Wednesday 27 January 2016

Holocaust Memorial Day – let’s not forget the leading role doctors played

Today is Holocaust Memorial Day when Britain marks the 71st anniversary of the liberation of Auschwitz-Birkenau, the largest of the Nazi death camps. This year’s theme is ‘Don’t stand by’.

More than one million people, mostly Jews, died at the Nazi camp (pictured) before it was liberated by allied troops on 27 January 1945. Overall, six million Jews were murdered in a systematic attempt to erase all traces of the Jewish race from Europe. 

But the horrific genocide of six million Jews was in fact only the final chapter in the Nazi holocaust story.

The detail of how it happened, and particularly the role of doctors in the process, is not at all well known.

What ended in the 1940s in the gas chambers of Auschwitz, Dachau and Treblinka had much more subtle beginnings in the 1930s in nursing homes, geriatric hospitals and psychiatric institutions all over Germany.

When the Nazis arrived, the medical profession was ready and waiting.

Twenty three physicians (see below) were tried at the so-called Nuremberg Doctors' Trial in 1946, which gave birth to the Nuremberg Code of ethics regarding medical experiments. 

Many others including some of the very worst offenders never came to trial (see list of main perpetrators here and full list here)

How did it actually happen?

Our story begins with Germany emerging from the First World War defeated, impoverished and demoralised.

Into this vacuum in 1920 Karl Binding, a distinguished lawyer, and Alfred Hoche, a psychiatrist, published a book titled ‘The granting of permission for the destruction of worthless life. Its extent and form'.

In it they coined the term ‘life unworthy of life’ and argued that in certain cases it was legally justified to kill those suffering from incurable and severely crippling handicaps and injuries. Hoche used the term ballastexistenzen (‘human ballast’) to describe people suffering from various forms of psychiatric disturbance, brain damage and retardation.

By the early 1930s a propaganda barrage had been launched against traditional compassionate 19th century attitudes to the terminally ill and when the Nazi Party came to power in 1933, 6% of doctors were already members of the Nazi Physicians League.

In June of that year Deutsches Arzteblatt, today still the most respected and widely read platform for medical education and professional politics in Germany, declared on its title page that the medical profession had ‘unselfishly devoted its services and resources to the goal of protecting the German nation from biogenetic degeneration’.

From this eugenic platform, Professor Dr Ernst Rudin, Director of the Kaiser Wilhelm Institute of Psychiatry of Munich, became the principle architect of enforced sterilisation. The profession embarked on the campaign with such enthusiasm, that within four years almost 300,000 patients had been sterilised, at least 50% for failing scientifically designed ‘intelligence tests’.

By 1939 (the year the war started), the sterilisation programme was halted and the killing of adult and paediatric patients began. The Nazi regime had received requests for ‘mercy killing’ from the relatives of severely handicapped children, and in that year an infant with limb abnormalities and congenital blindness (named Knauer) became the first to be put to death, with Hitler’s personal authorisation and parental consent.

This ‘test-case’ paved the way for the registration of all children under three years of age with ‘serious hereditary diseases’. This information was then used by a panel of ‘experts’, including three medical professors (who never saw the patients), to authorise death by injection or starvation of some 6,000 children by the end of the war.

Adult euthanasia began in September 1939 when an organisation headed by Dr Karl Brandt and Philip Bouhler was set up at Tiergartenstrasse 4 (T4). The aim was to create 70,000 beds for war casualties and ethnic German repatriates by mid-1941.

All state institutions were required to report on patients who had been ill for five years or more and were unable to work, by filling out questionnaires and chosen patients were gassed and incinerated at one of six institutions (Hadamar being the most famous).

False death certificates were issued with diagnoses appropriate for age and previous symptoms, and payment for ‘treatment and burial’ was collected from surviving relatives.

The programme was stopped in 1941 when the necessary number of beds had been created. By this time the covert operation had become public knowledge.

The staff from T4 and the six killing centres was then redeployed for the killing of Jews, Gypsies, Poles, Russians and disloyal Germans. By 1943 there were 24 main death camps (and 350 smaller ones) in operation.

Throughout this process doctors were involved from the earliest stage in reporting, selection, authorisation, execution, certification and research. They were not ordered, but rather empowered to participate. 

Leo Alexander, a psychiatrist with the Office of the Chief of Counsel for War Crimes at Nuremberg, described the process in his classic article 'Medical Science under Dictatorship' which was published in the New England Medical Journal in July 1949.

‘The beginnings at first were merely a subtle shift in emphasis in the basic attitude of the physicians. It started with the attitude, basic in the euthanasia movement that there is such a thing as a life not worthy to be lived. This attitude in its early stages concerned itself merely with the severely and chronically sick. Gradually the sphere of those to be included in this category was enlarged to encompass the socially unproductive, the ideologically unwanted, the racially unwanted and finally all non-Germans.’ 

The War Crimes Tribunal reported that ‘part of the medical profession co-operated consciously and even willingly’ with the ‘mass killing of sick Germans’.

Among their numbers were some of the leading academics and scientists of the day; including professors of the stature of Hallervorden (neuropathology), Pernkopf (anatomy), Rudin (psychiatry/genetics), Schneider (psychiatry), von Verschuer (genetics) and Voss (anatomy). None of these men were ever prosecuted while of the 23 defendants at Nuremberg, only two were internationally recognised academics.

It is easy to distance ourselves from the holocaust and those doctors who were involved. However, images of SS butchers engaged in lethal experiments in prison camps don’t fit the historical facts; the whole process was orchestrated through the collaboration of internationally respected doctors and the State.

With the advantage of hindsight we are understandably amazed that the German people and especially the German medical profession were fooled into accepting it. The judgement of the War Crimes Tribunal in 1949 as to how they were fooled was as follows. 

'Had the profession taken a strong stand against the mass killing of sick Germans before the war, it is conceivable that the entire idea and technique of death factories for genocide would not have materialized...but far from opposing the Nazi state militantly, part of the medical profession co-operated consciously and even willingly, while the remainder acquiesced in silence. Therefore our regretful but inevitable judgement must be that the responsibility for the inhumane perpetrations of Dr Brandt (pictured left)...and others, rests in large measure upon the bulk of the medical profession; because the profession without vigorous protest, permitted itself to be ruled by such men.' (War Crimes Tribunal. 'Doctors of Infamy'. 1948)

The lessons of history must never be forgotten and every new generation needs  re-educating about what really happened, not least the medical profession itself. 

Sunday 17 January 2016

Claims that DNA editing of human embryos will help infertile couples lack any evidence base

A scientist made her case last week to be the first in the UK to be allowed to genetically modify human embryos. 

The regulator, the Human Fertilisation and Embryology Authority (HFEA), considered her application last Thursday and will give a ruling later this month (Nature, Guardian, Mail, Telegraph). If approved the research could begin as early as March this year.

Dr Kathy Niakan (pictured), from the Francis Crick Institute in London, wants to use a new technique called CRISPR/Cas9 to ‘edit’ genes in day-old human embryos left over from IVF in order to discover what role they play in normal embryo development.

She plans to start with a gene called Oct4, which is thought to have a critical role in embryo development, using 20-30 donated embryos. If this is successful she plans to move on to testing 3-4 other genes, each again using a further 20-30 embryos.

The research is highly controversial, and not just because it results in the destruction of the embryos being studied (each will be destroyed and examined at seven days).

Although gene editing to treat some genetic disease in fully developed human beings appears to have huge promise (such as in the case of Layla Richards who was saved from terminal leukaemia in London last year), gene editing in embryos (germline gene editing) has come in for huge criticism internationally (see also here) and has so far only been attempted (unsuccessfully) in China.

This international criticism is mainly driven by concerns about safety and unforeseen consequences – introducing genetic changes into a day old embryo will mean that any genetic change will be expressed in every cell of the developing human being, including reproductive cells (sperm and egg), and will therefore be passed on down the generations.

CRISPR, however, can be applied with great precision and there is the very real possibility that it might be used in the future to treat – or perhaps even prevent – some genetic diseases by correcting genetic defects in embryos or foetuses. However it is still very early days.

Usually research like this needs to be conducted exhaustively using animals before it is attempted in humans. However Niakan argues that the genes she wishes to study are sufficiently different from their equivalents in animals to justify doing the research on human embryos.

Whenever scientists seek approval for controversial techniques, they tend to emphasise their potential therapeutic benefit in order to get regulators, parliamentarians and the general public on side.  This case is no exception.

Niakan is arguing that her research will provide a deeper understanding of the earliest moments of human life and could reduce miscarriages: ‘The reason why it is so important is because miscarriages and infertility are extremely common, but they're not very well understood. We believe that this research could really lead to improvements in infertility treatment and ultimately provide us with a deeper understanding of the earliest stages of human life.’

The media has picked up strongly on this theme with The Times (£) running the headline ‘GM embryos set to give massive boost to IVF success rates’:  ‘Britain’s first genetically engineered human embryos could lead to dramatic improvements in IVF and help to explain why so many women suffer miscarriages, according to the scientist leading the project.’

There are strong advocates for the research in Britain (see here and here) and an international collaboration (the Hinxton group) has made an earlier call for bans on germline gene editing to be lifted (see critique here).

Other voices have been raised in support. Hugh Whittall (£), the director of the Nuffield Council on Bioethics, said that there are ‘possible future scenarios in which a modification made in a research context — for example, to correct a disease-causing genetic mutation — could, if this were to become permissible, result in the birth of a child.’  

Sarah Norcross, Director of the Progress Educational Trust, has also jumped on the bandwagon saying: 'This is an important piece of basic scientific research. Recurrent miscarriage affects a huge number of people and it isn't greatly understood. People are just told to go away and try again. To improve our understanding of something like that, which has a huge impact on people, is really valuable.'

Professor Robin Lovell-Badge of the Crick Institute was a little more guarded, ‘If you found that there were people carrying a specific mutation which meant that their embryos would never implant [in the womb], then you could contemplate using the genome-editing technique to make germ-line changes which would then allow the offspring of that woman to be able to reproduce without having a problem.’

The clear implication is that some genetic defects which lead to embryo death or miscarriage are those that could be 'corrected' by CRISPR (ie single gene defects).

But is there any real evidence that embryo death or miscarriage is actually caused these sorts of genetic problems? Actually no.

If CRISPR could be made to work safely in embryos then it might conceivably have a role in correcting genes responsible for single gene disorders like cystic fibrosis, sickle cell disease, Fragile X syndrome, muscular dystrophy or Huntington disease. But again, is there any evidence that single gene disorders are responsible for failure of embryo implantation or miscarriage?

Very little, if any. It is mere speculation.

According to the American College of Obstetricians and Gynaecologists (ACOG), most miscarriages (about 60%) occur when an embryo receives an abnormal number of chromosomes during fertilisation (see also here). This is called aneuploidy. This type of genetic condition occurs by chance – there is no medical condition that causes it. However it becomes more common in women of increased reproductive age.

Down’s syndrome, Edward’s syndrome and Patau’s syndrome are the best known forms of aneuploidy. In each condition there is an additional chromosome – numbers 21, 18 and 13 respectively. Babies with these conditions are usually born alive but most other aneuploidies are lethal in utero – causing miscarriages or failed implantation.

The commonest cause of miscarriages are trisomy 16 and 22. In a 2015 study of 832 early miscarriages, 368 (44.23%) were found to be abnormal. 84.24% (310/368) of these were aneuploidies and 15.76% (58/368) were polyploidies. The first was trisomy 16 (121/310), followed by trisomy 22, and X monosomy. It may well be that trisomies of chromosomes other than 13, 18, 16, 21 and 22 (there are 23 chromosomes in each egg and sperm) prove lethal earlier in pregnancy or before implantation. It makes good sense.

According to the ACOG, in a small number of couples who have repeated miscarriages, one partner has a translocation, involving the abnormal transfer of one part of a chromosome to another  chromosome. Deletions and inversions may also play a role.

All of these chromosomal abnormalities (aneuploidy, translocations, deletions and inversions) may be present in sperm and/or eggs or may occur after fertilisation. Either way they end up in the embryo and fetus.

So what about failure of an early embryo to implant in the uterus? Implantation failure is related to either maternal factors or embryonic causes. Maternal factors include uterine anatomic abnormalities, thrombophilia, non-receptive endometrium and immunological factors. Failure of implantation due to embryonic causes is associated with either genetic abnormalities or other factors intrinsic to the embryo that impair its ability to develop in utero, to hatch and to implant.

The average implantation rate in IVF is about 25 %. Inadequate uterine receptivity is responsible for approximately two-thirds of implantation failures, whereas the embryo itself is responsible for only one-third of these failures. Again, aneuploidy and translocations are major reasons for embryo-related failure.

The key point to grasp here is that the genetic abnormalities which result in implantation failure (either in IVF or naturally) or miscarriage are chromosomal abnormalities, not abnormalities in single genes. But only abnormalities in single genes can be fixed with gene editing of the sort that the Crick Institute is proposing. Gene editing does not fix chromosomal abnormalities.

However this simple fact has not been made clear to the media, to decision makers or the public. In fact researchers like Niakin and Lovell-Badge, who must be aware of it, seem to have gone out of their way to fuel the misconception that gene editing will help infertility.

This, it seems, is both negligent and disingenuous, as the key factor that is driving the call to approve this new research is the supposed benefit to infertile couples. 

In reality, it seems to be more about satisfying scientific curiosity about how genes work in the normal development of the human embryo with any therapeutic application a distant dream.

British scientists have form in making wild and rash promises about new therapies in order to get approval for controversial research – the hype around animal-human hybrids and three parent embryos (mtDNA) are cases in point.

With respect to the latter David King, who runs the watchdog group Human Genetics Watchremarked when the UK’s fertility agency, the Human Fertilisation and Embryology Authority (HFEA), approved mtDNA work: ‘The decision is very disappointing, but comes as no surprise, since the HFEA can never say no to scientists.  These experiments are scientifically useless and morally very problematic. The research lobby has distorted the scientific facts in order to defuse criticism.’

Gene editing, as I said at the beginning of this article, has great therapeutic promise for treating and perhaps even preventing some genetic disease. But gene editing of the embryo (germline editing) is extremely controversial and potentially very dangerous. Scientists around the world think that we are mad in Britain to be pursuing it. 

At very least much more work is needed in animal models before we contemplate using it on human embryos; and especially we need to establish first in animals whether or not it is likely to have any benefit at all in preventing infertility before we start making rash promises about humans.

I am not alone in remaining sceptical and unconvinced.

Here’s hoping that the HFEA will pour cold water on Niakan’s proposed research. However, based on past form I am not holding my breath.