Update on Life Issues - October 2020

Coronovirus

Coronavirus – where to start?  And when to stop?  Our news screens are full of it, our lives are subject to it, and the misinformation is troubling.  Everyone, in addition to all those talking heads, has a view on it.  What follows is hopefully true information plus a set of questions and decent answers.  We need to grasp this – next year we will all be faced with a Covid-19 vaccine.

Vaccines – the basics
Vaccinations save millions of lives each year.  Vaccines prepare a person’s immune system to recognize and fight particular viral and bacterial infections.  If a vaccinated person is subsequently exposed to disease-causing organisms, the body is primed to fight and destroy them, thus preventing the illness.  Such a strategy already prevents 2 to 3 million global deaths each year from diseases like diphtheria, tetanus, pertussis, influenza and measles.

Lockdowns are temporary, vaccines are permanent (probably, maybe).  Vaccination is widely considered to be one of the long-term answers to controlling SARS-CoV-2, the virus that causes the disease Covid-19.  There is currently a concerted world-wide push to make it a vaccine-preventable disease.  So, how is vaccine progress made?  Typically, scientists take several years to prepare a vaccine before testing it on people.  Such early safety trials, known as phase 1 and phase 2, take several years to complete.  If all goes well – and it normally does not – then phase 3, the final stage, can begin, comparing thousands of people who receive the vaccine with thousands who are given a placebo.  It may take another three years to get these results.  Only then – a decade or more after the research was begun – will a vaccine manufacturer build a factory to make the successful product.  Then there is the distribution.  Getting a vaccination programme to 80% of global coverage generally takes about another 30 years.

Covid-19 vaccine strategies
That protracted procedure is clearly not the plan for Covid-19 vaccines – the world is in a hurry.  So the World Health Organisation (WHO) has already arranged a strategy, known as the Solidarity Vaccines Trial.  Several vaccines will be given at random to one large group of volunteers, while a smaller group will receive the placebo.  It has taken nine months to get off the ground, but this trial is due to start in late October with a small study in Latin America.


The US government has taken a different tack.  It has opted for a ‘harmonised approach’.  This will allow vaccine makers to run their own trials, but only if they follow certain guidelines and let the National Institutes of Health (NIH) test all of their volunteers in the same way.  In exchange for following these rules, the pharmaceutical companies will benefit from using the network of NIH clinical testing sites and they will receive some of the US Government’s promised $10 billion vaccine fund.

As of late October, AstraZeneca, Johnson & Johnson and Moderna have begun trials in this network.  Novavax and Sanofi are expected to start their phase 3 studies in the next couple of months.  But Pfizer, one of the front-runners, has not joined the network, opting instead to run its own hush-hush trials.

The UK has taken a third way, with up to six possible vaccines being developed and tested.  Of course, there is the well-known and much-favoured Covid-19 vaccine joint trial being conducted by AstraZeneca and the Oxford Vaccine Group, which began on 20 January.  It centres on an already well-studied, and regarded as safe, chimpanzee adenovirus vaccine vector (ChAdOx1), developed at Oxford’s Jenner Institute.  This was chosen as the most suitable vaccine technology for a SARS-CoV-2 vaccine as it can generate a strong immune response from just one dose – other potential vaccines may require a booster dose.

A feature of coronaviruses is those familiar club-shaped spikes on their surface coats.  This Oxford vaccine contains the genetic sequence of this surface spike protein inside the ChAdOx1 construct.  Once vaccinated, the surface spike protein is produced and this readies the patient’s immune system to attack if the virus ever infects the body.  If proved effective and granted approval, production of the AstraZeneca Oxford vaccine will be scaled up for distribution across the UK population and also to several other hard-hit countries.

Other UK trials exist.  For example, there is the Imperial trial being run by hVivo, a spin-off company from Queen Mary University of London.  Already some 2,000 people have signed up to be jabbed and a month later be exposed to the virus.  This vaccine works not by delivering a weakened form of Covid-19, but by delivering synthetic strands of the virus’s genetic code.  These instruct the patient’s cells to produce the SARS-CoV-2 spike surface protein and the required immune response and hence immunity to the virus.

And the University of Cambridge hopes to start clinical trials soon with its DIOS-CoVax2.  This DNA-based strategy uses computer-generated antigen structures that are encoded by vaccinating with synthetic genes.  These in turn re-programme the body’s immune system to produce antibodies against the virus.  And other UK trials exist, such as that from Synairgen with its experimental drug, SNG001 – an inhaled formulation of interferon-beta-1a, which has known antiviral properties.
In addition, the UK government has been busy securing doses of vaccines – recently 60 million doses of the inactivated Covid-19 vaccine, VLA2001, were purchased from the French company Valneva SE.  They will cost £450m for delivery in the second half of 2021 with the option for another 130 million doses for 2022 to 2025.  And other deals have already been signed for 340 million doses of various putative vaccines – we should have enough!

And besides this hunt for effective vaccines there is an on-going UK national clinical trial seeking to identify beneficial treatments for those already with Covid-19.  Known as the RECOVERY Trial, it is assessing the beneficial effects of the cheap and low-dose steroid, dexamethasone, plus other drugs, such as azithromycin, tocilizumab, convalescent plasma and REGN-COV2.

There are now more than 200 Covid-19 vaccine candidates under development globally, with about 40 of these in the human trial phases with 10 in phase 3.  And how will the winner(s) be selected?  The approval and authorization of a vaccine will depend on how much protection it provides in a phase 3 trial, in other words, on its efficacy.  In June, the US Food and Drug Administration (FDA) set 50% efficacy as the target.  But the efficacy of a vaccine in a clinical trial will not necessarily be the same as in a real-world setting.  Phase 3 trials have margins of error and the effective efficacy may be higher, or lower.

Furthermore, this current vaccine race has important downsides.  For instance, once a particular vaccine has proved sufficiently efficacious and has been selected for mass use, will other vaccine manufacturers drop out of trials, even if, in the long run, their product would have proved to be superior?  And because this first wave of vaccines is likely to be reserved for healthcare workers and other high-risk groups, does this imply that such valuable test ‘guinea pigs’, working in infected areas, will not be available and eligible to enter other new clinical trials?

Yet all of this means that by spring or summer 2021, there will probably be several coronavirus vaccines for consumers to choose from.  But the selection will be complex.  It is hoped, for example, that across all trials, some molecular signature in a vaccinated person’s blood will show they are protected.  However, there is no guarantee that such a signature will emerge.  And if it does, how long will it persist indicating that the person is still protected?  Our current knowledge about the short-term attributes of such vaccines is poor while their long-term traits remain largely unknown.  For example, the preservation of vaccine efficacy and the appearance of dangerous side effects are two big unknowns for the foreseeable future.

Vaccine general ethics
From all the candidate vaccines in production and in clinical trials, presumably some will become globally available.  Which to opt for?  Will only one be offered locally or nationally, or will there be a choice?  Will vaccination be mandatory?  That is unlikely based on a US survey conducted earlier this year which reported that less than 50% of respondents would commit to getting a coronavirus vaccine whenever it becomes available.  Famous entrepreneur and businessman Elon Musk has already unhelpfully stated that he and his family would not take a coronavirus vaccine even if it became immediately available.  ‘I am not at risk, neither are my kids’, he has rather foolishly said.

Of course, behaviours change in the real world.  But people with vaccine hesitancy and vaccine refusal exist.  The refusers are unlikely to be just conspiracy theorists, misinformed sceptics and anti-vaxxers.  An October 2020 report in The Lancet noted that 31 million people follow anti-vaccine groups on Facebook and around one in six British people were unlikely to agree to being vaccinated.  Maybe that is not so surprising when even hard-nosed scientists fail to agree on most aspects of Covid-19?

There is a palpable public mistrust over so many facets of Covid-19.  None of this has been helped by Russia and China apparently, and clandestinely, surging ahead.  Safety and transparency have been too often lacking – they are essential.  Pharmaceutical companies and their academic partners need to disclose and explain their protocols and results data.  Concerns about vaccines being too hastily approved, suspicion of the giant biotech corporations’ motives and the increase of vaccine misinformation are combining to erode the public’s trust in how vaccines are approved and used.

A prime example of this need for safety and transparency occurred in the UK with the much-favoured Oxford vaccine, produced by AstraZeneca in collaboration with Oxford University.  All was apparently going well until 6 September, when phase 3 trials of the Oxford vaccine were suspended by AstraZeneca in the UK, US and Brazil after a serious adverse reaction occurred in one of the nearly 30,000 test volunteers.  The female patient was rushed to hospital after she displayed symptoms of transverse myelitis (TM) – a rare condition affecting the spinal cord.  AstraZeneca stated that there would be a ‘voluntary pause of vaccination across all trials’ as part of ‘a standard review process’.  It was reported that by 12 September the trials had resumed, however, there was a dearth of information from AstraZeneca.  Perhaps this largely unexplained incident will serve as a wake-up call about the communication of vaccine testing and its safety and transparency.

No other seriously adverse effects have been reported.  However, high fever, body aches, headaches and exhaustion are some of the symptoms participants in Moderna’s and Pfizer's vaccine trials have suffered post-vaccination.  While the symptoms have been uncomfortable, and at times intense, they have typically subsided after a day or less.

Vaccine pro-life ethics

But there is another, and much more troublesome, issue surrounding Covid-19 vaccines.  Are some vaccines manufactured from aborted human material?  If so, are they ethically acceptable to be used by pro-life people?

Here is the most current newsworthy example.  It relates to the so-called AstraZeneca Oxford vaccine again.  Scientists at University of Oxford have engineered a chimpanzee cold virus that contains important fragments of the SARS-CoV-2 virus that causes Covid-19.  This chimpanzee cold virus is being grown in human fetal cells.  When injected into macaques, this engineered virus acts as a vaccine, triggering an immune response that protects these primates so that they do not develop serious disease.  But here is the rub.  These ‘human fetal cells’ come from a cell line known as HEK-293.  This was derived from the kidneys of a girl aborted in the Netherlands in 1972.  HEK-293 cells are commonly described as ‘immortalized epithelial cells’ and never as stem cells.  The line was cultured by Alex Van der Eb in the early 1970s at his laboratory at the University of Leiden, Holland.  The source of the cells was a healthy(?) aborted female fetus of unknown parentage.  The name HEK-293 was derived from Human Embryonic Kidney and it was one of Eb’s collaborator’s 293rd experiment.

Does this present a bioethical problem?  The aborted girl would by now probably be a 40-year-old mother with her own family.  Is the origin of HEK-293 sufficiently time-distant to make little or no difference?  Should we benefit from the body parts of a non-consenting human being?  Does our lack of direct involvement absolve us?  About these things, we will disagree.

Many human fetal cell lines, and HEK-293 in particular, have been obtained mostly from elective abortions that are not contemporary.  They have been used often and widely in medical therapies ranging from the production of anti-psychotic drugs to cancer immunotherapies, from vaccines against rabies and rubella to studies for treatments of Parkinson's disease, spinal cord injuries and degenerative diseases, such as motor neurone disease (MND).

Covid-19 and President Trump
It was perhaps fitting that the acerbic leader of the most powerful nation in the world should catch Covid-19 and subsequently inflame a global row about its treatment.  On 2 October, President Trump developed worrisome symptoms and tested positive for Covid-19.  He was flown to the Walter Reed Army Medical Center in Maryland, where, within 24 hours, he had received an experimental, cutting-edge antibody treatment not available to other Americans.  The White House stated that among his other on-going therapies Trump had received ‘a single 8-gram dose’ of ‘an emergency cocktail of anti-coronavirus antibodies’, known only as RGN-COV2.  Until it gets FDA approval it will lack an appropriate drug name.  It belongs to a promising new class of antiviral drugs, and is produced by Regeneron Pharmaceuticals of New York State.

The US king of misinformation, fake news and sloppy behaviour regarding Covid-19 had been infected and struck down, right in the midst of a presidential campaign.  Yet Mr Trump said he believed that RGN-COV2 had helped him vanquish his coronavirus infection in record time.  But there was more.  Here was the most pro-life US President ever, and an outspoken opponent of fetal tissue research, being accused, albeit mostly inaccurately, of taking drugs made with cells from an aborted fetus.  He was lambasted by his critics.  The UK newspaper Metro declared, ‘Trump faces hypocrisy allegations after it was revealed Regeneron is made from stem cells originally taken from an embryonic kidney.’  And the MIT Technology Review somewhat more accurately claimed, ‘Trump’s antibody treatment was tested using cells originally derived from an abortion.’  Social media users were harsher.  Here is one message, ‘So it turns out that monoclonal antibodies that Trump is on are from fetal stem cells.  So Trump is being treated/saved with dead babies.  Republicans?  Amy Barrett?  Pro-lifers?  Anybody?’

Was this true or was it fake news?  According to Regeneron, RGN-COV is manufactured in cells from Chinese hamster ovaries, so-called ‘CHO’ cells – not in human cells.  Nevertheless, the involvement of HEK-293 again arises.  But this cell line, originally derived from a human fetus, was being used in another way.  According to Regeneron, laboratory tests used to assess the potency of its antibodies employed a standardized supply of cells called HEK-293T, a stable clone of HEK-293, which over the years has been transformed from the original cell line, meaning it should no longer be considered as ‘fetal tissue’.
So, while Regeneron did not directly use human fetal cells to make the monoclonal antibody treatment given to Trump, it did use cells derived remotely from that 1972 Dutch abortion to make the targets for its antibodies – the mimics of the spike protein of the SARS-CoV-2 virus.  Monoclonal antibodies home in on specific targets.  To fight coronavirus, they are engineered precisely to attack the spike protein used by the virus to grapple onto cells.  To make sure their antibodies were working correctly, Regeneron needed to employ laboratory facsimiles of this spike protein, and for that, they used the HEK-293T cells.

Can this story be corroborated?  An official statement from the conservative, pro-life US-based Charlotte Lozier Institute by David Prentice and Tara Sander Lee gives a lengthy scientific explanation about the Regeneron therapy.  They conclude, ‘The president was not given any medicines to treat COVID-19 that involved the destruction of human life.  No human embryonic stem cells or human fetal tissue were used to produce the treatments President Trump received – period.  And finally, the anti-viral medicine remdesivir and the anti-inflammatory corticosteroid dexamethasone, also given to the president to treat COVID-19, are chemicals – no cells of any kind were used to produce these medicines.’

Moreover, a spokesperson for Regeneron explained, ‘We did not use human stem cells or human embryonic stem cells in the development of REGN-COV2.  We did use the HEK-293T cell line to test our antibodies’ ability to neutralize the SARS-CoV-2 virus.’  In other words, the HEK-239T tool, developed years ago, allowed Regeneron to determine which antibodies that had been developed might be most effective against the Covid-19 virus.  These cells were not used to create the antibody cocktail itself, but they were used to test its potency.

Further confirmatory evidence can be found on the Regeneron Pharmaceutical website under its ‘Regeneron Position Statement on Stem Cell Research’.  Part of it reads, ‘The stem cells most commonly used at Regeneron are mouse embryonic stem cells and human blood stem cells.  Currently, there are limited research efforts employing human-induced pluripotent stem cell lines derived from adult human cells and human embryonic stem cells that are approved for research use by the National Institutes of Health and created solely through in vitro fertilization.’  That is both honest and, in terms of the use of ‘human embryonic stem cells’, disappointing.

How to think and respond
Let us indulge in a little bioethical casuistry.  Can someone who considers abortion to be an evil, a grave injustice, use such medical therapies that were developed in a way that involved that injustice?  Yes, but with conditions.  Such therapies may be considered morally justifiable, but only if their use does not contribute to any future evil acts, and if their current use is occasioned by a grave proportionate reason.  In other words, the use of these vaccines must demand no contemporary evil abortions, and their current use must spring from a virtuous reason that is both seriously and urgently required.

However, some people may still be concerned about the morality of using vaccines, or other medicines, developed from cells historically linked to aborted fetuses.  Can a citizen of conscience, who is opposed to everyday abortion, use a vaccine to protect herself and her loved ones during this time of pandemic?  Yes, but they can also refuse, even if the vaccination is ethically justifiable.  However, society also has a right, and indeed, a moral obligation, to protect its citizens from illness and death.  Check out Matthew 7:12.  Therefore, justice demands that we balance our concerns with the competing interests in our communities.  Indeed, those who refuse to be vaccinated because of their moral concerns should also expect to be prohibited from entering public spaces, such as schools, restaurants, shops and airports, where they may unwittingly catch or spread the disease.  Nonetheless, no-one should rub raw another’s conscience – so disagreements among Christians and others may persist.  It is a classic Romans 14 situation.

In summary, we live in a complex, but not morally-neutral, world where we stand to benefit from the present and past actions of both virtuous and vicious men and women.  How can we apply bioethical, even biblical, principles to negotiate these complexities without losing our moral integrity?  In the current pandemic, citizens of good conscience may use Covid-19 vaccines derived with the aid, but not as current, active ingredients, of historically-obtained human fetal cell lines.  In addition, such men and women should avoid public scandal by first making their opposition to abortion absolutely clear.  The upshot of understanding these issues has been an increased global call for unimpeachably bioethical ‘clean’ vaccines.  That would be good.  People should not be forced to make the choice between being vaccinated against Covid-19 and acting against their consciences.

What are we to do?  It would be nice to live ethically pure lives.  But we live in the real world that is perforated with evil and sin.  We cannot go out and live in this world without interacting and being tainted by things and people we consider immoral or unethical.  Our thinking and our actions are often wrong and naïve.  When Boots the chemist started selling the morning-after pill, we boycotted its stores.  It did little except temporarily salve our consciences.  We now creep back to shop there occasionally.  Like many disasters, this Covid-19 pandemic is highlighting weaknesses in ourselves, in our worldviews, skill sets and systems.  What are we to do?  Live dangerously, but in the hands of God.


Abortion

BPAS and IVF
Here are two abbreviations nobody ever thought they would see juxtaposed.  The British Pregnancy Advisory Service (BPAS) is the UK’s leading provider of abortions.  According to its website, ‘We are the leading specialists of abortion advice and treatment in the UK, taking care of almost 80,000 women each year in over 70 reproductive healthcare clinics nationwide.’

 

BPAS is a not-for-profit charity, but its trade is abortion.  Ann Furedi, its CEO, is an abortion zealot.  She has said, ‘People talk about it as the lesser of two evils, and I think it’s important to recognise that what we do is actually a good thing; it’s good.’

 

BPAS makes its money by brutally terminating the lives of the unborn.  Therefore who is not stunned to learn that BPAS is planning to open a clinic in London for fertility services, such as IVF – starting beautiful lives – in Spring 2021?  BPAS and IVF are the oddest of bedfellows.  Making unborn children and also killing unborn children is a bizarre industry.  The parents of the very same child could even be double-charged.

 

Furedi asks, ‘So how can a charity, known internationally for its advocacy and provision of abortion services, argue for, and offer, IVF?’  Unsurprisingly in Furedi’s mind there is no conflict.  She answers, ‘Everything is contingent, everything depends on context, and everything is personal.  As an organisation, our core value is choice: the self-determination to decide if, when and with whom to have a child.  We have helped women to exercise that choice to end pregnancy, now we will help women to achieve pregnancy.’

 

If you regard abortion services as an acceptable part of women’s reproductive healthcare, then maybe BPAS-IVF is not such a weird project.  If you regard fertility care and abortion as antitheses, then BPAS-IVF will alarm you.

 

‘DIY’ abortions at home
Will the temporary become permanent?  Way back on 30 March, the UK Government announced a change to abortion legislation.  A ‘DIY’ early medical abortion (EMA), that is, up to 10 weeks of a pregnancy, could now be performed using mifepristone and misoprostol, as ‘pills by post’, entirely at home, by a woman on herself, without a doctor or another medical professional being present.  The change was announced without public consultation or parliamentary scrutiny.  A Government spokesperson insisted that, ‘This measure will be on a temporary basis and must follow a telephone or e-consultation with a doctor.’  Yet there are known dangers with such a policy.  For example, instances of severe bleeding, infections, undiagnosed ectopic pregnancies, unknown stages of gestation, a lack of mental health assessments, checks for correct dosages, patient identity, the presence of coercion, and so on.

 

During a House of Commons debate on 6 July, Victoria Atkins MP, Parliamentary Under Secretary of State at the Home Office, announced, ‘The Government consider that the right way forward is to undertake a public consultation on whether to make permanent the current Covid-19 measure allowing for home use of early medical abortion pills up to 10 weeks’ gestation for all eligible women’ and ‘I can confirm that we will keep the current Covid-19 measures in place until the public consultation concludes and a decision has been made.’

 

In the House of Lords on 9 July, in reply to a searching question tabled by Baroness Stroud on 30 June, Lord Bethell, Minister for Innovation, who also leads on Covid-19 policy, replied, ‘The Department is carefully monitoring the impact of and compliance with the temporary approval of home administration of both sets of abortion medication during the COVID-19 pandemic.  Officials have regular meetings with the Royal College of Obstetricians and Gynaecologists, the Care Quality Commission and abortion service providers to discuss the impact and any issues arising.’  And, ‘The Department is keeping under review when the temporary approval will be removed.’

 

Initially, the Government had promised only to keep the new regulations in place during the Covid-19 lockdown, but this was later extended to two years.  Now, ministers are considering keeping the current system permanently in place after it expires in 18 months’ time.

 

On 7 September, Lord Bethel, in answer to another question tabled on 28 July by Baroness Stroud, reaffirmed that, the Government has committed to undertake a public consultation on making permanent the COVID-19 measure allowing for home use of both pills for early medical abortion up to 10 weeks gestation for all eligible women.  The current COVID-19 measure will be kept in place until the public consultation concludes and a decision has been made.  Work to develop the consultation will begin soon and further details will be available in due course.

 

Here’s the thing.  Were these new measures introduced only for the period of Covid-19 emergencies and will they be only temporary?  There is still no date set, or content proposed, for that promised public consultation.


IVF and ARTs

Fertility treatments 2018
On 30 June, the HFEA published its annual Report entitled, Fertility treatment 2018: trends and figures.  UK statistics for IVF and DI treatment, storage, and donation.  The Report analysed data from all fertility treatments across the UK during 2018 and shows that IVF birth rates have increased for most patient groups.  For example, patients under 35 had a birth rate of 31% per embryo transferred, compared with only 9% in 1991, when the HFEA was established.


Other headline findings included a surge in ova and embryo freezing, increasing IVF success rates for some, a decrease in multiple births and a decrease in NHS funding for fertility treatments.
It reported that during 2018 about 54,000 patients underwent 68,724 fresh and frozen in vitro fertilisation (IVF) cycles and 5,651 donor insemination (DI) cycles at HFEA-licensed fertility clinics throughout the UK.

 

Since 2013, the number of ova and embryo storage cycles increased five-fold (523%) from 1,500 to just under 9,000 cycles in 2018 as freezing techniques improved and became more commonplace, and patients looked to future use as age, career and marriage prospects impacted on their options.  Frozen embryo transfer is rapidly gaining on fresh as the favoured transfer protocol – fresh transfers decreased by 11% (48,391 to 42,835) between 2013 and 2018, while frozen transfers almost doubled (13,421 to 25,889) accounting for 38% of all IVF cycles in 2018.  Vitrification is the new IVF snow queen.


The average birth rate per embryo transferred for all IVF patients was 23% a stubbornly static statistic.  Even so, rates have steadily increased for all patients aged under 43.  Age is still a key factor in IVF outcomes, with younger patients reporting higher success rates.  Birth rates for patients under 35 years old were 31% per embryo transferred, compared with below 5% for patients aged 43 and above when using their own ova.


The live birth rate per embryo transferred remains above 20% for each of the first three cycles of IVF treatment.  Using donor ova increased considerably the chance of a live birth to above 25%, but only 18% of patients aged 40 and older used donor ova.


The multiple birth rate decreased to 8% in 2018 for the first time a record low.  Fertility clinics have been working towards a target of 10% of women who become pregnant with twins or triplets – multiple births are still the biggest health risk to IVF mothers and their babies.  Transferring more than one embryo has no significant impact on the chance of a live birth but results in a 32% multiple birth rate for patients under 35.


The level of NHS funding for fertility treatment varies across the UK with 60% of cycles funded by the NHS in Scotland.  This compares with 45% in Northern Ireland, 41% in Wales and 35% in England.Bottom of Form

 
Family formations 2018
In September, the HFEA published another Report, Family formations in fertility treatment 2018.  It examines IVF and DI statistics for heterosexual, female same-sex and single patients in the UK.  The major findings are reported here.During 2018, fertility treatments were mostly (90%) used by patients in heterosexual relationships, followed by patients in female same-sex relationships (6.4%) and single patients (3.2%).


Patients in female same-sex relationships and single patients used IVF in 45% and 57% of their treatments respectively during 2018.  These were the highest proportions ever recorded. The remaining treatments used donor insemination (DI).IVF success rates, measured as births per embryo transferred were highest for patients in female same-sex relationships (31%), followed by patients in heterosexual relationships (23%) and single patients (17%).


DI birth rates per treatment cycle were highest for patients in female same-sex (15%) and heterosexual (14%) relationships, and lowest for single patients (9%) likely due to age differences.Most patients freezing ova had no partner (55%), followed by patients in heterosexual relationships (44%).  Patients thawing their own frozen ova for treatment were most commonly (88%) in heterosexual relationships.


NHS-funded IVF cycles were more common for patients in heterosexual relationships (39%) compared with patients in female same-sex relationships (14%) and single patients (6%).  Heterosexual couples had the highest NHS funding for DI (16%), though they were least likely to use DI (3% of treatments).  DI funding was 13% for patients in same-sex couples and 2% for single patients.  IVF ova-sharing programmes were used by patients in same-sex relationships (8%) and single patients (7%) compared with patients in heterosexual relationships (1%).


And the conclusion?  IVF was originally intended only for married couples, meaning a man and a woman.  IVF practice then followed the trend for cohabiting couples.  Now almost anyone and everyone, including same-sex couples and singles, can chose to use IVF.  Of course, IVF remains a treatment mainly for infertile heterosexual couples, but it entails costs, and not only the £5k per treatment cycle, but also the psychological, relationship and disappointment costs.  This HFEA Report highlights the correlation, though not necessarily causation, between IVF usage and the decline in marriage plus the breakdown of traditional family structures.  IVF always entails a high price.


‘Fertility equality’
This is the new slogan coined to reflect an emerging trend in the advance of so-called reproductive freedom.  According to the New York Times (22 July), ‘Still in its infancy, this movement envisions a future when the ability to create a family is no longer determined by one’s wealth, sexuality, gender or biology.’

 

What has driven this new cause?  Until April it was illegal in New York State to pay a surrogate to carry a baby.  The change in law was the result of a decade-long legislative battle which some activists have termed ‘fertility equality’.

 

One of its leading proponents is Ron Poole-Dayan, the founder and executive director of Men Having Babies, a New York non-profit organisation that helps gay men become fathers through surrogacy.  He has stated that, ‘This is about society extending equality to its final and logical conclusion.  True equality doesn’t stop at marriage.  It recognizes the barriers LGBTs face in forming families and proposes solutions to overcome these obstacles.’

 

Poole-Dayan and others believe that infertility should not be defined as merely a physical disorder, but a social one.  They argue that people gay, straight, single, married, male, female are not infertile because their bodies refuse to cooperate with baby making.  Rather, their specific life circumstances, like being a man with a same-sex partner, have rendered them unable to conceive or carry a child to term without medical intervention.  A novel category of ‘social infertility’ would provide those who are biologically unable to form families with the legal and medical mechanisms to do so.

 

According to Catherine Sakimura, of the National Center for Lesbian Rights, ‘We have this idea that infertility is about failing to become pregnant through intercourse, but this is a very hetero-centric viewpoint.  We must shift our thinking so that the need for assisted reproductive technologies is not a condition, but simply a fact.’

 

‘Fertility equality’ obviously has significant financial implications.  If it were recognised, US medical insurance companies, or the NHS in the UK, would be asked to cover procedures like sperm retrieval, ova donation, embryo creation and surrogacy, for heterosexual and gay couples and singles.  Legislators, such as Liz Linehan from Connecticut, recognise this but insist, ‘It’s a social justice issue.  It’s also a fiscal issue, this is also about fiscal injustice.  How will young LGBTs form families if they cannot afford it?’


Stop and think.  Have we been overtaken by this drive for equality on all levels and aspects of life?  Does not ‘fertility equality’ erase women and deny them their essential biological role?  Does it not depend largely upon the power of men, especially gay men to purchase the bodies of women?  Does it not eradicate womanhood and motherhood as we know it?
 

Ellie Anderson
She was a 16-year-old transgender girl, who lived in Stirling and died in July of ‘unascertained’ causes after commencing female hormone therapy.

 

Two years earlier, Ellie had her sperm frozen at Glasgow Royal Infirmary Fertility Clinic so that she could, one day, have her own biological children with the help of donor ova and a surrogate.  According to her mother, Louise, ‘As a teenager she delayed hormone blockers to save her sperm to enable her to have her own biological children.  She had made me promise that if anything were to happen to her, her children would be brought into the world.  I am going to do everything I can to honour her wishes.’

 

However, this is not legally possible in the UK the HFE Act (1990) requires the sperm sample to be destroyed. The Act contains provision for stored gametes to be retained for use by a partner in the event of the patient's death, but not for anyone else.


If Ellie had been in a relationship when she died, her partner would have had the right to ask for her sperm to be retained.  Her mother does not have that right.  Nevertheless, solicitors are planning to take the case to the Court of Session in Edinburgh to halt this.

 

Her lawyer described Mrs Anderson’s request as an ‘unusual, interesting, important and complex legal issue.’  ‘What we're trying to achieve would be to get an order from the Court that Ellie's mum would be entitled to make use of her sperm for the purpose that Ellie intended that being to create a genetic child of hers and a grandchild for Mrs Anderson.


’As of September, the Scottish NHS agreed to continue storing the dead teen's frozen sperm until her mother can bring the case to Court.  A Court date has been set for 30 November.  If Anderson is successful, a legal precedent could be established for parents to use their deceased children's gametes.

Who could have predicted such a sad bioethical dilemma consisting of transgenderism, posthumous sperm donation, ova donation, IVF, surrogacy and grand-motherhood?

 

Frozen ova storage limits
Sperm can be frozen and stored indefinitely.  The same is not true for ova.  Currently in the UK, there is a 55-year limit for storing ova for medical reasons, such as prior to cancer treatment to protect their survival.  But for social reasons the storage limit is 10 years, after which ova must be destroyed.

 

There is now a push to change this latter law.  At the end of September, the Nuffield Council on Bioethics published a Briefing Note entitled, Egg freezing in the UK.  It maintains that a longer storage period would give more people more time and more options.  The Government is currently assessing the 10-year rule.


Yet according to HFEA 2018 data, 85% of frozen ova are never thawed and used.  And not all thawed ova survive.  Moreover, only around a fifth of IVF treatments using a patient's own frozen ova result in the birth of a baby, with greater success for those aged under 35.  And there are the inevitable financial charges – ova collected and frozen for social reasons cost on average £3,350, with additional £500 to £1,500 costs for medication, plus storage costs at between £125 and £350 per year.

 

The Nuffield maintains that there appear to be few arguments against increasing the storage limit for social ova freezing.  Yet is does warn against the strategies of clinics that exploit women’s reproductive anxieties, including prosecco-fuelled marketing events and computer algorithms which target women with online advertisements.  Another of its concerns is ova freezing paid for by companies as an employment benefit.

 

Among the Nuffield Council’s conclusions is this statement, ‘There are few arguments against increasing storage limits for SEF [social egg freezing].  Those that are put forward are primarily against SEF per se rather than against an increase to the time limit.’  However, it may be argued that such a statement grossly underestimates the latent bioethical dilemmas of the technique.



Euthanasia and Assisted Suicide

UK doctors vote for assisted suicide?
In 2006, members of the British Medical Association (BMA), the UK’s largest union, adopted a policy of opposition to assisted suicide.  Now, after a February 2020 survey of its members, that opposition has declined.  Of the nearly 29,000 responding doctors and medical students (19% of all BMA members), for the first time, 50% believe the law should be changed to allow them to prescribe life-ending drugs for patients to self-administer.  That is an approval of assisted suicide rather than euthanasia.  A further 39% opposed this and 11% were undecided.

Asked whether the BMA should campaign for a change in the law, 40% said it should, 33% said it should maintain its policy of opposing a law change, and 21% said the BMA should change to a neutral stance and 6% were undecided.

Asked whether they would personally support a law change to allow doctors to deliver the fatal doses, 46% opposed such a change, 37% supported it and 17% were undecided.

Asked whether they would be personally willing in any way to participate in the assisted suicide process, 54% were opposed, 26% were supportive and 20% were undecided.  In other words, the doctors surveyed did not want to administer the life-ending drugs themselves, meaning they would be committing euthanasia.

BMA members from Northern Ireland, those registered with a licence to practise in the UK (rather than those unlicensed retired and medical students), GPs (as opposed to medical students), and those working in anaesthetics, emergency medicine, intensive care, obstetrics & gynaecology, oncology and palliative care were more opposed to assisted suicide.  Significantly, the latter groups are those who work in branches of medicine involving frequent contact with, and experience of, terminally-ill patients.

The BMA emphasised that the poll was not a vote and did not commit the BMA to any change in its formal opposition to assisted dying, explaining, ‘These detailed findings will make for an in-depth, considered debate on the future of the BMA’s policy when our members meet at the association’s next annual meeting in the summer 2021.  It is possible that doctors will then call for a formal change in the union’s stance on assisted suicide.

Unsurprisingly, the interpretation of the poll’s results have been varied.  Humanists UK, which supports the legalisation of assisted dying, described the survey as a ‘landmark’ moment and said, ‘The BMA looks like it must end its policy of opposing assisted dying.’  Dignity in Dying responded, ‘This is a historic vote and shows the majority of doctors support greater choice at the end of life.  The BMA’s official opposition to assisted dying is completely unrepresentative of its members.’  On the other hand, the Care Not Killing group said, ‘We are seeing strongest opposition to changing the law from those medics actually working most closely with terminally ill, elderly and disabled patients, compared to those who work in other non-related fields.’  And Baroness Finlay, professor of palliative care, has written, ‘Whatever view as a society we may take on this complex subject, one thing is clear: assisting people to take their own lives is not a role for doctors.  Decisions that involve balancing rights for some against protection for others are for the courts, not the consulting room.’

Last year, the Royal College of Physicians (RCP) faced criticism and a legal challenge from its members after it moved from a stance of opposition to one of neutrality based on the results of an online survey.  Its poll found that 43.4% of respondents said it should oppose the legalisation of assisted suicide, 31.6% said it should support legalisation, and 25% said it should be neutral.  Robert Buckland, the justice secretary, told the House of Commons last year that, ‘A change to the law in this sensitive area is a matter of conscience and a matter for Parliament rather than one of Government policy.’


RCGP legal challenge
The Royal College of General Practitioners (RCGP) has been threatened with legal proceedings unless it reconsiders its ‘irrational’ decision to continue to oppose any change in UK law to permit assisted dying.
The College had said on 21 February 2020 that its 2019 membership survey did not present a mandate to change its stance opposing assisted dying.  Critics have argued that most respondents voted for the College to change its policy from opposition to a neutral position, which would best reflect the results.

The survey, run by Savanta ComRes from 29 October to 15 December 2019, had 6,674 respondents, a response rate of just 13%.  Of these, 47% said that the RCGP should maintain its opposition to a change in the law, 40% supported a change in the law with safeguards, 11% favoured a neutral position and 2% abstained.  Dignity in Dying interpreted this as 51% in favour of a move from opposition.
In September 2020, two eminent members of the RCGP issued a letter calling for the RCGP Council to review urgently its decision to maintain its opposition to assisted dying.  Professor Aneez Esmail and Sir Sam Everington, high-profile members of the RCGP, have, in conjunction with the Good Law Project, issued a legal challenge that raises serious concerns that the decision taken by the Council at their meeting on 21 February 2020 was ‘irrational, failed to take into account relevant factors and took into account irrelevant factors.’  The legal challenge has been prepared by solicitors at Bindmans LLP with support from Dignity in Dying.


In the meantime, the RCGP commissioned medeConnect to conduct a poll of 1,000 GPs.  The results, released in September, showed that most GPs believe the College should not oppose legalisation of assisted suicide.  A total of 37% voted for adoption of a neutral position, 20% favoured supporting a law change and 35% agreed with retaining the position opposed to legalisation.


Professor Esmail stated, ‘[The medeConnent] poll shows most GPs disagree with Council’s decision on this issue, giving further evidence that the Council’s decision was out of touch.  It’s time for the College to reconsider its unrepresentative position, listen to the membership and adopt a neutral position so that they can truly represent their members and GPs’ views as a whole.’


Professor Everington declared, ‘All of us in general practice face the most challenging times we have ever known and we need more openness and accountability from our representative body.  It is imperative that the leadership at the RCGP gets its house in order, listens to the voices of its members and revisits this undemocratic decision.  GPs deserve better than a defensive, opaque establishment that protects a harmful status quo at all costs and without justification.’


The RCGP plans to survey its members on the assisted suicide issue in five years’ time.  Who could guess what will happen in the interim?


Assisted suicide in Ireland
Meanwhile, Ireland is still rushing madly to shed its traditional bioethical conservatism.  First, there was the legalisation of same-sex marriage, then abortion and now euthanasia.  Not so long ago, Ireland was ranked as the most charitable country in Europe and the second most charitable nation in the world.  What has happened?  It seems to dislike, even despise, both its most vulnerable young and old citizens.

Thus in early October, members of the Dáil Éireann, the lower house of the Irish Parliament (known as TDs), voted 81 to 71 to progress a private member’s Bill which would allow the option of ending one's life when terminally ill.  This was a significant defeat for the Government as the Dying with Dignity Bill 2020 passed its second stage.


A Coalition attempt to defer the issue to a special committee for a year was also defeated by 86 votes to 65, with most members having a free vote on this Bill as a matter of conscience.  The Dying with Dignity Bill 2020 will now go to the committee stage to be discussed in more detail.


The Irish Catholic Bishops’ Conference has responded by rightly saying, ‘Once assisted suicide is accepted in principle, it becomes very difficult to draw a line’ and referred to it as ‘always gravely sinful.’
If the Bill becomes law, it would allow Irish residents, living in Ireland for more than a year, and over the age of 18, to be assisted to die by a medical professional if they had stated that was their wish.  They must have an incurable and progressive illness which cannot be reversed by medical treatment and where they are likely to die as a result of their illness or issues related to it.  Bad news all round.


Assisted suicide in Victoria
More bad news.  The law in the Australian state of Victoria permitting assisted suicide was passed on 29 November 2017.  There was an 18-month implementation period before it came into force.  More bad news.  The publication of the third sixth-monthly report from the Voluntary Assisted Dying Review Board (VADRB) entitled, Report of operations January–June 2020 was published in August.  It allows an assessment of the first full year of deaths (19 June 2019 – 30 June 2020) since legalisation.

More bad news.  The Report’s key message – ten times more people than expected have chosen to end their lives under Victoria's landmark legislation in its first year of operation.  State government-sanctioned lethal medication was used to end the lives of 124 terminally-ill Victorians in the 12 months to June 2020.  This far surpasses the original estimates of just 12 people.  In 2019, Victoria’s premier, Daniel Andrews stated, ‘We anticipate in the first 12 months, based on overseas experience, around a dozen people that will access voluntary assisted dying.’  It has now been estimated that that number will stabilise at between 100 to 150 people annually.  Who knows?

As in other jurisdictions, unbearable pain was not a major factor among the reasons for requesting assisted dying.  In fact, the word ‘pain’ was cited only once.  Instead, the Report stated, ‘Loss of autonomy was frequently cited by applicants as a reason for requesting voluntary assisted dying.  Other reasons … included being less able to engage in activities that make life enjoyable, losing control of body functions, and loss of dignity.’

Assisted suicide in New Zealand
On 17 October, the Kiwis held a referendum on voluntary euthanasia (as well as voting in a general election and on the legality of personal use of cannabis).  Earlier in the year Parliament had already approved its End of Life Choice Act 2019, but the final binding decision rested with the public.

The question on the referendum paper (the first such use of a national ballot to determine a euthanasia outcome) was a simple, ‘Do you support the End of Life Choice Act coming into force?’  If approved, it will come into effect after 12 months, on October 2021.

The Act specifies the usual criteria – over 18, competent, terminal illness, 6 months to live, two doctors, and so on.  Yet the wording remains unavoidably vague.  For example, there is confusion over the meaning of ‘assisted dying’.  The Act talks about doctor- and self-administration, meaning both voluntary euthanasia and assisted suicide.  And the patient must ‘experience unbearable suffering that cannot be eased.’  That is impossible to define sufficiently tightly, nor is it necessarily equivalent to a ‘terminal illness’.
     
What is wrong with New Zealanders?  They seem to have lost their bioethical heads.  It was only in March that the country passed its Abortion Legislation Act 2020.  This did not tinker with niceties, such as weeks of pregnancy or those qualified to abort.  Instead it went for total decriminalisation.  In other words, abortion was no longer an action defined by protective legal statutes.  It was a mere healthcare matter.  Full stop.  Abortion in New Zealand is now available, without restrictions, to any woman, who is not more than 20 weeks pregnant.  Now euthanasia is heading in that same unfettered direction.  The results of the referendum are expected on 30 October.

Child euthanasia in the Netherlands
Doctors in the Netherlands can already legally euthanase babies up to 12 months old (with parental consent, of course!) as well as children over 12 years old, (with patient and parental consent).  What about those in between, those in the age gap?  They may soon be allowed.

In mid-October, the Health Minister, Hugo de Jonge, told the Dutch Parliament that it would soon be possible for, ‘a small group of terminally-ill children who agonize with no hope, and unbearable suffering’ to be lawfully euthanased.  He estimated that this change in the law would affect between five and ten children a year.  This, de Jonge implied, would be better than the current treatment of ‘terminal sedation’.  Apparently doctors want legal certainty rather than this ‘grey area’ between palliative care and life termination.

A report, published last year by three Dutch teaching hospitals, claimed that 84% of paediatricians in Holland agree with the Government’s proposal.  Yet the issue has proven to be extremely controversial and has resulted in months of robust debate within the four-party ruling coalition Government.  Opponents have argued, for instance that, of course, such young children cannot give proper consent.  And there has also been strong opposition from conservative Christian groups.  The intended policy is still under discussion.

Belgium is already worse.  From 2014, it became the first country to permit voluntary euthanasia of children.  Two Belgian children, aged 9 and 11, were the first to be euthanised in 2016 and 2017.

Assisted suicide and the CPS
On 17 August 2020, the UK’s Crown Prosecution Service (CPS) published its latest figures about prosecutions of those involved with assisted suicide, namely, those who may have breached the Suicide Act 1961.  The CPS policy on assisted suicide was originally published following a consultation exercise commenced in September 2009.  It provides guidance to prosecutors on the public interest factors to take into account in reaching decisions in cases of encouraging or assisting suicide.

From 1 April 2009 to 31 July 2020, there have been 162 cases referred to the CPS by the police that have been recorded as assisted suicide.  Of these, 107 were not proceeded with by the CPS and 32 cases were withdrawn by the police.


As of 31 July 2020, there are currently seven ongoing cases.  Three cases of encouraging or assisting suicide have been successfully prosecuted.  One case of assisted suicide was charged and acquitted after trial in May 2015 and nine cases were referred onwards for prosecution for homicide or other serious crimes.



Stem-Cell Technologies

 

3D printing cardiac organoids
Here is a fascinating incongruence – the physicality of 3D printing and the corporeality of a beating human heart.  After years of trying, a research group at the University of Minnesota has finally achieved the implausible.


Previously the scientists had followed a sensible protocol.  They used human induced pluripotent stem cells (iPSCs) and differentiated them into cardiac cells.  They then used 3D printing technology to graft them onto an extracellular matrix to give them structure.  Sensible, but ineffective.  The cells never reached a critical density to allow for the formation of beating organoids.


The research team was ready to abandon the project.  Then, according to Professor Brenda Ogle, the lead researcher at the Department of Biomedical Engineering in the University of Minnesota College of Science and Engineering, the unexpected occurred.  Two of her biomedical engineering PhD students, Molly Kupfer and Wei-Han Lin, suggested trying printing the stem cells first.  Eureka!


By 3D printing the stem cells and allowing them to reach a critical density before they are differentiated into heart cells, the team were able to demonstrate that it is possible to grow a 1.5cm beating heart organoid in less than a month.  Professor Ogle declared, 'I couldn't believe it when we looked at the dish in the lab and saw the whole thing contracting spontaneously and synchronously and able to move fluid.'  Some call it scientific serendipity.


Of course, these lab-grown, mini, beating, heart organoids are nowhere near as complex as a fully developed human heart, but this work should advance cardiac research and treatments.  Moreover, as Ogle has said, 'We can introduce disease and damage to the model and then study the effects of medicines and other therapeutics.'

Details of this ground-breaking discovery were published as ‘In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid’ by M Kupfer et al., in Circulation Research (2020, 127: 207–224).


Stem-cell treatments – bad
Stem-cell treatments can be good, bad or terrible.  Proponents of the good sort should continually warn against the bad and the terrible.  As has the US Food and Drug Administration (FDA), in a recent, strongly-worded paper entitled, ‘Identifying the Risks of Unproven Regenerative Medicine Therapies’ by P W Marks & S Hahn in the Journal of the American Medical Association (2020, 324: 241-242).

 

The authors are Stephen Hahn, the FDA’s new commissioner, and Peter Marks, the director of the Center for Biologics and Evaluation and Research (CBER).  They write, ‘… these [stem cell] products, whether autologous or allogeneic, are not inherently safe and may be associated with serious adverse consequences.’  They are specifically referring to unscrupulous clinics in the US advertising treatments for diseases and conditions ranging from autism to ageing.  But the safety and efficacy of their products are yet to be proven.  For instance, in 2017, three women became blind after receiving untested stem-cell treatment on their eyes at a Florida clinic.

 

They also warn that, ’… the increasing number of adverse events being reported following the widespread use of unapproved regenerative medicine therapies at hundreds of clinics across the country make it necessary for the FDA to act to prevent harm to individuals receiving them.’

 

To evaluate whether a particular cellular product complies with FDA regulations, the authors make practical recommendations for potential patients.  For people considering therapies involving a cellular product, the following three steps are suggested.  First, the patient should verify whether the product is FDA-approved or whether an investigational new drug (IND) application has been filed with the regulatory body.  Second, the patient must provide written informed consent to participate in a clinical trial under that IND and compliance with institutional review board (IRB) requirements.  Third, patients enrolled in the clinical trial should receive a summary of results after the clinical trial is completed.  In addition, Marks and Hahn strongly encourage patients (and their families, friends and doctors) to report adverse events.  Such reports will help the FDA to get a better picture of the full spectrum of adverse events.

 

On the other hand, there is good evidence that more and more patients, especially those with neurological disorders, such as multiple sclerosis (MS), motor neurone disease (MND) and Parkinson's disease, are increasingly seeking information about stem-cell treatments as therapeutic options for their illnesses.

 

Of course there are clinics that will attempt to fly under the FDA’s radar.  The authors therefore request engagement, ‘… to help to ensure that instead of remaining unintentionally or intentionally hidden, potentially harmful unapproved regenerative medicine therapies are identified and then removed from the market.’

 

Such strong warnings are sadly necessary.  The stem-cell treatment industry is riddled with cowboys and their snake-oil products.  They give legitimate clinics and effective products a bad name.  Stem-cell treatments in the USA, Europe and elsewhere may be decently regulated, but across the rest of the world, especially including China and India, there is a dangerous free-for-all bonanza.  Watch out for stem-cell treatments, good, bad and terrible.

 

How to mend a broken heart
US researchers have developed a new way to heal damaged heart tissue by implanting capsules containing stem cells near to the damaged heart.

 

During a heart attack, cardiac cells can die when deprived of oxygen.  The body can repair some of the damage with scar tissue, but this does not function in the same way as the original heart muscle and can lead to complications including further heart attacks.


Stem cells can be transformed into any of the body’s cell types, and in addition they can produce therapeutic molecules that can help to regenerate damaged tissues.  These are potentially promising treatment options.  However, when introduced into a body, stem cells can be recognised by the immune system and many can be destroyed.

How to decrease or overcome this stem-cell destruction?  That was the task tackled by Ravi Ghanta and his team from Baylor School of Medicine in Texas.  The team shielded about 30,000 stem cells in 'hydrogel' capsules.  The stem cells used were mesenchymal stem cells (MSCs), a type of stem cell produced in the bone marrow that had previously been shown to repair tissue after a heart attack.


Several of the 1.5mm capsules were implanted into rats that had experienced a heart attack.  After 28 days, animals treated with these capsules of shielded stem cells had 2.5 times more heart healing capacity than rats treated with unshielded stem cells that had been injected directly into the heart.

The study’s other lead author, Dr Omid Veiseh from Rice University in Texas, explained, 'The immune system doesn't recognise our hydrogels as foreign, and doesn't initiate a reaction against the hydrogel.  So we can load MSCs within these hydrogels, and the MSCs live well in the hydrogels.  They also secrete the same reparative factors that they normally do, and because the hydrogels are porous, the wound-healing factors just diffuse out.'

And Dr Ghanti claims that, ‘With further development, this combination of biomaterials and stem cells could be useful in delivering reparative therapy to heart attack patients.’  OK, only rats so far, humans next.


This work has been reported as, ‘Immune-modulatory alginate protects mesenchymal stem cells for sustained delivery of reparative factors to ischemic myocardium by R K Ghanta et al., in Biomaterials Science (2020, 8: 5061-5070).