Tribute to Tinbergen: The Place of Animal Behavior in Biology

Tinbergen is famous for emphasizing behavioral fieldwork and experimentation under natural circumstances, for founding the field of ethology, for getting a Nobel Prize, and for mentoring Richard Dawkins. He is known for dividing behavior studies into physiology, development, natural selection, and evolutionary history. In the decades since Tinbergen was active, some of the best research in animal behavior fuses Tinbergen's questions, connecting genes to behavioral phenotypes, for example. Behavior is the most synthetic of the life sciences, because observing the actions of an organism can tell us what all those physical and physiological traits are for. Insights from behavior tell us how traits in one individual impact those in another in ways that challenge our definition of an organism. Behavioral conflict and cooperation among animals has led to theory that explains within‐organism conflict and cooperation and human malfunctions of many kinds. Darwin certainly began the evolutionary study of behavior, but Tinbergen brought it forward to the heart of biology. The challenge for the future is to apply concepts from animal behavior across biology with tools that would have amazed Tinbergen.     

A Concept of Educational Activity for Schoolchildren

About two years ago, on a cool Southern California day, Vasili Davydov addressed a group of social scientists at the University of California, San Diego. He began his talk with a paradox. He had come, he said, to tell us about educational activity. He promised to exhibit principles that promote educational activity, and applied programs deriving from those principles. Then he laughed. "But you'll never see educational activity in the school," he said, and laughed again.     

Minireview: Mutations and Diseases of G Protein Coupled Receptors

Abstract

Currently known disease-causing mutations in G protein coupled receptors are reviewed and discussed in conjunction with other naturally occurring receptor mutations. Special emphasis is made on opsin, vasopressin and MSH receptor mutations and what they tell are begining to tell us about the inner workings of this superfamily of signalling molecules.     

Homogénéité ou hétérogénéité dans le métal des dépôts de l’Âge du Bronze : estimations sur leur formation à partir des isotopes du plomb

Lead isotope analysis was applied to three representative Late Bronze Age hoards from the Iberian Peninsula, for all of which compositional analyses are available. Unpublished isotopic evidence from the cave of Muricecs (Lleida) and the settlement of Las Lunas (Toledo) are compared to the published results for weapons from the Ría de Huelva, one of the most important Late Bronze Age hoards from Western Europe. Lead isotope analysis can tell us the sources of the metal used to make the artifacts in each hoard. The limited number of geologic reference points makes it difficult to determine all of the ore sources, but the analyses do give us evidence about the degree of homogeneity of the metal in the artifacts. As a result, one can separate metallic composition from artifact typology and thereby evaluate how the hoards were formed and what their functions were. Elemental analysis is unsuitable for this purpose because Late Bronze Age metals from Iberia are very homogenous and have few impurities.     

How Could Language Have Evolved?

The evolution of the faculty of language largely remains an enigma. In this essay, we ask why. Language''s evolutionary analysis is complicated because it has no equivalent in any nonhuman species. There is also no consensus regarding the essential nature of the language “phenotype.” According to the “Strong Minimalist Thesis,” the key distinguishing feature of language (and what evolutionary theory must explain) is hierarchical syntactic structure. The faculty of language is likely to have emerged quite recently in evolutionary terms, some 70,000–100,000 years ago, and does not seem to have undergone modification since then, though individual languages do of course change over time, operating within this basic framework. The recent emergence of language and its stability are both consistent with the Strong Minimalist Thesis, which has at its core a single repeatable operation that takes exactly two syntactic elements a and b and assembles them to form the set {a, b}.It is uncontroversial that language has evolved, just like any other trait of living organisms. That is, once—not so long ago in evolutionary terms—there was no language at all, and now there is, at least in Homo sapiens. There is considerably less agreement as to how language evolved. There are a number of reasons for this lack of agreement. First, “language” is not always clearly defined, and this lack of clarity regarding the language phenotype leads to a corresponding lack of clarity regarding its evolutionary origins. Second, there is often confusion as to the nature of the evolutionary process and what it can tell us about the mechanisms of language. Here we argue that the basic principle that underlies language''s hierarchical syntactic structure is consistent with a relatively recent evolutionary emergence.     

Sacrifice as the ideal hunt: a cosmological explanation for the origin of reindeer domestication

The Siberian Northeast shows striking parallels between the cosmologies of hunters and reindeer herders. What may this tell us about the transformation from hunting to pastoralism? This article argues for a structural identity between hunting and sacrifice, and for the domestication of the reindeer as the result of hunters' efforts to use sacrifice to control the accidental variables of the hunt. Hunters can practise their ethos of ‘trust’ with prey only through highly controlled ritual enactments. We describe two: the famous bear festival of the Amur Gulf region and the consecrated reindeer of the Eveny. Both express the same overall logic by which sacrifice functions as an ideal hunt. The animal is involved in a relation not of domination but of trust, while also undergoing a process of taming. We therefore suggest that the reindeer's domestication may be based not only on ecological or economic adaptations, but also on cosmology.     

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.     

Bioinformatics and discovery: induction beckons again

With the flood of information from genomics, proteomics, and microarrays, what we really need now is the computer software to tell us what it all means. Or do we?     

Book Reviews

Teach Yourself Genetics R. J. BERRY pp. xi+164, 24 figs. London: The English Universities Press Ltd, 1965. 7s. 6d. Reviewed by G. Haskell

The Tissues of The Body (5th ed.). SIR W. E. LE GROS CLARK xi+423 pp. Oxford: Clarendon Press, 1965. 55s. Reviewed by P. C. Williams

Nuffield Biology Texts and Teachers' Guides I. Introducing Living Things II. Life and Living Processes HI. The Maintenance of Life IV. Living Things in Action Longmans/Penguin 1966. Volume V, to be published April 1967—not reviewed. Reviewed by John Mattocks and Peter Prosser

Animal Biology A. J. GROVE and G. E. NEWELL In collaboration with J. D. CARTHY and E. H. MERCER University Tutorial Press. 7th Edition. 38s. 6d. Reviewed by W. H. Freeman     

To Imagine an Australian Museum

ABSTRACT

Museums are our memory banks. They tell us where we have come from. They also allow us to imagine where we are heading. Which is why it should trouble us that there has never been a truly Australian museum. Each of our state and federal museums has been built on Aboriginal collections, and each has been built on distinctly Western or European concepts, values, categories and practices. Some of these are unavoidable, but are they all? Are we too far down the path to restump the foundations of our institutions and the narratives they perpetuate in public life? The South Australian Museum holds one of the most important collections of Aboriginal material culture in the world. It is, therefore, given the story it can tell about ancient and enduring cultures, one of the most important collections of human heritage on our planet. What we do with such collections, and what we don’t, defines us. This is the great challenge of contemporary custodianship. These collections are calling us out. In this lecture I examine the South Australian Museum’s response to this challenge. Over the past two years our Museum has undertaken a comprehensive rethink of our policies and practices and the politics of both. We are also transforming the way we work with Aboriginal communities and custodians. This is not simply a question of how collections are displayed or exhibitions are developed. We are rethinking the terms of our custodianship, and the kind of truly Australian Museum that could evolve around those new foundations.     

There is,indeed, a misunderstanding: A reply to Hekala and Buell

We believe that the misunderstanding is on the part of Hekala and Buell. They criticize us for using data from different historic periods. If sociobiology has value in accounting for human conduct, sociobiological principles should operate in all cultures and in all eras. While our data may be incomplete in the eyes of historians, they are complete enough to inform us of the genetic relatedness of persons in real or potential conflicts and to tell us the outcomes of these conflicts.     

The Prion Protein Knockout Mouse: A Phenotype Under Challenge

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?Key Words: transmissible spongiform encephalopathy, amyloid, PrP     

Uncomprising activist: Richard Greener,first black graduate of Harvard College

This article investigates what narrations on the symbolic complex of virginity in the life-stories of second-generation women of Moroccan descent in The Netherlands can tell us about the ways these women construct, maintain and combine their various social identifications. It is demonstrated that these biographical narratives contain numerous episodes in which the women improvise upon and shift the meanings of Moroccan core-values like virginity and obedience to one's parents. It is argued that they do so in ways that allow their identifying with values that are cherished within Moroccan circles to be combined with upholding cultural notions that are highly valued by Dutch peers with whom they also identify. It is also pointed out, however, that their drawing upon multicultural capital to create new strategies of living is not without constraints.     

A prophet but not for profit: ethical value and character in Ghanaian Pentecostalism

The anthropological study of value has gained much currency in recent years. This article speaks to the importance of Pentecostal practices in understanding the qualitative aspects of value in Ghana. It demonstrates how practices relating to wealth accumulation and redistribution are in interaction with ethical evaluations about the character of charismatic Christian prophets. The moral evaluation of wealth of certain prophets, and the links perceived between their use of wealth and their character, tell us something about the moral climate in contemporary Ghanaian society, where wealth cannot simply be measured quantitatively (through acquiring riches), but also ought to be assessed qualitatively (discerned through the quality of one's acts).     

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 Development of Play in Preschoolers

The motives of play activity constitute a key question. It is no accident that views on play diverge most conspicuously with regard to the the stimuli leading to play. Theories of satisfaction, pleasure, internal primary drives and self-affirmation—all "in-depth theories"—are essentially theories of the motivating forces that give rise to play. The principal flaw in these conceptions is how they construe the motivating forces of play: they are situated in the subject, in the child and in the child's experiences. These theories discount the fact that these experiences are but secondary to an activity, i.e., they are symptomatic in that they indicate the activity is indeed taking place, but they tell us nothing about the real, objective, stimuli of the activity.     

The Prion Protein Knockout Mouse

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?     

A New Frontier for Palaeobiology: Earth's Vast Deep Biosphere

Diverse micro‐organisms populate a global deep biosphere hosted by rocks and sediments beneath land and sea, containing more biomass than any other biome except forests. This paper reviews an emerging palaeobiological archive of these dark habitats: microfossils preserved in ancient pores and fractures in the crust. This archive, seemingly dominated by mineralized filaments (although rods and coccoids are also reported), is presently far too sparsely sampled and poorly understood to reveal trends in the abundance, distribution, or diversity of deep life through time. New research is called for to establish the nature and extent of the fossil record of Earth's deep biosphere by combining systematic exploration, rigorous microanalysis, and experimental studies of both microbial preservation and the formation of abiotic pseudofossils within the crust. It is concluded that the fossil record of Earth's largest microbial habitat may still have much to tell us about the history of life, the evolution of biogeochemical cycles, and the search for life on Mars.     

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.”