David Ish-Horowicz FRS (1948-2024): outstanding scientific discovery, with a unique touch of selfless humanity Free

David as a young graduate student at the LMB (MRC Laboratory of Molecular Biology, University of Cambridge).

David Ish-Horowicz, affectionately known as ‘David Ish’ or just ‘Ish’ (‘man’ in Hebrew), died on 19 July 2024. He was one of the early pioneers of the application of molecular genetics to the understanding of pattern formation during development of the fruit fly Drosophila and the mechanism of segmentation in mammals. He will be sorely missed by many colleagues and generations of successful scientists he trained and mentored, as well as by his close family and friends. He set a powerful example of how to be an outstanding and influential scientist, while retaining his humility and humanity. David and his colleagues made seminal discoveries of genes that regulate segmentation and patterning in early Drosophila embryos, and the role of mRNA localization in the process. He cloned the Drosophila pair-rule gene hairy and characterized its molecular function as a helix-loop-helix protein, as well as the mechanism and function of its apical mRNA localization in the blastoderm embryo. Later, his lab cloned key vertebrate orthologues of Drosophila pattern formation genes, including Delta, the Notch ligand, elucidating the mechanism of segmentation in mammals. He was deservedly recognized for his important contributions by his election to the European Molecular Biology Organization (EMBO) in 1985, to the Royal Society in 2002 and by being awarded the Waddington Medal (the premier award from the British Society for Developmental Biology) in 2007.

David was part of a new wave of inspired scientists in the 1970s, who pioneered the cloning of genes previously only known through the effect on the organism of deleting or mutating them. This was the so-called ‘molecular biology revolution’, and was one of the most important technical innovations in biology. In modern times, cloning genes seems rather trivial, as we can now sequence a whole genome with ease for only a few hundred GBP. But in the 1970s, cloning a single gene was a major undertaking, requiring a single researcher to work for several years to achieve just that. Drosophila was the first complex multicellular organism in which cloning was applied at a large scale by the community to make revolutionary discoveries, leading to the award of a Nobel prize in 1995. David was part of the effort that followed the work underpinning the award of the Nobel prize. The overarching goal was to address one of the major mysteries in developmental biology: how a whole organism, with its numerous cell types and complex tissues and organs, can develop from a set of limited genetic instructions, starting with only a single simple cell the fertilized egg. The cloning in Drosophila of genes (such as hairy) that were key to this process was an important step, not only because it began to answer the question of how flies develop from a fertilized egg, but also because the same genes turned out to play very similar roles in mammals. This discovery was highly heretical as it had been believed since the 19th century that vertebrates and invertebrates developed their body patterns by completely distinct mechanisms. David and his colleagues played a leading part in cloning the mammalian homologues of some of the key genes discovered in flies, which turned conventional zoological thinking on its head.

Born in Manchester in 1948, the son of recently arrived Jewish immigrants, David attended Manchester Grammar School, then gained a degree in Natural Sciences at the University of Cambridge in 1966, specialising in chemistry. He stayed in Cambridge to carry out his PhD with Brian Clark at the LMB (the MRC Laboratory of Molecular Biology), completing his thesis in 1973 on the subject of tRNA in E. coli. David then moved to Basel (Switzerland) to Walter Gehring's laboratory at the Biozentrum, having been awarded an EMBO Long Term Fellowship. His PhD and postdoc were formative years for David. He not only worked on the molecular mechanisms underlying the heat-shock response, but also worked closely with a number of now famous scientists, including Gerry Rubin, Spyros Artavanis-Tsakonas, Christiane Nüsslein-Volhard and Eric Wieschaus. David established close life-long friendships with all four leaders and many others – a testament to his ability to establish intense and deep scientific bonds, and profound scientific dialogues with a diverse range of colleagues. Other key scientific and personal relationships that David established early on in his career included those with Trudi Schüpbach, Ruth Lehmann, Ruth Steward, Anne Ephrussi, Daniel St Johnston and Robert Singer, leading scientists and some of the leading lights in the RNA localisation community. The details of David's career are beautifully documented elsewhere by his nephew Jonathan Ish-Horowicz (Ish-Horowicz, 2024) and by Phil Ingham (Ingham, 2024a,b), one of David's earliest postdocs who went on to have a lab next door to David at the Developmental Biology Unit in Oxford.

Rather than recounting David's scientific achievements, I would like to focus on my personal reflections on his unique approach to science and scientific friendship, from which I strongly feel we all have a lot to learn. I was truly devastated at David's passing this year, but I was not alone. His funeral in July was a moving and positive occasion, attended by a large gathering from the scientific community, and by friends and family, all of whom adored and admired David. He was an outstanding scientist, of course, but perhaps the key to his popularity was his lack of ego, his sense of humour and his charming eccentricities, coupled with a deep commitment to scientific discourse, friendship and mentoring. At the funeral, a number of scientists, as well as family and friends, gave moving and humorous eulogies to David, recalling their deep relationship with affection. David inspired and trained several generations of influential scientists right up to last year, as he continued to be an active scientist more than 10 years after his official retirement date, including during the first period of his illness.

David's secret to successfully training the next generation involved an intensive period of initial training at the bench, while maintaining equally intense intellectual discourse. Yet he was a master at leaving his lab members to choose their own paths. This was certainly my experience. When I joined his lab in Oxford as a PhD student, David immediately sat me down for a long lecture on how to clone DNA. It started in the afternoon, and we had such a great time together that it went on long into the night. He was always interested in new and emerging technologies, as exemplified by one of his early highly cited papers on rapid and efficient cosmid cloning (Ish-Horowicz and Burke, 1981). I, too, always loved technology development, so David and I became instant friends, bonded by intense scientific curiosity, discourse on blue sky frontiers and technological risk taking. David and I continued a lifelong close friendship that was scientific and personal in equal measure. But I was not unique. David has had a very close scientific relationship with a number of other scientists, among others, Phil Ingham, Julian Lewis (Martin and Ish-Horowicz, 2014), Paul Martin and Nic Tapon. Paul Martin was a contemporary of mine as a PhD student in Julian Lewis' lab next door to ours in Oxford. Paul and David's scientific and personal friendship was so deep that David and Ros Diamond (David's wife) went on joint family holidays with Paul, Kate Nobes and their two daughters for many years until David's recent illness prevented him from travelling. David had a wonderful way with small children. When my own grown-up children heard of David's death they recounted fondly how he used to purr when they touched his beard.

David had a uniquely strong scientific intuition, which explains why so many famous scientists sought his time for profound and inspirational discussions. A key part of his character was that he always cared about other people's work and was willing to commit a lot of time, often without any personal gain, to furthering their thinking. He was very persuasive, with his charming, quirky discourse and ability to always see the best in people. When I joined his lab in 1986, David suggested I should work on the mechanism and function of mRNA localisation, at the time a very obscure phenomenon with almost no prior literature. David felt it would be important in the future, and persuaded me, with little evidence, to focus exclusively on this topic for my PhD. I have continued to work on mRNA localisation until today, as did an outstanding postdoc, Simon Bullock (now a group leader at the LMB in Cambridge), who joined David's lab after me to work on mRNA localisation.

David was unusually tolerant and supportive of his lab member's extra-curricular activities. He allowed me to take 7 weeks off at the end of the first year of my PhD to make a short documentary in Tibet. It was only years later that I understood why David was enlightened enough to allow me to do such an unconventional activity for a scientist. David explained to me that when he was a graduate student at the LMB in Cambridge, he spent his first year almost exclusively playing bridge for the University team and achieving very little scientifically. He still went on to produce a fine PhD thesis and publication. He believed and said explicitly that it takes all sorts to be a successful scientist, and people have to be given time to mature and find their own way.

David had many interests outside science and was an avid reader of Mac (computer) magazines as well as ‘Which?’. Everyone around him learnt many things from him through his passion and enthusiasm: where the best restaurants were, how to choose a good hi-fi or, in my case, a passion for the long-standing BBC Radio 4 soap opera The Archers. When I first arrived in David's lab, it was compulsory to learn to touch type by playing a competitive video game involving zapping words that fall from the sky to gain points. I tended to play the game every day after lunch at around 2pm, when David used to turn The Archers on at full volume on a radio situated in the middle of the lab. He felt that inflicting this on the entire lab was part of their scientific education. At first, I used to leave the room in horror to avoid listening to annoying stories about fictional farming communities in middle England. But after a while, I too became addicted, and I have not managed to kick the habit to this day.

When David retired from Cancer Research UK (CRUK) in London, there was a huge gathering and associated scientific symposium to celebrate his life achievements, as indicated by the wall of signatures of the attending delegates (see word cloud). However, this was only a retirement from running his lab at CRUK; David did not leave science, and science did not leave him. His commitment to science was so great that he continued to be immersed in its pursuit, right up to his death. He first obtained a part-time appointment, 2 days a week at the Laboratory for Molecular Cell Biology at University College London, doing some lecturing and sharing an office with another distinguished emeritus scientist, Martin Raff, a long-time co-author of Molecular Biology of the Cell, together with Julian Lewis and others. Not content with this part-time employment, David had an honorary appointment at the Francis Crick Institute in London, where he spent 1 day a week at seminars, chatting and mentoring. The remaining 2 days, he spent in Oxford in my lab. This was a very unusual arrangement, but worked very well for me, for David and for several generations of my lab members. At first, David spent some time learning techniques in the lab and producing some interesting data. But he then found greater pleasure in attending lab meetings, and supervising and mentoring graduate students and postdocs, who all loved him. This was a very productive relationship for us all, as David was an author on a number of my papers from this period, contributing inspirational ideas, precision writing, as well as attending some conferences to talk about the work. Above all, he made a real difference to the scientific training and lives of numerous graduate students and postdocs who overlapped with him in my lab.

The final chapter of David's life was spent in his home in Oxford with Ros, once he became ill with an inoperable brain tumour. Ros was not only the love of David's life, she was also intimately involved with all his scientific friendships, despite not being a scientist herself. David admired Ros as an architect and was also a huge fan of her wonderful culinary creations, being such a foodie himself. Despite the increasing impact of the tumour, David retained his acuity and sense of humour, as did Ros through very difficult times. By this point I had just moved my lab to Glasgow, but I visited David several times in Oxford. I found it remarkable that, even on my last visit a few weeks before his passing, David was able to hold his own in an intense scientific conversation, as well as showing an interest in the work of others and their welfare. David Ish was unique in his human and friendly approach to science. He left an indelible positive mark on everyone who met him, and we all can learn to bring out the human side of our scientific practice by trying to emulate David. We will miss him dearly.