Rho激酶抑制剂在神经退化性疾病上的应用

Rho激酶,又称Rho相关的卷曲蛋白激酶,是一类丝氨酸/苏氨酸蛋白激酶,被发现为小G蛋白Rho的下游作用底物。由于Rho激酶活性涉及神经细胞的功能,而且越来越多的研究表明抑制Rho激酶的活性在数种神经退行性疾病包括帕金森病、阿尔茨海默病、亨廷顿病、多发性硬化症,和肌萎缩性侧索硬化症等的实验模式中都有明显的效果。因此,Rho激酶已成为针对治疗神经性退化性疾病的一个热门标靶蛋白。本文探讨Rho激酶抑制剂在神经退化性疾病上的应用及发展,使神经退行性疾病能进一步提升治疗和在应用上的水平。     

The Problem of the "Formative" Elements of Consciousness in the Activity Theory of the Mind

The problem of the structure and psychological mechanisms of consciousness has a rich history, to which M. M. Bakhtin, G. G. Shpet, L. S. Vygotsky, and, later, A. N. Leont'ev and S. L. Rubinshtein all made significant contributions. It is our purpose in the present article to discuss only one aspect of this problem: the structure of individual consciousness. Pursuing the line of research delineated by Vygotsky, Leont'ev (1977) posed some cardinal questions: Of what is consciousness composed? How does it arise? What are its components? He called the latter the "formative elements" of consciousness. According to Leont'ev, there are three such "forming" elements: the sensory fabric of perception (or of an image), meaning, and sense. The inclusion of the sensory fabric in the structure of consciousness along with ostensive meaning and sense was a definite step forward along the path toward the ontologization of conceptions of consciousness.¹ But I think that individual consciousness construed in this way is still insufficiently ontological. Leont'ev's three "formative elements" do not completely account for the connection between consciousness and being (see M. M. Bakhtin, for whom consciousness "participates" in being and is essential for life). One might even reproach Leont'ev for a certain inconsistency: activity, although it is the source of consciousness, is itself not one of its "formative elements." Of course, he could answer this reproach by saying that the "formative elements" are structural elements, constituents, not generative elements. However, it seems to me that the distinction between constitutive and generative is very, very relative in any analysis of living consciousness, which is continually in the process of being constructed.     

XII. Something on Vision from Within

Earlier I attempted to show that Shpet was able to penetrate behind the external form of the word through its shell, which in itself is by no means simple, into its inner form, which proved to be immeasurably more complex than the external form. For me it still remains a mystery: How was he able to penetrate into the "living soul" of the word? Of course, he was helped in this by encyclopedic knowledge. He was, after all, a philosopher, a linguist, a psychologist, and an art cognoscente; he completed two years at the physics and mathematics and the history and philology departments of Kiev University. And Shpet also knew seventeen (!) languages. It seems to me that Shpet saw language (languages) and the word from within. He blended into the word rather than manipulated it. "Vision from within" is not a fantasy of my own. Goethe, who in the words of Ralph Waldo Emerson could see with his every pore, knew how to see from within. Ortega y Gasset in 1932 published a special article on this subject: "Goethe's vision from within." What Daniil Kharms saw from within was the absurd.     

Raymond Gosling: the man who crystallized genes

On April 25th 1953, three publications in Nature forever changed the face of the life sciences in reporting the structure of DNA. Sixty years later, Raymond Gosling shares his memories of the race to the double helix.It has not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.James D Watson and Francis HC Crick [1]By including this statement in their April 25th 1953 Nature article describing a model for the structure of DNA, Watson and Crick made one of the great understatements in history. In that moment, the seeds for the double helix''s infamy - alongside the names ''Watson'' and Crick'' - were sown. Lesser known outside scientific circles is that this article did not include one iota of experimental data: Watson and Crick, who were based at the University of Cambridge''s Cavendish laboratory, contributed deductive reasoning alone to the double helix model, albeit reasoning of an undoubtedly Nobel Prize-worthy standard. Instead, as has now been described many times, the model relied on X-ray diffraction data obtained by others, at King''s College, and these data did not reach Watson and Crick by entirely wholesome means [2]. To add to the insult, Watson and Crick''s report of the double helix did not fully credit the work of King''s as being essential to the construction of their model, although the King''s team did enjoy co-publication of their data alongside the double helix article, in the form of two articles in the same issue of Nature [3,4]. One of these articles described the X-ray diffraction work performed by senior researcher Rosalind E Franklin, together with PhD student Raymond G Gosling, and contained the highest quality diffraction patterns yet achieved for DNA [3]. It was these data that had proved invaluable in Watson and Crick''s quest for the double helix.Earlier still, before Franklin arrived at King''s, Gosling had achieved a major breakthrough in the search for DNA''s structure when he became the first person to crystallize genes, under the guidance of Maurice Wilkins, who was the lead author of the other King''s article to accompany Watson and Crick''s model [4].Watson published his controversial memoir of the discovery, aptly named ''The Double Helix'', in the 1960s [5], and in doing so propelled the story to worldwide fame, establishing DNA''s structure as an icon of science in the popular imagination. However, events were relayed in Watson''s book very much from his own point of view and at times, it has been argued, even verged on the fictitious.Aside from Watson, Ray Gosling is the only surviving member of the select group of seven scientists to feature as an author on one of the three Nature articles. Gosling and his wife, Mary, were kind enough to welcome Genome Biology into their home, where he shared with us his perspective of the events of 60 years ago.Elsewhere, Genome Biology has marked the anniversary by canvassing our Editorial Board for their opinions on the most important advances in the field since 1953 [6].     

Did Osler suffer from "paranoia antitherapeuticum baltimorensis"?: A comparative content analysis of The Principles and Practice of Medicine and Harrison's Principles of Internal Medicine, 11th edition

One of the most important legacies of Sir William Osler was his textbook The Principles and Practice of Medicine. A common criticism of the book when it was first published was its deficiency in the area of therapeutics. In this article, the 1st edition of The Principles and Practice of Medicine is compared with the 11th edition of Harrison''s Principles of Internal Medicine. The analysis focuses on the treatment recommendations for 4 conditions that were covered in both books (diabetes mellitus, ischemic heart disease, pneumonia and typhoid fever). Osler''s textbook dealt with typhoid fever and pneumonia at greater length, whereas Harrison''s placed more emphasis on diabetes mellitus and ischemic heart disease. Notwithstanding Osler''s reputation as a therapeutic nihilist, the 2 books devoted equivalent space to treatment (in terms of proportion of total sentences for the conditions). For all conditions except ischemic heart disease, Osler concentrated on general measures and symptomatic care. Throughout Osler''s textbook numerous negative comments are made about the medicinal treatment of various conditions. A more accurate statement about Osler''s therapeutic approach was that he was a "medicinal nihilist." His demand for proof of efficacy before use of a medication remains relevant.     

From discovering to understanding

Friedrich Miescher''s attempts to uncover the function of DNAIt might seem as though the role of DNA as the carrier of genetic information was not realized until the mid-1940s, when Oswald Avery (1877–1955) and colleagues demonstrated that DNA could transform bacteria (Avery et al, 1944). Although these experiments provided direct evidence for the function of DNA, the first ideas that it might have an important role in processes such as cell proliferation, fertilization and the transmission of heritable traits had already been put forward more than half a century earlier. Friedrich Miescher (1844–1895; Fig 1), the Swiss scientist who discovered DNA in 1869 (Miescher, 1869a), developed surprisingly insightful theories to explain its function and how biological molecules could encode information. Although his ideas were incorrect from today''s point of view, his work contains concepts that come tantalizingly close to our current understanding. But Miescher''s career also holds lessons beyond his scientific insights. It is the story of a brilliant scientist well on his way to making one of the most fundamental discoveries in the history of science, who ultimately fell short of his potential because he clung to established theories and failed to follow through with the interpretation of his findings in a new light.…a brilliant scientist well on his way to making one of the most fundamental discoveries in the history of science […] fell short of his potential because he clung to established theories…Open in a separate windowFigure 1Friedrich Miescher (1844–1895) and his wife, Maria Anna Rüsch. © Library of the University of Basel, Switzerland.It is a curious coincidence in the history of genetics that three of the most decisive discoveries in this field occurred within a decade: in 1859, Charles Darwin (1809–1882) published On the Origin of Species by Means of Natural Selection, in which he expounded the mechanism driving the evolution of species; seven years later, Gregor Mendel''s (1822–1884) paper describing the basic laws of inheritance appeared; and in early 1869, Miescher discovered DNA. Yet, although the magnitude of Darwin''s theory was realized almost immediately, and at least Mendel himself seems to have grasped the importance of his work, Miescher is often viewed as oblivious to the significance of his discovery. It would be another 75 years before Oswald Avery, Colin MacLeod (1909–1972) and Maclyn McCarthy (1911–2005) could convincingly show that DNA was the carrier of genetic information, and another decade before James Watson and Francis Crick (1916–2004) unravelled its structure (Watson & Crick, 1953), paving the way to our understanding of how DNA encodes information and how this is translated into proteins. But Miescher already had astonishing insights into the function of DNA.Between 1868 and 1869, Miescher worked at the University of Tübingen in Germany (Figs 2,​,3),3), where he tried to understand the chemical basis of life. A crucial difference in his approach compared with earlier attempts was that he worked with isolated cells—leukocytes that he obtained from pus—and later purified nuclei, rather than whole organs or tissues. The innovative protocols he developed allowed him to investigate the chemical composition of an isolated organelle (Dahm, 2005), which significantly reduced the complexity of his starting material and enabled him to analyse its constituents.Open in a separate windowFigure 2Contemporary view of the town of Tübingen at about the time when Miescher worked there. The medieval castle housing Hoppe-Seyler''s laboratory can be seen atop the hill at the right. © Stadtarchiv Tübingen, Germany.Open in a separate windowFigure 3The former kitchen of Tübingen castle, which formed part of Hoppe-Seyler''s laboratory. It was in this room that Miescher worked during his stay in Tübingen and where he discovered DNA. After his return to Basel, Miescher reminisced how this room with its shadowy, vaulted ceiling and its small, deep-set windows appeared to him like the laboratory of a medieval alchemist. Photograph taken by Paul Sinner, Tübingen, in 1879. © University Library Tübingen.In carefully designed experiments, Miescher discovered DNA—or “Nuclein” as he called it—and showed that it differed from the other classes of biological molecule known at that time (Miescher, 1871a). Most notably, nuclein''s elementary composition with its high phosphorous content convinced him that he had discovered a substance sui generis, that is, of its own kind; a conclusion subsequently confirmed by Miescher''s mentor in Tübingen, the eminent biochemist Felix Hoppe-Seyler (1825–1895; Hoppe-Seyler, 1871; Miescher, 1871a). After his initial analyses, Miescher was convinced that nuclein was an important molecule and suggested in his first publication that it would “merit to be considered equal to the proteins” (Miescher, 1871a).Moreover, Miescher recognized immediately that nuclein could be used to define the nucleus (Miescher, 1870). This was an important realization, as at the time the unequivocal identification of nuclei, and hence their study, was often difficult or even impossible to achieve because their morphology, subcellular localization and staining properties differed between tissues, cell types and states of the cells. Instead, Miescher proposed to base the characterization of nuclei on the presence of this molecule (Miescher, 1870, 1874). Moreover, he held that the nucleus should be defined by properties that are related to its physiological activity, which he believed to be closely linked to nuclein. Miescher had thus made a significant first step towards defining an organelle in terms of its function rather than its appearance.Importantly, his findings also showed that the nucleus is chemically distinct from the cytoplasm at a time when many scientists still assumed that there was nothing unique about this organelle. Miescher thus paved the way for the subsequent realization that cells are subdivided into compartments with distinct molecular composition and functions. On the basis of his observations that nuclein appeared able to separate itself from the “protoplasm” (cytoplasm), Miescher even went so far as to suggest the “possibility that [nuclein can be] distributed in the protoplasm, which could be the precursor for some of the de novo formations of nuclei” (Miescher, 1874). He seemed to anticipate that the nucleus re-forms around the chromosomes after cell division, but unfortunately did not elaborate on under which conditions this might occur. It is therefore impossible to know with certainty to which circumstances he was referring.Miescher thus paved the way for the subsequent realization that cells are subdivided into compartments with distinct molecular composition and functionsIn this context, it is interesting to note that in 1872, Edmund Russow (1841–1897) observed that chromosomes appeared to dissolve in basic solutions. Intriguingly, Miescher had also found that he could precipitate nuclein by using acids and then return it to solution by increasing the pH (Miescher, 1871a). At the time, however, he did not make the link between nuclein and chromatin. This happened around a decade later, in 1881, when Eduard Zacharias (1852–1911) studied the nature of chromosomes by using some of the same methods Miescher had used when characterizing nuclein. Zacharias found that chromosomes, such as nuclein, were resistant to digestion by pepsin solutions and that the chromatin disappeared when he extracted the pepsin-treated cells with dilute alkaline solutions. This led Walther Flemming (1843–1905) to speculate in 1882 that nuclein and chromatin are identical (Mayr, 1982).Alas, Miescher was not convinced. His reluctance to accept these developments was at least partly based on a profound scepticism towards the methods—and hence results—of cytologists and histologists, which, according to Miescher, lacked the precision of chemical approaches as he applied them. The fact that DNA was crucially linked to the function of the nucleus was, however, firmly established in Miescher''s mind and in the following years he tried to obtain additional evidence. He later wrote: “Above all, using a range of suitable plant and animal specimens, I want to prove that Nuclein really specifically belongs to the life of the nucleus” (Miescher, 1876).Although the acidic nature of DNA, its large molecular weight, elementary composition and presence in the nucleus are some of its central properties—all first determined by Miescher—they reveal nothing about its function. Having convinced himself that he had discovered a new type of molecule, Miescher rapidly set out to understand its role in different biological contexts. As a first step, he determined that nuclein occurs in a variety of cell types. Unfortunately, he did not elaborate on the types of tissue or the species his samples were derived from. The only hints as to the specimens he worked with come from letters he wrote to his uncle, the Swiss anatomist Wilhelm His (1831–1904), and his parents; his father, Friedrich Miescher-His (1811–1887), was professor of anatomy in Miescher''s native Basel. In his correspondence, Miescher mentioned other cell types that he had studied for the presence of nuclein, including liver, kidney, yeast cells, erythrocytes and chicken eggs, and hinted at having found nuclein in these as well (Miescher, 1869b; His, 1897). Moreover, Miescher had also planned to look for nuclein in plants, especially in their spores (Miescher, 1869c). This is an intriguing choice given his later fascination with vertebrate germ cells and his speculation on the processes of fertilization and heredity (Miescher, 1871b, 1874).Another clue to the tissues and cell types that Miescher might have examined comes from two papers published by Hoppe-Seyler, who wanted to confirm his student''s results, which he initially viewed with scepticism, before their publication. In the first, another of Hoppe-Seyler''s students, Pal Plósz, reported that nuclein is present in the nucleated erythrocytes of snakes and birds but not in the anuclear erythrocytes of cows (Plósz, 1871). In the second paper, Hoppe-Seyler himself confirmed Miescher''s findings and reported that he had detected nuclein in yeast cells (Hoppe-Seyler, 1871).In an addendum to his 1871 paper, published posthumously, Miescher stated that the apparently ubiquitous presence of nuclein meant that “a new factor has been found for the life of the most basic as well as for the most advanced organisms,” thus opening up a wide range of questions for physiology in general (Miescher, 1870). To argue that Miescher understood that DNA was an essential component of all forms of life is probably an over-interpretation of his words. His statement does, however, clearly show that he believed DNA to be an important factor in the life of a wide range of species.In addition, Miescher looked at tissues under different physiological conditions. He quickly noticed that both nuclein and nuclei were significantly more abundant in proliferating tissues; for instance, he noted that in plants, large amounts of phosphorous are found predominantly in regions of growth and that these parts show the highest densities of nuclei and actively proliferating cells (Miescher, 1871a). Miescher had thus taken the first step towards linking the presence of phosphorous—that is, DNA in this context—to cell proliferation. Some years later, while examining changes in the bodies of salmon as they migrate upstream to their spawning grounds, he noticed that he could, with minimal effort, purify large amounts of pure nuclein from the testes, as they were at the height of cell proliferation in preparation for mating (Miescher, 1874). This provided additional evidence for a link between proliferation and the presence of a high concentration of nuclein.Miescher''s most insightful comments on this issue, however, date from his time in Hoppe-Seyler''s laboratory in Tübingen. He was convinced that histochemical analyses would lead to a much better understanding of certain pathological states than would microscopic studies. He also believed that physiological processes, which at the time were seen as similar, might turn out to be very different if the chemistry were better understood. As early as 1869, the year in which he discovered nuclein, he wrote in a letter to His: “Based on the relative amounts of nuclear substances [DNA], proteins and secondary degradation products, it would be possible to assess the physiological significance of changes with greater accuracy than is feasible now” (Miescher, 1869c).Importantly, Miescher proposed three exemplary processes that might benefit from such analyses: “nutritive progression”, characterized by an increase in the cytoplasmic proteins and the enlargement of the cell; “generative progression”, defined as an increase in “nuclear substances” (nuclein) and as a preliminary phase of cell division in proliferating cells and possibly in tumours; and “regression”, an accumulation of lipids and degenerative products (Miescher, 1869c).When we consider the first two categories, Miescher seems to have understood that an increase in DNA was not only associated with, but also a prerequisite for cell proliferation. Subsequently, cells that are no longer proliferating would increase in size through the synthesis of proteins and hence cytoplasm. Crucially, he believed that chemical analyses of such different states would enable him to obtain a more fundamental insight into the causes underlying these processes. These are astonishingly prescient insights. Sadly, Miescher never followed up on these ideas and, apart from the thoughts expressed in his letter, never published on the topic.…Miescher seems to have understood that an increase in DNA was not only associated with, but also a prerequisite for cell proliferationIt is likely, however, that he had preliminary data supporting these views. Miescher was generally careful to base statements on facts rather than speculation. But, being a perfectionist who published only after extensive verification of his results, he presumably never pursued these studies to such a satisfactory point. It is possible his plans were cut short by leaving Hoppe-Seyler''s laboratory to receive additional training under the supervision of Carl Ludwig (1816–1895) in Leipzig. While there, Miescher turned his attention to matters entirely unrelated to DNA and only resumed his work on nuclein after returning to his native Basel in 1871.Crucially for these subsequent studies of nuclein, Miescher made an important choice: he turned to sperm as his main source of DNA. When analysing the sperm from different species, he noted that the spermatozoa, especially of salmon, have comparatively small tails and thus consist mainly of a nucleus (Miescher, 1874). He immediately grasped that this would greatly facilitate his efforts to isolate DNA at much higher purity (Fig 4). Yet, Miescher also saw beyond the possibility of obtaining pure nuclein from salmon sperm. He realized it also indicated that the nucleus and the nuclein therein might play a crucial role in fertilization and the transmission of heritable traits. In a letter to his colleague Rudolf Boehm (1844–1926) in Würzburg, Miescher wrote: “Ultimately, I expect insights of a more fundamental importance than just for the physiology of sperm” (Miescher, 1871c). It was the beginning of a fascination with the phenomena of fertilization and heredity that would occupy Miescher to the end of his days.Open in a separate windowFigure 4A glass vial containing DNA purified by Friedrich Miescher from salmon sperm. © Alfons Renz, University of Tübingen, Germany.Miescher had entered this field at a critical time. By the middle of the nineteenth century, the old view that cells arise through spontaneous generation had been challenged. Instead, it was widely recognized that cells always arise from other cells (Mayr, 1982). In particular, the development and function of spermatozoa and oocytes, which in the mid-1800s had been shown to be cells, were seen in a new light. Moreover, in 1866, three years before Miescher discovered DNA, Ernst Haeckel (1834–1919) had postulated that the nucleus contained the factors that transmit heritable traits. This proposition from one of the most influential scientists of the time brought the nucleus to the centre of attention for many biologists. Having discovered nuclein as a distinctive molecule present exclusively in this organelle, Miescher realized that he was in an excellent position to make a contribution to this field. Thus, he set about trying to better characterize nuclein with the aim of correlating its chemical properties with the morphology and function of cells, especially of sperm cells.His analyses of the chemical composition of the heads of salmon spermatozoa led Miescher to identify two principal components: in addition to the acidic nuclein, he found an alkaline protein for which he coined the term ‘protamin''; the name is still in use today; protamines are small proteins that replace histones during spermatogenesis. He further determined that these two molecules occur in a “salt-like, not an ether-like [that is, covalent] association” (Miescher, 1874). Following his meticulous analyses of the chemical composition of sperm, he concluded that, “aside from the mentioned substances [protamin and nuclein] nothing is present in significant quantity. As this is crucial for the theory of fertilization, I carry this business out as quantitatively as possible right from the beginning” (Miescher, 1872a). His analyses showed him that the DNA and protamines in sperm occur at constant ratios; a fact that Miescher considered “is certainly of special importance,” without, however, elaborating on what might be this importance. Today, of course, we know that proteins, such as histones and protamines, bind to DNA in defined stoichiometric ratios.Miescher went on to analyse the spermatozoa of carp, frogs (Rana esculenta) and bulls, in which he confirmed the presence of large amounts of nuclein (Miescher, 1874). Importantly, he could show that nuclein is present in only the heads of sperm—the tails being composed largely of lipids and proteins—and that within the head, the nuclein is located in the nucleus (Miescher, 1874; Schmiedeberg & Miescher, 1896). With this discovery, Miescher had not only demonstrated that DNA is a constant component of spermatozoa, but also directed his attention to the sperm heads. On the basis of the observations of other investigators, such as those of Albert von Kölliker (1817–1905) concerning the morphology of spermatozoa in some myriapods and arachnids, Miescher knew that the spermatozoa of some species are aflagellate, that is, lack a tail. This confirmed that the sperm head, and thus the nucleus, was the crucial component. But, the question remained: what in the sperm cells mediated fertilization and the transmission of hereditary traits from one generation to the next?On the basis of his chemical analyses of sperm, Miescher speculated on the existence of molecules that have a crucial part in these processes. In a letter to Boehm, Miescher wrote: “If chemicals do play a role in procreation at all, then the decisive factor is now a known substance” (Miescher, 1872b). But Miescher was unsure as to what might be this substance. He did, however, strongly suspect the combination of nuclein and protamin was the key and that the oocyte might lack a crucial component to be able to develop: “If now the decisive difference between the oocyte and an ordinary cell would be that from the roster of factors, which account for an active arrangement, an element has been removed? For otherwise all proper cellular substances are present in the egg,” he later wrote (Miescher, 1872b).Owing to his inability to detect protamin in the oocyte, Miescher initially favoured this molecule as responsible for fertilization. Later, however, when he failed to detect protamin in the sperm of other species, such as bulls, he changed his mind: “The Nuclein by contrast has proved to be constant [that is, present in the sperm cells of all species Miescher analysed] so far; to it and its associations I will direct my interest from now on” (Miescher, 1872b). Unfortunately, however, although he came tantalizingly close, he never made a clear link between nuclein and heredity.The final section of his 1874 paper on the occurrence and properties of nuclein in the spermatozoa of different vertebrate species is of particular interest because Miescher tried to correlate his chemical findings about nuclein with the physiological role of spermatozoa. He had realized that spermatozoa represented an ideal model system to study the role of DNA because, as he would later put it, “[f]or the actual chemical–biological problems, the great advantage of sperm [cells] is that everything is reduced to the really active substances and that they are caught just at the moment when they exert their greatest physiological function” (Miescher, 1893a). He appreciated that his data were still incomplete, yet wanted to make a first attempt to pull his results together and integrate them into a broader picture to explain fertilization.At the time, Wilhelm Kühne (1837–1900), among others, was putting forward the idea that spermatozoa are the carriers of specific substances that, through their chemical properties, achieve fertilization (Kühne, 1868). Miescher considered his results of the chemical composition of spermatozoa in this context. While critically considering the possibility of a chemical substance explaining fertilization, he stated that: “if we were to assume at all that a single substance, as an enzyme or in any other way, for instance as a chemical impulse, could be the specific cause of fertilization, we would without a doubt first and foremost have to consider Nuclein. Nuclein-bodies were consistently found to be the main components [of spermatozoa]” (Miescher, 1874).With hindsight, these statements seem to suggest that Miescher had identified nuclein as the molecule that mediates fertilization—a crucial assumption to follow up on its role in heredity. Unfortunately, however, Miescher himself was far from convinced that a molecule (or molecules) was responsible for this. There are several reasons for his reluctance, although the influence of his uncle was presumably a crucial factor as it was he who had been instrumental in fostering the young Miescher''s interest in biochemistry and remained a strong influence throughout his life. Indeed, when Miescher came tantalizingly close to uncovering the function of DNA, His''s views proved counterproductive, probably preventing him from interpreting his findings in the context of new results from other scientists at the time. Miescher thus failed to take his studies of nuclein and its function in fertilization and heredity to the next level, which might well have resulted in recognizing DNA as the central molecule in both processes.One specific aspect that diverted Miescher from contemplating the role of nuclein in fertilization was a previous study in which he had erroneously identified the yolk platelets in chicken oocytes as a large number of nuclein-containing granules (Miescher, 1871b). This led him to conclude that the comparatively minimal quantitative contribution of DNA from a spermatozoon to an oocyte, which already contained so much more of the substance, could not have a significant impact on the latter''s physiology. He therefore concluded that, “not in a specific substance can the mystery of fertilization be concealed. […] Not a part, but the whole must act through the cooperation of all its parts” (Miescher, 1874).It is all the more unfortunate that Miescher had identified the yolk platelets in oocytes as nuclein-containing cells because he had realized that the presumed nuclein in these granules differed from the nuclein (that is, DNA) he had isolated previously from other sources, notably by its much higher phosphorous content. But influenced by His''s strong view that these structures were genuine cells, Miescher saw his results in this light. Only several years later, based on results from his contemporaries Flemming and Eduard A. Strasburger (1844–1912) on the morphological properties of nuclei and their behaviour during cell divisions, and Albrecht Kossel''s (1853–1927) discoveries about the composition of DNA (Portugal & Cohen, 1977), did Miescher revise his initial assumption that chicken oocytes contain a large number of nuclein-containing granules. Instead, he finally conceded that the molecules comprising these granules were different from nuclein (Miescher, 1890).Another factor that prevented Miescher from concluding that nuclein was the basis for the transmission of hereditary traits was that he could not conceive of how a single substance might explain the multitude of heritable traits. How, he wondered, could a specific molecule be responsible for the differences between species, races and individuals? Although he granted that “differences in the chemical constitution of these molecules [different types of nuclein] will occur, but only to a limited extent” (Miescher, 1874).And thus, instead of looking to molecules, he—like his uncle His––favoured the idea that the physical movement of the sperm cells or an activation of the oocyte, which he likened to the stimulation of a muscle by neuronal impulses, was responsible for the process of fertilization: “Like the muscle during the activation of its nerve, the oocyte will, when it receives appropriate impulses, become a chemically and physically very different entity” (Miescher, 1874). For nuclein itself, Miescher considered that it might be a source material for other molecules, such as lecithin––one of the few other molecules with a high phosphorous content known at the time (Miescher, 1870, 1871a, 1874). Miescher clearly preferred the idea of nuclein as a repository for material for the cell—mainly phosphorous—rather than as a molecule with a role in encoding information to synthesize such materials. This idea of large molecules being source material for smaller ones was common at the time and was also contemplated for proteins (Miescher, 1870).The entire section of Miescher''s 1874 paper in which he discusses the physiological role of nuclein reads as though he was deliberately trying to assemble evidence against nuclein being the key molecule in fertilization and heredity. This disparaging approach towards the molecule that he himself had discovered might also be explained, at least to some extent, by his pronounced tendency to view his results so critically; tellingly, he published only about 15 papers and lectures in a career spanning nearly three decades.The modern understanding that fertilization is achieved by the fusion of two germ cells only became established in the final quarter of the nineteenth century. Before that time, the almost ubiquitous view was that the sperm cell, through mere contact with the egg, in some way stimulated the oocyte to develop—the physicalist viewpoint. His was a key advocate of this view and firmly rejected the idea that a specific substance might mediate heredity. We can only speculate as to how Miescher would have interpreted his results had he worked in a different intellectual environment at the time, or had he been more independent in the interpretation of his results.We can only speculate as to how Miescher would have interpreted his results had he worked in a different intellectual environment at the time…Miescher''s refusal to accept nuclein as the key to fertilization and heredity is particularly tragic in view of several studies that appeared in the mid-1870s, focusing the attention of scientists on the nuclei. Leopold Auerbach (1828–1897) demonstrated that fertilized eggs contain two nuclei that move towards each other and fuse before the subsequent development of the embryo (Auerbach, 1874). This observation strongly suggested an important role for the nuclei in fertilization. In a subsequent study, Oskar Hertwig (1849–1922) confirmed that the two nuclei—one from the sperm cell and one from the oocyte—fuse before embryogenesis begins. Furthermore, he observed that all nuclei in the embryo derive from this initial nucleus in the zygote (Hertwig, 1876). With this he had established that a single sperm fertilizes the oocyte and that there is a continuous lineage of nuclei from the zygote throughout development. In doing so, he delivered the death blow to the physicalist view of fertilization.By the mid-1880s, Hertwig and Kölliker had already postulated that the crucial component of the nucleus that mediated inheritance was nuclein—an idea that was subsequently accepted by several scientists. Sadly, Miescher remained doubtful until his death in 1895 and thus failed to appreciate the true importance of his discovery. This might have been an overreaction to the claims by others that sperm heads are formed from a homogeneous substance; Miescher had clearly shown that they also contain other molecules, such as proteins. Moreover, Miescher''s erroneous assumption that nuclein occurred only in the outer shell of the sperm head resulted in his failure to realize that stains for chromatin, which stain the centres of the heads, actually label the region where there is nuclein; although he later realized that virtually the entire sperm head is composed of nuclein and associated protein (Miescher, 1892a; Schmiedeberg & Miescher, 1896).Unfortunately, not only Miescher, but the entire scientific community would soon lose faith in DNA as the molecule mediating heredity. Miescher''s work had established DNA as a crucial component of all cells and inspired others to begin exploring its role in heredity, but with the emergence of the tetranucleotide hypothesis at the beginning of the twentieth century, DNA fell from favour and was replaced by proteins as the prime candidates for this function. The tetranucleotide hypothesis—which assumed that DNA was composed of identical subunits, each containing all four bases—prevailed until the late 1940s when Edwin Chargaff (1905–2002) discovered that the different bases in DNA were not present in equimolar amounts (Chargaff et al, 1949, 1951).Unfortunately, not only Miescher, but the entire scientific community would soon lose faith in DNA as the molecule mediating heredityJust a few years before, in 1944, experiments by Avery and colleagues had demonstrated that DNA was sufficient to transform bacteria (Avery et al, 1944). Then in 1952, Al Hershey (1908–1997) and Martha Chase (1927–2003) confirmed these findings by observing that viral DNA—but no protein—enters the bacteria during infection with the T2 bacteriophage and, that this DNA is also present in new viruses produced by infected bacteria (Hershey & Chase, 1952). Finally, in 1953, X-ray images of DNA allowed Watson and Crick to deduce its structure (Watson & Crick, 1953) and thus enable us to understand how DNA works. Importantly, these experiments were made possible by advances in bacteriology and virology, as well as the development of new techniques, such as the radioactive labelling of proteins and nucleic acids, and X-ray crystallography—resources that were beyond the reach of Miescher and his contemporaries.In later years (Fig 5), Miescher''s attention shifted progressively from the role of nuclein in fertilization and heredity to physiological questions, such as those concerning the metabolic changes in the bodies of salmon as they produce massive amounts of germ cells at the expense of muscle tissue. Although he made important and seminal contributions to different areas of physiology, he increasingly neglected to explore his most promising line of research, the function of DNA. Only towards the end of his life did he return to this question and begin to reconsider the issue in a new light, but he achieved no further breakthroughs.Open in a separate windowFigure 5Friedrich Miescher in his later years when he was Professor of Physiology at the University of Basel. In this capacity he also founded the Vesalianum, the University''s Institute for Anatomy and Physiology, which was inaugurated in 1885. This photograph is the frontispiece on the inside cover of a collection of Miescher''s publications and some of his letters, edited and published by his uncle Wilhelm His and colleagues after Miescher''s death. Underneath the picture is Miescher''s signature. © Ralf Dahm.One area, however, where he did propose intriguing hypotheses—although without experimental data to support them—was the molecular underpinnings of heredity. Inspired by Darwin''s work on fertilization in plants, Miescher postulated, for instance, how information might be encoded in biological molecules. He stated that, “the key to sexuality for me lies in stereochemistry,” and expounded his belief that the gemmules of Darwin''s theory of pangenesis were likely to be “numerous asymmetric carbon atoms [present in] organic substances” (Miescher, 1892b), and that sexual reproduction might function to correct mistakes in their “stereometric architecture”. As such, Miescher proposed that hereditary information might be encoded in macromolecules and how mistakes could be corrected, which sounds uncannily as though he had predicted what is now known as the complementation of haploid deficiencies by wild-type alleles. It is particularly tempting to assume that Miescher might have thought this was the case, as Mendel had published his laws of inheritance of recessive characteristics more than 25 years earlier. However, there is no reference to Mendel''s work in the papers, talks or letters that Miescher has left to us.Miescher proposed that hereditary information might be encoded in macromolecules and how mistakes could be corrected…What we do know is that Miescher set out his view of how hereditary information might be stored in macromolecules: “In the enormous protein molecules […] the many asymmetric carbon atoms allow such a colossal number of stereoisomers that all the abundance and diversity of the transmission of hereditary [traits] may find its expression in them, as the words and terms of all languages do in the 24–30 letters of the alphabet. It is therefore completely superfluous to see the sperm cell or oocyte as a repository of countless chemical substances, each of which should be the carrier of a special hereditary trait (de Vries Pangenesis). The protoplasm and the nucleus, that my studies have shown, do not consist of countless chemical substances, but of very few chemical individuals, which, however, perhaps have a very complex chemical structure” (Miescher, 1892b).This is a remarkable passage in Miescher''s writings. The second half of the nineteenth century saw intense speculation about how heritable characteristics are transmitted between the generations. The consensus view assumed the involvement of tiny particles, which were thought to both shape embryonic development and mediate inheritance (Mayr, 1982). Miescher contradicted this view. Instead of a multitude of individual particles, each of which might be responsible for a specific trait (or traits), his results had shown that, for instance, the heads of sperm cells are composed of only very few compounds, chiefly DNA and associated proteins.He elaborated further on his theory of how hereditary information might be stored in large molecules: “Continuity does not only lie in the form, it also lies deeper than the chemical molecule. It lies in the constituent groups of atoms. In this sense I am an adherent of a chemical model of inheritance à outrance [to the utmost]” (Miescher, 1893b). With this statement Miescher firmly rejects any idea of preformation or some morphological continuity transmitted through the germ cells. Instead, he clearly seems to foresee what would only become known much later: the basis of heredity was to be found in the chemical composition of molecules.To explain how this could be achieved, he proposed a model of how information could be encoded in a macromolecule: “If, as is easily possible, a protein molecule comprises 40 asymmetric carbon atoms, there will be 2⁴⁰, that is, approximately a trillion isomerisms [sic]. And this is only one of the possible types of isomerism [not considering other atoms, such as nitrogen]. To achieve the incalculable diversity demanded by the theory of heredity, my theory is better suited than any other. All manner of transitions are conceivable, from the imperceptible to the largest differences” (Miescher, 1893b).Miescher''s ideas about how heritable characteristics might be transmitted and encoded encapsulate several important concepts that have since been proven to be correct. First, he believed that sexual reproduction served to correct mistakes, or mutations as we call them today. Second, he postulated that the transmission of heritable traits occurs through one or a few macromolecules with complex chemical compositions that encode the information, rather than by numerous individual molecules each encoding single traits, as was thought at the time. Third, he foresaw that information is encoded in these molecules through a simple code that results in a staggeringly large number of possible heritable traits and thus explain the diversity of species and individuals observed.Miescher''s ideas about how heritable characteristics might be transmitted and encoded encapsulate several important concepts that have since been proven to be correctIt is a step too far to suggest that Miescher understood what DNA or other macromolecules do, or how hereditary information is stored. He simply could not have done, given the context of his time. His findings and hypotheses that today fit nicely together and often seem to anticipate our modern understanding probably appeared rather disjointed to Miescher and his contemporaries. In his day, too many facts were still in doubt and too many links tenuous. There is always a danger of over-interpreting speculations and hypotheses made a long time ago in today''s light. However, although Miescher himself misinterpreted some of his findings, large parts of his conclusions came astonishingly close to what we now know to be true. Moreover, his work influenced others to pursue their own investigations into DNA and its function (Dahm, 2008). Although DNA research fell out of fashion for several decades after the end of the nineteenth century, the information gleaned by Miescher and his contemporaries formed the foundation for the decisive experiments carried out in the middle of the twentieth century, which unambiguously established the function of DNA.As such, perhaps the most tragic aspect of Miescher''s career was that for most of his life he firmly believed in the physicalist theories of fertilization, as propounded by His and Ludwig among others, and his reluctance to combine the results from his rigorous chemical analyses with the ‘softer'' data generated by cytologists and histologists. Had he made the link between nuclein and chromosomes and accepted its key role in fertilization and heredity, he might have realized that the molecule he had discovered was the key to some of the greatest mysteries of life. As it was, he died with a feeling of a promising career unfulfilled (His, 1897), when, in actual fact, his contributions were to outshine those of most of his contemporaries.…he died with a feeling of a promising career unfulfilled […] when, in actual fact, his contributions were to outshine those of most of his contemporariesIt is tantalizing to speculate the path that Miescher''s investigations—and biology as a whole—might have taken under slightly different circumstances. What would have happened had he followed up on his preliminary results about the role of DNA in different physiological conditions, such as cell proliferation? How would his theories about fertilization and heredity have changed had he not been misled by the mistaken identification of what appeared to him to be a multitude of small nuclei in the oocyte? Or how would he have interpreted his findings concerning nuclein had he not been influenced by the views of his uncle, but also those of the wider scientific establishment?There is a more general lesson in the life and work of Friedrich Miescher that goes beyond his immediate successes and failures. His story is that of a brilliant researcher who developed innovative experimental approaches, chose the right biological systems to address his questions and made ground-breaking discoveries, and who was nonetheless constrained by his intellectual environment and thus prevented from interpreting his findings objectively. It therefore fell to others, who saw his work from a new point of view, to make the crucial inferences and thus establish the function of DNA.? Open in a separate windowRalf Dahm     

Can conscientious objection lead to eugenic practices against LGBT individuals?

In a recent article in this journal, Abram Brummett argues that new and future assisted reproductive technologies will provide challenging ethical questions relating to lesbian, gay, bisexual and transgender (LGBT) persons. Brummett notes that it is likely that some clinicians may wish to conscientiously object to offering assisted reproductive technologies to LGBT couples on moral or religious grounds, and argues that such appeals to conscience should be constrained. We argue that Brummett's case is unsuccessful because he: does not adequately interact with his opponents’ views; equivocates on the meaning of ‘natural’; fails to show that the practice he opposes is eugenic in any non‐trivial sense; and fails to justify and explicate the relevance of the naturalism he proposes. We do not argue that conscience protections should exist for those objecting to providing LGBT people with artificial reproductive technologies, but only show that Brummett's arguments are insufficient to prove that they should not.     

Haeckel,un darwinien allemand ?

German biologist Ernst Haeckel (1834–1919) is often considered the most renowned Darwinian in his country since, as early as 1862, he declared that he accepted the conclusions Darwin had reached three years before in On the Origin of Species, and afterwards, he continuously proclaimed himself a supporter of the English naturalist and championed the evolutionary theory. Nevertheless, if we examine carefully his books, in particular his General Morphology (1866), we can see that he carries on a tradition very far from Darwin's thoughts. In spite of his acceptance of the idea of natural selection, that he establishes as an argument for materialism, he adopts, indeed, a conception of evolution that is, in some respects, rather close to Lamarck's views. He is, thus, a good example of the ambiguities of the reception of Darwinism in Germany in the second part of the 19th century. To cite this article: S. Schmitt, C. R. Biologies 332 (2009).     

The A to T of historical evidence

Geneticists and historians collaborated recently to identify the remains of King Richard III of England, found buried under a car park. Genetics has many more contributions to make to history, but scientists and historians must learn to speak each other''s languages.The remains of King Richard III (1452–1485), who was killed with sword in hand at the Battle of Bosworth Field at the end of the War of the Roses, had lain undiscovered for centuries. Earlier this year, molecular biologists, historians, archaeologists and other experts from the University of Leicester, UK, reported that they had finally found his last resting place. They compared ancient DNA extracted from a scoliotic skeleton discovered under a car park in Leicester—once the site of Greyfriars church, where Richard was rumoured to be buried, but the location of which had been lost to time—with that of a seventeenth generation nephew of King Richard: it was a match. Richard has captured the public imagination for centuries: Tudor-friendly playwright William Shakespeare (1564–1616) portrayed Richard as an evil hunchback who killed his nephews in order to ascend to the throne, whilst in succeeding years others have leapt to his defence and backed an effort to find his remains.The application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient ChinaMolecular biologist Turi King, who led the Leicester team that extracted the DNA and tracked down a descendant of Richard''s older sister, said that Richard''s case shows how multi-disciplinary teams can join forces to answer history''s questions. “There is a lot of talk about what meaning does it have,” she said. “It tells us where Richard III was buried; that the story that he was buried in Greyfriars is true. I think there are some people who [will] try and say: “well, it''s going to change our view of him” […] It won''t, for example, tell us about his personality or if he was responsible for the killing of the Princes in the Tower.”The discovery and identification of Richard''s skeleton made headlines around the world, but he is not the main prize when it comes to collaborations between historians and molecular biologists. Although some of the work has focused on high-profile historic figures—such as Louis XVI (1754–1793), the only French king to be executed, and Vlad the Impaler, the Transylvanian royal whose patronymic name inspired Bram Stoker''s Dracula (Fig 1)—many other projects involve population studies. Application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient China.Open in a separate windowFigure 1The use of molecular genetics to untangle history. Even when the historical record is robust, molecular biology can contribute to our understanding of important figures and their legacies and provide revealing answers to questions about ancient princes and kings.Medieval historian Michael McCormick of Harvard University, USA, commented that historians have traditionally relied on studying records written on paper, sheepskin and papyrus. However, he and other historians are now teaming up with geneticists to read the historical record written down in the human genome and expand their portfolio of evidence. “What we''re seeing happening now—because of the tremendous impact from the natural sciences and particularly the application of genomics; what some of us are calling genomic archaeology—is that we''re working back from modern genomes to past events reported in our genomes,” McCormick explained. “The boundaries between history and pre-history are beginning to dissolve. It''s a really very, very exciting time.”…in the absence of written records, DNA and archaeological records could help fill in gapsMcCormick partnered with Mark Thomas, an evolutionary geneticist at University College London, UK, to try to unravel the mystery of one million Romano-Celtic men who went missing in Britain after the fall of the Roman Empire. Between the fourth and seventh centuries, Germanic tribes of Angles, Saxons and Jutes began to settle in Britain, replacing the Romano-British culture and forcing some of the original inhabitants to migrate to other areas. “You can''t explain the predominance of the Germanic Y chromosome in England based on the population unless you imagine (a) that they killed all the male Romano-Celts or (b) there was what Mark called ‘sexual apartheid'' and the conquerors mated preferentially with the local women. [The latter] seems to be the best explanation that I can see,” McCormick said of the puzzle.Ian Barnes, a molecular palaeobiologist at Royal Holloway University of London, commented that McCormick studies an unusual period, for which both archaeological and written records exist. “I think archaeologists and historians are used to having conflicting evidence between the documentary record and the archaeological record. If we bring in DNA, the goal is to work out how to pair all the information together into the most coherent story.”Patrick Geary, Professor of Western Medieval History at the Institute for Advanced Study in Princeton, New Jersey, USA, studies the migration period of Europe: a time in the first millennium when Germanic tribes, including the Goths, Vandals, Huns and Longobards, moved across Europe as the Roman Empire was declining. “We do not have detailed written information about these migrations or invasions or whatever one wants to call them. Primarily what we have are accounts written later on, some generations later, from the contemporary record. What we tend to have are things like sermons bemoaning the faith of people because God''s wrath has brought the barbarians on them. Hardly the kind of thing that gives us an idea of exactly what is going on—are these really invasions, are they migrations, are they small military groups entering the Empire? And what are these ‘peoples'': biologically related ethnic groups, or ad hoc confederations?” he said.Geary thinks that in the absence of written records, DNA and archaeological records could help fill in the gaps. He gives the example of jewellery, belt buckles and weapons found in ancient graves in Hungary and Northern and Southern Italy, which suggest migrations rather than invasions: “If you find this kind of jewellery in one area and then you find it in a cemetery in another, does it mean that somebody was selling jewellery in these two areas? Does this mean that people in Italy—possibly because of political change—want to identify themselves, dress themselves in a new style? This is hotly debated,” Geary explained. Material goods can suggest a relationship between people but the confirmation will be found in their DNA. “These are the kinds of questions that nobody has been able to ask because until very recently, DNA analysis simply could not be done and there were so many problems with it that this was just hopeless,” he explained. Geary has already collected some ancient DNA samples and plans to collect more from burial sites north and south of the Alps dating from the sixth century, hoping to sort out kinship relations and genetic profiles of populations.King said that working with ancient DNA is a tricky business. “There are two reasons that mitochondrial DNA (mtDNA) is the DNA we wished to be able to analyse in [King] Richard. In the first instance, we had a female line relative of Richard III and mtDNA is passed through the female line. Fortunately, it''s also the most likely bit of DNA that we''d be able to retrieve from the skeletal remains, as there are so many copies of it in the cell. After death, our DNA degrades, so mtDNA is easier to retrieve simply due to the sheer number of copies in each cell.”Geary contrasted the analysis of modern and ancient DNA. He called modern DNA analysis “[…] almost an industrial thing. You send it off to a lab, you get it back, it''s very mechanical.” Meanwhile, he described ancient DNA work as artisanal, because of degeneration and contamination. “Everything that touched it, every living thing, every microbe, every worm, every archaeologist leaves DNA traces, so it''s a real mess.” He said the success rate for extracting ancient mtDNA from teeth and dense bones is only 35%. The rate for nuclear DNA is only 10%. “Five years ago, the chances would have been zero of getting any, so 10% is a great step forward. And it''s possible we would do even better because this is a field that is rapidly transforming.”But the bottleneck is not only the technical challenge to extract and analyse ancient DNA. Historians and geneticists also need to understand each other better. “That''s why historians have to learn what it is that geneticists do, what this data is, and the geneticists have to understand the kind of questions that [historians are] trying to ask, which are not the old nineteenth century questions about identity, but questions about population, about gender roles, about relationship,” Geary said.DNA analysis can help to resolve historical questions and mysteries about our ancestors, but both historians and geneticists are becoming concerned about potential abuses and frivolous applications of DNA analysis in their fields. Thomas is particularly disturbed by studies based on single historical figures. “Unless it''s a pretty damn advanced analysis, then studying individuals isn''t particularly useful for history unless you want to say something like this person had blue eyes or whatever. Population level studies are best,” he said. He conceded that the genetic analysis of Richard III''s remnants was a sound application but added that this often is not the case with other uses, which he referred to as “genetic astrology.” He was critical of researchers who come to unsubstantiated conclusions based on ancient DNA, and scientific journals that readily publish such papers.…both historians and geneticists are becoming concerned about potential abuses or frivolous applications of DNA analysis in their fieldsThomas said that it is reasonable to analyse a Y chromosome or mtDNA to estimate a certain genetic trait. “But then to look at the distribution of those, note in the tree where those types are found, and informally, interpretively make inferences—“Well this must have come from here and therefore when I find it somewhere else then that means that person must have ancestors from this original place”—[…] that''s deeply flawed. It''s the most widely used method for telling historical stories from genetic data. And yet is easily the one with the least credibility.” Thomas criticized such facile use of genetic data, which misleads the public and the media. “I suppose I can''t blame these [broadcast] guys because it''s their job to make the programme look interesting. If somebody comes along and says ‘well, I can tell you you''re descended from some Viking warlord or some Celtic princess'', then who are they to question.”Similarly, the historians have reservations about making questionable historical claims on the basis of DNA analysis. Geary said the use of mtDNA to identify Richard III was valuable because it answered a specific, factual question. However, he is turned off by other research using DNA to look at individual figures, such as a case involving a princess who was a direct descendant of the woman who posed for Leonardo Da Vinci''s Mona Lisa. “There''s some people running around trying to dig up famous people and prove the obvious. I think that''s kind of silly. There are others that I think are quite appropriate, and while is not my kind of history, I think it is fine,” he said. “The Richard III case was in the tradition of forensics.”…the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological researchNicola Di Cosmo, a historian at the Institute for Advanced Study, who is researching the impact of climate change on the thirteenth century Mongol empire, follows closely the advances in DNA and history research, but has not yet applied it to his own work. Nevertheless, he said that genetics could help to understand the period he studies because there are no historical documents, although monumental burials exist. “It is important to get a sense of where these people came from, and that''s where genetics can help,” he said. He is also concerned about geneticists who publish results without involving historians and without examining other records. He cited a genetic study of a so-called ‘Eurasian male'' in a prestige burial of the Asian Hun Xiongnu, a nomadic people who at the end of the third century B.C. formed a tribal league that dominated most of Central Asia for more than 500 years. “The conclusion the geneticists came to was that there was some sort of racial tolerance in this nomadic empire, but we have no way to even assume that they had any concept of race or tolerance.”Di Cosmo commented that the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological research. “I believe that historians, especially those working in areas for which written records are non-existent, ought to be taking seriously the evidence churned out by genetic laboratories. On the other hand, geneticists must realize that the effectiveness of their research is limited unless they access reliable historical information and understand how a historical argument may or may not explain the genetic data” [1].Notwithstanding the difficulties in collaboration between two fields, McCormick is excited about historians working with DNA. He said the intersection of history and genomics could create a new scientific discipline in the years ahead. “I don''t know what we''d call it. It would be a sort of fusion science. It certainly has the potential to produce enormous amounts of enormously interesting new evidence about our human past.”     

Testing time for telomeres

Our knowledge of the importance of telomeres to health and ageing continues to grow. Some scientists are therefore commercializing their research, whereas others believe we need an even deeper understanding before we can interpret the results.After 30 years of research, the analysis of telomere length is emerging as a commercial biomarker for ageing and disease, as well as a tool in the search for new medications. Several companies offer tests for telomere length, and more are due to launch their products shortly. Even so, and despite the commercial enthusiasm, interpreting precisely what an individual''s telomeres mean for their health and longevity remains challenging. As a result, there is some division within the research community between those who are pushing ahead with ventures to offer tests to the public, and those who feel that telomere testing is not yet ready for prime time.Peter Lansdorp, a scientist at the British Columbia Cancer Agency and a professor at the University of British Columbia (Vancouver, Canada), founded his company, Repeat Diagnostics, in response to the number of questions and requests he received from physicians for tests for telomere length. The company became the first to offer commercial telomere testing in 2005 and now mainly serves medical researchers, although it makes its test available to the public through their physicians for C $400. Nevertheless, Lansdorp thinks that testing is of limited use for the public. “Testing [...] outside the context of research studies is in my view premature. Unfortunately I think some scientists are exploiting it,” he said. “At this point, I would discourage people from getting their telomeres tested unless there are symptoms in the family that may point to a telomere problem, or a disease related to a telomere problem. I don''t see why on Earth you would want to do that for normal individuals.”“Testing [...] outside the context of research studies is in my view premature. Unfortunately I think some scientists are exploiting it”Others are more convinced of the general utility of telomere tests, when used in combination with other diagnostic tools. Elizabeth Blackburn, Professor of Biology and Physiology at the University of California (San Francisco, USA), was a co-recipient of the Nobel Prize for Physiology or Medicine in 2009 for her part in the discovery of telomerase, the enzyme that replenishes telomeres (Sidebar A). She stressed that the point of telomere testing is to obtain an overall picture “using a marker that integrates many inputs, and produces a robust statistical association with [...] disease risks. It is not a specific diagnostic.” Telome Health, Inc. (Menlo Park, California, USA)—the company that Blackburn helped found and that she now advises in a scientific capacity—plans to begin selling its own US $200 telomere test later this year. “The science has been emerging at a rapid pace recently [...] for those who are familiar with the wealth of the evidence and the accumulated data, the overwhelming pattern is that there are clear associations with telomere maintenance, including longitudinal patterns, and health measures that have had well-tested clinical relevance,” she explained.

Sidebar A | Telomeres and telomerase

Telomeres are regions of repetitive DNA sequence that prevent the DNA replication process or damage from degrading the ends of chromosomes, essentially acting as buffers and protecting the genes closest to the chromosome ends. Russian biologist Alexei Olovnikov first hypothesized in the early 1970s that chromosomes could not completely replicate their ends, and that such losses could ultimately lead to the end of cell division (Olovnikov, 1973). Some years later, Elizabeth Blackburn, then a postdoctoral fellow in Joseph Gall''s lab at Yale University (New Haven, Connecticut, USA), and her colleagues published work suggesting that telomere shortening was linked with ageing at the cellular level, affected lifespan and could lead to cancer (Blackburn & Gall, 1978; Szostak & Blackburn, 1982). In 1984, Carol Greider, working as a postdoc in Blackburn''s lab at the University of California (Berkeley, USA), discovered telomerase, the enzyme that replenishes telomeres. Blackburn and Greider, together with Jack Szostak, were awarded the 2009 Nobel Prize in Physiology or Medicine for “the discovery of how chromosomes are protected by telomeres and the enzyme telomerase” (http://nobelprize.org/nobel_prizes/medicine/laureates/2009/).María Blasco, Director of the Centro Nacional de Investigaciones Oncológicas (CNIO; Spanish National Cancer Research Centre; Madrid, Spain), is similarly optimistic about the prospect of telomere testing becoming a routine health test. “As an analogy, telomere length testing could be similar to what has occurred with cholesterol tests, which went in [the] early 80s from being an expensive test for which no direct drug treatment was available to being a routine test in general health check-ups,” she said.Carol Greider, Professor and Director of Molecular Biology and Genetics at Johns Hopkins University (Baltimore, Maryland, USA) and co-recipient of the 2009 Nobel Prize with Blackburn, however, does not believe that testing is ready for widespread use, although she agreed that telomere length can reveal a lot about disease and is an important subject for research. “Certainly, right now, I think it''s very premature to be offering this kind of testing to the public. I don''t think that the research has yet told us about the risks, what we can actually say statistically with high confidence, so it''s unclear to me if there is any real value to the general public to testing telomeres,” she said.Blasco is Chief Scientific Advisor to Life Length, a CNIO spin-off company that launched its test last year to a storm of media attention. “For some scientists, there is always a question that needs to be solved or has not been sufficiently evaluated,” she said. “We have lots of information showing that telomere length is important for understanding ageing and certain diseases [...] New technologies have been developed that allow us now to measure telomere length in a large scale using a simple blood sample or a spit sample. The fact that the technology is here and the science is here makes this a good moment to market this testing.”“We have lots of information showing that telomere length is important for understanding ageing and certain diseases [...] the technology is here and the science is here”Apart from discussion of the science, companies that offer telomere testing are also encountering scepticism from ethicists and other scientists about the value of telomere-length testing for normal healthy people.Lansdorp, who is a medical doctor by training, thinks that practitioners are not yet ready to use and interpret the tests. “It''s a new field and there are good clinical papers out there, but the irony is that our work [that] has highlighted the value of these tests for specific clinical conditions [is] now being used [...] to make the point that it''s really important to have your telomeres tested, but the dots are not connected by a straight line,” he said.Jonathan Stein, Director of Science and Research at SpectraCell Laboratories (Houston, Texas, USA)—which offers its US $250 telomere test as an extension of its nutritional product line that is sold to family physicians, chiropractors and naturopaths—said that there has only really been demand for the telomere test from his company among physicians and their spouses, but not for use in the clinic. “Doctors are incredibly curious about [the test] and then when we do follow-ups in general, they tell us it''s interesting and they know it''s valuable, but they''re not entirely sure what it means to people. Where we go from the bench to bedside, there seems to be a real sticking point,” he said, adding that he thinks demand will increase as the public becomes increasingly educated about telomeres and health.Arthur Caplan, Professor of Bioethics and Director of the Center for Bioethics at the University of Pennsylvania (Philadelphia, USA), is not clear that even an educated public will be interested in what the test can tell them. “We don''t have any great reason to think that people will be interested in knowing facts about themselves [...] if they can''t do anything about it. I think most people would say ''I''m not going to spend money on this until you tell me if there''s something I can do to slow this process or expand my life''.” As such, he thinks that companies that are getting in early to ''cash in'' on the novelty of telomere testing are unlikely to see huge success, partly because the science is not yet settled.Calvin Harley, President and Chief Science Officer at Telome Health, disagrees. He thinks that two things will drive demand for telomere testing: the growing number of clinical studies validating the utility of the test, and the growing interest in lifestyle changes and interventions that help to maintain telomeres....two things will drive demand for telomere testing: the growing number of clinical studies [...] and [...] interest in lifestyle changes and interventions that help maintain telomeresBut these are early days. Jerry Shay, Professor of Cell Biology and Neuroscience at the University of Texas Southwestern Medical Center (Dallas, USA) and an adviser to the company Life Length, said that early adopters are likely to be the health conscious and the curious. “Some people will say, ''Well, look, I had my telomeres measured: I''m a 60 year old with 50-year-old telomeres'',” he explained. “It will have ''My telomeres are longer than your telomeres'' type of cocktail talk appeal. That''s fine. I have no problem with that as long as we can follow this sort of population and individuals over decades.”“It will have ''My telomeres are longer than your telomeres'' type of cocktail talk appeal [...] I have no problem with that as long as we can follow this sort of population and individuals...”Shay''s last point is the key—research and data collection. Even those commercializing telomere-length tests agree that our understanding of telomere biology, although extensive, is incomplete and that we have yet to unpick fully the links between telomeres and disease. Stefan Kiechl, a telomere researcher in the Department of Neurology at Innsbruck Medical University (Austria), published an article last year on telomere length and cancer (Willeit et al, 2010). “The appealing thing with telomere length measurements is that they allow the estimation of the biological—in contrast to the chronological—age of an organism. This was previously not possible. Moreover, long telomere length has been linked with a low risk of advanced atherosclerosis, cardiovascular disease and cancer, and, vice versa, short telomere length is associated with a higher risk of these diseases.”But, he said that problems remain to be resolved, such as whether telomere length can only be measured in cells that are readily available, such as leukocytes, and whether telomere length in leukocytes varies substantially from telomere length in other tissues and cells. “Moreover, there is still insufficient knowledge on which lifestyle behaviours and other factors affect telomere length,” he concluded.This might be a bumpy road. When Life Length announced its launch in May, newspapers carried headlines such as ''The £400 test that tells you how long you''ll live'', reporting: “A blood test that can show how fast someone is ageing—and offers the tantalizing possibility of estimating how long they have left to live—is to go on sale to the general public in Britain later this year” (Connor, 2011).The story was catchy, but Life Length officials are determined to explain that, despite the name of the company, its tests do not predict longevity for individuals. Blasco said that the word ''life'' in the name is meant as an analogy between telomeres and life. “A British newspaper chose to use this headline, but the company name has no intention to predict longevity,” she said. Instead, the name refers to extensive research correlating the shortened chromosome tips with the risk for certain diseases and personal habits, such as smoking, obesity, lack of exercise and stress, Blasco explained.Life Length''s test measures the abundance of short telomeres, as they claim that there is genetic evidence that short telomeres are the ones that are relevant to disease. “The preliminary results are exciting: we are observing that the percent of short telomeres with increasing age is more divergent between individuals than average telomere length for the same group of individuals,” Blasco explained. “This is exactly what you would expect from a parameter [abundance of short telomeres] that reflects the effects of environmental factors and lifestyle on people''s telomeres.” She noted that being in a lower quartile of average telomere length and the higher quartile of abundance of short telomeres would indicate that telomeres are shorter than normal for a given age, which has been correlated with a higher risk of developing certain diseases.So, what can be done about an abundance of short telomeres? Lansdorp said that, as a physician, he would be hard pressed to know what to tell patients to do about it. “The best measure of someone''s age and life expectancy is the date on their birth certificate. Telomere length, as a biomarker, shows a clear correlation with age at the population level. For an individual the value of telomere length is very limited,” he said. “I suspect there''s going to be a lot of false alarms based on biological variation as well as measurement errors using these less accurate tests.”“The best measure of someone''s age and life expectancy is the date on their birth certificate. [...] For an individual the value of telomere length is very limited”Harley, however, said that if telomere length were perfectly correlated with age, it would be a useless biomarker, except for in forensic work. “The differences in telomere length between individuals at any given age is where the utility lies [...] people with shorter telomeres are at higher risk for morbidity and mortality. In addition, there is emerging data suggesting that people with shorter telomeres respond differently to certain drugs than people with longer telomeres. This fits into the paradigm of personalized medicine,” he said....if telomere length were perfectly correlated with age, it would be a useless biomarker, except for in forensic workWhile he was at Geron Corporation, Harley was the lead discoverer of telomerase activators purified from the root of Astragalus membranaceus. Harley, Blasco and colleagues have published two peer-reviewed papers on one of those molecules, TA-65—one in humans and the other in mice (de Jesus et al, 2011; Harley et al, 2011). Both showed positive effects on certain health measures, and Blasco''s lab found that mice treated with TA-65 had improved health status compared with those given a placebo. “However, we did not see significant effects on longevity,” Blasco said.In the meantime, researchers are squabbling about the techniques used by the testing companies. Greider maintains that Flow-FISH (fluorescence in situ hybridization), which was developed by Lansdorp, is the gold standard used by clinical researchers and that it is the most reliable technique. Harley argues that the quantitative real-time (qRT)-PCR assay developed by the Blackburn lab is just as reliable, and easier to scale-up for commercial use. Blasco pointed out that, similarly to its rivals, the qFISH used by Life Length offers measurements of average telomere length, but that it is the only company to report the percentage of short telomeres in individual cells. In the end, Lansdorp suggested that the errors inherent in the tests, along with biological variations and cost, should give healthy people pause for thought about being tested.Ultimately, whichever test for telomere length is used and whatever the results can tell us about longevity and health, it is unlikely that manipulating telomere length will unlock the fountain of youth, à la Spanish explorer Juan Ponce de León y Figueroa (1474–1521). Nevertheless, telomere testing could become a key diagnostic tool for getting a few more years out of life, and it could motivate people to follow healthier lifestyles. As Kiechl pointed out, “[t]here is convincing evidence that calculation of an individual''s risk of cardiovascular disease [...] substantially enhances compliance for taking medicines and the willingness to change lifestyle. Knowing one''s biological age may well have similar favourable effects.”     

The puzzle of sympatry. Recent evidence supports the notion of sympatric speciation--the rise of new species in the same location--but the reasons for this phenomenon remain elusive

Sympatric speciation—the rise of new species in the absence of geographical barriers—remains a puzzle for evolutionary biologists. Though the evidence for sympatric speciation itself is mounting, an underlying genetic explanation remains elusive.For centuries, the greatest puzzle in biology was how to account for the sheer variety of life. In his 1859 landmark book, On the Origin of Species, Charles Darwin (1809–1882) finally supplied an answer: his grand theory of evolution explained how the process of natural selection, acting on the substrate of genetic mutations, could gradually produce new organisms that are better adapted to their environment. It is easy to see how adaptation to a given environment can differentiate organisms that are geographically separated; different environmental conditions exert different selective pressures on organisms and, over time, the selection of mutations creates different species—a process that is known as allopatric speciation.It is more difficult to explain how new and different species can arise within the same environment. Although Darwin never used the term sympatric speciation for this process, he did describe the formation of new species in the absence of geographical separation. “I can bring a considerable catalogue of facts,” he argued, “showing that within the same area, varieties of the same animal can long remain distinct, from haunting different stations, from breeding at slightly different seasons, or from varieties of the same kind preferring to pair together” (Darwin, 1859).It is more difficult to explain how new and different species can arise within the same environmentIn the 1920s and 1930s, however, allopatric speciation and the role of geographical isolation became the focus of speciation research. Among those leading the charge was Ernst Mayr (1904–2005), a young evolutionary biologist, who would go on to influence generations of biologists with his later work in the field. William Baker, head of palm research at the Royal Botanic Gardens, Kew in Richmond, UK, described Mayr as “one of the key figures to crush sympatric speciation.” Frank Sulloway, a Darwin Scholar at the Institute of Personality and Social Research at the University of California, Berkeley, USA, similarly asserted that Mayr''s scepticism about sympatry was central to his career.The debate about sympatric and allopatric speciation has livened up since Mayr''s death…Since Mayr''s death in 2005, however, several publications have challenged the notion that sympatric speciation is a rare exception to the rule of allopatry. These papers describe examples of both plants and animals that have undergone speciation in the same location, with no apparent geographical barriers to explain their separation. In these instances, a single ancestral population has diverged to the extent that the two new species cannot produce viable offspring, despite the fact that their ranges overlap. The debate about sympatric and allopatric speciation has livened up since Mayr''s death, as Mayr''s influence over the field has waned and as new tools and technologies in molecular biology have become available.Sulloway, who studied with Mayr at Harvard University, in the late 1960s and early 1970s, notes that Mayr''s background in natural history and years of fieldwork in New Guinea and the Solomon Islands contributed to his perception that the bulk of the data supported allopatry. “Ernst''s early career was in many ways built around that argument. It wasn''t the only important idea he had, but he was one of the strong proponents of it. When an intellectual stance exists where most people seem to have gotten it wrong, there is a tendency to sort of lay down the law,” Sulloway said.Sulloway also explained that Mayr “felt that botanists had basically led Darwin astray because there is so much evidence of polyploidy in plants and Darwin turned in large part to the study of botany and geographical distribution in drawing evidence in The Origin.” Indeed, polyploidization is common in plants and can lead to ‘instantaneous'' speciation without geographical barriers.In February 2006, the journal Nature simultaneously published two papers that described sympatric speciation in animals and plants, reopening the debate. Axel Meyer, a zoologist and evolutionary biologist at the University of Konstanz, Germany, demonstrated with his colleagues that sympatric speciation has occurred in cichlid fish in Lake Apoyo, Nicaragua (Barluenga et al, 2006). The researchers claimed that the ancestral fish only seeded the crater lake once; from this, new species have evolved that are distinct and reproductively isolated. Meyer''s paper was broadly supported, even by critics of sympatric speciation, perhaps because Mayr himself endorsed sympatric speciation among the cichlids in his 2001 book What Evolution Is. “[Mayr] told me that in the case of our crater lake cichlids, the onus of showing that it''s not sympatric speciation lies with the people who strongly believe in only allopatric speciation,” Meyer said.…several scientists involved in the debate think that molecular biology could help to eventually resolve the issueThe other paper in Nature—by Vincent Savolainen, a molecular systematist at Imperial College, London, UK, and colleagues—described the sympatric speciation of Howea palms on Lord Howe Island (Fig 1), a minute Pacific island paradise (Savolainen et al, 2006a). Savolainen''s research had originally focused on plant diversity in the gesneriad family—the best known example of which is the African violet—while he was in Brazil for the Geneva Botanical Garden, Switzerland. However, he realized that he would never be able prove the occurrence of sympatry within a continent. “It might happen on a continent,” he explained, “but people will always argue that maybe they were separated and got together after. […] I had to go to an isolated piece of the world and that''s why I started to look at islands.”Open in a separate windowFigure 1Lord Howe Island. Photo: Ian Hutton.He eventually heard about Lord Howe Island, which is situated just off the east coast of Australia, has an area of 56 km² and is known for its abundance of endemic palms (Sidebar A). The palms, Savolainen said, were an ideal focus for sympatric research: “Palms are not the most diverse group of plants in the world, so we could make a phylogeny of all the related species of palms in the Indian Ocean, southeast Asia and so on.”…the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common

Sidebar A | Research in paradise

Alexander Papadopulos is no Tarzan of the Apes, but he has spent a couple months over the past two years aloft in palm trees hugging rugged mountainsides on Lord Howe Island, a Pacific island paradise and UNESCO World Heritage site.Papadopulos—who is finishing his doctorate at Imperial College London, UK—said the views are breathtaking, but the work is hard and a bit treacherous as he moves from branch to branch. “At times, it can be quite hairy. Often you''re looking over a 600-, 700-metre drop without a huge amount to hold onto,” he said. “There''s such dense vegetation on most of the steep parts of the island. You''re actually climbing between trees. There are times when you''re completely unsupported.”Papadopulos typically spends around 10 hours a day in the field, carrying a backpack and utility belt with a digital camera, a trowel to collect soil samples, a first-aid kit, a field notebook, food and water, specimen bags, tags to label specimens, a GPS device and more. After several days in the field, he spends a day working in a well-equipped field lab and sleeping in the quarters that were built by the Lord Howe governing board to accommodate the scientists who visit the island on various projects. Papadopulos is studying Lord Howe''s flora, which includes more than 200 plant species, about half of which are indigenous.Vincent Savolainen said it takes a lot of planning to get materials to Lord Howe: the two-hour flight from Sydney is on a small plane, with only about a dozen passengers on board and limited space for equipment. Extra gear—from gardening equipment to silica gel and wood for boxes in which to dry wet specimens—arrives via other flights or by boat, to serve the needs of the various scientists on the team, including botanists, evolutionary biologists and ecologists.Savolainen praised the well-stocked researcher station for visiting scientists. It is run by the island board and situated near the palm nursery. It includes one room for the lab and another with bunks. “There is electricity and even email,” he said. Papadoupulos said only in the past year has the internet service been adequate to accommodate video calls back home.Ian Hutton, a Lord Howe-based naturalist and author, who has lived on the island since 1980, said the island authorities set limits on not only the number of residents—350—but also the number of visitors at one time—400—as well as banning cats, to protect birds such as the flightless wood hen. He praised the Imperial/Kew group: “They''re world leaders in their field. And they''re what I call ‘Gentlemen Botanists''. They''re very nice people, they engage the locals here. Sometimes researchers might come here, and they''re just interested in what they''re doing and they don''t want to share what they''re doing. Not so with these people. Savolainen said his research helps the locals: “The genetics that we do on the island are not only useful to understand big questions about evolution, but we also always provide feedback to help in its conservation efforts.”Yet, in Savolainen''s opinion, Mayr''s influential views made it difficult to obtain research funding. “Mayr was a powerful figure and he dismissed sympatric speciation in textbooks. People were not too keen to put money on this,” Savolainen explained. Eventually, the Leverhulme Trust (London, UK) gave Savolainen and Baker £70,000 between 2003–2005 to get the research moving. “It was enough to do the basic genetics and to send a research assistant for six months to the island to do a lot of natural history work,” Savolainen said. Once the initial results had been processed, the project received a further £337,000 from the British Natural Environment Research Council in 2008, and €2.5 million from the European Research Council in 2009.From the data collected on Lord Howe Island, Savolainen and his team constructed a dated phylogenetic tree showing that the two endemic species of the palm Howea (Arecaceae; Fig 2) are sister taxa. From their tree, the researchers were able to establish that the two species—one with a thatch of leaves and one with curly leaves—diverged long after the island was formed 6.9 million years ago. Even where they are found in close proximity, the two species cannot interbreed as they flower at different times.Open in a separate windowFigure 2The two species of Howea palm. (A) Howea fosteriana (Kentia palm). (B) Howea belmoreana. Photos: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.According to the researchers, the palm speciation probably occurred owing to the different soil types in which the plants grow. Baker explained that there are two soil types on Lord Howe—the older volcanic soil and the younger calcareous soils. The Kentia palm grows in both, whereas the curly variety is restricted to the volcanic soil. These soil types are closely intercalated—fingers and lenses of calcareous soils intrude into the volcanic soils in lowland Lord Howe Island. “You can step over a geological boundary and the palms in the forest can change completely, but they remain extremely close to each other,” Baker said. “What''s more, the palms are wind-pollinated, producing vast amounts of pollen that blows all over the place during the flowering season—people even get pollen allergies there because there is so much of the stuff.” According to Savolainen, that the two species have different flowering times is a “way of having isolation so that they don''t reproduce with each other […] this is a mechanism that evolved to allow other species to diverge in situ on a few square kilometres.”According to Baker, the absence of a causative link has not been demonstrated between the different soils and the altered flowering times, “but we have suggested that at the time of speciation, perhaps when calcareous soils first appeared, an environmental effect may have altered the flowering time of palms colonising the new soil, potentially causing non-random mating and kicking off speciation. This is just a hypothesis—we need to do a lot more fieldwork to get to the bottom of this,” he said. What is clear is that this is not allopatric speciation, as “the micro-scale differentiation in geology and soil type cannot create geographical isolation”, said Baker.…although molecular data will add to the debate, it will not settle it aloneThe results of the palm research caused something of a splash in evolutionary biology, although the study was not without its critics. Tod Stuessy, Chair of the Department of Systematic and Evolutionary Botany at the University of Vienna, Austria, has dealt with similar issues of divergence on Chile''s Juan Fernández Islands—also known as the Robinson Crusoe Islands—in the South Pacific. From his research, he points out that on old islands, large ecological areas that once separated species—and caused allopatric speciation—could have since disappeared, diluting the argument for sympatry. “There are a lot of cases [in the Juan Fernández Islands] where you have closely related species occurring in the same place on an island, even in the same valley. We never considered that they had sympatric origins because we were always impressed by how much the island had been modified through time,” Stuessy said. “What [the Lord Howe researchers] really didn''t consider was that Lord Howe Island could have changed a lot over time since the origins of the species in question.” It has also been argued that one of the palm species on Lord Howe Island might have evolved allopatrically on a now-sunken island in the same oceanic region.In their response to a letter from Stuessy, Savolainen and colleagues argued that erosion on the island has been mainly coastal and equal from all sides. “Consequently, Quaternary calcarenite deposits, which created divergent ecological selection pressures conducive to Howea species divergence, have formed evenly around the island; these are so closely intercalated with volcanic rocks that allopatric speciation due to ecogeographic isolation, as Stuessy proposes, is unrealistic” (Savolainen et al, 2006b). Their rebuttal has found support in the field. Evolutionary biologist Loren Rieseberg at the University of British Columbia in Vancouver, Canada, said: “Basically, you have two sister species found on a very small island in the middle of the ocean. It''s hard to see how one could argue anything other than they evolved there. To me, it would be hard to come up with a better case.”Whatever the reality, several scientists involved in the debate think that molecular biology could help to eventually resolve the issue. Savolainen said that the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common. New sequencing techniques should enable the team to obtain a complete genomic sequence for the palms. Savolainen said that next-generation sequencing is “a total revolution.” By using sequencing, he explained that the team, “want to basically dissect exactly what genes are involved and what has happened […] Is it very special on Lord Howe and for this palm, or is [sympatric speciation] a more general phenomenon? This is a big question now. I think now we''ve found places like Lord Howe and [have] tools like the next-gen sequencing, we can actually get the answer.”Determining whether sympatric speciation occurs in animal species will prove equally challenging, according to Meyer. His own lab, among others, is already looking for ‘speciation genes'', but this remains a tricky challenge. “Genetic models […] argue that two traits (one for ecological specialisation and another for mate choice, based on those ecological differences) need to become tightly linked on one chromosome (so that they don''t get separated, often by segregation or crossing over). The problem is that the genetic basis for most ecologically relevant traits are not known, so it would be very hard to look for them,” Meyer explained. “But, that is about to change […] because of next-generation sequencing and genomics more generally.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his viewsOthers are more cautious. “In some situations, such as on isolated oceanic islands, or in crater lakes, molecular phylogenetic information can provide strong evidence of sympatric speciation. It also is possible, in theory, to use molecular data to estimate the timing of gene flow, which could help settle the debate,” Rieseberg said. However, he cautioned that although molecular data will add to the debate, it will not settle it alone. “We will still need information from historical biogeography, natural history, phylogeny, and theory, etc. to move things forward.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his views. “I can only imagine that it would''ve been great fun to engage directly with him [on sympatry on Lord Howe],” Baker said. “It''s a shame that he wasn''t alive to comment on [our paper].” In fact, Mayr was not really as opposed to sympatric speciation as some think. “If one is of the opinion that Mayr opposed all forms of sympatric speciation, well then this looks like a big swing back the other way,” Sulloway commented. “But if one reads Mayr carefully, one sees that he was actually interested in potential exceptions and, as best he could, chronicled which ones he thought were the best candidates.”Mayr''s opinions aside, many biologists today have stronger feelings against sympatric speciation than he did himself in his later years, Meyer added. “I think that Ernst was more open to the idea of sympatric speciation later in his life. He got ‘softer'' on this during the last two of his ten decades of life that I knew him. I was close to him personally and I think that he was much less dogmatic than he is often made out to be […] So, I don''t think that he is spinning in his grave.” Mayr once told Sulloway that he liked to take strong stances, precisely so that other researchers would be motivated to try to prove him wrong. “If they eventually succeeded in doing so, Mayr felt that science was all the better for it.”? Open in a separate windowAlex Papadopulos and Ian Hutton doing fieldwork on a very precarious ridge on top of Mt. Gower. Photo: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.     

Isolation Discovery of the Role of Dihydrotestosterone: the Work of Jean D. Wilson

The Conversion of Testosterone to 5α-Androstan-17β-ol-3-one by Rat Prostate in Vivo and in Vitro (Bruchovsky, N., and Wilson, J. D. (1968) J. Biol. Chem. 243, 2012–2021)The Intranuclear Binding of Testosterone and 5α-Androstan-17β-ol-3-one by Rat Prostate (Bruchovsky, N., and Wilson, J. D. (1968) J. Biol. Chem. 243, 5953–5960)Jean Donald Wilson was born in 1932 in a small town in the Texas Panhandle. He attended the University of Texas at Austin, and although he was a pre-med student, he decided to major in chemistry and minor in zoology. He graduated in 1951 and enrolled in medical school at the University of Texas Southwestern Medical Center at Dallas, where he spent a summer working with Donald W. Seldin on the effects of adrenal hormones on acid-base balance in the rat.Open in a separate windowJean D. WilsonAfter earning his M.D. in 1955, Wilson decided to stay in Dallas and did a residency in internal medicine at the Parkland Memorial Hospital. During this time, he spent 6 elective months working with Marvin D. Siperstein on the effects of diets high in saturated and unsaturated fats on the metabolism and excretion of cholesterol and bile acids in rats.When Wilson completed his residency in 1958, the physician''s draft was in effect, and he went to the National Institutes of Health to work as a clinical associate in the National Heart Institute. He spent most of his time doing clinical duties, but he also managed to spend part of each day working in the laboratory with Sidney Udenfriend, investigating the mechanism of ethanolamine biosynthesis.In 1960, Wilson returned to UT Southwestern as an instructor in the department of internal medicine, where he remains today as the Charles Cameron Sprague Distinguished Chair in Biomedical Science.Since starting his laboratory at UT Southwestern, Wilson''s research has focused on two areas. The first is cholesterol. Between 1960 and 1972, he developed methods for the quantification of cholesterol synthesis, absorption, degradation, and excretion in intact animals, with the aim of understanding the feedback control of cholesterol synthesis and turnover. He also demonstrated that plasma cholesterol is synthesized in the intestinal wall and liver, which led to the development of paradigms that defined the contributions of diet and endogenous synthesis to cholesterol turnover in humans and baboons.Wilson''s second research focus has been on hormone action, specifically the mechanisms by which steroid hormones influence protein turnover in the urogenital tract. A leading theory in the early 1960s was that steroid hormones regulate protein biosynthesis by controlling amino acid transport into cells (1). However, Wilson found that testosterone administration increased protein synthesis in the male urogenital tract prior to enhancement of amino acid transport, indicating that the increase in protein biosynthesis was secondary to an increase in RNA formation (2). He later showed that gonadal steroids are physically concentrated at the sites of mRNA synthesis in target tissues (3), but chromatin''s insolubility made it difficult to figure out to which macromolecule the hormones were attached.In 1966, Nicholas Bruchovsky joined Wilson''s lab as a postdoctoral fellow. His project was to determine whether a testosterone-binding protein could be isolated from prostatic nuclei. He injected animals with tritiated testosterone and used gel exclusion chromatography to show that radioactivity was bound to the nuclear components. Bruchovsky decided to confirm the identity of the bound hormone, but when he tried to isolate the radioactive nuclear material using thin layer chromatography, he was able to recover only a very small amount of it. By examining the chromatograms in discrete sections, Wilson and Bruchovsky discovered that the majority of radioactivity co-migrated with dihydrotestosterone, a potent metabolite of testosterone. Over the next several months, Wilson and Bruchovsky showed that the prostate contained enzymes that were very active in converting testosterone to dihydrotestosterone, and dihydrotestosterone to androstanediol, and managed to partially characterize testosterone 5α-reductase, the chromatin-associated nuclear enzyme that converts testosterone to dihydrotestosterone. They wrote up these results in a paper reprinted here as the first Journal of Biological Chemistry (JBC) Classic.This paper is the first to attach biological significance to the formation of dihydrotestosterone within target cells for testosterone. It became a Current Contents Citation Classic and was cited more than 640 times between 1968 and 1980.Wilson and Bruchovsky followed up this paper with the second JBC Classic in which they looked at the localization of dihydrotestosterone. They intravenously administered [l,2-³H]testosterone to rats and used gel filtration to examine the nuclear extracts. Their results confirmed that dihydrotestosterone was the predominant form of hormone bound to chromatin, proving that dihydrotestosterone is the active form of testosterone in peripheral tissues. Wilson went on to show that mutations in the steroid 5α-reductase gene cause a form of male pseudohermaphroditism in humans.Wilson is the recipient of several honors and awards, including the American Academy of Arts and Sciences Amory Prize (1977), the Society for Endocrinology Henry Dale Medal (1991), the Worcester Foundation for Experimental Biology Gregory Pincus Award (1992), the Endocrine Society Fred Conrad Koch Award (1993), and the Association of American Physicians Kober Medal (1999). He also is a member of the National Academy of Sciences, the Institute of Medicine, the American Philosophical Society, and the American Academy of Arts and Sciences, and he is a fellow of the Royal College of Physicians.¹     

Itinerary of Truman G. Yuncker’s expeditions

Many of the systematically and historically valuable collections in the DePauw University Herbarium (DPU), Greencastle, Indiana, were made by Truman G. Yuncker during his numerous expeditions. He collected in large, and until then unexplored, areas of Honduras, and undertook several expeditions to islands in the South Pacific (Manua, Niue, and Tonga) and Hawaii. In his late years he collected in the West Indies and in Brazil. His extensive collections ofCuscuta (Cuscutaceae) and Piperaceae each became among the largest in the world. In this article an itinerary of his expeditions is presented.     

Darwin and Dostoyevsky: twins

The Russian poet Fyodor Dostoyevsky published an insightful treatise on human nature in his novel ‘The Brothers Karamazov'' in 1880. His account of humanity may offer as much insight into human nature for scientists as Darwin''s The Descent of Man.Late in the nineteenth century, Charles Darwin (1809–1882) and Fyodor Dostoyevsky (1821–1881) published accounts of their investigation of humankind. Darwin did so in 1871 in his book The Descent of Man, Dostoyevsky in 1880 in the parable of The Grand Inquisitor in his book The Brothers Karamazov. Last year we celebrated Darwin''s anniversary; for biologists, 2010—the 130th anniversary of Dostoyevsky''s book—might have been the year of Dostoyevsky.Dostoyevsky was familiar with Darwin''s doctrine and he was willing to admit “man''s descent from the ape”. An orthodox Christian, he put this sentiment in religious terms: “It does not really matter what man''s origins are, the Bible does not explain how God moulded him out of clay or carved him out of stone. Yet, he saw a difference between humans and animals: humans have a soul.The philosopher Nikolay Berdyayev noticed: “[Dostoyevsky] concealed nothing, and that''s why he could make astonishing discoveries. In the fate of his heroes he relates his own destiny, in their doubts he reveals his vacillations, in their ambiguity his self-splitting, in their criminal experience the secret crimes of his spirit.”The Grand Inquisitor can be read as Dostoyevsky''s treatise on human nature. In the tale, Jesus Christ revisits Earth during the period of the Inquisition and is arrested by the Church and sentenced to death. The Grand Inquisitor comes to visit Jesus in his prison cell to argue with him about their conceptions of human nature. He explains that humankind needs to be ruled to be happy and that the true freedom Jesus offered doomed humanity to suffering and unhappiness. Dostoyevsky''s superposition of these two points of view on humankind reminds us of the principle of complementarity, by which the physicist Niels Bohr attempted to account for the particle-wave duality of quantum physics.Dostoyevsky conceives of humans as complex, contradictory and inconsistent creatures. Humans perceive personal liberty as a burden and are willing to barter for it, as the Grand Inquisitor explained to Christ, for “miracle, mystery, and authority”. In addition, “the mystery of human being does not only rest in the desire to live, but in the problem: for what should one live at all?” We might say that these faculties make Homo sapiens a religious species. Not in the sense of believing in gods or a god, but in the sense of the Latin word religare, which means to bind, connect or enfold. Humans are mythophilic animals, driven by a need to find a complete explanation for events in terms of intentions and purposes.Research into the neurological bases of imagination, transcendence, metaphorability, art and religion, as well as moral behaviour and judgement (Trimble, 2007) is consistent with Dostoyevsky''s views. It has identified areas of the brain that have been labelled as the ‘god module'' or ‘god spot'' (Alper, 2001). These areas represent a new stratum of evolutionary complexity, an emergence specific to the human species. Their mental translations might be tentatively designated as the Darwinian soul, anchored in the material substrate and neither immortal nor cosmic. As consciousness and volition have become legitimate subjects of neuroscience (Baars, 2003), the Darwinian soul, and with it spirituality, seems to be ripe for scientific inquiry: the quest for meaning, creation and perception of metaphors, the experience of the trinity of Truth, Good and Beauty, the capacity for complex feelings that Immanuel Kant called sublimity, the thrill of humour and play, the power of empathy and the follies of boundless love or hate. Secularization does not erase the superstructure of spirituality: it is reflected, however queer it might seem, in the hypertrophy of the entertainment industry and also, more gloomily, in spiritual conflicts on a global scale.Dostoyevsky''s views on the human soul might be closer to those of Alfred Russel Wallace, who believed that an unknown force directed evolution towards an advanced organization. We can identify this ‘force'' as the second law of thermodynamics (Sharma & Annila, 2007). By moving evolving systems ever farther away from equilibrium, the second law eventually became the Creator of the ‘Neuronal God''.Christ, in the parable of the Grand Inquisitor, might be conceived of as a symbol of the truth outside the human world. Christ was listening to the assertions and questions of his interlocutor, but did not say a single word. His silence is essential to the parable.Similarly, the cosmos, to which humanity has been addressing its questions and predications, remains silent. By science, we increase knowledge only by tiny increments. The ‘god modules'' of our brains, unsatisfied and impatient, have hastily provided the full truth, deposited in the Holy Scripture. There are at least three books claiming to contain the revealed and hence unquestionable truth: the Judaic Torah, Christian Bible and Muslim Qur''an. A dogma of genocentrism in biology might offer an additional Scripture: the sequence of DNA in the genomes.Dostoyevsky''s legacy may suggest an amendment to the UN Charter. We, united humankind, solemnly declare: No truth has ever been revealed to us; we respect and tolerate each other in our independent searching and erring.     

Govindjee,an institution,at his 80th (really 81st) birthday in Třeboň in October, 2013: a pictorial essay

Govindjee (one name only), who himself is an institution, has been recognized and honored by many in the past for he is a true ambassador of “Photosynthesis Research” to the World. He has been called “Mr. Photosynthesis”, and compared to the Great Wall of China. To us in T?eboň, he has been a great research collaborator in our understanding of chlorophyll a fluorescence in algae and in cyanobacteria, and more than that a friend of the Czech “Photosynthesis” group, from the time of Ivan ?etlík (1928–2009) and of Zdeněk ?esták (1932–2008). Govindjee’s 80th (really 81st) birthday was celebrated by the Institute of Microbiology, Laboratory of Photosynthesis, by toasting him with an appropriate drink of a suspension of green algae grown at the institute itself. After my presentation, on October 23, 2013, of Govindjee’s contributions to photosynthesis, and his intimate association with the photosynthetikers (in Jack Myers’s words) of the Czech Republic, Govindjee gave us his story of how he began research in photosynthesis in the late 1950s. This was followed by a talk on October 25 by him on “Photosynthesis: Stories of the Past.” Everyone enjoyed his animated talk—it was full of life and enjoyment. Here, I present a brief pictorial essay on Govindjee at his 80th (really 81st) birthday in T?eboň during October 23–25, 2013.