in pornography and sadomacochism. Thomas Lynch, of the San Francisco Lesbian Gay Bisexual Transgender Community Centre said Castro was adjusting to its changing makeup (Telegraph Catherine Elsworth 24-04-06).

These factors combine with the preservation of potentially non-naturally viable genes through IVF and other treatments to raise serious questions about the future viability of the human genetic resources of the human species. Thus one can speculate that all the beneficent factors leading to sexual selection of humanity as a species are rapidly being replaced by detrimental or disruptive factors likely to undermine our future viability.

Into the centre of this debate has also come an assault on the very link between social sexuality and human regeneration which has seen social sexuality take centre stage in moves to make any form of sexual connection between consenting adults of either sex on the same footing as reproductive 'marriage'. We are thus seeing a heightened polarization between religious traditionalists who see marriage and the reproductive family as central and social libertarians who see any form of discrimination even between social and reproductive sex as reprehensible. Just as all of us who read this book were born as humans, so the reproductive process is the foundation of human 'relationship' and of human society in its widest and deepest sense. The implications of sexual union, extend from passion and infatuation, to belonging, loving empathy, then to parental commitment and finally to the whole genealogical fabric of a people in time and space. Without this fabric the institutions of society become a corrupt exercise in personal gratification to no meaningful end.

Although we may make love some ten thousand times in a lifetime and have fewer than ten offspring, so more than 99.9% of our sexual connections are social, this doesn't mean social sex is simply sensual recreation for gratification or adult bonding alone. To define relationship simply in these terms, whether heterosexual or homosexual, is perilous. There is an urgent need to for humanity to redefine its values to take into account and respect the evolutionary paradigm and how sexual complementarity and the deep connection between social sexuality and the reproductive passage of the generations gives us the full dimensions of what human 'relationship' means in terms of the entire social fabric and why and how we continue to engage as a society of living biological beings into the future.

Sex Determination and Sexual Imbalance

Humans across the planet have practised infanticide, particularly of girl children. The advent of abortion has drawn the lines of this battle right through the uterus. Female choice and its antithesis the right to life. Selective abortion has in turn become a battleground in which girl children become the overwhelming targets in countries from Saudi Arabia through India to China, Vietnam and Korea.

Now new technologies are making it possible for people to have selective conception and take the battle out of the ovary and into the IVF apparatus. The impact of such techniques in the West leads to planning of balanced families, but can lead to runaway selection for boys, just as abortion in turn has.

The first of these two techniques is a high quality version of sperm sorting:

Hundreds of couples are using a medical technique to choose the sex of their children, many for social reasons. The 'sperm sorting' procedure, which allows gender selection before conception, is particularly valuable in avoiding passing on genetic illnesses that usually affect only boys, such as haemophilia and muscular dystrophy. But Dr Harvey Stern, of the Genetics and IVF Institute in Fairfax, Virginia, said that of 200 couples who had used the procedure, 40 per cent had done so for non-medical reasons. Many of his patients, who paid E1400 ($4625), were seeking to 'balance out' families. 'There are concerns that some parts of the world would use it only to have boys ... We only do this for balancing families, not for a first child.' The Human Fertilisation and Embryology Authority, which regulates IVF and sperm donation in Britain, said the technique was legal, but it opposed using it for nonmedical reasons. Sperm are sent through a sorting machine one by one and stained with dye. A laser is then shone on each sperm to measure its fluorescence and the larger ones are separated out. Because 'female' sperm are slightly larger, carrying 2.8 per cent more DNA, it is possible to sort them out before conception (Sperm sorting and gender choice NZ Herald July 2001).

The second is much more expensive and has close to 100% reliability, but involves IVF to select and then implant a single fertilized embryo known to be of the desired sex (p 402).

Launching what he claims is the 'world's first 100 per cent guaranteed baby sex selection project,' British gynaeoologist Paul Rainsbury is unbothered by criticism that he is playing God. Dr Rainsbury offers parents the chance to choose the sex of their unborn child by embryo selection for the equivalent of about $25,000. Using existing in-vitro fertilization (IM technology, his clinics in Riyadh, Saudi Arabia and Naples, Italy, will take eggs and sperm from the couple, fertilise the eggs in a laboratory, then choose an embryo with the preferred sex to implant in the womb. Dr Rainsbury said the sex of the fertilised egg is evident after about 48 hours. The rate of live births will be the same as those for IVF. The difference is that the sex of any foetus that is born is '100 per cent guaranteed.' In Saudi Arabia, they love it.' Dr Rainsbury said his clinics have a place in a world where sex selection is already commonly practised but in cruel and inhumane way, the result of pressure to produce a male heir in many parts of the Middle and Far East and Africa. 'Around the world tens of thousands of babies, whose only crime was being born of the 'wrong' sex, are deliberately abandoned to starve and die.' (Doctor's happy playing God NZ Herald 19 Mar 1997).

PGD confirms a run of one sex does not arise from genetic predisposition (p 97) although hormones, social ranking and stability of relationships do bias the sex ratio (p 96).

Declining Fertility, Feminization of Nature and Ephemeral Males

Such techniques as ICSI exist in a context of fears that male fertility is declining, even without the intervention of such processes. Some have attributed this to the 'feminization of nature' associated with environmental pollution with estrogenic industrial chemicals (Cadbury R98, Colborn et. al. R127) with widespread effects on wildlife, from fish to frogs.

A study of 7,500 men attending the Aberdeen Fertility Centre suggests average sperm counts have dropped by 29% in 14 years. While the fall may be a result of more men coming forward for treatment, doctors are concerned by the findings. The results of the study were presented at a British Fertility Society meeting in Liverpool. In one of the biggest studies of its kind, researchers analysed nearly 16,000 semen samples taken from men attending the clinic between 1989 and 2002. They found that the average sperm count of men attending the clinic had dropped sharply. 'The drop in sperm counts must cause concern': Dr Siladitya Bhattacharya In 1989, the average sperm count of men with 'normal' amounts of sperm in their semen was 87 million sperm per millilitre. By 2002, that had dropped to just over 62 million sperm per millilitre (Fresh fears over men's fertility BBC 5 Jan 2004).

Bronte Stone at Reproductive Technology Laboratories in Los Angeles and his colleagues analysed sperm samples from 5081 men aged between 16 and 72. They found a deterioration in sperm quality and quantity after age 35. The study also found a decrease in the ratio of Y to X-bearing sperm once men hit 55, though it is not clear why (Men's sperm quality decreases at age 35 New Scientist 25 Jul 13).

There are several other features of this picture causing concern, including fewer men with healthy sperm, smaller testicles with more fibrous tissue, increasing testicular cancer. Many agents from tobacco to marijuana, and physical activities like riding a racing bike can also cause damage to sperm and the sperminal apparatus. At the same time there is confirmation that chemical pollutants thought harmless destroy male fertility in mice:

Pressure to control the pollution of drinking water by oestrogen and compounds that mimic the female sex hormone is growing following two worrying discoveries. Last week, Finnish scientists published the most convincing evidence yet that sperm production by men in industrialised countries is declining. Among the men who died in 1981, 56.4 per cent had normal, healthy sperm production. By 1991, however, this figure had dropped dramatically to 26.9 per cent. The average weight of the men's testes decreased over the decade, while the proportion of useless, fibrous tissue increased. The incidence of testicular cancer is increasing every year, and in Denmark now affects 1 per cent of young men. Meanwhile, an American team has found that octylphenol, an oestrogen mimic which is a breakdown product of a detergent used in the manufacture of paper, textiles and plastics, that pollutes many rivers, but which was thought to be relatively benign, can render male rats infertile within two months (Fresh Alarm over Threatened Sperm New Scientist 11th Jan 1997).

Women may be able to better gauge their own fertility based on the age their mother went through the menopause, a study has concluded:

Women whose mothers had an early menopause had far fewer eggs in their ovaries than those whose mothers had a later menopause, a Danish team found. Researchers looked at two accepted methods to assess how many eggs the women had - known as their 'ovarian reserve' - levels of anti-Mullerian hormone (AMH) and antral follicle count (AFC). Average AMH levels declined by 8.6%, 6.8% and 4.2% a year in the groups of women with mothers who had early, normal or late menopauses, respectively. A similar pattern was seen for AFC, with annual declines of 5.8%, 4.7% and 3.2% in the same groups, respectively (Fertility 'predicted by mother's age at menopause' BBC 7 Nov 2012).

A group of chemicals used widely in food packaging, toys and cosmetics has been linked to early menopause in women:

The findings of the United States study indicated women exposed to the highest levels of the chemicals, called phthalates, went through menopause on average 2.3 years earlier than women who were not exposed although there is no evidence of an acroos the population reduction in average age of menopause (Johnson M Chemical link to early menopause NZ Herald Oct 26 2012)

Men who lose the ability to produce sperm after chemotherapy might one day be able to regain their fertility:

Orwig and his team took samples of the cells from the testes of prepubescent and adult male rhesus macaques, and froze them. The monkeys were then given chemotherapy agents known to shut down sperm production. A few months later, the researchers injected each monkey's own spermatogonial stem cells back into its testes. Sperm production was re-established in nine of the 12 adult animals and started normally in three out of five prepubescent animals once they reached maturity. The resulting sperm were used to fertilise eggs and produce healthy embryos (Ferguson W Sperm stem cells restore male fertility New Scientist 5 Nov 2012).

Difficulties over measuring sperm counts and regional and seasonal fluctuations add to the dilemma of gaining an accurate picture. In a 1996 study sperm counts in the US appeared to have increased and there was a trend following overall fertility rates as well. However regional differences may confirm environmental effects.

American men are not suffering from declining sperm counts. What's more, sperm counts are closely correlated with birth rates. Fisch's findings contradict those of European researchers, who have been amassing evidence for a worldwide decline in sperm counts:

Fisch renewed sperm counts of 1283 men who banked sperm between 1970 and 1994 before they had a vasectomy, in Los Angeles, Roseville in Minnesota, and New York City. He found a statistically significant increase in New York and Minnesota and a slight but not statistically significant increase in California. The average sperm count rose from 77 million per millilitre in 1970 to 89 million/ml in 1994. Californian men had the lowest counts (73 million/ml). In Minnesota they were higher (101 million/ml), but New Yorkers held the record (131 million/ml). But Fisch also points out that variation from one year to the next could be greater than the variation over 25 years. The study that first put men on alert was Skakkebaek's huge multi-study analysis, in which he looked at the data from 61 sperm count studies in the medical literature since 1930, covering 14 947 men. He found that between 1940 and 1990, sperm counts fell by 60 per cent on average, and he concluded there was 'a genuine decline in semen quality' (Panic Over Sperm Counts May be Premature New Scientist 11 May 1996).

The effects on male fertility also appear to be reflected in a small but noticeable decline in male birth rates, which may also be related to pollution as the Seveso dioxin disaster caused a profound shift to only daughters in the most contaminated couples.

Male fetuses are generally less likely than females to come to term: although 125 males are conceived for every 100 females, only about 105 boys are born for every 100 girls. In the first half of this century, improvements in prenatal care reduced the number of miscarriages and stillbirths and hence increased the proportion of baby boys in most industrial countries. But since 1970 the trend has reversed: in the U.S., Canada and several European countries, the percentage of male births has slowly and mysteriously declined. So far the decrease has not been alarmingly large. In the US in 1970, 51.3 percent of all newborns were boys; by 1990, this figure had slipped to 51.2 percent. But in Canada the decline has been more than twice as great, and similar long-term drops have been reported in the Netherlands and Scandinavia. High exposures to certain pesticides may disrupt a father's ability to produce sperm cells with Y chromosomes-the gametes that beget boys. Other toxins may interfere with prenatal development, causing a disproportionate number of miscarriages among the frailer male embryos. (XY embryos require hormonal stimulation to produce masculine genitalia, which may make the unborn males more vulnerable to hazardous chemicals.) Perhaps the most striking example of a lopsided birth ratio occurred in Seveso, Italy, where a chemical plant explosion in 1976 released a cloud of dioxin into the atmosphere. Of the 74 children born to the most highly exposed adults from 1977 to 1984, only 35 percent were boys. And the nine sets of parents with the highest levels of dioxin in their blood had no boys at all (Where have all the boys Gone? Sci Am Jul 98 13).

An enigmatic diving of the male reproduction rate has been found at Aamjiwnaang community next door to the Sarnia-Lambton Chemical Valley complex in Ontario (McKenzie R461).

Similar depression of boys has been found in highly pollluted areas of Brazil. In the least polluted areas 51.7% of the babies born were male - but in the most polluted areas the percentage of males born decreased to 50.7%. In an experiemntal test on mice, males from a filtered air environment produced offspring with a 1.34 male/female ratio, while males that had been exposed to polluted air produced offspring with a 0.86 male/female ratio. Separate research found that pregnant mice exposed to air pollution were more likely to miscarry than those breathing filtered air.

The sex ratio can also be affected by stress in the mother. After 9-11, even as far away as California, in December 2001 there were 2% fewer males than expected and 29% fewer low-birthweight males, indicating premature loss of small male embryos by stressed mothers (R110). One can thus also see a basis for changes in the sex balance towards girls associated with lower classes in hypergamy (p 30).

More generally, several factors are combining to reduce the fertility of both human sexes:

Infertility is set to double in Europe over the next decade, a leading UK fertility expert has warned. One in seven couples now has trouble conceiving naturally, but Professor Bill Ledger from Sheffield University warned this could rise to one in three. He told a European fertility conference that women should be offered career breaks so they could have children younger, when they are more fertile. The incidence of chlamydia, a sexually transmitted infection which carries a risk of infertility, has doubled over the last decade - and 6% of girls under the age of 19 are currently classed as obese. A potential rise in male infertility could also affect couples, Professor Ledger said. Both the quality and quantity of sperm appeared to be in decline. 'The sustainability of the population of Europe is at risk because there are too few children being born. It is a threat to the future.' ('Infertility time bomb' warning Michelle Roberts BBC 20 June 2005).

Infertility however is increasingly a man's problem:

Infertility may be becoming more of a man's than a woman's problem, new figures suggest. Until now, both were level pegging - 40% of cases linked to men, 40% to women and 20% to joint problems. However, the European Society for Human Reproduction and Embryology found rates of an IVF treatment typically used to help male infertility have risen. It said a number of factors including declining sperm quality due to environmental toxins may be involved. Use of ICSI (intra-cytoplasmic sperm injection), in which a single sperm is injected into the egg to fertilise it, made up only 43% of IVF cycles in 1997, but accounted for 52% of cycles in 2002 (Male infertility 'is increasing' BBC 23 June 2005 Michelle Roberts).

As a potent reminder, high fertility in mid-life is associated with a sub-population of women who have exceptional anti-ageing DNA repair systems:

The very few women who have children after the age of 45 may be capable of doing so because anti-ageing mechanisms are more active in their bodies. Neri Laufer's team at Hadassah University Hospital in Jerusalem recruited eight women who had given birth naturally after the age of 45. His team compared levels of gene expression in the women's blood from with levels in six mothers of the same age who had chosen not to have any more children after 30. They found differences in 716 genes. Intriguingly, many of the genes that were more active in the fertile over-45s are involved in repairing DNA damage and preventing cell death. All the women were ultra-orthodox Ashkenazi Jews, but Laufer says preliminary results from a study of Bedouin women suggest the results apply to all (Fertility in middle age linked with anti-ageing New Scientist 21 June 2005 Michael Le Page).

Phytoestrogens can also have unforseen effects in women. Although the isoflavones in soya are both believed to reduce prostate cancer and reduce male virility in Asian countries, (NZ couples copulate around 144 times a year on average but Japanese only 35) soya phytoestrogens can also make sperm too 'frisky' too soon:

Women should avoid eating too much soya if they are trying for a baby. A study in humans has shown the genistein in soya sabotages the sperm as it swims towards the egg. Professor Lynn Fraser, from King's College London, said even tiny doses in the female tract could burn sperm out. The compound kick-started a reaction in a large proportion of the sperm that gives them the ability to fertilise an egg. In real life, this does not usually happen until the sperm have been inside the female for some hours and are close to completing their long swim towards the egg ( 'Avoid soya if you want a baby' BBC 21 June 2005 Michelle Roberts).

A study has shown that in cases of unexplained infertility, natural conception is more successful than a standard fertility treatment:

The study, by Pieternel Steures focused on couples with unexplained fertility problems who were estimated to have a 30-40% chance of conceiving spontaneously within 12 months. The fertility treatment, intrauterine insemination (IUI) with controlled ovarian hyperstimulation, involved using drugs to make the woman's ovaries produce eggs and inserting her partner's sperm directly into her womb. With the fertility treatment, 42 (33%) women conceived and 29 (23%) had ongoing pregnancies. Similarly, in the group that carried on trying to conceive naturally, 40 (32%) women conceived and 34 (27%) had ongoing pregnancies. Therefore, in terms of successful pregnancies, the fertility treatment added no benefit. Rarely, stimulating the ovary can lead to a life-threatening condition called Ovarian Hyperstimulation Syndrome.Given the serious health risks associated with this form of assisted reproduction, expectant management would be a better option for these couples, say the authors (BBC 14 July 2006).

Women may not be born with a limited number of eggs after all. The discovery of stem cells tucked away in human ovaries suggests that new eggs are actually produced throughout life. The finding could pave the way for new fertility treatments. Jonathan Tilly and his colleagues at Massachusetts General Hospital looked carefully at the number of oocytes – cells that develop into fertilisable eggs - in the ovary. Because total oocyte numbers drop throughout life, it was assumed that these cells were continually dying off. However, within the period it took for total cell numbers to drop by 500, the team viewed 1500 cells dying, suggesting that new cells were being made at the same time. Further investigation identified ovarian cells that appeared to be capable of producing new oocytes (Nature, DOI: 10.1038/nature02316).

The Three Parent Child and The Sexual Chimaera

Three-person IVF trial 'success' 2012 US scientists say a human and animal trial of a controversial new IVF treatment has yielded promising results. The findings in Nature magazine show healthy-looking embryos can be created from a mix of three adult donors. Human embryos were grown in the lab and some appeared normal, while monkeys born using the same technique remained fit and well, now aged three. A public consultation on the ethics of using this IVF in the UK is under way. Safety studies are still needed (Michelle Roberts, BBC, 24 Oct 2012, Journal refererence: Nature, doi.org/jk3).

Fig 8: Three parent procedures.

"Put the brakes on new IVF techniques to prevent mitochondrial disease being inherited." That's the message from a group of researchers. They worry that the mtDNA from the donor might be incompatible with the nuclear DNA from the parents, and cite a number of animal studies that indicate the treatment can profoundly change the expression of nuclear genes and affect cognition, lifespan and fertility, especially in males (Warning sounded over three-parent IVF safety New Scientist 19 Sep 2013).

These concerns have again reached atttention in 2016 with a study using women's eggs with healthy mitochondria and applying the donor mintochondrial technique, developing embryonic cell and tissue lines demonstrated that the small trace of around 0.2% of maternal mitochondria remaining can sometimes repopulate embryonic cells and become dominant over the donated mitochondria, potentially leading to a resurgence of mitochondrial disease (Yamada, M. et al. Cell Stem Cell doi:10.1016/j.stem.2016.04.001). The most dramatic rebound in carried-over mtDNA occurred when the nucleus of a woman with mitochondria common among Europeans was inserted into the egg cell of a woman with mitochondria usually found in people with African ancestry. In another study, it was found that in mice with mitochondria from both lab and distantly related wild populations, one mitochondrial lineage tended to dominate (Burgstaller, J. P. et al. 2014 Cell Rep. 7, 2031-41 ). If mitochondrial replacement does reach the clinic, Johnston says that donors should be chosen such that their mitochondria closely match those of the recipient mother. This sugests careul choice of a donor with similar mitochondria to the mother would be essential.

In June 2016 a study in Nature (doi:10.1038/nature18303) using healthy donor eggs, based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover.

In November 2016 a study transplanting human mitochondria into mice demonstrated that, even when the mother's mitochondria have defective genes, they can sometimes out-grow the donor mitochondria and lead to recurrence of the genetic defect, through the mother's mitochondria taking over again. The researchers found that some variants in the mitochondrial DNA's D loop allow the DNA to replicate faster and dominate slower replicating varieties. That happened even when the faster replicator contained a disease-causing mutation elsewhere. In other cases, both the mom's and the donor's mitochondrial DNA replicated at the same rate, but certain varieties of mitochondria gave cells a growth advantage. Those growth advantages are probably due to genes in the nucleus, which include ones that control mitochondrial growth. The aim is then to test donor mitochnodria in the lab using such methods to ensure that the donor mitochondria have a match to the mothers that will ensure no takeover occurs (Kang E. et al. 2016 Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature doi: 10.1038/nature20592 ).

Fig 8b: Transplanting the chromosome spindle from the mother's egg

A variety of techniques additional to IVF, involving various of forms of reproductive germ-line engineering, are emerging. These have major implications, because the genetic changes induced are heritable and will continue down the generations and be mixed with natural genes during sexual exchange. The techniques include mitochondrial transfers, fertilization with transplanted nuclei including stem cells, spermless fertilization using a second female haploid set, and even inter-sex chimeras. There are already scores of children in the US born by some of these techniques particularly those with genes from three parents, by injecting including mitochondria from another female to boost defective ones in the mother. There are about 30 children in the US who have already become germ-line genetically modified humans.

Scientists have confirmed that the first genetically altered humans have been born and are healthy. Up to 30 such children have been born, 15 of them as a result of one experimental programme at a US laboratory. The oldest of the children turns four in a month. But the technique has been criticised as unethical by some scientists and would be illegal in many countries, including the United Kingdom. Genetic fingerprint tests on two one-year-old children confirm that they contain a small quantity of additional genes not inherited from either parent, from the mitochondria of an egg from another female. The children were born following a technique called ooplasmic transfer. This involves taking some of the contents of the donor cell and injecting it into the egg cell of a woman with infertility problems. The additional genes were in mitochondria taken from a healthy donor. As many as 100,000 float in the cells cytoplasm (Genetically altered babies born BBC 4 May 2001).

But there was an outcry when the first two of the attempts had to be terminated because of genetic abnormalities.

The American doctor who trumpeted a fertility technique using three genetic parents failed to disclose that along with 15 healthy babies, it produced two fetuses with a rare genetic disorder. Experts are horrified because the fault can be passed to future generations. Dr Jacques Cohen denounced as 'hysterical' growing criticism of his claims that the research posed no risk. 'Many of the techniques I carry out in America are illegal in Britain but that does not mean they are immoral.' 27 infertile couples who could not conceive through IVF took part in the programme, in which an infertile woman's egg is mixed with her husband's sperm and parts of a younger woman's egg. In 30 attempts, 15 babies were born. Their maternal genes came from their true mothers and all appeared completely healthy. The researchers concluded there was no reason to believe the technique was harmful to foetuses or babies. But what Cohen's team failed to reveal was that though 15 babies were born, 17 foetuses were created. The first unborn foetus was aborted and the second miscarried after both developed a genetic anomaly called Turner's Syndrome, a rare disorder in which an X chromosome is missing. Two out of 17 far exceeds normal statistical expectation (Gene Technique Faulty NZ Herald May 21 2001).

The US acted within two months to ban the free use of this technique:

Does manipulating an egg prior to IVF turn it into an 'experimental product' that has to be regulated like a new drug or medical device? Yes, says the US Food and Drug Administration. This month, the agency wrote to several fertility clinics warning them that any treatments that genetically alter egg cells or embryos would constitute a 'clinical investigation' and so fall under the agency's authority. The announcement will effectively prevent clinics using a controversial technique known as 'ooplasmic transfer' (US puts its foot down on tinkering with IVF babies New Scientist 21 Jul 2001).

However in February 2016 the US National Academies of Sciences, Engineering and Medicine said US Food and Drug Administration (FDA) should approve clinical trials of a gene-therapy technique to create embryos with genetic material from three people (doi:10.1038/nature.2016.19290).

A variant of the technique has since been used (unsuccessfully) in China following the techniques of an American team using the nuclear transfer commonly used in cloning:

A woman has become pregnant through a procedure that combines a controversial IVF method with one of the techniques used for cloning. But the fetuses that resulted, although they did not survive to term, were certainly not clones. In fact, they had three genetic parents. The procedure involves transferring a fertilised nucleus from the mother's egg to an egg from another woman. Any child born this way would inherit the vast majority of its genes from its mother and father, like a normal baby, but the handful of genes found outside the nucleus, in the cell structures called mitochondria, would come from another woman. The latest work was done by John Zhang's team at the Sun Yatsen University of Medical Science in Guangzhou, China, with the help of Grifo's team. The donor eggs were emptied of their nuclei, and a fertilised nucleus from the woman's eggs transferred into each one. Five of the resulting embryos were implanted, resulting in a triplet pregnancy. Doctors reduced this to twins, but one fetus died at 24 weeks, and the other at 29 weeks (IVF creates fetuses with three parents New Scientist 18 oct 2003 12).

A variant of this technique has been approved in the UK:

UK scientists have won permission to create a human embryo that will have genetic material from two mothers.The Newcastle University team will transfer genetic material created when an egg and sperm fuse into another woman's egg. The groundbreaking work aims to prevent mothers from passing certain genetic diseases on to their unborn babies. (Embryo with two mothers approved BBC 8 Sep 2005).

An improvement in this technique has come from inserting mitochondria from other ovarian cells from the mother, however this may perpetuate the mitochondrial genetic defect:

Injecting a woman's eggs with fresh supplies of power-generating mitochondria from the egg of another woman is known to boost the success rate IVF. But there's a serious ethical hitch: any resulting embryos contain genetic material from three different people. Now doctors from Taiwan have isolated cumulus cells, which normally nestle around developing eggs in a woman's ovary, and extracted the mitochondria from these. They injected up to 5,000 mitochondria into each egg, 5% of the total number they already contain. They then fertilized the eggs in the lab, allowed them to grow into embryos and implanted them into the woman's uterus. Of 71 attempts, 35% resulted in a pregnancy and 20 babies were born. By contrast, only 6% of attempts without mitochondrial injection had previously resulted in pregnancy in the same group of patients, none of which had reached term. By contrast, with egg cells which remain quiescent in the ovary, cumulus cells are regularly refreshed so their mitochondria carry fewer defects.

Previous attempts to pep up women's eggs with fresh mitochondria have all suffered from ethical and safety concerns. One method, called cytoplasmic transfer, involves injecting cytoplasm and mitochondria from a healthy woman's egg into the egg of an infertile woman. The US Food and Drug Authority banned this technique in 2001 (except in clinical trials), because of concerns that it raises the risk of children suffering genetic abnormalities. There are also ethical concerns about creating an embryo containing the genetic material of three parents: the mother, the father, plus the small amount of DNA harboured in the donor woman's mitochondria. A related experimental, and also contentious, technique involves transplanting the entire nucleus from an infertile woman's egg into the egg of a healthy woman that has been stripped of its own nucleus. Because this technique replaces all the mitochondria in the egg, it could be used to help women whose own mitochondria carry a genetic disease that might be passed onto their children. A group in China revealed that they had tried this last year (Egg injection boosts fertility Helen Pearson Nature 20 October 2004 doi:10.1038/news041018-10).

At an extreme of identity blending, a sexual chimaera has been created containing cells of both sexes which would produce a hermaphroditic individual of two differing genetic identities at the cellular level. The long term aim of this is to prevent genetic diseases by introducing cells from another genetic source in the hope of compensating for genetic abnormalities. However it raises fundamental issues of a Frankenstein-like nature.

Fig 9: Chimera BBC

An experiment in the United States has created a mixed-sex human embryo. The team insists that the creation of an hermaphrodite human embryo was designed to cure illness, but critics say moral and ethical standards have been breached. The process creates a 'chimaera' - a blend of two embryos, each of which would have a distinct genetic identities. Any attempt to produce such a baby would provoke a worldwide ethical storm. In experiments using donated embryos, scientists from the Centers for Human Reproduction in New York and Chicago have taken the first step - and found that, in some cases, the introduced cells do proliferate and spread throughout the chimeric embryo. Their hope is that having even a small proportion of cells from a healthy embryo might prevent certain genetic diseases from arising .However, other experts have dismissed the idea as 'deeply flawed' - and say research into the issue, even in animals, should not continue. Any use of chimeric technology in human reproduction in the UK is illegal ('Merged embryo' cure hope attacked BBC 3 July 2003).

Such chimeras are by no means unknown in the human population. Some individuals have been found to consist of two genetically-distinct merged cell lines as a result of non-identical twins becoming integrated at an early embryonic stage. If both are of the same sex, this will result in a normal individual but cause sexual abnormalities and infertility if it occurs between a non-identical brother-sister twin chimaera. Such individuals can also confound paternity testing because some of their tissues display one genetic identity and others another. Most of us may in fact be micro-chimeric as a result of perfusion of individual cells both between a mother and child in-utero and between two normal twins. Such perfusion may actually help to avoid a mother developing immunity to her offspring (Ainsworth R3).

However scientists and ethicists are deeply concerned about the prospect of inheritable germ line engineering:

Attempting to rearrange genes and create future generations of perfect human beings is dangerous, irresponsible and should not be permitted now, a panel of United States experts says in a report. A committee of the American Association for the Advancement of Science has called for the creation of a public committee to monitor and oversee the increasingly sophisticated research into genetic modification. 'This would widen the gap between the. 'haves' and the 'have nots' to an unprecedented extent' the report said. The committee report. Evidence to the committee showed IGM research was not yet safe to use on humans. For each triumph there could be scores of animals born with terrible and usually lethal genetic problems (Inheritable Human Genetic Modification Opposed NZ Herald 20 Sep 2000).

Demise of the Egg and Sperm

Into this already heady mix enters the idea that we don't need an egg and a sperm at all to have effective fertilization, In a 2016 book The End of Sex and the Future of Human Reproduction (Harvard University Press), Henry Greely makes the case that people in the next few decades will stop using sexual reproduction for new offspring, instead using primordial stem cells and coaxing them to become eggs and sperm before fertilizing them in a clinic using IVF and PGD to determine their genetic characteristics, selecting them for those they desire such as intelligence, good teeth, resistence to disease etc. He claims such techniques would becoem cheaper than current IVF and enable a higher quality of choice of genetic offspring than sexually sired offspring. Sex would then cease to be a matter of fertilization and be merely for social bonding.

Several steps of this types of reproductive engineering have already been taken. The most outstanding of these is to prime a stem cell to convert into a surrogate ovarian follicle (Westphal R738, Johnson et al R343, Pilcher R542):

Last week, researchers in the US reported that they had transformed mouse embryonic stem cells into mature eggs in the lab, and a Japanese team has produced sperm in a similar way. Worryingly, more eggs will also be a boon to those who want to create living clones. Making eggs and sperm also has huge potential for helping infertile couples. It would depend on therapeutic cloning to generate embryonic stem cells, something that has yet to be achieved with human cells. But if that does happen, it could enable couples who cannot make their own eggs or sperm to have children who are a mixture of their genes, just like those conceived in the old-fashioned way. Yet these couples need not be old-fashioned couples. Some eggs in the latest experiments came from male stem cells. If the same can be done in humans, a gay couple could supply both egg and sperm to create their own child. That prospect will no doubt outrage some. It would certainly require a rethink of the laws covering parentage. But before this ever happens, we need to have a clear picture of the risks to any offspring born from artificially created eggs and sperm. Recently, a number of small studies found that IVF children have a higher risk of defects caused by errors in imprinting, the process by which genes in the embryo are switched on or off. The inability to generate the right pattern of imprinting has thwarted all past attempts to create artificial eggs and sperm. It is also the reason why cloning is so difficult and the rate of abnormalities in clones is so high (Brave new IVF New Scientist 10 May 2003).

In a follow-up (New Scientist 13 Dec 2003 19) mouse embryos were made by fertilizing eggs with immature sperm cells made from embryonic stem cells. In the same issue (14) frozen sperm stem cells were successfully used to rear live pups and some stem sperm have also produced live offspring ('Lab-made sperm' fertility hope BBC 10-7-06).

Sperm-like cells made from human embryonic stem cells Jul 09

Human embryonic stem cells have been coaxed into forming sperm-like cells, researchers report today1. The cells have some of the hallmarks of sperm — they can swim, for example — but require much more characterization before they can be embraced as an experimental model for the study of inherited diseases and infertility. Meanwhile, the use of such cells to help infertile couples to have children remains a distant prospect; in several countries, including the UK, it would actually be illegal even if they were properly characterised. In addition, the DNA packaged in reproductive cells is wiped clean of a chemical modification known as methylation, which involves the attachment of methyl groups to certain regions of the genome. These modifications are then added back in patterns characteristic of either sperm or egg cells. Methylation can affect gene expression, and if either demethylation or remethylation does not occur properly the results can be disastrous. About 3% of the resulting cells contained enough DNA for only one set of chromosomes, suggesting that meiosis had occurred. Some of these cells also formed tails and were motile.

Fig 10: Therapeutic reproductive cloning from stem cells New Scientist 10 May 2003

Researchers are very close to creating sperm outside of the body for the first time. The feat has already been achieved with eggs. It was accomplished with cells originally derived from mouse embryos, but most experts see no reason why the technique would not work with human embryonic stem cells too. If human eggs and sperm created this way are healthy - and it is a big if - the implications for reproductive technology and regenerative medicine would be immense. Intriguingly, eggs form from both female (XX) and male (XY) ESCs. That is because mammalian germ cells will go down the egg route unless signals produced by the testes tell the cells to become sperm. This is also why getting ESCs to turn into sperm is more complex. However, a team led by Toshiaki Noce at the Mitsubishi Kagaku Institute of Life Sciences in Tokyo may already have succeeded. According to a document found by New Scientist, the team allowed male mouse ESCs to develop spontaneously into various different types of cell, and picked out those that had begun turning into germ cells. These cells do not develop far in culture, but when Noce's team transplanted them into testicular tissue he found after three months that they had undergone meiosis and formed what appeared to be normal sperm. The critical next step would be to fertilise the artificial eggs with normal sperm, or use the artificial sperm to fertilise normal eggs. The big question is whether the resulting embryos will have normal imprinting and develop into healthy baby mice (Stem cells can become 'normal sperm' Sylvia Pagán Westphal New Scientist 7 May 2003).

More recently stem cells have been made into precursors of both sex cells:

Human embryonic stem cells have been coaxed in the lab to develop into the early forms of cells which eventually become eggs or sperm, UK researchers have revealed. Work by several groups has shown that a tiny proportion of human embryonic stem cells (ESCs) spontaneously develop into primordial germ cells when allowed to differentiate in a dish. In this latest study, Behrouz Aflatoonian and colleagues at the University of Sheffield, produced primordial germ cells which began to express the proteins characteristic of sperm cells, while others resembled eggs (Further steps towards artificial eggs and sperm 20 June 2005 NewSci. Michael Le Page).

These have now developed into mature eggs and sperm from the same stem line:

Stem cells from a mouse embryo have been coaxed into producing both eggs and sperm in the same dish. The eggs and sperm are the most mature yet grown in the lab, and the advance brings researchers closer to their ultimate aim: producing human eggs and sperm from adult body cells so that infertile men and women can have their own children. In 2003, Hans Schöler and colleagues reported that after such cells had been cultured for around 40 days, some of them spontaneously produced eggs. The following year, researchers led by George Daley, coaxed cells into producing sperm precursors, by adding retinoic acid. These cells did not form mature sperm, but were able to fertilize eggs when injected into them. Irina Kerkis, decided to see whether retinoic acid could trigger egg as well as sperm production (Cloning and Stem Cells, DOI: 10.1089/clo.2007.0031). They took cells cultured from a male mouse embryo and grew them into hollow balls called embryoid bodies, which look rather like early embryos. Then they grew them with retinoic acid for 4 days. Two weeks later they were surprised to see both eggs and sperm produced. Cells on the outside of the embryoid bodies turned into mature, elongated sperm, whereas cells on the inside formed follicles, which released eggs. The eggs developed into blastocysts that then 'hatched', a process that normally occurs just before an embryo implants into the uterus wall. Alan Trounson, a stem-cell researcher at Monash University in Melbourne, Australia, is impressed. 'I haven't seen sperm of that maturity produced in the lab,' he says. Applying the technique to humans would be controversial, not least because it raises the possibility that men might be able to produce eggs, and women sperm ('Mature sperm and eggs grown from same stem cells' Jo Marchant Nature doi:10.1038/news060619-13 23 June 2006).

In April last year, Karim Nayernia made headlines by taking bone marrow stem cells from adult men and making them develop into spermatogonia - cells that can give rise to immature sperm through meiosis. Since then, he claims to have repeated the feat for female bone marrow, opening the door for the creation of female sperm. Nayernia also claims to have made lab-grown male spermatogonia enter meiosis by culturing them with Sertoli cells - support cells from the testes that nurture developing sperm. 'One researcher claims to have produced spermatogonia - the precursors of sperm - from female bone marrow stem cells' (Aldhous P 2008 Are male eggs and female sperm on the horizon? New Scientist 2 Feb)

Male eggs might not be so hard to make. A Brazilian team led by Irina Kerkis claims to have made both sperm and eggs from cultures of male mouse embryonic stem cells (Cloning and Stem Cells, doi: 10.1089/clo.2007.0031). They are thinking about possibilities for same-sex human reproduction. 'We are starting experiments with human embryonic stem cells,' says Kerkis. If these are successful, then the next step will be to see if male eggs could be made from cells known as 'induced pluripotent stem cells'. These seem to behave just like embryonic stem cells, and can be made from adult skin cells using a genetic reprogramming technique pioneered by Shinya Yamanaka of Kyoto University in Japan (New Scientist, 24 November 2007, 7).

The therapeutic cloning technique to create eggs is deceptively simple. Extracting stem cells and growing them under high density causes them to adapt naturally to form the most basic unit of mammalian perpetuity the ovarian follicle, complete with an ovarian cycle, and can even be induced to 'ovulate' using lutenizing hormone:

The mammalian egg, the cell that holds the secret to fertility, cloning and cell rejuvenation, has been created outside the body for the first time. Researchers are very close to creating sperm in a similar way. The feat was accomplished with cells originally derived from mouse embryos, but most experts see no reason why the technique would not work with human embryonic stem cells too. If human eggs and sperm created this way are healthy - and it is a big if - the implications for reproductive technology and regenerative medicine would be immense. Most immediately, a cheap, limitless supply of human eggs would greatly accelerate research in keys fields such as infertility and therapeutic cloning. The method used to create eggs from embryonic stem cells (ESCS) was astonishingly simple. Instead of searching for chemicals that coax ESCs into becoming eggs, as many have attempted, Hans Schuler's team at the University of Pennsylvania just let mouse ESCs grow at high density. In these conditions, some of the cells form floating aggregates most scientists would discard as useless debris. But team member Karin Hilbner instead placed the clumps in new dishes. 'In four days they proliferated like crazy,' says Schuler. The aggregates seem to behave like miniature ovarian follicles in which small cells nurture a bigger cell that forms an egg. Further studies by the team revealed that these egg-like cells form by meiosis, and switch on the same key genes as normal eggs as they develop. The follicle-like structures make hormones such as oestradiol in amounts that rise and fall on the same time scale as the menstrual cycle. Adding a hormone called gonadotrophin triggers the expulsion of the egg cell into the culture dish, mimicking ovulation (Science, DOI: 10.1126/science.l083452). Intriguingly, eggs form from both female (XX) and male (XY) ESCs. That is because mammalian germ cells will go down the egg route unless signals produced by the testes tell the cells to become sperm. This is also why getting ESCs to turn into sperm is more complex. However, a team led by Toshiaki Noce at the Mitsubishi Kasei Institute of Life Sciences in Tokyo may already have succeeded. According to a document found by New Scientist, the team allowed male mouse ESCs to develop spontaneously into various different types of cell, and picked out those that had begun turning into germ cells. These cells do not develop far in culture, but when Noce's team transplanted them into testicular tissue he found after three months that they had undergone meiosis and formed what appeared to be normal sperm. Both teams have yet to perform the next, crucial step: fertilising the artificial eggs with normal sperm, or using the artificial sperm to fertilise normal eggs.

Other more meticulous methods have also been used achieve 'artificial' eggs which could also be fertilized without sperm:

'Birth of a miracle' Soon you may not need eggs or sperm to have children of your own New Scientist 7 Jul 2001 Men and women who can't produce sperm or eggs could one day have 'natural' children of their own thanks to a form of cloning. Gianpiero Palerino of Cornell University in New York has created artificial human eggs that contains just one set of a would-be mother's chromosomes. Such eggs could be fertilised with the partner's sperm, just like a normal egg. And in Australia, Orly Lacham-Kaplan of Monash University in Melbourne has shown that you can fertilise eggs, not with sperm, but with cells taken from elsewhere in the body. But there are still considerable obstacles to overcome before either technique could be used to create human babies. The trouble is that we inherit not just genes, but chemical marks, or imprints, that turn some genes off. Chromosomes taken from body cells have different patterns of imprinting to egg and sperm cells, and that could cause developmental abnormalities. This may be why some clones have problems (The next IVF revolution NS 10 may 2003).

The technique involves persuading a normal cell to go through simulated meiosis to form an egg with only one set of chromosomes. It could also enable same-sex couples to parent their own genetic children, terminating the intrinsic complementarity of the sexes:

A technique that uses cells from the body, rather than sperm, has been used to create embryos in mice. A way to fertilise human eggs without using sperm threatens to make men redundant. The technique which uses cells from any part of the body, rather than sperm has already been used to create embryos in mice. The research by Melbourne's Monash University aims to help men who have no sperm, or even sperm-raking cells, to father babies that are their own genetic offspring. But it could help lesbian couples to have baby girls that are genetically their own. Research team member Dr Orly Lacham-Kaplan said the sperm-free technique could, in theory at least, enable a lesbian couple to have a baby, with one woman contributing an egg and the second a cell to fertilise it. There are theoretical problems to overcome in combining the genes of two women, because aspects of development are controlled by a paternal gene when a maternal copy is turned off, and vice versa, as a result of a process called imprinting (p 346). 'But we have no proof yet that it is or is not a problem,' Dr Lacham-Kaplan said. Her team has succeeded in 'fertilising' a normal mouse egg by using an artificial gamete, a cell taken from the body of a male. This is remarkable because, unlike sperm, the body cell has two sets of chromosomes. To overcome that problem, the team exploited cellular machinery used by an unfertilised egg to eject a spare set of chromosomes when it meets sperm. During normal fertilisation, two sets of chromosomes in an egg are separated and one set is ejected in a package that biologists call the polar body, leaving a single set to combine with another set from the sperm. After 'fertilisation' of the mouse egg, the team used chemicals to persuade the egg to carry out the steps typical of normal fertilisation: it released its spare set of chromosomes into a polar body, only this time the body cell also expelled its spare set into a second polar body. The embryos go on to develop fairly normally in the laboratory and the team is about to transfer them into the wombs of mice (Spermless fertilization NZ Herald July 2001).

Fig 11: Parthenogenic mouse is a fertile mother Kono (R387)

The potential barriers of sexual imprinting (p 346) have already have been breached with the successful production of mice born without fathers through manipulation of oocyte imprinting, one raised to adulthood and bearing live offspring (Loebel and Tam R422, Kono et. al. R387):

Scientists have created two female mice without fertilising the eggs they grew from. The eggs had two sets of chromosomes from two female mice, rather than one from the mother and one from the father. The scientists say it would not yet work in humans. Tomohiro Kono and colleagues switched off a key gene in the donor eggs which affected imprinting - a barrier to parthenogenesis in mammals. By blocking expression of H19 in the immature mouse eggs associated with female imprinting, the researchers increased the activity of another gene Igf2 expressed in males (p 347). Igf2 manufactures a protein regulating growth in the developing foetus. These genes are sexually imprinted. The team injected the genetic material from the genetically-modified mouse eggs at an immature stage when maternal imprinting is thought to be erased into mature eggs with their own set of female-imprinted chromosomes. They then 'activated' the combined eggs, prompting them to start growing as an embryo. As a result of this modification, just two out of 598 mice embryos made it to full term. One of the surviving mice was used for testing, while another, which the researchers named Kaguya after a Japanese fairy tale character, was allowed to grow into an adult (Rincon P. Mice created without fathers BBC 21 April 2004).

Fertile baby mice have also been successfully reared from stem cells and induced primordial stem cells, for example from skin:

Fig 12: Stem cells become live pups

Using stem cells, a Japanese team has created healthy eggs that, once fertilised, grow into normal mouse pups. Last year, Katsuhiko Hayashi and his colleagues at Kyoto University in Japan found they could generate primordial germ cell (PGC)-like cells from either mouse embryonic stem cells or body cells that can turn into stem cells - known as induced pluripotent stem cells or IPSCs. What's more, the team managed to coax these into becoming sperm (Cell, DOI: 10.1016/j.cell.2011.06.052). Now Hayashi and his colleagues have created eggs from the PGC-like cells. They started with embryonic stem cells and IPSCs taken from a female mouse embryo. In separate experiments, the team coaxed each type of stem cell to form PGC-like cells. When these cells were surrounded by ovary cells, also taken from a mouse embryo, they formed immature egg cells. The team implanted these young egg cells into the ovaries of adult mice. Four weeks later, when Hayashi's team removed the ovaries, they found the cells had developed into mature eggs. When these eggs were fertilised with sperm and implanted into other mice, they were able to form embryos that developed into healthy mouse pups (Hamezekou J Mouse eggs created from stem cells for the first time New Scientist 4 Oct 2012, Science, doi: 10.1126/science.1226889).

In a 2016 tour de force of reproductive biology, scientists in Japan have transformed mouse skin cells into eggs in a dish, and used those eggs to birth fertile pups:

The report marks the first creation of eggs entirely outside a mouse. If the process could be made to work for humans, researchers could produce artificial eggs without needing to implant immature cells into ovaries to complete their development. Katsuhiko Hayashi, a reproductive biologist at Kyushu University in Fukuoka, led the group that announced the breakthrough on 17 October in Nature1. In 2012, when at the University of Kyoto, he and stem-cell biologist Mitinori Saitou reported taking skin cells down the pathway towards eggs: reprogramming them to embryonic-like stem cells and then into primordial germ cells (PGCs)2. These early cells emerge as an embryo develops, and later give rise to sperm or eggs. But to get the PGCs to form mature eggs, the researchers had to transfer them into the ovaries of living mice. The next advance came in July 2016, when a team led by Yayoi Obata, at the Tokyo University of Agriculture, reported transforming PGCs extracted from mouse foetuses into oocytes (egg cells) without using a live mammal3. Working with Obata, Hayashi and Saitou have now completed the cycle: from skin cells to functional eggs in a dish. With the use of in-vitro fertilization (IVF) techniques, 26 healthy pups were born (some originally from embryonic stem cells and some from reprogrammed skin cells). Hayashi says some of these animals gave birth to a second generation of mice (Mouse eggs made from skin cells in a dish Nature doi:10.1038/nature.2016.20817).

Sex on Ice: Transplanted Generations

Extending the use of frozen embryos to egg cells has resulted in children being born from eggs kept on ice. The frozen technology in both embryos and gamets leads to the possibility of offspring being awakened centuries after they were conceived or even centuries after their parents gametes were put in cold sotrage.

What should you do when you have a population that is shrinking and ageing amid a very low national birth rate? The government of the Japanese city of Urayasu thinks the answer is to pay for women to freeze their eggs. Working with Juntendo University Urayasu Hospital, the city has announced a three-year pilot project that will use public money to cover 80 per cent of the egg freezing costs for female residents aged between 25 and 34. The aim is to boost fertility rates by facilitating delayed childbearing; the eggs will be used up to the age of 45. This is the first “social” egg freezing subsidy programme of its kind (New Scientist 17 Jun 2016).

A mother has given birth to what are believed to be the first twins to be born in the UK from frozen eggs.

Isabella and Anna Fahey were born three weeks ago from eggs which had been kept in deep freeze storage at the Midlands Fertility Services (MFS) for two years. Their mother Margaret McNamee's own eggs were fertilised by her partner Michael Fahey's sperm. An MFS spokeswoman said only about 300 babies have been born worldwide from frozen egg fertility treatment (Twins born after two years on ice BBC 11 October 2005).

In 2015 French researchers have taken out a patent describing their technique to coax seminiferous tubules - tissue that produces sperm in the testes - taken from humans, rats or monkeys into producing mature sperm cells, although they are yet to submit details of their method and its results for peer review. Philippe Durand and Marie-Helene Perrard at the biotechnology company Kallistem in Lyon, France, say that their aim is to freeze tissue from pre-pubescent boys who need cancer treatment, so that they would still be able to father children in later life. Spermatogonia can be destroyed through radiation or chemotherapy, and boys who have not yet reached adolescence would be unable to have sperm samples frozen for use in adulthood.

There are a series of moves underway to separate our sexual organs from our bodies, so that defective organs can be stimulated to produce live sex cells, cancer patients who will be rendered infertile can save reproductive tissue so that women in careers can save frozen ovarian tissue to reawaken their reproductive capacity after their natural span of fecundity. Fertilized embryos can also be saved for later implantation. Sperm frozen for up to 21 years have been used to sucessfully father children. A woman has become pregnant naturally after slices of frozen ovarian itssue were reimplanted after 6 years because of cancer treatment (New Scientist 3 Jul 04 4). A woman has had her ovary transplanted on to her arm after an operation for cancer of the cervix so that she can later conceive by IVF. In a first n 2015 a woman conceived naturally after an ovary taken at the age of 13 on the edge of puberty before chemotherapy and grafted into her other defunct ovary at the age of 27 initiated menstrual periods and a successful natural pregancy (Hamzelou J 2015 All you need to know about conceiving babies from thawed ovaries New Scientist 10 Jun).

Technologically simplest is transplantation to a refrigerated environment:

The Royal Women's Hospital in Melbourne announced this week that it would freeze the embryos, eggs and ovarian tissues of couples who decide to delay starting a family for life-style reasons. But after an angry response from family and church groups, the hospital's director of surgery said an ethics committee had yet to approve the proposal. He said there was plenty of time to construct an ethical framework for delaying fertility, because more research was needed. One in 10 frozen embryos implanted resulted in a pregnancy, but the use of ovarian tissue was still experimental (Fertility on Ice still ethical dilemma NZ Herald 9 Sep 98).

The first (natural) human birth has taken place from frozen ovarian tissue:

A cancer patient made infertile by chemotherapy has, in a world first, given birth after revolutionary treatment, Belgian doctors say. Ovarian tissue from the Belgian mother, 32, was removed and frozen seven years ago before chemotherapy, then re-implanted into her pelvis last year. She conceived naturally and gave birth at Brussels' Cliniques Universitaires Saint-Luc this week, Lancet reported. Researchers said all young women with cancer should be offered the treatment (Woman left sterile gives birth BBC 23 September, 2004).

In the 1970s, fertility treatments such as egg freezing emerged as a way to extend the upper limit of the childbearing years. But these come with caveats of their own. Egg freezing would have required two weeks of hormone pills and injections, and frequent ultrasounds to monitor the ripening eggs. And each of these expensive, time-consuming, hormone-heavy cycles would only yield around 12 eggs. By contrast, if you bank ovarian tissue, you can theoretically preserve thousands of eggs after one short laparoscopic surgery.' (Ovary banks: Freezing the biological clock New Scientist 19 April 2012 Virginia Hughes).

Transplanted tissue has been used to successfully rear live young in monkeys:

Scientists in the US have produced the first live birth from transplanted ovarian tissue. Scientists from Oregon University removed part of the ovary in a rhesus monkey and transplanted it to another part of the body. When eggs matured on the transplanted tissue, they were collected in fertilised in the lab. The embryos were transplanted back into the womb and one developed into a healthy baby monkey (Fertility first with tissue transplant BBC 13 Oct 2003).

A baby has been born through a new technique to 'reawaken' the ovaries of women who had a very early menopause. A second woman has become pregnant using the same method. This condition, known as primary ovarian insufficiency, affects about 1 per cent of women and causes the ovaries to stop working before age 40. Since these women enter menopause at a young age, egg donation as the only option if they want to attempt to carry a pregnancy. The research involved 27 women with primary ovarian insufficiency. Their average age was 37. All had stopped menstruating nearly seven years earlier on average, and all agreed to have both ovaries removed as part of the experiment. Of this group, 13 women were found to still have residual follicles, which typically contain one immature egg. Human females are born with about 800,000 of these follicles. Most will remain dormant, but normally one follicle develops to maturity each month and releases an egg. The ovaries were dissected and treated with stimulant drugs to block a certain growth pathway, called PTEN, that causes the follicles to stay dormant. Small pieces of the ovaries were then transplanted back into the women near their fallopian tubes. Cutting up the ovaries also reduced the inhibition of another enzyme that inhibits whole organ growth. Eight of the 13 women showed signs of follicle growth, and were treated with hormones to stimulate ovulation. From that group, five developed mature eggs, which the researchers harvested for in vitro fertilization using the sperm of the women's partners. One woman received two embryos and carried a single pregnancy to term, with the birth done by C-section since the fetus was in a breech position at 37 weeks (Early menopause: Baby born after ovaries 'reawakened' BBC 30 September 2013).

Men can also transplant their testicular tissue into rodents and produce mature sperm:

A scientist in Japan claims that he has used the testes of rats and mice for this purpose. Sofikitis took spermatogonia from infertile men and injected them into the testes of rats and mice that had been specially bred to have defective immune systems, along with cells from the recipient rodent's eye. These cells-from the fluid just in front of the lens-secrete a protein called fas ligand, a signalling molecule that triggers immune cells to commit suicide. This eliminated the last vestiges of an immune response and allowed the spermatogonia to take. Sofikitis gave the injections to 10 rats and 8 mice. Five months later, he detected large numbers of mature human sperm in 3 rats and 3 mice. In one rat, he found fully motile sperm 'with better motility than that of many fertile men' (Of Mice and Men New. Sci. 13 Feb 99 4 ).

Some of these rat sperm have claimed to have already been used to sire human offspring and measures are underway to provide the same process for eggs:

Within the next year mice will be incubating the eggs of women who risk damaging their ovaries because of medical treatment, say Canadian scientists (Mice to the Rescue New Scientist 1 July 200). The team has already successfully harvested human eggs from the back muscles of rodents. The development is sure to be controversial. There was an outcry last year when Italian embryologist Severino Antinori claimed to have produced four babies using sperm grown in rats' testes (New Scientist, 27 Mar 99, 5).

Tokyo Japanese and United States researchers claimed a world first yesterday in transplanting human ovaries into mice, creating altered rodents that might produce human eggs. Scientists obtained the ovaries from three US women who had them removed for womb diseases. They dissected the ovary tissue into square pieces measuring just 2mm across. A total of 108 pieces were then injected into nine mice under the skin of the abdomen. Researchers injected hormones into the rodents to stimulate the growth of the ovarian tissue, which includes primitive human cells capable of developing into a mature ovum. After about two weeks some of the transplanted lines of human tissue developed into 'cumulus oophoms,' sacs which are the first stage in development of ova. 'We need to find out how we can nurture eggs from that stage. The basic idea was to create an egg bank for patients suffering infantile cancer who may survive into their adulthood md want to have a child' (Inserted Ovaries New Scientist 1 May 99

Parenthood now occurs in 'defiance of metaphysics' - through the use of frozen eggs and postmortem extraction, dead people are becoming parents. Sperm have been used to father children after a man's death sometimes without 'consent' from the corpse itself, or from frozen sperm banks:

In 1999 in California, a baby girl was born after sperm had been extracted from her dead father ('Great expectations' New Scientist 1 May 99).

Taking sperm from a corpse in New York state may soon be possible only if the man gave written consent before his death. A bill before the state legislature would also ensure that only the dead man's spouse or partner could request sperm retrieval. The bill marks the first serious attempt to regulate America's private fertility clinics, which are effectively governed only by the scruples of the doctors involved. (Life after death New Scientist 21 Mar 98).

Increasing demand for fertility treatment and stem cell research means hundreds of thousands of human eggs are being sought worldwide. Women from vulnerable socio-economic backgrounds are being exploited by being offered financial compensation for their eggs. Sharing the surplus eggs produced by a woman undergoing IVF treatment to become pregnant for use by other women, or for research can provide enough eggs without donation. Egg doning is also not without its risks, including maternal hypertension and hormonal over-stimulation OHSS.

A rare, but potentially fatal, risk of IVF treatment and egg donation is ovarian hyperstimulation syndrome (OHSS), caused by the drugs that are used to make the ovaries produce more eggs than normal. In mild and moderate cases, affecting up to 20% of women undergoing ovary stimulation, this leads to symptoms such as swelling and breathlessness that resolves. However, in about 1% the symptoms can become so severe that they are deadly. However the risks of death during a pregnancy remain much higher than the risks with IVF treatment (Safety of egg donation 'unclear' 30 Jun 2005 BBC):

At 29, Jackie Rushton was happily married, and she and her husband decided they wanted to start a family. But after two years of trying with no success, they decided to seek help and opted for IVF. Women undergoing IVF treatment are given hormone injections to make their ovaries produce more eggs than normal, which can then be harvested, fertilised in the lab and transplanted into the womb. 'On the seventh day of her treatment she was showing signs of overstimulation already. 'She was very bloated and she could hardly walk. She was very sore. But she just thought it was part of the treatment and that it would be worth it to have a baby. Doctors then noticed Jackie had higher than expected hormonal levels - a warning that OHSS was developing. However, it was decided that treatment should go ahead and doctors were able to collect 33 eggs - far more than the numbers normally harvested after this treatment. 'After that she was very sick. From then on, every day she got worse. The fluid pushed up into her lungs. 'I got a dreadful fright when I saw her. She looked so frail, like a wax doll in the bed.' Jackie's lungs became too weak and she died ('IVF treatment killed my daughter' 30 June 2005 BBC).

It has now been discovered maternal hypertension is halved if a sister is used as the donor:

A Korean team have found the risk is 5.4-fold higher if the egg comes from an unrelated donor - but only 2.2-fold if it comes from a sibling. Eggs donated by a sister are more likely to be genetically similar to the woman's own eggs than those from a stranger. The immune system is likely to play an important role in PIH in these women. The team looked at 61 women who they helped to become pregnant in their clinic using donor eggs and IVF treatment. Pregnancy-induced hypertension (PIH) is thought to occur in around 10% of pregnancies. When it is more severe, and called pre-eclampsia, it can be very serious, killing between three and five women and 500 and 600 babies a year in the UK (Donor eggs from sisters are safer BBC 21 June 05).

Fig 13: Evolution turning point?

Human Evolution: Accelerated, Inverted or Extinguished?

Attitudes to the current status of human evolution are varied. Some researchers have taken the position that we are still pretty much the same as the gatherer-hunters of 50,000 years ago. We have already discussed the differing time scales on which factors influencing human genetic makeup occurs, from the very long term trends in use of molecules such as prolactin, through gatherer-hunter traits in perception and sexuality to very rapid changes in allele frequency over cultural time scales. Simon Conway Morris for example considers effective weapons removed most of the threat of predators, and agricultural development beat back starvation, noting that the technological innovations that took place during the cultural period have been astounding with no sign that this was due to genetic changes. And that while we still haven't banished human hunger or disease from the planet, we are cushioning ourselves from many of the forces that shaped our biology for aeons.

Steve Jones says that culture and technology spelled the beginning of the end for evolution in its classic sense - natural selection of genes better suited to their environment. In the developed world, child mortality has declined drastically and family size tends to be small. Put simply, natural selection doesn't take place if everyone, regardless of the genes they carry, has two children who survive to reproduce. Jones also cites the low variation in human genomes. There is only about a 0.1 per cent difference between your DNA and that of any passerby, but among chimpanzees, the variation is at least five times that. Jones believes that modern life continues to chip away at the few remaining differences. For instance, mutations in the chromosomes of eggs or sperm become more common as parents age, but this source of genetic variation is disappearing because parental age is decreasing as couples tend to stop at two kids. What's more, in the past, some human mutations were preserved because they provided protection from disease. But as public health measures eliminate deaths from these diseases, the number of people who carry the mutation decreases. There is now also a great deal of mixing across the entire human gene pool, something which prevents the genetic isolation which makes species barriers able to emerge. With mutational fuel running low and the engine of natural selection idling, Jones concludes that our evolution is, at most, coasting slowly to a standstill. However, our genetic variability is still high enough to pose significant medical problems.

It is clear that genetic factors mean that new drugs often prove ineffective on a significant chunk of the population. Others such as Lynn Jorde consider that evolution is not slowing, but simply changing direction as new selective factors particularly associated with culture become the principal drivers. Agricultural developments may have made famine less frequent, he points out, but they have also caused people to live in larger, more densely populated areas, increasing the likelihood and impact of epidemics such as cholera and HIV. In addition, our frequent globe trotting has allowed disease organisms to hitch rides into even the most remote communities, presenting our immune systems with greater challenges. Science may have spawned medicine, but it has also unleashed an industrial and technological revolution that spews out radioactivity and chemicals that can contribute to an increase in our mutation rate-or act directly as selective forces.

Christopher Wills (R749) believes that as the deadly blows of past selective pressures disappeared, we began to be shaped by more subtle but equally persuasive forces and that rather than slowing us down, our culture has probably propelled us into developing at unprecedented speeds. Culture itself shapes our genes. In those societies where milk drinking is an ancient practice, for example, people have genes that allow them to digest the milk sugar lactose. People whose ancestors were not milk-drinkers tend to lack these mutations. Wills argues that today's globalisation increases the potential diversity of the human gene pool by bringing together such specialised versions of genes that had been separated through much of history to make new combinations that may never have been seen before. Wills argues that the major evolutionary influence of culture is to create new environments and select for human genetic diversity. Fine motor skills, for instance, may have been of less use when our ancestors were doing little more than smashing rocks. But in a more modern society you can benefit from both big muscles, and the delicate manipulations of a watchmaker. One talent of the human animal is to devise ever more exacting mental and physical challenges. Diversity itself can be selected for. Outside our species, for example, researchers have found that trees that are rare in forests reproduce more often than more common varieties. The thinking is that a sparse population gives species-specific parasites less of a chance to breed. Similarly rare traits are rewarded in our culture. Musical geniuses for example thrive precisely because they are exceptional talents and it is in intellectual and psychological areas that our culture generates the greatest advancement and diversity. Pivotal to this is evolution of the brain and the some third of our genes which are involved in this. Some genes also overlap the brain and other areas The dystrophin muscle gene, for example, which causes muscular dystrophy when faulty, is also expressed in the brain. So too are XRCC4 and Lig IV, which are involved in immunity. As a result, genetic changes that have improved muscle tone or our ability to fight disease could have had psychological or intellectual repercussions.

The influence of culture and particularly cultural attitudes to reproduction in an age of contraception bring us to the precipice of some searching questions. The decision not to have children, for example, has exactly the same evolutionary impact as losing a child through predation or disease. Do increases in the use of birth control select for better parents, because only those that really want children tend to have them? Or does it mean that a great many more children are born to parents who mess up their use of pills or condoms, selecting for parents who are less than careful, socially incompetent or maladjusted or less able to cope? On the other hand, selection against having children given choice might also be triggered by our genetic constitution. People who cope badly with stress in their lives often choose not to have children, so the effect may be a bloodless coup where those genes that allow us to deal with the stresses of modem life emerge victorious.

This brings us to a critical issue involving women and reproduction and the effects of culture. There has been a major trend in Western societies for women to seek careers and reduce or postpone their reproduction. This is partly associated with feminist rejection of the 'essentialist' role of mothering and partly to do with general attitudes to emancipation, equal opportunity and the unique skills women bring to the workplace. Such changes are certainly helping alleviate the population explosion as women in developing countries take the cue partly through television and seek smaller families, but it is also causing almost catastrophic declines in reproduction below replacement levels in countries from Italy to Japan, and here in New Zealand among middle class Europeans.

A study of 2710 female twins in a contemporary Western population in Australia (Kirk et. al. R378) has elucidated several key heritable and cultural factors affecting female reproductive fitness. Cultural factors had a big impact on the women's fitness - 50 to 60% of fitness is environmentally determined, but 40 to 50 per cent is genetic. Prominent among the cultural factors are education and religion. University-educated women have 35% lower fitness than those with less than seven years education, and Roman Catholic women have about 20% higher fitness than those of other religions. We can see here a striking negative relationship between educated women and reproduction and a positive one between religions advocating unrestrained reproduction and its incidence. This leads to some dangerous conclusions - that both education, which also to some degree reflects genetic factors involved in intelligence (about 50% genetic 15% uterine, and the rest divided between family, peers and culture) and freedom from religious conformity are being selectively bred out of the human population. Such trends carry over to other major religions which actively encourage reproduction, such as Islam, as reflected in the high birth rates and large adolescent populations in Iran, Palestine, Saudi Arabia and other countries.

When cultural factors of choice are taken aside and we turn to heritability, the conclusions are also striking. There is substantial heritable variation in fitness, with approximately 39% of the variance attributable to additive genetic effects, the remainder consisting of unique environmental effects and small effects from education and religion. The strongest genetic factor is a tendency of some women to begin reproducing earlier. Structural modeling, reveals significant genetic influences for all three life-history traits, age at menarche, age at first reproduction, and age at menopause, with heritability estimates of 0.50, 0.23, and 0.45, respectively. Strong genetic covariation with reproductive fitness was demonstrated for age at first reproduction. In later work they found that extroversion and neuroticism affected the 'fitness' score of women. And some 'social attitude dimensions' such as family values and militarism boosted fitness. These personality traits are about 50 per cent heritable and could contribute quite a lot of the genetic variance in fitness. It remains to be seen whether the family values were conservative or the shorter term reproductive investment strategy of sexually precocious girls growing up in single parent families.

Natural selection of this sort could have worrying implications. 'If our results are correct, one would predict steady selective pressure toward earlier reproduction,' says co-researcher Nick Martin, 'and selection against women who delay childbearing, and the traits that currently drive women to professional success'. So as society encourages women to have children later, the biological urge to have kids early could discourage them from having careers. 'The genes are pushing in the other direction,' says Owens. 'There's a fierce conflict between a career and wanting to reproduce' (New Scientist 5 May 2001).

Part of the solution to this problem has to lie in a better recognition both by those in the business community, in government, feminists, and mothers themselves that Western society needs to find better ways of acknowledging and integrating careers with mothering. The two have remained in opposition party because of intransigence in the work place aided by cultural attitudes to sex roles which do not respect the importance of biological mothering. A social revolution is needed here towards an intelligent matricentric society if we are going to enhance, let alone retain our qualities of intelligence, astuteness and non-militaristic freedom of choice.

Another innovation, genetic testing, has the capacity to strip bare all our subtle evolutionary characteristics of female reproductive inscrutability and male philandering. Paternity testing, in one step, places a searing spotlight on female infidelity, as well as men who sow wild oats who are being sought by women or governments for compensation. The penalties for women in many countries are dire. If female reproductive choice has been a paramount catalyst for human cultural and intellectual emergence, we need to respect it, perhaps even safeguard it with the same aura of sacredness that patriarchal religions have given to male paternity certainty. Males need to develop a culture of tolerance towards female reproductive choice and a preparedness to support children who may not be their own in the interests of our reproductive future, as well as the welfare of their partners.

There is a rising tide of expectation that human assisted reproduction will bring in techniques of germ-line engineering for all sufferers of genetic disabilities that will remove defective genes and replace them with 'healthy' ones. This leads to a new form of utopian social eugenics, in which virtually any trait, from the sex of a child, to their teeth, sexual orientation, extroversion, or love of sports, will be sought by prospective parents to enhance features they find desirable, resulting in distortion of the human gene pool at the behest of human whim. They could also be used to eliminate counter-cultural traits. Genes in development and brain function are profoundly interactive. This leads to another dangerous scenario where our entire natural evolutionary paradigm - as an evolutionarily stable strategy will be replaced by an auto-creationist technological life-expectancy in which human survival becomes totally subject to the brittle instabilities of advanced technology.