BACTERIAL AND CHEMICAL WARFARE—The Current Status

For fourteen years public attention has been focused so sharply on atomic weapons as to lose sight of other, less spectacular but equally significant advances in the art of warfare.In the shadows cast by brilliant research in nuclear physics are hidden startling advances in the field of chemical and biological weapons. These weapons, as now developed, are not only capable of producing mass casualties quite comparable with those of atomic bombs, but they also possess certain advantages which may make them the weapons of choice for an unscrupulous enemy.If war should come, it is the medical profession which will have the sole responsibility for protecting the citizens of California against these weapons, and we can therefore delay no longer in acquainting ourselves with their potentialities and characteristics.In this task, we are working under two serious handicaps. The first is that our classical medical training affords little appreciation of the real danger, and the second is the cloak of secrecy surrounding the entire subject.     

Can plant biochemistry contribute to understanding of invasion ecology?

Ecologists have long searched for an explanation as to why some plant invaders become much more dominant in their naturalized range than in their native range, and, accordingly, several non-exclusive ecological hypotheses have been proposed. Recently, a biochemical explanation was proposed--the "novel weapons hypothesis"--based on findings that Centaurea diffusa and Centaurea maculosa produce bioactive compounds (weapons) that are more active against na?ve plant species in the introduced range than against co-evolved species in the native range. In this Opinion article, we revise and expand this biochemical hypothesis and discuss experimental and conceptual advances and limitations.     

Selection on defensive traits in a sterile caste – caste evolution: a mechanism to overcome life‐history trade‐offs?

SUMMARY During development and evolution individuals generally face a trade-off between the development of weapons and gonads. In termites, characterized by reproductive division of labor, a caste evolved—the soldiers—which is completely sterile and which might be released from developmental trade-offs between weapons and testes. These soldiers are exclusively dedicated to defense. First, we investigated whether defensive traits are under selection in sterile termite soldiers using allometric analyses. In soldiers of the genus Cryptotermes phragmotic traits such as a sculptured and foreshortened head evolve rapidly but were also lost twice. Second, we compared the scaling relationships of these weapons with those in solitary insects facing a trade-off between weapons and gonads. Defensive traits consistently had lower slopes than nondefensive traits which supports the existence of stabilizing selection on soldier phragmotic traits in order to plug galleries. Moreover, soldier head widths were colony specific and correlated with the minimum gallery diameter of a colony. This can proximately be explained by soldiers developing from different instars. The scaling relationships of these termite soldiers contrast strikingly with those of weapons of solitary insects, which are generally exaggerated (i.e., overscaling) male traits. These differences may provide important insights into trait evolution. Trade-offs constraining the development of individuals may have been uncoupled in termites by evolving different castes, each specialized for one function. When individuals in social insect are "released" from developmental constraints through the evolution of castes, this certainly contributed to the ecological and evolutionary success of social insects.     

Harder,better, faster,stronger: Weapon size is more sexually dimorphic than weapon biomechanical components in two freshwater anomuran species

Sexual selection influences the evolution of morphological traits that increase the likelihood of monopolizing scarce resources. When such traits are used during contests, they are termed weapons. Given that resources are typically linked to monopolizing mating partners, theory expects only males to bear weapons. In some species, however, females also bear weapons, although typically smaller than male weapons. Understanding why females bear smaller weapons can thus help us understand the selective pressures behind weapon evolution. However, most of our knowledge comes from studies on weapon size, while the biomechanics of weapons, such as the size of the muscles, efficiency, and shape are seldom studied. Our goal was to test if the theoretical expectations for weapon size sexual dimorphism also occur for weapon biomechanics using two aeglid crab species. Males of both species had larger claws which were also stronger than female claws. Male claws were also more efficient than females' claws (although we used only one species in this analysis). For weapon shape, though, only one species differed in the mean claw shape. Regarding scaling differences, in both species, male claws had higher size scaling than females, while only one species had a higher shape scaling. However, male weapons did not have higher scaling regarding strength and efficiency than females. Thus, males apparently allocate more resources in weapons than females, but once allocated, muscle and efficiency follow a similar developmental pathway in both sexes. Taken together, our results show that sexual dimorphism in weapons involves more than differences in size. Shape differences are especially intriguing because we cannot fully understand its causes. Yet, we highlight that such subtle differences can only be detected by measuring and analysing weapon shape and biomechanical components. Only then we might better understand how weapons are forged.     

Bioterrorism: responding to an emerging threat

Only a few years ago bioterrorism was considered a remote concern but few today are complacent about the possibility of biological agents being intentionally used to cause widespread panic, disruption, disease and death. By its very nature, the biological weapons threat - with its close links to naturally occurring infectious agents and disease - requires a different paradigm than that for conventional terrorism, military strikes or attacks caused by other weapons of mass destruction. This evolving threat presents the medical, public health and scientific communities (importantly including biotechnology) with a set of difficult and pressing challenges. This article provides a brief overview of the threat from biological weapons, the nature of a bioterrorist attack and some of the issues that need to be addressed if we are to make meaningful progress to prevent or contain this disturbing and potentially catastrophic danger.     

Is diversification in male reproductive traits driven by evolutionary trade-offs between weapons and nuptial gifts?

Many male animals have evolved exaggerated traits that they use in combat with rival males to gain access to females and secure their reproductive success. But some male animals invest in nuptial gifts that gains them access to females. Both these reproductive strategies are costly in that resources are needed to produce the weapon or nuptial gift. In closely related species where both weapons and nuptial gifts are present, little is known about the potential evolutionary trade-off faced by males that have these traits. In this study, we use dobsonflies (order Megaloptera, family Corydalidae, subfamily Corydalinae) to examine the presence and absence of enlarged male weapons versus nuptial gifts within and among species. Many dobsonfly species are sexually dimorphic, and males possess extremely enlarged mandibles that they use in battles, whereas in other species, males produce large nuptial gifts that increase female fecundity. In our study, we show that male accessory gland size strongly correlates with nuptial gift size and that when male weapons are large, nuptial gifts are small and vice versa. We mapped weapons and nuptial gifts onto a phylogeny we constructed of 57 species of dobsonflies. Our among-species comparison shows that large nuptial gift production evolved in many species of dobsonfly but is absent from those with exaggerated weapons. This pattern supports the potential explanation that the trade-off in resource allocation between weapons and nuptial gifts is important in driving the diversity of male mating strategies seen in the dobsonflies, whereas reduced male–male competition in the species producing large spermatophores could be an alternative explanation on their loss of male weapons. Our results shed new light on the evolutionary interplay of multiple sexually selected traits in animals.     

Do reproductive characteristics of the species explain differences in the investment in weapon size present in males?

Sexually selected traits, such as male weapons, are highly variable in shape and size across species. However, little is known about the mechanisms that may govern this variation. Because males with greater investment in weapon size tend to win more fights, but also pay higher costs related to weapon development and maintenance, larger weapons should be expected only in species in which victory in male–male fights generate reproductive benefits that outweigh investment costs. Here, we hypothesized that the reproductive characteristics that increase the chances of winners to access females or to fertilize eggs will favor the evolution of larger weapons. To evaluate this hypothesis, we conducted a meta-analysis using arthropods as model organisms. To measure investment in weapon size, we gathered both Pearson correlation coefficient and the standardized (but non centralized) slope values for the relationship between weapon size and body size. We found that none of the reproductive characteristics we investigated was related to male weapon size. Thus, it seems that greater certainty of accessing a female or fertilizing female eggs with a victory does not modulate the investment in male weapon size. Perhaps the cost–benefit ratio between weapon size investment and reproductive success is not the main factor driving the variation in weapon size.     

Hazards,threats and risks: lessons from the past to a defensive attitude for the future

Since ever infectious diseases have been a major hazard for the armed forces in operations. Nowadays our nations are facing the threat of terrorism, including bioterrorism. This threat is much more related to the potential disorganization of the society than to the lethal effects of the agents. Biological weapons are considered more like terror weapons than like mass destruction weapons, hence the importance of preparing specific defence measures. The know-how acquired from the struggle against natural infectious diseases is a useful help to face the biological weapon threats and risks. Likewise, the defence attitude is based on three pillars: anticipating, managing, and restoring. This military as well as civilian defence attitude applies to six important functions: (1) alert, (2) detection, diagnosis and identification, (3) medical countermeasures (drugs, vaccines and sera), (4) medical care in hospital, (5) training and information, (6) research and development of dedicated technologies.     

It is not always about body size: evidence of Rensch's rule in a male weapon

In many species, sexual dimorphism increases with body size when males are the larger sex but decreases when females are the larger sex, a macro-evolutionary pattern known as Rensch''s rule (RR). Although empirical studies usually focus exclusively on body size, Rensch''s original proposal included sexual differences in other traits, such as ornaments and weapons. Here, we used a clade of harvestmen to investigate whether two traits follow RR: body size and length of the fourth pair of legs (legs IV), which are used as weapons in male–male fights. We found that males were slightly smaller than females and body size did not follow RR, whereas legs IV were much longer in males and followed RR. We propose that sexual selection might be stronger on legs IV length than on body size in males, and we discuss the potential role of condition dependence in the emergence of RR.     

A proposal for the classification of biological weapons sensu lato

Due to historical and legislation reasons, the category of bioweapons is rather poorly defined. Authors often disagree on involving or excluding agents like hormones, psychochemicals, certain plants and animals (such as weeds or pests) or synthetic organisms. Applying a wide definition apparently threatens by eroding the regime of international legislation, while narrow definitions abandon several important issues. Therefore, I propose a category of ‘biological weapons sensu lato’ (BWsl) that is defined here as any tool of human aggression whose acting principle is based on disciplines of biology including particularly microbiology, epidemiology, medical biology, physiology, psychology, pharmacology and ecology, but excluding those based on inorganic agents. Synthetically produced equivalents (not necessarily exact copies) and mock weapons are also included. This definition does not involve any claim to subject all these weapons to international legislation but serves a purely scholarly purpose. BWsl may be properly categorized on the base of the magnitude of the human population potentially targeted (4 levels: individuals, towns, countries, global) and the biological nature of the weapons’ intended effects (4 levels: agricultural-ecological agents, and non-pathogenic, pathogenic, or lethal agents against humans).     

A morphometric assessment of the intended function of cached Clovis points

A number of functions have been proposed for cached Clovis points. The least complicated hypothesis is that they were intended to arm hunting weapons. It has also been argued that they were produced for use in rituals or in connection with costly signaling displays. Lastly, it has been suggested that some cached Clovis points may have been used as saws. Here we report a study in which we morphometrically compared Clovis points from caches with Clovis points recovered from kill and camp sites to test two predictions of the hypothesis that cached Clovis points were intended to arm hunting weapons: 1) cached points should be the same shape as, but generally larger than, points from kill/camp sites, and 2) cached points and points from kill/camp sites should follow the same allometric trajectory. The results of the analyses are consistent with both predictions and therefore support the hypothesis. A follow-up review of the fit between the results of the analyses and the predictions of the other hypotheses indicates that the analyses support only the hunting equipment hypothesis. We conclude from this that cached Clovis points were likely produced with the intention of using them to arm hunting weapons.     

3D bioprinting and the current applications in tissue engineering

Bioprinting as an enabling technology for tissue engineering possesses the promises to fabricate highly mimicked tissue or organs with digital control. As one of the biofabrication approaches, bioprinting has the advantages of high throughput and precise control of both scaffold and cells. Therefore, this technology is not only ideal for translational medicine but also for basic research applications. Bioprinting has already been widely applied to construct functional tissues such as vasculature, muscle, cartilage, and bone. In this review, the authors introduce the most popular techniques currently applied in bioprinting, as well as the various bioprinting processes. In addition, the composition of bioink including scaffolds and cells are described. Furthermore, the most current applications in organ and tissue bioprinting are introduced. The authors also discuss the challenges we are currently facing and the great potential of bioprinting. This technology has the capacity not only in complex tissue structure fabrication based on the converted medical images, but also as an efficient tool for drug discovery and preclinical testing. One of the most promising future advances of bioprinting is to develop a standard medical device with the capacity of treating patients directly on the repairing site, which requires the development of automation and robotic technology, as well as our further understanding of biomaterials and stem cell biology to integrate various printing mechanisms for multi‐phasic tissue engineering.     

Biocatalytic nerve agent detoxification in fire fighting foams

Current events across the globe necessitate rapid technological advances to combat the epidemic of nerve agent chemical weapons. Biocatalysis has emerged as a viable tool in the detoxification of organophosphorus neurotoxins, such as the chemical weapons VX and sarin. Efficient detoxification of contaminated equipment, machinery, and soils are of principal concern. This study describes the incorporation of a biocatalyst (organophosphorus hydrolase, E.C. 3.1.8.1) into conventional formulations of fire fighting foam. The capacity of fire fighting foams to decrease volatilization of contained contaminants, increase surface wettability, and control the rate of enzyme delivery to large areas makes them useful vehicles for enzyme application at surfaces. The performance of enzyme containing foams has been shown to be not only reproducible but also predictable. An empirical model provides reasonable estimations for the amounts of achievable surface decontamination as a function of the important parameters of the system. Theoretical modeling illustrates that the enzyme-containing foam is capable of extracting agent from the surface and is catalytically active at the foam-surface interface and throughout the foam itself. Biocatalytic foam has proven to be an effective, "environmentally friendly" means of surface and soil decontamination.     

Scanning tunneling microscopy with applications to biological surfaces

Each major advance in the field of microscopy has eventually been translated into major advances in the biological and medical sciences. The scanning tunneling microscope (STM) offers exciting new ways of imaging biological surfaces with resolution to the sub-molecular scale. Rigid, conductive surfaces can readily be imaged with the STM with atomic resolution. Unfortunately, few biological surfaces are sufficiently conductive or rigid enough to be examined directly with the STM. At present, non-conductive surfaces can be examined in two ways: 1) Sufficiently thin molecular layers attached to conductive substrates so that tunneling can occur through the molecules; or 2) coating or replicating non-conductive surfaces with metal layers so as to make them conductive, then imaging with the STM. We present images of biological and organic molecules obtained with these techniques that demonstrate the possibilities and limitations of each. Future advances leading to atomic resolution STM of biological surfaces depend on significant progress in the art and science of making biomaterials compatible with the restrictions of the instrument.     

Ethical Responsibility for the Social Production of Tuberculosis

Approximately one in two hundred persons in the Marshall Islands have active tuberculosis (TB). We examine the historical antecedents of this situation in order to assign ethical responsibility for the present situation. Examining the antecedents in terms of Galtung’s dialectic of personal versus structural violence, we can identify instances in the history of the Marshall Islands when individual subjects made decisions (personal violence) with large-scale ecologic, social, and health consequences. The roles of medical experimenters, military commanders, captains of the weapons industry in particular, and industrial capitalism in general (as the cause of global warming) are examined. In that, together with Lewontin, we also identify industrial capitalism as the cause of tuberculosis, we note that the distinction between personal versus structural violence is difficult to maintain. By identifying the cause of the tuberculosis in the Marshall Islands, we also identify what needs be done to treat and prevent it.     

Commercializing medical technology

As medicine moves into the 21st century, life saving therapies will move from inception into medical products faster if there is a better synergy between science and business. Medicine appears to have 50-year innovative cycles of education and scientific discoveries. In the 1880’s, the chemical industry in Germany was faced with the dilemma of modernization to exploit the new scientific discoveries. The solution was the spawning of novel technical colleges for training in these new chemical industries. The impact of those new employees and their groundbreaking compounds had a profound influence on medicine and medical education in Germany between 1880 and 1930. Germany dominated international science during this period and was a training center for scientists worldwide. This model of synergy between education and business was envied and admired in Europe, Asia and America. British science soon after evolved to dominate the field of science during the prewar and post World War (1930’s–1970’s) because the German scientists fled Hitler’s government. These expatriated scientists had a profound influence on the teaching and training of British scientists, which lead to advances in medicine such as antibiotics. After the Second World War, the US government wisely funded the development of the medical infrastructure that we see today. British and German scientists in medicine moved to America because of this bountiful funding for their research. These expatriated scientists helped drive these medical advances into commercialized products by the 1980’s. America has been the center of medical education and advances of biotechnology but will it continue? International scientists trained in America have started to return to Europe and Asia. These American-trained scientists and their governments are very aware of the commercial potential of biotechnology. Those governments are now more prepared to play an active role this new science. Germany, Ireland, Britain, Singapore, Taiwan and Israel are such examples of this government support for biotechnology in the 21st century. Will the US continue to maintain its domination of biotechnology in this century? Will the US education system adjust to the new dynamic of synergistic relationships between the education system, industry and government? This article will try to address these questions but also will help the reader understand who will emerge by 2015 as the leader in science and education.     

Hijacking of eukaryotic functions by intracellular bacterial pathogens.

Intracellular bacterial pathogens have evolved as a group of microorganisms endowed with weapons to hijack many biological processes of eukaryotic cells. This review discusses how these pathogens perturb diverse host cell functions, such as cytoskeleton dynamics and organelle vesicular trafficking. Alteration of the cytoskeleton is discussed in the context of the bacterial entry process (invasion), which occurs either by activation of membrane-located host receptors ("zipper" mechanism) or by injection of bacterial proteins into the host cell cytosol ("trigger" mechanism). In addition, the two major types of intracellular lifestyles, cytosolic versus intravacuolar (phagosomal), which are the consequence of alterations in the phagosome-lysosome maturation route, are compared. Specific examples illustrating known mechanisms of mimicry or hijacking of the host target are provided. Finally, recent advances in phagosome proteomics and genome expression in intracellular bacteria are described. These new technologies are yielding valuable clues as to how these specialized bacterial pathogens manipulate the mammalian host cell.     

"A gentle and humane temper": humility in medicine

Humility is the medical virtue most difficult to understand and practice. This is especially true in contemporary medicine, which has developed a culture more characterized by arrogance and entitlement than by self-effacement and moderation. In such a culture, humility suggests weakness, indecisiveness, or even deception, as in false modesty. Nonetheless, an operational definition of medical humility includes four distinct but closely related personal characteristics that are central to good doctoring: unpretentious openness, honest self-disclosure, avoidance of arrogance, and modulation of self-interest. Humility, like other virtues, is best taught by means of narrative and role modeling. We may rightly be proud of contemporary medical advances, while at the same time experiencing gratitude and humility as healers.     

Application of inkjet printing to tissue engineering

Recent advances in organ printing technology for applications relating to medical interventions and organ replacement are described. Organ printing refers to the placement of various cell types into a soft scaffold fabricated according to a computer-aided design template using a single device. Computer aided scaffold topology design has recently gained attention as a viable option to achieve function and mass transport requirements within tissue engineering scaffolds. An exciting advance pioneered in our laboratory is that of simultaneous printing of cells and biomaterials, which allows precise placement of cells and proteins within 3-D hydrogel structures. This advance raises the possibility of spatially controlling not only the scaffold structure, but also the type of tissue that can be grown within the scaffold and the thickness of the tissue as capillaries and vessels could be constructed within the scaffolds. Here we summarize recent advances in printing cells and materials using the same device.     

Sub-Angstrom resolution enzyme X-ray structures: is seeing believing?

Recent technical advances in crystallographic analysis, particularly highly focused and high brilliance synchrotron beam lines, have significantly improved the resolutions that are attainable for many macromolecular crystal structures. The Protein Data Bank (http://www.rcsb.org/pdb/) contains an increasing number of atomic resolution structures, which are providing a wealth of structural information that was not previously visible in lower resolution electron density maps. Here, we review the importance of visualizing hydrogen atoms and multiple sidechain conformations or anisotropy, as well as substrate strain, at sub-Angstrom resolution. The additional structural features that are visible in the electron density maps as a result of atomic resolution data provide a better understanding of the catalytic mechanisms of cholesterol oxidase, ribonuclease A, beta-lactamase, serine proteases, triosephosphate isomerase and endoglucanase.