The birth of death, 30 years ago

Nearly 30 years ago, a few young scientists (let’s call them, with a lack of imagination, G, M and D) were pottering around on the periphery of science when they became aware of a type of cell death called apoptosis that was becoming fashionable. By phone (landline, of course) they discussed this, to them, new development – could it even enhance science. So they decided to convene a meeting, inviting some of the big names in cell death. None of the big names would come unless the meeting could be held somewhere exotic. So GDM decided on small hilltop town called Erice – a cobbled village of stunning views and ancient Greek temples, a history that has seen the influence of historic empires, currently a worldwide international school for physics (Ettore Majorana Foundation and Center for Scientific Culture; https://ettoremajoranafoundation.it). And the big shots came and the meeting was a great success and proved to be highly enlightening for GDM.

The participants were housed in a monastery – which wasn’t quite the ideal setting for GDM – a tavern or jazz club would have suited better. But in the paved garden where once celibate monks strolled, stood two huge barrels of Marsala wine – one dry, one sweet. And, of course, it was the custom, after a dinner of pasta and wine, to adjourn to the garden with its barrels and, among cell death cognoscenti and ignoramuses to engage in lively discussions about politics, sex, and occasionally science. We have no memory now of who amongst the cognoscenti said that the problem with the cell death field was that there is no dedicated journal, nor which of the three boys amongst G, M and D, said “OK, we’ll start one”. But having said that, we had no choice but to proceed.

So with a great deal of support from friends and colleagues acquainted to the publishing world, and having regained sobriety, we embarked on our journey. It may be significant that the first company to take on this unknown journal had just sold the Lancet, Fig. 1. Perhaps they saw in us the potential to restore their profits. To our positive surprise, Cell Death and Differentiation achieved an initial impact factor of 4.25 (and GDM still cherish the celebratory T shirt). As you all know, the journal’s metrics are now hovering around triple that. Fine, we may have inappropriately sown a seed in that monastery, but it is you all, the authors, editors and reviewers who have not only helped CDD survive, but flourish. A large Marsala to you all – and many many thanks.

Fig. 1: Issue number 1, 1994.

Cover of the the first issue, with the original editorial board and the three editorial offices in US, UK and Italy.

What better occasion, then, than this 30th anniversary with an entire year of celebrations, and what better venue than this, to celebrate the ultimate recognition of the crucial importance of apoptosis in biology. For it will be here, at Villa Mondragone in Rome in 1582, that Pope Gregorius XIII replaced the old inaccurate Julian (Cesarean) calendar with the still sun-based but far more reliable Gregorian version that we still use today. The focus of this gathering will be on cancer, precision medicine and artificial intelligence. The starting point will be 45 years since the identification of p53 by Levine [1] and Lane [2] in 1979. That work led to an immense literature laying a significantly improved understanding of cancer development. Nonetheless, still a large number of queries remain unexplored and need clarification. Hence, the original authors, as well as the new aficionados, will merge their experience with the new impact of virtual science. We plan also at least another international meeting in Suzhou, China, to celebrate the 40^th anniversary of a landmark event: the cloning of the T Cell Receptor (TCR). Indeed, in a few months it will be 40 years since the identification and cloning of the TCR. The hunt for the gene encoding the TCR, “The Holy Grail” of immunology, was a long and difficult task solved by Mak [3] and Davis [4], that then paved the way for numerous pivotal advancements, including CAR-T cell therapy [5]. Although CDD has published few papers on an active ancient and physiological cell death mechanism - the killing by cytotoxic T cells (Tc) of infected targets - largely because of the many established and specialized immunological journals - the cloning of the TCR was an enormous step towards understanding and eventually manipulating this process. With further recent developments in how Tc may also kill autologous cancer cells, we may start persuading our Tc (CAR-T, TCR-T) to eliminate breast or prostate cancer without the need for surgery and radiotherapy, and even to eliminate autoreactive immune cells that cause autoimmune diseases. Finally, we also hope to celebrate the identification of Bcl-2, 40 years ago. More meetings as well as reviews and individual celebrations will be organized by several editors to highlight crucial work performed in the last 30 years of science.

The ikigai for CDD, since its first conception, has been the advancement of quality science. This is something that gives CDD a sense of purpose, a reason for living, and a commitment to serving both authors and readers. On this, it has been a unique privilege for us to interact with excellent scientists, helping them to tackle complex problems, to navigate unchartered waters. The primu movens was cell death, but in time, the scope became broader, well integrated in the broader domain of cell biology, Fig. 2. Indeed, it was a unique fantastic privilege to witness, engage, and contribute to a forum of discussion to the golden age of programmed cell death, Fig. 3. Over time, the realization emerged that a single journal was not enough, said D, so GDM decided that it was time to move from basic science into disease. And here we said, let’s go with a sister journal. But then two were not sufficient, and GDM went into the third journal, thinking that the time was ready for pharmaceutical discovery. Now, although some initial questions are still debated, Fig. 4, all three journals, are flourishing and progressing with about eight thousand submissions annually. In the last 30 years, significant papers have been published, Tables 1–3, bringing all three journals at a respected standing, well ranked among classic biomedical journals, Table 4. Since our early days we liked to say that CDDpress, encapsulating all three journals, is where the “the impact is a fact, not a factor”.

Fig. 2: Topics maps.

Visualization map of topics score for Cell Death Differentiation (upper panel) and Cell Death Disease (lower panel). Subjects are distinct for the two journals, with a much wider interest than strict “apoptosis”, especially for the second journal that results a broad cell biology journal. We thank Vicky Johnson (Wiley) for supplying the data via Keyword Plus Cloud.

Fig. 3: Timeline of cell death.

Evolution of the field, starting from the early anecdotal observation by the neurobiologist Rita Levi-Montalcini (1942), the embryologist Gluckmann (1951), the hematologist Bessis (1955), and the biologist Tata (1960) clearly described distinct morphological phases of cell death. In the 1960s, working on insect development, Richard Lockshin recognized the coordinated death of sheets of cells – a process he termed Programmed Cell Death – and which he showed to be energy dependent and to require gene transcription. In 1966, John Saunders, in his review on ‘Death in embryonal systems’, was able to emphasize the central role of cell death in molding organisms during development [17]. A little later, Kerr, Wyllie, and Currie described a similar cell death morphology in mammals, but this time affecting individual cells within a tissue, and for which they coined the term apoptosis [18]. But something clicked in the late ‘80 with the pivotal work of Bob Horvitz on C. elegans and the discovery of essential genes like Ceds, p53, TCR, Bcl2 and caspases, when GDM organized a crucial meeting in Erice (Sicily) in 1992, when it was decided to give birth to death as a scientific journal [19]. We apologize for the absence of major contributions and contributors and latest evolution, like pyroptosis, necroptosis, ferroptosis, that we plan to expand during this coming year. At present, an explosion of scientific papers on cell death has nearly reached the incredible level of 3% of the entire scientific literature published every year, forcing us to follow CDD (1994) with two sister journals, CDDisease (2010) and CDDiscovery (2015).

Fig. 4: Timeline of cell death.

‘In nomen omen’ (Titus Maccius Plautus), more precisely ‘Nomina sunt omina’ [names are extremely important]. Introducing the term ‘programmed cell death’ (instead of dismantling of degradation), and more specifically ‘apoptosis’ was an inspired choice, stimulating curiosity and interest. However, names drag wanton significance with them, that should not influence science. Is death coming after life, or there is only one death (not for Red Blood Cells or Keratinocytes)? As discussed earlier [19], the common sense of death ethical issues (altruism, counter-evolution, myths) as some effect on our science. Currently new forms of death (necroptosis, pyroptosis, ferroptosis, ….) are expanding the interest, with distinct pathological application [20].

Table 1 Most cited CDD papers.

Table 2 Most cited CDDisease papers.

Table 3 Most cited CDDiscovery papers.

Table 4 Representative impact factors 2022.

Throughout the years, CDD has been the platform for numerous landmark publications, impossible to remember all. The first description of caspase 14 was originally reported by Peter Vandenabeele [6]. Juerg Tschopp – whose contributions are now celebrated with a dedicated CDD prize, defined the molecular mechanisms underlying the activation of the NALP3 inflammasome, influenced by low intracellular potassium concentration [7]. The identification of the tumorigenic population that sustains lung cancer contributes significantly to the molecular understanding and development of effective therapies [8]. Later on, Gibson defined the role of superoxide in autophagy [9]. Accordingly, autophagy formation as a cellular defence mechanism against polyQ72-inducing ER-stress-mediated cell death by degrading polyQ72 aggregates involves PERK/eIF2α phosphorylation inducing LC3 conversion [10]. Aaron Ciechanover, in collaboration Gerry Cohen, presented some of their always pivotal work on proteolysis [11]. Doug Green also has been a regular afficionado, reporting several exciting data on mitochondrial membrane permeabilization [12, 13]. More recently Andreas Strasser reported several significant findings work on lymphomagenesis [14,15,16]. While space constraints prevent us from acknowledging each contributor individually, we sincerely apologize for not providing the deserved tribute to all other landmark discoveries and their authors.

These interactions in the scientific community allowed the establishment of two prestigious awards. Both Prizes recognize active investigators who have conducted innovative, paradigm-shifting research that is worthy of significant and broad attention in the broader field of cell death and who have the capacity to transform our field. The CDD AWARD recipients include Andreas STRASSER (2015), Tak Wah MAK (2016), Shige NAGATA (2017), Karen VOUSDEN (2018), Carol PRIVES (2019), Arnie LEVINE (2020), Ivan DIKIC (2021), Marie HARDWICK (2022), Charles SWANTON (2023) and Junying YUAN (2024). The CDD Jurg Tschopp PRIZE was awarded to Fabio MARTINON (2015), Peter VANDENABEELE (2016), Doug GREEN (2017), Vishva DIXIT (2018), Xiaodong WANG (2019), David VAUX (2020), Peter Heinrich KRAMMER (2021), Klaus-Michael DEBATIN (2022), Manolis PASPARAKIS (2023) and Brent R. STOCKWELL (2024).

Reflecting on our past achievements, we now turn our gaze to the horizon, but what is next? The landscape science and consequently scientific communication is rapidly evolving. From the steam engine approach of 30 years ago, new challenges at a breakneck speed are ahead. The pace is even accelerating. These challenges include for example AI, virtual science, rapidity of discovery, opening of scientific communities in the east such as in China and India, social media, data sharing and accessibility, and, finally, the pervasive threat of misinformation. We need to develop together new approaches and integration among journal staff, editorial board members, advisors, reviewers and, most important, authors and readers. In fact the journal exists for you, and we hope the new CDD will be your voice. Whilst we owe a huge thank to our staff and collaborators, without who the journal would have never been so successful, our future commitment is for authors and readers.

This anniversary is not just a celebration of our successful past, but a pledge for a future filled with commitment and innovation.

So far, it has been a great journey.

We owe a huge thanks!