Review
Attention
Culture
Film & TV
Weirdness
5 min read

Ludwig’s clues to the answers we long for

Puzzles preserve a fully realised truth in the clue, and, if we are willing to persevere, we will be rewarded.
Two TV characters, a man and a woman, stand in front of a crossword cover walls of a room.
Anna Maxwell Martin, David Mitchell.
BBC.

The BBC have scored a bingeable hit with new comedy-drama Ludwig, starring David Mitchell as a maladroit puzzle-setter who is roped into a rather fabulous whodunnit. It involves his missing twin, a police detective whom he must impersonate in order to chase the trail of the disappearance.  While on the case he solves a few other conundrums, giving the show many intriguing, if knotty, narrative threads.  

It is not the first-time crossword setting and detective work have gone hand in hand. One of the very first cryptic crossword setters - the ‘grandfather’ of the genre - was Edward Powys Mathers, who also dashed off a mystery thriller, Cain’s Jawbone in 1934. The novel was provided to readers in the wrong order, with the simple but infuriating challenge to reconstruct the right sequence of pages based on maddeningly subtle internal clues. Despite offers of a cash prize, virtually no solutions were submitted.  

Such is the dilemma of a cryptic crossword setter - when is clever too clever? Puzzles can appeal so much to our pride; our desire to be part of an ‘in-group’ which understands the highbrow references to opera, Latin oratory, and cricket slang. Those who can outwit them are part of an elite rank. The Telegraph crossword of 13th January 1942 was used as an exercise to recruit for the ENIGMA codebreaking unit. Indeed, when Mathers all but invented the idea of a fully cryptic crossword in the Saturday Westminster Gazette in 1924, his challenges bore the banner ‘Crosswords for Supermen’.  

There is fundamental connectedness behind the world, and working on the presumption of such a unity allowed him to collect ideas and references from across the globe and throughout all history to form his tricksy clues. 

I’ve often started out on a cryptic crossword, hoping to discover that I am one such genius, only to bitterly give up shortly afterwards, irritated that I don’t have that instant ability to see the solutions. I stare at the riddle, wanting to be one of those people who can naturally recall information, connect ideas, or see what has been hidden in the tortuous clue. Surely the appeal of a show like Ludwig is that it gives us an aspirational glimpse at the peak of human mental prowess, even if Mitchell’s wannabe inspector is a little socially awkward. He still possesses a penetrating gaze that looks through the surface of things, to see what no one else can. He is one of those ‘supermen’ - beholden to no one, able to uniquely see the way things are all by himself.  

And yet, when Edward Powys Mathers died in 1939, he was referred to in his Observer obituary not as a kind of lone snobby genius, but “the gentlest of men… a saint”. It’s appropriate, as crosswords have long been a curiously churchy phenomenon: in the small list of great UK cryptic writers, two have been Anglican priests (Revd John Graham, known as Acaucaria, and Revd Canon A. F. Ritchie, or Afrit). Even Mathers’ fondness for Biblical allusions in his clues “led many to endow him with ecclesiastical rank” as Roger Millington’s book on Crosswords put it. Christian faith, because it is a religion built on the idea that God is with us in flesh, invites us to pay attention to the world around us. The world is not something to escape from, but is rather the place that, in Jesus Christ, God has come to meet us in. It makes you want to understand time, place, and culture, to better understand the God who has spoken through them, and given them meaning and destiny. In reference to this way of seeing things, Mathers was spoken of as a ‘catholic’ thinker in his obituary. This did not mean his church affiliation, but rather an instinct for seeing how everything is part of a greater whole. There is fundamental connectedness behind the world, and working on the presumption of such a unity allowed him to collect ideas and references from across the globe and throughout all history to form his tricksy clues.  

There is also a negative hint in this obituary clue, ‘catholic’. Crossworders work under a nom de plume (David Mitchell’s character John for instance, who goes by ‘Ludwig’). And while Mathers was indeed a generous, open-minded man, he sealed his reputation for difficulty by adopting the pseudonym ‘Torquemada’, in reference to a former Grand Inquisitor of the Spanish Inquisition. So, if Christians are alive to the interconnectedness of all things, we also have a reputation for the institutional guarding of those very mysteries. History shows believers have tortured those who do not come to their idea of what the answer is; indeed, they have set the questions for too long, in the eyes of many hostile to the faith.

Puzzles preserve a fully realised truth in the clue, and, if we are willing to persevere, and learn a new way of seeing, and of paying attention, we will be rewarded. 

But this is the tension that crosswords offer us - a very authentically Christian way to think about the way God spells things out for us which does not rely on a stark binary of ‘true’ or ‘false’. He reveals things like a puzzle; slowly, and cryptically. Some might fairly object to this comparison, on the grounds this would make God too ‘out there’ - far away from the intimate father that Jesus bids us address so familiarly. Does it make God too remote and enigmatic to say he is setting riddles for us? But actually, a puzzle does not deceive us, like a mask does. Puzzles preserve a fully realised truth in the clue, and, if we are willing to persevere, and learn a new way of seeing, and of paying attention, we will be rewarded. The answer is there, reaching out to us, if we only commit ourselves humbly to receiving it. It may cost us much effort and time. It may require us to learn things afresh. But this is part of the joy of trying to see, as St Paul puts it, "the mystery hidden for ages in God, who created all things”.  

Jesus himself spoke in parables, very much like cryptic clues. But this was no elitism, designed to cut out those without the high IQ of David Mitchell’s ‘Ludwig’. Arrogant intellect or love of one’s own status is, for Jesus, just as much a bar to those seeking a solution, because to find the answer requires a certain submission - a discipline - to see things as the puzzle-setter sees them. If we proceed only to do things our way, we remain blind: seeing we do not see, and hearing we do not hear, nor do we understand. 

Explainer
Biology
Culture
Ethics
9 min read

Ethics needs to catch-up with genetic innovation

Are we morally obliged to genetically edit?

John is Professor Emeritus of Cell and Molecular Biology at the University of Exeter.

An artistic visualisation of a DNA strand growing flowers from it.
Artist Nidia Dias visualises how AI could assist genomic studies.
Google Deepmind via Unsplash.

It makes me feel very old when I realise that Louise Brown, the first baby to be born via in vitro fertilisation (IVF), will be 47 years old on July 25th this year. Since her birth in 1978, over 10 million IVF-conceived babies have been born worldwide, of whom about 400,000 have been in the UK. Over that period, success rates have increased such that in some clinics, about 50 per cent of IVF cycles lead to a live birth. At the same time, there have also been significant advances in genetics, genomics and stem cell biology all of which, in relation to human embryos, raise interesting and sometimes challenging ethical issues. 

I start with a question: what is the ‘moral status’ of the early human embryo? Whether the embryo arises by normal fertilisation after sexual intercourse or by IVF, there is a phase of a few days during which the embryo is undergoing the earliest stages of development but has not yet implanted into the wall of the uterus; the prospective mother is not yet pregnant. In UK law, based on the Human Fertilisation and Embryology Act (1990), these early embryos are not regarded as human persons but nevertheless should be treated with some respect. Nevertheless, there are some who oppose this view and believe that from the ‘moment of conception’ (there actually isn’t such a thing – fertilisation takes several hours) embryos should be treated as persons. In ‘conventional’ IVF this debate is especially relevant to the spare embryos that are generated during each IVF cycle and which are stored, deep-frozen, in increasing numbers for possible use in the future.  

A further dimension was added to this area of debate when it became possible to test IVF embryos for the presence of genetic mutations that cause disease. This process is called pre-implantation genetic diagnosis and enables prospective parents who are at known risk of passing on a deleterious mutation to avoid having a child who possesses that mutation. But what about the embryos that are rejected? They are usually discarded or destroyed but some are used in research. However, those who hold a very conservative view of the status of the early embryo will ask what right we have to discard/destroy an embryo because it has the ‘wrong genes’. And even for the many who hold a less conservative view, there are still several questions which remain, including ‘which genetic variants we should be allowed to select against?; should we allow positive selection for genes known to promote health in some way?’; should we allow selection for non-therapeutic reasons, for example, sporting prowess?’ These questions will not go away and there are already indications that non-therapeutic selection is being offered in a small number of countries. 

Genetic modification 

This leads us on to think about altering human genes. Initially, the issue was genetic modification (GM) which in general involves adding genes. GM techniques have been used very successfully in curing several conditions, including congenital severe immune deficiency and as part of treatment programmes for certain very difficult childhood cancers. One key feature of these examples is that the genetic change is not passed on to the next generation – it just involves the body of someone who has already been born. Thus, we call them somatic genetic changes (from the Greek, sōmatikos, meaning ‘of the body’).  

Genetic modification which is passed on to the next generation is called germline GM which means that the genetic change must get into the ‘germ cells’, i.e., the sperm or egg. Currently, the only feasible way of doing this is to carry out the genetic modification on the very early embryo. At present however, with just one very specific exception, GM of human embryos is forbidden in all the countries where it would be possible to do it. There is firstly the question of deciding whether it is right to change the genetic makeup of a future human being in such a way that the change is passed to succeeding generations. Secondly, there are concerns about the long-term safety of the procedure. Although it would involve adding specific genes with known effects, the complexity of genetic regulation and gene interactions during human development means that scientist are concerned about the risks of unforeseen effects. And thirdly, germline GM emphasises dramatically the possibility of using GM for enhancement rather than for medical reasons.  

Genome editing 

This leads us to think about genome editing. In 2011, it was shown that a bacterial system which edits the genomes of invading viruses could also work in other organisms This opened up a large array of applications in research, agriculture and medicine. However, the ethical issues raised by genome editing are, in essence, the same as raised by GM and so there is still a universal prohibition of using the technique with human embryos: germline genome editing is forbidden. Despite this, a Chinese medical scientist, He Jiankui, announced in 2018 that he had edited the genomes of several embryos, making them resistant to HIV; two babies with edited genomes had already been born while several more were on the way. The announcement caused outrage across the world, including in China itself. He Jiankui was removed from his job and then, after a trial, was imprisoned for three years; his two colleagues who collaborated in this work received shorter sentences. 

At present the universal prohibition of human germline genome editing remains in place. However, the discussion has been re-opened in a paper by an Anglo-Australian group.  They suggest that we need to develop heritable (i.e. germline) polygenic genome editing in order to reduce significantly an individual's risk of developing degenerative diseases. These includecoronary artery disease, Alzheimer’s disease, major depressive disorder, diabetes and schizophrenia. I note in passing that one of the authors is Julian Savulescu at Oxford who is already well-known for his view that parents who are able to do so, are ‘morally obliged’ to seek to have genetically enhanced children, whether by PGD, GM or genome editing. The use of polygenic editing, which would, in all likelihood, be available only to the (wealthy) few, fits in well with his overall ethical position. Needless to say, the paper, published in the prestigious journal Nature, attracted a lot of attention in the world of medical genetics. It was not however, universally welcomed – far from it. Another international group of medical scientists and ethicists has stated that ‘Human embryo editing against disease is unsafe and unproven …’ and even go as far as to suggest that the technology is ‘… going to be taken up by people who are pushing a eugenics agenda …’ remain very pertinent. 

Harder still and harder 

I have no doubt that amongst different reader there will be a range of opinions about the topics discussed so far. For anyone who is Christian (or indeed an adherent of almost any religious faith), one of the difficulties is that modern science, technology and medicine have thrown up ethical questions that could not have even been dreamed of by the writers of the Bible (or of other religious texts). We just have to use our wisdom, knowledge and general moral compass (and for some, prayer) to try to reach a decision. And if what I have already written makes that difficult, some recent developments multiply that difficulty still more.  

In the early years of this century, scientists developed methods of transforming a range of human cells into ‘pluripotent’ stem cells, i.e., cells capable of growing into a wide range of cell types. It also became possible to get both induced stem cells and natural stem cells to develop into functional differentiated cells corresponding to specific body tissues. This has huge potential for repairing damaged organs. However, other applications are potentially much more controversial. In 2023, Cambridge scientists reported that they had used stem cells to create synthetic mouse embryos which progressed at least as far as brain and heart formation within the normal pattern of mouse embryo development. 

At about the same time, the Cambridge group used individual human embryonic stem cells (from the blastocyst stage of embryonic development), to ‘grow’ early human embryos in the lab. There is no intention to use these embryos to start a pregnancy – indeed, it would be illegal to do so – but instead to study a period of embryo development which is not permitted with ‘real’ human embryos (research must not continue past 14 days of development). But how should we regard synthetic embryos? What is their moral status? For those who hold a conservative view of the normal human embryo (see earlier), should we regard these synthetic embryos as persons? Neither does the law help us. The legal frameworks covering in vitro fertilisation and early embryos (Human Fertilisation and Embryology Acts, 1990, 2008) do not cover artificial embryos – they were unknown at the times the legislation was drawn up. Indeed, synthetic embryos/embryo models are, in law, not actually embryos, however much they look like/behave like early embryos. Earlier this month, the Human Fertilisation and Embryology Authority (HFEA) discussed these developments with a view to recommending new legislation, but this will not dispel an unease felt by some people, including the science correspondent of The Daily Telegraph, who wrote that this research is irresponsible.  

But there is more. In addition to synthetic embryos, the HFEA also discussed, the possible use of gametes – eggs and sperm – grown from somatic stem cells (e.g., from skin) in the lab. Some authors have suggested that the production of gametes in vitro is the ‘Holy Grail’ of fertility research. I am not so sure about that but it is clear that a lot of effort is going into this research. Success so far is limited to the birth of several baby mice, ‘conceived’ via lab-grown eggs and normal sperm. Nevertheless, it is predicted that lab-grown human eggs and sperm will be available within a decade. Indeed, several clinicians have suggested that these ‘IVGs’ (in vitro gametes) seem destined to become “a routine part of clinical practice”.  

The lab-grown gametes would be used in otherwise normal IVF procedures, the only novelty being the ‘history’ of the eggs and/or sperm. Clinicians have suggested that this could help couples in which one or both were unable to produce the relevant gamete, but who still wanted to have children. In this application, the use of IVGs poses no new ethical questions although we may be concerned about the possibility of the gametes carrying new genetic mutations. However, some of the more wide-ranging scenarios do at the least make us to stop and think. For example, it would be possible for a same-sex couple to have a child with both of them being a genetic parent (obviously for males, this would also involve a surrogate mother). More extremely, a person could have a child of which he or she was actually, in strictly genetic terms, both the ‘father’ and the ‘mother’. What are we to make of this? Where are our limits?  

Dr Christopher Wild, former director of International Agency for Research on Cancer, explores in depth many of the developments and issue I outlined above. His article on why a theology of embryos is needed, is clear, well-written, helpful and thought-provoking. 

 

This article is based on a longer blog post with full footnotes.  

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