For sale – ova and sperm
The economic crisis looms.  Pay rises are small or non-existent, redundancy is a grim prospect, new jobs remain few and far between.  Have you thought of becoming a gamete donor?  No, please don’t.  Yet the rewards have just increased substantially.

The HFEA announced in mid-October that it had ‘concerns about treating donors fairly and valuing their contribution’ as well as wishing to retain them and attract others.  Principally this means paying them more.  Currently, donors receive out-of-pocket expenses and a loss of earnings allowance capped at £250.  The new scheme will allow sperm donors to claim a fixed sum of £35 per visit including expenses.  Donors of ova will be compensated a fixed sum of £750 per cycle of donation including expenses.

There is something tawdry about this trading – selling and buying – of human gametes.  In a very real sense, the financial aspect is not the issue.  When the HFEA states that its new ‘proactive approach’ is to ‘ensure that donation continues to take place within a safe and ethical environment’, the latter two words jangle and jar.  What is ethical about such commerce?  Traded sperm and ova have lost their place and mystery.  Nowadays they have become mere biological materials, market commodities.

IVF 'adverse incidents'
As the demand for IVF increases – particularly as more women put childbearing on hold in favour of career advancement – so do the numbers of reported blunders, or what the HFEA calls, ‘adverse incidents’.  They are categorised as A, B, C, or ‘near miss’.  For example, a Grade A incident might involve an embryo mix-up, the death of a patient or an incident which affects a number of patients, such as a storage unit malfunction.

The recent publication of the HFEA’s Annual Report and Accounts 2010/11 recorded that in 2010 there were 564 serious errors or ‘near misses’ at UK fertility clinics.  That figure has trebled since 2007.  The number of very serious, Grade A or B, mistakes recorded in 2010 was 275.  Reported mistakes during 2010 included the wrong sperm being injected into the wrong ovum, embryos accidentally being destroyed or being transferred to the wrong woman.  The HFEA responded, somewhat lightly, by calling for a sense of proportion – it maintained that in the context of 50,000 IVF treatment cycles, the total errors amounted to only about 1 per cent.  Yes, but …...

Yet more problems with IVF?
Hyperstimulation of women’s ovaries has never been a good idea, yet it is an integral part of IVF.  Two preliminary studies have recently suggested that the practice can cause additional increased health risks to babies and to mothers.

The first report, by Alan Handyside, of the London Bridge Fertility, Gynaecology and Genetics Centre, and colleagues from eight countries, suggests that the stimulatory drugs used may lead to genetic defects in created embryos, especially among older women, that is, those over 35 years of age, undergoing IVF treatment.

But the problems appear to originate not as a result of faulty fertilisation, but in the chromosomes of the ova of these women.  Such chromosomal defects were thought to occur only during a woman’s fetal development – this recent study suggests that they can also occur during ovulation, hence the link to IVF ovarian stimulation.  Typically, older women undergoing IVF treatment are given higher doses of these drugs than their younger counterparts.  Maybe pushing the ovaries so unnaturally hard produces more ova with chromosomal defects.

The second study comes from Holland.  It compared 19,146 women, who received IVF treatment, with 6,006 sub-fertile women, who had not been treated with IVF.  After 15 years, a follow-up assessment suggested that ovarian stimulation during IVF may have caused ovarian malignancies, especially borderline ovarian tumours.  The IVF group had a 2-fold increased risk of ovarian malignancies compared with the non-IVF group.

Commenting on the Dutch study, the HFEA cautioned that the overall health risk from ovarian hyperstimulation remains extremely small.  According to the HFEA, the cumulative life-time risk for borderline ovarian cancer up to the age of 55 is just under 5 in 1,000 in the general population, compared with 7 in 1,000 undergoing IVF.  OK, these are preliminary studies, but ….

Have you flossed today?
Yet another cause, albeit minor, of women’s infertility has been identified.  It is poor oral hygiene.  Apparently it can be as deleterious as obesity and can delay conception by two months.  Australian scientists studied 3,500 women and found a negative association between periodontal disease and conception.  It is thought that gum inflammation affects the normal physiological functioning of the entire body, conception included.  Floss – yet another sensible and cheap way of avoiding IVF.

Stem Cell Technologies

More embryonic stem-cell hype?
Avid followers of stem-cell technologies are familiar with two distinct types of announcement – landmark and hype.  The former is perhaps best represented by the production of human induced pluripotent stem (iPS) cells in 2007 by Shinya Yamanaka.  The latter is epitomised by the work of Hwang Woo-suk, who shocked the world in 2005 by claiming to have cloned human embryos and to have created 11 embryonic stem-cell lines from them.  A year later he admitted that his experiments were fabricated and his results were faked.  Nobody has since claimed to have generated cloned human embryos.

Yet for some scientists, cloning humans remains the elusive (un)holy grail.  The 6 October edition of the journal, Nature reported another possible claimant.  The article, by Scott Noggle and colleagues at The New York Stem Cell Foundation Laboratory and Columbia University, was entitled, Human oocytes reprogram somatic cells to a pluripotent state.  Basically, cloning technology was used to reprogram human DNA, taken from an adult, and create embryonic stem cells.

First, some background. Somatic-cell nuclear transfer (SCNT) is the cloning technique used to create Dolly the sheep.  SCNT takes the nucleus, the genome, the DNA, from an adult cell – from the mammary gland of a mature sheep in Dolly’s case – and places it in an ovum from which the nucleus has been previously removed.  A little technical tweaking in the laboratory can cause this new cell to divide, as if it had been naturally fertilised, and so develop into an embryo.  In the case of Dolly, such a cloned embryo was then transferred to a surrogate mother sheep.

That was 1996 and animal – this is 2011 and human.  Noggle’s team applied SCNT to human ova and human adult skin cells.  Using this technique has previously produced a range of cloned mammalian embryos, but never with humans – any cloned human embryos have always ceased dividing prior to the blastocyst phase of some 70 to 100 cells – the stage necessary for the isolation of stem-cell lines.  Noggle and colleagues overcame this barrier by not removing the nucleus from each ovum.  In other words, each of their 13 newly-created embryos contained the DNA from three nuclei – one from the haploid ovum and two from the diploid adult skin cell.  Nevertheless, cellular development continued and the isolated embryonic stem cells were considered to be functionally normal, namely, pluripotent.

So is this work really ‘a major development’ and ‘an important step’ in stem-cell technology?  Its significance is claimed to be the possibility of generating personalized human stem cells for treating various diseases, such as that overworked publicity trio of Alzheimer’s, Parkinson’s and diabetes.  Hold the hype!  Is this recent report really a positive medical breakthrough?  Technically, such stem cells are genetically abnormal because they contained 69 chromosomes, so their value for even research purposes, let alone human therapies, must remain questionable.  Bioethically, the old problem remains – such stem cells can be harvested only by destroying human embryos.  Financially, the researchers controversially – violating the ethical guidelines of the US National Academy of Sciences, but deemed legal in New York – paid each woman $8,000 (pre-tax) for her ova donation.  At least Noggle and colleagues declared this – Hwang had previously obtained human ova unethically and illegally.  Ova are essential for this type of research and their supply is problematic – first, women may be easily coerced by such financial inducements, and second, their health may be put at risk by ovarian hyperstimulation procedures.  Nevertheless, 16 women provided 270 ova.  Sure, the work could perhaps be called ‘a minor scientific advance’ because it tweaks the SCNT process.  In other words, it is a minor breakthrough in human cloning research – scientists have long been able to create embryonic cell lines simply by destroying spare embryos from IVF treatments.  In terms of therapeutic uses, this new work would appear to be of little or no benefit.

In conclusion, this research represents a small development in cloning technology, but it has no direct application to medical treatments, or even drug testing and research.  Human cloning as a route to stem-cell based therapies has become a scientific side-show, similar to that of the recently-hyped, but now largely-dismissed, human admixed embryos.  This present work was merely a ‘proof-of-principle’ type of experiment.  Already the relatively-simple production of iPS cells – no ova and no embryo destruction – has demonstrated that cloning is not needed.  Moreover, the various current successes of adult stem-cell technology, in both medical research and human treatment, trounce all hyped expectations of cloning.  This report by Noggle and colleagues represents little more than another example of barefaced disrespect for, and a gross violation of, human life.  Such experimentation is unwarranted – it is not landmark, it is hype.

Embryonic stem-cell trials
The US biotech company, Geron made medical history in October 2010, when it commenced the world’s first-ever trial of human embryonic stem-cell therapy with a patient suffering from a spinal cord injury.  Then in July 2011, Advanced Cell Technology (ACT) began two additional clinical trials using embryonic stem cells.  The first was for Stargardt's macular dystrophy (SMD).  This is an incurable form of macular degeneration, which can cause blindness, generally in young people between 10 and 20 years old, by attacking the central part of the retina – the macula – and progressively causing impaired vision.  The second was for a common cause of blindness in the elderly, dry age-related macular degeneration (dry AMD).  Both ACT trials are using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells.

Now comes news of the first embryonic stem-cell trial to be conducted in Europe, scheduled to begin during December 2011.  In September, the Medicines and Healthcare Products Regulatory Agency (MHRA) approved the trial as a joint venture between ACT and Moorfields Eye Hospital in London.  The proposed initial treatment will be carried out on twelve patients suffering from SMD.

The trial will inject each patient’s eye with between 50,000 and 200,000 replacement cells, known as retinal pigment epithelial (RPE) cells, and more specifically the ACT product, branded as MA09-hRPE.  These have been derived from human embryos.  Some observers have tried to soften the truth about the embryo destruction by comments such as, ‘… the stem-cell line in question was created using a donated embryo of just a few cells.’  Gifted and small.  Yes, yes – we’ve heard it all before.

Other forms of blindness are regarded as potential targets for embryonic stem-cell therapies.  But let no one forget that adult stem cells have been used for more than 10 years in treating, for example, corneal blindness, with great patient success and well substantiated in several peer-reviewed science journals.

[Added on Monday 14 November 2011.  Today, Geron abruptly announced that it was abandoning its embryonic stem-cell trial.  Geron blamed the decision on, ‘… capital scarcity and uncertain economic conditions’.  Others claimed that the trial was both poorly-designed and over-ambitious – spinal cord injuries are too complex and effect too few people, and so returns, curative and economic, might take up to 10 years.  Others cited the recent ban imposed on embryo patenting by the European Court of Justice.

I fear another explanation.  A few days before the Geron announcement, I had e-mailed the company because I knew that one of their four initial patients had been injected 365 days ago with GRNOPC1 and had therefore recently been physically and medically assessed according to Geron’s one-year protocol.  Geron had previously declared, somewhat ambiguously, that, ‘GRNOPC1 has been well tolerated with no serious adverse events.’  But I asked specifically, had it produced any positive effects upon the patient’s condition?  I received no reply.  It may be that GRNOPC1 was simply not working – therefore continuing the trial would be futile.  However, my concern is that some negative side-effect had occurred, or, perhaps more likely, was about to occur if the trial continued.  Maybe the proliferation of cysts or the onset of various cancers were imminent. Such disorders have been commonly reported in animal trials using embryonic stem cells.  Indeed, they were the cause of much of the FDA’s prolonged delay in approving Geron’s trial with human patients.

Whatever the truth, we may never know.  But suddenly, much of the hype surrounding putative embryonic stem-cell cures has evaporated.  Already several commentators have jumped ship and ‘discovered’ the successes of current therapies that use adult stem cells.  Surprise, surprise!]

Good news from the iPS cell camp
Human induced pluripotent stem (iPS) cells are ‘cells-in-waiting’.  Since their method of production was discovered in 2007 they have become the focus of numerous research projects. Their potential benefits in regenerative medicine are enormous.  But they are NOT yet ready to be used in human clinical trials.

Another step towards that goal has recently been announced in Nature by a team of scientists at the Sanger Institute and the University of Cambridge.  For the first time, scientists have cleanly corrected a human gene mutation in a patient's stem cells.  They took skin cells from a patient with a mutation in a gene called alpha1-antitrypsin, which is responsible for making a protein that protects against inflammation.  People with this inherited mutation are unable to release the protein properly from the liver – its accumulation there can cause liver cirrhosis and lung emphysema.

Ordinary skin cells, taken from the patient, were reprogrammed to create iPS cells.  The genome of these cells was then snipped, at the site of the genetic fault, using a technique known as a zinc finger nuclease, and a correct version of the gene was finally inserted by means of a DNA transporter called piggyBac.  The corrected stem cells were then converted into human liver cells and inserted into a mouse – where they worked normally.

None can fail to be amazed at the outcome of these cutting-edge techniques.  They may herald the first steps towards personalized cell therapy for genetic liver disorders.  Perhaps in 10 years time such a protocol could even supersede liver transplants in human patients with all their disadvantages of costly and complex procedures, plus a lifetime of anti-rejection drugs.

To realise such a hope, scientists need methods of introducing DNA, repairing the defective gene, removing all foreign DNA and verifying the changes.  This work appears to have achieved all those goals.  From skin cells to tailor-made, patient-specific liver cells – without embryo creation, without cloning, without embryo destruction, without Brave New World alarms – breathtaking!

M became severely brain damaged in 2003 as a result of viral brainstem encephalitis.  Earlier, she had been misdiagnosed as being in PVS, now she has a higher state of awareness, known as a ‘minimally conscious state’.  She is unable to talk and apparently has no awareness or consciousness of her surroundings.  The use of the latest testing methods is crucial in proper diagnosis and Mr J. Baker stipulated that all such cases cannot come to court until such analysis, ‘formal assessment tools’, has been completed.

Her family and close relatives had argued that she is in pain and that her artificial feeding and hydration by tube should be withdrawn.  They pleaded that she might be allowed to ‘die in peace’ and that it was cruel to keep her alive against her wishes, though the latter were only verbal and never part of a formal ‘advance decision’ and therefore were discounted by the Judge.

The Official Solicitor and the health authority that is caring for her strongly opposed the application, arguing that M may be able to communicate.  They maintained that M was clinically stable and expressed a range of responses including the ability to smile and cry.  She apparently also responds to music and conversation and can track people and objects with both eyes.

The legal arguments were heard during a Court of Protection hearing in London in July.  In his final September judgement, Mr Justice Baker stated that M had ‘some positive experiences’ and that there was a ‘reasonable prospect’ that those experiences could be extended.  And importantly he declared, ‘The factor which does carry substantial weight, in my judgment, is the preservation of life.  Although not an absolute rule, the law regards the preservation of life as a fundamental principle.’

This has been a momentous case.  It had the potential to bring in a serious bioethical downgrade, a giant step on the slippery slope, from the approval of killing patients in PVS to those in a ‘minimally conscious state’.  The rot started in 1993 with the case of Anthony Bland.  The House of Lords then ruled that the supply of food and water, in the form of artificial feeding and hydration by tube, was ‘medical treatment’, rather than basic nursing care, and thus could be withdrawn.  The result – the inevitable death of the patient.  Since 1993, a total of 43 PVS patients in the UK have died after courts have ordered that such ‘treatment’ could be ended in the ‘best interests’ of the patient.  This M case is materially different because she is in only a ‘minimally conscious state.  If the judgement had gone the other way, then hundreds of vulnerable patients with severe brain damage would now be at risk to the withdrawal of life-maintaining care.

The Martin case
Martin, as he has become known, is a 46-year-old-man who wants to die.  He was fit and active until three years ago when a brainstem stroke left him almost completely paralysed and requiring round-the-clock care.  He is suffering from the condition known as ‘locked in syndrome’ – he has some limited movement of his head and eyes and can communicate via a computer.

His repeated requests to be allowed to die have been ignored and no one, including his wife, is willing to organise a trip for him to die at the Dignitas clinic in Switzerland.  However, in August, human rights lawyers at Leigh Day & Co in London took up his case.  They believe that Martin has the right of assistance to help him to travel to Dignitas, but also the right to the services of a palliative care doctor in the UK to ease his death if he decides to refuse food and water.  If such a court case were successful, it would alter the euthanasia landscape – the seriously ill and disabled could end their own lives in the UK.  As one of the lawyers has stated, ‘There would be no more planes to Switzerland.’