How serendipity shaped a life; an interview with John W. Saunders,Jr. by John F. Fallon

John W. Saunders Jr. is an outstanding contributor to the field of Developmental Biology. His analyses of the apical ectodermal ridge, discovery and study of the zone of polarizing activity, insights into cell death in development, and analytical studies of feather patterns are part of a legacy to developmental biology. The body of his published work remains central to the understanding of limb development and is a major reason for the premiere place that the developmental biology of limbs holds in our research and teaching today. Beyond these things known to nearly everyone, there is John's role as teacher that is equally impressive. His one-on-one style, in small groups or from the podium is engaging, encompassing, and above all else, enthusiastic about the study of the development of living things. His love of developmental biology comes through to students of all ages and is inspirational. And, of course, inimitable charm accompanies the substance of any interaction with John. He still teaches in the Embryology Course at MBL Woods Hole. Recent students say that hearing his lectures and his involvement in the laboratory are highlights of the course. His continued knowledge of science and delight in new advances is a model for students to follow and they recognize it. John Saunders is a scientist and educator par excellence. His contributions have stood the test of time. His personal interactions with colleagues and students have enriched their lives in innumerable ways, large and small. His is a lifetime of outstanding achievements. In this interview, he reflects on his six--going on seven--decades in science and his personal enjoyment of recent advances in Developmental Biology.     

Halcyon days with Bill Arnold

The circumstances that led to the discovery that plants luminesce after they are illuminated are described, as are other discoveries that would not have been possible were it not for the fortuitous association I had with my dear and most admirable friend, W.A. Arnold, to whom this special issue is dedicated.     

Lymphotoxin and TNF: How it all began—A tribute to the travelers

The journey from the discoveries of lymphotoxin (LT) and tumor necrosis factor (TNF) to the present day age of cytokine inhibitors as therapeutics has been an exciting one with many participants and highs and lows; the saga is compared to that in “The Wizard of Oz”. This communication summarizes the contributions of key players in the discovery of the cytokines and their receptors, the changes in nomenclature, and the discovery of the LT family’s crucial role in secondary and tertiary lymphoid organs. The remarkable advances in therapeutics are detailed as are remaining problems. Finally, special tribute is paid to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old.     

Molecular polymorphism: How much is there and why is there so much?

The evidence for genetic variation can be traced to Mendel's experiments: The discovery of the laws of heredity was made possible by the expression of segregating alleles. Since that time, the study of genetic variation in natural populations has been characterized by a gradual discovery of ever-increasing amounts of genetic variation. In the early decades of this century geneticists thought that an individual is homozygous at most gene loci and that individuals of the same species are genetically almost identical. Recent discoveries suggest that, at least in outcrossing organisms, the DNA sequences inherited one from each parent are likely to be different for nearly every gene locus in every individual; ie, that every individual may be heterozygous at most, if not all, gene loci. But the efforts to obtain precise estimates of genetic variation have been thwarted for various reasons.     

Discovering DNA: Friedrich Miescher and the early years of nucleic acid research

In the winter of 1868/9 the young Swiss doctor Friedrich Miescher, working in the laboratory of Felix Hoppe-Seyler at the University of Tübingen, performed experiments on the chemical composition of leukocytes that lead to the discovery of DNA. In his experiments, Miescher noticed a precipitate of an unknown substance, which he characterised further. Its properties during the isolation procedure and its resistance to protease digestion indicated that the novel substance was not a protein or lipid. Analyses of its elementary composition revealed that, unlike proteins, it contained large amounts of phosphorous and, as Miescher confirmed later, lacked sulphur. Miescher recognised that he had discovered a novel molecule. Since he had isolated it from the cells’ nuclei he named it nuclein, a name preserved in today’s designation deoxyribonucleic acid. In subsequent work Miescher showed that nuclein was a characteristic component of all nuclei and hypothesised that it would prove to be inextricably linked to the function of this organelle. He suggested that its abundance in tissues might be related to their physiological status with increases in “nuclear substances” preceding cell division. Miescher even speculated that it might have a role in the transmission of hereditary traits, but subsequently rejected the idea. This article reviews the events and circumstances leading to Miescher’s discovery of DNA and places them within their historic context. It also tries to elucidate why it was Miescher who discovered DNA and why his name is not universally associated with this molecule today. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

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Moulin-Quignon et Homo heidelbergensis. Contextes épistémologiques et enjeux taxinomiques

In 1863, when a human mandible was discovered in the quarry of Moulin-Quignon (Abbeville, Somme), it completed the demonstration of Jacques Boucher de Perthes (1788–1868) proving the existence of an ante-diluvian man. However, this discovery was quickly questioned and would eventually disqualify even the site itself and the industries it had delivered. The recent re-examination of these fossils brought to light in 1863 (one mandible) and 1864 (28 bones and teeth), now housed at the Muséum national d’Histoire naturelle (musée de l’Homme), has confirmed their attribution to Homo sapiens. In the light of current knowledge, this attribution is incompatible with the stratigraphic provenance of these anthropological remains, whose age is estimated between 670–650,000 years. In fact, direct radiocarbon dating of these bones dates them back to a historical period, between the 13th and 18th centuries, which confirms their intrusive nature in the deposit. In this paper, after describing the discovery and rediscovery of the site, we will question who is the man who could have been discovered at Moulin-Quignon. This will be the occasion for a review of human evolution, in the context of the taxonomic upheavals of the 1950s and 1960s, in Western Europe in the Middle Pleistocene, where recent discoveries attest to a significant variability among Homo heidelbergensis, some of which are already strongly involved in the Neanderthal lineage. This retrospective will voluntarily follow the course of paleo-antropological research throughout the 20th century in order to highlight, as discoveries are made, changes in paradigms and practices.     

Biological design — a neglected art

I ought now, perhaps, to offer a summary of what I have been trying to convey in this lecture — but I am haunted by the failure which attended an effort, by an eminent scholar of this city, to do something of the same kind many years ago. Sir John Sheppard, Provost of King's, once gave a public lecture during one of the University's ceremonial gatherings. His subject was the Trojan War. The large audience sat spellbound in admiration of his depth of insight, breadth of knowledge and grasp of detail. As he was leaving after the meeting, a young man came up to him and explained that he was a graduate studuent engaged in research on the economic consequences of the Trojan War. He had, however, been spellbound by the lecture and had been too engrossed to write anything down. Would Sir John be so kind as to lend him his notes so that he could make a summary of the lecture? “My dear chap”, said Sheppard, “I'd be delighted; here are my notes — use them as you wish and let me have them back whenever they have served your purpose”. So saying he handed the young man a postcard on which was written: Agamemnon — Achilles — Agamemnon.I hope that members of the audience won't mind if I leave them to make their own summary of my remarks to which they have listened so patiently this evening.     

The Living State

As biologists we can contribute to quantum chemistry only by clearing up the mechanism of some of the biological processes, thereby opening the way to their quantum chemical analysis. We have tried to do this by isolating and identifying the central catalysts of those processes. One of us (A.S.-G.) studied biological oxidations first in the plants that turn dark on exposure to air such as potatoes, apples and pears. He found the central catalyst of these oxidations to be a catechol derivative that oxidized to o-diquinol which forms dark complexes with protein. After this, he turned to the oxidation of plants that do not turn dark and identified two catalysts, one of which was ascorbic acid, the other succinic acid. His third problem was the generation of motion, the function of muscle. This study led to the discovery of a new protein, which he discovered with I. Banga at the University of Szeged, Hungary. They called it “actin” because it made the inactive myosin act to contract. This discovery has an unusual history. It was never published because just when they were about to publish, Hitler occupied Hungary and Szent-Gyorgyi had to disappear “underground” separated from Banga and science. Our present interest is in the “Living State”, one of the most important phenomena, the central substance of which seems to be methoxyhydroquinone (1–6).     

Strasburger’s legacy to mitosis and cytokinesis and its relevance for the Cell Theory

Eduard Strasburger was one of the most prominent biologists contributing to the development of the Cell Theory during the nineteenth century. His major contribution related to the characterization of mitosis and cytokinesis and especially to the discovery of the discrete stages of mitosis, which he termed prophase, metaphase and anaphase. Besides his observations on uninucleate plant and animal cells, he also investigated division processes in multinucleate cells. Here, he emphasised the independent nature of mitosis and cytokinesis. We discuss these issues from the perspective of new discoveries in the field of cell division and conclude that Strasburger's legacy will in the future lead to a reformulation of the Cell Theory and that this will accommodate the independent and primary nature of the nucleus, together with its complement of perinuclear microtubules, for the organisation of the eukaryotic cell.     

Tumor microenvironment indoctrination

Nastiness of cancer does not only reside in the corruption of cancer cells by genetic aberrations that drive their sustained proliferative power—the roots of malignancy—but also in its aptitude to reciprocally sculpt its surrounding environment and cellular stromal ecosystem, in such a way that the corrupted tumor microenvironment becomes a full pro-tumorigenic entity. Such a contribution had been appreciated three decades ago already, with the discovery of tumor angiogenesis and extracellular matrix remodeling. Nevertheless, the recent emergence of the tumor microenvironment as the critical determinant in cancer biology is paralleled by the promising therapeutic potential it carries, opening alternate routes to fight cancer. The study of the tumor microenvironment recruited numerous lead-scientists over the years, with distinct perspectives, and some of them have kindly accepted to contribute to the elaboration of this special issue entitled Tumor microenvironment indoctrination: An emerging hallmark of cancer.     

How does the histone code work?

Patterns of histone post-translational modifications correlate with distinct chromosomal states that regulate access to DNA, leading to the histone-code hypothesis. However, it is not clear how modification of flexible histone tails leads to changes in nucleosome dynamics and, thus, chromatin structure. The recent discovery that, like the flexible histone tails, the structured globular domain of the nucleosome core particle is also extensively modified adds a new and exciting dimension to the histone-code hypothesis, and calls for the re-examination of current models for the epigenetic regulation of chromatin structure. Here, we review these findings and other recent studies that suggest the structured globular domain of the nucleosome core particle plays a key role regulating chromatin dynamics.     

Alexander von Humboldt and the hand-beast: A contribution to palaeontology from the last universal scholar

Despite a certain interest in the discipline, Alexander von Humboldt did not personally contribute much to the progress of palaeozoology. His most remarkable input derived from a communication about hand-like archosaur footprints from the Buntsandstein at the very acme of the important controversy that the discovery of these fossils generated (1835). Humboldt thought that the tracks were probably from a possum-like marsupial, but he did not discount that they could be from a primate. This study is characterized by its superficiality: both the anatomical comparisons and the considerations of the functional morphology of locomotion are very poor. Its effect on the scientific community proved about nil, in both the short and the long run, and Humboldt may himself have doubted his initial conclusions in later years. Nevertheless, in contrast with some contemporaneous renowned geognosts, he had no hesitation from the beginning that the footprints were genuine. He also did not hesitate to weaken the belief of the time on the timing of the succession of organised beings in geological ages, naturally without lapsing into “antiprogressionism”.     

On whose shoulders we stand - the pioneering entomological discoveries of Károly Sajó

The excellence of Károly Sajó as a researcher into Hungary’s natural history has been undeservedly neglected. Yet he did lasting work, especially in entomology, and a number of his discoveries and initiatives were before their time.Born in 1851 in Győr, he received his secondary education there and went to Pest University. He taught in a grammar school in 1877–88 before spending seven years as an entomologist at the National Phylloxera Experimental Station, later the Royal Hungarian State Entomological Station. Pensioned off at his own request in 1895, he moved to Őrszentmiklós, where he continued making entomological observations on his own farm and wrote the bulk of his published materials: almost 500 longer or shorter notes, articles and books, mainly on entomological subjects.Sajó was among the first in the world to publish in 1896 a study of how the weather affects living organisms, entitled Living Barometers. His Sleep in Insects, which appeared in the same year, described his discovery, from 1895 observations of the red turnip beetle, Entomoscelis adonidis (Pallas, 1771), of aestivation in insects – in present-day terms diapause.It was a great loss to universal entomology when Sajó ceased publishing about 25 years before his death. His unpublished notes, with his library and correspondence, were destroyed in the World War II. His surviving insect collection is now kept in the Hungarian Natural History Museum, Budapest.     

DNA testing and domestic dogs

There are currently about 80 different DNA tests available for mutations that are associated with inherited disease in the domestic dog, and as the tools available with which to dissect the canine genome become increasingly sophisticated, this number can be expected to rise dramatically over the next few years. With unrelenting media pressure focused firmly on the health of the purebred domestic dog, veterinarians and dog breeders are turning increasingly to DNA tests to ensure the health of their dogs. It is ultimately the responsibility of the scientists who identify disease-associated genetic variants to make sensible choices about which discoveries are appropriate to develop into commercially available DNA tests for the lay dog breeder, who needs to balance the need to improve the genetic health of their breed with the need to maintain genetic diversity. This review discusses some of the factors that should be considered along the route from mutation discovery to DNA test and some representative examples of DNA tests currently available.     

How Cells Activate ATR

ATR is a critical upstream regulator of checkpoint responses to incompletely replicated and damaged DNA. However, it had not been understood how the kinase activity of ATR is switched on during checkpoint responses. TopBP1 and its homologs are necessary for both DNA replication and checkpoint control. A recent report from this laboratory demonstrated that TopBP1 functions as an activator of ATR. It had been known that TopBP1 accumulates at sites of replicative stress and DNA damage. Thus, interaction of ATR with a critical protein at stalled replication forks and sites of DNA damage triggers its activation. This finding helps to explain how aberrant DNA structures in the genome induce ATR-dependent signaling processes.     

Roy Walford and the immunologic theory of aging

Roy Walford died on April 27, 2004, at the age of 79. His contributions to gerontological research in such diverse areas as caloric restriction, genetics of lifespan, immunosenescence, DNA repair and replicative senescence were truly remarkable in their depth and innovation. Significantly, most of the areas that he pioneered during his illustrious research career remain the "hot" areas of current gerontological research. In this sense, he has achieved the most important type of immortality. His death was a major personal and professional loss to numerous scientists within the gerontological community. In launching this new journal on Immunity and Ageing, it is highly fitting, therefore, to remember him on the anniversary of his death by briefly reviewing the contributions of Roy Walford to this important facet of gerontology. Indeed, it was Roy who actually first coined the commonly used term "immunosenescence".     

Focus: 50 Years of DNA Repair: The Yale Symposium Reports: Early Days of DNA Repair: Discovery of Nucleotide Excision Repair and Homology-Dependent Recombinational Repair

The discovery of nucleotide excision repair in 1964 showed that DNA could be repaired by a mechanism that removed the damaged section of a strand and replaced it accurately by using the remaining intact strand as the template. This result showed that DNA could be actively metabolized in a process that had no precedent. In 1968, experiments describing postreplication repair, a process dependent on homologous recombination, were reported. The authors of these papers were either at Yale University or had prior Yale connections. Here we recount some of the events leading to these discoveries and consider the impact on further research at Yale and elsewhere.     

Translational science: past, present, and future

The concept of translational science is at least 15 years old. However, in its most recent incarnation, it represents the identification of a funding category designed to encourage academic participation in a critical stage of the drug discovery and product development process. It is hoped that this will make the process both shorter and more efficient. In this review, the author first considers the historical development of the pharmaceutical R&D process. The place of translational science in the process, the scientific techniques involved, and aspects of the business environment necessary for its success are then considered. Translational science does not displace preclinical development. Both concepts are relevant to the paramount importance of successfully and expeditiously bridging the gap between preclinical science and clinical testing, "from bench to bedside." Translational science is particularly likely to stimulate biomarker research in the universities and related business community and will probably give a modest boost to early clinical testing and commercialization of discoveries within the academic setting. Whether there will be a consequent improvement in the quality and efficiency of the overall process remains to be seen.     

Huntington disease--another chapter rewritten.

To those of us who began life when humans had 48 chromosomes and who began working in genetics when the (by then 46) chromosomes had no bands and chromosome 4 could not reliably be distinguished from chromosome 5, the mere ability to diagnose and correlate the clinical phenotypes of genetic disorders with their molecular genotypes is a source of continuing astonishment and pleasure. Indeed, molecular genetic analysis of neurogenetic disorders such as Huntington disease (HD) has provided a steady stream of challenges and surprises to all who believe the genetic principles that they were taught about these disorders. The paper by Rubinsztein et al. in this issue of the journal highlights yet another surprise, which was adumbrated even in the initial paper announcing the discovery of the HD gene: incomplete penetrance of HD gene mutations.